Female Libido Enhancer  – Bremelanotide

Bremelanotide is a compound that is currently under investigation for its potential uses in managing reperfusion injury, female sexual dysfunction or hemorrhagic shock. The chemical may also see success in managing modulate inflammation or limiting the effects of ischemia.

N-Acetyl-L-norleucyl-L-alpha-aspartyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-lysine (2-7)-lactam

Bremelanotide,  PT 141, CAS NO.: 189691-06-3

Bremelanotide ⁱ/ˌbrɛmɨˈlænətaɪd/ (formerly PT-141) is a compound under drug development by Palatin Technologies as a treatment for female sexual dysfunction, hemorrhagic shock and reperfusion injury. It functions by activating the melanocortin receptors MC1R and MC4R, to modulate inflammation and limiting ischemia.^[2] It was originally tested for intranasal administration in treating female sexual dysfunction but this application was temporarily discontinued in 2008 after concerns were raised over adverse side effects of increased blood pressure. As of December 2014, Palatin is conducting a human Phase 3 study^[3] using a subcutaneous drug delivery system that appears to have little effect on blood pressure.

Palatin, in collaboration with European licensee Gedeon Richter, is developing an sc formulation of the synthetic peptide bremelanotide (PT-141; BMT), a melanocortin MCR-4 agonist and a synthetically modified analog of PT-14, also analogous to alpha-melanocyte-stimulating hormone (alpha-MSH), for the potential treatment of female sexual dysfunction (FSD) including hypoactive sexual desire disorder (HSDD)

The Bremelanotide or PT-141 is a mean that explains the revolution caused by the medical world in a silent but attractive manner in the human health related study. Bremelanotide is the latest arrival from the company called Palatin Technologies which forms the basic treatment for the hemorrhagic shock and reperfusion injury.( In short about the company, the Palatin Technologies is the owner of this research and is located in New Jersey. Hence this medicine is a Jersey based Product. And regarding the product under research, is waiting for the approval from the Food and Drug Association. Once this is done, the company has targeted to reach those customers, whom the Viagra has approached. This has the effect of helping the male patients suffering with an erectile dysfunction syndrome. Also if it gets the approval as a treatment measure for the female sexual dysfunction, then this medicine is expected to bring a relief to the post-menopausal and also supports or provides their sexual happiness and also they are checking regarding thehyposexual desire disorder. This is expected to be a blockbuster, if released. So this medicine is waiting for a confirmation as well as an approval.

In February 2015, a randomized, double-blind, placebo-controlled, open-label extension, phase III trial (NCT02338960; BMT-302, Reconnect Study) was initiated in the US in premenopausal women (expected n = 550) with hypoactive sexual desire disorder to evaluate the efficacy and safety of bremelanotide. At that time, the trial was expected to complete in July 2017

Study – Potential Use Erectile Dysfunction

One study has explored the potential use of bremelanotide as a replacement for natural peptide melanocyte stimulating hormones for the sake of treating erectile dysfunction.

• The goal of this study was to determine if the effects of bremelanotide stimulating sexual desire that was shown in male rats could be replicated in the brains of female rats. To do this, hormone primed female rats in a control group and a test group that were treated with bremelanotide and known to have consummatory sexual disorders was introduced to a group of male rats and the reactions were measured.

• Heart racing, hops and darts, pacing and customary sexual behaviors were assessed while the brain was stimulated. The stimulation of specific molecular markers within the brain was examined to determine arousal in the female subjects.

• Results indicated that the females saw an increase in sexual behavior when bremelanotide was applied to the limbic and hypothalamic regions of their brains. It is suggested that this was because the chemical that stimulated the mPOA terminals, leading to activated dopamine in the brain.

Additional study is necessary to determine the extent of the effects bremelanotide has on the brain and natural stimulating chemicals.

Bremelanotide and Ongoing Research

This is an advanced research involved even now. This functions by activating the Melanocortin, which is a group of peptide hormones which includes the adrenocorticotropic hormone and also the different forms of the melanocyte stimulating hormones. These melanocortins are produced or prepared from the proopiomelanocortin in the pituitary glands. The melanocortin releases or exert their effects by making a bind with the melanocortin and thereby activating it).The Bremelanotide functions by activating the melanocortin receptors and thereby makes a modulation in the inflammation. This is actually produced for making use in treating the sexual dysfunction. Due to certain reasons; the process of researching was kept under hold in recently, since it created some adverse side effects of increased blood pressure. In the chemistry of the preparation of the bremelanotide, the Peptide Melanaton II forms the basic compound. This compound is tested using a sunless tanning agent.

The actual information about the peptide melanaton has the effect of making sexual arousal and speed as well as sudden erections and some other side effects. However, there are several other measures taken to test the property of the same under several other health situations to make a detailed study about the chemical compound structure to make a change in the combination of the chemical structure. This medicine has made a revolution in the field of science of the human structure. When made a deep verification of the compound structure of the chemical study showed the following information. The structural design has an appearance of white colored powder like material, which has an accurate purity of nearly 98%. The actual molecular weight of the compound formed is around 1025.2. This compound has the collective share of Amino acids in the composition, peptide and acetate contents also.

The study of the compound structure PT-141 has an enhanced support of making a recombination that produces a different profile of the same medicine but in a different standard with different properties that may support the human requirement.

Bremelanotide PT-141 is known for its aphrodisiac properties

Development

Bremelanotide was developed from the peptide hormone Melanotan II which underwent testing as a sunless tanningagent. In initial testing, Melanotan II did induce tanning but additionally caused sexual arousal and spontaneous erections as unexpected side effects in nine out of the ten original male volunteer test subjects.^[4]

In studies, bremelanotide was shown to induce lordosis in an animal model^[5] and was also effective in treating sexual dysfunction in both men (erectile dysfunction or impotence) and women (sexual arousal disorder). Unlike Viagra and other related medications, it does not act upon the vascular system, but directly increases sexual desire via the nervous system.^[6]

A Phase III clinical trial was scheduled to begin in the first half of 2007, but was delayed until August 2007. On August 30, Palatin announced that the U.S. Food and Drug Administration had expressed serious concerns regarding therisk/benefit ratio of bremelanotide with regards to the side effect of increased blood pressure. The FDA stated that it would consider alternate uses for bremelanotide, including as a treatment for individuals who do not respond to more established ED treatments. However, On May 13, 2008, Palatin Technologies announced it had “discontinued development of Bremelanotide for the treatment of male and female sexual dysfunction” while concurrently announcing plans to develop it as a treatment for hemorrhagic shock instead.^[7] The company additionally announced intentions to focus its attention on another compound, PL-6983, that causes lower blood pressure in animal models.^[8]Palatin has since re-initiated Bremelanotide studies for ED and FSD using a subcutaneous delivery method. On August 12, 2009, the company announced that in a double-blind study of 54 volunteers bremelanotide failed to evoke the hypertensive side effects seen with the nasal delivery system used in prior studies, concluding that “variability of uptake” inherent in intranasal administration of the drug resulted in “increases in blood pressure and gastrointestinal events…primarily related to high plasma levels in [only] a subset of patients” and that subcutaneous administration of the drug circumvented the potential for this side effect.^[8] Palatin has completed a human Phase 2B study utilizing subcutaneous administration and reported positive results.^[9]

Structure

Bremelanotide is a cyclic hepta-peptide lactam analog of alpha-melanocyte-stimulating hormone (alpha-MSH) that activates the melanocortin receptors MC3-R and MC4-R in thecentral nervous system. It has the amino acid sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH or cyclo-[Nle⁴, Asp⁵, D-Phe⁷, Lys¹⁰]alpha-MSH-(4-10). It is a metabolite of Melanotan II that lacks the C-terminal amide function.

Bremelanotide

Systematic (IUPAC) name
(3S,6S,9R,12S,15S,23S)-15-[(N-acetyl-L-norleucyl)amino]-9-benzyl-6-{3-[(diaminomethylidene)amino]propyl}-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaa zacyclotricosane-23-carboxylic acid
Clinical data
Legal status	US: Unscheduled
Pharmacokinetic data
Half-life	120 minutes[1]
Identifiers
CAS number	189691-06-3
ATC code	None
PubChem	CID 9941379
ChemSpider	8116997
UNII	6Y24O4F92S
KEGG	D06569
ChEMBL	CHEMBL2070241
Chemical data
Formula	C50H68N14O10
Molecular mass	1025.2 g/mol

Sexual dysfunction, including both penile erectile dysfunction or impotence and female sexual dysfunction, are common medical problems. Significant effort has been devoted over the last twenty or more years to develop methods, devices and compounds for treatment of sexual dysfunction. While more effort has been undertaken for treatment of penile erectile dysfunction, female sexual dysfunction is also an area to which significant research and effort has been devoted.

At present, one commonly used orally administered drug for treatment of sexual dysfunction in the male is Viagra®, a brand of sildenafil, which is a phosphodiesterase 5 inhibitor, increasing the persistence of cyclic guanosine monophosphate and thereby enhancing erectile response. There are several other medical treatment alternatives currently available depending on the nature and cause of the impotence problem. Some men have abnormally low levels of the male hormone testosterone, and treatment with testosterone injections or pills may be beneficial. However, comparatively few impotent men have low testosterone levels. For many forms of erectile dysfunction, treatment may be undertaken with drugs injected directly into the penis, including drugs such as papaverin, prostaglandin E₁, phenoxybenzamine or phentolamine. These all work primarily by dilating the arterial blood vessels and decreasing the venous drainage. Urethral inserts, such as with suppositories containing prostaglandin, may also be employed. In addition, a variety of mechanical aids are employed, including constriction devices and penile implants.

A variety of treatments have also been explored for female sexual dysfunction, including use of sildenafil, although the Food and Drug Administration has not specifically approved such use. Testosterone propionate has also been employed to increase or augment female libido.

Melanocortin receptor-specific compounds have been explored for use of treatment of sexual dysfunction. In one report, a cyclic α-melanocyte-stimulating hormone (“α-MSH”) analog, called Melanotan-II, was evaluated for erectogenic properties for treatment of men with psychogenic erectile dysfunction. Wessells H. et al., J Urology 160:389-393 (1998); see also U.S. Pat. No. 5,576,290, issued Nov. 19, 1996 to M. E. Hadley, entitled Compositions and Methods for the Diagnosis and Treatment of Psychogenic Erectile Dysfunction and U.S. Pat. No. 6,051,555, issued Apr. 18, 2000, also to M. E. Hadley, entitled Stimulating Sexual Response in Females. The peptides used in U.S. Pat. Nos. 5,576,290 and 6,051,555 are also described in U.S. Pat. No. 5,674,839, issued Oct. 7, 1997, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Cyclic Analogs of Alpha-MSH Fragments, and in U.S. Pat. No. 5,714,576, issued Feb. 3, 1998, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Linear Analogs of Alpha-MSH Fragments. Melanotan-II is a peptide of the following formula:

Additional related peptides are disclosed in U.S. Pat. Nos. 5,576,290, 5,674,839, 5,714,576 and 6,051,555. These peptides are described as being useful for both the diagnosis and treatment of psychogenic sexual dysfunction in males and females. These peptides are related to the structure of melanocortins.

In use of Melanotan-II, significant erectile responses were observed, with 8 of 10 treated men developing clinically apparent erections, and with a mean duration of tip rigidity greater than 80% for 38 minutes with Melanotan-II compared to 3.0 minutes with a placebo (p=0.0045). The drug was administered by subcutaneous abdominal wall injection, at doses ranging from 0.025 to 0.157 mg/kg body weight. Transient side effects were observed, including nausea, stretching and yawning, and decreased appetite.

The minimum peptide fragment of native α-MSH needed for erectile response is the central tetrapeptide sequence, His⁶-Phe⁷-Arg⁸-Trp⁹ (SEQ ID NO:1). In general, all melanocortin peptides share the same active core sequence, His-Phe-Arg-Trp (SEQ ID NO:1), including melanotropin neuropeptides and adrenocorticotropin. Five distinct melanocortin receptor subtypes have been identified, called MC1-R through MC5-R, and of these MC3-R and MC4-R are believed to be expressed in the human brain. MC3-R has the highest expression in the arcuate nucleus of the hypothalamus, while MC4-R is more widely expressed in the thalamus, hypothalamus and hippocampus. A central nervous system mechanism for melanocortins in the induction of penile erection has been suggested by experiments demonstrating penile erection resulting from central intracerebroventricular administration of melanocortins in rats. While the mechanism of His-Phe-Arg-Trp (SEQ ID NO:1) induction of erectile response has not been fully elucidated, it has been hypothesized that it involves the central nervous system, and probably binding to MC3-R and/or MC4-R.

Other peptides and constructs have been proposed which are ligands that alter or regulate the activity of one or more melanocortin receptors. For example, International Patent Application No. PCT/US99/09216, entitled Isoquinoline Compound Melanocortin Receptor Ligands and Methods of Using Same, discloses two compounds that induce penile erections in rats. However, these compounds were administered by injection at doses of 1.8 mg/kg and 3.6 mg/kg, respectively, and at least one compound resulted in observable side effects, including yawning and stretching. Other melanocortin receptor-specific compounds with claimed application for treatment of sexual dysfunction are disclosed in International Patent Application No. PCT/US99/13252, entitled Spiropiperidine Derivatives as Melanocortin Receptor Agonists.

Both cyclic and linear α-MSH peptides have been studied; however, the peptides heretofore evaluated have had an amide or —NH₂ group at the carboxyl terminus. See, for example, Wessells H. et al., J Urology, cited above; Haskell-Luevano C. et al., J Med Chem 40:2133-39 (1997); Schiöth H. B. et al., Brit J Pharmacol 124:75-82 (1998); Schiöth H. B. et al., Eur J Pharmacol 349:359-66 (1998); Hadley M. E. et al., Pigment Cell Res 9:213-34 (1996); Bednarek M. A. et al., Peptides20:401-09 (1999); U.S. Pat. Nos. 6,054,556, 6,051,555 and 5,576,290; and, International Patent Applications PCT/US99/04111 and PCT/US98/03298. While significant research has been conducted in an effort to determine the optimal structure of α-MSH peptides, including a variety of structure-function, agonist-antagonist, molecular modeling and pharmacophore studies, such studies have relied upon peptides with an art conventional —NH₂ group at the carboxyl terminus. Further, it has long been believed that biologically active neuropeptides, including α-MSH peptides, are amidated, with an —NH₂ group at the carboxyl terminus, and that such amidation is required both for biological activity and stability. See, for example, Metabolism of Brain Peptides, Ed. G. O’Cuinn, CRC Press, New York, 1995, pp. 1-9 and 99-101.

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Bioorganic and Medicinal Chemistry Letters, 2005 ,  vol. 15,  4  pg. 1065 – 1068

http://www.sciencedirect.com/science/article/pii/S0960894X04014842

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US6794489

In a preferred embodiment, the invention provides the peptide

Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH  Compound 1

The peptide of Compound 1 has a formula of C₅₀H₆₈N₁₄O₁₀, and a net molecular weight of 1025.18. This peptide may be synthesized by solid-phase means and purified to greater than 96% purity by HPLC, yielding a white powder that is a clear, colorless solution in water. The structure of Compound 1 is:

In general, the peptide compounds of this invention may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare the compounds of this invention.

The peptides of this invention may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. Where the compounds of this invention include an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.

The invention provides a pharmaceutical composition that includes a peptide of this invention and a pharmaceutically acceptable carrier. The carrier may be a liquid formulation, and is preferably a buffered, isotonic, aqueous solution. Pharmaceutically acceptable carriers also include excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as hereafter described.

EXAMPLE 1

Peptide Synthesis

The peptide Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH was synthesized by standard solid phase peptide synthesis methods, and is a cyclic heptapeptide melanocortin peptide analog with a free acid at the carboxyl terminus and an acetylated amino group at the amino terminus, with the structure:

The peptide has a net molecular weight of 1025.18, and is supplied in an acetate salt form. The peptide is a white, odorless amorphous hygroscopic powder, soluble in 0.9% saline, composed of C₅₀H₆₈N₁₄O₁₀. For synthesis, an Fmoc-Lys(R³)-p-alkoxybenzyl alcohol resin was transferred to a solid phase peptide synthesizer reactor with a mechanical stirrer. The R³group, such as 1-(1′-adamantyl)-1-methyl-ethoxycarbonyl (Adpoc), allyloxycarbonyl (Aloc) or 4-methyltrityl (Mtt), was removed and the next Fmoc-protected amino acid (Fmoc-Trp(Boc)-OH) was added to the resin through standard coupling procedures. The Fmoc protective group was removed and the remaining amino acids added individually in the correct sequence, by repeating coupling and deprotection procedures until the amino acid sequence was completed. After completion of coupling with the last Fmoc-amino acid derivative, Fmoc-Nle-OH, and cleavage of the Fmoc protective group, the exposed terminal amino group was acetylated with acetic anhydride and pyridine in N,N-dimethylformamide (DMF). The peptide-resin was dried and the Lys and Asp protective groups cleaved. The Lys and Asp deprotected peptide resin was suspended in a suitable solvent, such as DMF, dichloromethane (DCM) or 1-methyl-2-pyrrolidone (NMP), a suitable cyclic coupling reagent, such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) or N,N′-dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCCl/HOBt) was added, and coupling initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM). After cyclization, the peptide-resin was washed and the peptide cleaved from the resin and any remaining protective groups using trifluoroacetic acid (TFA) in the presence of water and 1,2-ethanedithiol (EDT). The final product was precipitated by adding cold ether and collected by filtration. Final purification was by reversed phase HPLC using a C₁₈ column. The purified peptide was converted to acetate salt by passage through an ion-exchange column.

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WO2014071339

Compounds of the Invention.

in a preferred embodiment of the present invention, fie rneianocortin receptor agonist is;

Ac-Nie”Cyc/o{-Asp-His–D–Phe-Arg–Trp»Lys)–OH (bremeianotide)

The peptide of bremeianotide has a formula of C_saH_esN< C½, and a net mofecufar weight of 1025.18, This peptide may be synthesized by conventional means, including either solid-phase or Squid-phase techniques, and purified to greater than 99% purity by HPLC, yielding a white powder that is a clear, colorless solution in water. The structure of bremeianotide is:

in one embodiment of the invention, bremeianotide is synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of ^‘well-known procedures utilizing a variety of resins and reagents may be used to prepare bremeianotide.

Bremeianotide may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacefie, maieic, citric, tartaric, oxalic, succinic or methanesu!fonic acid. The acetate salt form is especially useful.

in a preferred embodiment, bremelanotide is an acetate salt form, and is formulated in a buffered aqueous solution including giycerin, and prepackaged in a syringe and auto-injector device. In alternative embodiments, bremelanotide is any pharmaceutically acceptable salt form, and is formulated in any pharmaceutically acceptable aqueous solution, the aqueous solution optionally including one or more salts, such as sodium chloride, one or more acids, such as citric acid, and one or more additional ingredients, including cellulose or derivatives thereof, saccharides o

polysaccharides such as dextrose, and any of a wide variety of surfactants, chelating agents and preservatives.

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US20050222014

In yet another embodiment of the present invention, the melanocortin receptor agonist is:
Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH PT-141

The peptide of PT-141 has a formula of C₅₀H₆₈N₁₄O₁₀, and a net molecular weight of 1025.18. This peptide may be synthesized by conventional means, including either solid-phase or liquid-phase techniques, and purified to greater than 99% purity by HPLC, yielding a white powder that is a clear, colorless solution in water. The structure of PT-141 is:

In one embodiment of the invention, PT-141 is synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare PT-141.

PT-141 may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, citric, tartaric, oxalic, succinic or methanesulfonic acid. The acetate salt form is especially useful. Where the compounds of this invention include an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.

In a preferred embodiment, PT-141 is an acetate salt form, and is formulated in a buffered aqueous solution including glycerin, prepackaged in a metered unit dose intranasal delivery device. In alternative embodiments, PT-141 is any pharmaceutically acceptable salt form, and is formulated in any pharmaceutically acceptable aqueous solution, the aqueous solution optionally including one or more salts, such as sodium chloride, one or more acids, such as citric acid, and one or more additional ingredients, including cellulose or derivatives thereof, saccharides or polysaccharides such as dextrose, and any of a wide variety of surfactants, chelating agents and preservatives. In one preferred embodiment, PT-141 is administered to patients in volumes of 100 μL, with the quantity of PT-141 delivered determined by the concentration thereof. As described hereafter, in one preferred embodiment a metered unit dose contains 7.5 mg of PT-141.

While certain embodiments of the present invention are described primarily in the context of PT-141, it is to be understood that other melanocortin receptor agonists may be employed. For example, the metallopeptide melanocortin receptor agonists disclosed in WO 02/064091, filed on Feb. 13, 2001, and U.S. Ser. No. 10/640,755, filed on Aug. 13, 2003, both entitled Melanocortin Metallopeptides for Treatment of Sexual Dysfunction; and WO 01/13112, filed on Jun. 14, 2000, entitled Melanocortin Metallopeptide Constructs, Combinatorial Libraries and Applications, may be employed. In addition, the peptidomimetic melanocortin receptor agonists disclosed in U.S. Ser. No. 10/776,419, filed on Feb. 10, 2004, entitled Peptidomimetics of Biologically Active Metallopeptides; the pyrrolidine melanocortin receptor agonists disclosed in U.S. Ser. No. 10/766,657, filed on Feb. 10, 2004, entitled Pyrrolidine Melanocortin-Specific Compounds; and the bicyclic melanocortin receptor agonists disclosed in PCT/US04/01505, filed on Jan. 20, 2004, entitled Bicyclic Melanocortin-Specific Compounds, may also be employed. Also particular preferred are the piperazine melanocortin agonists disclosed in PCT/US04/01462, filed on Jan. 20, 2004 and U.S. Ser. No. 10/762,079, filed on Jan. 20, 2004, both entitled piperazine Melanocortin-Specific Compounds; the melanocortin agonists disclosed in WO 03/006620, filed on Jul. 11, 2002, entitled Linear and Cyclic Melanocortin Receptor-Specific Peptides; WO 04/005324, filed on Jul. 9, 2003, entitled Peptide Compositions for Treatment of Sexual Dysfunction; PCT/US00/18217, filed on Jun. 29, 2000 and U.S. Ser. No. 10/040,547, filed on Jan. 4, 2002, entitled Compositions and Methods for Treatment of Sexual Dysfunction; and U.S. Ser. No. 10/638,071, filed on Aug. 8, 2003, entitled Cyclic Peptide Compositions and Methods for Treatment of Sexual Dysfunction. The entire disclosure of each of the foregoing are incorporated here by reference. It is to be understood that the foregoing listing of patent applications disclosing melanocortin receptor agonists is intended to only be exemplary, and that other melanocortin receptor agonists, whether heretofore known or hereafter developed, may similarly be used in the practice of this invention.

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NMR prediction

External links

• Palatin Technologies The company that has developed bremelanotide.
• US 6,794,489 bremelanotide (PT-141) patent (Appl. No.:040547)
• US 6,579,968 bremelanotide (PT-141) patent (Appl. No.:066501)
• Bremelanotide Edguider Forum

Retosiban, GSK221149A

820957-38-8

MW 494.5827, MF C27 H34 N4 O5

Oxytocin antagonist

Threatened pre-term labour

PHASE 3 GSK

UNII-GIE06H28OX, GSK 221149A,  820957-38-8,

(3R,6R)-6-((S)-sec-butyl)-3-(2,3-dihydro-1H-inden-2-yl)-1-((R)-1-(2-methyloxazol-4-yl)-2-morpholino-2-oxoethyl)piperazine-2,5-dione

3(R)-(2,3-Dihydro-1H-inden-2-yl)-1-[1(R)-(2-methyloxazol-4-yl)-2-(4-morpholinyl)-2-oxoethyl]-6(R)-[1(S)-methylpropyl]piperazine-2,5-dione

(3R.6R)-3-(2,3-dihvdro-1 H-inden-2-v0-1 -\( R)-1 -(2-methyl-1 ,3-oxazol-4- yl)-2-(4-morpholinyl)-2-oxoethyll-6-r(1S -1-methylpropyn-2.5- piperazinedione

2,​5-​Piperazinedione, 3-​(2,​3-​dihydro-​1H-​inden-​2-​yl)​-​1-​[(1R)​-​1-​(2-​methyl-​4-​oxazolyl)​-​2-​(4-​morpholinyl)​-​2-​oxoethyl]​-​6-​[(1S)​-​1-​methylpropyl]​-​, (3R,​6R)​-

Morpholine, 4-[(2R)-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl](2-methyl-4-oxazolyl)acetyl]-

Retosiban (GSK-221,149-A)^[1][2] is an oral drug which acts as a selective, sub-nanomolar (K_i = 0.65 nM) oxytocin receptor antagonist with >1400-fold selectivity^[3] over the related vasopressin receptors and is being developed by GlaxoSmithKline for the treatment of preterm labour.^[4][5]

Retosibanis an oxytocin (OT) antagonist in phase III clinical trials at GlaxoSmithKline for the prevention of preterm labor. OT antagonism is widely known to inhibit spontaneous uterine contractions.

Retosiban is a diketopiperazine nonpeptide compound with high potency and selectivity for the OT receptor over vasopressin receptors.

This  candidate has been shown to block oxytocin-induced uterine contractions when administered intravenously and to exhibit oral activity

ATOSIBAN

RETOSIBAN 106

BARUSIBAN

L-368899

L-371257

PAPER

Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: Synthesis, pharmacokinetics, and in vivo potency
J Med Chem 2012, 55(2): 783

http://pubs.acs.org/doi/abs/10.1021/jm201287w

 PAPER

The discovery of GSK221149A: A potent and selective oxytocin antagonist
Bioorg Med Chem Lett 2008, 18(1): 90

http://www.sciencedirect.com/science/article/pii/S0960894X07013170

GSK221149A and other tertiary amides were prepared in four steps via the Ugi reaction as outlined in Scheme . A 2:1 mixture of diastereoisomers 24 was formed with the desirable (R)-diastereoisomer being the minor product. Hydrogenation of crude 24 furnished the cyclised phenol 25, again enriched with the undesirable (S)-diastereoisomer.

Activation of the mixture 25 with carbonyl diimidazole followed by the addition of 2 N HCl promoted epimerisation at the exocyclic position and yielded the acids 26 with the required (R)-diastereoisomer as the major product.

Acid activation with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate followed by the addition of morpholine and subsequent column chromatography yielded homo-chiral GSK221149A.

PATENT

WO 2005000840

http://www.google.co.in/patents/EP1641787A1?cl=en

Example 3

(3R.6R)-3-(2,3-dihvdro-1 H-inden-2-v0-1 -\( R)-1 -(2-methyl-1 ,3-oxazol-4- yl)-2-(4-morpholinyl)-2-oxoethyll-6-r(1S -1-methylpropyn-2.5- piperazinedione ( 2R)-[(benzyloxycarbonyl)amino](2,3-dihydro-1 H-inden-2-yl)ethanoic acid (35.84g, 0.110mol) in a 500mL round bottomed flask was treated with 2,2,2-trifluoroethanol (165mL) followed by methanol (55ml) and triethylamine (11.13g, 15.33mL, 0.110mmol) the slurry was stirred for 3.5hrs until dissolution was observed. The solution was then added to (D)- allo Isoleucine methyl ester hydrochloride (20g, .110mol) in a separate flask. The slurry was stirred until dissolution was observed. 2-methyl-4- formyloxazole (12.24g, 0.110mmol) was then added followed by 2- benzyloxyphenylisocynanide (23.04g, 0.110mmol). The dark brown reaction mixture was then stirred at 20-25°C for 24hrs. The solution was then concentrated to a volume of ca. 130mL by distillation at reduced pressure.

The solution was the diluted with dichloromethane (200mL) and washed with water (2 x 200mL). The organic phase was then diluted with N-methyl pyrrolidinone (460mL) was and the dichloromethane removed by stirring at 40°C under vacuum for 2hrs. Acetic acid 46mL) was then added followed by palladium on carbon catalyst (69. Og of 10% Pd wt, 57% water, Johnson Matthey type 87L) and the mixture hydrogenated under balloon pressure of hydrogen with rapid stirring for 2hrs. The reaction mixture was then filtered, washed through with ethyl acetate (960mL) and washed with 3%w/v aq sodium chloride solution (960mL). The biphasic mixture was filtered and the organic phase separated and washed with 3%w/v aq sodium chloride solution (2 x 960mL). The organic solution was then diluted with ethyl acetate (200mL) and concentrated by distillation at atmospheric pressure by distilling out 385mL of solvent. The concentrated solution at 20-25°C was treated with 1 ,1′-carbonyldiimidazoIe (21.46g, 0.132mol) and stirred at 20-25°C for 1 hr then treated with water (290mL) and stirred rapidly at 20-25°C for 24hr. The mixture was allowed to settle and the ethyl acetate layer separated and discarded. The aqueous phase was washed with ethyl acetate (290mL) and the mixture allowed to settle and the aqueous phase was separated and acidified to pH 1-2 by the addition of concentrated hydrochloric acid (18mL).

The aqueous phase was then extracted into ethyl acetate (290mL and then 145mL). The combined ethyl acetate solution was then concentrated by distillation at atmospheric pressure to a volume of ca. 93mL. This solution was then diluted with tetrahydrofuran (62mL) and treated with triethylamine (11.02g, 15.20mL, 0.109mol) and cooled to -78°C. The solution was then treated with trimethylacetyl chloride (4.81 g, 4.92mL, 39.90mmol) and stirred at – 78°C for 7hr. The reaction mixture was then treated with a solution of morpholine (15.82g, 15.83mL, 0.181 mol) in tetrahydrofuran (23mL) and stirred at -78°C for 1hr 20mins before being allowed to warm to 20-25°C. The solution was then diluted with ethyl acetate (76mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 153mL) followed by water (153mL). The organic solution was then diluted with ethyl acetate (54mL) and distilled down to a volume of 69mL at atmospheric pressure. The solution was then cooled to 20-25°C at which point crystallisation of the title compound occurred. The slurry of was then cooled further to 0°C before the title compound was isolated by filtration and sucked dry. Yield 8.92g.

 SYN WILL BE UPDATED.. ……………KEEP WATCHING

References

• 1  Liddle J, Allen MJ, Borthwick AD, Brooks DP, Davies DE, Edwards RM, Exall AM, Hamlett C, Irving WR, Mason, AM, McCafferty GP, Nerozzi F, Peace S, Philp J, Pollard D, Pullen MA, Shabbir SS, Sollis SL, Westfall TD, Woollard PM, Wu C, Hickey DM (January 2008). “The discovery of GSK221149A: A potent and selective oxytocin antagonist”. Bioorganic & Medicinal Chemistry Letters 18 (1): 90–94. doi:10.1016/j.bmcl.2007.11.008. PMID 18032036.
• 2
• Borthwick, A. D.; Liddle, J. (January 2013). “Retosiban and Epelsiban: Potent and Selective Orally available Oxytocin Antagonists”. In Domling, A. Methods and Principles in Medicinal Chemistry: Protein-Protein Interactions in Drug Discovery. Weinheim: Wiley-VCH. pp. 225–256. ISBN 978-3-527-33107-9.
• 3
• McCafferty GP, Pullen MA, Wu C, Edwards RM, Allen M.J, Woollard PM, Borthwick AD, Liddle J, Hickey DM, Brooks DP, Westfall TD (March 2007). “Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat”. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 293: R299–R305. doi:10.1152/ajpregu.00057.2007. PMID 17395790.
• 4
• USAN Council (2007). “Statement on a Nonproprietary Name Adopted by the USAN Council” (PDF).
• 5  Borthwick AD, Liddle J (July 2011). “The Design of Orally Bioavailable 2,5-Diketopiperazine Oxytocin Antagonists: From Concept to Clinical Candidate for Premature Labour”. Medicinal Research Reviews 31 (4): 576–604. doi:10.1002/med.20193. PMID 20027670.

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OTHER INFO

http://pubs.acs.org/doi/abs/10.1021/jm201287w

A six-stage stereoselective synthesis of indanyl-7-(3′-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3′-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK_i > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2′,6′-dimethyl-3′-pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pK_i = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.

EPELSIBAN

(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione (69)

69 as a white solid (2.4 g, 45%). Recystallisation from ethyl acetate/hexane (1:3) gave colorless needles (75%) mp 140 °C. ¹H NMR (CDCl₃) δ 7.49 (d, J = 7.8 Hz, 1H, pyridyl-4H), 7.26–7.15 (m, 4H, indanyl-arylH), 7.10 (d, J =8.1 Hz, 1H, pyridyl-5H), 6.68 (s, 1H, NCHpyridyl), 6.49 (d, J = 2.8 Hz, 1H, lactam-NH), 4.10 (dd, J = 10.1 Hz, 4.0 Hz, 1H, NCHindanyl), 4.01 (d, J = 4.5 Hz, NCHsec-butyl), 3.75–2.71 (m, 13H, 8× morpholinyl-H, indanyl-3H, -1H, -2H), 2.62 and 2.58 (2s, 6H, pyridyl-2Me,-6Me), 1.64–1.52 (m, 1H, CHHMe), 0.98–0.79 (m, 2H, CHHMe, CHMeCH₂), 0.70 (t, J = 7.1 Hz, 3H, CH₂Me), 0.45 (d, J = 6.8 Hz, 3H, CHMe). LCMS m/z 519 (MH⁺) single component, gradient 2 (t_R 2.70 min). HRMS calcd for C₃₀H₃₈N₄O₄ (MH⁺) 519.29658, found 519.29667. HPLC: 100% (t_R 10.388 min).

To a warm solution of 69 (2.66 g, 5.1 mmol) in acetone (40 mL) was added a solution of benzene sulfonic acid (0.81 g, 5.1 mmol) in acetone (40 mL), and the resulting solution was heated to boiling and allowed to cool to room temperature during 48 h. The resulting crystals were filtered off, air-dried on the filter pad to give the besylate (3.214 g, 92.6%) as white crystals of 69B mp 179–183 °C. ¹H NMR (CD₃OD) δ 8.30 (d, 1H, J = 8.1 Hz, pyridyl-4H), 7.84–7.80 (m, 2H, PhSO₃^– 2× ortho-H), 7.78 (d, J = 8.3 Hz, 1H, pyridyl-5H), 7.45–7.38 (m, 3H, PhSO₃^– 2× meta-H, para-H), 7.23–7.09 (m, 4H, indanyl-arylH), 6.08 (broad s, 1H, NCHpyridyl), 4.00 (d, J = 4.6 Hz, 1H, NCHsec-butyl), 3.92 (d, J = 9.9 Hz, 1H, NCHindanyl), 3.78–3.39 and 3.14–2.80 (m, 13H, 8× morpholinyl-H, indanyl-3H, -1H, -2H)), 2.79 and 2.78 (2s, 6H, pyridyl-2Me, -6Me), 1.85–1.74 (m, 1H, CHHMe), 1.59–1.48 (m, 1H, CHHMe), 1.15–1.01 (m, 1H, CHMeCH₂), 0.92 (d, J = 6.3 Hz, 3H, CHMe), 0.85 (t, J = 7.3 Hz, 3H, CH₂Me). LCMS m/z 519 MH⁺ single components, t_R 2.72 min; circular dichroism (CH₃CN) λ_max 225.4 nm, dE −15.70, E15086; λ_max 276 nm, dE 3.82, E5172. HRMS calcd for C₃₀H₃₈N₄O₄ (MH⁺) 519.2971, found 519.2972. Anal. (C₃₀H₃₈N₄O₄·C₆H₆O₃S·3.0H₂O) C, H, N, S.

…………..

Updates

—

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST ,  INDIA
web link

ABOUTME

BRAND ANTHONYCRASTO

COLLECTION OF SITE LINKS

Retosiban

Systematic (IUPAC) name
(3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-(morpholin-4-yl)-2-oxoethyl]piperazine-2,5-dione
Clinical data
Legal status	Non-regulated
Identifiers
CAS number	820957-38-8
ATC code	None
PubChem	CID 96025669
ChemSpider	23323798
UNII	GIE06H28OX
KEGG	D08986
Synonyms	GSK-221,149-A
Chemical data
Formula	C27H34N4O5
Molecular mass	494.58 g/mol

Brexpiprazole

ブレクスピプラゾール

NDA is considered filed as of September 9, 2014 (60 days after submission). The PDUFA date is July 11, 2015.

Brexpiprazole (/brɛksˈpɪprəzoʊl/ breks-pip-rə-zohl; also called OPC-34712) is a novel D2 dopamine partial agonist investigational product currently in clinical trials for the treatment of depression, schizophrenia, and attention deficit hyperactivity disorder(ADHD).^[1]Although it failed Stage 2 trials for ADHD, it has been designed to provide improved efficacy and tolerability (e.g., lessakathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).^[2]

OPC-34712 is an antidepressant and antipsychotic drug candidate awaiting approval in the U.S. for the treatment of schizophrenia and also as adjunctive treatment of major depressive disorder (MDD). The product is in phase III clinical trials for the treatment of agitation associated with Alzheimer’s disease. Phase III clinical trials are also underway for the treatment of post-traumatic stress disorder (PTSD).

Phase II clinical trials are also ongoing for use as adjunctive therapy in adults with attention deficit hyperactivity disorder (ADHD). The compound is being developed by Otsuka Pharmaceutical. In 2011, a codevelopment and commercialization agreement was signed by Lundbeck and Otsuka Pharmaceutical in Latin and North America, Australia and Europe for the treatment of psychiatric disorders.

The drug is being developed by Otsuka, and is considered to be a successor^[3] of its top-selling antipsychotic agent aripiprazole(brand names: Abilify, Aripiprex). Otsuka’s US patent on aripiprazole expired on October 20, 2014;^[4] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.^[5]

Brexpiprazole (1) , a serotonin–dopamine activity modulator, is an investigational new drug currently in phase-III clinical trials for the treatment of depression, schizophrenia, and attention deficit hyperactivity disorder.(1A) Brexpiprazole is also considered to be a possible successor to the top-selling antipsychotic agent aripiprazole.(2A)

1. 1A……….Phase II and Phase III Drugs in U.S. Development for Depression, Anxiety, Sleep Disorders, Psychosis & ADHD, 2011. http://www.neurotransmitter.net/newdrugs.html(accessed Jan 27, 2015).
2. 2A…………FDA accepts new schizophrenia drug filing, 2014.http://www.pharmafile.com/news/194878/fda-accepts-new-schizophrenia-drug-filing(accessed Jan 27, 2015).

   Brexpiprazole

   In the clinical program, brexpiprazole demonstrated improvement in symptoms in both schizophrenia and as adjunctive therapy in major depressive disorder (MDD)

   July 2015 is the anticipated completion timing of the FDA’s review (based on PDUFA timeline)Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) today announced that the U.S. Food and Drug Administration (FDA) has determined that the New Drug Application (NDA) for brexpiprazole for monotherapy in adult patients with schizophrenia and for adjunctive treatment of major depressive disorder (MDD) in adult patients is sufficiently complete to allow for a substantive review, and the NDA is considered filed as of September 9, 2014 (60 days after submission). The PDUFA date is July 11, 2015.The NDA is supported by seven completed placebo-controlled clinical phase II or III studies in the proposed indications – three studies in schizophrenia and four studies with brexpiprazole as adjunctive therapy in MDD. The dossier included data from more than 6,000 participants of whom more than 5,000 received brexpiprazole.

   Brexpiprazole in adult patients with schizophreniaOne clinical phase II and two clinical phase III placebo-controlled studies have been completed using brexpiprazole in adult patients suffering from schizophrenia. Across the three studies more than 1,700 patients have been randomized.In the first pivotal phase III study randomizing approximately 625 patients, brexpiprazole 2mg/day and 4 mg/day both demonstrated greater improvement of symptoms relative to placebo as measured by change from baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at week 6 (p<0.05). Results of the key secondary endpoint supported primary results.In the second pivotal phase III study randomizing approximately 650 patients, brexpiprazole 4 mg/day again demonstrated greater improvement of symptoms relative to placebo (p<0.05) in change from baseline in the PANSS Total Score at Week 6. Brexpiprazole 2 mg/day showed numerical improvement (p>0.05) over placebo at Week 6.The results from the clinical phase II studyi were presented at the 24th Annual US Psychiatric and Mental Health Congress in November 2011. The study showed a clinically meaningful improvement from baseline measured by PANSS total score at week 6, although it did not achieve statistical separation from placeboii.In the placebo-controlled phase II and III studies, the rates of discontinuation due to adverse events were 8.1% for patients receiving brexpiprazole compared to 12.7% of patients receiving placebo; the only adverse event that occurred in more than 5% of brexpiprazole patients and more frequently than placebo was akathisia (5.8% vs. 4.5%).

   Brexpiprazole as adjunctive therapy in major depressive disorder (MDD) Four studies have been included in the dossier using brexpiprazole as adjunctive therapy for adult patients suffering from MDD who had demonstrated a consistent, inadequate response to at least two regimens of prior antidepressant treatment. Patients with MDD and an inadequate response to one to three antidepressants were enrolled and received antidepressants for 8 weeks, single blinded, in the two phase III studies. Patients with an inadequate response during this prospective phase were provided antidepressant therapy and randomized adjunctive treatment with either brexpiprazole or placebo for 6 weeks. The primary efficacy endpoint was the change in MADRS (Montgomery–Åsberg Depression Rating Scale) Total Score from baseline at week 6. MADRS is a commonly used scale to assess the range of symptoms in patients with MDD. Across the four studies, more than 3,900 patients entered the prospective phase and more than 1,800 patients were included in the randomized phase of the studies.The first pivotal phase III results were presented in a poster session at the 22nd European Psychiatry Association Congress (EPA) in March 2014. This two-arm phase III study randomized approximately 380 patients and demonstrated an improvement of symptoms with an antidepressant plus 2 mg brexpiprazole that was greater than an antidepressant plus placebo (p<0.001)The second pivotal phase III study was a three-arm study in which approximately 675 patients were randomized to treatment with an antidepressant plus either placebo, 1 mg brexpiprazole or 3 mg brexpiprazole.v Patients in both brexpiprazole treatment groups showed greater improvement in symptoms as measured by the MADRS compared to placebo (1 mg p>0.05, 3 mg p<0.05). Results of the second pivotal phase III study in MDD have not yet been published.

   The first clinical phase IIvi study randomized approximately 425 patients in four arms and was presented at the 164th Annual Meeting of the American Psychiatric Association in May 2011. Patients exhibited greater improvements than adjunctive placebo in MADRS Total score with the 1.5 (±0.5) mg/day dose of brexpiprazole after six weeks of treatment (p<0.05 vs. placebo). The second phase II study in MDD randomizing approximately 372 patients has not yet been published but supports the findings in the first studies.Across the four placebo-controlled phase II and III studies, over 90% of patients completed the studies. The rates of discontinuation due to adverse events were 2.9% for patients receiving brexpiprazole compared to 0.8% of patients receiving placebo; the only adverse events that occurred in more than 5% of brexpiprazole patients and more frequently than placebo were akathisia (8.6% vs. 2.8%) and weight increased (7.3 vs. 1.9%).Full data from the four clinical phase III studies in the two indications will be made available through scientific disclosure at upcoming medical congresses and in scientific publications. Data from the clinical phase III program in schizophrenia and adjunctive therapy in MDD has been submitted to the 53rd Congress of American College of Neuropsychopharmacology (ACNP) on 7-11 December 2014 in Phoenix, Arizona.

   About brexpiprazole (OPC-34712)Brexpiprazole is a novel investigational psychotropic compound discovered by Otsuka and under co-development with Lundbeck. Brexpiprazole is a serotonin-dopamine activity modulator (SDAM) that acts as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors.

Partnership with Lundbeck

In November 2011, Otsuka and Lundbeck have announced a global alliance.^[6] Lundbeck has given Otsuka an upfront payment of $200 million, and the deal includes development, regulatory and sales payments, for a potential total of $1.8 billion. Specifically for OPC-34712, Lundbeck will obtain 50% of net sales in Europe and Canada and 45% of net sales in the US from Otsuka.

The partnership has been presented by Otsuka to its investors as a good fit for several reasons:^[7]

• Geographic strategy: Otsuka in Japan, Asia, US; Lundbeck in Europe, South America and emerging markets
• Research strategy: Otsuka has knowledge in antipsychotics, Lundbeck in anti-depressant and anxiolytic.
• CNS strategy: Otsuka has a robust portfolio in next-generation CNS drugs, while Lundbeck covers a wide range of CNS conditions from Alzheimer’s to schizophrenia.
• Similar corporate culture

Clinical trials

OPC-34712 is currently in clinical trials for adjunctive treatment of MDD, adjunctive treatment of adult ADHD and schizophrenia.^[8]

Major depression

Phase II

The Phase 2 multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three ADTs in the current episode. The study was designed to assess the efficacy and safety of OPC-34712 as an adjunctive treatment to standard ADT. The ADTs included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.^[9]

Phase III

A new Phase III study is currently in the recruiting stage: “Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)”.^[10] Its goal is “to compare the effect of OPC-34712 to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with Major Depressive Disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT”. Estimated enrollment is 1250 volunteers.

Adult ADHD

Phase II

• Study of the Safety and Efficacy of OPC-34712 as a Complementary Therapy in the Treatment of Adult Attention Deficit/Hyperactivity Disorder (STEP-A)^[11] The company did not move the product to Phase III, and it is presumed this drug failed Phase II trials for the disorder.

Schizophrenia

Phase I

• Trial to Evaluate the Effects of OPC-34712 on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder^[12]

Phase II

• A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia^[13]

Phase III

• Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)^[14]
• Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)^[15]
• Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)^[16]
• A Long-term Trial of OPC-34712 in Patients With Schizophrenia^[17]

Conferences

• Phase II results were presented at the American Psychiatric Association’s 2011 annual meeting in May 2011.^[18]

• The drug has been presented at the 2nd Congress of Asian College of Neuropsychopharmacology^[19] in September 2011.

• At the US Psychiatric and Mental Health Congress in November 2011 in Vegas, Robert McQuade presented the Phase II Trial results for Schizophrenia^[20]

Side effects

The most common adverse events associated with OPC-34712 (all doses of OPC-34712 cumulatively greater than or equal to 5 percent vs. placebo) were upper respiratory tract infection (6.9% vs. 4.8%), akathisia (6.6% vs. 3.2%), weight gain (6.3% vs. 0.8%), and nasopharyngitis (5.0% vs. 1.6%).^[21]

Drug interactions

Based on information given on the consent forms, it seems OPC-34712 is a substrate of CYP2D6 and CYP3A4, like its predecessor Aripiprazole. Participants in the clinical trials are advised to avoid grapefruit, Seville oranges and related citruses.

Pharmacology

Brexpiprazole acts as a partial agonist of the 5-HT_1A, D₂, and D₃ receptors, and as an antagonist of the 5-HT_2A, 5-HT_2B, 5-HT₇, α_1A-, α_1B-, α_1D-, and α_2C-adrenergic, and H₁receptors.^[22] It has negligible affinity for the mACh receptors.^[22]

Dosage

• As an adjunct to standard antidepressant therapy in adult patients with major depressive disorder:
  • Phase II trials: 1.5 ± 0.5 mg.
  • Phase III trials: 1 or 3 mg depending on group.^[10]
• For schizophrenic/schizoaffective subjects, dosage is 4 or 12 mg.^[23]
• For ADHD, the dose was thought to be 0.25 to 2 mg/day.^[11]

Patents

• U.S. Patent 8,071,600
• WIPO PCT/JP2006/317704
• Canadian patent: 2620688^[24]
• WO 2013162046
• WO 2013161830
•  WO 2013162048
• WO 2013015456
• JP 2008115172
• WO 2006112464

PAPER

Figure 1. Brexpiprazole (1) and intermediate 18.

2-Chloro-6-fluorobenzaldehyde was converted to 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride (18), an intermediate in the synthesis of brexpiprazole, via a five-step sequence in 54% overall yield. This procedure requires no expensive catalyst and avoids the side products produced in the coupling step in the reported process. Several kilograms of compound 18 were prepared using this economical and scalable process.

1-(Benzo[b]thiophen-4-yl)piperazine Dihydrochloride (18)

Compound 10 (1.5 kg, 4.71 mol) was dissolved in ………………..DELETED…………………, and then dried to give compound 18 (1.17 kg, 85% yield). HPLC for compound 18 (t_R = 6.3 min, identical to authentic sample) 99.8% purity; HPLC method B.

18:

¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 9.65 (s, 2H), 7.75 (d, J = 5.5 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 5.5 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 3.30 (s, 8H).

¹³C NMR (100 MHz, DMSO-d₆): δ 146.92, 140.62, 133.40, 126.50, 125.06, 121.91, 117.73, 112.56, 48.52, 43.00.

MS (ESI, eV): m/z = 219.1 [M + H]⁺.

 ………..

PATENT

http://www.google.com/patents/US20140187782

A 4-(1-piperazinyl)benzo[b]thiophene compound represented by Formula (1):

is useful for various medicines such as antipsychotic drugs. Moreover, a 4-(1-piperazinyl)benzo[b]thiophene compound represented by Formula (4):

wherein R¹ is a hydrogen atom or a protecting group, is useful as an intermediate for synthesizing the compound represented by Formula (1).

Reference Example 30 and Example 1 of PTL 1 specifically disclose a method for producing a benzo[b]thiophene compound (the reaction scheme shown below). In Reference Example 30, 4-(1-piperazinyl)benzo[b]thiophene is produced by heating under reflux a mixture comprising 14.4 g of 4-bromobenzo[b]thiophene, 29.8 g of anhydrous piperazine, 9.3 g of sodium tert-butoxide, 0.65 g of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), 0.63 g of tris(dibenzylideneacetone)dipalladium (0), and 250 ml of toluene (step X).

However, the reaction of the step X produces a relatively large amount of by-products that can hardly be separated, and the purity of the compound (4a) is thus inevitably reduced. Moreover, although column purification is performed to increase the purity of the compound (4a), it is very difficult to completely remove by-products, even by column chromatography purification. For this reason, there is a demand for the development of a novel method for producing the compound (4a) with high yield and high purity.

Furthermore, by-products contained in the compound (4a) inevitably reduce the purity of the compound (1) in the subsequent step Y. Since the method described in PTL 1 requires purification by column chromatography to obtain the target compound (1) with high purity, the method is not suitable for the industrial process of mass production. In addition, according to the method, incorporation of by-products that can hardly be separated is inevitable, and high-purity products usable as active pharmaceutical ingredients cannot be produced without purification by column chromatography.

CITATION LISTPatent Literature

• PTL 1: Japanese Unexamined Patent Publication No. 2006-316052 Non Patent Literature
• NPL 1: Tetrahedron Lett., 2004, 45, 9645

Example 4

Synthesis of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one

After 1-benzo[b]thiophen-4-yl-piperazine hydrochloride (10.6 g), potassium carbonate (5.8 g), and DMF (50 ml) were stirred at 30 to 40° C. for about 30 minutes, 7-(4-chlorobutoxy)-1H-quinolin-2-one (10.0 g) and potassium iodide (6.9 g) were added. The mixture was stirred at 90 to 100° C. for 2 hours. While the temperature of the mixture was maintained at 60° C. or more, water (150 ml) was added dropwise over a period of 10 minutes or more. After the mixture was cooled to 10° C. or less, the precipitated crystals were collected by filtration, and washed with water and then with ethanol.

After ethanol (325 ml) and acetic acid (25 ml) were added to the precipitated crystals, the mixture was stirred under reflux for dissolution. Concentrated hydrochloric acid (3.6 ml) was added at around 70° C., and the mixture was cooled. After confirming the precipitation of crystals, the mixture was heated again and stirred under reflux for 1 hour. After the mixture was cooled to 10° C. or less, the precipitated crystals were collected by filtration and washed with ethanol.

After ethanol (191 ml) and water (127 ml) were added to the precipitated crystals, the mixture was stirred under reflux for dissolution. After activated carbon (0.89 g) was added, the mixture was stirred under reflux for 30 minutes and then hot filtered. After activated carbon was removed, the mixture was heated again for dissolution. After 25% aqueous sodium hydroxide solution (5.8 ml) was added at approximately 70° C., the mixture was stirred under reflux for 30 minutes, after which water (64 ml) was added at approximately 70° C. After the mixture was stirred at 40° C. for 30 minutes, the precipitated crystals were collected by filtration at 40° C. or less, then washed with water, and dried to obtain 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one as white crystals.

Yield: 14.30 g

¹H-NMR (DMSO-d₆) δ ppm;

1.6-1.75 (2H, m), 1.75-1.9 (2H, m), 2.44 (2H, t, J=7.0 Hz), 2.55-2.70 (4H, m), 3.00-3.15 (4H, m), 4.06 (2H, t, J=6.3 Hz), 6.30 (1H, d, J=9.5 Hz), 6.75-6.85 (2H, m), 6.88 (1H, d, J=7.5 Hz), 7.27 (1H, dd, J=8 Hz, 8 Hz), 7.40 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=9.5 Hz), 7.61 (1H, d, J=8 Hz), 7.69 (1H, d, J=5.5 Hz), 7.80 (1H, d, J=9.5 Hz), 11.58 (1H, bs).

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PATENT

http://www.google.com/patents/WO2006112464A1?cl=en

Example 1

Preparation of 7- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butoxy] -lH-quinolin-2-one

A mixture of 9.0 g of 7- ( 4-chlorobutoxy) -IH- quinolin-2-one, 10 g of 1-benzo [b] thiophene-4-yl- piperazine hydrochloride, 14 g of potassium carbonate, 6 g of sodium iodide and 90 ml of dimethylformamide was stirred for 2 hours at 8O⁰C. Water was added to the reaction solution and precipitated crystals were separated by filtration. The crystals were dissolved in a mixed solvent of dichloromethane and methanol, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane .-methanol = 100:3). Recrystallized from ethanol, 13.6 g of 7- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butoxy] -lH-quinolin-2-one in the form of a white powder was obtained.

Melting point 183.5-184.5⁰C

¹H-NMR ( DMSO-dg) δppm:

1.6-1.75 (2H, m) , 1.75-1.9(2H, m) , 2.44(2H, t, J=7Hz) , 2.5-2.8(4H, m) , 2.9-3.2(4H, m) , 4.06(2H, t, J=6.5Hz), 6.3O(1H, d, J=9.5Hz), 6.75-6.85 (2H, m) , 6.88(1H, d, J=7.5Hz), 7.27 (IH, dd, J=8Hz, 8Hz), 7.40 (IH, d, J=5.5Hz), 7.55 (IH, d, J=9.5Hz), 7.61(1H, d, J=8Hz) , 7.69(1H, d, J=5.5Hz), 7.8O(1H, d, J=9.5Hz), 11.59(1H, bs) .

……………….

PATENT

7- [ 4- ( 4-benzo[b]thiophen-4- yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one

The dihydrate of the benzothiophene compound represented by Formula (I) or of a salt thereof according to the present invention can be produced from an anhydride of the benzothiophene compound or of a salt thereof.

The benzothiophene compound (in the form of an

anhydride) of Formula (I), from which the dihydrate of the present invention is produced, is a known compound, and can be obtained by the production method disclosed in Example 1 of

JP2006-316052A or according to Reference Examples 1 and 2

Fig. 1 shows the ^-NMR spectrum of the dihydrate of the benzothiophene compound represented by Formula (I) prepared in Example 1.

Fig. 2 shows the X-ray powder diffraction pattern of the dihydrate of the benzothiophene compound represented by

Formula (I) prepared in Example 1.

Fig. 3 shows the infrared absorption spectrum of the dihydrate of the benzothiophene compound represented by Formula (I) prepared in Example 1.

Fig. 4 shows the Raman spectrum of the dihydrate of the benzothiophene compound represented by Formula (I) prepared in Example 1.

Fig. 5 shows the ^XH- MR spectrum of the benzothiophene compound represented by Formula (I) prepared in Example 2.

Reference Example 1: Synthesis of 7-(4-chlorobutoxy)-lH-quinolin- 2-one Methanol (149 L) , 7-hydroxy-lH-quinolin-2-one (14.87 kg), and potassium hydroxide (6.21 kg) were mixed and stirred. After dissolution, l-bromo-4-chlorobutane (47.46 kg) was further added thereto and the resulting mixture was stirred under reflux for seven hours. Thereafter, the mixture was stirred at 10° C for one hour. The precipitated crystal was centrifuged and washed with methanol (15 L). The wet crystal was collected and placed in a tank. Water (149 L) was added thereto, followed by stirring at room temperature. After centrifugation, the resulting solid was washed with water (30 L). The wet crystal was collected and placed in a tank. After adding methanol (74 L), the mixture was stirred under reflux for one hour, cooled to 10° C, and then stirred. The precipitated crystal was centrifuged and washed with methanol (15 L). The separated crystal was dried at 60° C to obtain 7- (4-chlorobutoxy) -lH-quinolin-2-one (15.07 kg).

Reference Example 2: Synthesis of 7- [ 4- ( 4-benzo[b] thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one

Water (20 L), potassium carbonate (1.84 kg), 1- benzo[b] thiophen-4-yl-piperazine hydrochloride (3.12 kg), and ethanol (8 L) were mixed and stirred at 50° C. 7- ( 4-Chlorobutoxy) – lH-quinolin-2-one (2.80 kg) obtained in Reference Example 1 was added to the mixture and stirred under reflux for nine hours.

After concentrating the solvent (8 L) under ordinary pressure, the mixture was stirred at 90° C for one hour and then cooled to 9° C . The precipitated crystal was centrifuged and then

sequentially washed with water (8 L) and ethanol (6 L). The separated crystal was dried at 60° C to obtain a crude product. The crude product (4.82 kg) and ethanol (96 L) were mixed in a reaction vessel, and acetic acid (4.8 L) was introduced into the reaction vessel. The mixture was stirred under reflux for one hour to dissolve the crude product. After introducing

hydrochloric acid (1.29 kg), the mixture was cooled to 10° C. The mixture was heated again, refluxed for one hour, and cooled to 7° C. The precipitated crystal was centrifuged and washed with ethanol (4.8 L). The separated crystal was dried at 60° C to obtain 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-l-yl)butoxy] -1H- quinolin-2-one hydrochloride (5.09 kg). The resulting 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] -lH-quinolin-2-one hydrochloride (5.00 kg), ethanol (45 L), and water (30 L) were mixed in a reaction vessel. The mixture was stirred under reflux to dissolve the 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-l- yl)butoxy] -lH-quinolin-2-one hydrochloride. Activated carbon (500 g) and water (5 L) were added thereto, and an activated carbon treatment was conducted under reflux for 30 minutes. After performing hot filtration, a solution containing sodium hydroxide (511 g) dissolved in water (1.5 L) was flowed into the reaction vessel while stirring the filtrate under reflux. After stirring under reflux for 30 minutes, water (10 L) was introduced thereto and the mixture was cooled to approximately 40° C. The

precipitated crystal was centrifuged and washed with water (125 L). The separated crystal was dried at 80° C to obtain 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] – lH-quinolin-2-one (3.76 kg).

Example 1: Preparation of 7- [ 4- ( 4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one dihydrate

The 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-1- yl)butoxy] -lH-quinolin-2-one (3.2 kg) obtained in Reference

Example 2, ethanol (64 L) , water (74 L) , and acetic acid (1.77 kg) were mixed in a reaction vessel to prepare an acidic liquid mixture. The mixture was stirred under reflux to dissolve the 7- [ 4- ( 4-benzo[b] thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2- one (reflux temperature: 84° C). After cooling to -5°C, the solution obtained above was introduced, over a period of 30 minutes, into a solution containing 25% sodium hydroxide (5.9 kg) and water (54 L) that was cooled to 0°C, to prepare a liquid mixture with pHlO. After being stirred at 5° C or below for one hour, the mixture was heated to 20 to 30° C and further stirred for-seven hours . The precipitated crystal was filtered and washing with water (320 L) was performed, until alkali in the solid component disappeared (i.e.. until the pH value of the filtrate became 7 ) . The solid component was then air-dried until its weight became constant to obtain a white solid 7-[4-(4- benzofb] thiophen-4-yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one dihydrate (unground, 3.21 kg).

Fig. 1 shows the ^XH-NMR spectrum (D SO-d₆, TMS) of the dihydrate prepared by the aforesaid method. As shown in Fig. 1, in the ^- MR spectrum (DMSO-d₆, TMS) , peaks were observed at 1.64 ppm (tt, J = 7.4 Hz, J = 7.4 Hz, 2H) , 1.80 ppm (tt, J = 7.0 Hz, J = 7.0 Hz, 2H), 2.44 ppm (t, J = 7.5 Hz, 2H) , 2.62 ppm (br, 4H) , 3.06 ppm (br, 4H) , 3.32 ppm (s, 4H + H₂0) , 4.06 ppm (t, J = 6.5 Hz, 2H), 6.29 ppm (d, J = 9.5 Hz, 1H), 6.80 ppm (d, J = 2.5 Hz, 1H) , 6.80 ppm (dd, J = 2.5 Hz, J = 9.0 Hz, 1H) , 6.88 ppm (d, J = 7.5 Hz, 1H), 7.27 ppm (dd, J = 7.8 Hz, J = 7.8 Hz, 1H) , 7.40 ppm (dd, J = 0.5 Hz, J = 5.5 Hz, 1H), 7.55 ppm (d, J = 9.0 Hz, 1H) , 7.61 ppm (d, J = 8.0 Hz, 1H) , 7.69 ppm (d, J = 5.5 Hz, 1H) , 7.80 ppm (d, J = 9.5 Hz, 1H), and 11.57 ppm (s, 1H) .

The X-ray powder diffraction spectrum of the dihydrate prepared by the aforesaid method was measured using an X-ray diffractometer (D8 ADVANCE, available from Bruker AXS). Fig. 2 shows the X-ray powder diffraction spectrum. As shown in Fig. 2, in the X-ray powder diffraction spectrum, diffraction peaks were observed at 2Θ = 8.1° , 8.9° , 15.1° , 15.6° , and 24.4° . Other than those mentioned above, the diffraction peaks were also observed at 2Θ = 11.6°.. 12.2°, 14.0°, 16.3°, 18.1°, 18.4°, 18.9°, 19.5°, 20.5°, 21.5°, 22.6°, 23.3°, 25.0°, 26.1°, 26.4°, 27.1°. 28.1°, 28.5°, 28.9°, 29.8°, 30.4°, 30.7°, 31.6°, 32.9°, 33.9°, 34.4°, 35.2°, 36.0°, 36.7°, 37.4° , and 38.3°.

The IR (KBr) spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 3 shows the IR (KBr) spectrum. As shown in Fig. 3, in the IR (KBr) spectrum, absorption bands were observed in the vicinity of wavenumbers 3509 cm^“1, 2934 cm^“1, 2812 cm^“1, 1651 cm^“1, 1626 cm^“1, 1447 cm^“1, 1223 cm^“1 and 839 cm^“1.

The Raman spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 4 shows the Raman spectrum. As shown in Fig. 4, in the Raman spectrum, absorption bands were observed in the vicinity of wavenumbers 1497 cm^“1, 1376 cm^“1, 1323 cm^“1, 1311 cm^“1, 1287 cm^“1, 1223 cm^“1, and 781 cm^“1.

Other than those mentioned above, absorption was also observed in the vicinity of wavenumbers 1656 cm^“1, 1613 cm^“1, 1563 cm^“1, 1512 cm^“1, 1468 cm^“1, 1446 cm^“1, 1241 cm^“1, 1203 cm^“1, 1145 cm^“1, 1096 cm^“1, 1070 cm^“1, 971 cm^“1, and 822 cm^“1.

The water content of the dihydrate prepared by the aforesaid method was measured using a moisture meter (CA-100, available from Mitsubishi Chemical Analytech Co., Ltd.) by the Karl Fischer method. As a result, the dihydrate had a water content of 7.79% by weight.

Example 2; Preparation of finely ground dihydrate

Dihydrate crystal (2.73 kg) obtained in Example 1 was ground using a jet mill. Here, the air pressure was set at 5 kgf/cm², and the rotational speed of the feeder was set at 20 rpm. As a result, finely ground 7-[4-(4-benzo[b]thiophen-4-yl- piperazin-1-yl)butoxy] -1H-quinoli -2-one dihydrate (2.61 kg,

95.6%) was obtained.

The dihydrate (finely ground product) thus obtained had a mean particle diameter of 5.5 um. The mean particle diameter was measured using a Microtrack HRA, manufactured by Nikkiso Co., Ltd.

Fig. 5 shows the ^-NMR spectrum (DMSO-d₆, TMS) of the dihydrate prepared by the above method. As shown in Fig. 5, in the ^- MR spectrum (DMSO-d₆, TMS), peaks were observed at 1.64 ppm (tt, J = 7.3 Hz, J = 7.3 Hz, 2H), 1.80 ppm (tt, J = 6.9 Hz, J = 6.9 Hz, 2H), 2.44 ppm (t, J = 7.3 Hz, 2H) , 2.62 ppm (br, 4H) , 3.06 ppm (br, 4H) , 3.32 ppm (s, 4H + H₂0) , 4.06 ppm (t, J = 6.5 Hz, 2H), 6.29 ppm (d, J = 9.5 Hz, 1H) , 6.80 ppm (d, J = 2.5 Hz , 1H) , 6.80 ppm (dd, J = 2.3 Hz, J = 9.3 Hz, 1H) , 6.88 ppm (d, J = 7.5 Hz, 1H), 7.27 ppm (dd, J = 8.0 Hz, J = 8.0 Hz, 1H) , 7.40 ppm (d, J = 5.5 Hz, 1H), 7.55 ppm (d, J = 9.5 Hz , 1H) , 7.61 ppm (d, J = 8.0 Hz, 1H), 7.69 ppm (d, J = 5.5 Hz, 1H) , 7.80 ppm (d, J = 9.5

Hz, 1H), and 11.57 ppm (s, 1H) .

The X-ray powder diffraction spectrum of the dihydrate prepared by the aforesaid method was measured in the same manner as in Example 1. Fig. 6 shows the X-ray powder diffraction spectrum. As shown in Fig. 6, in the X-ray powder diffraction spectrum, diffraction peaks were observed at 2Θ = 8.2° , 8.9° ,

15.2° , 15.7° and 24.4° .

Other than those mentioned above, the diffraction peaks were also observed at 2Θ = 6.8°, 12.2°, 14.0°, 14.5″, 17.4°,

18.1°, 18.5°, 19.0°, 19.2°, 19.6°, 20.3°, 20.6°, 21.5°, 22.7°,

23.4°, 25.0°, 26.1°, 27.1°, 28.6°, 29.0°, 30.4°, 34.0°, 34.5°,

35.3° , and 36.7° .

The IR (KBr) spectrum of the dihydrate prepared by the aforesaid method was measured in the same manner as in Example 1.

Fig. 7 shows the IR (KBr) spectrum. As shown in Fig. 7, in the IR

(KBr) spectrum, absorption bands were observed in the vicinity of wavenumbers 3507 cm^“1, 2936 cm^“1, 2812 cm^“1, 1651 cm^“1, 1626 cm^“1,

1447 cm^“1, 1223 cm^“1 and 839 cm^“1.

The Raman spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 8 shows the Raman spectrum.

As shown in Fig. 8, in the Raman spectrum, absorption bands were observed in the vicinity of wavenumbers 1496 cm^‘1, 1376 cm^“1, 1323 cm^‘1, 1311 cm^“1, 1286 cm^“1, 1223 cm^“1, and 781cm^“1.

Other than those mentioned above, absorption was also observed in the vicinity of wavenumbers 1656 cm^“1, 1614 cm^“1, 1563 cm^“1, 1512 cm^“1, 1467 cm^“1, 1446 cm^“1, 1241 cm^“1, 1203 cm^“1, 1145 cm^“1,

1095 cm^“1, 1069 cm^“1, 971 cm^“1, and 822 cm^“1.

The water content of the dihydrate prepared by the aforesaid method was measured using a moisture meter (CA-100, available from Mitsubishi Chemical Analytech Co., Ltd.) by the

Karl Fischer method. As a result, the dihydrate had a water content of 6.74% by weight . Example 3 : Preparation of 7- [ 4- ( 4-benzo[b] thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one dihydrate

7- [ 4- ( 4-Benzo[ ] thiophen-4-yl-piperazin-1-yl)butoxy] – lH-quinolin-2-one (5.0 kg), ethanol (100 L), water (115 L), and DL-lactic acid (2.29 kg) were mixed to prepare an acidic liquid mixture. The liquid mixture was stirred under reflux to dissolve the 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-l-yl)butoxy] -1H- quinolin-2-one (reflux temperature: 82° C). After cooling to -5°C, the solution obtained above was introduced, over a period of about 15 minutes, into a solution containing sodium hydroxide (1.48 kg) and water (135 L) that was cooled to 1°C, to prepare a liquid mixture with pHll. After being stirred at approximately 2 to 5° C for three hours, the mixture was heated to 45° C and

further stirred at 45 to 50° C for two hours. The precipitated crystal was filtered and washing with water (200 L) was performed until alkali in the solid component disappeared (i.e., until the pH value of the filtrate became 7). The solid component was further washed with a liquid mixture of ethanol (15 L) and water (20 L). The solid component was then dried at room temperature until its weight became constant to obtain a white solid 7- [4- (4- benzo[b] thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2-one dihydrate (unground, 5.11 kg).

The dihydrate thus obtained was the same as that obtained in Example 1.

The Raman spectrum of the dihydrate prepared by the aforesaid method was measured. Fig. 9 shows the Raman spectrum. As shown in Fig. 9, in the Raman spectrum, absorption bands were observed in the vicinity of wavenumbers 1497 cm^“1, 1376 cm^“1, 1323 cm^“1, 1311 cm^“1, 1287 cm^“1, 1223 cm^“1, and 782 cm^“1.

Other than those mentioned above, absorption was also observed in the vicinity of wavenumbers 1656 cm^“1, 1614 cm^“1, 1563 cm^“1, 1512 cm^“1, 1468 cm^“1, 1446 cm^“1, 1241 cm^“1, 1203 cm^“1, 1145 cm^“1, 1126 cm^“1, 1096 cm^“1, 1070 cm^“1, 972 cm^“1, and 822 cm^“1.

…………………….

PATENT

http://www.google.com/patents/WO2006112464A1?cl=en

…………………..

PATENT

http://www.google.com/patents/US20110152286

References

 ………

Regulatory and Commercial Status

STATUS FOR MS:Phase III

HIGHEST STATUS ACHIEVED (FOR ANY CONDITION):

Marketing Authorization Application for the treatment of pancreatic cancer has been filed with the European Medicines Agency (16 October 2012)

Marketing Authorization Application for the conditional approval in the treatment of pancreatic cancer has been accepted by the European Medicines Agency (30 October 2012)

Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumors in animals, specifically dogs.^[1][2] Since its introduction in November 2008 it has been distributed under the commercial name Masivet. It has been available in Europe since the second part of 2009. In the USA it is distributed under the name Kinavet and has been available for veterinaries since 2011.

Masitinib is being studied for several human conditions including cancers. It is used in Europe to fight orphan diseases.^[3]

Mechanism of action

Masitinib inhibits the receptor tyrosine kinase c-Kit which is displayed by various types of tumour.^[2] It also inhibits the platelet derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR).

http://www.google.com/patents/WO2012136732A1?cl=en

In a preferred embodiment of the above-depicted treatment, the active ingredient masitinib is administered in the form of masitinib mesilate; which is the orally bioavailable mesylate salt of masitinib – CAS 1048007-93-7 (MsOH); C28H30N6OS.CH3SO3H; MW 594.76:

http://www.google.com/patents/WO2004014903A1?cl=en

003 : 4-(4-Methyl-piperazin-l-ylmethyl)-N-[3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl] -benzamide

4-(4-Methyl-piperazin-l-yl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)- phenyl] -benzamide

beige brown powder mp : 128-130°C

1H RMN (DMSO-d⁶) δ = 2.15 (s, 3H) ; 2.18 (s, 3H) ; 2.35-2.41 (m, 4H) ; 3.18-3.3.24 (m, 4H) ; 6.94 (d, J = 8.9 Hz, 2H) ; 7.09 (d, J = 8.4 Hz, IH) ; 7.28-7.38 (m, 3H) ; 7.81 (d, J = 8.9 Hz, 2H) ; 8.20-8.25 (m, IH) ; 8.40 (dd, J = 1.6 Hz, J = 4.7 , IH) ; 8.48 (d, J = 1.9 Hz, IH) ; 9.07 (d, J = 1.5 Hz, IH) ; 9.35 (s, IH) ; 9.84 (s, IH)

……………

http://www.google.com/patents/WO2008098949A2?cl=en

EXAMPLE 4 N- [4-Methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide derivatives

Method A In a reactor and under low nitrogen pressure, add 4-Methyl-N3-(4-pyridin-3-yl-thiazol- 2-yl)-benzene-l,3-diamine (95 g, 336.45 mmol), dichloromethane (2 L). To this suspension cooled to temperature of 5°C was added dropwise 2M/n-hexane solution of trimethylaluminium (588 mL). The reaction mixture was brought progressively to 15°C, and maintained for 2 h under stirring. 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (100 g, 402.71 mmol) in dichloromethane (200 mL) was added for 10 minutes. After 1 h stirring at room temperature, the reaction mixture was heated to reflux for 20 h and cooled to room temperature. This solution was transferred dropwise via a cannula to a reactor containing 2N NaOH (2.1 L) cooled to 5°C. After stirring for 3 h at room temperature, the precipitate was filtered through Celite. The solution was extracted with dichloromethane and the organic layer was washed with water and saturated sodium chloride solution, dried over MgSO₄ and concentrated under vacuum. The brown solid obtained was recrystallized from /-Pr₂O to give 130.7 g (78%) of a beige powder.

Method B Preparation of the acid chloride

To a mixture of 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid dihydrochloride (1.0 eq), dichloromethane (7 vol) and triethylamine (2.15 eq), thionyl chloride (1.2 eq) was added at 18-28°C . The reaction mixture was stirred at 28-32°C for 1 hour. Coupling of acid chloride with amino thiazole To a chilled (0-5⁰C) suspension of 4-Methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene- 1,3-diamine (0.8 eq) and thiethylamine (2.2 eq) in dichloromethane (3 vol), the acid chloride solution (prepared above) was maintaining the temperature below 5°C. The reaction mixture was warmed to 25-30⁰C and stirred at the same temperature for 1O h. Methanol (2 vol) and water (5 vol) were added to the reaction mixture and stirred. After separating the layers, methanol (2 vol), dihloromethane (5 vol) and sodium hydroxide solution (aqueous, 10%, till pH was 9.5-10.0) were added to the aqueous layer and stirred for 10 minutes. The layers were separated. The organic layer was a washed with water and saturated sodium chloride solution. The organic layer was concentrated and ethanol (2 vol) was added and stirred. The mixture was concentrated. Ethanol was added to the residue and stirred. The product was filtered and dried at 50-55⁰C in a vaccum tray drier. Yield = 65-75%.

Method C

To a solution of 4-methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene-l,3-diamine (1.0 eq) in DMF (20 vol) were added successively triethylamine (5 eq), 2-chloro-l- methylpyridinium iodide (2 eq) and 4-(4-methyl-piperazin-l-ylmethyl)-benzoic acid (2 eq). The reaction mixture was stirred for 7 h at room temperature. Then, the mixture was diluted in diethyl ether and washed with water and saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using an elution of 100% EtOAc to give a yellow solid.

Yield = 51%.

¹H NMR (CDCl₃) : δ = 9.09 (IH, s, NH); 8.52 (IH, br s); 8.27 (IH, s); 8.13 (IH, s);

8.03 (IH, s); 7.85 (2H, d, J= 8.3Hz); 7.45 (2H, m); 7.21-7.38 (4H, m); 6.89 (IH, s);

3.56 (2H, s); 2.50 (8H, br s); 2.31 (6H, br s).

MS (CI) m/z = 499 (M+H)⁺.

An additional aspect of the present invention relates to a particular polymorph of the methanesulfonic acid salt of N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide of formula (IX).

(VI)

Hereinafter is described the polymorph form of (IX) which has the most advantageous properties concerning processability, storage and formulation. For example, this form remains, dry at 80% relative humidity and thermodynamically stable at temperatures below 200⁰C.

The polymorph of this form is characterized by an X-ray diffraction pattern illustrated in FIG.I, comprising characteristic peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degrees θ, and is also characterized by differential scanning calorimetry (DSC) illustrated in FIG.II, which exhibit a single maximum value at approximately 237.49 ± 0.3 ⁰C. X-ray diffraction pattern is measured using a Bruker AXS (D8 advance). Differential scanning calorimetry (DSC) is measured using a Perking Elmer Precisely (Diamond DSC).

This polymorph form can be obtained by treatement of 4-(4-Methyl-piperazin-l- ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide with 1.0 to 1.2 equivalent of methanesulfonic acid, at a suitable temperature, preferably between 20-80⁰C.

The reaction is performed in a suitable solvent especially polar solvent such as methanol or ethanol, or ketone such as acetone, or ether such as diethylether or dioxane, or a mixture therof. This invention is explained in example given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Preparation of the above-mentioned polymorph form of 4-(4-Methyl-piperazin-l- ylmethyl)-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide methanesulfonate .

4-(4-Methyl-piperazin- 1 -ylmethyl)-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino) phenyl] -benzamide (1.0 eq) was dissolved in ethanol (4.5 vol) at 65-70⁰C. Methanesulfonic acid (1.0 eq) was added slowly at the same temperature. The mixture was cooled to 25-30⁰C and maintained for 6 h. The product was filtered and dried in a vacuum tray drier at 55-60⁰C. Yield = 85-90%. Starting melting point Smp = 236°C.

References

1. Hahn, K.A.; Oglivie, G.; Rusk, T.; Devauchelle, P.; Leblanc, A.; Legendre, A.; Powers, B.; Leventhal, P.S.; Kinet, J.-P.; Palmerini, F.; Dubreuil, P.; Moussy, A.; Hermine, O. (2008). “Masitinib is Safe and Effective for the Treatment of Canine Mast Cell Tumors”. Journal of Veterinary Internal Medicine 22 (6): 1301–1309. doi:10.1111/j.1939-1676.2008.0190.x. ISSN 0891-6640.
2.  Information about Masivet at the European pharmacy agency website
3.  Orphan designation for Masitinib at the European pharmacy agency website

WO2004014903A1	Jul 31, 2003	Feb 19, 2004	Ab Science	2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors
WO2008098949A2	Feb 13, 2008	Aug 21, 2008	Ab Science	Process for the synthesis of 2-aminothiazole compounds as kinase inhibitors
EP1525200B1	Jul 31, 2003	Oct 10, 2007	AB Science	2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors
US7423055	Aug 1, 2003	Sep 9, 2008	Ab Science	2-(3-Aminoaryl)amino-4-aryl-thiazoles for the treatment of diseases
US20080207572 *	Jul 13, 2006	Aug 28, 2008	Ab Science	Use of Dual C-Kit/Fgfr3 Inhibitors for Treating Multiple Myeloma

Systematic (IUPAC) name
4-[(4-Methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)-1,3-thiazol-2-yl]amino}phenyl)benzamide
Clinical data
Trade names	Masivet, Kinavet
AHFS/Drugs.com	International Drug Names
Identifiers
CAS Registry Number	790299-79-5
ATC code	L01XE22
PubChem	CID 10074640
ChemSpider	8250179
ChEMBL	CHEMBL1908391
Chemical data
Formula	C28H30N6OS
Molecular mass	498.64 g/mol

Patent	Submitted	Granted
2-(3-Aminoaryl)amino-4-aryl-thiazoles for the treatment of diseases [US7423055]	2004-06-10	2008-09-09
2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors [US2005239852]	2005-10-27
Use of C-Kit Inhibitors for Treating Fibrosis [US2007225293]	2007-09-27
Use of Mast Cells Inhibitors for Treating Patients Exposed to Chemical or Biological Weapons [US2007249628]	2007-10-25
Use of c-kit inhibitors for treating type II diabetes [US2007032521]	2007-02-08
Use of tyrosine kinase inhibitors for treating cerebral ischemia [US2007191267]	2007-08-16
Use of C-Kit Inhibitors for Treating Plasmodium Related Diseases [US2008004279]	2008-01-03
Tailored Treatment Suitable for Different Forms of Mastocytosis [US2008025916]	2008-01-31
2-(3-AMINOARYL) AMINO-4-ARYL-THIAZOLES AND THEIR USE AS C-KIT INHIBITORS [US2008255141]	2008-10-16
Use Of C-Kit Inhibitors For Treating Inflammatory Muscle Disorders Including Myositis And Muscular Dystrophy [US2008146585]	2008-06-19

Patent	Submitted	Granted
Aminothiazole compounds as kinase inhibitors and methods of using the same [US8940894]	2013-05-10	2015-01-27
Aminothiazole compounds as kinase inhibitors and methods of using the same [US8492545]	2012-03-08	2013-07-23

Patent	Submitted	Granted
Use of Dual C-Kit/Fgfr3 Inhibitors for Treating Multiple Myeloma [US2008207572]	2008-08-28
PROCESS FOR THE SYNTHESIS OF 2-AMINOTHIAZOLE COMPOUNDS AS KINASE INHIBITORS [US8153792]	2010-05-13	2012-04-10
COMBINATION TREATMENT OF SOLID CANCERS WITH ANTIMETABOLITES AND TYROSINE KINASE INHIBITORS [US8227470]	2010-04-15	2012-07-24
Anti-IGF antibodies [US8580254]	2008-06-19	2013-11-12
COMBINATIONS FOR THE TREATMENT OF B-CELL PROLIFERATIVE DISORDERS [US2009047243]	2008-07-17	2009-02-19
TREATMENTS OF B-CELL PROLIFERATIVE DISORDERS [US2009053168]	2008-07-17	2009-02-26
Anti-IGF antibodies [US8318159]	2009-12-11	2012-11-27
SURFACE TOPOGRAPHIES FOR NON-TOXIC BIOADHESION CONTROL [US2010226943]	2009-08-31	2010-09-09
EGFR/NEDD9/TGF-BETA INTERACTOME AND METHODS OF USE THEREOF FOR THE IDENTIFICATION OF AGENTS HAVING EFFICACY IN THE TREATMENT OF HYPERPROLIFERATIVE DISORDERS [US2010239656]	2010-05-10	2010-09-23
ANTI CD37 ANTIBODIES [US2010189722]	2008-08-08	2010-07-29

1. ChemIDplus Advanced

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Note: Compound name must be entered under “Substance Identification” and then “Names and Synonyms” selected to view synonyms.

2. “Human Medicines” page

AB Science website

Accessed on 22 Feb 2012 from http://www.ab-science.com/.

3. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.

Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Castéran N, Borge L, Hajem B, Lermet A, Sippl W, et al.

PLoS One. 2009; 4(9):e7258. Epub 2009 Sep 30. PMID: 19789626. Abstract

4. Masitinib mesylate application for conditional approval

Food and Drug Administration, 15 Dec 2010

Accessed on 22 Feb 2012 from http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM245243.pdf.

5. Scientific discussion for the approval of Masivet

European Medicines Agency, Nov 2008

Accessed on 22 Feb 2012 from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/veterinary/000128/WC500064714.pdf.

6. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: a randomised, placebo-controlled phase 2 trial.

Piette F, Belmin J, Vincent H, Schmidt N, Pariel S, Verny M, Marquis C, Mely J, Hugonot-Diener L, Kinet J-P, et al.

Alzheimers Res Ther. 2011; 3(2):16. Epub 2011 Apr 19. PMID: 21504563. Abstract

7. Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study.

Tebib J, Mariette X, Bourgeois P, Flipo R-M, Gaudin P, Le Loët X, Gineste P, Guy L, Mansfield CD, Moussy A, et al.

Arthritis Res Ther. 2009; 11(3):R95. Epub 2009 Jun 23. PMID: 19549290. Abstract

8. AB Science announces recruitment of first patient in phase 3 study of masitinib in progressive multiple sclerosis

Businesswire.com, 6 Sep 2011

Accessed on 22 Feb 2012 from http://www.businesswire.com/news/home/20110906006398/en/AB-Science-announces-recruitment-patient-phase-3.

9. Masitinib in Patients with Progressive or Relapse-Free Secondary Multiple Sclerosis

ClinicalTrials.gov, 13 Sep 2011

Accessed on 22 Feb 2012 from http://clinicaltrials.gov/ct2/show/study/NCT01433497.

10. Masitinib in Patients with Primary Progressive Multiple Sclerosis (PPMS) or Relapse-Free Secondary Multiple Sclerosis (SPMS)

ClinicalTrials.gov, 10 Oct 2011

Accessed on 22 Feb 2012 from http://clinicaltrials.gov/ct2/show/NCT01450488.

11. Phase II study of oral masitinib mesilate in imatinib-naïve patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST).

Le Cesne A, Blay J-Y, Bui B N, Bouché O, Adenis A, Domont J, Cioffi A, Ray-Coquard I, Lassau N, Bonvalot S, et al.

Eur J Cancer. 2010 May; 46(8):1344-51. Epub 2010 Mar 06. PMID: 20211560. Abstract

12. “Veterinary Medicines” page

AB Science website

Accessed on 22 Feb 2012 from http://www.ab-science.com/.

Editors’ Pick

13. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study.

Vermersch P, Benrabah R, Schmidt N, Zéphir H, Clavelou P, Vongsouthi C, Dubreuil P, Moussy A, Hermine O

BMC Neurol. 2012 Jun 12; 12(1):36. PMID: 22691628. Abstract

14. AB Science confirms the filing for the Marketing Authorization Application to the European Medicines Agency of masitinib in the treatment of pancreatic cancer

AB Science, 16 Oct 2012

Accessed on 1 Nov 2012 from http://www.ab-science.com/file_bdd/1350403049_absciencepancreasemafilingvdefven.pdf.

15. European Medicines Agency accepts Marketing Authorization Application for conditional approval of masitinib in the treatment of pancreatic cancer

AB Science, 30 Oct 2012

Accessed on 1 Nov 2012 from http://www.ab-science.com/file_bdd/1351622639_abscienceresultph3pancreasvdefuk.pdf.

16. Launch of a phase 3 clinical trial in the treatment of Alzheimer’s disease with masitinib

AB Science, 20 May 2013

Accessed on 21 May 2013 from http://www.ab-science.com/file_bdd/1369064860_absciencepressreleasephase3alzenfinal.pdf.

17. Masitinib is being investigated in the treatment of amyotrophic lateral sclerosis (ALS)

The Wall Street Journal, 4 Nov 2013

Accessed on 6 Nov 2013 from http://online.wsj.com/article/PR-CO-20131104-908831.html?dsk=y.

18. BRIEF-AB Science says DSMB recommends continuation of phase 3 masitinib study

Reuters, 6 Oct 2014

Accessed on 14 Oct 2014 from http://www.reuters.com/article/2014/10/06/absciencesa-brief-idUSFWN0S100120141006.

19. Neuroprotective effect of masitinib in rats with postischemic stroke.

Kocic I, Kowianski P, Rusiecka I, Lietzau G, Mansfield C, Moussy A, Hermine O, Dubreuil P

Naunyn Schmiedebergs Arch Pharmacol. 2014 Oct 26. Epub 2014 Oct 26. PMID: 25344204.Abstract

 AB SCIENCE HEADQUARTER
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Tel. : +33 (0)1 47 20 00 14
Fax. : +33 (0)1 47 20 24 11

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Evofosfamide, HAP-302 , TH-302

Evofosfamide

Names
IUPAC name (1-Methyl-2-nitro-1H-imidazol-5-yl)methyl N,N’-bis(2-bromoethyl)phosphorodiamidate
Other names TH-302; HAP-302
Identifiers
CAS Registry Number	918633-87-1
ChemSpider	10157061
InChI[show]
Jmol-3D images	Image
PubChem	11984561
SMILES[show]
Properties
Molecular formula	C9H16Br2N5O4P
Molar mass	449.04 g·mol−1
Solubility in water	6 to 7 g/l

TH-302 is a nitroimidazole-linked prodrug of a brominated derivative of an isophosphoramide mustard previously used in cancer drugs

evofosfamide (first disclosed in WO2007002931), useful for treating cancer.

Threshold Pharmaceuticals and licensee Merck Serono are codeveloping evofosfamide, the lead in a series of topoisomerase II-inhibiting hypoxia-activated prodrugs and a 2-nitroimidazole-triggered bromo analog of ifosfamide, for treating cancer, primarily soft tissue sarcoma and pancreatic cancer (phase 3 clinical, as of April 2015).

In November 2014, the FDA granted Fast Track designation to the drug for the treatment of previously untreated patients with metastatic or locally advanced unresectable soft tissue sarcoma.

Evofosfamide (INN,^[1] USAN;^[2] formerly known as TH-302) is an investigational hypoxia-activated prodrug that is in clinical development for cancer treatment. The prodrug is activated only at very low levels of oxygen (hypoxia). Such levels are common in human solid tumors, a phenomenon known as tumor hypoxia.^[3]

Evofosfamide is being evaluated in clinical trials for the treatment of multiple tumor types as a monotherapy and in combination with chemotherapeutic agents and other targeted cancer drugs
Discovered at Threshold, TH-302 is a hypoxia-activated prodrug (HAP) designed to exploit low oxygen levels in hypoxic tumor regions. Therapeutics that specifically target resistant hypoxic zones could provide significant additional antitumor activity and clinical benefit over current chemotherapeutic and radiation therapies.

Evofosfamide (TH-302) was developed by Threshold Pharmaceuticals Inc. (Threshold).^[4] The company is located in South San Francisco, CA, USA.

In 2012, Threshold signed a global license and co-development agreement for evofosfamide with Merck KGaA, Darmstadt, Germany, which includes an option for Threshold to co-commercialize eofosfamide in the United States. Threshold is responsible for the development of evofosfamide in the soft tissue sarcoma indication in the United States. In all other cancer indications, Threshold and Merck KGaA are developing evofosfamide together.^[5] From 2012 to 2013, Merck KGaA paid 110 million US$ for upfront payment and milestone payments to Threshold. Additionally, Merck KGaA covers 70% of all evofosfamide development expenses.^[6]
Discovered at Threshold, TH-302 is a hypoxia-activated prodrug (HAP) designed to exploit low oxygen levels in hypoxic tumor regions. Therapeutics that specifically target resistant hypoxic zones could provide significant additional antitumor activity and clinical benefit over current chemotherapeutic and radiation therapies.

History

SEE

WO2007002931

http://www.google.com/patents/WO2007002931A2?cl=en

Example 8

Synthesis of Compounds 25, 26 [0380] To a solution of 2-bromoethylammmonium bromide (19.4 g) in DCM (90 mL) at – 1O⁰C was added a solution OfPOCl₃ (2.3 mL) in DCM (4 mL) followed by addition of a solution of TEA (14.1 mL) in DCM (25 mL). The reaction mixture was filtered, the filtrate concentrated to ca. 30% of the original volume and filtered. The residue was washed with DCM (3×25 mL) and the combined DCM portions concentrated to yield a solid to which a mixture of THF (6 mL) and water (8 mL) was added. THF was removed in a rotary evaporator, the resulting solution chilled overnight in a fridge. The precipitate obtained was filtered, washed with water (10 mL) and ether (30 mL), and dryed in vacuo to yield 2.1 g of:

Isophosphoramide mustard

can be synthesized employing the method provided in Example 8, substituting 2- bromoethylammmonium bromide with 2-chloroethylammmonium chloride. Synthesis of Isophosphoramide mustard has been described (see for example Wiessler et al., supra).

The phosphoramidate alkylator toxin:

was transformed into compounds 24 and 25, employing the method provided in Example 6 and the appropriate Trigger-OH.

Example 25

Synthesis of l-N-methyl-2-nitroimidazole-5-carboxylis acid

A suspension of the nitro ester (39.2 g, 196.9 rnmol) in IN NaOH (600 mL) and water (200 mL) was stirred at rt for about 20 h to give a clear light brown solution. The pH of the reaction mixture was adjusted to about 1 by addition of cone. HCl and the reaction mixture extracted with EA (5 x 150 mL). The combined ethyl acetate layers were dried over MgS O4 and concentrated to yield l-N-methyl-2-nitroimidazole-5-carboxylis acid (“nitro acid”) as a light brown solid (32.2 g, 95%). Example 26

Synthesis of l-N-methyl-2-nitroimidazole-5-carboxylis acid

A mixture of the nitro acid (30.82 g, 180.23 mmol) and triethylamine (140 niL, 285 mmol) in anhydrous THF (360 mL) was stirred while the reaction mixture was cooled in a dry ice-acetonitrile bath (temperature < -20 ⁰C). Isobutyl chloroformate (37.8 mL, 288 mmol) was added drop wise to this cooled reaction mixture during a period of 10 min and stirred for 1 h followed by the addition of sodium borohydride (36 g, 947 mmol) and dropwise addition of water during a period of 1 h while maintaining a temperature around or less than O⁰C. The reaction mixture was warmed up to O⁰C. The solid was filtered off and washed with THF. The combined THF portions were evaporated to yield l-N-methyl-2- nitroimidazole-5-methanol as an orange solid (25 g) which was recrystallized from ethyl acetate.

……………………………………….

WO-2015051921

EXAMPLE 1

1

N-Formylsarcosine ethyl ester 1 (1 ,85 kg) was dissolved in toluene (3,9 kg) and ethyl formate (3,28 kg) and cooled to 10 °C. A 20 wt-% solution of potassium tert-butoxide (1 ,84 kg) in tetrahydrofuran (7,4 kg) was added and stirring was continued for 3h. The reaction mixture was extracted 2x with a solution of sodium chloride in water (10 wt-%) and the combined water extracts were washed lx with toluene.

Aqueous hydrogen chloride (25% wt-%; 5,62 kg) was added to the aqueous solution, followed by ethylene glycol (2,36 kg). The reaction mixture was heated to 55-60 °C for lh before only the organic solvent residues were distilled off under vacuum.

Aqueous Cyanamide (50 wt-%, 2,16 kg) was then added at 20 °C, followed by sodium acetate (3,04 kg). The resulting reaction mixture was heated to 85-90 °C for 2h and cooled to 0-5 °C before a pH of ~ 8-9 was adjusted via addition of aqueous sodium hydroxide (32% wt-%; 4,1 kg). Compound 3 (1,66 kg; 75%) was isolated after filtration and washing with water.

Ή-NMR (400 MHz, d6-DMSO): δ= 1,24 (3H, t, J= 7,1 Hz); 3,53 (3H, s); 4,16 (2H, q, J= 7,0 Hz) ; 6,15 (s, 2 H); 7,28 (s, 1H).

HPLC (R_t = 7,7 min): 97,9% (a/a).

REFERENCES

1

• WHO Drug Information; Recommended INN: List 73
• 2
• Adopted Names of the United States Adopted Names Council
• 3
• Duan J; Jiao, H; Kaizerman, J; Stanton, T; Evans, JW; Lan, L; Lorente, G; Banica, M et al. (2008). “Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs”. J. Med. Chem. 51 (8): 2412–20. doi:10.1021/jm701028q. PMID 18257544.
• 4
• Website of Threshold Pharmaceuticals Inc.
• 5
• Threshold Pharmaceuticals and Merck KGaA Announce Global Agreement to Co-Develop and Commercialize Phase 3 Hypoxia-Targeted Drug TH-302 – Press release from 3 February 2012
• 6

Threshold Pharmaceuticals Form 8-K from 3 Nov 2014

DHAKA BANGLADESH

.

Steamers and ferries in Sadarghat Port

Kawran Bazar

.

Dry fish sellers at the Karwan Dry Fish Market (Bazar), Dhaka, Bangladesh.

Cas 51543-39-6,

MW 244.26,

• [1,1′-Biphenyl]-4-acetic acid, 2-fluoro-α-methyl-, (S)-
• (+)-(S)-Flurbiprofen
• (+)-Flurbiprofen
• (2S)-2-(2-Fluoro-1,1′-biphenyl-4-yl)propanoic acid
• (2S)-2-(2-Fluoro-4-biphenyl)propanoic acid

• (S)-Flurbiprofen
• Dexflurbiprofen
• Esflurbiprofen
• S-(+)-Flurbiprofen
• d-Flurbiprofen

On October 20, 2014, Taisho filed for manufacturing and marketing approval for TT-063 from the Ministry of Health, Labour and Welfare as a new drug candidate that will follow the Type 2 diabetes treatment Lusefi®, which was launched in May 2014. TT-063 is a patch formulation that has been co-developed by Taisho and TOKUHON Corporation with the aim of obtaining an indication for osteoarthritis. In Phase 3 clinical trials comparing TT-063 with therapeutic drugs already on the market, TT-063 has been found to be more effective than the control drugs in patients with osteoarthritis of the knee joint (January 16, 2014 announcement ).

Furthermore, Taisho is also preparing to file for approval from the Ministry of Health, Labour and Welfare for CT-064, an oral formulation of the osteoporosis treatment agent Bonviva launched in August 2013. Taisho has confirmed the effectiveness of CT-064 for osteoporosis patients through Phase 3 clinical trials (September 22, 2014 announcement).

In the central nervous system field, TS-091 transitioned from Phase 1 to Phase 2 in Japan in May 2014. Clinical trials of TS-091 have commenced to confirm the effectiveness of this drug in patients with central disorders of hypersomnolence. In addition, Phase 1 clinical trials of TS-091 have commenced overseas. TS-111 and TS-121 are undergoing Phase 1 clinical trials overseas with the aim of obtaining an indication for depression.
Faced with intensifying competition in new drug discovery, we will jointly implement R&D activities with research institutions outside the Taisho Group, and with companies in Japan and overseas, as we work to enhance our drug development pipeline (lineup of drugs in development). Our goal is to discover many more new drugs, primarily in our priority fields.

2-(6-methoxynaphthalen-2-yl) propanoic acid By way of illustration, chemically, flurbiprofen is 2-(2-fluoro-4-biphenylyl) propionic acid and is described in US Patent No. 3,755,427. NSAIDs, such as flurbiprofen, are usually supplied as a racemate. However, recently there has been renewed interest in the separate enantiomers of flurbiprofen, i.e. S-flurbiprofen and R-flurbiprofen.

R-Flurbιprofen

S-Flurtιprofen

Flurbiprofen is a potent inhibitor of cyclooxygenase (both COX-I and COX-2) in humans and it is understood that the inhibitory effect lies predominantly in the S- enantiomer.

Flurbiprofen is generally produced in the form of a racemic compound. It is known that from the racemic compound, flurbiprofen having a high optical purity can be produced by an optical resolution method using, for example, an optically active amine compound, such as α-phenylethylamine, as an optical resolution agent, as is described in US Patent No. 5,599,969. In addition, whether dealing with racemic, S- or R- 2-aryl propionic acid, there is also a need to make the synthetic process as efficient as possible.

Example 2 – Ibuprofen

Example 2.1 Resolution procedure

Racemic ibuprofen (530g) is dissolved in toluene (1335ml) and methanol (900ml).

The mixture is heated to dissolve the solid. S-1-Phenylethylamine (247g) is dissolved in toluene (200ml) and the solution is added with stirring at 60⁰C over about 3 hours while the temperature is maintained at about 65-70⁰C. The mixture is cooled gradually to 0 to 5⁰C to induce crystallisation and stirred at this temperature for 1 hour. The crystals are filtered off, washed with toluene (600ml) and dried in a Vacuum oven at 55⁰C to form crude S-ibuprofen / S-1-phenylethylamine salt (635g).

Crude S-ibuprofen / S-1-phenylethylamine salt (635g) is stirred with toluene (1930ml) and methanol (800ml) and the mixture is heated to 6O⁰C to dissolve the solid. The solution is cooled gradually to 0 to 5°C to induce crystallisation. The crystals are filtered off and dried in a vacuum oven at 55°C to form pure S-ibuprofen / S-I- phenylethylamine salt (510g). This recrystallisation of the S-ibuprofen / S-I- phenylethylamine salt may be repeated if necessary to upgrade the enantiomeric purity if required.

Pure S-ibuprofen / S-1-phenylethylamine salt (485g) is mixed with toluene (1700ml) with stirring. Water (300ml) and concentrated hydrochloric acid (17Og) are added and

÷ibe mixture is stirred at 60⁰C. The lower aqueous layer is separated off and the upper organic layer is retained. The hydrochloric acid wash is repeated, then the toluene solution is washed with water. Water (370ml) and 47% sodium hydroxide

(118g) are added and the solution is heated to 60⁰C and allowed to settle. The lower aqueous layer is separated and the upper toluene layer is washed with water. The aqueous phases are combined and heptane (420ml) is added. Hydrochloric acid

(130g) is added and the mixture is heated to 60⁰C, stirred and settled. The organic layer is separated off and washed with water. The solution is cooled to -10⁰C to induce crystallisation and the crystals are separated off by filtration, washed with heptane and dried under vacuum to yield (S)-ibuprofen (28Og) at an enantiomeric purity of over 99%.

Example 2.2 Racemisation procedure

Toluene/methanol mother liquors from the filtration of crude S-ibuprofen / S-I- phenylethylamine salt in the resolution procedure (2400ml, containing an estimated 130g of ibuprofen) is charged into a 3 L 3 necked round bottomed flask and methanol and toluene are distilled out at atmospheric pressure (volume removed approximately 1400 ml). The batch is then cooled to around 60°C and washed twice with hydrochloric acid (20 ml concentrated hydrochloric acid in 200 ml of water), and then twice with water (200 ml). Toluene is charged (80 ml) followed by methanol (200 ml) and caustic soda solution (45Og of 28% w/w solution, 5 molar equivalents). The mixture is heated to reflux for about 6 hours. Solvent is then removed at atmospheric pressure until the vapour temperature reaches approximately 85°C. The mixture is cooled to around 60°C and concentrated hydrochloric acid is charged at about 60 to 70°C until the pH of the mixture is 1 or less. The layers are allowed to separate and the bottom aqueous layer removed. The organic layer is washed with water (200 ml) and then azeotroped to dryness using a Dean and Stark trap. A solution of racemic ibuprofen in toluene remains.

…………………………………………

PATENT

 http://www.google.com/patents/CN104478703A?cl=en

Preparation of R – (+) _ flurbiprofen:

 The racemic flurbiprofen as a starting material, to obtain an intermediate product of formula I as shown and then the ester prepared as shown in Formula II with 5-isosorbide monobenzyl ether, ester hydrolysis after obtained R – (+) – flurbiprofen;

wherein, in formula I, X is Cl or Br;

(2) by the R – (+) _ flurbiprofen obtained (RS) – flurbiprofen:

 The R _ (+) _ flurbiprofen 200mg, potassium hydroxide 150mg, 0. 5mL water into IOmL reaction flask and heated to 120 ° C and held for 2h, then water was added 15mL, cooled to room temperature, the resulting stirring the mixed solution with 10% hydrochloric acid to pH = 0. 5, extracted with ethyl acetate, combined several layers, washed with water until neutral, the organic solvent is recovered, the resulting residue was added at 60~90 ° C under an appropriate amount of petroleum ether by recrystallization, obtained (RS) – flurbiprofen 100mg, 50% yield.

 (3) Preparation of (S) -⑴- flurbiprofen:

 In 25mL single-necked flask, followed by adding (RS) – flurbiprofen 123mg, Portugal TOA 29. 8mg, isopropanol lmL, the mixture was stirred at reflux until clear, half the amount of the solvent evaporated under reduced pressure except , set the refrigerator overnight. The precipitate was collected by suction filtration as white crystals, after washing a small amount of isopropanol, which was dissolved in water, washed with 10% aqueous sodium hydroxide (10% NaOH mean mass fraction) adjusted pH = 13, the sheet-like precipitate was filtered off Portuguese octylamine white crystals. The resulting filtrate was added dropwise with stirring 10% hydrochloric acid to pH = 1, extracted with ethyl acetate, the organic layer was washed with water to recover the solvent, the resulting residue was purified by an appropriate amount of petroleum ether and recrystallized at 60~90 ° C. The product was collected by filtration, and dried in vacuo to give a white (S) – (+) _ flurbiprofen needle crystal 45. 3mg, 65% yield, mp 102~103 ° C, [α] = + 44 ° (C = 1, methanol), ee value of 92.6% (ee value measurement method: (S) – (+) – flurbiprofen after chiral amine derivatization reagents, by HPLC analysis).

wherein in step (3) is a byproduct eleven R _ (+) _ flurbiprofen, its follow step (1) of racemic reused.

 Step (1) of the specific operation is as follows:

 (la) 1:. Synthesis of 2,6-sorbitol dehydration -D- -5- benzyl ether: 4: 3

 250ml volumetric flask isosorbide 18. 25g (125mmol), lithium hydroxide monohydrate 5. 25g (125mmol) and 60ml of dimethyl sulfoxide (DMSO), heated to 90 ° C, stirred for 30min, constant pressure equalizing dropping funnel was added dropwise benzyl chloride 14. 4ml (125mmol), 90 ° C the reaction 19-20h, reaction mixture was adjusted to pH 1 with 2M hydrochloric acid, extracted with ethyl acetate (50ml * 3), the organic layers combined, washed with water ( 30ml * 2), dried over anhydrous sodium sulfate overnight, filtered and concentrated residue Cheng baby gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give a cream solid, that is 1: 4: 3: 2,6 Dehydration -D- sorbitol -5- benzyl ether 24. 5g, m.p. 59 ~61 ° C.

 (Ib) · 2- (2- fluoro-4-biphenylyl) propionyl chloride Synthesis

 50ml vial before racemic flurbiprofen was added 2. 44g (IOmmol), anhydrous toluene 20ml, freshly distilled thionyl chloride was added dropwise 0. 8ml (Ilmmol), N, N- dimethylformamide amide (DMF) 2 dropwise, stirred at room temperature 2h, the solvent was distilled off under reduced pressure to give a pale yellow gum, i.e., 2- (2-fluoro-4-biphenylyl) propionyl chloride, it was used directly in the reaction without isolation.

 (lc). R-2- (2- fluoro-4-biphenylyl) propionic acid 5- isosorbide monobenzyl ether ester synthesis

 The (Ib) resulting acid chloride was dissolved in 20ml of dry toluene was added dropwise at room temperature, dimethyl amine 3. 5ml, solid precipitation, stirred for about Ih, ice salt bath, a bath temperature of minus 10-15Ό, stirred at this temperature IOmin so, and then the constant pressure dropping funnel (Ia) 5 isosorbide monobenzyl ether (2. 83g, 12mmol) in toluene, keeping the reaction temperature, stirring 8h. The ice bath was removed and the reaction mixture under reduced pressure to remove the solvent, the residue was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate overnight, ethyl acetate was removed under reduced pressure, the residue was a white gel, recrystallized from petroleum ether to give a white solid that R-2- (2- fluoro-4-biphenylyl) propionic acid 5- isosorbide monobenzyl ether ester 3. 65g (7. 88mmol), in order to put the racemic flurbiprofen yield based on 78.8%.

(ld) R – Synthesis of flurbiprofen – (+)

 Under ice bath (Ic) obtained R-2- (2- fluoro-4-biphenylyl) propionic acid monobenzyl ether isosorbide 5- ester 2. 3Ig (5mmol) was dissolved in 20ml of acetone / water (1/1) was added Iml hydrochloric acid to adjust pH to 3, stirred for 3-4h, the reaction solution was extracted with ethyl acetate (20ml * 2), sash organic layer was washed with ice (10ml * 2), dried over anhydrous sodium sulfate overnight , filtration, and the filtrate was concentrated, the residue was recrystallized from ether to give white crystals, i.e. L-flurbiprofen 1.02g (4 18mmol.), yield 83.5%, optical purity 93% (HPLC method); input-racemic flurbiprofen dollars, the total yield of 78.8% * 83.5% = 65.8%.

 Step (1) reaction of the formula:

RACEMIC

Flurbiprofen CAS : 5104-49-4 : 2-Fluoro-a-methyl[1,1¢-biphenyl]-4-acetic acid Additional Names: 2-(2-fluoro-4-biphenylyl)propionic acid; 3-fluoro-4-phenylhydratropic acid Manufacturers’ Codes: BTS-18322; U-27182 Trademarks: Adfeed (Lead Chem.); Ansaid (Pfizer); Antadys (Thžamex); Cebutid (Boots); Froben (Boots); Flurofen (Boots); Ocufen (Allergan); Stayban (Boots); Zepolas (Mikasa) Molecular Formula: C15H13FO2 Molecular Weight: 244.26 Percent Composition: C 73.76%, H 5.36%, F 7.78%, O 13.10% Literature References: Prepn: FR M5737; Adams et al., US 3755427 (1968, 1973 both to Boots Co., Ltd.). Pharmacology: Chalmers et al., Ann. Rheum. Dis. 31, 319 (1972); ibid. 32, 58 (1973); Glenn et al., Agents Actions 3, 210 (1973); Nishizawa et al.,Thromb. Res. 3, 577 (1973). HPLC determn in urine and plasma: J. M. Hutzler et al., J. Chromatogr. B 749, 119 (2000). Symposium on pharmacokinetics and clinical efficacy in pain management: Am. J. Med. 80, Suppl. 3A, 1-157 (1986). Properties: Crystals from petr ether, mp 110-111°. Slightly sol in water (pH 7.0); readily sol in most polar solvents. Melting point: mp 110-111° Therap-Cat: Anti-inflammatory; analgesic.

 

 

Taisho Pharmaceutical Co., Ltd. (大正製薬株式会社 Taishō Seiyaku Kabushiki-gaisha^?) (TYO: 4535) is a Japanese pharmaceutical company based in Tokyo.

.

////////////

TIRUPATI, INDIA
.

Tirupati తిరుపతి
City
Clockwise from top: Tirumala Venkateswara Temple, Tirumala ghat road, City skyline and Chandragiri fort
Tirupati Location in Andhra Pradesh, India
Coordinates: 13.65°N 79.42°ECoordinates: 13.65°N 79.42°E
Country	India
State	Andhra Pradesh
Region	Rayalaseema
District	Chittoor
Government
• Member of Parliament	Varaprasad Rao Velagapalli
Area
• City	24 km2 (9 sq mi)
Elevation	161 m (528 ft)
Population (2011)[1]
• City	287,035
• Density	12,000/km2 (31,000/sq mi)
• Metro[2]	459,985
Languages
• Official	Telugu
Time zone	IST (UTC+5:30)
PIN	517501
Telephone code	+91–877
Vehicle registration	AP 03
Website	Tirupati Mucnicipal Corporation

.

.
Kapila Theertham in Tirupati

Food Service During Tirumala Tirupati Devastanam’s ‘Srinivasa Kalyanam Utsavam’ at MARG Swarnabhoomi

Regulatory and Commercial Status

STATUS FOR MS:Phase III

HIGHEST STATUS ACHIEVED (FOR ANY CONDITION):

Marketing Authorization Application for the treatment of pancreatic cancer has been filed with the European Medicines Agency (16 October 2012)

Marketing Authorization Application for the conditional approval in the treatment of pancreatic cancer has been accepted by the European Medicines Agency (30 October 2012)

Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumors in animals, specifically dogs.^[1][2] Since its introduction in November 2008 it has been distributed under the commercial name Masivet. It has been available in Europe since the second part of 2009. In the USA it is distributed under the name Kinavet and has been available for veterinaries since 2011.

Masitinib is being studied for several human conditions including cancers. It is used in Europe to fight orphan diseases.^[3]

Mechanism of action

Masitinib inhibits the receptor tyrosine kinase c-Kit which is displayed by various types of tumour.^[2] It also inhibits the platelet derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR).

……………………..

http://www.google.com/patents/US7423055

Compound Synthesis

General: All chemicals used were commercial reagent grade products. Dimethylformamide (DMF), methanol (MeOH) were of anhydrous commercial grade and were used without further purification. Dichloromethane and tetrahydrofuran (THF) were freshly distilled under a stream of argon before use. The progress of the reactions was monitored by thin layer chromatography using precoated silica gel 60F 254, Fluka TLC plates, which were visualized under UV light. Multiplicities in ¹H NMR spectra are indicated as singlet (s), broad singlet (br s), doublet (d), triplet (t), quadruplet (q), and multiplet (m) and the NMR spectrum were realized on a 300 MHz Bruker spectrometer.

3-Bromoacetyl-pyridine, HBr Salt

Dibromine (17.2 g, 108 mmol) was added dropwise to a cold (0° C.) solution of 3-acetyl-pyridine (12 g, 99 mmol) in acetic acid containing 33% of HBr (165 mL) under vigourous stirring. The vigorously stirred mixture was warmed to 40° C. for 2 h and then to 75° C. After 2 h at 75° C., the mixture was cooled and diluted with ether (400 mL) to precipitate the product, which was recovered by filtration and washed with ether and acetone to give white crystals (100%). This material may be recrystallised from methanol and ether.

IR (neat): 3108, 2047, 2982, 2559, 1709, 1603, 1221, 1035, 798 cm⁻¹—⁻¹H NMR (DMSO-d⁶) δ=5.09 (s, 2H, CH₂Br); 7.88 (m, 1H, pyridyl-H); 8.63 (m, 1H, pyridyl-H); 8.96 (m, 1H, pyridyl-H); 9.29 (m, 1H, pyridyl-H).

Methyl-[4-(1-N-methyl-piperazino)-methyl]-benzoate

To methyl-4-formyl benzoate (4.92 g, 30 mmol) and N-methyl-piperazine (3.6 mL, 32 mmol) in acetonitrile (100 mL) was added dropwise 2.5 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 1 h. After slow addition of sodium cyanoborohydride (2 g, 32 mmol), the solution was left stirring overnight at room temperature. Water (10 mL) was then added to the mixture, which was further acidified with 1N HCl to pH=6-7. The acetonitrile was removed under reduced pressure and the residual aqueous solution was extracted with diethyl ether (4×30 mL). These extracts were discarded. The aqueous phase was then basified (pH>12) by addition of 2.5N aqueous sodium hydroxyde solution. The crude product was extracted with ethyl acetate (4×30 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure to afford a slightly yellow oil which became colorless after purification by Kugelrohr distillation (190° C.) in 68% yield.

IR(neat): 3322, 2944, 2802, 1721, 1612, 1457, 1281, 1122, 1012—¹H NMR(CDCl₃) δ=2.27 (s, 3H, NCH₃); 2.44 (m, 8H, 2×NCH₂CH₂N); 3.53 (s, 2H, ArCH₂N); 3.88 (s, 3H, OCH₃); 7.40 (d, 2H, J=8.3 Hz, 2×ArH); 7.91 (d, 2H, J=8.3 Hz, 2×ArH)—³C NMR (CDCl₃) δ=45.8 (NCH₃); 51.8 (OCH₃); 52.9 (2×CH₂N); 54.9 (2×CH₂N); 62.4 (ArCH₂N); 128.7 (2×ArC); 129.3 (2×ArC); 143.7 (ArC); 166.7 (ArCO₂CH₃)-MS CI (m/z) (%) 249 (M+1, 100%).

2-Methyl-5-tert-butoxycarbonylamino-aniline

A solution of di-tert-butyldicarbonate (70 g, 320 mmol) in methanol (200 mL) was added over 2 h to a cold (−10° C.) solution of 2,4-diaminotoluene (30 g, 245 mmol) and triethylamine (30 mL) in methanol (15 mL). The reaction was followed by thin layer chromatography (hexane/ethyl acetate, 3:1) and stopped after 4 h by adding 50 mL of water. The mixture was concentrated in vacuo and the residue was dissolved in 500 mL of ethyl acetate. This organic phase was washed with water (1×150 mL) and brine (2×150 mL), dried over MgSO₄, and concentrated under reduced pressure. The resulting light brown solid was washed with small amounts of diethyl ether to give off-white crystals of 2-methyl-5-tert-butoxycarbonylamino-aniline in 67% yield.

IR (neat): 3359; 3246; 2970; 1719; 1609; 1557; 1173; 1050 cm⁻¹—¹H NMR (CDCl₃): δ=1.50 (s, 9H, tBu); 2.10 (s, 3H, ArCH₃); 3.61 (br s, 2H, NH₂); 6.36 (br s, 1H, NH); 6.51 (dd, 1H, J=7.9 Hz, 2.3 Hz, ArH); 6.92 (d, 1H, J=7.9 Hz, ArH); 6.95 (s, 1H, ArH)—¹³C NMR (CDCl₃) δ=16.6 (ArCH₃); 28.3 (C(CH₃)₃); 80.0 (C(CH₃)₃); 105.2 (ArC); 108.6 (ArC); 116.9 (ArC); 130.4 (ArC—CH₃); 137.2 (ArC—NH); 145.0 (ArC—NH₂); 152.8 (COOtBu) MS ESI (m/z) (%): 223 (M+1), 167 (55, 100%).

N-(2-methyl-5-tert-butoxycarbonylamino)phenyl-thiourea

Benzoyl chloride (5.64 g, 80 mmol) was added dropwise to a well-stirred solution of ammonium thiocyanate (3.54 g, 88 mmol) in acetone (50 mL). The mixture was refluxed for 15 min, then, the hydrobromide salt of 2-methyl-5-tert-butoxycarbonylamino-aniline (8.4 g, 80 mmol) was added slowly portionswise. After 1 h, the reaction mixture was poured into ice-water (350 mL) and the bright yellow precipitate was isolated by filtration. This crude solid was then refluxed for 45 min in 70 mL of 2.5 N sodium hydroxide solution. The mixture was cooled down and basified with ammonium hydroxide. The precipitate of crude thiourea was recovered by filtration and dissolved in 150 mL of ethyl acetate. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate, 1:1) to afford 63% of N-(2-methyl-5-tert-butoxycarbonylamino)phenyl-thiourea as a white solid.

IR (neat): 3437, 3292, 3175, 2983, 1724, 1616, 1522, 1161, 1053 cm^{−1— 1}H NMR (DMSO-d₆) δ=1.46 (s, 9H, tBu); 2.10 (s, 3H, ArCH₃); 3.60 (br s, 2H, NH₂); 7.10 (d, 1H, J=8.29 Hz, ArH); 7.25 (d, 1H, J=2.23 Hz, ArH); 7.28 (d, 1H, J=2.63 Hz, ArH); 9.20 (s, 1H, ArNH); 9.31 (s, 1H, ArNH)—¹³C NMR (DMSO-d⁶) δ=25.1 (ArCH₃); 28.1 (C(CH₃)₃); 78.9 (C(CH₃)₃); 16.6 (ArC); 117.5 (ArC); 128.0 (ArC); 130.4 (ArC—CH₃); 136.5 (ArC—NH); 137.9 (ArC—NH); 152.7 (COOtBu); 181.4 (C═S)—MS CI(m/z): 282 (M+1, 100%); 248 (33); 226 (55); 182 (99); 148 (133); 93 (188).

2-(2-methyl-5-tert-butoxycarbonylamino)phenyl-4-(3-pyridyl)-thiazole

A mixture of 3-bromoacetyl-pyridine, HBr salt (0.81 g, 2.85 mmol), N-(2-methyl-5-tert-butoxycarbonylamino)phenyl-thiourea (0.8 g, 2.85 mmol) and KHCO₃ (˜0.4 g) in ethanol (40 mL) was heated at 75° C. for 20 h. The mixture was cooled, filtered (removal of KHCO₃) and evaporated under reduced pressure. The residue was dissolved in CHCl₃ (40 mL) and washed with saturated aqueous sodium hydrogen carbonate solution and with water. The organic layer was dried over Na₂SO₄ and concentrated. Colum chromatographic purification of the residue (hexane/ethyl acetate, 1:1) gave the desired thiazole in 70% yield as an orange solid

IR(neat): 3380, 2985, 2942, 1748, 1447, 1374, 1239, 1047, 938—¹H NMR (CDCl₃) δ=1.53 (s, 9H, tBu); 2.28 (s, 3H, ArCH₃); 6.65 (s, 1H, thiazole-H); 6.89 (s, 1H); 6.99 (dd, 1H, J=8.3 Hz, 2.3 Hz); 7.12 (d, 2H, J=8.3 Hz); 7.35 (dd, 1H, J=2.6 Hz, 4.9 Hz); 8.03 (s, 1H); 8.19 (dt, 1H, J=1.9 Hz, 7.9 Hz); 8.54 (br s, 1H, NH); 9.09 (s, 1H, NH)—¹³C NMR (CDCl₃) δ=18.02 (ArCH₃); 29.2 (C(CH₃)₃); 81.3 (C(CH₃)₃); 104.2 (thiazole-C); 111.6; 115.2; 123.9; 124.3; 131.4; 132.1; 134.4; 139.5; 148.2; 149.1; 149.3; 153.6; 167.3 (C═O)—MS Cl (m/z) (%): 383 (M+1, 100%); 339 (43); 327 (55); 309 (73); 283 (99); 71 (311).

2-(2-methyl-5-amino)phenyl-4-(3-pyridyl)-thiazole

2-(2-methyl-5-tert-butoxycarbonylamino)phenyl-4-(3-pyridyl)-thiazole (0.40 g, 1.2 mmol) was dissolved in 10 mL of 20% TFA/CH₂Cl₂. The solution was stirred at rool temperature for 2 h, then it was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The organic layer was washed with aqueous 1N sodium hydroxide solution, dried over MgSO₄, and concentrated to afford 2-(2-methyl-5-amino)phenyl-4-(3-pyridyl)-thiazole as a yellow-orange solid in 95% yield. This crude product was used directly in the next step.

A 2M solution of trimethyl aluminium in toluene (2.75 mL) was added dropwise to a cold (0° C.) solution of 2-(2-methyl-5-amino)phenyl-4-(3-pyridyl)-thiazole (0.42 g, 1.5 mmol) in anhydrous dichloromethane (10 mL) under argon atmosphere. The mixture was warmed to room temperature and stirred at room temperature for 30 min. A solution of methyl-4-(1-N-methyl-piperazino)-methyl benzoate (0.45 g, 1.8 mmol) in anhydrous dichloromethane (1 mL) and added slowly, and the resulting mixture was heated at reflux for 5 h. The mixture was cooled to 0° C. and quenched by dropwise addition of a 4N aqueous sodium hydroxide solution (3 mL). The mixture was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (3×20 mL) and dried over anhydrous MgSO₄. (2-(2-methyl-5-amino)phenyl-4-(3-pyridyl)-thiazole) is obtained in 72% after purification by column chromatography (dichloromethane/methanol, 3:1)

IR (neat): 3318, 2926, 1647, 1610, 1535, 1492, 1282, 1207, 1160, 1011, 843—

¹H NMR (CDCl₃) δ=2.31 (br s, 6H, ArCH₃+NCH₃); 2.50 (br s, 8H, 2×NCH₂CH₂N); 3.56 (s, 2H, ArCH₂N); 6.89 (s, 1H, thiazoleH); 7.21-7.38 (m, 4H); 7.45 (m, 2H); 7.85 (d, 2H, J=8.3 Hz); 8.03 (s, 1H); 8.13 (s, 1H); 8.27 (s, 1H); 8.52 (br s, 1H); 9.09 (s, 1H, NH)—

¹³C NMR (CDCl₃) δ 17.8 (ArCH₃); 46.2 (NCH₃); 53.3 (NCH₂); 55.3 (NCH₂); 62.8 (ArCH₂N); 99.9 (thiazole-C); 112.5; 123.9; 125.2; 127.5; 129.6; 131.6; 133.7; 134.0; 137.6; 139.3; 142.9; 148.8; 149.1; 166.2 (C═O); 166.7 (thiazoleC-NH)—

MS CI (m/z) (%): 499 (M+H, 100%); 455 (43); 430 (68); 401 (97); 374 (124); 309 (189); 283 (215); 235 (263); 121 (377); 99 (399).

………………………

http://www.google.com/patents/WO2012136732A1?cl=en

In a preferred embodiment of the above-depicted treatment, the active ingredient masitinib is administered in the form of masitinib mesilate; which is the orally bioavailable mesylate salt of masitinib – CAS 1048007-93-7 (MsOH); C28H30N6OS.CH3SO3H; MW 594.76:

http://www.google.com/patents/WO2004014903A1?cl=en

003 : 4-(4-Methyl-piperazin-l-ylmethyl)-N-[3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl] -benzamide

4-(4-Methyl-piperazin-l-yl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)- phenyl] -benzamide

beige brown powder mp : 128-130°C

1H RMN (DMSO-d⁶) δ = 2.15 (s, 3H) ; 2.18 (s, 3H) ; 2.35-2.41 (m, 4H) ; 3.18-3.3.24 (m, 4H) ; 6.94 (d, J = 8.9 Hz, 2H) ; 7.09 (d, J = 8.4 Hz, IH) ; 7.28-7.38 (m, 3H) ; 7.81 (d, J = 8.9 Hz, 2H) ; 8.20-8.25 (m, IH) ; 8.40 (dd, J = 1.6 Hz, J = 4.7 , IH) ; 8.48 (d, J = 1.9 Hz, IH) ; 9.07 (d, J = 1.5 Hz, IH) ; 9.35 (s, IH) ; 9.84 (s, IH)

……………

http://www.google.com/patents/WO2008098949A2?cl=en

EXAMPLE 4 N- [4-Methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide derivatives

Method A In a reactor and under low nitrogen pressure, add 4-Methyl-N3-(4-pyridin-3-yl-thiazol- 2-yl)-benzene-l,3-diamine (95 g, 336.45 mmol), dichloromethane (2 L). To this suspension cooled to temperature of 5°C was added dropwise 2M/n-hexane solution of trimethylaluminium (588 mL). The reaction mixture was brought progressively to 15°C, and maintained for 2 h under stirring. 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (100 g, 402.71 mmol) in dichloromethane (200 mL) was added for 10 minutes. After 1 h stirring at room temperature, the reaction mixture was heated to reflux for 20 h and cooled to room temperature. This solution was transferred dropwise via a cannula to a reactor containing 2N NaOH (2.1 L) cooled to 5°C. After stirring for 3 h at room temperature, the precipitate was filtered through Celite. The solution was extracted with dichloromethane and the organic layer was washed with water and saturated sodium chloride solution, dried over MgSO₄ and concentrated under vacuum. The brown solid obtained was recrystallized from /-Pr₂O to give 130.7 g (78%) of a beige powder.

Method B Preparation of the acid chloride

To a mixture of 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid dihydrochloride (1.0 eq), dichloromethane (7 vol) and triethylamine (2.15 eq), thionyl chloride (1.2 eq) was added at 18-28°C . The reaction mixture was stirred at 28-32°C for 1 hour. Coupling of acid chloride with amino thiazole To a chilled (0-5⁰C) suspension of 4-Methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene- 1,3-diamine (0.8 eq) and thiethylamine (2.2 eq) in dichloromethane (3 vol), the acid chloride solution (prepared above) was maintaining the temperature below 5°C. The reaction mixture was warmed to 25-30⁰C and stirred at the same temperature for 1O h. Methanol (2 vol) and water (5 vol) were added to the reaction mixture and stirred. After separating the layers, methanol (2 vol), dihloromethane (5 vol) and sodium hydroxide solution (aqueous, 10%, till pH was 9.5-10.0) were added to the aqueous layer and stirred for 10 minutes. The layers were separated. The organic layer was a washed with water and saturated sodium chloride solution. The organic layer was concentrated and ethanol (2 vol) was added and stirred. The mixture was concentrated. Ethanol was added to the residue and stirred. The product was filtered and dried at 50-55⁰C in a vaccum tray drier. Yield = 65-75%.

Method C

To a solution of 4-methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene-l,3-diamine (1.0 eq) in DMF (20 vol) were added successively triethylamine (5 eq), 2-chloro-l- methylpyridinium iodide (2 eq) and 4-(4-methyl-piperazin-l-ylmethyl)-benzoic acid (2 eq). The reaction mixture was stirred for 7 h at room temperature. Then, the mixture was diluted in diethyl ether and washed with water and saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using an elution of 100% EtOAc to give a yellow solid.

Yield = 51%.

¹H NMR (CDCl₃) : δ = 9.09 (IH, s, NH); 8.52 (IH, br s); 8.27 (IH, s); 8.13 (IH, s);

8.03 (IH, s); 7.85 (2H, d, J= 8.3Hz); 7.45 (2H, m); 7.21-7.38 (4H, m); 6.89 (IH, s);

3.56 (2H, s); 2.50 (8H, br s); 2.31 (6H, br s).

MS (CI) m/z = 499 (M+H)⁺.

An additional aspect of the present invention relates to a particular polymorph of the methanesulfonic acid salt of N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide of formula (IX).

(VI)

Hereinafter is described the polymorph form of (IX) which has the most advantageous properties concerning processability, storage and formulation. For example, this form remains, dry at 80% relative humidity and thermodynamically stable at temperatures below 200⁰C.

The polymorph of this form is characterized by an X-ray diffraction pattern illustrated in FIG.I, comprising characteristic peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degrees θ, and is also characterized by differential scanning calorimetry (DSC) illustrated in FIG.II, which exhibit a single maximum value at approximately 237.49 ± 0.3 ⁰C. X-ray diffraction pattern is measured using a Bruker AXS (D8 advance). Differential scanning calorimetry (DSC) is measured using a Perking Elmer Precisely (Diamond DSC).

This polymorph form can be obtained by treatement of 4-(4-Methyl-piperazin-l- ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide with 1.0 to 1.2 equivalent of methanesulfonic acid, at a suitable temperature, preferably between 20-80⁰C.

The reaction is performed in a suitable solvent especially polar solvent such as methanol or ethanol, or ketone such as acetone, or ether such as diethylether or dioxane, or a mixture therof. This invention is explained in example given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Preparation of the above-mentioned polymorph form of 4-(4-Methyl-piperazin-l- ylmethyl)-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide methanesulfonate .

4-(4-Methyl-piperazin- 1 -ylmethyl)-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino) phenyl] -benzamide (1.0 eq) was dissolved in ethanol (4.5 vol) at 65-70⁰C. Methanesulfonic acid (1.0 eq) was added slowly at the same temperature. The mixture was cooled to 25-30⁰C and maintained for 6 h. The product was filtered and dried in a vacuum tray drier at 55-60⁰C. Yield = 85-90%. Starting melting point Smp = 236°C.

NMR PREDICT

CAS NO. 1048007-93-7, methanesulfonic acid,4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-yl-1,3-thiazol-2-yl)amino]phenyl]benzamide H-NMR spectral analysis

CAS NO. 1048007-93-7, methanesulfonic acid,

4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-yl-1,3-thiazol-2-yl)amino]phenyl]benzamide C-NMR spectral analysisPREDICT

References

1. Hahn, K.A.; Oglivie, G.; Rusk, T.; Devauchelle, P.; Leblanc, A.; Legendre, A.; Powers, B.; Leventhal, P.S.; Kinet, J.-P.; Palmerini, F.; Dubreuil, P.; Moussy, A.; Hermine, O. (2008). “Masitinib is Safe and Effective for the Treatment of Canine Mast Cell Tumors”. Journal of Veterinary Internal Medicine 22 (6): 1301–1309. doi:10.1111/j.1939-1676.2008.0190.x. ISSN 0891-6640.
2. Information about Masivet at the European pharmacy agency website
3. Orphan designation for Masitinib at the European pharmacy agency website

WO2004014903A1	Jul 31, 2003	Feb 19, 2004	Ab Science	2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors
WO2008098949A2	Feb 13, 2008	Aug 21, 2008	Ab Science	Process for the synthesis of 2-aminothiazole compounds as kinase inhibitors
EP1525200B1	Jul 31, 2003	Oct 10, 2007	AB Science	2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors
US7423055	Aug 1, 2003	Sep 9, 2008	Ab Science	2-(3-Aminoaryl)amino-4-aryl-thiazoles for the treatment of diseases
US20080207572 *	Jul 13, 2006	Aug 28, 2008	Ab Science	Use of Dual C-Kit/Fgfr3 Inhibitors for Treating Multiple Myeloma

Systematic (IUPAC) name
4-[(4-Methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)-1,3-thiazol-2-yl]amino}phenyl)benzamide
Clinical data
Trade names	Masivet, Kinavet
AHFS/Drugs.com	International Drug Names
Identifiers
CAS Registry Number	790299-79-5
ATC code	L01XE22
PubChem	CID 10074640
ChemSpider	8250179
ChEMBL	CHEMBL1908391
Chemical data
Formula	C28H30N6OS
Molecular mass	498.64 g/mol

Patent	Submitted	Granted
2-(3-Aminoaryl)amino-4-aryl-thiazoles for the treatment of diseases [US7423055]	2004-06-10	2008-09-09
2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors [US2005239852]	2005-10-27
Use of C-Kit Inhibitors for Treating Fibrosis [US2007225293]	2007-09-27
Use of Mast Cells Inhibitors for Treating Patients Exposed to Chemical or Biological Weapons [US2007249628]	2007-10-25
Use of c-kit inhibitors for treating type II diabetes [US2007032521]	2007-02-08
Use of tyrosine kinase inhibitors for treating cerebral ischemia [US2007191267]	2007-08-16
Use of C-Kit Inhibitors for Treating Plasmodium Related Diseases [US2008004279]	2008-01-03
Tailored Treatment Suitable for Different Forms of Mastocytosis [US2008025916]	2008-01-31
2-(3-AMINOARYL) AMINO-4-ARYL-THIAZOLES AND THEIR USE AS C-KIT INHIBITORS [US2008255141]	2008-10-16
Use Of C-Kit Inhibitors For Treating Inflammatory Muscle Disorders Including Myositis And Muscular Dystrophy [US2008146585]	2008-06-19

Patent	Submitted	Granted
Aminothiazole compounds as kinase inhibitors and methods of using the same [US8940894]	2013-05-10	2015-01-27
Aminothiazole compounds as kinase inhibitors and methods of using the same [US8492545]	2012-03-08	2013-07-23

Patent	Submitted	Granted
Use of Dual C-Kit/Fgfr3 Inhibitors for Treating Multiple Myeloma [US2008207572]	2008-08-28
PROCESS FOR THE SYNTHESIS OF 2-AMINOTHIAZOLE COMPOUNDS AS KINASE INHIBITORS [US8153792]	2010-05-13	2012-04-10
COMBINATION TREATMENT OF SOLID CANCERS WITH ANTIMETABOLITES AND TYROSINE KINASE INHIBITORS [US8227470]	2010-04-15	2012-07-24
Anti-IGF antibodies [US8580254]	2008-06-19	2013-11-12
COMBINATIONS FOR THE TREATMENT OF B-CELL PROLIFERATIVE DISORDERS [US2009047243]	2008-07-17	2009-02-19
TREATMENTS OF B-CELL PROLIFERATIVE DISORDERS [US2009053168]	2008-07-17	2009-02-26
Anti-IGF antibodies [US8318159]	2009-12-11	2012-11-27
SURFACE TOPOGRAPHIES FOR NON-TOXIC BIOADHESION CONTROL [US2010226943]	2009-08-31	2010-09-09
EGFR/NEDD9/TGF-BETA INTERACTOME AND METHODS OF USE THEREOF FOR THE IDENTIFICATION OF AGENTS HAVING EFFICACY IN THE TREATMENT OF HYPERPROLIFERATIVE DISORDERS [US2010239656]	2010-05-10	2010-09-23
ANTI CD37 ANTIBODIES [US2010189722]	2008-08-08	2010-07-29

1. ChemIDplus Advanced

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Note: Compound name must be entered under “Substance Identification” and then “Names and Synonyms” selected to view synonyms.

2. “Human Medicines” page

AB Science website

Accessed on 22 Feb 2012 from http://www.ab-science.com/.

3. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.

Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Castéran N, Borge L, Hajem B, Lermet A, Sippl W, et al.

PLoS One. 2009; 4(9):e7258. Epub 2009 Sep 30. PMID: 19789626. Abstract

4. Masitinib mesylate application for conditional approval

Food and Drug Administration, 15 Dec 2010

Accessed on 22 Feb 2012 from http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM245243.pdf.

5. Scientific discussion for the approval of Masivet

European Medicines Agency, Nov 2008

Accessed on 22 Feb 2012 from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/veterinary/000128/WC500064714.pdf.

6. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: a randomised, placebo-controlled phase 2 trial.

Piette F, Belmin J, Vincent H, Schmidt N, Pariel S, Verny M, Marquis C, Mely J, Hugonot-Diener L, Kinet J-P, et al.

Alzheimers Res Ther. 2011; 3(2):16. Epub 2011 Apr 19. PMID: 21504563. Abstract

7. Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study.

Tebib J, Mariette X, Bourgeois P, Flipo R-M, Gaudin P, Le Loët X, Gineste P, Guy L, Mansfield CD, Moussy A, et al.

Arthritis Res Ther. 2009; 11(3):R95. Epub 2009 Jun 23. PMID: 19549290. Abstract

8. AB Science announces recruitment of first patient in phase 3 study of masitinib in progressive multiple sclerosis

Businesswire.com, 6 Sep 2011

Accessed on 22 Feb 2012 from http://www.businesswire.com/news/home/20110906006398/en/AB-Science-announces-recruitment-patient-phase-3.

9. Masitinib in Patients with Progressive or Relapse-Free Secondary Multiple Sclerosis

ClinicalTrials.gov, 13 Sep 2011

Accessed on 22 Feb 2012 from http://clinicaltrials.gov/ct2/show/study/NCT01433497.

10. Masitinib in Patients with Primary Progressive Multiple Sclerosis (PPMS) or Relapse-Free Secondary Multiple Sclerosis (SPMS)

ClinicalTrials.gov, 10 Oct 2011

Accessed on 22 Feb 2012 from http://clinicaltrials.gov/ct2/show/NCT01450488.

11. Phase II study of oral masitinib mesilate in imatinib-naïve patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST).

Le Cesne A, Blay J-Y, Bui B N, Bouché O, Adenis A, Domont J, Cioffi A, Ray-Coquard I, Lassau N, Bonvalot S, et al.

Eur J Cancer. 2010 May; 46(8):1344-51. Epub 2010 Mar 06. PMID: 20211560. Abstract

12. “Veterinary Medicines” page

AB Science website

Accessed on 22 Feb 2012 from http://www.ab-science.com/.

Editors’ Pick

13. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study.

Vermersch P, Benrabah R, Schmidt N, Zéphir H, Clavelou P, Vongsouthi C, Dubreuil P, Moussy A, Hermine O

BMC Neurol. 2012 Jun 12; 12(1):36. PMID: 22691628. Abstract

14. AB Science confirms the filing for the Marketing Authorization Application to the European Medicines Agency of masitinib in the treatment of pancreatic cancer

AB Science, 16 Oct 2012

Accessed on 1 Nov 2012 from http://www.ab-science.com/file_bdd/1350403049_absciencepancreasemafilingvdefven.pdf.

15. European Medicines Agency accepts Marketing Authorization Application for conditional approval of masitinib in the treatment of pancreatic cancer

AB Science, 30 Oct 2012

Accessed on 1 Nov 2012 from http://www.ab-science.com/file_bdd/1351622639_abscienceresultph3pancreasvdefuk.pdf.

16. Launch of a phase 3 clinical trial in the treatment of Alzheimer’s disease with masitinib

AB Science, 20 May 2013

Accessed on 21 May 2013 from http://www.ab-science.com/file_bdd/1369064860_absciencepressreleasephase3alzenfinal.pdf.

17. Masitinib is being investigated in the treatment of amyotrophic lateral sclerosis (ALS)

The Wall Street Journal, 4 Nov 2013

Accessed on 6 Nov 2013 from http://online.wsj.com/article/PR-CO-20131104-908831.html?dsk=y.

18. BRIEF-AB Science says DSMB recommends continuation of phase 3 masitinib study

Reuters, 6 Oct 2014

Accessed on 14 Oct 2014 from http://www.reuters.com/article/2014/10/06/absciencesa-brief-idUSFWN0S100120141006.

19. Neuroprotective effect of masitinib in rats with postischemic stroke.

Kocic I, Kowianski P, Rusiecka I, Lietzau G, Mansfield C, Moussy A, Hermine O, Dubreuil P

Naunyn Schmiedebergs Arch Pharmacol. 2014 Oct 26. Epub 2014 Oct 26. PMID: 25344204.Abstract

AB SCIENCE HEADQUARTER
3, Avenue George V
75008 PARIS – FRANCE
Tel. : +33 (0)1 47 20 00 14
Fax. : +33 (0)1 47 20 24 11

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

TAJIKISTAN

Tajikistan – Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Tajikistan

The territory that now constitutes Tajikistan was previously home to several ancient cultures, including the city of Sarazm of the Neolithic and the Bronze Age, …

‎Dushanbe – ‎Tajik language – ‎Emomali Rahmon – ‎Civil war in Tajikistan

.

EVOGLIPTIN
CAS: 1222102-29-5 FREE

HCL……1246960-27-9

tartare.. 1222102 -51-3

Dong-A Pharmaceutical. Co., Ltd, 동아제약 주식회사
2-Piperazinone, 4-((3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl)-3-((1,1-dimethylethoxy)methyl)-, (3R)-
R)-4-((R)-3-Amino-4-(2,4,5-trifluorophenyl)-butanoyl)-3-(t-butoxymethyl)-piperazin-2-one

4-[3(R)-Amino-4-(2,4,5-trifluorophenyl)butyryl]-3(R)-(tert-butoxymethyl)piperazin-2-one hydrochloride

DA-1229

see…http://www.allfordrugs.com/2015/07/03/evogliptin/

DA-1229 is a dipeptidyl peptidase IV (CD26) inhibitor currently being developed in phase III clinical studies at Dong-A for the treatment of type 2 diabetes.

In 2014, Eurofarma aquired rights for product development and commercialization in Brazil.

If above image is not clear then see at…….http://www.allfordrugs.com/2015/07/03/evogliptin/

86…………H. J. Kim, W. Y. Kwak, J. P. Min, J. Y. Lee, T. H. Yoon, H. D. Kim, C. Y. Shin, M. K.
Kim, S. H. Choi, H. S. Kim, E. K. Yang, Y. H. Cheong, Y. N. Chae, K. J. Park, J. M.
Jang, S. J. Choi, M. H. Son, S. H. Kim, M. Yoo and B. J. Lee, Bioorg. Med. Chem. Lett.,
2011, 21 (12), 3809-3812.
[87] …………K. S. Lim, J. Y. Cho, B. H. Kim, J. R. Kim, H. S. Kim, D. K. Kim, S. H. Kim, H. J. Yim,
S. H. Lee, S. G. Shin, I. J. Jang and K. S. Yu, Br. J. Clin. Pharmacol., 2009, 68 (6), 883-
890.

…………………………………..

WO 2010114291

http://www.google.co.in/patents/WO2010114291A2?cl=en

Formula 1

Korea Patent Publication No. 2008-0094604 the call to the scheme, as indicated by A Ⅰ) of formula (II) beta-compound of formula 3 is already substituted heterocyclic compound having 1-hydroxy-benzotriazole group (HOBT) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and reacting with a tertiary amine to prepare a compound of formula (4) connected by peptide bonds; Ⅱ) beta comprises the step of reacting under acidic conditions a compound of the formula (4) – a method of manufacturing the heterocyclic compounds of the formula I having an amino group is disclosed.

– Scheme A]

(Wherein, PG is a protecting group.)

In this case, the beta of the formula (2) of Scheme A – a compound having an amino group is prepared in addition to the DPP-IV inhibitor International Publication represented by Formula 1 WO03 / 000181, WO03 / 004498, WO03 / 082817, WO04 / 007468, WO04 / 032836, WO05 / 011581, WO06 / 097175, WO07 / 077508, WO07 / 063928, WO08 / 028662 WO08 / it may be used for the production of different DPP-IV inhibitors according 087,560 and can be prepared in a number of ways.

To, the compound of Formula 2 is an example as shown in Scheme J. Med.Chem. 2005; 141, and Synthesis 1997; it can be produced by the known method described in 873.

Specifically, (2S) – (+) – 2,5- dihydro-3,6-dimethoxy-2-isopropyl-pyrazine 2,4,5-trifluoro-react with benzyl bromide and acid treatment, and then the amine an ester compound obtained by the protection reaction. Ester compounds are hydrolyzed to re-3- (2,4,5-trifluoro-phenyl) -2-amino-propionic acid tert such as isobutyl chloroformate, triethylamine or diisopropylethylamine to give the amine, and then using diazomethane to form a diazo ketone, and then may be prepared by reaction with silver benzoate. However, the reaction can be performed at low temperature (-78 ℃) or high alpha-amino acid to purchase and use, and may have a risk of problems such as the need to use large diazomethane.

To a different process for preparing a compound of Formula 2 as shown in scheme Tetrahedron: Asymmetry 2006; It is known in 2622; 205 or similarly Bioorganic & Medicinal Chemistry Letters 2007.

That is, a 1,1′-carbonyl-2,4,5 which the phenyl trifluoroacetic acid activated using the following imidazole mono-methyl words potassium carbonate is reacted with the beta-keto ester compound is prepared. This produced an enamine ester using ammonium acetate and ammonium solution, the ester compound chloro (1,5-cyclooctadiene) rhodium (I) dimer using a chiral ferrocenyl ligands I the reaction of the high-pressure hydrogen with a chiral primary amine with a beta-amino ester compound after production and can lead to hydrolysis to prepare a compound of formula (2). However, use of expensive metal catalyst has a problem that must be performed in high pressure hydrogenation.

The method for preparing a compound of Formula 2 is disclosed in International Publication No. WO 04/87650.

Specifically, 2,4,5-fluorophenyl reagent is oxalyl chloride, the acid activated acid with 2,2-dimethyl-1,3-dioxane-4,6-dione, and after the reaction of methanol and the resulting material at reflux to prepare a corresponding compound. With a selective reducing reagents which enantiomers (S) -BINAP-RuCl ₂ and hydrogen through a reaction (S) – producing a compound having coordinated to each other, it again after the decomposition, and the singer O- benzyl hydroxyl amine and the coupling reaction and the intermediate is prepared. To do this, the resulting intermediate tree azodicarboxylate and diisopropyl azodicarboxylate presence ring condensation reaction, treated with an aqueous solution of lithium hydroxide to (R) – while having the formula (II) coordinated to the amine group protected with a benzyl-O- the compound can be produced. However, the method has a problem as a whole to be prepared by the reaction yield to be low and a long processing time to perform the reaction.

Thus, the conventional known method for producing a compound of the general formula (2) has the disadvantage of using expensive reagents, or not suitable for commercial mass-production method by a long synthesis time yield is also low.

In addition, the compound represented by General Formula (3), as described in Korea Patent Publication No. 2008-0094604 call, can be prepared by way of reaction schemes.

Specifically, the starting material D- serine methyl ester is substituted by a hydroxy group when reflux again substituted by trityl chloride as methoxy groups converted to the aziridine compound.

[Scheme 3]

………………………………

WO 2010114292

http://www.google.com/patents/WO2010114292A2?cl=en

…………………………………

Discovery of DA-1229: a potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes
Bioorg Med Chem Lett 2011, 21(12): 3809

http://www.sciencedirect.com/science/article/pii/S0960894X11004859

A series of β-amino amide containing substituted piperazine-2-one derivatives was synthesized and evaluated as inhibitors of dipeptidyl pepdidase-4 (DPP-4) for the treatment of type 2 diabetes. As results of intensive SAR study of the series, (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-(t-butoxymethyl)-piperazin-2-one (DA-1229) displayed potent DPP-4 inhibition pattern in several animal models, was selected for clinical development.

 http://www.luye.cn/en/uploads//2014-07/21/_1405936452_zr21xh.pdf

//////////

see gliptins at…..http://drugsynthesisint.blogspot.in/p/gliptin-series.html

Dong-A Pharm. Co., Ltd, Yongin-si, Gyeonggi-do, Republic of Korea.

GEMIGLIPTIN

1-[2(S)-Amino-4-[2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]-4-oxobutyl]-5,5-difluoropiperidin-2-one

PHASE 3, DPP-IV inhibitor, Lg Life Sciences Ltd.

CAS 911637-19-9

Mol. Formula:   C18H19F8N5O2

Gemigliptin (rINN), previously identified as LC15-0444, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.^[1] It is well known that glucose lowering effects of DPP-4 inhibitors are mainly mediated by GLP-1 and gastric inhibitory polypeptide (GIP) incretin hormones which are inactivated by DPP-4.

Gemigliptin was initially developed solely by LG Life Sciences. In 2010, Double-Crane Pharmaceutical Co. (DCPC) joined with LGLS to co-develop the final compound and collaborate on the marketing of the drug in China. LGLS also announced on Nov., 2010 that NOBEL Ilac has been granted rights to develop and commercialize gemigliptin in Turkey.

Gemigliptin, a dipeptidyl peptidase IV (CD26; DPP-IV; DP-IV) inhibitor, is currently undergoing phase III clinical trials at LG Life Sciences as an oral treatment for type II diabetes. The company is also testing the compound in phase II/III clinical studies for the treatment of patients with cisplatin-induced acute kidney injury.

DPP IV inhibitors have glucose-lowering effects mediated by GLP-1 incretin hormone which is inactivated by DPP IV. In 2010, gemigliptin was licensed to Beijing Double-Crane Pharmaceutical by LG Life Sciences for distribution and supply in China for the treatment of type 2 diabetes.

A New Drug Application (NDA) for gemigliptin in the treatment of type 2 diabetes was submitted to the Korea Food & Drug Administration (KFDA) in July 2011. Then on June 27, 2012, the KFDA has approved the manufacture and distribution of LG Life Sciences’ diabetes treatment, Zemiglo, the main substance of which is gemigliptin. Clinical trials for evaluating the safety and efficacy of gemigliptin in combination with metformin have been completed.

…………

Efficient synthesis of gemigliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus, has been developed. Gemigliptin were prepared from two key API starting materials, DP18 and DP57, in 75~80% yield and >99% purity over three steps under the GMP control: coupling, deprotection of N-Boc group, and final crystallization with L-tartaric acid. All steps were conducted in the same solvent system and the intermediates were isolated by simple filtration without distillation of solvent. The established process was validated obviously through the three consecutive batches for a commercial production.

………..IN CASE IMAGES NOT VISIBLE …….SEE THIS AT ………http://www.allfordrugs.com/2015/07/06/gemigliptin/

GO TO MY OTHER SITE FOR SYNTHESIS

(3S)-3-amino-4-(5,5-difluoro-2-oxopiperidino)-1-[2,4-di(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]butan-1-one
Clinical data
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	94% (rat), 73% (dog), 26% (monkey)
Biological half-life	3.6 h (rat), 5.2 h (dog), 5.4 h (monkey)
Identifiers
CAS Registry Number	911637-19-9
ATC code	A10BH06
PubChem	CID: 11953153
ChemSpider	10127461
UNII	5DHU18M5D6
Synonyms	LC15-0444
Chemical data
Formula	C18H19F8N5O2
Molecular mass	489.36 g/mol

……………….

History

The NDA for gemigliptin was submitted to KFDA in July, 2011 and it was approved on June 27, 2012. By the end of 2012, gemigliptin will be marketed in Korea as Zemiglo which is the fifth new DPP-4 inhibitor diabetes treatment in the world.

Mechanism of action

DPP-4 is a serine protease located on the cell surfaces throughout the body. In plasma, DPP-4 enzyme rapidly inactivates incretins including GLP-1 and GIP which are produced in the intestine depending on the blood glucose level and contribute to the physiological regulation of glucose homeostatis. Active GLP-1 and GIP increase the production and release of insulin by pancreatinc beta cells. GLP-1 also reduces the scretion of glucacon by pancreatic alpha cells, thereby resulting in a decreased hepatic glucose production. However these incretins are rapidly cleaved by DPP-4 and their effects last only for a few minutes. DPP-4 inhibitors block the cleavage of the gliptins and thus lead to an increasee insulin level and a reduced glucagon level in a glucose-dependent way. This results in a decrease of fasting and postprandial glycemia, as well as HbA1c levels.^[2]

Preclinical studies

Gemigliptin is a competitive, reversible DPP-4 inhibitor (IC50 = 16 nM) with excellent selectivity over other critical human proteases such as DPP-2, DPP-8, DPP-9, elastase,trypsin, urokinase and cathepsin G. Gemigliptin was rapidly absorbed after single oral dosing and the compound was eliminated with a half-life of 3.6 h, 5.2 h, and 5.4 h in the rat, dog, and monkey, respectively.

The bioavailability of gemigliptin in the rat, dog, and monkey was species-dependent with the values of 94%, 73%, and 26%, respectively. Following the oral administration of gemigliptin in the rat, dog and monkey, about 80% inhibition of plasma DPP-4 activity were observed at the plasma levels of 18 nM, 14 nM and 4 nM, respectively.

In the diet-induced obese (DIO) mice, gemigliptin reduced glucose excursion during OGTT in a dose dependent manner with the minimum effective dose of 0.3 mg/kg and enhanced glucose-stimulated plasma GLP-1 increase in a dose dependent manner reaching the maximum effect at the dose of 1 mg/kg.

Following 4 week oral repeat dosing in the DIO mice, gemigliptin reduced significantly HbA1c with the minimum effective dose of 3 mg/kg. In the beagle dog, gemigliptin significantly enhanced active GLP-1, decreased glucagon, and reduced glucose excursion during OGTT following a single dosing.

Studies on animals suggest its positive effect on hepatic and renal fibrosis .^[3][4] Data on human patients are still inconclusive .^[5]

Clinical studies

The dose-range finding phase 2 study was performed and 145 patients (91men and 54 women) with type 2 diabetes mellitus were enrolled. All three doses (50,100 and 200 mg groups) of gemigliptin significantly reduced the HbA_1c from baseline compared to the placebo group without a significant difference between the doses.

Subjects with a higher baseline HbA_1c (≥8.5%) had a greater reduction in HbA_1c. Insulin secretory function, as assessed using homeostasis model assessment-beta cell, C-peptide and the insulinogenic index, improved significantly with gemigliptin treatment. Insulin sensitivity, as assessed using homeostasis model assessment-insulin resistance, also improved significantly after 12 weeks of treatment.

The 50 and 200 mg groups had significantly reduced total cholesterol and low-density lipoprotein cholesterol levels at 12 weeks compared to the placebo group.

The incidences of adverse events were similar in all study subjects. Gemigliptin monotherapy (50 mg for 12 weeks) improved the HbA_1c, FPG level, oral glucose tolerance testresults, β-cell function and insulin sensitivity measures, and was well tolerated in subjects with type 2 diabetes.

Results of Phase 3 clinical trials which have been finished recently will be updated near future.

…………..

WO 2006104356

 http://www.google.co.in/patents/WO2006104356A1?cl=en

EXAMPLE 83: Synthesis of l-(f2SV2-amino-4-r2.4-bisftrifluoromethylV5.8-dihvdropyridor3.4-d]pyrimidin-7f6H^‘)

-yl1-4-oxobutyll-5.5-difluoropiperidin-2-one [1960]

[1961] 21 mg of the title compound was obtained in a yield of 56% at the same manner as in EXAMPLE 1, except that 42 mg (0.071 mmol) of t-butyl

{(lS)-3-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-l-[(5,5

-difluoro-2-oxpiperidin-l-yl)methyl]-3-oxpropyl}carbamate obtained in

PREPARATION 143 was used. [1962] ¹K NMR (CD₃OD) δ 5.05-4.92 (2H, m), 3.98-3.91 (2H, m), 3.85-3.79 (2H, m),

3.70-3.59 (2H, m), 3.54-3.48 (IH, m), 3.36-3.33 (2H, m), 3.24 (IH, bra), 3.14 (IH, bra), 2.83-2.76 (IH, m), 2.72-2.53 (3H, m), 2.43-2.34 (2H, m) [1963] Mass (m/e) 490 (M+l)

[1964]

[1965] PREPARATION 144: Synthesis of t-butyl

(riSV3-r2.4-bisrtrifluoromethylV5.8-dihvdropyridor3.4-d]pyrimidin-7r6HVyl]-l-(rr2 S)-2-methyl-5-oxomorpholin-4-yl1methyl 1 -3-oxpropyl 1 carbamate

[1966] 14 mg of the title compound was obtained in a yield of 17% at the same manner as in PREPARATION 45, except that 43.7 mg (0.138 mmol) of (3S)-3-[(t-butoxycarbonyl)amino]-4-[2(S)-2-methyl-5-oxomoφholin-4-yl]-butanoic acid obtained in PREPARATION 55 and 42.5 mg (0.138 mmol) of 2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloric acid salt (product of PREPARATION 127) were used.

[1967] ¹K NMR (CDCl₃) δ 5.85-5.83 (IH, m), 5.09-4.92 (IH, m), 4.95-4.78 (IH, m),

4.23-4.08 (3H, m), 4.04-3.76 (3H, m), 3.73-3.66 (IH, m), 3.46-3.38 (IH, m), 3.36-3.21 (2H, m), 3.18-3.10 (2H, m), 2.96-2.81 (IH, m), 2.61-2.50 (IH, m), 1.43-1.41 (9H, m), 1.28-1.24 (3H, m)

[1968] Mass (m/e) 470 (M+l-Boc)

…………..

WO 2012030106

https://www.google.com/patents/WO2012030106A2?cl=en

Reaction Scheme 1

PREPARATION 1: Synthesis of diethyl 2,2-difluoropentanedioate

To a solution of ethyl bromodifluoroacetate (33.2 g) in tetrahydrofuran (94.0 g) was added ethyl acrylate (8.2 g) and copper powder (10.9 g). After heating to 50℃, TMEDA (9.5 g) was added dropwise and the reaction mixture was then stirred for 3 hours at the same temperature. Upon disappearance of ethyl acrylate as the starting material, to the reaction solution was added methyl t-butyl ether (MTBE, 73.7 g) followed by addition of 10% aqueous ammonium chloride solution (49.8 g) dropwise, and the mixture was then stirred for 30 minutes. The remaining copper residue was removed by filtration through a celite, and methyl t-butyl ether (MTBE, 66.3 g) was added to separate the layers. The separated organic layer was washed successively with 10% aqueous NH₄Cl solution (66.3 g) and 3 N aqueous hydrochloric acid solution (99.6 g) in order and then distilled under reduced pressure to obtain 55.0 g of the desired title compound.

¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, J=7.2 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H), 2.37-2.49 (m, 2H), 2.55 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 4.29 (q, J=7.2 Hz, 2H).

PREPARATION 2: Synthesis of ethyl 4,4-difluoro-5-hydroxypentanoate

14.8 g of the compound obtained from the above Preparation 1 was diluted with ethanol (20.4 g) and tetrahydrofuran (69.1 g) and then cooled to 0℃. To this solution was slowly added sodium borohydride (NaBH₄, 3.5 g) stepwise while keeping the internal temperature below 30℃. After confirming completion of the reaction by ¹H NMR, the reaction solution was cooled to the temperature of 10℃ and 10% aqueous ammonium chloride solution (77.7 g) was slowly added. The remaining boron compound was filtered through celite, and the filtrate was distilled under reduced pressure to remove tetrahydrofuran. Then, ethyl acetate (105.2 g) was added to separate the layers, and the organic layer was distilled under reduced pressure to obtain 10.8 g of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 1.23 (t, J=7.2 Hz, 3H), 2.15-2.29 (m, 2H), 2.49 (t, J=7.2 Hz, 2H), 3.69 (t, J=12.0 Hz, 2H), 4.12 (q, J=4.0 Hz, 2H).

EXAMPLE 1: Synthesis of ethyl 4,4-difluoro-5-{[(trifluoromethyl)sulfonyl]oxy}- pentanoate

To the solution of 10.8 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (100.2 g) was added pyridine (7.0 g), and then the mixture was cooled to -5.0℃. After completion of cooling, trifluoromethane sulfonic acid anhydride (20.1 g) was slowly added dropwise while keeping the reaction temperature below 6.3℃. After stirring the reaction solution for 30 minutes, 1.5 N hydrochloric acid solution was added dropwise at 0℃ to separate the layers. The aqueous layer as separated was back-extracted twice with dichloromethane (33.4 g), and the extracts were combined with the organic layer separated from the above and then distilled under reduced pressure to obtain 19.7 g of the title compound as a yellow oil.

¹H NMR (500 MHz, CDCl₃) δ 1.27 (t, J=7.2 Hz, 3H), 2.29-2.39 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 4.55 (t, J=11.6 Hz, 2H).

EXAMPLE 2-1: Synthesis of ethyl 4,4-difluoro-5-{[(nonafluorobutyl)sulfonyl]- oxy}pentanoate

To the solution of 100.0 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (300.0 ml) was added pyridine (65.7 g), and the mixture was then cooled to -10.0℃. After completion of cooling, nonafluorobutanesulfonic anhydride (477.4 g) was slowly added dropwise. After stirring the reaction solution for 3 hours, 1.0 N hydrochloric acid solution (300.0 ml) was added dropwise to separate the layers. The aqueous layer as separated was back extracted once with dichloromethane (500.0 ml), and the extracts were combined with the organic layer separated from the above and then distilled under reduced pressure to obtain 177.5 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.26 (t, 3H, J=7.3 Hz), 2.30-2.36 (m, 2H), 2.58 (t, 2H, J=7.4 Hz), 4.16 (q, 2H, J=7.3 Hz), 4.57 (t, 2H, J=11 Hz).

EXAMPLE 2-2: Synthesis of ethyl 4,4-difluoro-5-{[(nonafluorobutyl)sulfonyl]- oxy}pentanoate

To the solution of 500.0 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (1000.0 ml) was added triethylamine (389.0 g), and the mixture was then cooled to 0℃. After completion of cooling, perfluorobutanesulfonyl chloride (948.80 g) was slowly added dropwise. The reaction solution was stirred for 3 hours at room temperature, distilled under reduced pressure, dissolved in methyl t-butyl ether (MTBE, 3000.0 ml) and then washed three times with water. The organic layer thus obtained was dehydrated with magnesium sulfate, filtered through a celite and then distilled under reduced pressure to obtain 960.0 g of the title compound.

EXAMPLE 3: Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-oxo- pentanoate

To 25.0 g of the starting material, (3S)-3-[(t-butoxycarbonyl)amino]-4-oxo- pentanoic acid, was added t-butanol (96.9 g) followed by the addition of Boc₂O (25.4 g) and dimethylaminopyridine (DMAP, 62.0 g, 0.5 mol%) at room temperature, and the reaction mixture was then stirred for 23 hours at 40℃. Upon completion of the reaction, ethylene dichloride (62.3 g) in t-butanol was added, and the mixture was then distilled under reduced pressure to obtain 30.7 g of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 1.47 (s, 9H), 2.71 (dd, J=4.8, 16.4 Hz, 1H), 2.88 (dd, J=4.4, 16.4 Hz, 1H), 3.75 (s, 3H), 4.53 (m, 1H), 5.44 (br d, J=8.0 Hz, 1H).

EXAMPLE 4: Synthesis of tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy- butanoate

30.7 g of the compound obtained from the above Example 3 was dissolved in ethanol (112.3 g) and, after lowering the internal temperature to 10.5℃ sodium borohydride (NaBH₄, 5.7 g) was slowly added dropwise. This reaction solution was stirred while maintaining the temperature below 22℃. After confirming completion of the reaction by ¹H NMR and TLC, to the reaction solution was slowly added 3.0 N hydrochloric acid solution (30.7 g) dropwise at the internal temperature of 10℃ followed by addition of diluted 0.2% hydrochloric acid solution (100.0 g). The reaction solution was adjusted to pH 3~4 with addition of 9.0% aqueous hydrochloric acid solution, and then back-extracted twice with ethyl acetate (100.0 g) and toluene (44.0 g). The organic layer thus obtained was distilled under reduced pressure to obtain 25.1 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.44 (s, 9H), 1.45 (s, 9H), 2.48-2.57 (m, 2H), 3.69 (d, J=4.9 Hz, 1H), 3.97 (m, 1H), 5.22 (bs, 1H).

EXAMPLE 5: tert-butyl (3S)-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]- butanoate

To 25.1 g of the compound obtained from the above Example 4 was added dichloromethane (133.0 g) and triethylamine (148.0 g), and the mixture was then cooled to 0℃. To this reaction solution was slowly added methanesulfonyl chloride (11.8 g) diluted with dichloromethane (39.9 g) dropwise for 50 minutes while maintaining the internal temperature below 12℃. After completion of the reaction, the reaction solution was washed with 0.5 N aqueous hydrochloric acid solution (120.0 g) and water (100.4 g), and then distilled under reduced pressure to obtain 31.5 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.44 (s, 9H), 1.46 (s, 9H), 2.62 (d, J=6.0 Hz, 2H), 3.04 (s, 3H), 4.21 (m, 1H), 4.30 (d, J=5.2 Hz, 2H), 5.16 (br d, J=7.2 Hz, 1H).

EXAMPLE 6: Synthesis of tert-butyl (3S)-4-azido-3-[(tert-butoxycarbonyl)amino]- butanoate

Sodium azide (NaN₃, 11.6 g) was diluted with dimethylacetamide (DMAc, 260.0 g). After elevating the internal temperature to 80℃, a solution of 31.5 g of the compound, as obtained from the above Example 5, diluted with dimethylacetamide (DMAc, 45.0 g) was added thereto. The reaction proceeded at 80℃ for 2 hours. To the reaction solution were added toluene (251.0 g) and water (320.0 g) to separate the layers. The organic layer thus obtained was distilled under reduced pressure to obtain 24.0 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.47 (s, 9H), 1.49 (s, 9H), 2.49 (d, J=6.0 Hz, 2H), 3.44-3.55 (m, 2H), 4.09 (br s, 1H), 5.14 (br s, 1H).

EXAMPLE 7: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- butanoate

To 21.0 g of the compound obtained from the above Example 6 was added tetrahydrofuran (93.3 g) followed by the addition of triphenylphosphine (PPh₃, 21.0 g) at 40℃, the mixture was stirred for 2 hours at the same temperature, and water (3.8 g) was then added thereto. The reaction solution was distilled under reduced pressure, and the resulting triphenylphosphine oxide solid was diluted with toluene (26.0 g) and n-hexane (41.0 g), and then filtered off. The filtrate was adjusted to pH 2~3 with 1.0 N aqueous hydrochloric acid solution (110.0 g) and then subjected to separation of the layers. To remove any residual triphenylphosphine oxide solid, the aqueous layer obtained above was washed with dichloromethane (100.0 g) and then adjusted to pH 8~9 with 28% aqueous ammonia solution (7.6 g). The aqueous solution thus obtained was extracted with dichloromethane (100.0 g) and distilled under reduced pressure to obtain 8.5 g of the title compound as a white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.44 (s, 9H), 1.45 (s, 9H), 2.45 (d, J=6.1 Hz, 2H), 2.77 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 5.22 (br s, 1H).

EXAMPLE 8: Synthesis of N,N-dibenzyl-L-N(Boc)-aspartamide 4-tert-butyl ester

N-Boc-L-aspartic acid 4-t-butyl ester (29.0 g, 0.10 mol) was added to THF (200 ml). After cooling to temperature below -5℃, to the reaction solution was added isobutylchloroformate (13.0 ml, 0.10 mol) followed by addition of N-methyl morpholine (12.0 ml, 0.10 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise dibenzylamine (21.1 ml, 0.11 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (300.0 mL) and 1 N hydrochloric acid to separate the layers, and distilled under reduced pressure to precipitate a solid. The solid was filtered and washed with ethyl acetate (100 ml), and then the washings were concentrated by distillation again under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (41.7 g, 0.89 mol).

¹H NMR (400 MHz, CDCl₃) δ: 7.32 (m, 5H), 7.20 (m, 5H), 5.39 (d, J=7.2 Hz, 1H), 5.30 (m, 1H), 4.87-4.77 (m, 2H), 4.48-4.39 (m, 2H), 2.72 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.56 (dd, J=15.8 Hz, J=6.4 Hz, 1H), 1.43 (s, 9H), 1.37 (s, 9H).

Mass (ESI, m/z): 491 (M+Na), 469 (M+H), 413 (M-55).

EXAMPLE 9: Synthesis of N, N-diallyl-L-N(Boc)-aspartamide 4-tert-butyl ester

L-N(Boc)-aspartic acid 4-t-butyl ester (5.00 g, 17.3 mol) was added to THF (50 ml). After cooling to temperature below -5℃, to the reaction solution was added isobutylchloroformate (2.26 ml, 17.3 mol) followed by addition of N-methyl morpholine (1.90 ml, 17.3 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise diallylamine (2.35 ml, 19.0 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (60 ml) and 1 N hydrochloric acid and, after separating the layers, concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (6.0 g, 16.3 mol).

¹H NMR (400 MHz, CDCl₃) δ: 5.78 (m, 2H), 5.30 (m, 1H), 5.23-5.11 (m, 1H), 5.30 (m, 1H), 4.93 (m, 1H), 4.11-3.84 (m, 4H), 2.68 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.51 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 1.44 (s, 9H), 1.42 (s, 9H).

Mass (ESI, m/z): 391 (M+Na), 369 (M+H), 313 (M-55).

EXAMPLE 10: Synthesis of N,N-dibenzyl-4-amino-3(S)-N(Boc)-aminobutanoic acid 4-tert-butyl ester

10.0 g of the compound obtained from the above Example 8, Ru₃(CO)₁₂ (136 mg, 1mol%), and diphenylsilane (19.7 ml, 106.7 mmol) were added to tetrahydrofuran (50 ml), and the reaction solution was stirred under reflux for over 40 hours. The reaction solution was extracted with ethyl acetate (200 ml) and concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (4.7 g, 10.5 mmol).

¹H NMR (400 MHz, CDCl₃) δ: 7.31-7.20 (m, 10H), 5.12 (bs, 1H), 3.90 (bs, 1H), 3.63 (d, J=12.0 Hz, 2H), 3.48 (d, J=12.0 Hz, 2H), 3.24 (m, 1H), 3.16 (bs, 1H), 2.42 (m, 2H), 1.81 (m, 1H), 1.59 (m, 9H), 1.46 (s, 9H), 1.06 (s, 9H).

Mass (ESI, m/z): 455 (M+H), 441 (M-13).

EXAMPLE 11: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- 4-oxobutanoate

360.0 g of the starting material, N-Boc-Asp(O-t-Bu)OH, together with Boc₂O (353.0 g) and ammonium bicarbonate (NH₄HCO₃, 123.9 g) was added to dimethylformamide (1174.6 g), and pyridine (61.0 g) was added dropwise thereto at room temperature, and the reaction mixture was then stirred for about 3 hours. Upon completion of the reaction, water (1440 ml) and toluene (1800 ml) were added to the reaction solution and stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to remove t-butanol and toluene to obtain the title compound, which was directly used in the next reaction.

EXAMPLE 12: Synthesis of (S)-tert-butyl 3-(tert-butoxycarbonylamino)-3-cyanopropanoate

To the compound obtained from Example 11 was added dimethylformamide (1019.5 g) followed by addition of cyanuric chloride (112.0 g) dropwise for 1.5 hours at temperature below 25℃. The reaction solution was stirred for one hour at room temperature, and then 0.1 N aqueous sodium hydroxide solution (1850.0 g) and toluene (1860 ml) were added thereto to separate the layers. The organic layer thus obtained was washed once again with water (700 ml) and then distilled under reduced pressure to obtain 318.3 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ: 1.44 (s, 9H), 1.45 (s, 9H), 2.45 (d, J=6.1 Hz, 2H), 2.77 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 5.22 (br s, 1H).

EXAMPLE 13: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- butanoate

To 212.1 g of the compound obtained from the above Example 12 was added acetic acid (4000 ml) followed by addition of 20 wt% Pd(OH)₂ (1.1 g) at 40℃. The mixture was stirred for 8 hours while keeping the internal temperature below 45℃ and 3 atmospheric pressure of hydrogen. Upon completion of the reaction, the reaction solution was distilled under reduced pressure to remove acetic acid, diluted with toluene (640 L) and then filtered through a celite. To the filtrate was added 0.25 N aqueous hydrochloric acid solution (1060 ml) to separate the layers. The aqueous layer thus obtained was basified with aqueous ammonia solution (543.1 g) and then extracted with methyl t-butyl ether (MTBE, 1000 ml). The organic layer thus obtained was distilled under reduced pressure to obtain 185.0 g of the title compound.

EXAMPLE 14: Synthesis of 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo- piperidin-1-yl)-butyric acid t-butyl ester

Triethylamine (13.2 g) was added to 16.0 g of the compound obtained from the above Example 1 or 2-1 or 2-2, and 14.1 g of the compound obtained from the above Example 7 or 13, and the mixture was then stirred for 21 hours at 40℃. Then, dichloromethane (154.8 g) and acetic acid (18.3 g) were added, and the mixture was stirred for 5 hours at room temperature. To the resulting reaction solution was added 0.5 N aqueous hydrochloric acid solution (116.8 g) and then, the mixture was stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to obtain 23.6 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ: 1.42 (s, 9H), 1.46 (s, 9H), 2.27 (m, 2H), 2.40-2.64 (m, 4H), 3.20 (dd, J=4.3, 13.5 Hz, 1H), 3.56-3.70 (m, 2H), 3.76-3.91 (m, 2H), 4.16 (m, 1H), 5.20 (d, J=8.6 Hz, 1H).

EXAMPLE 15: Synthesis of 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo- piperidin-1-yl)-butyric acid

23.6 g of the compound obtained from the above Example 14 was added to dichloromethane (20.0 g) followed by addition of H₃PO₄ (30.0 g), and the mixture was stirred for 16 hours at room temperature. After confirming the detachment of all of t-butyl group and t-butyloxycarbonyl group, the reaction solution was adjusted to pH 7.0~8.0 with 10 N aqueous hydrogen peroxide, and Boc₂O (16.0 g) was added thereto. After completion of the addition, 10 N aqueous hydrogen peroxide was used to maintain the pH of the reaction solution at 8.0~9.0. After stirring for 3 hours, the resulting sodium phosphate was filtered off, and the filtrate was then adjusted to pH 2.0~3.0 with 3.0 N aqueous hydrochloric acid solution. The resulting solid was filtered and dried under nitrogen to obtain 14.5 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ: 1.32 (s, 9H), 2.20-2.43 (m, 6H), 3.26-3.31 (m, 2H), 3.61 (m, 1H), 3.81 (m, 1H), 4.02 (m, 1H), 6.73 (d, J=8.6 Hz, 1H), 12.16 (s, 1H).

For the title compound resulting from the above, its enantiomeric isomers―i.e. S-form and R-form―were measured by HPLC (high-performance liquid chromatography), and an excess of the enantiomeric isomers (S vs. R form) (enantiomeric excess; ee) was then calculated as being ee > 99%. On the other hand, in case of the Comparative Example prepared according to the prior method based on WO 06/104356, as described below, the excess (ee) of enantiomeric isomers (S vs. R form) was 80%. From this, it can be identified that the compound of formula (2) having an optically high purity could be obtained according to the method of the present invention.

COMPARATIVE EXAMPLE 1: Synthesis of 3-t-butoxycarbonylamino-4-(5,5- difluoro-2-oxo-piperidin-1-yl)-butyric acid t-butyl ester

COMPARATIVE EXAMPLE 1-1: Synthesis of methyl 5-amino-4,4-difluoro- pentanoate HCl

To 10.0 g of the compound obtained from Example 1 was added 40 ml of anhydrous ammonia solution (7 M solution in methanol), and the mixture was stirred for 3 hours. The reaction solution was distilled and 30 ml of hydrochloric acid solution saturated with methanol was added dropwise thereto. The reaction mixture was stirred at room temperature and then distilled to obtain 7.2 g of the title compound as a white solid.

¹H NMR (500 MHz, CD₃OD) δ: 2.35 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 3.49 (t, J=15.3 Hz, 2H), 3.68 (s, 3H).

COMPARATIVE EXAMPLE 1-2: Synthesis of 3-t-butoxycarbonylamino-4-(5,5- difluoro-2-oxo-piperidin-1-yl)-butyric acid t-butyl ester

To the solution of the compound (1.93 g), as obtained from the above Example 4, dissolved in dichloromethane (20.0 g) and H₂O (4.0 g) were added NaBr (0.8 g) and TEMPO (11 mg, 1 mol%). To this reaction solution was slowly added a solution of 5% NaOCl (11.5 g) and NaHCO₃ (1.7 g) dissolved in H₂O (12.0 g) dropwise for about 2 hours while maintaining the temperature below 5℃. Upon completion of dropwise addition, the reaction solution was stirred for 30 minutes to separate the layers. To the organic layer thus obtained was added the compound (1.6 g) obtained from the above Comparative Example 1-1. After stirring for 15 minutes at room temperature, NaBH(OAc)₃ (2.23 g) was added to the reaction solution. After stirring for about 19 hours, 10% aqueous NaHCO₃ solution (20.0 g) and 0.5 N aqueous hydrochloric acid solution (20.0 g) were added dropwise to the reaction solution to separate the layers. The organic layer thus obtained was dehydrated under anhydrous MgSO₄ to obtain 2.0 g (yield 73%) of the same title compound as Example 14, as a yellow solid. For the title compound resulting from the above, its enantiomeric isomers―i.e., S-form and R-form―were measured by HPLC (high-performance liquid chromatography), and an excess (ee) of the enantiomeric isomers (S vs. R form) was then calculated as being ee = 80%.

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ANTHONY MELVIN CRASTO

Fispemifene, HM 101

Fispemifene; UNII-3VZ2833V08;

cas 341524-89-8

2-[2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]ethoxy]ethanol

Treatment of Hypogonadism

Androgen Decline in the Aging Male (Andropause) in phase 2

Fispemifene is the Z-isomer of the compound of formula (I)

WO 01/36360 describes a group of SERMs, which are tissue-specific estrogens and which can be used in women in the treatment of climacteric symptoms, osteoporosis, Alzheimer’s disease and/or cardiovascular diseases without the carcinogenic risk. Certain compounds can be given to men to protect them against osteoporosis, cardiovascular diseases and Alzheimer’s disease without estrogenic adverse events (gynecomastia, decreased libido etc.). Of the compounds described in said patent publication, the compound (Z)-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol (also known under the generic name fispemifene) has shown a very interesting hormonal profile suggesting that it will be especially valuable for treating disorders in men. WO 2004/108645 and WO 2006/024689 suggest the use of fispemifene for treatment or prevention of age-related symptoms in men, such as lower urinary tract symptoms and diseases or disorders related to androgen deficiency in men.

Quatrx had been conducting phase II clinical development for the treatment of androgen decline in the aging male. Unlike testosterone replacement therapies that are typically topical or injection therapies, fispemifene is an oral treatment and is not a formulation of testosterone. Fispemifene utilizes the body’s normal feedback mechanism to increase testosterone levels. Originally developed at Hormos, QuatRx gained rights to the drug candidate following a merger of the companies pursuant to which Hormos became a wholly-owned subsidiary of QuatRx.

Known methods for the syntheses of compounds like ospemifene and fispemifene include rather many steps. WO 02/090305 describes a method for the preparation of fispemifene, where, in a first step, a triphenylbutane compound with a dihydroxysubstituted butane chain is obtained. This compound is in a second step converted to a triphenylbutene where the chain is 4-chlorosubstituted. Then the desired Z-isomer is crystallized. Finally, the protecting group is removed to release the ethanol-ethoxy chain of the molecule.

Fispemifene is a selective estrogen receptor modulator (SERM) studied in phase II clinical trials at Forendo Pharma for the treatment low testosterone in men. The compound is also in phase II clinical studies at Apricus for the treatment of men with secondary hypogonadism.

In 2013, Forendo Pharma acquired the drug from Hormos Medical for the treatment of male low testosterone.

In 2014, Apricus Biosciences acquired U.S. rights for development and commercialization

PATENT

https://www.google.com/patents/US7504530

EXAMPLE 2 2-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-ethanol (Compound I)

{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-acetic acid ethyl ester was dissolved in tetrahydrofuran at room temperature under nitrogen atmosphere. Lithium aluminium hydride was added to the solution in small portions until the reduction reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution. The product was extracted into toluene, which was dried and evaporated in vacuo. The residue was purified with flash chromatography with toluene/triethyl amine (9.5:0.5) as eluent. Yield 68%.

¹H NMR (200 MHz, CDCl₃):

2.92 (t, 2H, ═CH ₂CH₂Cl),

3.42 (t, 2H, ═CH₂ CH₂ Cl),

3.59-3.64 (m, 2H, OCH₂CH₂O CH₂CH ₂OH),

3.69-3.80 (m, 4H, OCH₂ CH ₂OCH ₂ CH₂OH),

3.97-4.02 (m, 2H, OCH₂CH₂OCH₂CH₂OH),

6.57 (d, 2H, aromatic proton ortho to oxygen),

6.78 (d, 2H, aromatic proton meta to oxygen),

7.1-7.43 (m, 10H, aromatic protons).

………….

PATENT

WO 2001036360

https://www.google.com/patents/WO2001036360A1?cl=en

……………

PATENT

WO 2002090305

 http://www.google.co.in/patents/WO2002090305A1?cl=en

EXAMPLE

a) [2-(2-chloroethoxy)ethoxymethyl]benzene

is prepared from benzyl bromide and 2-(2-chloroethoxy)ethanol by the method described in literature (Bessodes, 1996).

b) {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}phenylmethanone

The mixture of 4-hydroxybenzophenone (16.7 g, 84.7 mmol) and 48 % aqueous sodium hydroxide solution (170 ml) is heated to 80 °C. Tetrabutylammonium bromide (TBABr) (1.6 g, 5.1 mmol) is added and the mixture is heated to 90 °C. [2-(2-Chloroethoxy)ethoxymethyl]benzene (18. g, 84.7 mmol) is added to the mixture during 15 min and the stirring is continued for additional 3.5 h at 115-120 °C. Then the mixture is cooled to 70 °C and 170 ml of water and 170 ml of toluene are added to the reaction mixture and stirring is continued for 5 min. The layers are separated and the aqueous phase is extracted twice with 50 ml of toluene. The organic phases are combined and washed with water, dried with sodium sulphate and evaporated to dryness. Yield 31.2 g.

Another method to prepare {4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}phenyl- methanone is the reaction of 2-(2-benzyloxyethoxy)ethyl mesylate with 4- hydroxybenzophenone in PTC-conditions.

Η NMR (CDCI3): 3.64-3.69 (m, 2H), 3.74-3.79 (m, 2H), 3.90 (dist.t, 2H), 4.22 (dist.t, 2H), 4.58 (s, 2H), 6.98 (d, 2H), 7.28-7.62 (m, 8H), 7.75 (td, 2H), 7.81 (d, 2H).

c) 1- {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol

R = BENZYL

Lithium aluminum hydride (1.08 g, 28.6 mmol) is added into dry tetrahydrofuran (60 ml) under nitrogen atmosphere. Cinnamaldehyde (6.65 g, 50 mmol) in dry tetrahydrofuran (16 ml) is added at 24-28 °C. The reaction mixture is stirred at ambient temperature for 1 h. {4-[2-(2- Benzyloxyethoxy)ethoxy]phenyl}-phenyl-methanone (14.0 g, 37 mmol) in dry tetrahydrofuran (16 ml) is added at 50-55 °C. The reaction mixture is stirred at 60 °C for 3 h. Most of tetrahydrofuran is evaporated. Toluene (70 ml) and 2 M aqueous hydrogen chloride (50 ml) are added. The mixture is stirred for 5 min and the aqueous layer is separated and extracted with toluene (30 ml). The toluene layers are combined and washed with 2M HC1 and water, dried and evaporated. The product is crystallized from isopropanol as a mixture of stereoisomers (8.8 g, 50 %).

Η NMR (CDCI3 ): 1.75-2.10 (m, 2H), 3.20-4.16 (m, 1 OH), 4.52 and 4.55 (2s, together 2H), 6.61 and 6.88 (2d, together 2H), 6.95-7.39 (m, 15H), 7.49 and 7.57 (2d, together 2H).

d) Z- 1 – {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl-but- 1-ene

R = BENZYL

1 – {4- [2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol (10.0 g, 19.5 mmol) is dissolved in toluene (50 ml). Triethylamine (2.17 g, 21.4 mmol) is added to the solution and the mixture is cooled to -10 °C. Thionyl chloride (6.9 g, 58.5 mmol) is added to the mixture at -10 – ±0 °C. The mixture is stirred for 1 hour at 0-5 °C, warmed up to 70 °C and stirred at this temperature for 4 hours. Solvent is evaporated, the residue is dissolved to toluene, washed three times with 1M HC1 solution and twice with water. The Z-isomer of the product is crystallized from isopropanol-ethyl acetate. Yield 3.0 g. The filtrate is purified by flash chromatography to give E-isomer.

Z-isomer: Η NMR (CDCI3): 2.91 (t, 2H), 3.41 (t, 2H), 3.55-3.85 (m, 6H), 3.99 (dist.t, 2H), 4.54 (s, 2H), 6.40 (s, 1H), 6.56 (d, 2H), 6.77 (d, 2H), 7.10- 7.50 (m, 15H)

E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.82 (m, 4H), 3.88 (dist.t, 2H), 4.15 (dist.t, 2H), 4.58 (s, 2H), 6.86 -7.45 (m, 19H)

FINAL STEP

e) 2- {2-[4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy } ethanol:

Z- 1 – {4-[2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl -but- 1-ene (3.8 g, 7.4 mmol) is dissolved in ethyl acetate under nitrogen atmosphere , Zn powder (0.12 g, 1.85 mmol) and acetyl chloride (1.27 g, 16.3 mmol) are added and the mixture is stirred at 50 °C for 3 h (Bhar, 1995). The reaction mixture is cooled to room temperature, water (10 ml) is added and stirring is continued for additional 10 min. The aqueous layer is separated and the organic phase is washed with 1 M aqueous hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in methanol (16 ml) and water (4 ml). The acetate ester of the product is hydrolysed by making the mixture alkaline with sodium hydroxide (1 g) and stirring the mixture at room temperature for 1 h. Methanol is evaporated, water is added and the residue is extracted in ethyl acetate and washed with 1 M hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in toluene (25 ml), silica gel (0.25 g) is added and mixture is stirred for 15 min. Toluene is filtered and evaporated to dryness. The residue is crystallised from heptane-ethyl acetate (2:1). The yield is 71 %.

Z-isomer: 1H NMR (CDCI3): 2.92 (t, 2H), 3.41 (t, 2H), 3.58-3.63 (m, 2H), 3.69-3.80 (m, 4H), 3.96-4.01 (m, 2H), 6.56 (d, 2H), 6.78 (d, 2H), 7.10-7.40 (m, 10H).

Z ISOMER IE FISPEMIFENE

E-2- {2- [4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy} ethanol is prepared analogously starting from E-l-{4-[2-(2-benzyloxy- ethoxy)ethoxy]phenyl} -4-chloro- 1,2-diphenyl-but-l-ene. The product is purified by flash chromatography with toluene-methanol (10:0.5) as eluent.

E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.79 (m, 4H), 3.85-3.90 (m, 2H), 4.13-4.17 (m, 2H), 6.85-7.25 (m, 2H).

Debenzylation of 1 – {4-[2-(2-benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2- diphenyl-but- 1-ene is also carried out by hydrogenation with Pd on carbon as a catalyst in ethyl acetate-ethanol solution at room temperature.

………….

PATENT

http://www.google.com/patents/US5491173

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

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Toremifene

2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine

Toremifene; Acapodene; Farestone; Z-Toremifene; Toremifeno; Toremifenum

cas 89778-26-7

Launched – 1988.Orion (FI), greast cancer

1. Citrate, Toremifene, GTx-006
   NK-622
   • 89778-27-8
2. Fareston
3. FC 1157a
4. FC-1157a
5. FC1157a
6. Toremifene
7. Toremifene Citrate
8. Toremifene Citrate (1:1)
9. Toremifene, (E)-Isomer
10. • C₂₆H₂₈ClNO · C₆H₈O₇
    • Molecular Weight 598.08Toremifene Citrate

Toremifene is a first generation selective estrogen receptor modulator (SERM). Like TAMOXIFEN, it is an estrogen agonist for bone tissue and cholesterol metabolism but is antagonistic on mammary and uterine tissue.

The company GTx is conducting phase III clinical trials for the prevention of prostate cancer in men who have been diagnosed with high grade prostatic intraepithelial neoplasia (PIN).

Toremifene citrate is an oral selective estrogen receptor modulator (SERM) which helps oppose the actions of estrogen in the body. Licensed in the United States under the brand name Fareston, toremifene citrate is FDA-approved for use in advanced (metastatic)breast cancer. It is also being evaluated for prevention of prostate cancer under the brand name Acapodene.^[1]

In 2007 the pharmaceutical company GTx, Inc was conducting two different phase 3 clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects of androgen deprivation therapy (ADT) (especially vertebral/spine fractures and hot flashes, lipid profile, and gynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. Results of these trials are expected by first quarter of 2008^[2]

An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009,^[3] and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.^[4]

Originally developed at Orion, toremifene was subsequently licensed to Nippon Kayaku in Japan and to Asta Medica (now, part of Meda) in Germany.

Synthesis

 ……….

PATENT

http://www.google.com/patents/CN104230723A?cl=en

Toremifene (Toremifene), chemical name (Z) -4- chloro-1,2-diphenyl–1- [4- (2- (N, N- dimethylamino) ethoxy yl) phenyl] -1-butene, having the structure I.Toremifene to tamoxifen (Tamoxifen) analogues with anti-estrogenic activity, can be used in the treatment of hormone-dependent breast cancer, and its E-isomer has the presence of estrogenic activity, E isomers toremifene may counteract anti-estrogenic activity, and therefore isomeric purity is essential toremifene.Toremifene was developed in 1983 by the Finnish Famos company, listed in 1996 by the Orion company in the EU, the trade name Fareston, 2002 to enter the country, the trade name of toremifene.

RJ Toivola et al., European Patent EP95875, disclosed in U.S. Patent US4696949A synthetic route toremifene, that following a synthetic route, the synthetic route to phenol as a raw material, by acylation, rearrangement, alkyl group and an addition reaction to give 1,2-diphenyl -1- [4- [2- (N, N- dimethylamino) ethoxyphenyl]] – 1,4-diol (Compound 5) as the key intermediate, further HCl in ethanol or hydrochloric acid elimination reaction occurs, then get toremifene thionyl chloride reaction. The main problem with this approach is that the elimination reaction of the compound 5 in ethanol occurs when hydrochloric acid or concentrated hydrochloric acid, the resulting triaryl alcohol butyrate (Compound 6) having a Z / E configuration, both the ratio of 1: 2 ~ 2: 1, stereo selectivity is not high, and there are 5% of the cyclization by-product; on the Z / E configuration Miyoshi butyric fractional crystallization of alcohol, you can get pure Z-type Miyoshi butyric alcohol , but the yield is only 41%; then, Z-type Miyoshi butyric alcohol chlorination reaction occurs in the action of thionyl chloride, the purified product toremifene.

 U.S. Patent US5491173A also reported another synthetic route toremifene namely the following two synthetic routes. The route to the aryl ketone (Compound 7) with a phenyl Grignard reagent addition reaction of ketone carbonyl groups to give triaryl-butanediol (compound 5), which is the elimination of toremifene and chlorinated reaction products happen again.

 Chinese Patent Publication No. CN1125716A application reported an efficient synthesis of Z-type Miyoshi butyric alcohol (compound 6) method, US4696949A compared with the US patent, the method mild conditions, reduce the acid concentration and reaction temperature, reaction time, triarylphosphine butanediol (Compound 5) in concentrated hydrochloric acid or concentrated hydrochloric isopropanol or ethanol effect of concentrated hydrochloric acid, can be 60-78% selectivity and 95% yield of type 2 Miyoshi butyric alcohol But after Publication No. 0 02,126,969 attached eight patent applications after the inventor repeated experiments show that the technique disclosed in the patent application programs can not achieve their claimed technical effect.

 Publication No. CN102126969A of Chinese patent applications through the intermediate Miyoshi butyric alcohol occurs at a catalytic converter configuration of concentrated hydrochloric acid, while taking advantage of differences in solubility, so E- type Miyoshi butyric alcohol continuously into Z-type Miyoshi butyric alcohol (compound 6) precipitates, thereby undermining the balance, so that one of the E-type Miyoshi butyric alcohol continuously into Z-type Miyoshi butyric alcohol (compound 6) to give the Z-Miyoshi butyric alcohol ( Compound 6) and then get toremifene thionyl chloride after chlorination. Although to some extent, improve the yield, but increased operating procedure, is not conducive to industrial production.

Currently, the key intermediate is patent protected, and z-type Miyoshi butyric alcohol (compound 6) stereoselective low yield and isolated intermediates, to solve this problem, to overcome technical barriers to foreign pharmaceutical companies, urgent need to find a simple process, low cost, easy to separate and viable for large-scale production of synthetic routes.

To achieve the above object, according to one aspect of the present invention, there is provided a method of synthesizing toremifene, synthetic method comprising: a step S1, so that a compound having the structural formula II with a compound B having the structural formula III C occurs Mike Murray to give compound D having the structural formula IV; step S2, the Compound D and Compound E or Compound E of the hydrochloride salt of the formula V having a phenolic hydroxyl group on the occurrence of a selective alkylation reaction, to give a compound having the structural formula VI F; step S3, the compound F is reacted with thionyl chloride to give toremifene, wherein,

 Formula II is:

Structural formula III as follows:

Formula IV is

Of formula V is C1CH2CH2N (CH 3) 2; formula VI is

FIG. 1 illustrates the present invention obtained in Example 1 H NMR spectrum of compound D of implementation;

FIG. 2 shows the 1 H NMR spectrum of the present invention, the compound obtained in Example F;

FIG. 3 shows the present invention is a proton nuclear magnetic resonance spectrum of toremifene obtained in Example.

Figure 1, which shows a spectrum of results for Che bandit? (400 cm take, 01 ^ 0) 3 = 9.20 (! 8,1 1), 7.37 (^ = 7.4 to take, 2 1!), 7.30- 7. 23 (m, 3H), 1.22- 7. 15 (m, 2H), 7. 15 – 7. 06 ( m, 3H), 6. 61 (dd, J = 9. 0, 2. 2Hz, 2H), 6. 49 -. 6. 32 (m, 2H), 4 48 (s, 1H), 3 30 (. m, 2H), 2 55 (t, J = 7. 5Hz, 2H);. F proton nuclear magnetic resonance spectrum of the compound attached to the

Figure 2, showing spectrum results Che NMR (400MHz, DMSO) δ = 7. 36 (d, J = 7. 3Hz, 2H), 7. 31 – 7. 25 (m, 3H), 7. 21 – 7. 10 (m, 5H), 6. 75 – 6. 69 (m , 2H), 6. 59 (d, J = 8. 8Hz, 2H), 4. 49 (s, 1H), 3. 88 (t, J = 5. 8Hz, 2H), 3. 31 (d, J = 4. 3Hz, 2H), 2. 57 (t, J = 7.5Hz, 2H), 2.52 (t, J = 4.6Hz, 2H), 2 15 (s, 6H);.

Tommy remifentanil NMR hydrogen spectrum in Figure 3 attached, showing spectrum results Che NMR (400MHz, CDC13) δ = 7. 41 -. 7. 33 (m, 2H), 7 29 (dt, J = 7. 1, 2. 9Hz, 3H), 7. 20 (dd, J = 10. 0, 4. 3Hz, 2H), 7. 13 (dd, J = 7. 1, 4. 3Hz, 3H), 6.87- 6. 72 (m, 2H), 6. 57 (dd, J = 6. 8, 4. 8Hz, 2H), 3. 92 (t, J = 5. 8Hz, 2H), 3. 41 (t, J = 7. 5Hz, 2H), 2. 92 (t, J = 7. 5Hz, 2H), 2. 63 (t, J = 5. 8Hz, 2H), 2. 28 (s, 6H).

The synthetic routes above synthetic method are as follows:

Synthesis of toremifene:

To a 2L reaction flask 1. 1L of toluene, 110g (0. 28mol) obtained in the above step Z configuration compound F, mixed to obtain a sixth system, the cooling system to the sixth mixed 0~5 ° C , was slowly added dropwise 99. 93g (0. 84mol) thionyl chloride addition was complete the formation of the seventh mixed system, the mixed system was slowly warmed to a seventh ll〇 ° C, for 1 hour to obtain a third product system, stop The third product heating and cooling system to 15~25 ° C, the third product system slowly poured into 1L of water, adding NaOH solution to a pH 9~10 and get the second system, the second in and a system for liquid separation, and the resulting aqueous phase to obtain a second solution was extracted with 1L toluene extraction, the organic phase of the second extraction solution and liquid separation were combined and concentrated to give crude toremifene, the crude product was mass ratio of 1 : mixed solvent of ethyl acetate and acetone 1 crystals to give 103. 7g toremifene products.

Synthesis of toremifene:

[0062] To a 5L reaction flask 3. 3L of toluene, 110g (0. 28mol) obtained in the above step Z configuration compound F, mixed to obtain a sixth system, the cooling system to the sixth mixed 0~5 ° C , was slowly added dropwise 33. 31g (0. 28mol) thionyl chloride addition was complete the formation of the seventh mixed system, the mixed system was slowly warmed to a seventh ll〇 ° C, after the reaction for 6 hours to obtain a third product system, stop The third product heating and cooling system to 15~25 ° C, the third product system slowly poured into 1L of water, potassium carbonate solution to a pH 9~10 and get the second system, the second and system for liquid separation, and the resulting aqueous phase to obtain a second solution was extracted with 1L ethyl acetate, the organic phase after the second extraction solution and liquid separation were combined and concentrated to give crude toremifene, the crude product was quality ratio was crystallized from acetone to give 92. 2g toremifene products.

Purity of toremifene following method:

[0107] to take the product, add the mobile phase dissolved and diluted into 1ml of 1. Omg solution containing, according to HPLC octadecylsilane bonded silica as a filler to square 1% trifluoroacetic acetic acid aqueous solution (A) and acetonitrile (B) as the mobile phase gradient elution (T = Omin 10% B; T = lOmin 95% B; T = 12min 100% B; T = 15min 10% B), detection wavelength 210nm; area normalization method to calculate the Z configuration purity compound F, where F Z configuration compound retention time of 6. 76min. The purity of the above calculation or Z configuration detection obtained compound D, compound D Z configuration and E configuration of the weight ratio, toremifene yield and purity are reported in Table 1 below.

……………..

PATENT

http://www.google.com/patents/US5491173

c) 4-chloro-1,2-diphenyl-1-[4-[2-(N ,N-dimethylamino)ethoxy]phenyl]-1-butene (Z and E)

(Z)-isomer: The reaction is performed under dry conditions. 42.4 g of (Z)-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino )ethoxy]phenyl]-1-buten-4-ol are dissolved in 250 ml of chloroform. Then 23.8 g of thionyl chloride areadded dropwise. The mixture is refluxed 3 h. The solvent is evaporated, after which the product is recrystallized from ethyl acetate. The yield ofthe hydrochloride salt is 36.7 g (83%), m.p. 194°-6° C. The base can be liberated from the Salt with 1M sodium carbonate solution, after which the base is extracted in toluene. The toluene solution is dried and the solvent is evaporated. The free base has m.p. 108°-10° C. (from acetone).

¹ H-NMR-spectrum (CDCl₃): δ 2.27 (6H, s), 2.63 (2H, t), 2.91 (2H, t), 3.41 (2H, t), 3.92 (2H, t), 6.54 (2H, d), 6.79 (2H. d), 7.15(5H, s), 7.31 (5H, s). MS: m/z 405/407 (M⁺, 7/3), 72 (20), 58 (100).

The citric acid salt can be prepared as follows: 40.6 g of the (Z)-isomer as a free base are dissolved in 175 ml of warm acetone and 24.3 g of citric acid are dissolved in 100 ml of warm acetone. The solutions are combined and the mixture is allowed to cool. The citrate, m.p. 160°-162° C., is collected by filtration.

(E)-isomer: The compound is prepared from (E)-1,2-diphenyl-1-[4-[2-(N ,N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol in the same manner as the corresponding (Z)-isomer. The hydrochloride salt is crystallized from toluene. The yield is 35.8 g (81%) of a product having m.p. 183°-5° C. The base can be liberated from the salt in the same manner as the corresponding (Z)-isomer. It has m.p. 69°-71° C. (from hexane).

¹ H-NMR-spectrum (CDCl₃): b 2.34 (6H, s), 2.74 (2H, t), 2.97 (2H,t), 3.43 (2H, t), 4.08 (2H, t), 6.80-7.30 (14H, m).

MS: m/z 405/407 (M⁺, 7/3) 72 (19) 58 (100)

EXAMPLE 4

4-chloro-1,2-diphenyl-1-[4-[2-(N ,N-diethylamino)ethoxy]phenyl ]-1-butene (Z and E)

43.3 g of 1,2-diphenyl-1-[4-[2-(N,N-diethylamino)ethoxy]phenyl]butane-1,4-diol (pureenantiomer pairs or their mixture: m.p. of (RR,SS)-pair is 107°-9° C.)is suspended in 250 ml of toluene, after which 25ml toluene is distilled off to dry the solution. The mixture is cooled to 0° C. with stirring. While stirring and keeping the temperature at 0° C. or a little below, 47.6 g of thionyl chloride of good qualityare added. The mixture is stirred for 1 h at 0° C. and the temperature is then allowed to rise to 22° C. The mixture is stirred at 80° C. until the reaction is completed (about 3 h). After that, water is added to decompose the excess of thionyl chloride followed by 20% sodium hydroxide solution to liberate the product from itshydrochloride salt. The aqueous layer is discarded and the toluene layer iswashed with water. Then the solvent is evaporated to leave a mixture of (Z)- and (E)isomers (Z:E 7:3) as an oil in quantitative yield.

(Z)-isomer: The (Z)-isomer is isolated from the isomer mixture above as thehydrochloride salt because of the low melting point of the free base. The m.p. of the hydrochloride salt is 178°-80° C. The (Z)-isomermay be freed from its salt by any normal method.

¹ H-NMR-spectrum (CDCl₃): δ 1.01 (6H, t), 2.57 (4H, q), 2.77 (2H, t), 2.91 t), 3.41 (2H, t), 3.90 t), 6.53 (2H, d), 6.78 (2H, d), 7.15 (5H, s), 7.31 (5H, s). (E)-isomer:

¹ H-NMR-spectrum (CDCl₃): δ 1.07 (6H, t), 2.66 (4H, q), 2.89 (2H, t), 2.97 (2H, t), 3.42 (2H, t), 4.07 (2H, t), 6.90-7.20 (10H, m).

……………….

SEE

http://www.google.co.ug/patents/EP0095875B1?cl=en

………….

http://www.intechopen.com/books/topics-on-drug-metabolism/electrochemical-methods-for-the-in-vitro-assessment-of-drug-metabolism

References

1.  Price N, Sartor O, Hutson T, Mariani S. Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer. Clin Prostate Cancer 2005;3:211-4. PMID 15882476
2.  “GTx’s Phase III Clinical Development of ACAPODENE on Course Following Planned Safety Review” (Press release). GTx Inc. 2007-07-12. Retrieved 2006-07-14.
3.  “GTx Announces Toremifene 80 mg NDA Accepted for Review by FDA” (Press release).
4.  “GTx and Ipsen End Prostate Cancer Collaboration due to Costs of FDA-Requested Phase III Study”. 2 Mar 2011

Toremifene

Systematic (IUPAC) name
2-{4-[(1Z)-4-chloro-1,2-diphenyl-but-1-en-1-yl]phenoxy}-N,N-dimethylethanamine
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a608003
Pharmacokinetic data
Protein binding	more than 99.5%
Biological half-life	5 days
Identifiers
CAS Registry Number	89778-26-7
ATC code	L02BA02
PubChem	CID: 3005573
IUPHAR/BPS	4325
DrugBank	DB00539
ChemSpider	2275722
UNII	7NFE54O27T
KEGG	D08620
ChEBI	CHEBI:9635
ChEMBL	CHEMBL1655
Chemical data
Formula	C26H28ClNO
Molecular mass	405.959 g/mol

///////

Verubecestat (MK-8931)

Merck Alzheimer’s drugs Verubecestat (MK-8931) is an oral β- amyloid precursor protein cleaving enzyme (BACE1 or β-secretase enzyme) inhibitor, is currently in Phase III clinical trials

Verubecestat
MK 8931, MK-8931, SCH 900931
2-Pyridinecarboxamide, N- (3 – ((5R) -3-amino-5,6-dihydro-2,5-dimethyl-1 , 1-dioxido-2H-1,2,4-thiadiazin-5-yl) -4-fluorophenyl) -5-fluoro-

N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide

CAS : 1286770-55-5

C₁₇ H₁₇ F₂ N₅ O₃ S, 409.41
Mechanism: Oral β- amyloid precursor protein cleavage enzyme (BACE) inhibitors
Indications: Alzheimer’s disease
Development progress: phase III clinical
Companies: Merck

Verubecestat (MK-8931) is a small-molecule inhibitor of beta-secretase cleaving enzyme (BACE) 1 and BACE2 in development by Merck for the treatment of Alzheimer’s Disease.

MK-8931 is a beta-secretase 1 (BACE1) inhibitor in phase III development for the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer’s disease at Merck & Co. The company is also conducting phase II/III trials for the treatment of Alzheimer’s type dementia.

Smiles: C [C @] 1 (CS (= O) (= O) N (C (= N1) N) C) c2cc (ccc2F) NC (= O) c3ccc (cn3) F

COSY PREDICT

PATENT

https://www.google.co.in/patents/CN102639135A?cl=en

Scheme 3a:

https://www.google.co.in/patents/CN102639135A?cl=en

Scheme 3b:

The amine A (Scheme 3a, step 4) (13.7 g) in n-butanol (150 mL) was added a slurry solution of cyanogen bromide (5M, in MeCN). The resulting mixture was heated to reflux for 4 hours. The mixture was concentrated to 1/3 of original volume. To this mixture was added Et20 (200 mL). The resulting solid was removed by filtration, and the solid was washed with Et20 (2x). The solid was partitioned between EtOAc and saturated Na2CO3 (aq). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 10.6 g

Scheme 10:

The nitro compound (Scheme 3b) (2. 50 g, 6. 0 mmol) of Et0H (150 mL) was degassed (To this solution was bubbled with nitrogen time 3 min). To this solution was added Pd / C (10% w / w, 50% water, 698 mg). The mixture was placed in a nitrogen atmosphere. Exhaust, and backfilled with H2 (3x). The obtained mixture at room temperature, followed by stirring under H2 balloon for 2 hours. Bubbling nitrogen gas, and the mixture was purged, filtered through Celite, and concentrated.Small plug filtered through a silica gel column, eluting with EtOAc, and the product was purified to give the aniline (2. 2g, 97%).

SEE

PATENT

http://www.google.co.in/patents/WO2011044181A1?cl=en

SNAPSHOT

SYNTHESIS CONSTUCTION

AND

ON RXN WITH WITH BuLi GIVES

THIS GIVES

THIS ON TREATMENT WITH BrCN

ON BOC2O TREATMENT GIVES

GIVES ON HYDGN

REACTION WITH

GIVES

FINAL COMPD Verubecestat

1H NMR PREDICT

13C NMR PREDICT

Updated…….WATCH OUT FOR MORE

https://www.google.co.in/patents/US8729071?cl=en

Steps 1-4:

These steps were performed using similar procedures to those described in steps 1-4 of Scheme 1a.

Step 5:

To a solution of the amine from step 4 (10.5 g, 36 mmol) in CH₂Cl₂ (200 mL) was added benzoylisothiocyanate (4.3 mL, 1.1 eq.). The resulting solution was stirred at RT for 2.5 days. Additional benzoylisothiocyanate (0.86 mL, 0.2 eq.) was added and the solution was stirred at RT for an additional 2 hours. The solution was then concentrated in vacuo.

A portion of this material (6.5 g, ˜14 mmol) was dissolved in MeOH (200 mL). To this solution was added Na₂CO_{3 (s)} (1.52 g, 14 mmol). The resultant mixture was stirred at RT for 45 min. After that time, a slight excess of HOAc was added to the solution. The mixture was then concentrated. The residue was partitioned between CH₂Cl₂ and ½ sat. NaHCO_{3 (aq.)}. The aqueous layer was extracted with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The thiourea (˜4.9 g) was carried onto the next reaction without further purification.

Step 6:

Example 15 was prepared using a method similar to that described in Scheme 1a step 6.

To a shiny of amine A (Scheme 3a step 4) (13.7 grams) in n-butanol (150 mL) was added a solution of cyanogen bromide (5M in MeCN). The resultant mixture was heated to reflux for 4 hours. The mixture was concentrated to ⅓ of the original volume. To the mixture was added Et₂O (200 mL). The resultant solid was removed via filtration and the solid was washed with Et₂O (2×). The solid was partitioned between EtOAc and sat. Na₂CO₃ (aq.). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to afford 10.6 grams of Ex. 15. This material was converted to the t-butyl carbamate using a procedure similar to that described in Scheme 3.

Step 7:

A mixture of the bromide (3.00 g, 6.92 mmol), benzophenone imine (1.39 mL, 8.30 mmol), Pd₂(dba)₃ (0.634 g, 0.692 mmol), John-Phos (0.413 g, 1.38 mmol), sodium tert-butoxide (2.13 g, 22.1 mmol), and toluene (51 mL) was degassed (vacuum/N₂). The mixture was then stirred at 65° C. under nitrogen for 3 h. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of Celite and rinsed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was then dissolved in methanol (76 mL) and the resulting solution was charged with hydroxyl amine hydrochloride (2.16 g, 31.1 mmol) and sodium acetate (2.55 g, 31.1 mmol). The reaction mixture was stirred at room temperature for 40 min. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine (100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/heptane) to afford the amino pyridine (0.880 g, 34%).

To a flame-dried flask was added a pyridyl bromide (Table IIb, Entry 15, 1.5 g, 3.3 mmol), Pd₂(dba)₃ (305 mg, 0.3 mmol), (2-biphenyl)di-tert-butylphosphine (200 mg, 0.7 mmol), sodium tert-butoxide (1.02 g, 0.011 mmol), benzophenone imine (670 ul, 4 mmol), and toluene (21 mL). The mixture was evacuated under vacuum and back-filled with N₂ (3×). The mixture was stirred at 60° C. for 1 h. After filtration through celite, the filtrate was concentrated. The crude residue was dissolved in 36 mL of methanol, and hydroxyl amine hydrochloride (458 mg, 6.6 mmol) and sodium acetate (541 mg, 6.6 mmol) were added. The reaction was stirred for 35 min and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the combined organic portions were dried over magnesium sulfate and concentrated. The crude residue was purified by a flash silica column (50% ethyl acetate/hexane) to get an aminopyridine product (730 mg, 68%).

A solution of the nitro compound (Scheme 3b) (2.50 g, 6.0 mmol) in EtOH (150 mL) was degassed by bubbling N₂ through the solution for 3 min. To this solution was added Pd/C (10% w/w, 50% H₂O, 698 mg.). The mixture was placed under an atmosphere of N₂. The atmosphere was evacuated and back-filled with H₂ (3×). The resulting mixture was stirred at RT under a H₂ balloon for 2 h. The mixture was purged by bubbling N₂ through it, filtered through Celite and concentrated. The product was purified by filtering through a small plug of silica gel column eluting with EtOAc to afford the aniline (2.2 g, 97%).

ENTRY 25

MH+: 410.0, HPLC1.79 min, LCMSMETHOD D

Method D:

• Column: Agilent Zorbax SB-C18 (3.0×50 mm) 1.8 uM

Mobile phase: A: 0.05% Trifluoroacetic acid in water

• • B: 0.05% Trifluoroacetic acid in acetonitrile

Gradient: 90:10 (A:B) for 0.3 min, 90:10 to 5:95 (A:B) over 1.2 min, 5:95 (A:B) for 1.2 min.

Flow rate: 1.0 mL/min

UV detection: 254 and 220 nm

Mass spectrometer: Agilent 6140 quadrupole

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SD-809,  Deutetrabenazine

• Tetrabenazine-d₆

(3RS,11Brs)-9,10-di((2H3)methoxy)-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-one

2H-​Benzo[a]​quinolizin-​2-​one, 1,​3,​4,​6,​7,​11b-​hexahydro-​9,​10-​di(methoxy-​d₃)​-​3-​(2-​methylpropyl)​-​, (3R,​11bR)​-​rel–

2H-Benzo(a)quinolizin-2-one, 1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-, (3R,11bR)-rel-

2H-Benzo(a)quinolizin-2-one, 1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-, (3R,11bR)-rel-

(RR,SS)-1,3,4,6,7,11b-Hexahydro-9,10-di(methoxy-d₃)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

(3RS,11Brs)-9,10-di((2H3)methoxy)-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-one
Treatment of Chorea Associated with Huntington Disease

SD-809 was granted Orphan Drug Designation for the treatment of HD by the FDA in November 2014 and became part of Teva’s CNS portfolio with the acquisition of Auspex Pharmaceuticals in May 2015.

Teva announced that the New Drug Application (NDA) for SD-809 (deutetrabenazine) has been accepted by the U.S. Food and Drug Administration (FDA) for the treatment of chorea associated with Huntington disease (HD), a rare and fatal neurodegenerative disorder caused by the progressive breakdown of nerve cells in the brain that affects about five to seven people per 100,000 in western countries, according to the World Health Organization.

…………………….

Patent for preparing tetrabenazine

http://www.google.com/patents/WO2012081031A1?cl=en

Chemically tetrabenazine is cis rac -1, 3, 4, 6, 7, 1 lb-hexahydro-9, 10-dimethoxy-3-(2- methylpropyl)-2Hbenzo[a]quinolizin-2-one and it is represented by compound of structural formula I.

Formula 1

The proprietary name of tetrabenazine is Xenazine and is marketed by Biovail Americas. Xenazine is indicated for the treatment of chorea associated with Huntington’s disease. U.S. patent no. 2,830,993 discloses a process for the preparation of tetrabenazine compound of structural formula I wherein 1 -carbethoxymethyl-6, 7-dimethoxy-l , 2, 3, 4- tetrahydroisoquinoline compound of structural formula IV is being reacted with mono- isobutylmalonic acid dimethyl ester compound of structural formula V and paraformaldehyde in methanol solvent to get l-carbethoxymethyl-2 (2, 2-dicarbomethoxy-4-methyl-n-pentyl)-6, 7- dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline compound of structural formula VI. The 1- carbethoxymethyl-2(2,2-dicarbomethoxy-4-methyl-n-pentyl)-6,7-dimethoxy-l ,2,3,4- tetrahydroisoquinoline compound of structural formula VI is subjected to Dieckmann cyclization , hydrolysis and decarboxylation to get tetrabenazine compound of structural formula I, which is recrystallized from di-isopropyl ether solvent.

Formula I

Scheme I

U. S. patent no. 4,678,792 discloses a process for the preparation of 6, 7-dimethoxy-3, 4- dihydroisoquinoline compound of structural formula VII wherein 2-(3, 4-dimethoxyphenyl)- ethylamine compound of structural formula II is being reacted with chloral hydrate at 120°C to get N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III. The N- formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III is further reacted with polyphosphoric acid to get 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII. The 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is being used as an intermediate for the preparation of tetrabenazine compound of structural formula I.

Formula III

Formula II

Polyphosphoric acid

Formula VII

Scheme II

Bull. Korean Chem. Soc. 2002 Volume (23). No. l , page no. 149 discloses N-formylation of various amines and alcohols with formic acid in toluene.

U.S. patent publication no. 2010/0130480 discloses a process for the preparation of 6, 7- dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII by reacting 2-(3, 4- dimethoxyphenyl)-ethylamine compound of structural formula II with hexamethylenetetramine in presence of acetic acid or trifluoroacetic acid.

Hexamethylenetetramine

Formula II Formula VII

U.S. patent publication no. 2008/0167337 discloses a process for the preparation of tetrabenazine compound of structural formula I wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is reacted with 3-dimethylaminomethyl-5-methyl-hexan-2-one methiodide compound of structural formula VIII to get crude tetrabenazine compound. The crude tetrabenazine compound was purified by employing flash column chromatography technique and

Formula VIII Formula I

The prior-art processes for preparing N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III produces below mentioned compound of structural formula XVII, XVIII, XIX, XX, XXI and XXII as a by-product of the reaction due to the demethylation and formylation of resulting hydroxy compounds.

Formula XX Formula XXI Formula XXII

The compounds of structural formula XVII, XVIII, XIX, XX, XXI and XXII are being carry- forwarded into the further steps of reactions of preparing tetrabenazine compound of structural formula I and therefore there is a need in the art to develop an improved process of preparing 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII, which obviates the prior-art problems. Accordingly there is provided a process of preparing tetrabenazine compound of structural formula I wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is being formed without the formation of above mentioned compounds of structural formula XVII, XVIII, XIX, XX, XXI and XXII.

EXAMPLE: PROCESS FOR THE PREPARATION OF SUBSTANTIAL PURE CRYSTALLINE FORM A OF TETRABENAZINE

Stage A: Process for the preparation of 6, 7-dimethoxy-3, 4-dihydroisoquinoIine

Step 1 : Process for the preparation of N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine

A solution of 2-(3, 4-dimethoxyphenyl)-ethylamine (500gm) in toluene (2000ml) was added formic acid (150gm) at 25°C, the resulting reaction mixture was diluted with toluene (500ml) and heated up to 45°C. The reaction mixture was maintained at 40-45°C for 5 hours and then the resulting reaction mixture was concentrated under reduced pressure at 50°C to get the title compound

Yield: 570gm

Purity: 99.98% (By HPLC)

Step 2: Process for the preparation of 6, 7-dimethoxy-3, 4-dihydroisoquinoline

A solution of N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine (250gm) obtained from step 1 in toluene (500ml) and polyphosphoric acid (50gm) was heated at 110°C for 5 hours. The resulting reaction mixture was cooled to 50°C, quenched with water (500ml) and pH of the resulting solution was adjusted to about 8.3 with aqueous solution of sodium hydroxide [sodium hydroxide (690gm) + water (690ml)]. The resulting reaction mass was extracted by ethyl acetate (2 1250ml), dried over anhydrous sodium sulfate (50gm) and concentrated under reduced pressure to get 6, 7-dimethoxy-3, 4-dihydroisoquinoline (190gm).

Yield: 215gm

Purity: 99.67% (By HPLC)

Stage B: Process for the preparation of 3-((dimethylamino) methyi)-5-methylhexan-2-one methiodide

Step 1 : Process for the preparation of 3-((dimethylamino) methyl)-5-methylhexan-2-one Dimethylamine hydrochloride (180gm) and paraformaldehyde (lOOgm) were added to a solution of 5-methylhexan-2-one (900ml) in methanol (1600ml). The resulting reaction mass was heated at reflux for 12 hours, and then the pH was adjusted to about 8.75 with aqueous solution of sodium hydroxide [sodium hydroxide(90gm) + water (900ml)] at 25 °C. The resulting reaction solution was extracted by toluene (2x1234ml). The organic layer was dried over anhydrous sodium sulfate (50gm) and concentrated under reduced pressure to get title compound.

Yield: 900gm

Purity: 99.80% (By HPLC)

Step 2: Process for the preparation of 3-((dimethylamino) methyl)-5-methylhexan-2-one methiodide

Methyl iodide (323gm) was added dropwise to a solution of 3-((dimethylamino) methyl)-5- methylhexan-2-one (195gm) obtained from step 1 , in ethyl acetate (1650ml) at 25-30°C in 30 minutes. The resulting reaction mixture was stirred at 25 °C for 12 hours and then the resulting solids were filtered, washed with water (200ml) and suck-dried to get wet compound (400gm). The wet compound was slurried with water (1000ml) at 25°C for 1 hour and then it was again filtered, washed with water (200ml) and dried at 45-50°C to get title compound

Yield: 300gm

Purity: 99.86% (By HPLC)

Stage C: Preparation of substantial pure crystalline form A of Tetrabenazine

3-((Dimethylamino) methyl)-5-methylhexan-2-one methiodide (80gm) was added to the solution of 6, 7-dimethoxy-3, 4-dihydroisoquinoline (40gm) in isopropanol (288ml) at 25°C and the resulting reaction mass was heated at 40-45°C for 15 hours. The resulting insoluble material was filtered, washed with isopropanol (80ml) and filtrate was concentrated under reduced pressure up to the 150ml reaction volume. The reaction solution was diluted with methylene dichloride (1200ml) and water (1000ml) and pH was adjusted to 8.5 with sodium hydroxide solution [10%, 100ml]. The organic layer was separated, washed with water (3 x 1000ml) and concentrated under reduced pressure to obtain residue. The residue was dissolved in methanol (300ml) at 50°C, and resulting solution was treated with an activated carbon (20gm) at 50-60°C for 30minutes and then it was filtered and filtrate was further stirred at 20-25°C for 2 hours. The resulting solids were filtered, washed with methanol (150ml), dried at 50-55°C for 8 hours. The resulting solids were milled, sifted through 40 mesh sieve and micronized.

Yield: 65gm

Purity: 99.96% (By HPLC)

………………………

PAPER

A concise synthesis of tetrabenazine and dihydrotetrabenazine is described. The key feature of this synthesis is the intramolecular aza-Prins-type cyclization of an amino allylsilane via oxidative C–H activation.

http://www.hgxb.com.cn/EN/abstract/abstract12047.shtml

……………
PAPER

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126153/

The TBZ (4) for these reactions was prepared by reacting 3,4-dihydro-6,7-dimethoxyisoquinoline (3) and the Mannich base (2) as shown in Scheme 1.¹⁴ The α,β-unsaturated TBZ (5), which was the original substrate, was obtained by further treatment with chloranil in refluxing benzene.

…………….

http://www.google.ga/patents/WO2008154243A1?cl=en

Example 10 Removal The Boc Protecting Group From First Intermediate 12 And Amino Cyclization Provide (+)-Tetrabenazine XVII

[0063] First intermediate 12 (1.0 eq) was dissolved in 10% Me₂S- dichloromethane to provide an 82 mM solution. The solution was cooled to 0 ⁰C and triisopropylsilane (1.1 eq.) followed by TFA (precooled to 0 ⁰C) was added to the reaction mixture to provide a final concentration of 41 mM. The reaction mixture was permitted to stir at 0 ⁰C for 1 h. Following the allotted time the reaction mixture was quenched at 0 ⁰C by the addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove the majority of the dimethylsulfide. The mixture was extracted with five portions of dichloromethane, and the combined organic extracts were washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure to provide the crude product as a yellow solid. The crude product was recrystallized from 3.5% dimethoxyethane in hexanes. The resulting colorless crystals were washed with hexanes to provide pure (+)- tetrabenazine (XVII) 46%: mp 126.0 ⁰C (3.5% DME-hexanes) (a crystal polymorph was observed at 116 ⁰C); [α]²⁶ _D +37.2 (c 0.41, CH₂Cl₂); ¹H NMR (CD₂Cl₂) δ 0.89 (apparent t, J = 7.2 Hz, 6H), 0.98 (ddd, J = 12, 6.0, 4.0 Hz, IH), 1.59-1.68 (m, IH), 1.74 (ddd, J = 12, 5.9, 5.7 Hz, IH), 2.32 (apparent t, J = 11.7 Hz, IH), 2.46 (apparent t, J = 12.3 Hz, IH), 2.55 (ddd, J = 12, 10.0, 3.8 Hz, IH), 2.65-2.73 (m, 2H), 2.83 (dd, J = 5.5, 2.8Hz, IH), 2.97-3.07 (m, IH), 3.07-3.14 (m, IH), 3.25 (dd, J =9.7, 6.3 Hz, IH), 3.47 (apparent d, J = 12Hz, IH), 3.75 (s, 3H), 3.77 (s, 3H), 6.55 (s, IH), 6.60 (s, IH) ¹³C NMR (CD₂Cl₂) δ 21.98, 23.02, 25.51, 29.46, 35.16, 47.47, 47.63, 50.47, 55.87, 56.01, 61.47, 62.46, 108.46, 111.72, 126.37, 128.96, 147.65, 147.98, 209.72; HRMS-(ESI+) calcd for (C₁₉H₂₇NO₃ + H) ([M+H]⁺ 318.2069, found 318.2082.

…………….

US 20150152099

………….

WO 2015077520

NBI-98854 (CAS # 1025504-59-9), (S)-(2R,3R,l lbR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,1 lb-hexahydro-lH-pyrido[2,l-a]isoquinolin-2-yl 2-amino-3-methylbutanoate, is a VMAT2 inhibitor. NBI-98854 is currently under investigation for the treatment of movement disorders including tardive dyskinesia. WO 2008058261; WO 2011153157; and US 8,039,627. NBI-98854, a valine ester of (+)-a-dihydrotetrabenazine, in humans is slowly hydrolyzed to (+)-a-dihydrotetrabenazine which is an active metabolite of tetrabenazine.

NBI-98854

EXAMPLE 1

D6-(±)-3-Isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-lH-pyrido[2,l-a]isoquinolin-2(l lbH)-one ((±)-Tetrabenazine-<d6)

Step 1

[0193] Jgrt-butyl 3,4-dihydroxyphenethylcarbamate : A solution of dopamine

hydrochloride (209 g, 1.11 mol, 1.00 equiv), sodium carbonate (231 g, 2.75 mol, 2.50 equiv) and di-tert-butyl dicarbonate (263 g, 1.21 mol, 1.10) in 2.4 L tetrahydrofuran / water (5: 1) was stirred at 20°C for 2.5 h. After the starting material was consumed completedly, the reaction was diluted with ethyl acetate (2 L) and washed with water (2×600 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure until two volumes of solvent was left. The precipitated solid was isolated by filtration and dried under vacuum to give 254 g (91%) of ieri-butyl 3,4-dihydroxyphenethylcarbamate as white solid. Ή-ΝΜΪ (300 MHz, CDC1₃) 8.72 (s, 1H), 8.62 (s, 1H), 6.79 (m, 1H), 6.62 (m, 1H), 6.51 (m, 1H), 6.40 (m, 1H), 3.03 (m, 2H), 2.50 (m, 2H), 1.37 (s, 1H). LC-MS: m /z = 254 (MH) ⁺.

Step 2

[0194] D6-fert-butyl 3,4-dimethoxyphenethylcarbamate: A solution of ieri-butyl 3,4-dihydroxyphenethylcarbamate (127 g, 397 mmol, 1.00 equiv), potassium carbonate (359.3 g, 2.604 mmol, 3.00 equiv) and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane ) (68.64 g, 0.26 mmol, 0.03 equiv) in acetone (800 mL) was stirred at 38°C. After 30 min., CD₃I (362 g, 2.604 mmol, 3.00 equiv) was added to the reaction, and the mixture was stirred at 38°C for 12 h. Then an additional CD3I (120 g, 0.868 mmol, 1.00 equiv) was added to the solution and the solution was stirred for 5 h. Then the mixture was cooled to room temperature and the solid was filtered. The filtrate was concentrated under vacuum. The resultant solid was dissolved in H2O (300 mL) and extracted with EA (3×300 mL), the organic layers was combined and concentrated under vacuum to give 114 g (79%) of de-tert-butyl 3,4-dimethoxyphenethylcarbamate as white

solid. ^-NMR (300 MHz, CDC1₃) <Π.39 (m, 5H), 6.82 (m, 1H), 6.73 (m, 2H), 5.12 (s, 1H), 3.45 (m, 2H), 2.77 (m, 2H). LC-MS: m /z = 288 (MH) ⁺.

Step 3

[0195] D6-2-(3,4-dimethoxyphenyl)ethanamine: A solution of de-tert-butyl 3,4-dimethoxyphenethylcarbamate (128 g, 455.26 mmol, 1.00 equiv) in ethyl acetate (1.5 L) was stirred at room temperature. Then HC1 gas was introduced into the reaction mixture for 2h. The precipitated solid was isolated by filtration. The solid was dissolved in 300 mL of water. The pH value of the solution was adjusted to 12 with sodium hydroxide (solid). The resulting solution was stirred for 1 h at 5-10°C. The resulting solution was extracted with 6×800 mL of ethyl acetate and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum to give 64 g (78%) of d6-2-(3,4-dimethoxyphenyl)ethanamine as yellow oil.

^-NMR (300 MHz, CDC ) 6.77 (m, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 2.96 (m, 2H), 2.71 (m, 2H), 1.29 (s, 2H). LC-MS: m /z = 182 (MH) ⁺.

Step 4

[0196] D6-N-r2-(3,4-dimethoxy-phenyl)ethyllformamide: A solution of d₆-2-(3,4-dimethoxyphenyl)ethanamine (69 g, 368 mmol, 1.00 equiv) in ethyl formate(250 mL) was heated under reflux overnight. The solution was concentrated under vacuum to give 71 g (91%) of d6-N-[2-(3,4-dimethoxy-phenyl)ethyl]formamide as yellow solid. The crude solid was used in next step without purification. ^-NMR (300 MHz, CDCb) £8.17 (s, 1H), 6.81 (m, 3H), 5.53 (br, 1H).3.59 (m, 2H), 2.81 (t, 2H, / = 6.9 Hz). LC-MS: m /z = 216 (MH) ⁺.

Step 5

[0197] D6-6,7-dimethoxy-3,4-dihvdroisoguinoline: A solution of d6-N-[2-(3,4-dimethoxy-phenyl)ethyl]formamide (71 g, 329 mmol, 1.00 equiv) in phosphorus oxychloride (100 mL) was stirred at 105°C for 1 h. Then the solution was concentrated under vacuum to remove

phosphorus oxychloride. The residual oil was dissolved in ice / water. The solution was made basic with potassium carbonate with cooling. The basic aqueous solution was extracted with dichloromethane. The collected organic phase was dried using sodium sulfate and then filtered. The dichloromethane was removed by concentration under vacuum to give an orange oil.

Purification by silica gel (ethyl acetate:petroleum ether = 1: 1 ~ ethyl acetate) to give 43 g (66%) of d6-6,7-dimethoxy-3,4-dihydroisoquinoline as orange solid (yield 66%). Ή-ΝΜΡ (300 MHz, CDC1₃) 8.24 (s, 1H), 6.82 (s, 1H), 6.68 (s, 1H), 3.74 (m, 2H), 2.69 (t, 2H, J = 12 Hz). LC-MS: m /z = 198 (MH) ⁺.

Step 6

[0198] Trimethyl(5-methylhex-2-en-2-yloxy)silane: To a cold (-78°C), stirred solution of j-PrMgBr (500 mL of 2 M solution in tetrahydrofuran, 1 mol, 1.00 equiv) in anhydrous tetrahydrofuran (1 L) was added Cul (19.02 g, 0.1 mol, 0.10 equiv) and the resultant mixture was stirred for 15 min at -78°C. Anhydrous hexamethylphosphorous triamide (358.4 g, 2 mmol, 2 equiv) was added and after 20 min, a solution of methyl vinyl ketone (70 g, 0.1 mol, 1.00 equiv), trimethylsilyl chloride (217 g, 0.2 mol, 2.00 equiv), in tetrahydrofuran (200 mL) was added dropwise over 30 min. After the reaction mixture was stirred at -78 °C for lh, triethylamine (20.2g, 200 mmol, 2.00 equiv) was added and the resulting mixture stirred for 10 min at 0 °C. To this was added ie/ -butyl methyl ether (2 L), and the solution was washed with 5% ammonia solution (6×300 mL). Then the organic phase was dried over sodium sulfate and concentrated under vacuum at 25°C to give 155 g crude product as yellow liquid. The liquid was purified by distilling (64-68°C/40 mmHg) to provide 118 g (63.3%) of trimethyl(5-methylhex-2-en-2-

yloxy)silane (E:Z = 56 : 44) as a colorless oil. ^XH-NMR (300 MHz, J₆-DMSO) 4.58 (m, 0.56H), 4.43 (m, 0.44H), 1.73 (s, 1.69H), 1.66 (s, 1.32H), 1.53 (m, 1H), 0.84 (m, 6 H), 0.15(m, 9H).

Step 7

[0199] 3-r(Dimethylamino)methyl1-5-methylhexan-2-one: To a stirred solution of trimethyl(5-methylhex-2-en-2-yloxy)silane (118 g, 633 mmol, 1.00 equiv) in anhydrous acetonitrile (800 mL) was added N-methyl-N-methylenemethanaminium iodide (128.8 g, 696.3 mmol, 1.10 equiv) in several batches and the resultant mixture was stirred at 20°C overnight. Then the solution was concentrated under vacuum to remove the solvent. The residue was dissolved in 400 mL 1 N HC1 (aq.) and extracted with ieri-butyl methyl ether. Then the water phase was basiced with 2 N aq. NaOH and extracted with ie/ -butyl methyl ether. The organic phase was dried and concentrated under vacuum. The liquid was purified by distilling (80°C/0.5 mmHg) to provide 50 g (46%) of 3-[(dimethylamino)methyl]-5-methylhexan-2-one as a colorless oil. ^XH-NMR (300 MHz, J₆-DMSO) £0.92 (d, 3H), 0.98 (d, 3H), 1.11-1.23 (m, 1H), 1.23-1.38 (m, 1H), 1.54-1.70 (m, 1H), 2.30 (s, 3H), 3.01 (s, 9H), 3.10-3.32 (m, 2H), 3.81-3.88 (m, 1H).

Step 8

[0200] 2-Acetyl-N,N V,4-tetramethylpentan-l-aminium iodide: A solution of 3-[(dimethylamino)methyl]-5-methylhexan-2-one (50 g, 15.00 mmol, 1.00 equiv) and methyl iodide (4.26 g, 30.00 mmol, 2.00 equiv) in 50 mL diethyl ether was stirred overnight at room temperature. The precipitated solid was isolated by filtration and dried under vacuum to give 79 g (86%) of 2-acetyl-N,N,N,4-tetramethylpentan-l-aminium iodide as white solid. ^XH-NMR (300 MHz, Je-DMSO) 0.89-0.98 (m, 6H), 1.11-1.20 (m, 1H), 1.40 (m, 1H), 1.66 (m, 1H), 2.30 (s, 3H), 3.01(s, 9H), 3.21 (m, 2H), 3.85 (m, 1H).

Step 9

[0201] Ρό- (±) -tetrabenazine : A solution of d6-6,7-dimethoxy-3,4-dihydroisoquinoline (33.4 g, 169 mmol, 1.10 equiv) and 2-acetyl-N,N,N,4-tetramethylpentan-l-aminium iodide (48 g, 153 mmol, 1.00 equiv) in 300ml of methanol was heated under reflux for 48 h. Then 150 mL water was added. The solution was cooled to room temperature. The precipitated solid was isolated by filtration and dried under vacuum to give 38 g of crude d6-tetrabenazine as yellow solid. The crude tetrabenazine was dissolved in ieri-butyl methyl ether (15 volumes), the mixture was heated until the solid was almost dissolved. The yellow solid which was unsolvable was filtered. The filtrate was concentrated under vacuum until 2 volumes ieri-butyl methyl ether was left. The solid was filtered and collected. The above solid was dissolved in ethanol (4 volumes), then the mixture was heated until the solid was dissolved. The solution was stirred and cooled to room temperature at the rate of 20°C/h. Then the mixture was stirred at 0°C for lh. The precipitated solid was isolated by filtration and dried under vacuum to give 25 g (50.4%) of tetrabenazine-<d6 as white solid.

^-NMR (300 MHz, CD₂C1₂) £6.61 (s, 1H), 6.55 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.50 (d, 1H, / = 12 Hz), 3.27 (dd, 1H, / = 11.4Hz, / = 6.3 Hz), 3.11 (m, 2H), 2.84 (dd, 1H, / = 10.5 Hz, / = 3 Hz), 2.74 (m, 2H), 2.56 (m, 2H), 2.31 (t, 1H, J = 12 Hz), 1.76 (m, 1H), 1.63 (m, 1H), 0.98 (m, 1H), 0.89 (m, 6H).

LC-MS: m /z = 324 (MH) ⁺.

………………

NMR PREDICT

Watch out will be updated……………….

Rob Koremans, MD, President and CEO of Global Specialty Medicines at Teva.

Michael Hayden, M.D., Ph.D., President of Global R&D and Chief Scientific Officer at Teva