LASMIDITAN

LASMIDITAN, COL-144 , LY-573144

613677-28-4 HYDROCHLORIDE
439239-90-4 (free base)

2,4,6-Trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide

2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide

CoLucid Pharmaceuticals, PHASE 3, MIGRAINE

UNII:760I9WM792

Lasmiditan (COL-144) is an investigational drug for the treatment of acute migraine. It is being developed by Eli Lilly and is in phase III clinical trials. It is a first-in-class “neurally acting anti-migraine agent” ditan.

WO-2018010345,  from Solipharma and the inventor on this API. Eli Lilly , following its acquisition of CoLucid Pharmaceuticals , is developing lasmiditan, a 5-HT 1f agonist, for treating acute migraine.

WATCH THIS SPACE, SYNTHESIS COMING………..

SYN 2

Mechanism of action

Lasmiditan is a serotonin receptor agonist that, like the unsuccessful LY-334,370, selectively binds to the 5-HT_1F receptor subtype. A number of triptans have been shown to act on this subtype as well, but only after their affinity for 5-HT_1B and 5-HT_1D has been made responsible for their anti-migraine activity. The lack of affinity for these receptors might result in fewer side effects related to vasoconstriction compared to triptans in susceptible patients, such as those with ischemic heart disease, Raynaud’s phenomenon or after a myocardial infarction,^[1] although a 1998 review has found such side-effects to rarely occur in patients taking triptans.^[2][3]

Discovery and development

Lasmiditan was discovered by Eli Lilly and Company and was out-licensed to CoLucid Pharmaceuticals in 2006, until CoLucid was bought by Eli Lilly in 2017 to reacquire the drug.^[4] The drug is protected by patents until 2031.^[5]

Phase II clinical trials for dose finding purposes were completed in 2007 for an intravenous form^[6] and in early 2010 for an oral form.^[7]Two separate Phase III clinical trials for the oral version are currently ongoing under special protocol agreements with the US Food and Drug Administration (FDA). Eli Lilly has stated that they intend to submit a new drug application to the FDA in early 2018.^[5]

As of 2017, three phase III clinical trials have been completed or are in progress. The SPARTAN trial compares placebo with 50, 100, and 200 mg of lasmiditan.^[8] SAMURAI compared placebo with 100 and 200 mg doses of lasmidatin. In 2016, CoLucid announced that the trial had met its primary and secondary endpoints of patients being pain-free two hours after dosing.^[5] GLADIATOR is an open-labelstudy comparing 100 and 200 mg doses of lasmidatin in patients that received the drug as part of a prior trial.^[9] In August 2017 topline results from the SPARTAN trial showed that the drug induced met its primary and secondary endpoints in the trial. The primary result showed a statistically significant improvement in pain relief relative to placebo 2 hours after the first dose. The secondary result showed a statistically significantly greater percentage of patients were free of their most bothersome symptom (MBS) compared with placebo at two hours following the first dose. ^[10]

Novel crystalline forms of a 5-HT1F receptor agonist, particularly lasmiditan – designated as Forms 1-3 and A-D – processes for their preparation and compositions comprising them are claimed. Also claim is their use for treating anxiety, fatigue, depression, premenstrual syndrome, trauma syndrome, memory loss, dementia (including Alzheimer’s), autism, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, epilepsy, anorexia nervosa, alcoholism, tobacco abuse, mutism and trichotillomania.

Biological Activity

Lasmiditan (also known as COL-144 and LY573144) is a high-affinity, highly selective serotonin (5-HT) 5-HT(1F) receptor agonist.

In vitro binding studies show a K(i) value of 2.21 nM at the 5-HT(1F) receptor, compared with K(i) values of 1043 nM and 1357 nM at the 5-HT(1B) and 5-HT(1D) receptors, respectively, a selectivity ratio greater than 470-fold. Lasmiditan showed higher selectivity for the 5-HT(1F) receptor relative to other 5-HT(1) receptor subtypes than the first generation 5-HT(1F) receptor agonist LY334370.

In two rodent models of migraine, oral administration of lasmiditan potently inhibited markers associated with electrical stimulation of the trigeminal ganglion (dural plasma protein extravasation, and induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis).

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

PATENT

WO 03084949

https://www.google.co.in/patents/WO2003084949A1?cl=en

8. 2,4,6-Trifluoro-N-[6-(l -methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide mono-hydrochloride salt

Combine 2-amino-6-(l-methylpiperidin-4-ylcarbonyl)pyridine (0.20 g, 0.92 mmol), 2,4,6-Trifluorobenzoyl chloride (0.357 g, 1.84 mmol), and 1 ,4-Dioxane (10 mL), and stir while heating at reflux. After 3 hr., cool the reaction mixture to ambient temperature and concentrate. Load the concentrated mixture onto an SCX column (lOg), wash with methanol, and elute with 2M ammonia in methanol. Concentrate the eluent to obtain the free base of the title compound as an oil (0.365 g (>100%)). Dissolve the oil in methanol (5 mL) and treat with ammonium chloride (0.05 g, 0.92 mmol). Concentrate the mixture and dry under vacuum to obtain the title compound. HRMS Obs. m/z 378.1435, Calc. m/z 378.1429; m.p. 255°C (dec).

Examples

21. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide

Add triethylamine (10.67 mL, 76.70 mmol, 2.4 eq) to a solution of 2-amino-(6-(l- methylpiperidin-4-ylcarbonyl)-pyridine (7g, 31.96 mmol, 1 eq) in anhydrous THF (100 mL) under a nitrogen atmosphere. Add 2,4,6-triflubenzoylchloride (7.46g, 5 mL, 38.35 mmol, 1.20 eq) dropwise at room temperature. After 2 hrs., add additional 2,4,6- triflubenzoylchloride (0.75 mL, 0.15 eq) and triethylamine (1.32 mL, 0.3 eq) to the reaction mixture and agitate the mixture for an additional 3 hrs. Quench the reaction with distilled water (10 mL) and 30%o NaOH (15 mL). Stir the resulting biphasic system for 1 hour and then separate the phases. Extract the organic fraction by adding H₂O (75 mL) and acetic acid (12 mL), followed by cyclohexane (70 mL). Wash the organic fraction with H₂O (50 mL) containing acetic acid (1 mL). Combine all the aqueous fractions and washes and neutralize the mixture with 30% NaOH (15 mL). Extract with methyl-tert- butyl ether (MTBE) (3×50 mL). Combine the organic fractions and dry with MgSO₄, filter, concentrate under reduce pressure, and vacuum dry at room temperature, to obtain the title compound as a light-brown solid (11.031 g, 91 % yield).

Mass spectrum, (Electrospray) m/z = 378 (M+l); Η NMR (250 MHz, Chloroform-D) ppm 1.54 (m, 2 H) 2.02 (m, 2 H) 2.13 (t, J=l 1.48 Hz, 2 H) 2.29 (s, 3 H) 2.80 (m, J=l 1.96 Hz, 1 H) 3.56 (m, 1 H) 4.26 (d, J=7.87 Hz, 1 H) 6.17 (d, J=8.50 Hz, 1 H) 6.75 (m, 2 H) 7.45 (t, J=7.87 Hz, 1 H) 7.53 (m, 1 H) 7.95 (s, 1 H); ¹³C-NMR: (62.90 MHz, Chloroform-D) ppm 202.78; 162.6 (dm C-F-couplings); 162.0 (m C-F-couplings); 160.1 (m C-F-couplings); 158.1 ; 150.0; 139.7; 1 19.3; 1 17.9; 1 10.2 (m C-F-couplings); 100.9 (m C-F-couplings); 55.2; 46.5; 41.9; 28.1

22. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide mono-hydrochloride salt

Dissolve 2,4,6-trifluoro-N-[6-(l-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide – free base (5g, 23.26mmol) in isopropanol (50 mL) at room temperature and add a solution of 3.3 M diethylether/HCl (8 mL). Heat the reaction mixture under reflux for 30 minutes. Cool the reaction mixture to room temperature and agitate for 2 hrs. Filter the resulting white precipitate and rinse with isopropanol (5 mL). Dry the residual solid under reduce pressure at 40°C overnight to obtain the title compound (5.12 g, 93% yield). M.p. 223-224°C (sublimation); Η NMR (400 MHz, d6-DMSO) d ppm 1.94 (m, 2 H) 2.14 (m, J=11.15 Hz, 2 H) 2.74 (s, 3 H) 2.99 (m, J=9.19 Hz, 2 H) 3.49 (m, J=1 1.15 Hz, 2 H) 3.77 (m, 1 H) 7.41 (t, J=8.71 Hz, 2 H) 7.78 (d, J=7.43 Hz, 1 H) 8.10 (t, J=7.92 Hz, 1 H) 8.37 (d, J=6.85 Hz, 1 H) 10.50 (s, 1 H) 1 1.51 (s, 1 H); ¹³C-NMR: (100.61 MHz, Chloroform-D) ppm 200.7; 130.6-158.0 (m, C-F-couplings); 150.4; 150.1; 140.2; 118.5; 1 18.2; 11 1.9; 101.3 (t, C-F couplings); 52.8; 42.6; 25.2

23. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]- benzamide hemi-succinate salt

Add succinic acid (0.25g, 2.148 mmol, 0.5eq) to a solution of 2,4,6-trifluoro-N-[6-

(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide – free base (1.62g, 4.297 mmol, leq) in acetone (16.2 mL), at room temperature. Warm the solution under reflux for 30 minutes. Cool the solution to room temperature and filter off the resulting white precipitate. Rinse the precipitate with acetone (0.2 mL) and dry under vacuum at 50°C for 16 hours to provide the title compound (1.5g, 80% yield). M.p. 198.5°C; mass spectrum (Electrospray) m/z = 495.45

The following examples are prepared by combinatorial chemistry techniques as follows:

Examples 24-54

Combine R-acid (300 μL of 0.5M solution in dimethylformamide (DMF)), HATU (57 mg, 0.15 mmol), collidine (19 μL, 0.15 mmol), 2-amino-(6-(l-methylpiperidin-4- ylcarbonyl)-pyridine and DMF (1.5 mL), and agitate for 48 hr. Dilute the reaction mixture with 10% acetic acid in methanol (0.5 L). Load the resulting reaction mixture onto a 2 g SCX column. Wash the column thoroughly with methanol and then elute with 1 M ammonia in methanol. Concentrate the eluent and further purify the product by high- throughput mass guided chromatography. This procedure is repeated in parallel for examples 24-54.

Examples 55-58

Heat R-acid chloride (300 μL of 0.5M solution in pyridine) to 55°C, add 2-amino- (6-(l-methylpiperidin-4-ylcarbonyl)-pyridine (200 μL of 0.5M solution in pyridine), and continue heating the reaction mixture for 24 hr. Concentrate the reaction mixture and then dilute with 10% Acetic acid in methanol (0.5 mL) and methanol (0.5 mL). Load the resulting reaction mixture directly onto a 2 g SCX column. Thoroughly wash the column with methanol and then elute the column with 1 M ammonia in methanol. Concentrate the eluent and then further purify the product by high- throughput mass guided chromatography. This procedure is repeated in parallel for examples 55-58.

Examples 59-71

Heat 2-amino-(6-(l-methylpiperidin-4-ylcarbonyl)-pyridine (200 μL of 0.5M solution in pyridine) to 55°C then add R-acid chloride (0.10 mmol), heat for 2 hr. Concentrate the reaction mixture and then dilute with 10% Acetic acid in methanol (0.5 mL) and methanol (0.5 mL). Load the resulting reaction mixture directly onto a 2 g SCX column. Thoroughly wash the column with methanol and then elute the column with 1 M ammonia in methanol. Concentrate the eluent and then further purify the product by high-throughput mass guided chromatography. This procedure is repeated in parallel for examples 59-71.

PATENT

WO 2018010345

References

Lasmiditan

Clinical data
Routes of administration	By mouth, intravenous
ATC code	none
Legal status
Legal status	Investigational
Identifiers
IUPAC name[show]
CAS Number	439239-90-4
PubChem CID	11610526
IUPHAR/BPS	3928
ChemSpider	9785281
UNII	760I9WM792
KEGG	D10338
Chemical and physical data
Formula	C19H18F3N3O2
Molar mass	377.36 g/mol
3D model (JSmol)	Interactive image

/////////////LASMIDITAN, phase III, LILY, COL-144 , LY-573144, CoLucid Pharmaceuticals, PHASE 3, MIGRAINE

CN1CCC(CC1)C(=O)C2=NC(=CC=C2)NC(=O)C3=C(C=C(C=C3F)F)F.CN1CCC(CC1)C(=O)C2=NC(=CC=C2)NC(=O)C3=C(C=C(C=C3F)F)F.C(CC(=O)O)C(=O)O