Amorphous form of an akt inhibiting pyrimidinyl-cyclopentane compound, compositions and methods thereof

Patent metadata

Field	Value
Publication number	US-2016152575-A1
Application number	US-201615018636-A
Country	US
Kind code	A1
Filing date	Feb 8, 2016
Priority date	May 17, 2012
Publication date	Jun 2, 2016
Grant date	—

Abstract

Disclosed is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride, forms, formulations, pharmaceutical compositions, processes of manufacturing and methods of use thereof.

First claim

What is claimed is:

1 . A crystalline form of (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride having X-ray diffraction pattern that includes a characteristic peak at about 7.1.

2 . The crystalline form of claim 2 , further comprising one or more characteristic peaks selected from 8.4, 8.8, 10.5, 12.7, 13.7, 13.9, 17.4, 21.1 and 22.3.

3 . A liquid fill capsule comprising (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride and a solvent selected from mono-esters, di-esters, tri-esters and combinations thereof, of fatty acids (C 3-20 alkyl or C 8-18 alkyl) and glycerol, ethylene glycol, propylene glycol or polyethylene glycol.

4 . The capsule of claim 3 , wherein the solvent is selected from glyceryl stearate, esters of natural fatty, stearic and palmitic acids with glycerin, alkylglycol caprylates, propylene glycol monocaprylate, polyethyleneglycol glyceryl laurate, polyethyleneglycol glyceryl oleate, polyethyleneglycol glyceryl linoleate, propylene glycol monolaurate, poloxamer, polyethyleneglycol, propylene glycol, glycerol, d-alpha tocopheryl polyethyleneglycol succinate, polyethyleneglycol caprylic or capric glyceride, and esters of caprylic or capric fatty acids with glycerin or propylene glycol.

5 . The capsule of claim 3 , wherein the solvent is propylene glycol caprylate or propylene glycol monolaurate.

6 . A crystalline composition comprising (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride and solvent selected from the group consisting of capryol glycol, lauryl glycol, MEK, MIBK, MTBK, chloroform, dichloromethane, ethyl acetate, toluene, chlorobenzene, ethylbenzene, THF, 2-methylTHF, 1,2-dichloroethane, ortho-xylene, meta-xylene, para-xylene, anisole, methyl acetate, cumene, tetralin, propyl acetate, isopropyl acetate, diisobutyl ketone, isobutyl acetate, t-butyl acetate, amyl acetate, glycerol triacetate, 1,2-dimethoxyethane, 1,2-diethoxyethane, 2,2-dimethoxypropane, ethyl ether, t-butyl methyl ether, water and mixtures thereof.

7 . The composition of claim 6 , further comprising said solvent solvated to said (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride.

8 . The composition of claim 7 , further comprising said (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride solvated in a 1:1 molar ratio with said solvent.

9 . The composition of claim 7 , further comprising said (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride solvated in a w/w % (solvent:compound) in the range of about 0.1% to about 20%.

10 . Mesomorphous (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride.

11 . A process of producing mesomorphous (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride, comprising contacting (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride with a solvent comprising antisolvent, and removing said solvent.

12 . The process of claim 11 , wherein said solvent has solubility greater than about 20 mg/mL for (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride.

13 . The process of claim 12 , wherein said solvent comprises water, ethyl acetate, methanol, ethanol, isopropanol, 2-butanol, t-butanol and 2-methoxy ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, chloroform, dichloromethane, 1,2-dichloroethane or acetone.

14 . The process of claim 12 , wherein said solvent comprises ethyl acetate.

15 . The process of claim 14 , wherein said solvent comprises ethyl acetate:isopropanol in 1:1 mixture.

16 . The process of claim 11 , wherein said antisolvent has solubility less than about 20 mg/mL for (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride.

17 . The process of claim 16 , wherein said antisolvent comprises pentane, hexane, cyclohexane, heptane, ethyl acetate, iso-propyl acetate, methyl t-butyl ether (MTBE) or methyl iso-butyl ketone.

Assignees

• Genentech Inc

Inventors

• Chakravarty Paroma
• Kothari Sanjeev
• Gosselin Francis
• Savage Scott J
• Stults Jeffrey

Classifications

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/517 Primary

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D239/70 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title