Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to a novel crystalline form of N- (trans-4- isopropylcyclohexylcarbonyl)-D-phenylalanine and a process for preparing the same.
• N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine has therapeutic utility in depressing blood glucose levels in the management of Type 2 diabetes mellitus.
• N-(trans-4-iso ⁇ ropylcyclohexylcarbonyl)-D-phenylalanine is disclosed in Japanese Patent Application No. 63-54321 (equivalent to EP-A-196222 and US 4,816,484).
• the Japanese application describes how the compound may be crystallized from aqueous methanol to yield crystals having a melting point of 129°C to 130° C. These crystals are referred as "B-type". These B-type crystals suffer from problems of instability, especially when subjected to mechanical grinding.
• a novel process for the production of novel crystalline form "C" of N-(trans-4- isopropylcyclohexylcarbonyl)-D-phenylalanine by reacting D-phenylalanine methylester HCl with z.ra '- ⁇ -isopropylcyclohexane carboxylic acid in presence of propane phosphonic acid anhydride or LiOH-Al 2 0 3 in halogenated hydrocarbon solvents such as dichloromethane, dichloroethane at a temperature between -10° C to 90° C followed by base hydrolysis.
• the product can be obtained by reacting trans-4- isopropylcyclohexane carbonyl chloride with D-phenylalanine methylester HCl in halogenated hydrocarbon solvents such as dichloromethane, dichloroethane in presence of base such as triethylamine, pyridine at a temperature between -10°C to 90° C followed by base hydrolysis.
• halogenated hydrocarbon solvents such as dichloromethane, dichloroethane in presence of base such as triethylamine, pyridine
• the new crystal from "C" of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine thus produced have at least one, and preferably all, of the following properties:
• Yet another aspect of the invention includes a N-(trans-4- isopropylcyclohexylcarbonyl)-D-phenylalanine Form C for use in the preparation of a medicament for treating Type 2 diabetes mellitus.
• This invention also includes a pharmaceutical composition comprising a therapeutically effective amount of crystals of Form C N-(trans-4- isopropylcyclohexylcarbonyl)-D-Phenylalanine.
• Another aspect of the invention relates to a method for treating patients suffering from type 2 diabetes mellitus by administering a therapeutically effective amount of the pharmaceutical composition of Form C of N-(trans-4- isopropylcyclohexylcarbonyl)-D-Phenylalanine.
• FIG. 1 shows a powder X-ray diffraction pattern of form C crystals of N-(trans- 4-isopropylcyclohexylcarbonyl)-D-phenylalanine;
• FIG. 2 shows an infra red absorption spectrum of form C crystals of N-(trans-4- isopropylcyclohexylcarbonyl)-D-phenylalanine;
• the water miscible solvent in step (a) is selected from methanol, ethanol, isopropanol, or a mixture of these, preferably methanol.
• the base in step (b) is selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or a mixture of these preferably potassium carbonate.
• the precipitate obtained in step (g) is suspended in water before filtration and drying to get N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine form C.
• N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester is prepared by: reacting D-Phenylalanine methyl ester hydrochloride with trans-4-isopropylcyclohexane carboxylic acid in the halogenated hydrocarbons - filtering the reaction mixture; concentrating to get N-(trans-4-isopropylcyclohexylcarbonyl)-D- phenylalanine methyl ester.
• the first step in the above process for the preparation of N-(trans-4- isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester is carried out in the presence of propane phosphonic acid anhydride, LiOH adsorbed in aluminium oxide or triethylamine.
• An alternate method for producing N-(trans-4- isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester comprises the steps of reacting D-Phenylalanine methyl ester hydrochloride with trans-4- isopropylcyclohexane carbonyl chloride in halogenated hydrocarbon solvents and in the presence of a base, - filtering the reaction mixture; concentrating to get N-(trans-4-isopropylcyclohexylcarbonyl)-D- phenylalanine methyl ester.
• the halogenated hydrocarbon solvents are selected from dichloromethane or dichloroethane.
• the base are selected from triethylamine or pyridine.
• the reaction temperature is -10 ° to 90 ° C.
• N-(frans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester D-Phenylalanine methyl ester hydrochloride (lOg, 0.046 mol) was suspended in a solution of triethylamine (33 mL) in dichloromethane (50 mL); the mixture was cooled to 0-5 °C and trans-4-isopropylcyclohexane carboxylic acid (7.9 g, 0.046 mol) was added to the reaction mixture.
• D-Phenylalanine methyl ester hydrochloride (20g, 0.092 mol) was suspended in a solution of triethylamine (66 mL) in dichloroethane (100 mL) and the mixture was stirred for 1 h at room temperature.
• D-Phenylalanine methyl ester hydrochloride (26g, 0.12 mol) was suspended in a solution of triethylamine (85 mL) in dichloromethane (125 mL) and the mixture was cooled to 0-5 °C.
• a solution of trans-4-isopropylcyclohexane carbonyl chloride (25 g, 0.13 mol) in dichloromethane (75 mL) was added dropwise over a period of 10 minutes, maintaining the temperature at 0-5° C and stirred for 12 hours at ambient temperature.
• the reaction mixture was washed with 1.5 N HCl, 5% sodium bicarbonate solution and brine.
• the organic layer was concentrated to yield 38g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.
• N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine To suspension of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester (38 g, 0.11 mol) in methanol (600 mL), a solution of potassium carbonate (80g, 0.57 mol) in water (400 mL) was added and the reaction mixture was stirred for 12 h at ambient temperature. Water (1500 mL) was added and pH was adjusted to 2.0 by adding 6N HCl. The mixture was extracted using ethyl acetate (3 x 400 mL) and the combined extract was washed with brine.
• the compound showed a sharp melting point of 128 - 129 °C.
• X-ray diffraction pattern and infra red absorption spectrum of the final compound was recorded and identified as form C crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D- phenylalanine.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• Medicinal Chemistry (AREA)
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• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
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• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Engineering & Computer Science (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Epidemiology (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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Cited By (10)

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• 2002
  • 2002-04-29 KR KR10-2004-7015883A patent/KR20040111490A/ko not_active Ceased
  • 2002-04-29 AU AU2002304281A patent/AU2002304281A1/en not_active Abandoned
  • 2002-04-29 JP JP2004501362A patent/JP4137053B2/ja not_active Expired - Fee Related
  • 2002-04-29 HR HR20040920A patent/HRP20040920A2/xx not_active Application Discontinuation
  • 2002-04-29 EP EP02733208A patent/EP1499586A4/en not_active Withdrawn
  • 2002-04-29 SK SK5005-2004A patent/SK287644B6/sk not_active IP Right Cessation
  • 2002-04-29 HU HU0500259A patent/HUP0500259A2/hu unknown
  • 2002-04-29 US US10/508,364 patent/US7314955B2/en not_active Expired - Fee Related
  • 2002-04-29 MX MXNL04000084A patent/MXNL04000084A/es not_active Application Discontinuation
  • 2002-04-29 WO PCT/IN2002/000114 patent/WO2003093222A1/en not_active Ceased
  • 2002-04-29 CZ CZ2004997A patent/CZ2004997A3/cs unknown
  • 2002-04-29 CA CA002481322A patent/CA2481322A1/en not_active Abandoned
• 2004
  • 2004-09-28 IL IL16432704A patent/IL164327A0/xx unknown

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