Isethionate salt of a selective CKD4 inhibitor

• US 7,345,171 B2
• Filed: 07/06/2004
• Issued: 03/18/2008
• Est. Priority Date: 07/11/2003
• Status: Active Grant

• Current Assignee: Warner-Lambert Company LLC (Pfizer Inc.)
• Original Assignee: Warner-Lambert Company LLC (Pfizer Inc.)
• Inventors: Erdman, David Thomas, Beylin, Vladimar G., Blackburn, Anthony Clyde, Toogood, Peter Laurence
• Primary Examiner(s): Berch; Mark L
• Assistant Examiner(s): Jaisle; Cecilia M
• Application Number:
  US10/884,927
• Publication Number:
  US 20050059670A1
• Time in Patent Office: 1,351 Days
• Field of Search: 544/279
• US Class Current: 544/279
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Disclosed are polymorphs of the isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one,

which is a selective cyclin-dependent kinase 4 (CDK4) inhibitor useful for treating inflammation and cell proliferative diseases such as cancer and restenosis.

Claims

1. A method of making a crystalline isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, the method comprising:

combining a solution of isethionic acid and a first solvent with a dispersion of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one and water to produce a first mixture;

freeze-drying the first mixture to give an amorphous salt;

mixing the amorphous salt with a second solvent to produce a second mixture that includes a crystalline isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, the second solvent being the same as or different than the first solvent; and

optionally heating the second mixture, cooling the second mixture, or heating and cooling the second mixture.

3. The method of claims 1 or 2, wherein the first and second solvents are water miscible.

4. The method of claims 1 or 2, wherein the first and second solvents are alcohols.

5. The method of claims 1 or 2, wherein the first and second solvents are MeOH.

6. The method of claims 1 or 2, wherein the first mixture or the second mixture, respectively, is produced by combining approximately equimolar amounts of isethionic acid and 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one.

7. The method of claim 1 or 2, further comprising agitating the second mixture at a temperature ranging from about 30°

C. to about 60°

C.

8. The method of claim 1 or 2, further comprising cooling the second mixture to a temperature at or below about 0°

C.

2. A method of making an isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one comprising:

providing a seed crystal of an isethionate salt form of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

adding the seed crystal to a dispersion of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl -pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one and a first solvent to produce a first mixture;

combining the first mixture with a solution of isethionic acid and a second solvent to produce a second mixture that includes the isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one; and

optionally heating the second mixture, cooling the second mixture, or heating and cooling the second mixture.

9. A method of making an isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one the method comprising:

reacting 4-{6-[6-(1-butoxy-vinyl )-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester with isethionic acid in a first solvent and water to give a mixture that includes a di-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one.

10. The method of claim 9, further comprising adding a hindered base to the reaction mixture to give a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one.