Novel Process and Formulations

• US 20080268044A1
• Filed: 11/15/2006
• Published: 10/30/2008
• Est. Priority Date: 11/15/2005
• Status: Abandoned Application

• Current Assignee: Glaxo Group Limited (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Kasparec, Jiri, Spoors, Paul G., Taggart, John J., Blatcher, Philip, Diederich, Ann M., Appleby, John Robert George, Lloyd, Richard S., Abu Khalil, As'ad, Vernon, Lois E., Humphries, Lesley Anne
• Application Number:
  US12/093,191
• Publication Number:
  US 20080268044A1
• Time in Patent Office: Days
• US Class Current: 424/464
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 35/00 Antineoplastic agents
• 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
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides for a novel process of making 6-carboxylic acid derivatives of pyrido[2,3-d]pyrimidin-7-one'"'"'s, as well as a novel process for making 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}pyrido[2,3-d]pyrimidin-7(8H)-one, and salts thereof.

Claims

1. A sustained-release pharmaceutical composition comprising a water-soluble salt of 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, and a sustained release formulation.

2. The sustained release composition according to claim 1 wherein the salt is the tosylate salt.

3. The sustained release composition according to claim 1 wherein substantially all of the active agent is released from the formulation from about 2 to about 24 hours after administration to a patient.

4. The sustained release composition according to claim 1 which has an in vitro dissolution profile as determined by the basket apparatus of the USP (USP I, Chapter <

711>

) in which about 40 to about 60% of the active agent is dissolved after 3 hours.

5. The sustained release composition according to claim 1 which has an in vitro dissolution profile as shown in Examples 2 and 3 in FIG. 1;

as shown in Examples 2, 3 and 4 in FIG. 2;

or as shown in Examples 5 and 6 in FIG. 4.

6. The sustained release composition according to claim 1 which has an in vivo plasma concentration/time profile wherein the Area Under the Curve value is between 80% and 125% for each of Example 1 to 6 as depicted in FIG.

7-17. -17. (canceled)

18. An orally deliverable immediate release tablet comprising 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate in the form of a tablet.

19. The tablet according to claim 18 wherein the compound is present in an amount of 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg per tablet.

20. An orally deliverable tablet comprising a water-soluble salt of 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one dispersed in a matrix comprising a hydrophilic polymer in the form of a tablet.

21. The tablet according to claim 20 wherein the water soluble salt is a tosylate salt.

22. The tablet according to claim 20 wherein the hydrophilic polymer is selected from at least one member of the group consisting of hydroxypropyl methylcellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose.

23-24. -24. (canceled)

27. The compound 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate.

28. A pharmaceutical composition comprising the compound according to claim 27 and a pharmaceutically acceptable carrier or diluent.

29. The pharmaceutical composition according to claim 28 wherein the composition is in a unit dosage form for oral administration selected from a tablet, capsule, sachet, soft gel capsule, suspension, solution;

or is a composition for topical administration selected from a liquid, gel, cream, suspension, or suppository;

or is a composition for injection selected from an injectable gel, an intravenous, an intraocular, or intramuscular injectable.

30. A method of treatment, including prophylaxis, of a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by the activity of the p38 kinase comprising administering an effective amount of a compound or composition according to claim 27 to a mammal in need thereof.

31. The method according to claim 30 wherein the condition or disease state is rheumatoid arthritis, acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease, atherosclerosis, neuropathic pain, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and multiple myeloma.

32. A composition according comprising a compound according to claim 27 and a second therapeutic agent.

33. The composition according to claim 32 wherein the second therapeutic agent is a disease modifying antirheumatic drug selected from abatacept, entanercept, infliximab, adalimumab, methotrexate, hydroxychloroquine, sulfasalazi, leflunomide, Anakinra, rituximab, a corticosteroid, an NSAID, a COX-2 inhibitors, or a nonacetylated salicylates.

49. A process for producing a compound of Formula (III)

50. The process according to claim 49 wherein the thioacids derivative is thioacetic acid, thiobenzoic acid, thioproprionic acid, sodium thioacetate, potassium thioacetate, lithium thioacetate, cesium thioacetate, or magnesium thioacetate.

51. The process according to claim 50 wherein the thioacids derivative is thioacetic acid.

52. The process according to claim 49 which further comprises an organic solvent, optionally in combination with water.

53. The process according to claim 52 wherein the solvent is selected from THF, toluene, DMF, n-methylpyrrolidine, methylene chloride, ethyl acetate, 2-methyl-THF, dioxane, DIPEA, pyridine, or acetonitrile.

54. The process according to claim 49 wherein the reaction is conducted at about 20 to about 50°

C.

34. A compound of the formula:

35. The compound according to claim 34 wherein R_1′

is independently selected from halogen, or C_1-4alkyl.

48. The compound according to claim 34 which is

4-(4-fluoro-2-methylphenyl)-2-(methylthio)-7-oxo-8-(2,6-difluorophenyl)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid;

4-(2,4-difluorophenyl)-2-(methylthio)-7-oxo-8-(2,4,6-trifluorophenyl)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid; and

8-(2,6-difluorophenyl)-4-(2-methyl-5-(methoxycarbonyl)phenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid.

55. A process for producing a compound of Formula (II) according to claim 34 which comprises reacting a compound of Formula (IV)

56. The process according to claim 55 wherein the condensation agent is meldrum'"'"'s acid.

57. The process according to claim 55 wherein the base is cesium hydroxide, cesium carbonate, sodium acetate, 2,4,6-collidine, DIPEA, DBN, dihexylamine, diethylamine, 2,6-dimethylpiperidine, di-secbutylamine, isopropylamine, isoquinoline, 2,6,-lutidine, N-methylpiperidine, pyridine, pyrrolidine, or triethylamine.

59. The process according to claim 55 wherein the organic solvent is selected from THF, toluene, DMF, n-methylpyrrolidine, methylene chloride, ethyl acetate, 2-methyl-THF, dioxane, or acetonitrile.

74. The process according to claim 55 wherein the compound of Formula (II) is decarboxylated in situ to yield a compound of Formula (III).

75. The process according to claim 55 wherein the compound of Formula (IV) is

4-(4-fluoro-2-methylphenyl)-2-(methylthio)-7-oxo-8-(2,6-difluorophenyl)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid;

4-(2,4-difluorophenyl)-2-(methylthio)-7-oxo-8-(2,4,6-trifluorophenyl)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid;

or

8-(2,6-difluorophenyl)-4-(2-methyl-5-(methoxycarbonyl)phenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid.

76. The process according to claim 74 wherein the compound of Formula (III) is

8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(methylthio)pyrido[2,3-D]pyrimidin-7(8H)-one;

or

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl benzoic methyl ester;

or

4-(2,4-Difluorophenyl)-8-(2,4,6-trifluorophenyl)-2-(methylthio)pyrido[2,3-D]pyrimidin-7(8H)-one.

36-47. -47. (canceled)

58. (canceled)

60-73. -73. (canceled)

77-78. -78. (canceled)

79. A polymorphic form, Form 1, of 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate substantially as shown in at least one of the X-ray diffraction pattern of FIG. 5, the differential scanning calorimetry thermogram of FIG. 9, and the infrared spectrum of FIG. 13 (a) and/or 13(b).

83. The polymorphic form, Form 1 according to claim 79 which is of substantially pure crystalline form.

84. A composition comprising a polymorphic form, Form 1 according to claim 79 wherein at least 30% by weight of total 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate in said composition is present as said polymorphic form.

85. The composition according to claim 84 wherein at least 50% by weight of polymorphic form, Form 1 is present.

86. The composition according to claim 84 wherein at least 70% by weight of polymorphic form, Form 1 is present.

87. The composition according to claim 84 wherein at least 90% by weight of polymorph Form 1 is present.

88. A pharmaceutical composition comprising a polymorphic form, Form 1 of 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)-ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate, according to claim 79 and a pharmaceutically acceptable excipient or carrier.

89. A process for the preparation of a polymorphic form, Form 1 according to claim 79 comprising

a) dissolving 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate in a solvent which is methylene chloride and a co-solvent and warming if necessary to give a solution;

b) cooling the solution of step (a), optionally in an ice bath or optionally seed the solution with 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one tosylate polymorphic form, Form 1 to yield crystalline polymorphic form, Form 1.

90. The process according to claim 89 wherein the Form 1 produced in pure or substantially pure.

91. A process for the preparation of a polymorph according to claim 79 comprising suspending the tosylate in a solvent which is chloroform or a chloroform so-solvent mixture and then cooled for formation of polymorphic form, Form 1.

92. The process according to claim 91 wherein the co-solvent is methanol or ethanol.

93. The process according to claim 91 wherein the solvent is chloroform.

80. A polymorphic form, Form 1, of 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate wherein said polymorphic form is characterized by an x-ray diffraction pattern comprising peaks expressed in terms of 2 theta angles, wherein

i) said x-ray diffraction pattern comprises a peak at 8.2+/−

0.1°

;

or

ii) said x-ray diffraction pattern comprises peaks at 7.5 and 8.2+/−

0.1°

;

or

iii) said x-ray diffraction pattern comprises peaks at 7.5, 8.2, and 9.9+/−

0.1°

;

or

iv) said x-ray diffraction pattern comprises peaks at 7.5, 8.2, 9.9, and 13.0+/−

0.1°

;

or

v) said x-ray diffraction pattern comprises peaks at 7.5, 8.2, 9.9, 13.0, and 16.3+/−

0.1°

;

or

vi) said x-ray diffraction pattern comprises peaks at 7.5, 8.2, 9.9, 13.0, 16.3, 19.8, and 21.1+/−

0.1°

;

or

vii) said x-ray diffraction pattern comprises peaks at 7.5, 8.2, 9.9, 13.0, 16.3, 19.8, 21.1 and 21.8+/−

0.1°

.

81. A polymorphic form, Form 1 of 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate having a powder X-ray diffraction pattern comprising a characteristic peak, in terms of 2θ

at about 7.5+/−

0.1° and

8.2+/−

0.1° and

at least 3 additional characteristic peaks in terms of 2θ

, selected from 9.9+/−

0.1°

, 13.0+/−

0.1°

, 16.3+/−

0.1°

, 19.8+/−

0.1°

, 21.1+/−

0.1° and

21.8+/−

0.1°

.

82. A polymorphic form, Form 1 of 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate wherein said polymorphic form is characterized by an infrared spectrum comprising one or more characteristic peaks selected from about 3442, 3219, 3072, 2935, 1697, 1654, 1619, 1558, 1501, 1479, 1454, 1382, 1360, 1341, 1314, 1282, 1247, 1150, 1119, 1107, 1076, 1062, 1030, 1011, 1005, 983, 947, 913, 876, 838, 820, 798 and 709 cm⁻

1, and having a melt onset as calculated by DSC of about 230°

C.

94-99. -99. (canceled)

100. A polymorphic form, Form 4, of 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate substantially as shown in the X-ray diffraction pattern of FIG. 8, or differential scanning calorimetry thermogram of FIG. 12, or the infrared spectrum of FIG. 16(a) and/or 16(b).

101-116. -116. (canceled)

117. The compound 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, tosylate in amorphous form.

118. A pharmaceutical composition comprising the amorphous compound according to claim 117 and a pharmaceutically acceptable carrier or diluent.