CRYSTALLINE L-ARGININE SALT OF (R)-2-(7-(4-CYCLOPENTYL-3- (TRIFLUOROMETHYL)BENZYLOXY)-1,2,3, 4-TETRAHYDROCYCLO-PENTA [B]INDOL-3-YL)ACETIC ACID(COMPOUND1) FOR USE IN SIPI RECEPTOR-ASSOCIATED DISORDERS

• US 20190330153A1
• Filed: 04/09/2019
• Published: 10/31/2019
• Est. Priority Date: 06/22/2015
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Blackburn, Anthony C., Castro, Ryan O., Hadd, Mark Allen, Ma, You-An, Montalban, Antonio Garrido, Rueter, Jaimie Karyn, Selvey, Lee Alani, Shakya, Sagar Raj, Carlos, Marlon
• Granted Patent: US 10,676,435 B2
• Time in Patent Office: Days
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 279/12 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 279/14 : being further substituted by carboxyl groups
• CPC Class Codes: C07D 209/94 : containing carbocyclic rings other than six-membered

Abstract

The present invention relates to, inter alia, a novel crystalline free-plate habit or morphology, processes for preparing the crystalline free-plate habit, and uses of the crystalline free-plate habit of the L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid (Compound 1) in the treatment of S1P₁ receptor-associated disorders, for example, diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), cancer, and conditions characterized by an underlying defect in the vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g., as may occur in inflammation, tumor development, and atherosclerosis).

Claims

1. A method for treating an S1P₁ receptor-associated disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;

wherein said crystalline free-plate habit has a BET specific surface area of about 0.1 m²/g to about 5.0 m²/g.

2. The method according to claim 1, wherein the crystalline free-plate habit has a BET specific surface area of about 0.6 m²/g to about 4.0 m²/g.

3. A method according to claim 1, wherein the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ

, at 8.2°

±

0.2°

, 16.4°

±

0.2θ

, and 20.5°

±

0.2°

.

4. The method according to claim 1, wherein the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ

, at 8.2°

±

0.2°

, 16.4°

±

0.2°

, 20.5°

±

0.2°

, and 24.6°

±

0.2°

.

5. The method according to claim 1, wherein the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ

, at 8.2°

±

0.2°

, 16.4°

±

0.2°

, 20.5°

±

0.2°

, 24.6°

±

0.2°

, 28.8°

±

0.2°

, and 37.3°

±

0.2°

.

6. The method according to claim 1, wherein the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.0°

C. to 208.5°

C. at a scan rate of 10°

C./minute.

7. The method according to claim 1, wherein the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5°

C. to 208.1°

C. at a scan rate of 10°

C./minute.

8. The method according to claim 1, wherein the crystalline free-plate habit has a differential scanning calorimetry trace conducted at a scan rate of 10°

C./minute comprising an endotherm substantially as depicted in any one of FIGS. 6 to 10 and FIGS. 22 to 25.

9. The method according to claim 1, wherein the crystalline free-plate habit has a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein said crystalline free-plate habit gains about 0.3% weight or less at 90% RH.

10. The method according to claim 1, wherein the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ

, at 8.2°

±

0.2°

, 16.4°

±

0.2°

, 20.5°

±

0.20, and 24.6°

±

0.2°

;

2) a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5°

C. to t 208.5°

C. at a scan rate of 10°

C./minute;

3) a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein said crystalline free-plate habit gains about 0.3% weight or less at 90% RH; and

/or

4) a BET specific surface area of about 0.6 m²/g to about 4.0 m²/g.

11. The method according to claim 1, wherein the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ

, at 8.2°

±

0.2°

, 16.4°

±

0.2°

, 20.5°

±

0.2°

, 24.6°

±

0.2°

, 28.8°

±

0.20, and 37.3°

±

0.2°

;

2) a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5°

C. to 208.1°

C. at a scan rate of 10°

C./minute;

3) a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein said crystalline free-plate habit gains about 0.2% weight or less at 90% RH; and

/or

4) a BET specific surface area of about 0.6 m²/g to about 4.0 m²/g.

64. The method accordingly to claim 1, wherein said disorder is selected from the group consisting of:

a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, and a microbial or viral infection or disease.

65. The method accordingly to claim 1, wherein said disorder is a disease or disorder mediated by lymphocytes.

66. The method accordingly to claim 1, wherein said disorder is an autoimmune disease or disorder.

67. The method accordingly to claim 1, wherein said disorder is an inflammatory disease or disorder.

68. The method accordingly to claim 1, wherein said disorder is a microbial or viral infection or disease.

69. The method accordingly to claim 1, wherein said disorder is selected from the group consisting of:

biliary cirrhosis, primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, tissue or solid organ grafts, arthritis, psoriatic arthritis, rheumatoid arthritis, diabetes, type I diabetes and the disorders associated therewith, myasthenia gravis, demyelinating disease, multiple sclerosis, ischemia-reperfusion injury, renal ischemia-reperfusion injury, cardiac ischemia-reperfusion injury, inflammatory skin disease, psoriasis, atopic dermatitis, acne, hyperproliferative skin disease, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, systemic lupus erythematosus, asthma, uveitis, myocarditis, allergy, atherosclerosis, brain inflammation, Alzheimer'"'"'s disease, traumatic brain injury, spinal cord injury, cerebral infarction, pathologic angiogenesis, primary tumor growth, metastatic tumor growth, diabetic retinopathy, cancer, chronic pulmonary disease, acute lung injury, acute respiratory disease syndrome, and sepsis.

70. The method accordingly to claim 1, wherein said disorder is selected from the group consisting of:

biliary cirrhosis, primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, psoriasis, atopic dermatitis, acne, arthritis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, multiple sclerosis, and systemic lupus erythematosus.

71. The method accordingly to claim 1, wherein said disorder is biliary cirrhosis, primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, psoriasis, atopic dermatitis, acne, arthritis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, multiple sclerosis, and systemic lupus erythematosus.

72. The method accordingly to claim 1, wherein said disorder is primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, psoriasis, atopic dermatitis, acne, arthritis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, multiple sclerosis, and systemic lupus erythematosus.

73. The method accordingly to claim 1, wherein said disorder is psoriasis.

74. The method accordingly to claim 1, wherein said disorder is atopic dermatitis.

75. The method accordingly to claim 1, wherein said disorder is arthritis.

76. The method accordingly to claim 1, wherein said disorder is psoriatic arthritis.

77. The method accordingly to claim 1, wherein said disorder is rheumatoid arthritis.

78. The method accordingly to claim 1, wherein said disorder is inflammatory bowel disease.

79. The method accordingly to claim 1, wherein said disorder is Crohn'"'"'s disease.

80. The method accordingly to claim 1, wherein said disorder is ulcerative colitis.

81. The method accordingly to claim 1, wherein said disorder is multiple sclerosis.

82. The method accordingly to claim 1, wherein said disorder is systemic lupus erythematosus.

12-63. -63. (canceled)

83. A method for preparing a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, said method comprising the steps of:

a) heating a first mixture comprising L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, a water-miscible anti-solvent, and water to a first heating temperature to form a second mixture;

b) cooling said second mixture to a first cooling temperature followed by adding a first additional amount of said water-miscible anti-solvent to said second mixture while maintaining said first cooling temperature and thereafter heating to a second heating temperature to form a suspension;

c) cycling Step b) optionally once or twice; and

d) cooling said suspension to a second cooling temperature to form said crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

84. The method according to claim 83, wherein said water-miscible anti-solvent comprises a solvent selected from the group consisting of:

acetonitrile, acetone, tetrahydrofuran, and C₂-C₄ alkanol.

85. The method according to claim 83, wherein said water-miscible anti-solvent comprises 2-propanol.

89. The method according to claim 83, wherein said first heating temperature is about 60°

C. to about 83°

C.

90. The method according to claim 83, wherein after heating to said first heating temperature said second mixture is substantially a homogeneous solution.

91. The method according to claim 83, wherein Step a) is conducted at a stir rate of about 50 rpm to about 250 rpm.

92. The method according to claim 83, wherein said first cooling temperature is about 50°

C. to about 70°

C.

93. The method according to claim 83, wherein said cycling Step b) is conducted once.

94. The method according to claim 83, wherein said cycling Step b) is conducted twice.

95. The method according to claim 83, wherein said second heating temperature is at a temperature to retain said suspension.

96. The method according to claim 83, wherein said second cooling temperature is about 50°

C. to about 70°

C.

97. The method according to claim 83, wherein after cooling to said second cooling temperature, said method further comprises the step of cooling said suspension to a third cooling temperature of about 10°

C. to about 30°

C.

98. The method according to claim 83, wherein said method further comprises the step of isolating said crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

99. The method according to claim 98, wherein said isolating comprises filtering said crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

100. The method according to claim 99, wherein after filtering, said crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a BET specific surface area of about 0.1 m²/g to about 5.0 m²/g.