COMPOUNDS THAT MODULATE INTRACELLULAR CALCIUM

• US 20100305200A1
• Filed: 12/10/2008
• Published: 12/02/2010
• Est. Priority Date: 12/12/2007
• Status: Active Grant

• Current Assignee: Calcimedica, Inc.
• Original Assignee: Calcimedica, Inc.
• Inventors: King, Frank, Pei, Yazhong, Stauderman, Kenneth A., Whitten, Jeffrey P., Velicelebi, Gonul
• Granted Patent: US 8,389,567 B2
• Time in Patent Office: Days
• US Class Current: 514/447
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07D 207/456 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
• CPC Class Codes: C07D 213/55 : Acids; Esters
• CPC Class Codes: C07D 213/80 : in position 3
• CPC Class Codes: C07D 231/38 : Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 231/40 : Acylated on said nitrogen atom
• CPC Class Codes: C07D 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/74 : Naphthothiophenes
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases, disorders or conditions that would benefit from inhibition of SOC channel activity.

Claims

1. A compound of Formula (I), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

79. A method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of claim 102 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

81. The method of claim 79, wherein the disease, disorder or condition in a mammal is selected from diseases/disorders involving inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, organ transplant rejection, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma, psoriasis, multiple sclerosis, Sjogren'"'"'s syndrome, and autoimmune diseases or disorders.

82. The method of claim 81 wherein the disease, disorder, or condition is rheumatoid arthritis.

83. The method of claim 81 wherein the disease, disorder, or condition is psoriasis.

84. The method of claim 81 wherein the disease, disorder, or condition is organ transplant rejection.

85. The method of claim 81 wherein the disease, disorder, or condition is multiple sclerosis.

86. The method of claim 81 wherein the disease, disorder, or condition is inflammatory bowel disease.

87. The method of claim 86 wherein the inflammatory bowel disease is ulcerative colitis.

102. The compound of claim 1 having the structure of Formula (VI):

103. The compound of claim 102 wherein X is C₁-C₆alkyl.

104. The compound of claim 103 wherein X is CH₃.

105. The compound of claim 103 wherein X is CH₂CH₃.

106. The compound of claim 102 wherein X is substituted with a substituent selected from F, Cl, Br, I, —

CN, —

NO₂, —

OH, —

CF₃, —

OCF₃, —

OR⁸, C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₁-C₆heteroalkyl.

107. The compound of claim 102 wherein the substituent is selected from F, Cl, Br, and I.

108. The compound of claim 102 having the structure

109. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of claim 102 or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

110. A method of modulating store-operated calcium (SOC) channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of claim 102 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

111. A method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of claim 102 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

113. A method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal comprising administering a compound of claim 102 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

2-78. -78. (canceled)

80. (canceled)

88-101. -101. (canceled)

112. (canceled)

114. (canceled)