OA13115A - Beta-carbolines useful for treating inflammatory disease. - Google Patents

Info

Publication number

OA13115A

OA13115A OA1200500279A OA1200500279A OA13115A OA 13115 A OA13115 A OA 13115A OA 1200500279 A OA1200500279 A OA 1200500279A OA 1200500279 A OA1200500279 A OA 1200500279A OA 13115 A OA13115 A OA 13115A

Authority

OA

OAPI

Prior art keywords

hydrogen

aliphatic

halo

ring

amino

Prior art date

2003-04-09

Links

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• 208000027866 inflammatory disease Diseases 0.000 title claims abstract description 11
• AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title abstract description 16
• 150000001875 compounds Chemical class 0.000 claims abstract description 171
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 40
• 201000010099 disease Diseases 0.000 claims abstract description 28
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
• 201000011510 cancer Diseases 0.000 claims abstract description 13
• 239000003112 inhibitor Substances 0.000 claims abstract description 8
• 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 7
• 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 6
• 125000004076 pyridyl group Chemical group 0.000 claims abstract description 6
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 5
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 5
• 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 5
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 5
• 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 4
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims abstract description 4
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims abstract description 4
• 230000001404 mediated effect Effects 0.000 claims abstract description 3
• 125000001931 aliphatic group Chemical group 0.000 claims description 151
• 239000001257 hydrogen Substances 0.000 claims description 143
• 229910052739 hydrogen Inorganic materials 0.000 claims description 143
• -1 piperazinyl,pyrrolidinyl Chemical group 0.000 claims description 110
• 201000006417 multiple sclerosis Diseases 0.000 claims description 88
• 125000005843 halogen group Chemical group 0.000 claims description 82
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 71
• 150000002431 hydrogen Chemical group 0.000 claims description 69
• 125000000623 heterocyclic group Chemical group 0.000 claims description 67
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 61
• 229910052757 nitrogen Inorganic materials 0.000 claims description 57
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 40
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 39
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
• 125000001072 heteroaryl group Chemical group 0.000 claims description 35
• 125000003118 aryl group Chemical group 0.000 claims description 32
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
• 125000003545 alkoxy group Chemical group 0.000 claims description 26
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 22
• 125000004043 oxo group Chemical group O=* 0.000 claims description 20
• 239000008194 pharmaceutical composition Substances 0.000 claims description 20
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
• 125000000217 alkyl group Chemical group 0.000 claims description 17
• 125000002947 alkylene group Chemical group 0.000 claims description 15
• 229910052799 carbon Inorganic materials 0.000 claims description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 13
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 13
• 229910052717 sulfur Inorganic materials 0.000 claims description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
• 239000011593 sulfur Substances 0.000 claims description 10
• 210000000988 bone and bone Anatomy 0.000 claims description 9
• 125000006239 protecting group Chemical group 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 7
• 125000001188 haloalkyl group Chemical group 0.000 claims description 7
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 6
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
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• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
• 201000004681 Psoriasis Diseases 0.000 claims description 4
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
• 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 4
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
• 208000034578 Multiple myelomas Diseases 0.000 claims description 3
• 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 3
• 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 3
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 3
• 230000000010 osteolytic effect Effects 0.000 claims description 3
• 206010060862 Prostate cancer Diseases 0.000 claims description 2
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
• 125000003275 alpha amino acid group Chemical group 0.000 claims 3
• 208000014829 head and neck neoplasm Diseases 0.000 claims 2
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
• SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 1
• 201000005202 lung cancer Diseases 0.000 claims 1
• 208000020816 lung neoplasm Diseases 0.000 claims 1
• 208000026037 malignant tumor of neck Diseases 0.000 claims 1
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 1
• 125000000719 pyrrolidinyl group Chemical group 0.000 abstract description 6
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 199
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 147
• 238000000034 method Methods 0.000 description 129
• 239000000243 solution Substances 0.000 description 128
• 239000007787 solid Substances 0.000 description 117
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 110
• 239000000203 mixture Substances 0.000 description 99
• 239000000543 intermediate Substances 0.000 description 98
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 97
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• 229910001868 water Inorganic materials 0.000 description 86
• 238000005160 1H NMR spectroscopy Methods 0.000 description 82
• 239000005695 Ammonium acetate Substances 0.000 description 78
• 235000019257 ammonium acetate Nutrition 0.000 description 78
• 229940043376 ammonium acetate Drugs 0.000 description 78
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 77
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 65
• 235000019439 ethyl acetate Nutrition 0.000 description 63
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
• 238000005481 NMR spectroscopy Methods 0.000 description 53
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
• 239000011541 reaction mixture Substances 0.000 description 42
• 238000006243 chemical reaction Methods 0.000 description 39
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
• 210000004027 cell Anatomy 0.000 description 38
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 37
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
• 239000012267 brine Substances 0.000 description 34
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 32
• 238000003756 stirring Methods 0.000 description 32
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• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
• 239000010410 layer Substances 0.000 description 28
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 27
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 26
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• 235000019253 formic acid Nutrition 0.000 description 22
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 21
• 229940093499 ethyl acetate Drugs 0.000 description 21
• 108091000080 Phosphotransferase Proteins 0.000 description 20
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• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• 229910000027 potassium carbonate Inorganic materials 0.000 description 16
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 15
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• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 10
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