KR20060006031A - 염증 질환 치료에 유용한 베타-카르볼린 - Google Patents

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Publication number

KR20060006031A

KR20060006031A KR1020057019268A KR20057019268A KR20060006031A KR 20060006031 A KR20060006031 A KR 20060006031A KR 1020057019268 A KR1020057019268 A KR 1020057019268A KR 20057019268 A KR20057019268 A KR 20057019268A KR 20060006031 A KR20060006031 A KR 20060006031A

Authority

KR

South Korea

Prior art keywords

aliphatic

hydrogen

halo

ring

carboline

Prior art date

2003-04-09

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

Links

• Espacenet
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• AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical compound N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title claims abstract description 19
• 208000027866 inflammatory disease Diseases 0.000 title claims abstract description 10
• 150000001875 compounds Chemical class 0.000 claims abstract description 195
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 52
• 201000010099 disease Diseases 0.000 claims abstract description 44
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
• 201000011510 cancer Diseases 0.000 claims abstract description 13
• 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 7
• 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 7
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 7
• 125000002757 morpholinyl 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
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims abstract description 5
• 125000004076 pyridyl group Chemical group 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
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims abstract description 5
• 230000001404 mediated effect Effects 0.000 claims abstract description 4
• 125000001931 aliphatic group Chemical group 0.000 claims description 176
• 238000000034 method Methods 0.000 claims description 158
• 229910052739 hydrogen Inorganic materials 0.000 claims description 156
• 239000001257 hydrogen Substances 0.000 claims description 149
• -1 hydroxy, amino Chemical group 0.000 claims description 129
• 201000006417 multiple sclerosis Diseases 0.000 claims description 90
• 125000005843 halogen group Chemical group 0.000 claims description 82
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 77
• 150000002431 hydrogen Chemical class 0.000 claims description 71
• 229910052757 nitrogen Inorganic materials 0.000 claims description 63
• 125000000623 heterocyclic group Chemical group 0.000 claims description 56
• 125000001072 heteroaryl group Chemical group 0.000 claims description 53
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 39
• 125000003545 alkoxy group Chemical group 0.000 claims description 38
• 125000003118 aryl group Chemical group 0.000 claims description 37
• 150000003839 salts Chemical class 0.000 claims description 33
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 32
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 30
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 27
• 125000000217 alkyl group Chemical group 0.000 claims description 24
• 229910052799 carbon Inorganic materials 0.000 claims description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims description 21
• 125000004043 oxo group Chemical group O=* 0.000 claims description 20
• 238000011282 treatment Methods 0.000 claims description 17
• 125000005842 heteroatom Chemical group 0.000 claims description 15
• 125000001424 substituent group Chemical group 0.000 claims description 13
• 229910052717 sulfur Inorganic materials 0.000 claims description 13
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 12
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
• 125000004122 cyclic group Chemical group 0.000 claims description 10
• 239000003937 drug carrier Substances 0.000 claims description 10
• 230000002401 inhibitory effect Effects 0.000 claims description 10
• 125000006239 protecting group Chemical group 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 239000011593 sulfur Substances 0.000 claims description 9
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
• 206010025323 Lymphomas Diseases 0.000 claims description 5
• 208000006673 asthma Diseases 0.000 claims description 5
• 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 5
• 208000006545 Chronic Obstructive Pulmonary 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
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 4
• 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 3
• 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 3
• 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 3
• 206010027476 Metastases Diseases 0.000 claims description 2
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
• 206010060862 Prostate cancer Diseases 0.000 claims description 2
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
• KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 2
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
• 230000009401 metastasis Effects 0.000 claims description 2
• 230000000010 osteolytic effect Effects 0.000 claims description 2
• 201000002528 pancreatic cancer Diseases 0.000 claims description 2
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 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
• 125000003341 7 membered heterocyclic group Chemical group 0.000 claims 1
• 206010058467 Lung neoplasm malignant Diseases 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
• 150000003464 sulfur compounds Chemical class 0.000 claims 1
• 229940122296 IKK2 inhibitor Drugs 0.000 abstract 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 219
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 163
• 239000000243 solution Substances 0.000 description 143
• 239000007787 solid Substances 0.000 description 134
• 238000005160 1H NMR spectroscopy Methods 0.000 description 131
• 239000000203 mixture Substances 0.000 description 105
• 239000000543 intermediate Substances 0.000 description 103
• 230000014759 maintenance of location Effects 0.000 description 82
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 79
• 239000005695 Ammonium acetate Substances 0.000 description 78
• 235000019257 ammonium acetate Nutrition 0.000 description 78
• 229940043376 ammonium acetate Drugs 0.000 description 78
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 70
• 235000019439 ethyl acetate Nutrition 0.000 description 70
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
• 239000011541 reaction mixture Substances 0.000 description 57
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
• VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 53
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 51
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 46
• 238000006243 chemical reaction Methods 0.000 description 44
• HHZQETZZACUFHE-UHFFFAOYSA-N 6-chloro-9h-pyrido[3,4-b]indol-8-amine Chemical compound C12=CC=NC=C2NC2=C1C=C(Cl)C=C2N HHZQETZZACUFHE-UHFFFAOYSA-N 0.000 description 40
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 39
• 239000012267 brine Substances 0.000 description 38
• 210000004027 cell Anatomy 0.000 description 38
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 38
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 35
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
• 239000000047 product Substances 0.000 description 34
• 238000001914 filtration Methods 0.000 description 32
• 238000010561 standard procedure Methods 0.000 description 32
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
• 239000010410 layer Substances 0.000 description 30
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• 239000012044 organic layer Substances 0.000 description 25
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
• 235000019253 formic acid Nutrition 0.000 description 23
• 239000000725 suspension Substances 0.000 description 23
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 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 22
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
• 239000003921 oil Substances 0.000 description 22
• 235000019198 oils Nutrition 0.000 description 22
• 229920006395 saturated elastomer Polymers 0.000 description 22
• 208000024891 symptom Diseases 0.000 description 21
• 230000002829 reductive effect Effects 0.000 description 20
• 238000003756 stirring Methods 0.000 description 20
• 239000011734 sodium Substances 0.000 description 19
• 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 18
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
• 239000003795 chemical substances by application Substances 0.000 description 17
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
• HNTZKNJGAFJMHQ-UHFFFAOYSA-N 2-methylpyridine-3-carboxylic acid Chemical compound CC1=NC=CC=C1C(O)=O HNTZKNJGAFJMHQ-UHFFFAOYSA-N 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 16
• 102000001284 I-kappa-B kinase Human genes 0.000 description 16
• 108060006678 I-kappa-B kinase Proteins 0.000 description 16
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• 239000002002 slurry Substances 0.000 description 16
• 239000002904 solvent Substances 0.000 description 16
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
• 239000003458 I kappa b kinase inhibitor Substances 0.000 description 14
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 14
• 239000012458 free base Substances 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• 239000000843 powder Substances 0.000 description 14
• 239000002244 precipitate Substances 0.000 description 14
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 13
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 13
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• 150000003840 hydrochlorides Chemical class 0.000 description 13
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• GGFMPVNNFQUOMK-UHFFFAOYSA-N 6-chloro-7-fluoro-8-nitro-9h-pyrido[3,4-b]indole Chemical compound N1C2=CN=CC=C2C2=C1C([N+](=O)[O-])=C(F)C(Cl)=C2 GGFMPVNNFQUOMK-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
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• 238000002360 preparation method Methods 0.000 description 12
• 206010035226 Plasma cell myeloma Diseases 0.000 description 11
• 229910052786 argon Inorganic materials 0.000 description 11
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 11
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
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• 125000001188 haloalkyl group Chemical group 0.000 description 10
• 201000000050 myeloid neoplasm Diseases 0.000 description 10
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• 229910052708 sodium Inorganic materials 0.000 description 10
• DFHOVKRFNRGDMK-INIZCTEOSA-N 2-[(5s)-5-[(6-chloro-9h-pyrido[3,4-b]indol-8-yl)carbamoyl]-2,2-dimethylmorpholin-4-yl]acetic acid Chemical compound C1OC(C)(C)CN(CC(O)=O)[C@@H]1C(=O)NC1=CC(Cl)=CC2=C1NC1=CN=CC=C12 DFHOVKRFNRGDMK-INIZCTEOSA-N 0.000 description 9
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
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• 239000002253 acid Substances 0.000 description 9
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• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• 238000004440 column chromatography Methods 0.000 description 9
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• DFHOVKRFNRGDMK-UHFFFAOYSA-N 2-[5-[(6-chloro-9h-pyrido[3,4-b]indol-8-yl)carbamoyl]-2,2-dimethylmorpholin-4-yl]acetic acid Chemical compound C1OC(C)(C)CN(CC(O)=O)C1C(=O)NC1=CC(Cl)=CC2=C1NC1=CN=CC=C12 DFHOVKRFNRGDMK-UHFFFAOYSA-N 0.000 description 8
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• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
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• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 7
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• MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 6
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• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
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• OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 6
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• HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 6
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