BRPI0610209A2 - derivados espiro tricìclicos como moduladores de crth2 - Google Patents

Info

Publication number

BRPI0610209A2

BRPI0610209A2 BRPI0610209-3A BRPI0610209A BRPI0610209A2 BR PI0610209 A2 BRPI0610209 A2 BR PI0610209A2 BR PI0610209 A BRPI0610209 A BR PI0610209A BR PI0610209 A2 BRPI0610209 A2 BR PI0610209A2

Authority

BR

Brazil

Prior art keywords

chloro

pyrrolidin

indol

spiro

trioxo

Prior art date

2005-05-24

Links

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• Global Dossier
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• 125000003003 spiro group Chemical group 0.000 title claims abstract description 113
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
• 230000002757 inflammatory effect Effects 0.000 claims abstract description 19
• 208000026935 allergic disease Diseases 0.000 claims abstract description 17
• 201000010099 disease Diseases 0.000 claims abstract description 17
• 230000000694 effects Effects 0.000 claims abstract description 14
• 208000017520 skin disease Diseases 0.000 claims abstract description 13
• 230000002265 prevention Effects 0.000 claims abstract description 8
• 102000009389 Prostaglandin D receptors Human genes 0.000 claims abstract description 5
• 108050000258 Prostaglandin D receptors Proteins 0.000 claims abstract description 5
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 608
• 150000001875 compounds Chemical class 0.000 claims description 265
• -1 aryl C1-6 alkyl Chemical group 0.000 claims description 173
• 238000000034 method Methods 0.000 claims description 167
• 230000008569 process Effects 0.000 claims description 105
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 77
• 125000003118 aryl group Chemical group 0.000 claims description 51
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 48
• 239000002253 acid Substances 0.000 claims description 48
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
• PMUSHWPXVHTZGK-UHFFFAOYSA-N spiro[indole-3,3'-pyrrolidine] Chemical compound C1NCCC21C1=CC=CC=C1N=C2 PMUSHWPXVHTZGK-UHFFFAOYSA-N 0.000 claims description 41
• 125000001072 heteroaryl group Chemical group 0.000 claims description 40
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 39
• 125000000217 alkyl group Chemical group 0.000 claims description 29
• 229910052736 halogen Inorganic materials 0.000 claims description 24
• 239000001257 hydrogen Substances 0.000 claims description 23
• 229910052739 hydrogen Inorganic materials 0.000 claims description 23
• 150000002367 halogens Chemical class 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 19
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 18
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 17
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
• 230000029936 alkylation Effects 0.000 claims description 15
• 238000005804 alkylation reaction Methods 0.000 claims description 15
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
• 208000024376 chronic urticaria Diseases 0.000 claims description 15
• 239000003814 drug Substances 0.000 claims description 15
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 14
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
• 125000003545 alkoxy group Chemical group 0.000 claims description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• 125000000304 alkynyl group Chemical group 0.000 claims description 11
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 10
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 10
• 208000006673 asthma Diseases 0.000 claims description 10
• 150000002431 hydrogen Chemical group 0.000 claims description 10
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• 208000017983 photosensitivity disease Diseases 0.000 claims description 9
• 238000002360 preparation method Methods 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 101100439663 Arabidopsis thaliana CHR7 gene Proteins 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
• 150000001412 amines Chemical class 0.000 claims description 8
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 7
• 125000004442 acylamino group Chemical group 0.000 claims description 7
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
• 201000008937 atopic dermatitis Diseases 0.000 claims description 7
• 229940079593 drug Drugs 0.000 claims description 7
• CKKSEJYXORHSPF-UHFFFAOYSA-N 1'-benzyl-5-chlorospiro[1h-indole-3,3'-pyrrolidine]-2,2',5'-trione Chemical compound C12=CC(Cl)=CC=C2NC(=O)C1(C1=O)CC(=O)N1CC1=CC=CC=C1 CKKSEJYXORHSPF-UHFFFAOYSA-N 0.000 claims description 6
• 201000004624 Dermatitis Diseases 0.000 claims description 6
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• 208000002029 allergic contact dermatitis Diseases 0.000 claims description 6
• 201000005884 exanthem Diseases 0.000 claims description 6
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• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
• 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 5
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 5
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 5
• 208000002205 allergic conjunctivitis Diseases 0.000 claims description 5
• 201000010105 allergic rhinitis Diseases 0.000 claims description 5
• 208000024998 atopic conjunctivitis Diseases 0.000 claims description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
• 230000007062 hydrolysis Effects 0.000 claims description 5
• 238000006460 hydrolysis reaction Methods 0.000 claims description 5
• 201000006417 multiple sclerosis Diseases 0.000 claims description 5
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
• 201000002481 Myositis Diseases 0.000 claims description 4
• 206010051246 Photodermatosis Diseases 0.000 claims description 4
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
• DPSHFWYUACHYPX-UHFFFAOYSA-N spiro[imidazolidine-4,3'-indole] Chemical compound N1CNCC21C1=CC=CC=C1N=C2 DPSHFWYUACHYPX-UHFFFAOYSA-N 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
• 229940124530 sulfonamide Drugs 0.000 claims description 3
• GPISXRRGSWJYSS-UHFFFAOYSA-N 1'-benzyl-5-chlorospiro[1H-indole-3,4'-pyrrolidine]-2,2'-dione Chemical compound C(C1=CC=CC=C1)N1CC2(CC1=O)C(NC1=CC=C(C=C12)Cl)=O GPISXRRGSWJYSS-UHFFFAOYSA-N 0.000 claims description 2
• ZBLQINMHWPBDTQ-UHFFFAOYSA-N 2-[5-chloro-2,2',5'-trioxo-1'-(quinolin-2-ylmethyl)spiro[indole-3,3'-pyrrolidine]-1-yl]acetic acid Chemical compound C12=CC(Cl)=CC=C2N(CC(=O)O)C(=O)C11C(=O)N(CC=2N=C3C=CC=CC3=CC=2)C(=O)C1 ZBLQINMHWPBDTQ-UHFFFAOYSA-N 0.000 claims description 2
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
• CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims description 2
• 206010021247 idiopathic urticaria Diseases 0.000 claims description 2
• 208000027866 inflammatory disease Diseases 0.000 claims description 2
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 2
• 125000005843 halogen group Chemical group 0.000 claims 2
• FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims 2
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
• 125000006516 2-(benzyloxy)ethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
• 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 claims 1
• 206010002198 Anaphylactic reaction Diseases 0.000 claims 1
• BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims 1
• WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims 1
• 208000003455 anaphylaxis Diseases 0.000 claims 1
• 230000009610 hypersensitivity Effects 0.000 claims 1
• 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims 1
• 238000004519 manufacturing process Methods 0.000 claims 1
• 230000002981 neuropathic effect Effects 0.000 claims 1
• 239000000543 intermediate Substances 0.000 description 196
• 238000004949 mass spectrometry Methods 0.000 description 170
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 160
• 229960000583 acetic acid Drugs 0.000 description 124
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 119
• 235000011054 acetic acid Nutrition 0.000 description 115
• 239000007787 solid Substances 0.000 description 99
• 238000004128 high performance liquid chromatography Methods 0.000 description 90
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 64
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
• 239000000203 mixture Substances 0.000 description 57
• 239000002904 solvent Substances 0.000 description 56
• 235000019439 ethyl acetate Nutrition 0.000 description 54
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 52
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 49
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 48
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 47
• 239000000243 solution Substances 0.000 description 47
• JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 46
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 42
• 239000002585 base Substances 0.000 description 29
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• 235000019341 magnesium sulphate Nutrition 0.000 description 29
• 238000003756 stirring Methods 0.000 description 28
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
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• 239000000377 silicon dioxide Substances 0.000 description 25
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
• BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 description 24
• BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 description 24
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 23
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• 150000001649 bromium compounds Chemical class 0.000 description 16
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• 239000011541 reaction mixture Substances 0.000 description 16
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• 125000003342 alkenyl group Chemical group 0.000 description 8
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• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
• 230000000875 corresponding effect Effects 0.000 description 8
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• 208000010247 contact dermatitis Diseases 0.000 description 6
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
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