BR112012002157B1 - Composto de espiro anel contendo nitrogênio, sua composição farmacêutica, seu inibidor de janus quinase, seu agente terapeutico ou preventivo, e seu uso - Google Patents

Info

Publication number

BR112012002157B1

BR112012002157B1 BR112012002157-5A BR112012002157A BR112012002157B1 BR 112012002157 B1 BR112012002157 B1 BR 112012002157B1 BR 112012002157 A BR112012002157 A BR 112012002157A BR 112012002157 B1 BR112012002157 B1 BR 112012002157B1

Authority

BR

Brazil

Prior art keywords

compound

pharmaceutically acceptable

acceptable salt

hydrate

mixture

Prior art date

2009-07-31

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 468
• 239000003795 chemical substances by application Substances 0.000 title claims abstract description 24
• 230000003449 preventive effect Effects 0.000 title claims abstract description 16
• 230000001225 therapeutic effect Effects 0.000 title claims abstract description 16
• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
• 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 14
• 229940122245 Janus kinase inhibitor Drugs 0.000 title claims abstract description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title abstract description 6
• 150000003839 salts Chemical class 0.000 claims abstract description 121
• 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims abstract description 14
• 238000002054 transplantation Methods 0.000 claims abstract description 14
• 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 13
• 208000026935 allergic disease Diseases 0.000 claims abstract description 13
• 208000024908 graft versus host disease Diseases 0.000 claims abstract description 13
• 206010052779 Transplant rejections Diseases 0.000 claims abstract description 12
• 210000000056 organ Anatomy 0.000 claims abstract description 12
• 239000000126 substance Substances 0.000 claims description 142
• 229920006395 saturated elastomer Polymers 0.000 claims description 86
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
• 102000015617 Janus Kinases Human genes 0.000 claims description 13
• 108010024121 Janus Kinases Proteins 0.000 claims description 13
• 125000004432 carbon atom Chemical group C* 0.000 claims description 12
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 12
• 125000001424 substituent group Chemical group 0.000 claims description 12
• 201000004681 Psoriasis Diseases 0.000 claims description 11
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 11
• 125000005843 halogen group Chemical group 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 201000010099 disease Diseases 0.000 claims description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 5
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 5
• 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 5
• 108010019437 Janus Kinase 2 Proteins 0.000 claims description 5
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 5
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
• 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 4
• 206010013774 Dry eye Diseases 0.000 claims description 4
• 108010019421 Janus Kinase 3 Proteins 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 239000001257 hydrogen Substances 0.000 claims description 4
• 229910052739 hydrogen Inorganic materials 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 3
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
• 201000008937 atopic dermatitis Diseases 0.000 claims description 3
• 239000000470 constituent Substances 0.000 claims description 3
• 125000005842 heteroatom Chemical group 0.000 claims description 3
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 125000006413 ring segment Chemical group 0.000 claims description 3
• 229910052717 sulfur Chemical group 0.000 claims description 3
• 125000004434 sulfur atom Chemical group 0.000 claims description 3
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
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• 102000006500 Janus Kinase 3 Human genes 0.000 claims 2
• 229940124384 agent for atopic dermatitis Drugs 0.000 claims 1
• 239000012453 solvate Substances 0.000 abstract description 49
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 376
• 239000000203 mixture Substances 0.000 description 292
• 239000000243 solution Substances 0.000 description 240
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• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 189
• -1 1,1-dimethylbutyl Chemical group 0.000 description 154
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 129
• 230000002829 reductive effect Effects 0.000 description 124
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• 239000002904 solvent Substances 0.000 description 111
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 102
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• 238000006243 chemical reaction Methods 0.000 description 81
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• 239000011541 reaction mixture Substances 0.000 description 58
• 239000011780 sodium chloride Substances 0.000 description 58
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 57
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• 238000002360 preparation method Methods 0.000 description 39
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• 239000010410 layer Substances 0.000 description 36
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• 230000014759 maintenance of location Effects 0.000 description 35
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
• 239000007787 solid Substances 0.000 description 34
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 34
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
• 239000002585 base Substances 0.000 description 31
• 238000000034 method Methods 0.000 description 31
• 239000000725 suspension Substances 0.000 description 31
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
• 239000000706 filtrate Substances 0.000 description 30
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 28
• 235000017557 sodium bicarbonate Nutrition 0.000 description 28
• 230000035484 reaction time Effects 0.000 description 26
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 24
• JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 23
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 23
• 229910000343 potassium bisulfate Inorganic materials 0.000 description 23
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
• 239000002253 acid Substances 0.000 description 22
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 21
• 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 21
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• 230000002401 inhibitory effect Effects 0.000 description 21
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• 150000001412 amines Chemical class 0.000 description 20
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
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• 229910000027 potassium carbonate Inorganic materials 0.000 description 15
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
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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 14
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
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• 125000006239 protecting group Chemical group 0.000 description 13
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• KPQPHSJNRLPASK-UHFFFAOYSA-N 3-but-3-en-2-yl-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound C=CC(C)C1(C(O)=O)CCCN(C(=O)OC(C)(C)C)C1 KPQPHSJNRLPASK-UHFFFAOYSA-N 0.000 description 11
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• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
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• 239000012046 mixed solvent Substances 0.000 description 8
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• BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 6
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