TWI324064B - Indolylmaleimide derivatives - Google Patents
Indolylmaleimide derivatives Download PDFInfo
- Publication number
- TWI324064B TWI324064B TW092107388A TW92107388A TWI324064B TW I324064 B TWI324064 B TW I324064B TW 092107388 A TW092107388 A TW 092107388A TW 92107388 A TW92107388 A TW 92107388A TW I324064 B TWI324064 B TW I324064B
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- group
- formula
- hexahydro
- diazaspiro
- Prior art date
Links
- WIQRSJOCVVPMPS-UHFFFAOYSA-N 3-(1h-indol-2-yl)pyrrole-2,5-dione Chemical class O=C1NC(=O)C(C=2NC3=CC=CC=C3C=2)=C1 WIQRSJOCVVPMPS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 84
- -1 4,7-diazaspiro[2.5]octyl-7-yl Chemical group 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 21
- 210000004027 cell Anatomy 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 11
- 230000002757 inflammatory effect Effects 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 7
- 230000002519 immonomodulatory effect Effects 0.000 claims description 7
- 230000001506 immunosuppresive effect Effects 0.000 claims description 7
- 239000003472 antidiabetic agent Substances 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 230000001154 acute effect Effects 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 5
- 229960002930 sirolimus Drugs 0.000 claims description 5
- 229940127003 anti-diabetic drug Drugs 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 3
- 229930105110 Cyclosporin A Natural products 0.000 claims description 3
- 108010036949 Cyclosporine Proteins 0.000 claims description 3
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 229960001265 ciclosporin Drugs 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- 230000000699 topical effect Effects 0.000 claims description 3
- 101150013553 CD40 gene Proteins 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 claims description 2
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 claims description 2
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 claims description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 claims description 2
- 101000914496 Homo sapiens T-cell antigen CD7 Proteins 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- 102100025390 Integrin beta-2 Human genes 0.000 claims description 2
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 claims description 2
- HIEKJRVYXXINKH-ADVKXBNGSA-N N1([C@H]2CC[C@H](C[C@H]2OC)/C=C(\C)[C@H]2OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@]3(O)O[C@@H]([C@H](C[C@H]3C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]2C)=O)CC)C=NN=N1 Chemical compound N1([C@H]2CC[C@H](C[C@H]2OC)/C=C(\C)[C@H]2OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@]3(O)O[C@@H]([C@H](C[C@H]3C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]2C)=O)CC)C=NN=N1 HIEKJRVYXXINKH-ADVKXBNGSA-N 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 claims description 2
- 102100027208 T-cell antigen CD7 Human genes 0.000 claims description 2
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 208000015114 central nervous system disease Diseases 0.000 claims description 2
- 229960000556 fingolimod Drugs 0.000 claims description 2
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 claims description 2
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 claims description 2
- KASDHRXLYQOAKZ-XDSKOBMDSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-XDSKOBMDSA-N 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims 2
- 239000005557 antagonist Substances 0.000 claims 2
- 238000002689 xenotransplantation Methods 0.000 claims 2
- 241000251468 Actinopterygii Species 0.000 claims 1
- 102100027207 CD27 antigen Human genes 0.000 claims 1
- 208000014997 Crohn colitis Diseases 0.000 claims 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 claims 1
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 claims 1
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 claims 1
- 201000004681 Psoriasis Diseases 0.000 claims 1
- 229940123578 Selectin antagonist Drugs 0.000 claims 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 206010003246 arthritis Diseases 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 230000000973 chemotherapeutic effect Effects 0.000 claims 1
- 229940044683 chemotherapy drug Drugs 0.000 claims 1
- 229940124622 immune-modulator drug Drugs 0.000 claims 1
- 230000036039 immunity Effects 0.000 claims 1
- 229940124589 immunosuppressive drug Drugs 0.000 claims 1
- 229910052747 lanthanoid Inorganic materials 0.000 claims 1
- 150000002602 lanthanoids Chemical class 0.000 claims 1
- 150000007965 phenolic acids Chemical class 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 239000002412 selectin antagonist Substances 0.000 claims 1
- 208000024891 symptom Diseases 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 79
- 235000019439 ethyl acetate Nutrition 0.000 description 36
- 238000012360 testing method Methods 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000007858 starting material Substances 0.000 description 15
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000003556 assay Methods 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 102000003923 Protein Kinase C Human genes 0.000 description 8
- 108090000315 Protein Kinase C Proteins 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 206010036790 Productive cough Diseases 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 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
- 230000000694 effects Effects 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 208000024794 sputum Diseases 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241000237858 Gastropoda Species 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 210000003802 sputum Anatomy 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 102000001253 Protein Kinase Human genes 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 3
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- 230000003187 abdominal effect Effects 0.000 description 3
- 230000001028 anti-proliverative effect Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 208000026278 immune system disease Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 3
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 3
- 210000001165 lymph node Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- YSUKTZGLXYSDAI-UHFFFAOYSA-N C1CC12NCCN(C2)C=2NC1=CC=CC=C1C2 Chemical compound C1CC12NCCN(C2)C=2NC1=CC=CC=C1C2 YSUKTZGLXYSDAI-UHFFFAOYSA-N 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 2
- 101150020891 PRKCA gene Proteins 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 108700008625 Reporter Genes Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- 230000029918 bioluminescence Effects 0.000 description 2
- 238000005415 bioluminescence Methods 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical compound [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 102000054766 genetic haplotypes Human genes 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 229960004580 glibenclamide Drugs 0.000 description 2
- 229960000346 gliclazide Drugs 0.000 description 2
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 229940124302 mTOR inhibitor Drugs 0.000 description 2
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052979 sodium sulfide Inorganic materials 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000003971 tillage Methods 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 description 1
- DNTQTNXUBQIWFE-UHFFFAOYSA-N 1-sulfanylpiperazine Chemical compound SN1CCNCC1 DNTQTNXUBQIWFE-UHFFFAOYSA-N 0.000 description 1
- LMJDWRWZTXQWTI-UHFFFAOYSA-N 2,3,3a,4,5,6-hexahydro-1h-indole Chemical compound C1CCC=C2NCCC21 LMJDWRWZTXQWTI-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- HKADVYITENDRTP-UHFFFAOYSA-N 2-[3-(4,7-diazaspiro[2.5]octan-7-yl)naphthalen-1-yl]acetamide Chemical compound C=1C2=CC=CC=C2C(CC(=O)N)=CC=1N(C1)CCNC21CC2 HKADVYITENDRTP-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- CSELKLIMQOUJMY-UHFFFAOYSA-N 4-benzyl-4,7-diazaspiro[2.5]octane Chemical compound C=1C=CC=CC=1CN1CCNCC11CC1 CSELKLIMQOUJMY-UHFFFAOYSA-N 0.000 description 1
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241001674044 Blattodea Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 241000208199 Buxus sempervirens Species 0.000 description 1
- RGLCIANCCCIREW-UHFFFAOYSA-N C(C)(=O)OCC.C(CCC)[Sn](CCCC)CCCC Chemical compound C(C)(=O)OCC.C(CCC)[Sn](CCCC)CCCC RGLCIANCCCIREW-UHFFFAOYSA-N 0.000 description 1
- 238000011749 CBA mouse Methods 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N Cyclohexylamine Natural products NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- 206010052097 Dawn phenomenon Diseases 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 102000036530 EDG receptors Human genes 0.000 description 1
- 108091007263 EDG receptors Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 229940124226 Farnesyltransferase inhibitor Drugs 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 102400000932 Gonadoliberin-1 Human genes 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101500026183 Homo sapiens Gonadoliberin-1 Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101100456320 Homo sapiens NR3C2 gene Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940122199 Insulin secretagogue Drugs 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- 206010022680 Intestinal ischaemia Diseases 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 229940124761 MMP inhibitor Drugs 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- ZYTPOUNUXRBYGW-YUMQZZPRSA-N Met-Met Chemical compound CSCC[C@H]([NH3+])C(=O)N[C@H](C([O-])=O)CCSC ZYTPOUNUXRBYGW-YUMQZZPRSA-N 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 241000257229 Musca <genus> Species 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 101150003511 NR3C2 gene Proteins 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 208000013901 Nephropathies and tubular disease Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 101150010978 PRKCE gene Proteins 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 102000014458 Protein Kinase C-epsilon Human genes 0.000 description 1
- 108010078137 Protein Kinase C-epsilon Proteins 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241001506137 Rapa Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 229940121908 Retinoid X receptor agonist Drugs 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- 101100365570 Schizosaccharomyces pombe (strain 972 / ATCC 24843) sfc3 gene Proteins 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 108010026951 Short-Acting Insulin Proteins 0.000 description 1
- 229940123958 Short-acting insulin Drugs 0.000 description 1
- 238000003324 Six Sigma (6σ) Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical group [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010044541 Traumatic shock Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000007997 Tricine buffer Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- SDUXEUXOJVHRTH-UHFFFAOYSA-L [Sr++].[O-]P([O-])=O Chemical class [Sr++].[O-]P([O-])=O SDUXEUXOJVHRTH-UHFFFAOYSA-L 0.000 description 1
- 210000003815 abdominal wall Anatomy 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-UHFFFAOYSA-N 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229960001445 alitretinoin Drugs 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- WTDVBCFDCDLEPI-UHFFFAOYSA-N aminoazanium;2,2,2-trifluoroacetate Chemical compound [NH3+]N.[O-]C(=O)C(F)(F)F WTDVBCFDCDLEPI-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- ZDQSOHOQTUFQEM-XCXYXIJFSA-N ascomycin Natural products CC[C@H]1C=C(C)C[C@@H](C)C[C@@H](OC)[C@H]2O[C@@](O)([C@@H](C)C[C@H]2OC)C(=O)C(=O)N3CCCC[C@@H]3C(=O)O[C@H]([C@H](C)[C@@H](O)CC1=O)C(=C[C@@H]4CC[C@@H](O)[C@H](C4)OC)C ZDQSOHOQTUFQEM-XCXYXIJFSA-N 0.000 description 1
- ZDQSOHOQTUFQEM-PKUCKEGBSA-N ascomycin Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C\C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-PKUCKEGBSA-N 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229930195545 bengamide Natural products 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000002457 bidirectional effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960003362 carbutamide Drugs 0.000 description 1
- VDTNNGKXZGSZIP-UHFFFAOYSA-N carbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 VDTNNGKXZGSZIP-UHFFFAOYSA-N 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DIOQZVSQGTUSAI-NJFSPNSNSA-N decane Chemical compound CCCCCCCCC[14CH3] DIOQZVSQGTUSAI-NJFSPNSNSA-N 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- LQTKUVQELKGVSF-UHFFFAOYSA-N ethyl 2-(3-hydroxynaphthalen-1-yl)acetate Chemical compound C1=CC=C2C(CC(=O)OCC)=CC(O)=CC2=C1 LQTKUVQELKGVSF-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000002309 gasification Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960003468 gliquidone Drugs 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- DVQVBLBKEXITIK-UHFFFAOYSA-N glybuthiazol Chemical compound S1C(C(C)(C)C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 DVQVBLBKEXITIK-UHFFFAOYSA-N 0.000 description 1
- 229950011569 glybuthiazol Drugs 0.000 description 1
- NFRPNQDSKJJQGV-UHFFFAOYSA-N glyhexamide Chemical compound C=1C=C2CCCC2=CC=1S(=O)(=O)NC(=O)NC1CCCCC1 NFRPNQDSKJJQGV-UHFFFAOYSA-N 0.000 description 1
- 229950008290 glyhexamide Drugs 0.000 description 1
- RHQSNARBXHRBNP-UHFFFAOYSA-N glypinamide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 RHQSNARBXHRBNP-UHFFFAOYSA-N 0.000 description 1
- 229950009188 glypinamide Drugs 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 229960001442 gonadorelin Drugs 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 101150090422 gsk-3 gene Proteins 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- IENZCGNHSIMFJE-UHFFFAOYSA-N indole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2NC=CC2=C1 IENZCGNHSIMFJE-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000002473 insulinotropic effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000010416 ion conductor Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 125000004252 isoindol-1-yl group Chemical group [H]N1C([H])=C2C([H])=C([H])C([H])=C([H])C2=C1* 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 201000010666 keratoconjunctivitis Diseases 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000516 lung damage Toxicity 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- RSHAOIXHUHAZPM-UHFFFAOYSA-N magnesium hydride Chemical compound [MgH2] RSHAOIXHUHAZPM-UHFFFAOYSA-N 0.000 description 1
- 229910012375 magnesium hydride Inorganic materials 0.000 description 1
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Inorganic materials [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 108010085203 methionylmethionine Proteins 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- AFOGBLYPWJJVAL-UHFFFAOYSA-N phenbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=CC=C1 AFOGBLYPWJJVAL-UHFFFAOYSA-N 0.000 description 1
- 229950008557 phenbutamide Drugs 0.000 description 1
- 229940080469 phosphocellulose Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- JLEXUIVKURIPFI-UHFFFAOYSA-N tris phosphate Chemical compound OP(O)(O)=O.OCC(N)(CO)CO JLEXUIVKURIPFI-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Dermatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Neurology (AREA)
- Hematology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Transplantation (AREA)
- Gastroenterology & Hepatology (AREA)
- Ophthalmology & Optometry (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
Description
玖、發明說明: 【發明所屬之技術領域】 晞二醯亞胺衍生物,其製 歸二醯亞胺衍生物,其製 本發明係關於一種吲哚基順丁 法及含彼等之醫藥組合物。 【發明内容】 本叙明係關於一種α引哚基順丁 法及含彼等之醫藥組合物。 更特別地,本發明提供—種式1化合物
其中 I為CH3 ; CH2_CH3或異丙基, 為’鹵素,Cl-6烷氧基或CN6烷基,及以下之 I- R為式(a)之基團
⑻ 其中 R1為六氫吼畊-1-基,其視情況地在3或4位置經ch3取 代;或4,7-二氮螺[2.5]辛-7-基; R2 為 Cl ; Br ; CF3 或 CH3 ;及 R3為 Η ; CH3或 CF3 ;在 R^H,RAH 或 Ch3,rah及
Ri為4-甲基-l-六氫。比畊基時,I不為ch^ci ;或 84363 1324064 II. R為式(b)之基團
n< (b) 其中 R·4為卜六氫吡畊基,其在3及/或4位置經CH3取代;或 4,7 - 一氮螺[2.5]辛-7-基,在R4為4 -曱基六氮〇比π井基 時,Ra不為Η或CH3 ;或 III. R為式(c)之殘基
其中 R〗4為1 -六氫。比啡基,其視情況地在3及/或4位置經cH3 取代,或在3位置經乙基、苯基- Ci·4院基、Ci-4烧氧基 -Cu烧基或鹵素-Cw烧基取代;或4,7-二氮螺[2.5]辛 -7-基;
R15 為鹵素;CF3 或 CH3 ;在 R16 為 CH3,Ra 為 Η或 CH3, Rb為R,4為4-曱基-1-六氫D比畊基時,r15不為ch3 ;及 R16 為 Η ; CH3 ; CH2-CH3 或 CF3 ;在 R15 為 Cl,Ra為 Η或 CH3 ’ Rb為為4 -甲基-1-六氫0比ρ井基時,r|6不為 Η ;或 IV. R為式(d)之基團
(d) 84363 1324064 其中R8為1-六氫吡畊基、3·甲基_六氫吡畊·丨_基或4·芊 基-六氫吡畊-1 _基;或 ν· R為式(e)之基團 ⑼ οά, 其中R9為4,7-二氮螺[2_5]辛·7_基;或六氫吼嗜」-基, /、在3位置經甲基或乙基取代,而且視情況地在*位置 經甲基取代。 式I化合物可以自由形式或以鹽形式存在,例如,有機或 無機酸(例如,氫氯酸、己酸、i氟乙酸)之加成鹽。 應了解式I化合物可以光學異構物、外消旋物或非立體異 構物之形式存在。例如,在六氫。比π井基殘基之3位置帶有取 代基之環碳原子為不對稱且可具有R•或s_組態。應了解本 發明包含所有鏡像異構物及其混合物。鏡像異構物優於外 消紅物。關於呈現所述不對稱碳原子之原料可應 考量。 燒^絲基可為錢或分支。苯基4_4基較佳為宇 土或本乙基。在C"烷氡基_C14烷基中,烷氧基部份較佳為 甲氧基或乙氧基,及烧基部份較佳為甲基或乙基;適宜之 :例為,例如’2-甲氧基乙基。齒素可為「。、份或卜 為F C1或Br。鹵素-ClM烷基為其中一或多個H經鹵素 U^’C1«)mMHCH2C1、CH2MCF3。。 尺較佳為式⑷、(c)或(e) ’較佳為⑷。 在式⑷或⑷之基團[r2或心較佳為各對m"為對 84363 1324064 位。R3較佳為對]^為間位。在式(e)之基團中,Rg較佳為4 7_ 一氬螺[2.5]辛-7-基;在為在3位置經取代之六氫。比„井泉 時’其具有R或S組態。 本發明亦包括一種製備式I化合物之方法’此方法包含式 11化合物 其 與
(II) 式III化合物反應 R-CH2-CO-NH2 (ΠΙ) 其中R如以上所定義, 及在需要之處,將以自由形式得到之所得式〗化合物轉化成 鹽形式或在適當之處反之。 此方法可在強鹼(例如,t_BU0K)存在下方便地進行,例 如’如WQ G2/38561專利所揭示’此揭示在此併人作為參考 ,而且如實例所描述。 式II與III化合物可依照已知方法製冑,例如,如w〇 02/38561專利所揭示’此揭示在此併入作為參考,而且如 實例所描述。 雖然並未特別地敘述原料製造’化合物為已知的,或可 如此技藝已知之方法或如下所述類似地製備。 以下實例為本發明之描述而無任何限制。 84363 丄 THF = FCC = TBAF = BINAP = Pd2(dba)3 = 四氫呋喃 急驟管柱層析術 氟化四丁録 2,2'-貳(二苯膦)-1,1,-聯萘 pd(〇)-貳(二亞苄基丙酮) 【實施方式】 實例1 : 3-[2-氣-3 -甲其s μ田甘 ^ Τ | -5-(4-甲基-六氫吡畊_Ν基)·苯基] -4-(1Η-吲哚·3_基)-吡咯_2,5_二酮 c,0iadr0 〇 將2-[2-氣_3_甲基基_六氫。比0井小基)·苯基]-乙醯 胺(211毫克,0.75毫莫耳)與3-吲哚乙醛酸酯(27〇毫克,i 35 毫莫耳)溶於THF (5毫升)。加入第三Bu〇KkTHF (2 98毫升 4田i )之1 · 0 Μ溶液且混合物在3 5 °C搜拌過夜。將反應以 AcOEt (20毫升)稀釋且以H2〇(2〇毫升)與鹽水(1〇毫升)清洗 。將有機相以NazSCU乾燥且將溶劑蒸發。殘渣藉Fcc純化 (AeOEt/AcOH/H2〇 7: 1: 1)而提供於其乙酸鹽形式之標題 化合物。1H NMR (DMS0, 400 ΜΗζ) δ 2.16 (s,3H),2.3 1 (s,3H), 2-32-2.38 (m, 4H), 2.97-3.10 (m, 4H), 6.61 (d, J=8.0 Hz, 1H), 6-71-6.77 (m> 2H), 7.04 (d, J=2.8 Hz, 1H), 7.08 (dd, J= 7.4, 7.2 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 11.05 (br s, 1H),11.90 (br s,1H) ; ES-MS : 435 [M+H]+。 作為原料之2-[2-氯-3-曱基-5-(4-曱基·六氫吡畊-1-基)-笨基] 84363 -10- 1324064 乙醯胺可如下製備:
將(5 -漠-2-氯-3 -甲基-苯基)-乙酸曱醋(2.0克,7.2毫莫耳)、 N-曱基六氫吡畊(960微升,8.6毫莫耳)與Cs2C〇3 (3 3克, 10.1毫莫耳)懸浮在甲苯(80毫升)中。加入Pd(〇Ac)2(8l毫克 ’ 〇·36毫莫耳)與BINAP (224毫克’ 0·36毫莫耳)且反應在1〇〇 C授拌過夜。使混合物經石夕藻土過渡且將溶劑蒸發。殘、、杳 藉 FCC 純化(AcOEt/AcOH/H2O60: 15: 15)而提供 2-[2_ 氣 3 曱基-5-(4-甲基-六氫吼p井-1-基)-苯基]_乙酸甲酯。將酯懸浮 在25%之NH4〇H (60毫升)中。混合物在rT攪拌過夜且將沉 澱濾出而產生醯胺。4 NMR (DMSO, 400 ΜΗζ) δ 2.20 (s 3H) 2.27 (s, 3H), 2.40-2.45 (m, 4H), 3.07-3.13 (m, 4H), 3.48 (s, 2H), 6.78 (s, 1H), 6.82 (s, 1H), 6.91 (br s, 1H), 7.34 (br s, 1H) 〇
84363 -11 - 1324064 氣-乙基)-苯。將中間物再溶於MeOH(80毫升)且加熱至7〇 C。逐滴加入NaOMe於MeOH之5,4 Μ溶液(28.4毫升)且反應 在70°C攪拌3小時。將反應冷卻至RT且加入濃1128〇4 (1〇毫 升)。反應在回流攪拌1小時。將混合物以HA (2〇〇毫升)稀 釋且以CHAl2萃取(2 X 200毫升)。將組合有機相以Na2S〇4 乾燥且將溶劑蒸發。殘渣藉FCC純化(己烷/CH2Cl2 9 : is i • 1)而^供(5 -漠-2 -氣-3 -曱基-苯基)-乙酸甲g旨。1h nMR (CDC135 400 MHz) δ 2.26 (s, 3H), 3.61 (s, 3H), 3.63 (s, 2H), (s,1H),7.21 (s, 1H)。 依照實例1之步驟但是使用適當之原料,可得到其中R為 如以下表1所示之式(a)殘基之式I化合物。 表1 實例 R丨 r2 R3 Ra Rb M.S.資料 2 -(4-曱基-六氫。比啡-1-基) 2-CH3 3-CH3 ch3 H MH+429 3 -(4-曱基-六氫。比畊-1 -基) 2-CH3 3-CH3 Η H MPT415 4 -(4~曱基-六氫井-1-基) 2-C1 3-CH3 ch3 H MH" 449 5 1-六氫°比畊基 2-C1 3-CH3 Η H MH"42l 6 1-六氫。比畊基 2-C1 3-CH3 ch3 H ΜΪΤ435 7 3-R-曱基-六氫°比畊-1-基 2-C1 3-CH3 ch3 H MHM49 8 3-R-曱基·六氫。比哨*-1-基 2-C1 3-CH3 H H MPf435 9 1-六氫。比17井基 2-C1 3-CF3 ch3 H 1^503 10 1-六氫。比畊基 2-C1 3-CF3 H H MH+489 11 -(4-曱基-六氫σ比Ρ井-1-基) 2-C1 3-CH3 H CH(CH3)2 MH+477 84363 -12- 1324064 12 -(4-甲基-六氫°比°井_1_基) 2-C1 3-CH3 Η ch3 MH+449 13 _(4-曱基-六氫°比啡-1-基) 2-C1 3-CH3 Η CH2-CH3 MH+463 14 -(4-甲基-六氫。比畊-1-基) 2-C1 3-CH3 Η Cl MHM69 15 -(4-甲基-六氫。比畊-1-基) 2-C1 3-CH3 Η F MHM53 16 -(4,7-二氮螺[2.5]辛-7-基) 2-C1 Η Η CH2-CH3 MH"462 17 _(4,7-二氮螺[2.5]辛-7-基) 2-C1 Η Η Cl 細468 18 _(4,7·二氣螺[2·5]辛 基) 2-C1 Η Η ch3 ΜΗ" 447 19 -(4,7-二氮螺[2_5]辛-7-基) 2-C1 Η Η H MET 434 實例 20 3-[3-(4,7-二氮螺[2.5]辛-7-基)-萘-1-基]-4-(1-曱 基-1Η - °弓丨。朵-3 -基)_。比0各-2,5 _二酮
將2-[3-(4,7-二氮螺[2.5]辛-7-基)-萘-卜基]-乙醯胺(1〇〇毫 克’ 0_30毫莫耳)與(1-甲基-1Η-吲哚-3-基)-氧-乙酸甲酯(97 毫克,0.44毫莫耳)與無水THF共沸三次,然後溶於無水THF (3毫升)。在RT經20分鐘逐滴加入KOtBu於THF (1.2毫升)之 1.0 Μ溶液。5分鐘後’ TLC分析顯示原料完全轉化。藉由 添加水(5毫升)以中止反應。將反應以EtO Ac稀釋且以飽和 NH4C1水溶液清洗2次。將水層以EtOAc反萃取2次。將組合 有機層以N a2 S Ο 4乾燥且將溶劑蒸發。殘渣藉f c c純化 (EtO Ac/Ac OH/H2〇 800: 55: 45)而提供標題化合物如其乙 酸鹽。將化合物溶於MeOH/TFA且將溶劑去除產生標題化合 84363 -13- 1324064 物如其三氟乙酸鹽。NMR (DMSO, 400 MHz) δ 0,95 (Μ, 4Η), 3.39 (br, 4Η), 3.49 (br, 2H), 3.86 (s, 3H), 6.16 (d, J=7.9 Hz? 1H), 6.46 (dd, J=6.6/7.9 Hz, 1H;, 7.00 (dd, J = 6.6/7.9 Hz, !Η), 7.13 (dd, J = 7.6/7.6 Hz, 1H), 7.40 (m, 4H), 7.55 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 9.10 (br, 2H), 11.17 (s, 1H) ; ES-MS : 463 [M + H]+ 0 作為原料之2-[3-(4,7-二氮螺[2.5]辛-7-基)-萘-1-基]-乙醯胺 可如下製備:
已)將2-[3-(4-爷基-4,7-二氮螺[2.5]辛-7-基)-奈-1-基]-乙酿 胺(280毫克,0.73毫莫耳)與HC1於MeOH之1.25 Μ溶液共沸2 次。將殘渣溶於EtOH (1 0毫升)。加入鈀於木炭上(1 0%,77 毫克),及在氫大氣(1 atm)下將混合物在RT攪拌14小時及在 5〇°C攪拌2小時。將混合物過濾及將濾液濃縮。殘渣藉FCC 純化(EtOAc/AcOH/H20 75 0 : 83 : 68 至 600 : 150 : 150)而產 生含0.7當量AcOH之標題化合物。1H NMR (DMSO,400 MHz) δ 0.53 (m, 4H), 1.78 (s, AcOH), 2.93 (ddd, 2H), 3.04 (s, 2H), 3.16 (ddd, 2H), 3.76 (s, 2H), 6.94 (br, 1H), 6.99 (s, 1H), 7.25 (dd, 1H), 7.26 (s, 1H), 7.35 (dd, J = 6.7/7.8, 1H), 7.49 (br, 1H), 7.69 (d, J=7.8, 1H), 7.88 (d, J=10.0, 1H); ES-MS : 296 [M + H]+。 b) 2-[3-(4-芊基-4,7-二氮螺[2.5]辛-7-基)_萘-丨-基卜乙醯胺 在氬大氣下將[3-(4-芊基-4,7-二氮螺[2·5]辛-7-基)-萘-1-基] 84363 -14- 1324064 •乙酸乙酯(3 47毫克,0.84毫莫耳)與曱醯胺(126毫克,2.80 毫莫耳)溶於DMF (1毫升)。將溶液加熱至i〇5°c,及在15分 鐘内逐滴加入NaOMe(155微升之於MeOH之5.4M溶液,45 毫克’ 0.84毫莫耳)。在105°C 30分鐘後,TLC分析顯示原料 完全消耗。將反應混合物冷卻至RT,以水稀釋,及以Et〇Ac 萃取。將EtOAc層以水清洗2次。去除溶劑及藉Fcc純化 (EtOAc/MeOH 98: 2 至 96: 4 至 90: 1〇)產生標題化合物。 NMR (CDC13j 400 MHz) δ 0.71 (ddd, 2Η), 0.89 (ddd, 2H), 3.10 (ddd, 2H), 3.16 (s, 2H), 3.31 (ddd, 2H), 3.93 (s, 2H), 3.99 (s, 2H), 5.33 (br, 1H), 5.42 (br, 1H), 7.11 (s, 1H), 7.23 (d, J = 2.0, 1H), 7.32 (m, 5H), 7.37 (dd, J = 6.7 Hz, 1H), 7.45 (dd, J = 6.7 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H) ; ES-MS : 386 [M + H]+。 c) [3-(4-芊基_4,7-二氮螺[2.5]辛-7-基)-萘-1-基]-乙酸乙酯 在氬大氣下將(3-三氟甲磺醯氧基-萘-丨—基卜乙酸乙酯(5〇〇 毫克,1.38毫莫耳)溶於無水THF(10毫升)。加入4-芊基·4,7-二氮螺[2.5]辛烷(325毫克,1.61毫莫耳),繼而加入κ3ρ〇4 (410毫克,1_93毫莫耳)、Pd2(dba)3(62毫克,0.069毫莫耳)
與聯苯-2-基-二第三丁基磷酸酯(21毫克,〇 〇69毫莫耳)。將 反應混合物加熱至80。(:。4小時後,TLC分析顯示原料完全 消耗。將反應混合物冷卻至RT,過濾及濃縮。殘渣藉fCC 純化(己烷/EtOAc 100: 〇至 90: 10至 80: 20 至 70: 30至 〇: 100)提供標題化合物。1H NMR (CDC13,400 ΜΗζ) δ 0.69 (ddd, 2Η), 0.86 (ddd, 2H), 1.24 (t, J=7.0 Hz, 3H), 3.09 (ddd, 84363 -15- 1324064 2H), 3.19 (s, 2H), 3.31 (ddd, 2H), 3.93 (s, 2H), 4.02 (s, 2H), 4.17 (q, J = 7.0 Hz, 2H), 7.08 (s, 1H), 7.21 (s, 1H), 7.33 (m, 6H), 7.42 (dd, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz,1H) ; ES-MS : 415 [M+H]+。 d) (3-二氣甲石黃酿乳基-奈-1-基)-乙酸乙西旨
在氬大氣下將(3-羥基-萘-1-基)-乙酸乙酯(1.67克,7·25毫莫 耳)溶於CH2C12 (20毫升)。加入η比。定(ι·ΐ7毫升,1.15克,14_50 毫莫耳)’及將反應混合物冷卻至〇°C,此時逐滴加入三氟 曱磺酸酐(1.79毫升’ 3.07克,10.88毫莫耳)。將反應混合物 加溫至RT ’及在RT 1小時後,TLC分析顯示原料完全消耗 。將反應混合物以EtOAc稀釋及以h20清洗2次。將組合有 機層以Na2S〇4乾燥,將溶劑去除,及殘渣藉FCC純化(己烷 /EtOAc 100: 0至 97: 3至 95: 5 至 93: 7至 90: 10)產生標題 化合物。1H NMR (DMSO, 400 ΜΗζ) δ 1.19 (t, J = 7.2 Hz,3H), 4.11 (q, J = 7.2 Hz, 2H), 4.38 (s, 2H), 7.60 (d, J = 3.0 Hz, 1H), 7.70 (m, 2H), 8.03 (m5 1H), 8.12 (m, 2H) ; ES-MS: 362 [M + H]+ 〇 e) (3 -起基-秦一I -基)-乙酸乙酿 將(3-苄氧基-萘-1-基)-乙酸乙酯(2·43克,7.58毫莫耳)溶於 MeOH(50毫升)。加入鈀於木炭上(8〇7毫克),在氫大氣(1 atm)下將反應混合物在RT攪拌14小時。將反應混合物過濾 。濃縮產生純標題化合物。4 NMR CDMSO, 400 ΜΗζ) δ 1.18 84363 -16- 1324064 (t, J = 7.2 Hz, 3H), 4.05 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H), 7.04 (d, J=1.8 Hz, 1H), 7.06 (d, J=1.8, 1H), 7.30 (t, J = 7.8, 1H), 7.40 (t, J = 7.8, 1H), 7.70 (d, J = 7.8, 1H), 7.80 (d, J = 7.8 Hz, iH) ; ES-MS : 230 [M + H]+。 f) (3-苄氧基-萘-1-基)-乙酸乙酯 在氬大氣下將3-芊氧基-1-溴-萘(5.64克,18.01毫莫耳)溶於 無水DMF( 100毫升)。加入三丁錫基-乙酸乙酯(7.47克,19.81 毫莫耳),及二氣化[貳(三鄰曱苯膦)]鈀(11)(2.83克,3.60毫 莫耳)與溴化辞(11)(5.27克,23.41毫莫耳)。將反應混合物 加熱至80°C 3小時。將反應混合物以EtOAc稀釋及以稀鹽 水清洗2次(反萃取)。將組合有機層以Na2S04乾燥,將溶劑 去除,及殘邊藉FCC純化(己院/EtOAc 100 : 〇至97.5 : 2.5 至95 : 5至90 : 1 0)。仍含錫殘渣之所得油在EtOAc/1 N NaOH 之1 : 1混合物(200毫升)中攪拌1小時。將混合物以EtOAc 萃取。將組合有機層以H2〇清洗2次(反萃取),以Na2S〇4乾 無及濃縮。殘 >查猎FCC純化(己烧/ EtOAc 1〇〇 : 〇至97 : 3至 95 : 5至93 : 7至92 : 8至90 : 10)產生標題化合物。iHNMR (DMS0,400 MHz) δ 1 · 1 8 (t,J = 7·2 Hz,3Η),4.1 0 (q J = 7 2
Hz, 2H), 4.11 (s, 2H), 5.25 (s, 2H), 7.21 (d, J = 3.〇 Hz, 1H), 7.41 (m, 8H), 7.5j (d, J=6.6 Hz, 1H), 7.84 (dd, J = 7 2 Hz 1H) ;ES-MS : 320 [M + H]+。 g) 3 -爷氧基- l->臭-奈 在氛大氣下將4-漠-萘-2-醇(5·0克’ 22.41毫莫耳)溶於無水 DMF (50毫升)。加入氫化鈉(986毫克之於礦物油中之6〇% 84363 -17- 1324064 懸浮,592毫克,24·65毫莫耳)且將混合物在5(rc攪拌丨小時 。在冷卻至RT後,加入溴化苄基(3 46毫升,4 %克,a·" 毫莫耳)與碘化四丁銨(828毫克,2 Μ毫莫耳)。在rt Μ小 時後,將反應混合物以EtOAc稀釋。將溶液以半濃縮鹽水 清洗2次(反萃取)。將組合有機層以Na2S〇4乾燥,將溶劑去 除,及殘)查精FCC純化(己貌/ Et〇Ac 100 : 0至95 : 5至90 : 10)產生標題化合物。1H NMR (CDC13, 400 ΜΗζ;) δ 522 h 2Η), 7.25 (d, J=1.5 Hz, 1H), 7.45 (m, 7H), 7.64 (d, J = 2.4, 1H), 7.75 (d, J = 7.8, 1H), 8.17 (d, J=7.8, 1H) ; ES-MS : 312 [M + H]+ 〇 依照實例20之步驟,可得到其中r為如表2所示之式(b)殘 基之式I化合物。 表2 實例 R4 Ra M.S.資料 21 3-R-曱基-六氫。比畊-1-基 ch3 MIT 452 22 -(4,7-二氮螺[2.5]辛-7-基) ch3 Μϊί^ 464 23 -(4,7-二氮螺[2.5]辛-7-基) Η MIT 450 24 3-R-曱基-六氫。比畊-1-基 Η ΜΗ+438 25 3-S-曱基-六氫吡畊-1-基 ch3 ΜΗ+452 26 3-S-曱基-六氫吡畊-1-基 Η MET 438 27 4_曱基-3-S-甲基·六氫。比σ井小基 ch3 ΜΗ^ 466 28 4_曱基-S-S-甲基-六氫丼_ι_基 --—-------- Η ΜΗ" 452 84363 -18- 1324064 依照以上或WO 02/38561專利之實例56揭示之步驟但是 使用適當之原料,可得到其中R為如以下表3所示之式(c)殘 基之式I化合物。 表3 實例 Rl4 4位置 之Rl5 5位置 之Rl6 Ra Rb M.S.資料 29 -(4-甲基-六氣。比p井-1-基) Cl ch3 H H MH+ 437 30 -(4-曱基-六氫。比畊-1-基) Br H H H MH+ 469 31 -(4-甲基-六氫吼-井-1-基) Br ch3 H H MH+ 483 32 -(4-曱基-六氫。比畊-1-基) Br H ch3 H MH+ 483 λ η _(4_甲基-六鼠α比ρ井_1_基) cf3 H H H MH+ 457 34 -(4-甲基-六氫。比畊-1-基) cf3 H ch3 H MH+471 35 3-R-甲基-六氫。比畊-1-基 Cl ch3 H H MH+ 437 36 -(4,7-二氮螺 Ρ.5]辛-7-基) Cl ch3 H H MH+ 449 37 1-六氫。比ρ井基 Cl ch3 H H MH+ 423 38 4-曱基-3-R-甲基-六氫吡畊-1-基 Cl ch3 H H MH+451 39 3-R-曱氧基乙基-六氫吼畊-1-基 Cl ch3 H H MH+481 40 3-R-乙基-六氮nitp井-1-基 Cl ch3 H H MH+451 41 3-R-芊基-六氫。比畊-1-基 Cl ch3 H H MH+514 42 3-S-曱基-六氮。比3井-1-基 Cl ch3 H H MH+ 437 43 4-曱基-六氫吡畊-1-基 Cl ch3 H CH2-CH2-CH3 MH+ 479 44 3-CH2F-六氫吡畊-1-基 Cl ch3 H H MH+ 453 45 4-曱基-六氫。比畊-1-基 Cl ch3 H F MH+ 455 46 4-曱基-六氫。比畊-1-基 Cl ch3 H ch(ch3)2 MH+ 479 47 4-曱基-六氫。比畊-1-基 Cl ch3 H Cl MtT 471 48 4-曱基-六氫。比畊-1-基 Cl ch3 H OCH3 MVt 467 49 4-甲基-六氫。tt畊-1-基 Cl ch3 H ch3 MH+451 50 4-曱基-六氫。比畊-1-基 Cl ch3 H CH2-CH3 MH+ 465 84363 -19- 1324064 51 4-曱基-六氫。比畊-1-基 cf3 H H CH2-CH3 MH+ 485 52 4-曱基-六氫。比畊-1-基 cf3 H H ch3 MH+471 53 4-曱基-六氫吡畊-1-基 F H H H MHM07 54 4-曱基-六氫。比哨-1-基 F H H ch3 MH+421 55 4-曱基-六氫。比畊-1-基 F H H CH2-CH3 MH+ 435 56 4-甲基-六氫。比畊-1-基 F CH2-CH3 H ch3 MH+ 449 57 4-甲基-六氫。比畊-1-基 F CH2-CH3 H H MH+ 435 58 4-曱基-六氫。比畊-1-基 F CH2-CH3 H CH2-CH3 MH+ 463 59 4-甲基-六氫吼畊-1-基 F ch3 H H MH+421 60 4-曱基-六氫。比畊-卜基 F ch3 H ch3 MH+ 435 61 4-曱基-六鼠°比喷-1-基 F ch3 H CH2-CH3 MH+ 449 依照以上或WO 02/38561專利之實例163揭示之步驟但是 使用適當之原料,可得到其中R為如以下表4所示之式(d)殘 基之式I化合物。 表4 實例 Rs Ra M.S.資料 62 3-S-曱基-六氫吡畊-1-基 ch3 MH+ 452 63 3-R-曱基-六氫吡畊-1-基 Η MH+ 438 64 3-R-甲基-六氫。比畊-1-基 ch3 MH+ 452 65 4- +基- l-六氮°比0井基 Η MH+ 514 66 4 -卞基-1-六氮吼13井基 ch3 MH+ 528 67 1 -六氫π比畊基 ch3 MH+ 438 68 1 -六鼠吼ρ井基 H MH+ 424 84363 -20- 1324064 [例69 : 3-[3-(4,7-二氮螺[2.5]辛-7-基)-異喳啉·〖_基] -4-(7 -曱基-1H·吲哚-3-基)-吡咯-2,5-二輞
將2-[3-(4,7-一氮螺[2.5]辛-7-基)-異p奎嚇·_1-基]-乙醯胺 (4.95克,16.70毫莫耳)與(7·甲基_1Η-叫卜朵_3_基)_氧_乙酸甲 酯(5.44克’ 25.05毫莫耳)與無水THF共沸兩次。然後加入無 水THF (100毫升),及在氬大氣下在20分鐘内逐滴加入 KOtBu(於THF之1.0 Μ溶液,50毫升,50毫莫耳)。又90分 鐘後,TLC分析顯示原料完全轉化。將反應混合物以η2〇豨 釋及以EtOAc萃取2次。將組合有機層以飽和NH4C1水溶液 清洗2次(反萃取),以Na2S04乾燥及濃縮。藉FCC純化 (CH2Cl2/MeOH 100 : 0至 94 : 6至 98 : 2至 96 : 4至 92 : 8至 90 ·· 10)產生標題化合物,藉EtOH/AcOH溶液濃縮將其轉化成 其乙酸鹽。1H NMR (DMSO, 400 ΜΗζ) δ 0_26-0_53 (br,4H), 1.89 (s, 3H, CH3COOH), 2.36 (s, 3H), 2.80 (br m, 2H), 3.15-3.48 (br m, 2H), 6.14 (d, J = 8.2 Hz, 1H), 6.44 (dd, J = 8.2/7.4 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 7.00 (s, 1H), 7.02 (dd, J = 8.2/8.2 Hz, 1H), 7.40 (dd, J = 8.2/8.2 Hz, 1H), 7.59 (d, J = 8.2 Hz,1H),7.63 (d, J = 8.2 Hz, 1H),7.63 (d,J = 8.2 Hz, 1H), 7.97 (d, J = 2.9 Hz, 1H), 11.04-11.21 (br, 1H), 11.86 (d, J=2.9 Hz,1H) ; ES-MS : 464 [M + H]+。 84363 -21 - 作為原料之2-[3-(4,7-二氮螺[2.5]辛-7-基)-異喳啉-1-基]乙 驢胺可如下製備: ΝΗ a) 將2-[3-(4-字基_4,7_二氮螺[2.5]辛_7•基)·異喹啉小基]_ 乙醯胺(490毫克,!·27毫莫耳)溶於無水^^〇11 (5毫升p加 入Pd於木炭上(14〇毫克)與曱酸銨(2〇〇毫克,317毫莫耳)。 在回流1小時後(T=75°C ),加入又一份曱酸銨(2〇〇毫克,317 毫莫耳)。1小時後,TLC分析顯示原料完全轉化。在過濾及 濃縮後,將殘渣溶於CHWh且以水清洗(加入2 N Na〇H成為 pH 10)。將有機相以NhSO4乾燥且將溶劑去除。藉FCC純 化(EtOAC/AcOH/H20 750 : 83 : 68至 700 : 1 1〇 : 9〇至 65〇 : 1 30: 120至600: 150: 1 50)提供標題化合物如其貳乙酸鹽 。4 NMR (DMS0, 4〇〇 ΜΗζ) δ 〇·46_〇.52 (m,4H),2 88 ⑴ J = 5.5, 2H), 3.35 (s, 2H), 3.49 (t, J = 5.5, 2H), 3.94 (s, 2H), 6.77 (s,1H),7.00 (br s,1H),7.18-7.25 (m,1H),7.45-7.56 (m, 2H), 7.60-7.65 (m, 1H), 7.95 (d, J = 9.9, 1H) 〇 ES-MS : 297 [M + H]+ 〇 b) 2-[3-(4-苄基-4,7-二氮螺[2.5]辛·7_基)_異喹啉_丨_基]_乙 醯胺 在氬大氣下將[3-(4-芊基-4,7-二氮螺[25]辛_7_基)_異喳啉 -1-基]-乙酸乙酯(700毫克,1.68毫莫耳)溶於無水1)1^17。加 入甲醯胺(224微升,254毫克,5‘64毫莫耳),及將反應混合 -22· 84363 1324064 物加熱至105°C。在此溫度在20分鐘内逐滴加入NaOMe (3 12 微升之於MeOH之5.4 Μ溶液,91毫克,1.68毫莫耳)。在105 C 3 0分鐘後,TLC分析顯示原料完全消耗。將反應混合物 冷部至RT ’繼而加入水及以EtOAc萃取。將有機層以η20 清洗(2次)’以NaACU乾燥及濃縮》殘渣藉FCc純化(己烷 /EtOAc 1 : 1至 1 : 3至 0: 1〇〇 至 EtOAc/MeOH 98 : 2)提供標 題化合物。1H NMR(DMSO, 400 ΜΗζ) δ 0.68-0.70 (m,2H), 0.82-0.88 (m, 2H), 3.08 (t, J = 4.4, 2H), 3.45 (s, 2H), 3.58 (t, J = 4.4, 2H), 3.96 (s, 2H), 4.27 (s, 2H), 5.3-5.5 (br, 1H), 6.55-6.7 (br, 1H), 6.72 (s, 1H), 7.26-7.36 (m, 6H), 7.51 (t, J = 8.8, 1H), 7.60 (d, J = 9.9, 1H), 8.02 (d, J = 9.9, 1H) ; ES-MS :387 [M+H]+。 c) [3-(4-苄基-4,7-二氮螺[2·5]辛-7-基)-異p奎淋-i_基]乙酸 乙酯 在氬下混合(3 -氯-異喳啉-1-基)_乙酸乙酯(2.5克,10.01毫莫 耳)、4-苄基-4,7-二氮螺[2.5]辛烷(2.23克,11.01毫莫耳)、 &〇1311(1.06克,11.01毫莫耳)、8以^(249毫克,0_40毫 莫耳)與乙酸Ιε(π)(180毫克’(K80毫莫耳)。在加入脫氣之 無水二噚烷(36毫升)後’將懸浮液加熱至85 °C。在85°C 25
分鐘後’ HPLC分析顯示7 1 %之轉化率。將混合物冷卻至rt ’以EtOAc稀釋’及以仏0與NH4C1飽和水溶液清洗(反萃取) 。將組合有機層以Na2S〇4乾燥’將溶劑去除,及殘渣藉FCC 純化(己烷 /EtO Ac 100: 〇至 96: 4至 93: 7至 90: 10至 85: 15)提供標題化合物。1η NMR (DMSO, 400 ΜΗζ) δ 0.58-0.61 84363 -23- 1324064 (m, 2H), 0.70.0.73 (m, 2H), Ms (t, J = 8 8? 3h)j 2 9g ㈣.5, 2H),3.39 (s,2H),3.49 (t,J = 5 5, 2h),3 別(s,2h), 4-12 (s,2H)5 4.12 (q, 1 = 8.8, 2H), 5.59 (s5lH),7.14.7.19(m5 6H), 7.39(, 1 = 8.8, 1H)S 7.51 (d, ^9.9, !H), 7.78 (d, J = 9.9> 1H),ES-MS : 417 [M + H]+。 d) (3-氣-異p奎琳_1_基)_乙酸乙酯 #1,1,1,3,3,3-^f ; 2〇37^ ^ 1262 毫莫耳)溶於無水甲苯(150毫升)。在冷卻至_听後,在2〇 分鐘内緩慢地加入n_BuLi (79¾升之於己烷中之i6 M溶液 ,126·2毫莫耳)。將白色懸浮液在_78〇(:攪拌15分鐘及在rt 授掉15分鐘,然後得到透明亮黃色溶液。經插管將此溶液 引入含Pd2(dba)3 (1.39克’ 1>51毫莫耳)與(2,_二環己基鱗酿 基-聯苯-2-基)-二曱胺(1.25克,3.18毫莫耳)之第二二頸燒 瓶中。在RT攪拌1〇分鐘後,將透明暗紅色溶液冷卻至_1〇 °C。在5分鐘内加入乙酸第三丁酯(15 7毫升,13 5克, 毫莫耳)。在-10°C 10分鐘後,將ι,3-二氣_異喹啉(1〇 〇克, 5 0.4 9 ^:矣耳)_人加入。使暗紅色溶液加溫至rt。在rt 3 〇 分在里後,TLC分析顯示原料完全轉化。使反應混合物通過2 公分矽石墊過濾’將其以EtOAc/MeOH 98 : 2清洗。濃縮後 ’殘渣藉FCC純化(曱笨/CH2Ci2 2 : 1至曱苯/Et0Ac 100 : 〇 至 99 : 1至 98 : 2至 97 : 3至 96 : 4至 94 : 6至 90 : 10)提供(3· 氣·異喹啉,1-基)-乙酸第三丁酯。將此化合物溶於Hci之飽 和乙醇溶液(200毫升)且回流15分鐘。濃縮提供定量產率之 標題化合物。'H NMR (DMSO, 400 ΜΗζ) δ 1.17 (t,J = 8.8 84363 -24- 1324064 3H), 4.11 (q, J = 8.8, 2H), 4.28 (s, 2H), 7.51-7.57 (m, 1H), 7.61 (s, 1H), 7.61-7.66 (m, 1H), 7.72 (d, J = 8.8, 1H), 7.98 (d, J = 8.8,1H) ; ES-MS : 250 [M + H]+。 依照實例69之步驟但是使用適當之原料,可得到其中R 為如以下表5所示之式(e)殘基之式I化合物。 表5 實例 r9 Ra Rb M.S.資料 70 -(4,7-二氮螺[2.5]辛-7-基) ch3 Η ΜΡΓ465 71 3 -乙基-六氣。比哨"-1-基 ch3 Η MH+467 72 -(4,7-二氮螺[2.5]辛-7-基) Η Η MET 451 73 3 -乙基-1 -六鼠σ比哨基 Η Η MET 453 74 3-R-曱基-六氫。比畊-1-基 ch3 Η MH+453 75 3-R-甲基-六氫。比畊-1-基 Η Η MHM39 76 3-S-曱基-六氫吡畊-1-基 ch3 Η MIT453 77 3-S-曱基-六氮。比ρ井-1-基 Η Η MH+439 78 4-曱基-3-S-甲基-六氫。比畊-1-基 ch3 Η MH"467 79 4-曱基-3-S-甲基-六鼠°比啡-1-基 Η Η MH+453 80 4,7-二氮螺[2.5]辛-7-基 ch3 Η MH+464 81 4,7-二氮螺[2.5]辛-7-基 Η F MH+479 82 4,7-二氮螺[2.5]辛-7-基 ch2-ch3 Η 479 83 4,7-二氮螺[2.5]辛-7-基 Η ch(ch3)2 MHM95 84 4/7-二氮螺R.5]辛-7-基 Η och3 MH+471 84363 -25 - 1324064 85 4,7_二氮螺[2.5]辛枣基 ch3 ch2-ch3 MIT451 86 4,7-二氮螺[2.5]辛-7-基 ---- Η CH2-CH3 MH+465 87 4,7-二氮螺[2·5]辛 _7_ 基 --- ch(ch3)2 H MPT451 88 4,7-二氮螺[2.5]辛 _7_ 基 ch3 ch3 MHU79 89 4,7-二氮螺[2.5]辛-7-基 ch3 Cl MH"499 90 4,7-二氮螺[2·5]辛-7-基 H Cl ΜΐΤ485 91 4,7-二氮螺[2.5]辛-7-基 CH2-CH3 ch3 MHM92 92 3-乙基-六氫。比__ι-基 ch2-ch3 ch2-ch3 MHM94 實例80之化合物轉化成為其貳_三氟乙酸鹽或乙酸鹽。 自由形式或醫藥可接受鹽形式之式〗化合物呈現有價值 之藥理性質’例如,抑制蛋白激酶C (PKC)(例如,如α、β 、δ、ε、η或Θ活性之PKc異構體),因抑制τ_細胞對細胞活 素(例如,IL-2)之增殖回應而抑制丁_細胞活化與增殖(例如 ,抑制Τ-細胞或細胞活素(例如,江_2)製造),例如,如活 體外與活體内測試所示,因此顯示可用於治療。 A.活體外 1.蛋白激酿C檢鹼 依,日>?、公開方法(D. Geiges 等人之 Biochem. Pharmacol. 1997 ; 53 : 865-875)測試式I化合物對不同pkc異構體之活 性。此檢驗係在已事先以Sigmacote (Sigma SL-2)矽化之96-井聚丙烯微量滴定板(Costar 3794)中實行。反應混合物(50 微升)含10微升相關PKC同工酶與25微升測試化合物一起 ,及15微升含200微克/毫升精蛋白硫酸酯、10 Mg(N03)2 84363 -26- 1324064 、10 μΜ ATP (Boehringer 519987)、與 3750 Bq之 33Ρ-ΑΤΡ (Hartmann Analytic SFC3(H,1 lOTBq/毫莫耳)於 20 mM Tris- 緩衝液pH 7.4+ 0·1°/。BSA之混合溶液。在微量滴定板搖動 培育器(Biolabo Scientific Instruments)中在 32°C 實行培育 15分鐘。藉由加入1〇微升〇·5 μ Na2EDTA,pH 7.4而中止反 應’在溫和壓力下將5 0微升混合物量滴至預濕填纖維素紙 (Whatmann 3698-915)上。以100微升偏移h2〇清洗未加入 ATP。紙在0.5% H3P〇4中清洗2次15分鐘繼而在EtOH中5分 鐘。然後將紙乾燥且置於全濾器(Packard 60052 19)中,及 在Topcount放射性計數器(Packard)中計數前以1 〇微升/井之 Microscint-0 (Packard 60 1361 1)覆蓋。依照上述方法,藉由 培育一系列範圍為1 -1 〇〇〇 μΜ之抑制劑稀釋液而固定地實 行IC5 〇測量。IC5 〇值係由帶入乙狀曲線之圖表計算。 2. 蛋白激酶ce檢鹼 在上述檢驗條件下使用人類重組子ρκχθ。在此檢驗中, 式I化合物呈現具ICso^l μΜ之PKCe。實例33與69之化合物 在此檢驗中呈現各具6_8與12.1111^之1(35〇之?〖€0。 3. 蛋白激醢Ca烚給 自 Oxford Biomedical Research得到人類重組子 pKCa且 在以上A. 1部份所述檢驗條件下使用。在此檢驗中,式I化 合物呈現具ICso^l μΜ之PKC0。實例29之化合物在此檢驗 中呈現具4.3 ηΜ之IC50之PKCa。 4·蛋白激酶CB1檢驗 自 Oxford Biomedical Research得到人類重組子ρκ〇:β1 且 84363 -27- 1324064 在以上A. 1部份所述檢驗條件下使用。在此檢驗中,式I化 合物呈現具IC5〇Sl μΜ之ΡΚΧΘ。實洌33之化合物在此檢驗 中呈現具19.6 ηΜ之IC5〇之ΡΚΧβΙ。 5 ·香白激酿C δ檢驗 自Oxford Biomedical Research得到人類重組子PKC5且在 A. 1部份所述檢驗條件下使用。在此檢驗中,式I化合物呈 現具IC5〇Sl μΜ之ΡΚΟΘ。實例29之化合物在此檢驗中呈現 具 20 nM之 IC5。之 ΡΚΧδ。 6. 蛋白激酶C ε檢驗 自Oxford Biomedical Research得到人類重組子PKCs且在 A. 1部份所述檢驗條件下使用。在此檢驗中,式j化合物呈 現具ICso^l μΜ之ΡΚΧΘ。實例69之化合物在此檢驗中呈現 具 18 ηΜ之 IC5〇之 PKCs。 7·蛋白激酶Cri檢鹼 自Pan Vera得到人類重组子PKCr)且在Α· 1部份所述檢驗 條件下使用。在此檢驗中’式I化合物呈現具IC5〇 $ 1 之 ΡΚΧΘ。實例29之化合物在此檢驗中呈現具27.4 ηΜ之IC50 之 ΡΚΧη。 8 GD28共模擬檢給 此檢驗係以 Baumann G 等人在 Transplant.Proc. 1992 ; 24 .4 j-8所述之經人類白細胞介素_2_促進子/報告子基因構造 轉染之Jurkat細胞實行,β_半乳糖苷報告子基因經螢光素酶 基因(de Wet J.等人之 Mol. Cell Biol. 1987, 7(2),725-737) 取代。如下以固相偶合抗體或佛;:支醇肉豆蔻酸酯乙酸酯 84363 -28- 1324064 (PMA)及Ca + +離子導體離子黴素模擬細胞。在rt將抗體傳 導模擬Microlite TM1微量滴定板(Dynatech)每井塗以3微克 /毫升山羊抗鼠IgG Fc抗體(Jackson)於55微升磷酸鹽缓衝鹽 水(PBS) 3小時。在RT以2%牛血漿白蛋白(BSA)於PBS(每井 300微升)培育2小時而去除抗體後將板加蓋。在以每井300 /微升PBS清洗3次後,加入1〇奈克/毫升抗τ細胞受體抗體 /(WT31,Becton & 與 300 奈克/ 毫升抗 CD28 抗體
(15E8)於50微升之2% BSA/PBS作為模擬抗體,而且在4°C
培育過夜。最後將板以每井300微升PBS清洗3次。在分離 板中製備七份在檢驗介質(含50 μΜ 2-氫硫基乙醇、100單 位/毫升盤尼西林與1〇〇微克/毫升鏈黴素之rPMI 1640/10% 胎牛血漿(FCS))中複製之測試化合物三倍連續稀釋液,混 合經轉染Jurkat細胞(繁殖體Κ22 290_Η23)及在37。(:於50/〇 C〇2中培育30分鐘。然後將1 00微升含1 X 1 〇5個細胞之此混 合物轉移至塗抗體檢驗板。同時以4〇奈克/毫升pmA與2 μΜ 離子黴素培育100微升。在37°C於5% C02中培育5.5小時後 ,藉生物發光測量測定螢光素酶含量。將板以5〇〇 g離心1〇 分鐘且藉輕彈去除上清液。加入含25 mM Tris-磷酸鹽,pH
7·8、2 mM DTT、2 mM 1,2-二胺基環己烷-Ν,Ν,Ν',Ν-四乙酸 、1 0% (ν/ν)甘油與 1 〇/。(v/v) Triton X-1 00之溶胞緩衝液( 每井20微升)。在RT將板在固定搖動下培育丨〇分鐘。在自動 加入每井50微升含20 mM Tricine 、 1.07 mM (MgC03)4Mg(0H)2 x 5H20、2.67 mM MgS04、0_1 mM EDTA 、33.3 mM DTT、270 μΜ 共酶 A、470 μΜ 螢光素(Chemie 84363 -29- 1324064
Brunschwig AG)、530 μΜ ATP,pH 7.8之螢光素酶反應緩 衝液後,以生物發光讀取機(芬蘭Helsinki之Labsystem)評定 螢光素酶活性。落後時間為0,5秒,總測量時間為1或2秒。 低對照值為得自抗T細胞受體-或PMA-模擬細胞之光單位 ,高對照則得自無任何測試樣品之抗T細胞受體/抗CD28-或PMA/離子徽素-模擬細胞。將所有之值減去低對照。在 測試化合物存在下得到之抑制計算為高對照之抑制百分比 。在50%抑制所得之測試化合物濃度(IC5())係由劑量回應曲 線測定。在此檢驗中,式I化合物呈現具IC5〇g 1 μΜ之抗T細 胞受體/抗CD28與ΡΜΑ/離子黴素模擬jurkat細胞。實例29 之化合物在此檢驗中具20 nM之IC5〇。 9.異源混合淋巴細胞反應(MLR) 依照標準步驟(J. Immunol· Methods.,1973, 2, 279 與 Meo 等人之 Immunological Methods,紐約,Academic Press, 1 979 227-39)實行雙向MLR。簡言之’在含i〇% FCS、100單位/ 毫升盤尼西林、100微克/毫升鏈黴素(瑞士 Basei之Gibco BRL)、50 μΜ 2-氫硫基乙醇(瑞士 Buchs之Fluka)與連續稀釋 化合物之RPMI介質中,培育得自CBA與BALB/c鼠之脾臟細 胞(在平底組織培養微量滴定板中每井丨.6 x 1 〇5個得自各菌 株之細胞,總共3 ‘2 X 1 05個)。每種化合物重複地實行七次 二倍稀釋步驟。在培育4曰後,加入1 3H-胸苷。在又5 小時培育期間後培養細胞’及依照標準步驟測定加入之3h_ 胸苷。MLR之背景值(低對照)為僅BALB/c細胞增殖。將所 有之值減去低對照。取無任樣品之高對照作為1 〇〇%增殖。 84363 •30- 1324064 計算樣品之抑制百分比,及測定50%抑制所需濃度(ic5G值) 。在此檢驗中,實例29之化合物在此檢驗中具28ηΜ2Ι(:5〇 。在人類MLR中測試時,式丨化合物亦呈現在nM範圍之 值。 10· GSK-3 β之抑华ι|. GSK-3P結合檢驗係在96井聚丙烯板中以5〇微升反應實 行,各反應含於DMSO(各種濃度)中之20 mM氣化鎂、4〇 μΜ ATP、2 mM DTT、88·5 μΜ生物素化且碟酸化creB-肤基質 (生物素-KRREILSRRPS(P04)YR-〇H ; Q. M. Wang 等人之 J. Biol. Chem. 269, 14566-14574, 1994) ' [γ-33Ρ]ΑΤΡ (l μ ci) 與2微升測試化合物。加入15微升之〇δΚ-3β (各種濃度)且 混合物在3(TC培育1小時。藉由將25微升混合物轉移至含 13 0微升1.8 5%磷酸之磷纖維素板而中止反應。在真空下以 1,85%鱗酸將薄膜中自由放射性核苷洗出(5次)。最後一次 清洗後’將板轉移至轉接板且將5 0微升閃爍混合液 (Microscint-20,Packard,型錄號碼#20-133)各井,及在直 立計數器中將放射活性量計數。式〗化合物在此檢驗令為活 性。亦在其他之標準GSK-3 β結合檢驗中使用其他之基質 (例如’商業可得者)測試式Hb*合物。 B ·活體内 查多植 使用之菌種組合:Lewis (RT1單元型)與BN (RT1單元型) 雄鼠。使用吸入性異氟烷將動物麻醉。經下腹靜脈將移植 鼠肝素化同時經主動脈放血後,打開胸腔且將心臟快速地 84363 -31 - 1324064 、邠。將主動脈與分離末稍結紮至第一 將頭臂幹分開。將左肺動脈 刀又 邊打η μ ^ 糸及刀開且將右側分開但左 邊打開。將所有其他之企管解剖、結 體心臟移至冰鹽水中。 且將移植 -糟由將腎下腹主動脈與腹靜脈解剖及十字夾緊而準備受 ^移植物係使用剛單纖絲縫線,在移植體頭臂幹盘受 間及受體右肺動脈對受體腹靜脈以背對側吻:術 I。將夾子移除’在後腹部將移植物綁緊,以溫鹽水清 腹部内容且將動物縫合’及使其在加熱料下復原。每 日經腹壁拍打移植體心臟觸診而監測移植物存活率。在心 心止時視為完全排斥。以130毫克/公斤每日2次之每日 口服劑量施以式!化合物之動物得到移植物存活率增加。 移植物相對宿本棍# 將得自WiStar/F大鼠之脾臟細胞(2 χ ι〇7個)皮下注射至 ⑽Ur/F X Fischer 344) Fi雜種大鼠之右後腳掌巾。左腳掌 不處理。將動物連續4日(0_3)以測試化合物治療。在第7日 去除胭肌淋巴節,;5也丨ρ + 朴匕即及冽疋兩個對應淋巴節之重量差。比較 貫驗组之淋巴節重量差與未以測試化合物治療之動物組之 對應淋巴即重里差’結果表示成淋巴節放大之抑制(以百分 比表示)。在此檢驗中,以3 〇毫克/公斤每日2次之劑量施以 貫例29之化合物時,得到} 〇〇%抑制。 因此,式I化合物可用於τ淋巴細胞及/或pKc導致疾病之 治療及/或預防,例如,器官或組織同種或異種移植之急性 或L !·生排斥、移植物相對宿主疾病、動脈粥樣硬化、由於 84363 -32- 丄 W4U64 =傷:如血管成形)造成之血管閉合、狹心症肥胖、χ 、損傷葡萄糖容忍度、多囊性印巢症、高血壓、心 萎性梗塞性肺病、CNS疾病(如阿兹海默爾症或肌 人斗貝石匕)、癌症、傳染疾病(如AIDS)、敗也性休克或成 ^痛苦徵候群、局部缺血/再灌注傷害(例如,=梗 :中'腸局部缺血、腎衰竭或出血性休克或外傷休克 性外傷)°式1化合物亦可用於了細胞導致急性或慢 病或自身免疫疾病之治療及/或預 :生關郎炎'骨關節炎、系統性紅斑狼瘡、橋本f狀腺::,、 關即炎、重症肌無力、第1或Η型糖尿病及其伴隨疾 贈 血管病、糖尿病增殖性視網膜病、糖尿病斑點水 :?二:病與黎明現象、呼吸疾觀喘或發' I 肺•害)、發炎性肝傷害、發炎性腎小球傷害、免 二 徵:發炎性與過度增殖性皮膚病(如牛皮·' ::皮膚穴、過敏性接觸皮膚炎、刺激性接觸皮 :、疹性皮膚炎、油性皮脂皮膚炎)、發炎性眼疾(例如、 舌格倫症候群、角膜結膜炎或葡萄臈炎)、發炎性腸炎, 倫^症或潰瘍結腸炎。對於以上之用途,所需劑量當= 把樂杈式、治療之特定病況及所需效果而不同 ^見 :〇毫克/公斤體重之每曰劑量通常顯示得到令人滿二: 果。在較大型哺乳動物,例如,人類,指示之每曰::、、、。 約〇·5毫克至約2_毫克之範圍,例如,其可分成至^為 4次之劑量或以阻滯形式方便地施藥。 夕〜日 式I化合物可藉任何途徑施藥,特別是經腸胃如 月艮, 84363 1324064 例如,藥錠或膠囊之形式,或非經腸胃,例如,可注射一 液或懸浮液之形式’局部性’例如,洗劑、凝膠、軟膏洛 或乳霜之形式,或為鼻部或栓劑形式。含自由形式或醫藥 可接文鹽形式之式I化合物結合至少一殺 ’、 悝西樂可接跫載劑 或稀釋劑之醫藥組合物可藉由混合醫藥可接受載劑 ,而以習知方式製&。例如’ π服施藥之單位劑量形式含 約〇. 1毫克至約500毫克之活性物質。 3 局部施藥為,例如,對皮膚。局部施藥之其他 眼睛。 > %馮對 式I化合物可以自由形式或醫藥可接受鹽形式施藥,例如 ,如上所示。此鹽可以習知方式製備且呈現如自由化合物 之相同活性程度。 依照以上,本發明進一步提供: 1 一種對需要此治療之病患預防或治療T淋巴細胞及/或 PKC或GSK-3 β導致之疾病(例如,如上所示)之方法 此方法包含對該病患施以有效量之式〗化合物或其醫 藥可接受鹽; ' 2 一種對需要此治療之病患預防或治療急性或慢性移植 排斥或Τ細胞導致之發炎性或免疫性疾病(例如,如上 所示)之方法,此方法包含對該病患施以有致量之式J 化合物或其醫藥可接受鹽; • 一種式1化合物,自由形式或醫藥可接受鹽形式,例如 ,在以上1.1與1 2所示之方法中作為醫藥劑之用途。 .一種醫藥組合物,其用於,例如,如以上1,1與丨2之方 84363 • 34· 1324064 法,其包含自由形式或醫藥可接受鹽形式之式〗化合物 結合其醫藥可接受稀釋劑或載劑。 4_ 一種式I化合物或其醫藥可接受鹽用於製備用於如以 上1_1與1.2之方法之醫藥組合物之用途。 式I化合物可如單獨活性成分或與免疫調節體系之其他 藥物或消炎性試劑(例如,用於治療或預防同種或異種移植 急性或慢性排斥或發炎性或免疫疾病)一起施藥。例如,其 可與以下組合使用:環孢菌素或子囊菌素或其免疫抑制性 同系物或衍生物,例如,環孢菌素A ' ISA Τχ247 ' fk_5〇6 、ABT-281、ASM 981 ; mTOR抑制劑,例如,雷帕黴素 (raPamycin)、40-O-(2-羥基)乙基雷帕黴素、CCI779、Abt578 或雷帕系,例如,AP23573等;皮質類固醇;環磷醯胺; 硫唑嘌呤;曱胺喋呤;具有加速淋巴細胞歸位性質之edg 受體顯效藥,例如,FTY 720或其同系物;里夫諾米德 (leflunomide)或其同系物;米若里賓(miz〇dbine);黴酚酸 ,莫飛提爾(mo fetil)黴盼酸鹽;15-去氧基史普瓜林 (spergualine)或其同系物;免疫抑制性單細胞抗體,例如, 白細胞受體之單細胞抗體,例如,MHC、CD2、CD3、CD4
、CD lla/CD18、CD7、CD25、CD 27、B7、CD40、CD45 、CD58、CD 137、ICOS、CD150 (SLAM)、0X40、4-1BB 或其配位子’例如’ CD 1 54 ;或其他之免疫調節性化合物 ,例如,具有CTLA4或其突變體之至少一部份細胞外域之 重組子結合分子,例如,結合至非CTLA4蛋白序列之CTLA4 或其突變體之至少一部份細胞外域,例如,CTLA4Ig(例如 84363 ‘35- 1324064 ,例如,LEA29Y,或其 或其他
,代號AT CC 68629)或其突變體 黏附分子抑制劑,例如,mAb< 於芳香酶抑制劑、抗***、拓撲異構酶〗抑制劑、拓撲異 構酶Π抑制劑、微管活性劑、烷化劑、組蛋白去乙醯酶抑 制劑、呢酯(farnesyl)轉移酶抑制劑、〇〇12抑制劑、MMp 抑制劑、mTOR抑制劑、抗腫瘤抗代謝物、普拉丁(piatin) 化合物、降低蛋白激酶活性之化合物與其他抗血管生成化 合物、戈那瑞林(gonadorelin)顯效藥、抗雄激素' 班醯胺 (bengamides)、貳膦酸鹽、抗增殖性抗體、與提莫若羅米德 (temozolomide),或抗糖尿病藥物、胰島素促分泌劑或胰島 素分泌增強劑,例如’磺醯基脲,例如,曱苯績丁脉 (tolbutamide)、氟石黃丙月尿(chlorpropamide)、妥拉續月尿 (tolazamide)、醋石黃己月尿(acetohexamide)、4 -氣-N-[(l-°比嘻 咬基胺基)戴基]-苯績酿胺(glyCOpyrarnide)、格列本脲 (glibenClamide)(優降糖(glyburide))、格列齊特(gliclazide) 、1-丁基-3-間胺醯脲(metanilylurea)、磺胺丁腸(carbutamide) 、格列波脲(glibonuride) '格列吡嗪(glipizide)、格列喹酮 (gliquidone)、格列索克皮得(giisoxepid)、甘丁噻唑 (glybuthiazole)、格列丁唑(gnbuzole)、甘己醯胺 (glyhexamide)、格列嘧啶(giymidine) ' 甘平醯胺 (glypinamide)、芬丁醯胺(phenbutamide)或甲苯基環己醯胺 84363 -36- 1324064 (tolylcyclamide),口服促胰島素劑衍生物,例如,短期作 用胰島素增強劑,例如’美格里丁尼德(meglitinide)、瑞帕 格林尼德(repaglinide),笨基乙酸衍生物,例如,納德格林 尼德(nateglinide) ’ DPP IV抑制劑,例如,ΐ·{2-[(5-氛基 α比 啶-2-基)胺基]乙胺基}乙醯基-(2S)-氰基比咯咬二氫氣酸 鹽、LAF237、GLP-1或GLP-1顯效藥同系物,或胰島素敏感 劑,例如’過氧化物酶體增殖劑活化受體γ顯效藥(ppARW ,例如,齊格塔酮(glitazone)、非齊格塔酮型,如N_(2_笨 曱酿基本基)-L -路胺酸同系物,例如,g I - 2 6 2 5 7 0,戍亞氧 基二酮(oxolidinedione),例如,JTT5(H,雙重 ρΡΑΙΙγ/ρρΑΚα 顯效藥,例如,DRF-5541 58、NC-2100或NN-622,視網搭 衍生物X受體顯效藥或視網醛X (rexin〇id),例如,2-^ — (3,5,5,8,8-五甲基-5,6,7,8-四氫-2-萘基)_環丙基]_吡啶_5_羧 酉义4 [〇,5,5,8,8-五曱基·5,6,7,8-四氩-2-萘基)-2-幾基]•苯 曱酸、9-順視網酸或其同系物、衍生物或其醫藥可接受鹽。 依照以上,本發明提供進一步態樣: 5. —種界定以上之方法 、PKC或Τ細胞活化與增殖抑制劑, 醫藥可接受鹽形式之式;!化合物,與 其包含將治療有效量之GSK-3 β 例如,自由形式或 第二藥物物質共同 (例如’附帶地或連續地)施藥,該第二藥物物質為免疫 抑制性、免疫調節性、、消炎性、抗增殖性或抗糖尿病 藥物,例如,如上所示。 其包含 a) GSK-30、PKC 例如’自由形式或醫藥可 6. —種治療組合,例如,套件, 或Τ細胞/¾化與增殖抑制劑, 84363 -37- 接受鹽形式之式〗化合物,及b)至少一種選自免疫抑制 性、免疫調節性、消炎性、抗增殖性或抗糖尿病藥物 之第二試劑。成分a)與成分b)可附帶地或連續地使用。 此套件可包含其施藥指示。 在將GSK 3 β、pkc或T細胞活化與增殖抑制劑(例如,式工 匕口物)、’.α合其他免疫抑制性/免疫調節性、消炎性、抗增 :性或抗糖尿病治療劑(例如,用於預防或治療以上指定: 植排斥或發炎性或免疫疾病)施藥時,共同施 節性、消炎™或抗糖尿 否為類固醇或二、'視所使用之共同藥物型式(例如,其是 而不同。 仏違素)、使用之特定藥物、治療之病況等 、 丹有令人感# 趣之活體外與 /、居體内活性 84363 -38 -
Claims (1)
1324064 第092107388號專利申請案 | 中文申請專利範圍替換本(97年10月f 拾、申請專利範圍: 1_ 一種式I化合物或其鹽
其中 Ra為 Η ; CH3 ; CH2-CH3或異丙基, Rb為Η;齒素;。-6烷氧基或Ci6烷基及 基團 其中 為4’7-二氮螺[2.5]辛_7_基;或卜六氫D"基,其 在3位置經乙基取代,而且視情況地在4位置經曱基 2. 3. 4. 取代六氫t井基,其在位置3與4經曱基取代。 根據申請專利範圍第i項之化合物,其係為3_[3_(4,7二 氮螺[2.5]辛_7_基)_異喹啉·基] ’ J H (卜甲基-1H-啕哚-3- 基)-吡咯-2,5-二酮或其鹽。 根據申請專利範圍第2項之化合物, 冉係為乙酸鹽。 一種製備根據申請專利範圍第1項 , 9 1式I化合物之方法 ,此方法包含 84363-971017.doc (II)
a) 將式II化合物 - 其中Ra與Rb如申請專利範圍第1項所定義, ’ 與式III化合物反應 R-CH2-CO-NH2 (III) 其中R如申請專利範圍第1項所定義, b) 將以自由形式得到之所得式I化合物轉化成鹽形式或·· 在適當之處反之。 5‘-種用於治療或預防器官或組織同種或異種移植之急 性或慢性排斥或T細胞導致之發炎或自身免疫疾病之醫 藥組合物,其包含根據申請專利範圍第丨至3項中任一項 之式I化合物或其醫藥可接受鹽結合其醫藥可接受稀釋 劑或載劑。 6. 根據申請專利範圍第5項之組合物,其係用於治療或預 防CNS疾病、癌症、傳染疾病、風濕性關節炎、多發性· 關節炎、第I或II型糖尿病、氣喘、免疫性導致疾病之皮 膚徵候、牛皮癖、發炎性腸炎、克倫氏症或潰廣結腸炎。 7. 根據申請專利範圍第5或6項之組合物,其局部施藥途徑 為對皮膚或對眼睛。 ' 8. 一種用於治療或預防器官或組織同種或異種移植之魚 性或慢性排斥或Τ細胞導致之發炎或自.身免疫疾病之= 合,其包含a)根據申請專利範圍第丨至3項中任一項之式 84363-971017.doc 1324064 I化合物, 可接受鹽形式,及b)
i化合物,其係為自由形式或醫藥^ 至少-種選自免疫抑制性、免疫調 殖性、化學治療性或抗糖尿病藥物 Geflunomide:)或其同系物、米若里声(miz〇ribine}、黴酚 酸、莫飛提爾(mofetil)黴酚酸鹽、15-去氧基史普瓜林 (spergualine)或其同系物、免疫抑制性單細胞抗體、免 疫調節性化合物與黏附分子抑制劑。 10·根據申請專利範圍第9項之組合,其中第二試劑選自環 孢菌素 A、ISA Tx247、FK-506、ABT-281、ASM 981、 雷帕黴素(rapamycin)、40-0-(2-經基)乙基雷帕黴素、 FTY 720、CTLA4Ig、LFA-1對抗劑、選擇素對抗劑、VLA-4 對抗劑與 MHC、CD2、CD3、CD4、CDlla/18、CD7、 CD25、CD27、B7、CD40、CD45、CD58 ' CD137、ICOS 、CD 150、0X40、4-1BB與其配位子之單細胞抗體。 84363-97I017.doc
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0207729A GB0207729D0 (en) | 2002-04-03 | 2002-04-03 | Organic compounds |
GB0303323A GB0303323D0 (en) | 2003-02-13 | 2003-02-13 | Organic compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
TW200306818A TW200306818A (en) | 2003-12-01 |
TWI324064B true TWI324064B (en) | 2010-05-01 |
Family
ID=28676503
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW097141220A TW200918046A (en) | 2002-04-03 | 2003-04-01 | Indolylmaleimide derivatives |
TW092107388A TWI324064B (en) | 2002-04-03 | 2003-04-01 | Indolylmaleimide derivatives |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW097141220A TW200918046A (en) | 2002-04-03 | 2003-04-01 | Indolylmaleimide derivatives |
Country Status (26)
Country | Link |
---|---|
US (5) | US20050119274A1 (zh) |
EP (1) | EP1490355B1 (zh) |
JP (1) | JP4247125B2 (zh) |
KR (2) | KR100942329B1 (zh) |
CN (1) | CN100351251C (zh) |
AR (1) | AR039209A1 (zh) |
AT (1) | ATE517888T1 (zh) |
AU (1) | AU2003224031B2 (zh) |
BR (1) | BR0308979A (zh) |
CA (1) | CA2477774C (zh) |
CO (1) | CO5611127A2 (zh) |
CY (1) | CY1111982T1 (zh) |
DK (1) | DK1490355T3 (zh) |
EC (2) | ECSP045254A (zh) |
IL (1) | IL163892A0 (zh) |
MX (1) | MXPA04009632A (zh) |
MY (1) | MY137566A (zh) |
NO (1) | NO329166B1 (zh) |
NZ (1) | NZ535613A (zh) |
PE (1) | PE20040079A1 (zh) |
PL (1) | PL213480B1 (zh) |
PT (1) | PT1490355E (zh) |
RU (1) | RU2340610C2 (zh) |
SI (1) | SI1490355T1 (zh) |
TW (2) | TW200918046A (zh) |
WO (1) | WO2003082859A1 (zh) |
Families Citing this family (91)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6645970B2 (en) * | 2000-11-07 | 2003-11-11 | Novartis Ag | Indolylmaleimide derivatives |
PE20040079A1 (es) * | 2002-04-03 | 2004-04-19 | Novartis Ag | Derivados de indolilmaleimida |
GB0303319D0 (en) * | 2003-02-13 | 2003-03-19 | Novartis Ag | Organic compounds |
US20070142401A1 (en) * | 2003-10-27 | 2007-06-21 | Novartis Ag | Indolyl-pyrroledione derivatives for the treatment of neurological and vascular disorders related to beta-amyloid generation and/or aggregation |
US7582631B2 (en) | 2004-01-14 | 2009-09-01 | Amgen Inc. | Substituted heterocyclic compounds and methods of use |
PT1709030E (pt) | 2004-01-19 | 2008-07-01 | Novartis Ag | Derivados da indolilmaleimida |
US20070232658A1 (en) * | 2004-04-08 | 2007-10-04 | Jurgen Wagner | Protein Kinase C Inhibitors for the Treatment of Autoimmune Diseases and of Transplant Rejiction |
GB0410713D0 (en) | 2004-05-13 | 2004-06-16 | Novartis Ag | Organic compounds |
GB0504203D0 (en) * | 2005-03-01 | 2005-04-06 | Novartis Ag | Organic compounds |
JP4747364B2 (ja) | 2005-04-04 | 2011-08-17 | 独立行政法人産業技術総合研究所 | 紫外線皮膚炎抑止剤およびアトピー性皮膚炎抑止剤 |
GB0507918D0 (en) | 2005-04-19 | 2005-05-25 | Novartis Ag | Organic compounds |
EP1885454A2 (en) | 2005-05-04 | 2008-02-13 | DeveloGen Aktiengesellschaft | Use of gsk-3 inhibitors for preventing and treating pancreatic autoimmune disorders |
GB0511060D0 (en) | 2005-05-31 | 2005-07-06 | Novartis Ag | Organic compounds |
RU2008104510A (ru) * | 2005-07-11 | 2009-08-20 | Новартис АГ (CH) | Производные индолилмалеинимида |
EP1749523A1 (en) * | 2005-07-29 | 2007-02-07 | Neuropharma, S.A. | GSK-3 inhibitors |
EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
EP2275095A3 (en) | 2005-08-26 | 2011-08-17 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
ZA200802857B (en) | 2005-09-14 | 2009-09-30 | Takeda Pharmaceutical | Dipeptidyl peptidase inhibitors for treating diabetes |
KR101368988B1 (ko) | 2005-09-16 | 2014-02-28 | 다케다 야쿠힌 고교 가부시키가이샤 | 디펩티딜 펩티다제 억제제 |
JP2009512711A (ja) | 2005-10-21 | 2009-03-26 | ブレインセルス,インコーポレイティド | Pde阻害による神経新生の調節 |
EP3332807B1 (en) | 2005-10-26 | 2023-02-22 | Novartis AG | Use of anti il-1beta antibodies |
CA2625210A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
ES2481671T3 (es) | 2005-11-21 | 2014-07-31 | Novartis Ag | Inhibidores de mTOR en el tratamiento de tumores endocrinos |
GB0601744D0 (en) | 2006-01-27 | 2006-03-08 | Novartis Ag | Organic compounds |
US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
GB0605691D0 (en) * | 2006-03-21 | 2006-05-03 | Novartis Ag | Organic Compounds |
AU2007249399A1 (en) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
GB0613162D0 (en) * | 2006-06-30 | 2006-08-09 | Novartis Ag | Organic compounds |
EP2056831A2 (en) * | 2006-08-23 | 2009-05-13 | Novartis AG | Use of pkc inhibitors in particular indolylmaleimide derivatives in ocular diseases |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
TW200838536A (en) | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
EP2091535A1 (en) * | 2006-12-07 | 2009-08-26 | Novartis AG | Use of pkc inhibitors in transplantation |
CN101558062A (zh) | 2006-12-19 | 2009-10-14 | 诺瓦提斯公司 | 作为激酶抑制剂的吲哚基马来酰亚胺衍生物 |
CN101754682B (zh) * | 2007-05-16 | 2014-11-12 | 布里格姆妇女医院 | 突触核蛋白病的治疗 |
KR102606597B1 (ko) | 2007-05-29 | 2023-11-29 | 노파르티스 아게 | 항-il-1-베타 치료법에 대한 신규 적응증 |
US20090054513A1 (en) * | 2007-08-22 | 2009-02-26 | Response Scientific, Inc. | Method of managing blood glucose levels, insulin levels and/or insulin receptor functionality in individuals with diabetes, polycystic ovarian syndrome and/or alzheimer's disease |
US7943163B2 (en) * | 2007-08-22 | 2011-05-17 | Response Scientific, Inc. | Medical food or nutritional supplement, method of manufacturing same, and method of managing diabetes |
EP2209916B1 (en) | 2007-11-08 | 2011-12-21 | Novartis AG | Gene expression signatures for chronic/sclerosing allograft nephropathy |
PE20091522A1 (es) * | 2007-12-21 | 2009-10-29 | Novartis Ag | Composicion farmaceutica solida que contiene 3-(1.h-indol-3-il)-4-[2-(4-metil-piperazin-1-il)-quinazolin-4-il]-quinazolin-4-il]-pirrol-2,5-diona |
US8268834B2 (en) | 2008-03-19 | 2012-09-18 | Novartis Ag | Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme |
ES2331451B1 (es) * | 2008-06-30 | 2010-10-21 | Consejo Superior De Investigaciones Cientificas (Csic) | Inmunosupresor basado en la interrupcion de la interaccion tcr-nck. |
US8475790B2 (en) | 2008-10-06 | 2013-07-02 | Bristol-Myers Squibb Company | Combination of CD137 antibody and CTLA-4 antibody for the treatment of proliferative diseases |
DE202008014557U1 (de) | 2008-10-27 | 2009-03-12 | Eberhard-Karls-Universität Tübingen Universitätsklinikum | Therapeutische Verwendung |
WO2010099217A1 (en) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
CN101671329B (zh) * | 2009-06-17 | 2012-11-07 | 东华大学 | 3-氨基醇取代的吲哚马来酰亚胺化合物、其制备和应用 |
WO2011006119A2 (en) | 2009-07-09 | 2011-01-13 | The Scripps Research Institute | Gene expression profiles associated with chronic allograft nephropathy |
TW201119651A (en) | 2009-10-26 | 2011-06-16 | Lg Life Sciences Ltd | Pharmaceutical composition comprising indole compound |
US8791100B2 (en) | 2010-02-02 | 2014-07-29 | Novartis Ag | Aryl benzylamine compounds |
AU2011234644B2 (en) | 2010-03-30 | 2014-07-17 | Novartis Ag | PKC inhibitors for the treatment of B-cell lymphoma having chronic active B-cell-receptor signalling |
UA112517C2 (uk) | 2010-07-06 | 2016-09-26 | Новартіс Аг | Тетрагідропіридопіримідинові похідні |
US8785648B1 (en) | 2010-08-10 | 2014-07-22 | The Regents Of The University Of California | PKC-epsilon inhibitors |
DK2609118T3 (en) | 2010-08-23 | 2017-04-03 | Univ Texas | Anti-OX40 antibodies and methods for their use |
CZ305457B6 (cs) * | 2011-02-28 | 2015-09-30 | Ústav organické chemie a biochemie, Akademie věd ČR v. v. i. | Pyrimidinové sloučeniny inhibující tvorbu oxidu dusnatého a prostaglandinu E2, způsob výroby a použití |
UY34072A (es) | 2011-05-17 | 2013-01-03 | Novartis Ag | Derivados sustituidos de indol |
WO2013001445A1 (en) | 2011-06-27 | 2013-01-03 | Novartis Ag | Solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives |
BR112014000314A2 (pt) | 2011-07-08 | 2017-01-10 | Novartis Ag | derivados de pirrolo pirimidina |
JP2014530851A (ja) | 2011-10-21 | 2014-11-20 | ノバルティスアーゲー | Pi3kモジュレータとしてのキナゾリン誘導体 |
US20140348848A1 (en) | 2011-12-02 | 2014-11-27 | Dhananjay Kaul | Anti-il-1beta (interleukin-1beta) antibody-based prophylactic therapy to prevent complications leading to vaso-occlusion in sickle cell disease |
BR112014014327A2 (pt) | 2011-12-15 | 2017-06-13 | Novartis Ag | uso de inibidores da atividade ou função de pi3k |
EP2794594A1 (en) | 2011-12-22 | 2014-10-29 | Novartis AG | Quinoline derivatives |
PL2794600T3 (pl) | 2011-12-22 | 2018-06-29 | Novartis Ag | Pochodne 2,3-dihydro-benzo[1,4]oksazyny i powiązane związki jako inhibitory kinazy fosfoinozytydu-3 (PI3K) do leczenia np. reumatoidalnego zapalenia stawów |
EA201590886A1 (ru) | 2012-11-07 | 2015-08-31 | Новартис Аг | Замещенные производные индола |
TW201422625A (zh) | 2012-11-26 | 2014-06-16 | Novartis Ag | 二氫-吡啶并-□衍生物之固體形式 |
WO2014085381A1 (en) | 2012-11-29 | 2014-06-05 | Novartis Ag | Pharmaceutical combinations |
EP2948134B1 (en) | 2013-01-24 | 2020-03-04 | Palvella Therapeutics, Inc. | Compositions for transdermal delivery of mtor inhibitors |
WO2014128612A1 (en) | 2013-02-20 | 2014-08-28 | Novartis Ag | Quinazolin-4-one derivatives |
WO2014174478A1 (en) | 2013-04-26 | 2014-10-30 | Novartis Ag | Pharmaceutical combinations of a pkc inhibitor and a c-met receptor tyrosine kinase inhibitor |
WO2015179773A1 (en) | 2014-05-22 | 2015-11-26 | The Scripps Research Institute | Tissue molecular signatures of kidney transplant rejections |
BR112016003229A8 (pt) | 2013-09-22 | 2020-02-04 | Calitor Sciences Llc | composto, composição farmacêutica, e, uso de um composto ou de uma composição farmacêutica |
KR101630806B1 (ko) | 2013-11-14 | 2016-06-16 | 대한민국 | 돼지의 초위성체 마커를 이용한 개체식별 방법 |
US9512084B2 (en) | 2013-11-29 | 2016-12-06 | Novartis Ag | Amino pyrimidine derivatives |
WO2015148867A1 (en) | 2014-03-28 | 2015-10-01 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
KR20160141855A (ko) | 2014-04-24 | 2016-12-09 | 노파르티스 아게 | 포스파티딜이노시톨 3-키나제 억제제로서의 아미노 피라진 유도체 |
PT3134396T (pt) | 2014-04-24 | 2019-12-16 | Novartis Ag | Derivados de amino piridina como inibidores da fosfatidilinositol 3-quinase |
PL3134395T3 (pl) | 2014-04-24 | 2018-07-31 | Novartis Ag | Pochodne pirazyny jako inhibitory 3-kinazy fosfatydyloinozytolu |
US11104951B2 (en) | 2014-05-22 | 2021-08-31 | The Scripps Research Institute | Molecular signatures for distinguishing liver transplant rejections or injuries |
US10443100B2 (en) | 2014-05-22 | 2019-10-15 | The Scripps Research Institute | Gene expression profiles associated with sub-clinical kidney transplant rejection |
EP3180003B1 (en) | 2014-07-01 | 2022-01-12 | The Regents of the University of California | Pkc-epsilon inhibitors |
JO3589B1 (ar) | 2014-08-06 | 2020-07-05 | Novartis Ag | مثبطات كيناز البروتين c وطرق استخداماتها |
US10259882B2 (en) | 2015-05-07 | 2019-04-16 | Agenus Inc. | Anti-OX40 antibodies |
WO2017044434A1 (en) | 2015-09-11 | 2017-03-16 | Sunshine Lake Pharma Co., Ltd. | Substituted heteroaryl compounds and methods of use |
US11447557B2 (en) | 2015-12-02 | 2022-09-20 | Agenus Inc. | Antibodies and methods of use thereof |
CA3041340A1 (en) | 2016-11-09 | 2018-05-17 | Agenus Inc. | Anti-ox40 antibodies, anti-gitr antibodies, and methods of use thereof |
IL267869B2 (en) | 2017-01-06 | 2023-10-01 | Palvella Therapeutics Inc | Non-aqueous preparations of mTOR inhibitors and methods of use |
WO2018175302A1 (en) | 2017-03-20 | 2018-09-27 | Sienna Biopharmaceuticals, Inc. | Polymer conjugates targeting c-src with reduced exposure |
EP3600440A1 (en) | 2017-03-20 | 2020-02-05 | Sienna Biopharmaceuticals, Inc. | Reduced exposure conjugates modulating therapeutic targets |
JP7254076B2 (ja) | 2017-11-19 | 2023-04-07 | サンシャイン・レイク・ファーマ・カンパニー・リミテッド | 置換ヘテロアリール化合物及び使用方法 |
WO2019143874A1 (en) | 2018-01-20 | 2019-07-25 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
CN110551103B (zh) | 2018-05-30 | 2022-08-23 | 北京大学深圳研究生院 | 一种jak3选择性抑制剂 |
WO2020010073A1 (en) | 2018-07-02 | 2020-01-09 | Palvella Therapeutics, Inc. | ANHYDROUS COMPOSITIONS OF mTOR INHIBITORS AND METHODS OF USE |
MX2021014157A (es) | 2019-05-23 | 2022-01-04 | Novartis Ag | Formas cristalinas de un inhibidor btk. |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ227850A (en) * | 1988-02-10 | 1991-11-26 | Hoffmann La Roche | Indole substituted pyrrole derivatives; preparatory process and medicaments for use against inflammatory immunological, bronchopulmonary or vascular disorders |
KR20010085305A (ko) * | 1998-07-30 | 2001-09-07 | 미즈노 마사루 | 이치환된 말레이미드 화합물 및 그의 의약 용도 |
US6281356B1 (en) * | 1999-12-22 | 2001-08-28 | Hoffmann-La Roche Inc. | Substituted pyrroles |
HUP0301431A2 (hu) | 2000-07-27 | 2003-08-28 | F. Hoffmann-La Roche Ag. | 3-Indolil-4-fenil-1H-pirrol-2,5-dion-származékok, mint glikogén szintáz kináz-3béta inhibitorok, eljárás az előállításukra és ezeket tartalmazó gyógyszerkészítmények |
US6645970B2 (en) * | 2000-11-07 | 2003-11-11 | Novartis Ag | Indolylmaleimide derivatives |
DE60140201D1 (en) * | 2000-11-07 | 2009-11-26 | Novartis Ag | Indolylmaleimidderivative als proteinkinase-c-inhibitoren |
PE20040079A1 (es) * | 2002-04-03 | 2004-04-19 | Novartis Ag | Derivados de indolilmaleimida |
US20070142401A1 (en) * | 2003-10-27 | 2007-06-21 | Novartis Ag | Indolyl-pyrroledione derivatives for the treatment of neurological and vascular disorders related to beta-amyloid generation and/or aggregation |
-
2003
- 2003-04-01 PE PE2003000330A patent/PE20040079A1/es not_active Application Discontinuation
- 2003-04-01 TW TW097141220A patent/TW200918046A/zh unknown
- 2003-04-01 TW TW092107388A patent/TWI324064B/zh not_active IP Right Cessation
- 2003-04-01 AR ARP030101128A patent/AR039209A1/es active IP Right Grant
- 2003-04-02 IL IL16389203A patent/IL163892A0/xx unknown
- 2003-04-02 CN CNB038053438A patent/CN100351251C/zh not_active Expired - Lifetime
- 2003-04-02 RU RU2004132203/04A patent/RU2340610C2/ru not_active IP Right Cessation
- 2003-04-02 US US10/510,027 patent/US20050119274A1/en not_active Abandoned
- 2003-04-02 CA CA2477774A patent/CA2477774C/en not_active Expired - Lifetime
- 2003-04-02 KR KR1020077007917A patent/KR100942329B1/ko not_active IP Right Cessation
- 2003-04-02 JP JP2003580325A patent/JP4247125B2/ja not_active Expired - Lifetime
- 2003-04-02 WO PCT/EP2003/003470 patent/WO2003082859A1/en active Application Filing
- 2003-04-02 DK DK03720413.8T patent/DK1490355T3/da active
- 2003-04-02 BR BR0308979-7A patent/BR0308979A/pt not_active IP Right Cessation
- 2003-04-02 AT AT03720413T patent/ATE517888T1/de active
- 2003-04-02 MY MYPI20031225A patent/MY137566A/en unknown
- 2003-04-02 PL PL371322A patent/PL213480B1/pl unknown
- 2003-04-02 PT PT03720413T patent/PT1490355E/pt unknown
- 2003-04-02 NZ NZ535613A patent/NZ535613A/en not_active IP Right Cessation
- 2003-04-02 EP EP03720413A patent/EP1490355B1/en not_active Expired - Lifetime
- 2003-04-02 MX MXPA04009632A patent/MXPA04009632A/es active IP Right Grant
- 2003-04-02 AU AU2003224031A patent/AU2003224031B2/en not_active Expired
- 2003-04-02 KR KR1020047015591A patent/KR100886521B1/ko not_active IP Right Cessation
- 2003-04-02 SI SI200332053T patent/SI1490355T1/sl unknown
-
2004
- 2004-08-27 EC EC2004005254A patent/ECSP045254A/es unknown
- 2004-09-15 CO CO04091784A patent/CO5611127A2/es active IP Right Grant
- 2004-10-26 NO NO20044613A patent/NO329166B1/no not_active IP Right Cessation
-
2006
- 2006-10-12 US US11/546,690 patent/US7358253B2/en not_active Expired - Lifetime
- 2006-10-12 US US11/546,693 patent/US7235555B2/en not_active Expired - Lifetime
-
2007
- 2007-10-25 US US11/977,565 patent/US20080108628A1/en not_active Abandoned
-
2008
- 2008-02-21 US US12/034,675 patent/US7534808B2/en not_active Expired - Lifetime
- 2008-12-12 EC EC2008005254A patent/ECSP085254A/es unknown
-
2011
- 2011-10-27 CY CY20111101021T patent/CY1111982T1/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI324064B (en) | Indolylmaleimide derivatives | |
JP4234426B2 (ja) | プロテインキナーゼcインヒビターとしてのインドリルマレイミド誘導体 | |
RU2373201C2 (ru) | Индолилмалеимидные производные | |
JP2009280592A (ja) | インドリルマレイミド誘導体 | |
CN101558062A (zh) | 作为激酶抑制剂的吲哚基马来酰亚胺衍生物 | |
WO2018214796A1 (zh) | 一类异吲哚酮-酰亚胺环-1,3-二酮-2-烯化合物、其组合物和用途 | |
JP4549387B2 (ja) | タンパク質キナーゼc阻害剤としての置換ピロール−2,5−ジオン | |
KR20070020401A (ko) | 인돌릴말레이미드 유도체 | |
MXPA06008159A (en) | Indolylmaleimide derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |