CN1146545C - 苯甲酰基哒嗪 - Google Patents
苯甲酰基哒嗪 Download PDFInfo
- Publication number
- CN1146545C CN1146545C CNB008100306A CN00810030A CN1146545C CN 1146545 C CN1146545 C CN 1146545C CN B008100306 A CNB008100306 A CN B008100306A CN 00810030 A CN00810030 A CN 00810030A CN 1146545 C CN1146545 C CN 1146545C
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- CN
- China
- Prior art keywords
- phenyl
- compound
- general formula
- carbonyl
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- VDWSVBMVZLRATD-UHFFFAOYSA-N phenyl(pyridazin-3-yl)methanone Chemical class C=1C=CN=NC=1C(=O)C1=CC=CC=C1 VDWSVBMVZLRATD-UHFFFAOYSA-N 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims description 88
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 229910052801 chlorine Inorganic materials 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 16
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- ZESWUEBPRPGMTP-UHFFFAOYSA-N 4-nitrobenzamide Chemical compound NC(=O)C1=CC=C([N+]([O-])=O)C=C1 ZESWUEBPRPGMTP-UHFFFAOYSA-N 0.000 claims description 7
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 2
- 238000010306 acid treatment Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 11
- 206010006895 Cachexia Diseases 0.000 abstract description 7
- 206010040047 Sepsis Diseases 0.000 abstract description 5
- 208000030507 AIDS Diseases 0.000 abstract description 4
- 208000006673 asthma Diseases 0.000 abstract description 4
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 4
- 201000006417 multiple sclerosis Diseases 0.000 abstract description 4
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 3
- 206010009900 Colitis ulcerative Diseases 0.000 abstract description 3
- 208000011231 Crohn disease Diseases 0.000 abstract description 3
- 206010012438 Dermatitis atopic Diseases 0.000 abstract description 3
- 206010027476 Metastases Diseases 0.000 abstract description 3
- 201000004681 Psoriasis Diseases 0.000 abstract description 3
- 206010052779 Transplant rejections Diseases 0.000 abstract description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 abstract description 3
- 201000008937 atopic dermatitis Diseases 0.000 abstract description 3
- 208000027866 inflammatory disease Diseases 0.000 abstract description 3
- 206010006458 Bronchitis chronic Diseases 0.000 abstract description 2
- 208000001132 Osteoporosis Diseases 0.000 abstract description 2
- 206010006451 bronchitis Diseases 0.000 abstract description 2
- 208000007451 chronic bronchitis Diseases 0.000 abstract description 2
- 230000012010 growth Effects 0.000 abstract description 2
- 230000001173 tumoral effect Effects 0.000 abstract 2
- 201000001320 Atherosclerosis Diseases 0.000 abstract 1
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 abstract 1
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 abstract 1
- 208000026935 allergic disease Diseases 0.000 abstract 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract 1
- 208000013223 septicemia Diseases 0.000 abstract 1
- 208000017520 skin disease Diseases 0.000 abstract 1
- -1 isobutyl- Chemical group 0.000 description 76
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 26
- 238000000034 method Methods 0.000 description 20
- 239000002585 base Substances 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000003708 ampul Substances 0.000 description 6
- 239000003999 initiator Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- KWAYEPXDGHYGRW-UHFFFAOYSA-N 3-nitrobenzamide Chemical compound NC(=O)C1=CC=CC([N+]([O-])=O)=C1 KWAYEPXDGHYGRW-UHFFFAOYSA-N 0.000 description 5
- BLNVISNJTIRAHF-UHFFFAOYSA-N 4-chlorobenzamide Chemical compound NC(=O)C1=CC=C(Cl)C=C1 BLNVISNJTIRAHF-UHFFFAOYSA-N 0.000 description 5
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 208000026500 emaciation Diseases 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- NXTNASSYJUXJDV-UHFFFAOYSA-N 3-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC(C(Cl)=O)=C1 NXTNASSYJUXJDV-UHFFFAOYSA-N 0.000 description 4
- USEDMAWWQDFMFY-UHFFFAOYSA-N 4-cyanobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(C#N)C=C1 USEDMAWWQDFMFY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UHBGYFCCKRAEHA-UHFFFAOYSA-N P-toluamide Chemical compound CC1=CC=C(C(N)=O)C=C1 UHBGYFCCKRAEHA-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- MJTGQALMWUUPQM-UHFFFAOYSA-N m-Chlorobenzamide Chemical compound NC(=O)C1=CC=CC(Cl)=C1 MJTGQALMWUUPQM-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WHIHIKVIWVIIER-UHFFFAOYSA-N 3-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1 WHIHIKVIWVIIER-UHFFFAOYSA-N 0.000 description 3
- VKPLPDIMEREJJF-UHFFFAOYSA-N 3-methoxybenzamide Chemical compound COC1=CC=CC(C(N)=O)=C1 VKPLPDIMEREJJF-UHFFFAOYSA-N 0.000 description 3
- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 description 3
- GUCPYIYFQVTFSI-UHFFFAOYSA-N 4-methoxybenzamide Chemical compound COC1=CC=C(C(N)=O)C=C1 GUCPYIYFQVTFSI-UHFFFAOYSA-N 0.000 description 3
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010039361 Sacroiliitis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000026139 Memory disease Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 102000018594 Tumour necrosis factor Human genes 0.000 description 2
- 108050007852 Tumour necrosis factor Proteins 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 229940099259 vaseline Drugs 0.000 description 2
- 239000000273 veterinary drug Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AGEBJYJJWHBPJT-UHFFFAOYSA-N $l^{1}-oxidanylsulfonylmethane Chemical compound CS([O])(=O)=O AGEBJYJJWHBPJT-UHFFFAOYSA-N 0.000 description 1
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- IRSVDHPYXFLLDS-UHFFFAOYSA-N 2,4-dichloro-1-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1Cl IRSVDHPYXFLLDS-UHFFFAOYSA-N 0.000 description 1
- HETVWNJEAWTHHK-UHFFFAOYSA-N 2,4-dinitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C([N+]([O-])=O)=C1 HETVWNJEAWTHHK-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- VTXNOVCTHUBABW-UHFFFAOYSA-N 3,4-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C(Cl)=C1 VTXNOVCTHUBABW-UHFFFAOYSA-N 0.000 description 1
- VIOBGCWEHLRBEP-UHFFFAOYSA-N 3,4-dimethoxybenzoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1OC VIOBGCWEHLRBEP-UHFFFAOYSA-N 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- FVOAKYSSAARGKC-UHFFFAOYSA-N 3-methylbenzamide Chemical compound [CH2]C1=CC=CC(C(N)=O)=C1 FVOAKYSSAARGKC-UHFFFAOYSA-N 0.000 description 1
- YHOYYHYBFSYOSQ-UHFFFAOYSA-N 3-methylbenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1 YHOYYHYBFSYOSQ-UHFFFAOYSA-N 0.000 description 1
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical group CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WEJHBEDHLLBJFW-UHFFFAOYSA-N 4-(trifluoromethyl)benzamide Chemical compound NC(=O)C1=CC=C(C(F)(F)F)C=C1 WEJHBEDHLLBJFW-UHFFFAOYSA-N 0.000 description 1
- OXZYBOLWRXENKT-UHFFFAOYSA-N 4-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=C(C(Cl)=O)C=C1 OXZYBOLWRXENKT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
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- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P11/08—Bronchodilators
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- 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
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- 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
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- 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
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Abstract
本发明涉及通式(I)的苯甲酰基衍生物和其生理上可接受的盐和溶剂化物,其中R1、R2、R3、R4、R5和R6定义见权利要求1。所说衍生物抑制磷酸二酯酶IV并可用于过敏疾病、哮喘、慢性支气管炎、过敏性湿疹、牛皮癣和其它皮肤病,炎症、自身免疫疾病如风湿病样关节炎、多发性硬化、可罗恩氏病、糖尿病或溃疡性结肠炎、移植排斥反应、恶病质、肿瘤生长或肿瘤转移、脓毒病、记忆疾病、粥样硬化和AIDS的治疗。
Description
本发明涉及通式I化合物和它们的生理可接受的盐和溶剂化物,
其中
R1、R2各自独立地代表H、OH、OA、SA、SOA、SO2A、F、Cl或A’2N-(CH2)n-O-,
R1和R2一起代表-O-CH2-O-,
R3、R4各自独立地代表H、A、卤素、OH、OA、NO2、NHA、NA2、CN、COOH、COOA、NHCOA、NHSO2A或NHCOOA,
R5、R6各自独立地代表H或C1-6烷基,
A是可以被1-5个F和/或Cl原子取代的C1-10烷基,C3-7环烷基,C5-10亚烷基环烷基或C2-8链烯基,
A’是1、2、3、4、5或6个C原子的烷基,
n是1、2、3或4,
卤素是F、Cl、Br或I。
在例如J.Med.Chem.38,4878(1995)中描述了1-苯甲酰基四氢哒嗪作为黄体酮受体配位体。
类似的化合物也在DE19632549A1中公开。
本发明的目的是寻找有价值的新化合物,特别是可以用作制备药物的化合物。
发现通式I化合物和它们的盐和溶剂化物非常有药物价值并有很好的耐受性。
特别是,它们显示了对磷酸二酯酶IV的选择性抑制,这与细胞内cAMP的增加有关(N.Sommer等,天然药物,1,244-248(1995))。
PDE IV的抑制可以被监测,例如类似C.W.Davis在Biochim.Biophys.Acta 797,354-362(1984)的方法。
本发明化合物可用于治疗哮喘疾病。PDE IV抑制剂的抗哮喘作用被例如T.J.Torphy等,在Thorax,46,512-523(1991)中描述并通过例如T.Olsson,Acta allergologica26,438-447(1971)的方法测定。
因为cAMP抑制破骨细胞并刺激破骨细胞(S.Kasugai等,M681和K.Miyamoto,M682,美国骨和矿物研究学会18届年会,1996),所以本发明化合物可以用于治疗骨质疏松。
此化合物还显示了对TNF(肿瘤坏死因子)产生的对抗作用,因此适用于过敏性和炎性疾病、自身免疫疾病的治疗,例如风湿病样关节炎、多发性硬化、可罗恩氏病、糖尿病或溃疡性结肠炎、移植排斥反应、恶病质和脓毒病。
本发明的化合物的抗炎性作用和它们对于治疗例如自身免疫的疗效例如多发性硬化或风温性关节炎可以通过类似N.Sommer等,天然药物1,244-248(1995)或L.Sekut等,Clin.Exp.Immunol.100,126-132(1995)方法测定。
本发明化合物可以用于恶病质的治疗。抗恶病质作用可以通过恶病质TNF-依赖模型试验(P.Costelli等,J.Clin.Invest.95,2367ff.(1995);J.M.Argiles等,Med.Res.Rev.17,477ff(1997))。
PDE IV抑制剂也可以抑制肿瘤细胞的生长并适于治疗肿瘤(D.Marko等,Cell Biochem.Biophys.28,75ff.(1998))。PDEIV抑制剂对肿瘤的治疗在例如WO9535281、WO9517399或WO9600215中描述。
PDE IV抑制剂可以防止脓毒病模型的死亡,因此适用于脓毒病的治疗(W.Fischer等,Biochem.Pharmacol.45,2399ff.(1993))。
它们进一步可用于治疗记忆疾病,粥样硬化、特应性皮炎和AIDS。
PDE IV抑制剂关于哮喘、炎性疾病、糖尿病、特应性皮炎、牛皮癣、AIDS、恶病质、肿瘤生长或肿瘤转移的治疗在例如EP779291中描述。
通式I化合物可以用作人用药物活性化合物和兽用药物。它们可以进一步用作药物活性化合物制备的中间体。
本发明涉及通式I的化合物和按权利要求1的通式I化合物和它们的盐和溶剂化物的制备方法,特征在于通式II的化合物与通式III的化合物反应
其中
R1和R2定义如上,
其中
R3、R4、R5、R6定义如权利要求1,和
L是Cl、Br、OH或反应性酯化OH基,
或通式IV化合物与通式V的化合物反应
其中
R1、R2和R5如权利要求1定义,
其中
R3、R4、R6如权利要求1定义,和
L是Cl、Br、OH或反应性酯化OH基,
或通式VI化合物与通式VII的化合物反应
其中
R1、R2、R5和R6如权利要求1定义,
其中
R3、R4如权利要求1定义,和
L是Cl、Br、OH或反应性酯化OH基,
和/或用酸处理通式I碱性化合物,将其转变成盐。
通式I化合物的溶剂化物是指惰性溶剂分子与通式I化合物的加成物,这是它们相互吸引的结果。溶剂化物如单-或二水合物或醇化物。
以上和以下R1、R2、R3、R4、R5、R6和L如果不特别地另外说明,如通式I、II、III、IV、V、VI和VII中的定义。
A优选烷基,更优选被1-5个氟和/或氯原子取代的烷基,更优选环烷基。
在上式中,烷基优选有1、2、3、4、5、6、7、8、9或10个碳原子的非支链烷基,优选1、2、3、4、5或6个碳原子,并优选甲基、乙基、三氟甲基、五氟乙基或丙基,更优选异丙基、丁基、异丁基、仲丁基或叔丁基,还优选正戊基、新戊基、异戊基或正己基。特别优选基、乙基、三氟甲基、丙基、异丙基、丁基、正戊基、正己基或正癸基。
优选3-7个碳原子的环烷基,优选环丙基和环丁基,更优选环戊基或环己基和环庚基;特别优选环戊基。
链烯基优选烯丙基、2-或3-丁烯基、异丁烯基、仲丁烯基;更优选4-戊烯基、异戊烯基或5-己烯基。
亚烷基优选非支链并优选亚甲烷基或亚乙烷基,更优选亚丙烷基或亚丁烷基。
优选5-10个碳原子的亚烷基环烷基并优选亚甲基环丙基、亚甲基环丁基,更优选亚甲基环戊基、亚甲基环己基或亚甲基环庚基,还优选亚乙基环丙基、亚乙基环丁基、亚乙基环戊基、亚乙基环己基或亚乙基环庚基、亚丙基环戊基、亚丙基环己基、亚丁基环戊基或亚丁基环己基。
A’优选甲基、乙基、丙基或丁基。
N优选2或3。
卤素优选F、Cl或Br和也可以是I。
R1和R2可以相同或不同并在苯环的3-或4-位。它们例如彼此独立地为羟基、-S-CH3、-SO-CH3、-SO2-CH3、F、Cl、Br或I或一起为亚甲基二氧基。优选它们为甲氧基、乙氧基、丙氧基、环戊氧基或氟-、二氟-或三氟甲氧基、或1-氟-、2-氟-、1,2-二氟-、2,2-二氟-、1,2,2-三氟-或2,2,2-三氟乙氧基。
R1特别优选甲氧基、乙氧基、环戊氧基或异丙氧基。
R2特别优选甲氧基或乙氧基。
R3优选A、F、Cl、Br或I、羟基、烷氧基、苯氧基、硝基、烷氨基、环烷氨基、二烷氨基、烷基环烷基氨基、NHCO烷基、NHCO环烷基、NHSO2烷基、NHSO2环烷基、NHCOO烷基或NHCOO环烷基,其中烷基和环烷基的定义如上。特别优选R3是硝基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、戊氧基、己氧基或癸氧基、Cl或F、NCOOCH3、NCOOC2H5、NSO2CH3、NCOCH3或NCOCH(CH3)2。
R3特别优选在苯环的3-或4-位。R4优选是H。
被R3/R4取代的苯环优选为苯基、邻-、间-或对甲基苯基、邻-、间-或对乙基苯基、邻-、间-或对丙基苯基、邻-、间-或对异丙基苯基、邻-、间-或对叔丁基苯基、邻-、间-或对-N,N-二甲氨基苯基、邻-、间-或对-硝基苯基、邻-、间-或对羟基苯基、邻-、间-或对甲氧基苯基、邻-、间-或对乙氧基苯基、邻-、间-或对异丙氧基苯基、邻-、间-或对丁氧基苯基、邻-、间-或对戊氧基苯基、邻-、间-或对己氧基苯基、邻-、间-或对癸氧基苯基、邻-、间-或对三氟甲基苯基、邻-、间-或对氟苯基、邻-、间-或对氯苯基、邻-、间-或对溴苯基、邻-、间-或对乙酰氨基苯基、邻-、间-或对异丙基羰基氨基苯基、邻-、间-或对甲磺酰基氨基苯基、邻-、间-或对乙磺酰基氨基苯基、
邻-、间-或对甲氧基羰基氨基苯基、邻-、间-或对乙氧基羰基氨基苯基,更优选2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二甲基苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二羟基苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氟苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氯苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二甲氧基苯基。
R5、R6优选独立地为H或甲基。
在整个本发明中多次出现的所有基团都可以相同或不同,即是互相独立的。
本发明涉及那些特别是至少一个基团是上述优选的定义之一的通式I化合物。一些优选化合物可以以下亚式Ia-Ih表示,其对应于通式I并且其中的基团没有明确定义时是指同通式I的定义,但是其中
在Ia中R1和R2各自独立地代表OA;
在Ib中R1和R2各自独立地代表OA,
A是1-10个碳原子的烷基或3-7个碳原子的环烷基;
在Ic中R1和R2各自独立地代表OA,
A是1-10个碳原子的烷基或3-7个碳原子的环烷基,
R3、R4各自独立地代表H、NO2、Cl、CF3、CN或OA;
在Id中R1和R2各自独立地代表OA,
A是14-10个碳原子的烷基或3-7个碳原子的环烷基,
R3、R4各自独立地代表H、NO2、Cl、CF3、CN或OA,
R5、R6各自独立地代表H或甲基;
在Ie中R1是OA或3-7个碳原子的环烷氧基,
R2是OA,
A是1-6个碳原子的烷基,
R3、R4各自独立地代表H、NO2、Cl、CF3、CN、COOA或OA,
R5、R6是H;
在If中R1是OH、OA或3-7个碳原子的环烷氧基,
R2是OH或OA,
A是1-6个碳原子的烷基,
R3、R4各自独立地代表H、NO2、Cl、CF3、CN、COOA或OA,
R5、R6各自独立地是H或A;
在Ig中R1是OH、OA或3-7个碳原子的环烷氧基或A’N-(CH2)n-O-,
R2是OH或OA,
A是1-6个碳原子的烷基,
A’是1、2、3或4个碳原子的烷基,
R3、R4各自独立地代表H、NO2、Cl、CF3、CN、COOA或OA,
R5、R6各自独立地是H或A;
n是2或3;
在Ih中R1是OH、OA或3-7个碳原子的环烷氧基或A’N-(CH2)n-O-,
R2是OH或OA,
A是1-6个碳原子的烷基,
A’是1、2、3或4个碳原子的烷基,
R3、R4各自独立地代表H、NO2、Cl、CF3、CN、COOA或OA,
R5、R6是H;
n是2或3;
通式I化合物和制备它们的起始物,可以通过其它已知的方法制备,例如文献方法(如Houben-Weyl标准方法,Methoden derorganischen Chemie[有机化学方法],Georg-Thieme-Verlag,Stuttgart),即反应条件是已知的和适合于上述反应。一些改变也是已知的,但不再具体叙述。
在通式II-IV化合物中,R1和R2如上定义,特别是优选定义同上。
如果L是反应活性的酯化了的羟基,优选1-6个碳原子的烷基磺酰基氧基(优选甲磺酰基氧基)或6-10个碳原子的芳基磺酰基氧基(优选苯基-或对甲苯基磺酰基氧基),还优选2-萘磺酰基氧基)。
如果需要,起始物也可以就地制备,它们无需从反应混合物中分离而立即继续反应以制备通式I化合物。
另一方面,也可以分步进行反应。
通式I化合物优选通过通式II化合物与通式III化合物反应获得。
通式II和III的起始物在某些情况下是已知的。如果它们不是已知的,可以通过本身已知的方法制备。
具体地说,通式II化合物与通式III化合物在惰性溶剂的存在或不存在下,在约-20-约150℃,优选20-100℃下进行。
适合的惰性溶剂是例如烃如己烷、石油醚、苯、甲苯或二甲苯;氯化烃如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚如乙醚、二异丙醚、四氢呋喃(THF)或二噁烷;乙二醇醚如乙二醇单甲醚或乙二醇单乙醚、乙二醇二甲醚;酮如丙酮或丁酮;酰胺如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈如乙腈;亚砜如二甲基亚砜(DMSO);硝基化合物如硝基甲烷或硝基苯;酯如乙酸乙酯或上述溶剂的混合物。
通式I化合物也可以通过通式IV和通式V化合物反应制备。
作为规律起始物的通式IV和V化合物是已知的。如果不是已知的,它们可通过本身已知的方法制备。
在通式III、V和VII化合物中,-CO-L基是预活化的羧酸,优选羧酸酰卤。
通式IV化合物与通式V化合物的反应在同通式II化合物与通式III化合物反应的相同条件下进行,涉及反应时间、温度和溶剂。
通式I化合物还可以通过通式VI化合物和通式VII化合物反应制备。作为规律,通式VI和VII起始物是已知的。因此,例如通式VI的化合物在DE19826841中描述。如果不是已知的,它们可通过本身已知的方法制备。
通式VI化合物与通式VII化合物的反应在相同条件下进行,所涉及的反应时间、温度和溶剂同通式II化合物与通式III化合物的反应条件。
用酸可将通式I的碱基转变成酸加成盐,例如将当量的碱和酸在例如乙醇的惰性溶剂中反应,然后蒸发。此反应可能的酸特别是那些制备可药用盐的酸。因此,可以使用的无机酸如硫酸、硝酸、氢卤酸如盐酸或氢溴酸、磷酸如正磷酸、氨基磺酸,和有机酸特别是脂族、脂环族、芳脂族、芳族或杂环单-或多元羧酸、磺酸或硫酸,如甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸或乙磺酸、乙烷二磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸、萘磺酸和萘二磺酸和十二烷基硫酸。与非药用酸形成的盐,如苦味酸盐,可以用于分离和/或提纯通式I化合物。
另一方面,如果需要,也可以从它们的盐与碱(例如氢氧化钠或氢氧化钾或碳酸钠或碳酸钾)释放出通式I的游离碱。
本发明涉及作为药物的通式I化合物和它们的可药用盐和溶剂化物。
本发明还涉及作为磷酸二酯酶IV抑制剂的通式I化合物和它们的可药用盐和溶剂化物。
本发明进一步涉及使用通式I化合物和/或它们的可药用盐和/或溶剂化物制备药物,特别是非化学方法。它们可以与适量的至少一种固体、液体和/或半液体赋形剂或辅助剂混合,如果适合,与一种或多种其它活性化合物联合使用。
本发明进一步涉及含至少一种通式I化合物和/或一种药用盐和/或溶剂化物的药物制剂。
这些制剂可以用于人用药或兽药。适用的赋形剂是适于胃肠(如口服)或胃肠外给药或局部给药且不与新化合物反应的有机或无机物,例如水、植物油、苯甲醇、亚烷基二醇、聚乙二醇、甘油三乙酸酯、明胶、糖类如果糖或淀粉、硬脂酸镁、滑石和凡士林。特别是由于口服给药的片剂、丸剂、包衣片、胶囊剂、粉剂、颗粒剂、糖浆、糖汁或滴剂,直肠给药的栓剂,用于胃肠外给药的溶液优选油或水溶液和悬浮液、乳液或植入物,和用于局部给药的软膏、乳膏或粉末。新化合物也可冻干和以例如注射制剂的制备方法进行冻干。此制剂可以灭菌和/或含例如润滑剂、防腐剂、稳定剂和/或湿润剂、乳化剂、影响渗透压的盐、缓冲物、着色剂、调味剂的辅助剂和/或一种或多种其它活性化合物如一种或多种维生素。
通式I化合物和它们的生理上可接受的盐和溶剂化物可以用于因cAMP(环状磷酸腺甙)水平升高导致的疾病以抑制或预防炎症和肌肉松弛等。本发明PDE IV抑制剂特别适用于治疗过敏性疾病、哮喘、慢性支气管炎、过敏性湿疹、牛皮癣和其它皮肤病,炎症、自身免疫疾病如风湿病样关节炎、多发性硬化、可罗恩氏病、糖尿病或溃疡性结肠炎、移植排斥反应、恶病质、肿瘤生长或肿瘤转移、脓毒病、记忆疾病、粥样硬化和AIDS。
作为规律,本发明化合物给药剂量优选为1-500mg,特别优选5-100mg每剂量单位。日剂量优选约0.02-10mg/kg体重。对于每位患者的具体剂量取决于多种因素,例如所用化合物的疗效、年龄、体重、健康状况、性别、饮食、给药时间和给药途径、以及代谢途径。对于特别严重的疾病可以使用联合药物治疗。优选口服给药。
上述和下述的所有温度都以℃表示。在以下实施例中,“惯用后处理”是指:如果需要,加水,调整混合物,如果需要,根据终产物的构成调节至pH2-10,并以乙酸乙酯或二氯甲烷萃取,分离有机相,硫酸钠干燥和蒸发,并将残余物通过硅胶色谱和/或结晶提纯。
实施例1
用0.96g 4-硝基苯甲酰氯的10ml二氯甲烷溶液处理2.2g 4-氨基-N-{3-[3-(3-乙氧基-4-甲氧基苯基)-5,6-二氢-4H-哒嗪-1-羰基]-苯基}苯甲酰胺(“A”)[在室温下,在3.5g阮内镍的存在下,由4-硝基-N-{3-[3-(3-乙氧基-4-甲氧基苯基)-5,6-二氢-4H-哒嗪基-1-羰基]-苯基}苯甲酰胺的150ml四氢呋喃溶液催化氢化制备]和0.6ml吡啶的70ml二氯甲烷溶液,并搅拌20小时。除去溶剂并将混合物以惯用方法处理。重结晶后,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-4H-1-哒嗪羰基]-苯基氨基羰基}苯基)-4-硝基-苯甲酰胺,熔点272℃。
以类似的方法通过“A”
与苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)苯甲酰胺,熔点267℃;
与3-硝基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-硝基苯甲酰胺,熔点204℃;
与2,4-二氯苯甲酰氯反应,得到N-(4-{3-[3-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]苯基氨基羰基}苯基)-2,4-二氯苯甲酰胺,熔点253℃;
与3-氯苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-氯苯甲酰胺,熔点219℃;
与4-氯苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-氯苯甲酰胺,熔点253℃;
与3,4-二氯苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3,4-二氯苯甲酰胺,熔点224℃;
与4-三氟甲基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-三氟甲基苯甲酰胺,熔点262℃;
以3-氨基-N-{3-[3-(3-乙氧基-4-甲氧基苯基)-5,6-二氢-4H-哒嗪-1-羰基]-苯基}苯甲酰胺(“B”)为起始物,以类似的方法得到以下化合物
N-(3-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)苯甲酰胺,熔点146℃;
N-(3-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-硝基苯甲酰胺,熔点228℃;
N-(3-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-硝基苯甲酰胺,熔点245℃;
N-(3-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-氯苯甲酰胺,熔点128℃;
N-(3-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-氯苯甲酰胺,熔点207℃;
N-(3-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-2,4-二氯苯甲酰胺,熔点210℃;
N-(3-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-甲氧基苯甲酰胺,熔点208℃。
以类似的方法通过“A”
与4-甲氧基羰基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-甲氧基羰基苯甲酰胺,熔点248-250℃;
与4-氰基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-氰基羰基苯甲酰胺,熔点243-245℃;
与2,4-二硝基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-2,4-二硝基基苯甲酰胺,熔点246-247℃;
与4-氟苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-氟甲基苯甲酰胺,
与4-丁氧基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-丁氧基苯甲酰胺,
与4-戊氧基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-戊氧基苯甲酰胺,
与4-乙氧基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基)苯基)-4-乙氧基苯甲酰胺,
与3,4-二甲氧基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基)苯基)-3,4-二甲氧基苯甲酰胺,
与3-甲基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-甲基苯甲酰胺,
与3-甲氧基苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-甲氧基苯甲酰胺。
类似地4-氨基-N-{4-[3-(3-乙氧基-4-甲氧基苯基)-5,6-二氢-4H-哒嗪-1-羰基]-苯基}苯甲酰胺(“C”)
与苯甲酰氯反应,得到N-(4-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基)苯基)苯甲酰胺,熔点278℃;
与3-硝基苯甲酰氯反应,得到N-(4-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-硝基苯甲酰胺,熔点284℃;
与4-硝基苯甲酰氯反应,得到N-(4-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-硝基苯甲酰胺,熔点279℃;
与3-氯苯甲酰氯反应,得到N-(4-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-氯苯甲酰胺,熔点278℃;
与4-氯苯甲酰氯反应,得到N-(4-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-氯苯甲酰胺,熔点281℃;
与3-甲氧基苯甲酰氯反应,得到N-(4-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-甲氧基苯甲酰胺,熔点228-230℃;
与4-甲氧基苯甲酰氯反应,得到N-(4-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-甲氧基苯甲酰胺,熔点331℃;
与4-甲基苯甲酰氯反应,得到N-(4-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-甲基苯甲酰胺,熔点298℃;
与4-氰基苯甲酰氯反应,得到N-(4-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-氰基苯甲酰胺,熔点258℃。
类似地3-氨基-N-{4-[3-(3-乙氧基-4-甲氧基苯基)-5,6-二氢-4H-哒嗪-1-羰基]-苯基}苯甲酰胺(“C”)
与苯甲酰氯反应,得到N-(3-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)苯甲酰胺,熔点217-218℃;
与3-硝基苯甲酰氯反应,得到N-(3-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-硝基苯甲酰胺,熔点269-271℃;
与4-硝基苯甲酰氨反应,得到N-(3-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-硝基苯甲酰胺,熔点279℃;
与3-氯苯甲酰氯反应,得到N-(3-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-氯苯甲酰胺,熔点232-233℃;
与4-氯苯甲酰氯反应,得到N-(3-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-氯苯甲酰胺,熔点270℃;
与3-甲氧基苯甲酰氯反应,得到N-(3-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-甲氧基苯甲酰胺,熔点237-239℃;
与4-甲氧基苯甲酰氯反应,得到N-(3-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-甲氧基苯甲酰胺,熔点248-249℃;
与4-甲基苯甲酰氯反应,得到N-(3-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-甲基苯甲酰胺,熔点254-255℃;
与4-氰基苯甲酰氯反应,得到N-(3-{4-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-氰基苯甲酰胺,熔点260℃;
实施例2
以类似实施例1的方法,将4-氨基-N-{3-[3-(3-异丙氧基-4-甲氧基苯基)-5,6-二氢-4H-哒嗪-1-羰基]-苯基}苯甲酰胺(“D”)
与4-硝基苯甲酰氯反应,得到N-(4-{3-[3-(3-异丙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-硝基苯甲酰胺,熔点202℃。
以类似实施例1的方法,将4-氨基-N-{3-[3-(3-环戊氧基-4-甲氧基苯基)-5,6-二氢-4H-哒嗪-1-羰基]-苯基}苯甲酰胺(“E”)
与3-硝基苯甲酰氯反应,得到N-(4-{3-[3-(3-环戊氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-3-硝基苯甲酰胺,熔点208℃;
与4-氯苯甲酰氯反应,得到N-(4-{3-[3-(3-环戊氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-氯苯甲酰胺,熔点257℃;
与4-氰基苯甲酰氯反应,得到N-(4-{3-[3-(3-环戊氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-氰基苯甲酰胺,熔点271℃。
实施例3
以类似实施例1的方法,将N-{3-[3-(3-乙氧基-4-甲氧基苯基)-5,6-二氢-4H-哒嗪-1-羰基]-苯基}-N-甲基-4-甲基氨基苯甲酰胺
与4-氯苯甲酰氯反应,得到N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基-N-甲基氨基羰基}苯基)-N-甲基-4-氯苯甲酰胺,无定形。
实施例4
以类似实施例1的方法,获得N-(4-{3-[3-(3-环戊氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]苯基氨基羰基}苯基)-4-硝基苯甲酰胺,熔点202-205℃,和N-(4-{3-[3-(3-N,N-二甲基氨基乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]苯基氨基羰基}苯基)-4-硝基苯甲酰胺,熔点274℃。
以下实施例涉及药物制剂:
实施例A:注射安瓿
用2N盐酸调解100g通式I活性化合物和5g磷酸氢二钠的3升双蒸水溶液至pH6.5,灭菌过滤,置注射安瓿中,在无菌条件下冻干并无菌密封。每个注射安瓿中含5mg活性化合物。
实施例B:栓剂
将20g通式I活性化合物混合在100g大豆磷脂和1400g可可酯的混合物中,倾倒入栓模中并冷却。每个栓含20mg活性化合物。
实施例C:溶液
制备1g通式I活性化合物、9.38g NaH2PO4·H2O、28.48gNa2HPO4·12H2O和0.1g氯化苄烷铵的940ml双蒸水溶液。调节至pH6.8,定容至1升并用紫外线照射灭菌。此溶液可用作滴眼液。
实施例D:软膏
在无菌条件下,将500mg通式I活性化合物与99.5g凡士林混合。
实施例E:片剂
将1kg通式I活性化合物、4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石和0.1kg硬脂酸镁的混合物通过惯用方法制片,每片中含10mg活性化合物。
实施例F:包衣片
以实施例E类似的方法压片,然后以惯用的方法以蔗糖、马铃薯淀粉、滑石、黄蓍胶和着色剂包衣。
实施例G:胶囊
以惯用方法,将2kg的通式I的活性化合物分散在硬明胶胶囊中,每粒胶囊含20mg活性化合物。
实施例H:安瓿
将1kg的通式I活性化合物在60升双蒸水中的溶液过滤灭菌,分装在安瓿中,在无菌条件下冻干和灭菌密封。每个安瓿含10mg活性化合物。
实施例I:吸入喷雾剂
将14g通式I活性化合物溶解在10升等渗氯化钠溶液中,并将溶液分装在可商业购得的具有泵装置的喷雾瓶中。此溶液用于口或鼻喷雾。喷雾一次量(约0.1ml)相应剂量约为0.14mg。
Claims (6)
2.权利要求1的通式I化合物或它们的生理可接受的盐,其中的化合物是
N-(4-{3-[3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢-1-哒嗪基羰基]-苯基氨基羰基}苯基)-4-硝基苯甲酰胺。
3.权利要求1的通式I化合物或它们的盐的制备方法,特征在于通式II的化合物与通式III的化合物反应
其中
R1和R2定义如上,
其中
R3、R4、R5、R6定义如权利要求1,和
L是Cl、Br、OH或反应性酯化的OH基,
或通式IV化合物与通式V的化合物反应
其中
R1、R2和R5如权利要求1定义,
其中
R3、R4、R6如权利要求1定义,和
L是Cl、Br、OH或反应性酯化的OH基,
或通式VI化合物与通式VII的化合物反应
其中
R1、R2、R5和R6如权利要求1定义,
其中
R3、R4如权利要求1定义,和
L是Cl、Br、OH或反应性酯化的OH基,
或用酸处理通式I的碱性化合物,将其转变成盐。
4.权利要求1的通式I化合物或其生理上可接受的盐在制备磷酸二酯酶IV抑制剂药物中的应用。
5.药物组合物,其特征在于含至少一种权利要求1的通式I化合物或一种其生理上可接受的盐。
6.药物组合物的生产方法,其特征是权利要求1的通式I化合物或一种其生理上可接受的盐与至少一种适量的固体、液体或半液体赋形剂或辅助剂混合。
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DE19932315.1 | 1999-07-10 | ||
DE19932315A DE19932315A1 (de) | 1999-07-10 | 1999-07-10 | Benzoylpyridazine |
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EP (1) | EP1194411B1 (zh) |
JP (1) | JP2003504358A (zh) |
KR (1) | KR20020019923A (zh) |
CN (1) | CN1146545C (zh) |
AR (1) | AR024672A1 (zh) |
AT (1) | ATE269311T1 (zh) |
AU (1) | AU763005B2 (zh) |
BR (1) | BR0012328A (zh) |
CA (1) | CA2378595A1 (zh) |
CZ (1) | CZ200212A3 (zh) |
DE (2) | DE19932315A1 (zh) |
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NO (1) | NO20020096D0 (zh) |
PL (1) | PL353175A1 (zh) |
PT (1) | PT1194411E (zh) |
SI (1) | SI1194411T1 (zh) |
SK (1) | SK72002A3 (zh) |
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US20050070529A1 (en) * | 2001-02-12 | 2005-03-31 | Merk Pantent Gmbh | Use of type 4 phosphodiesterase inhibitors in myocardial diseases |
MXPA04003668A (es) * | 2001-10-31 | 2004-07-22 | Merck Patent Gmbh | Inhibidores de fosfodiesteresa de tipo 4 y usos de los mismos. |
EP1441730B1 (en) | 2001-11-05 | 2006-08-09 | Merck Patent GmbH | Hydrazono-malonitriles |
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DE19632549A1 (de) * | 1996-08-13 | 1998-02-19 | Merck Patent Gmbh | Arylalkanoylpyridazine |
DE19826841A1 (de) * | 1998-06-16 | 1999-12-23 | Merck Patent Gmbh | Arylalkanoylpyridazine |
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1999
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Also Published As
Publication number | Publication date |
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PL353175A1 (en) | 2003-11-03 |
BR0012328A (pt) | 2007-01-02 |
MXPA02000317A (es) | 2002-07-30 |
KR20020019923A (ko) | 2002-03-13 |
AU763005B2 (en) | 2003-07-10 |
CA2378595A1 (en) | 2001-01-18 |
AR024672A1 (es) | 2002-10-23 |
JP2003504358A (ja) | 2003-02-04 |
AU6688300A (en) | 2001-01-30 |
ES2220513T3 (es) | 2004-12-16 |
ZA200201087B (en) | 2003-07-30 |
HUP0201828A2 (hu) | 2002-12-28 |
NO20020096L (no) | 2002-01-09 |
NO20020096D0 (no) | 2002-01-09 |
ATE269311T1 (de) | 2004-07-15 |
US6696446B1 (en) | 2004-02-24 |
SI1194411T1 (en) | 2004-10-31 |
SK72002A3 (en) | 2002-05-09 |
DE50006829D1 (de) | 2004-07-22 |
WO2001004099A1 (de) | 2001-01-18 |
HK1048116A1 (zh) | 2003-03-21 |
HUP0201828A3 (en) | 2003-02-28 |
PT1194411E (pt) | 2004-11-30 |
EP1194411B1 (de) | 2004-06-16 |
CZ200212A3 (cs) | 2002-04-17 |
DK1194411T3 (da) | 2004-10-18 |
CN1360581A (zh) | 2002-07-24 |
EP1194411A1 (de) | 2002-04-10 |
DE19932315A1 (de) | 2001-01-11 |
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