CN1163884A - 作为药物有效成分的二甲基-(3-芳基-丁-3-烯基)-胺化合物 - Google Patents
作为药物有效成分的二甲基-(3-芳基-丁-3-烯基)-胺化合物 Download PDFInfo
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- CN1163884A CN1163884A CN97103487A CN97103487A CN1163884A CN 1163884 A CN1163884 A CN 1163884A CN 97103487 A CN97103487 A CN 97103487A CN 97103487 A CN97103487 A CN 97103487A CN 1163884 A CN1163884 A CN 1163884A
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- Prior art keywords
- expression
- alkyl
- condition
- methyl
- benzyl
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- 239000004480 active ingredient Substances 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 239000003513 alkali Substances 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 229910052801 chlorine Inorganic materials 0.000 claims description 29
- 229910052731 fluorine Inorganic materials 0.000 claims description 27
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 18
- 230000000202 analgesic effect Effects 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 7
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 3
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 150000002902 organometallic compounds Chemical class 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 158
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 35
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 24
- -1 clodronic acid diaryl ester Chemical class 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 239000005051 trimethylchlorosilane Substances 0.000 description 17
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 16
- 235000019253 formic acid Nutrition 0.000 description 16
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 239000000203 mixture Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000004821 distillation Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 238000003825 pressing Methods 0.000 description 8
- 208000002193 Pain Diseases 0.000 description 7
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 description 6
- BZRRKCWIPYYGLW-UHFFFAOYSA-N Cl.CN(CC(C)C(=C)C=1C=C(C=CC1)O)C Chemical compound Cl.CN(CC(C)C(=C)C=1C=C(C=CC1)O)C BZRRKCWIPYYGLW-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 230000036407 pain Effects 0.000 description 6
- FZPDGVOXZFKFHI-MFGIPTIESA-N 4-[(z)-5-(dimethylamino)-4-methylpent-2-en-3-yl]phenol;hydrochloride Chemical compound Cl.CN(C)CC(C)/C(=C/C)C1=CC=C(O)C=C1 FZPDGVOXZFKFHI-MFGIPTIESA-N 0.000 description 5
- 239000000470 constituent Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- IWJTXTSZGVMTQC-UHFFFAOYSA-N 3-[5-(dimethylamino)-2,4-dimethylpent-2-en-3-yl]phenol;hydrochloride Chemical compound Cl.CN(C)CC(C)C(=C(C)C)C1=CC=CC(O)=C1 IWJTXTSZGVMTQC-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000036571 hydration Effects 0.000 description 4
- 238000006703 hydration reaction Methods 0.000 description 4
- 229940127240 opiate Drugs 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- TZOOYBCJSXMJPM-UOOGNVTLSA-N 3-[(z,4r)-5-(dimethylamino)-4-methylpent-2-en-3-yl]phenol;hydrochloride Chemical compound Cl.CN(C)C[C@H](C)/C(=C/C)C1=CC=CC(O)=C1 TZOOYBCJSXMJPM-UOOGNVTLSA-N 0.000 description 3
- TZOOYBCJSXMJPM-BEOAFFHPSA-N Cl.CN(C)C[C@@H](C)\C(=C/C)C1=CC=CC(O)=C1 Chemical compound Cl.CN(C)C[C@@H](C)\C(=C/C)C1=CC=CC(O)=C1 TZOOYBCJSXMJPM-BEOAFFHPSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 150000004054 benzoquinones Chemical class 0.000 description 3
- 208000022371 chronic pain syndrome Diseases 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
- 229910052736 halogen Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- XLQSXGGDTHANLN-UHFFFAOYSA-N 1-bromo-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(Br)C=C1 XLQSXGGDTHANLN-UHFFFAOYSA-N 0.000 description 2
- UJBOOUHRTQVGRU-UHFFFAOYSA-N 3-methylcyclohexan-1-one Chemical compound CC1CCCC(=O)C1 UJBOOUHRTQVGRU-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-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
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
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- 150000002900 organolithium compounds Chemical class 0.000 description 2
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- 230000004044 response Effects 0.000 description 2
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 description 1
- ICBPURKUPVLVCM-UHFFFAOYSA-N 1,5-dimethyl-2-phenylpyrazol-3-one;2-hydroxy-2-phenylacetic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1.CN1C(C)=CC(=O)N1C1=CC=CC=C1 ICBPURKUPVLVCM-UHFFFAOYSA-N 0.000 description 1
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- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical class O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 1
- IRGWVAWLHXDKIX-PBCQUBLHSA-N 3-[(1r,2r)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]phenol;hydrochloride Chemical compound Cl.CN(C)C[C@H]1CCCC[C@]1(O)C1=CC=CC(O)=C1 IRGWVAWLHXDKIX-PBCQUBLHSA-N 0.000 description 1
- TZOOYBCJSXMJPM-MFGIPTIESA-N 3-[(Z)-5-(dimethylamino)-4-methylpent-2-en-3-yl]phenol hydrochloride Chemical compound Cl.CN(C)CC(C)/C(=C/C)C1=CC=CC(O)=C1 TZOOYBCJSXMJPM-MFGIPTIESA-N 0.000 description 1
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- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
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Abstract
描述了二甲基-(3-芳基-丁-3-烯基)-胺化合物、其制备方法以及将这些化合物作为药物有效成分的用途。
Description
本发明涉及二甲基-(3-芳基-丁-3-烯基)-胺化合物及其制备方法和这些化合物在药物中的用途。
慢性疼痛疾病或非慢性疼痛疾病的治疗在医学中具有很大的重要性。当前在世界范围内需要除阿片类外另外的表现良好效果的疼痛治疗方法。迫切需要适用于病人(可理解为成功地及满意地治疗病人的疼痛)的、目标定向地治疗慢性疼痛疾病或非慢性疼痛疾病的方法,最近在应用镇痛药领域或在感受伤害的基础研究中出现的大量科学论文中证明了这点。
尽管阿片类产生一系列的副作用、如成瘾性和药物依赖、呼吸抑制、胃肠抑制作用和顽强便秘,但多年来仍一直将其用作治疗疼痛的镇痛药。因此,它们只能遵照例如特殊处方管制的特别措施长期或高剂量用药(Goodman,Gilman,The Pharmaceutical Basis of Therapeutics,Pergamon Press,New York,1990)。
盐酸曲马多-盐酸(1RS,2RS)-2-二-甲氨基甲基-1-(3-甲氧基苯基)-环己醇-在主要起作用的镇痛药中占有特殊地位,因为这种有效成分作为疼痛的强抑制剂而无众所周知的阿片类的副作用(J.Pharmacol.Exptl.Ther.267,331(1993))。曲马多是一种外消旋体,由等量的(+)对映体和(-)对映体组成。该有效成分在体内生成同样以对映体混合物存在的代谢物O-去甲基曲马多。研究表明,曲马多的两个对映体及曲马多代谢物的两个对映体都在镇痛作用方面起作用(J.Pharmacol.Exptl.Ther.260,275(1992))。
本发明的潜在目的包括研制具有镇痛作用、适用于治疗严重疼痛、而无典型阿片类产生的副作用的物质。
目的也包括要研制的物质不应表现用曲马多治疗的某些情况中发生的例如恶心和呕吐的副作用。
现已发现,用某些二甲基-(3-芳基-丁-3-烯基)-胺可满足要研制的物质的需要。这些物质与曲马多相比,其区别是显著增强的确定的镇痛作用。
其中R1是C1-5烷基而R2表示H或C1-5烷基,或R1和R2一起表示-(CH2)2-4-、-(CH2)2-CHR7或-CH2-CHR7-CH2-,R3表示H或C1-5烷基,R4表示H、OH、C1-4烷基、O-C1-4烷基、O-苄基、CF3、O-CF3、Cl、F或OR8,R5表示H、OH、C1-4烷基、O-C1-4烷基、O-苄基、CHF2、CF3、O-CF3、Cl、F或OR8,而R6表示H、OH、C1-4烷基、O-C1-4烷基、O-苄基、CF3、O-CF3、Cl、F或OR8,条件是R4、R5和R6中的两个基团是H,或R4和R5一起表示-CH=C(R9)-O-或-CH=C(R9)-S-,条件是R6是H,或R5和R6一起表示-CH=CH-C(OR10)=CH-,条件是R4是H,R7表示C1-8烷基、C3-8环烷基、CO-C1-4烷基、O-苄基、CF3、Cl或F,R8表示CO-C1-5烷基、PO(O-C1-4烷基)2、CO-C6H4-R11、CO(O-C1-5烷基)、CO-CHR12-NHR13、CO-NH-C6H3-(R14)2或未取代或取代的吡啶基、噻吩基、噻唑基或苯基基团,R9表示H或C1-4烷基,R10表示H或C1-3烷基,R11表示邻位的OC(O)-C1-3烷基或间位或对位的CH2-N-(R15)2,其中R15表示C1-4烷基或两个基团R15与N一起代表4-吗啉基基团,R12和R13相同或不同,表示H或C1-6烷基或C3-8环烷基,或R12和R13一起表示-(CH2)3-8-,R14表示H、OH、C1-7烷基、O-C1-7烷基、苯基、O-芳基、CF3、Cl或F,条件是两个基团R14相同或不同,作为对映体或消旋体,只是要排除其中R1和R2一起是-(CH2)3-,R3、R4和R6表示H,而R5是OCH3的式I化合物的消旋体。
推荐的二甲基-(3-芳基-丁-3-烯基)-胺化合物相应地是式I其中R1是C1-3烷基而R2是H或C1-3烷基,R3表示H或C1-3烷基,R4表示H、OH、CF3、Cl、F或OR8,R5表示H、OH、C1-4烷基、O-C1-4烷基、O-苄基、CHF2、CF3、Cl、F或OR8,而R6表示H、OH、O-C1-4烷基、O-苄基、CF3、Cl、F或OR8,条件是R4、R5和R6中的两个基团是H,或R4和R5一起表示-CH=C(R9)-O-或-CH=C(R9)-S-,条件是R6是H,或R5和R6一起表示-CH=C(OR10)=CH-,条件是R4是H,R7表示C1-4烷基、CF3、Cl或F。特别适合的式I的二甲基-(3-芳基-丁-3-烯基)-胺化合物是其中R1是CH3或C3H7,而R2表示H或CH3或CH2CH3,或R1和R2一起表示-(CH2)2-3-或-(CH2)2-CHR7,R3表示H或CH3或CH2CH3,R4表示H或OH,R5表示H、OH、OCH3、CHF2或OR8,而R6表示H、OH或CF3,条件是R4、R5和R6中的两个基团是H,或R4和R5一起表示-CH=C(CH3)-S-,条件是R6是H,或R5和R6一起表示-CH=CH-C(OH)=CH-,条件是R4是H,而R8表示CO-C6H4-R11,其中R11表示邻位的OC(O)-C1-3烷基。特别推荐的二甲基-(3-芳基-丁-3-烯基)-胺化合物是其中R1表示CH3,而R2表示H或CH3,或R1和R2一起表示-(CH2)2-3-或-(CH2)2-CH(CH3)-,R3表示H或CH3,R4表示H,R5表示OH或OR8,R6是H,而R8表示CO-C6H4-R11,其中R11表示邻位的OC(O)-CH3。
本发明也涉及制备式I的二甲基-(3-芳基-丁-3-烯基)-胺化合物的方法,其中R1是C1-5烷基而R2表示H或C1-5烷基,或R1和R2一起表示-(CH2)2-4-、-(CH2)2-CHR7或-CH2-CHR7-CH2-,R3表示H或C1-5烷基,R4表示H、C1-4烷基、O-C1-4烷基、O-苄基、CF3、O-CF3、Cl或F,R5表示H、C1-4烷基、O-C1-4烷基、O-苄基、CHF2、CF3、O-CF3、Cl或F,而R6表示H、C1-4烷基、O-C1-4烷基、O-苄基、CF3、O-CF3、Cl或F,条件是R4、R5和R6中的两个基团是H,或R4和R5一起表示-CH=C(R9)-O-或-CH=C(R9)-S-,条件是R6是H,或R5和R6一起表示-CH=CH-C(OR10)=CH-,条件是R4是H,R7表示C1-8烷基、C3-8环烷基、O-C1-4烷基、O-苄基、CF3、Cl或F,R9表示H或C1-4烷基,R10表示H或C1-3烷基,其中排除其中R1和R2一起表示-(CH2)3-,R3、R4和R6表示H,而R5是OCH3的式I化合物,其特征在于,将式II的β-二甲基氨基酮与式III的有机金属化合物(其中Z表示MgCl、MgBr、MgI或Li)反应,生成式IV的叔醇随后脱水生成式I化合物。
β-二甲基氨基酮与式III的Grignard化合物(其中Z表示MgCl、MgBr、MgI)或与式III的有机锂化合物的反应可以在例如乙醚和/或四氢呋喃的脂族醚中、于-70-+60℃进行。可以加入或不加入载体试剂(最好是1,2-二溴乙烷),进行与Grignard化合物的反应。通过卤素/锂交换,通过式III化合物(其中Z表示Cl、Br、I)例如与正丁基锂在己烷溶液反应,获得式III的有机锂化合物。得到的式IV叔醇可以用酸、特别是甲酸或盐酸,在0-100℃脱水。
本发明也涉及制备式I的二甲基-(3-芳基-丁-3-烯基)-胺化合物的方法,其中R1是C1-5烷基而R2表示H或C1-5烷基,或R1和R2一起表示-(CH2)2-4-、-(CH2)2-CHR7或-CH2-CHR7-CH2-,R3表示H或C1-5烷基,R4、R5和R6中的一个基团表示OH,而其余两个基团是H,R7表示C1-8烷基、C3-8环烷基、O-C1-4烷基、O-苄基、CF3、Cl或F,其特征在于,将式I化合物(其中R4、R5和R6中的一个基团表示O-CH3、而其余两个基团是H)与氢化二异丁基铝反应,或将式I的化合物(R4、R5和R6中的一个基团表示O-苄基,而其余两个基团是H)还原性去苄基。
通常在例如甲苯的芳烃中、在60-130℃进行二甲基-(3-芳基-丁-3-烯基)-胺化合物与氢化二异丁基铝的反应(Synthesis 1975,617;DE 2409 990,DE 24 09 991;Chem.Abstr.84,59862(1974))。
本发明式I化合物(其中R4、R5和R6中的一个基团表示O-苄基)的还原性去苄基可以在例如活性炭的载体物质上铂或钯的存在下、在例如乙酸或C1-4烷醇的溶剂中氢的存在下、在1-100巴的压力和20-100℃的温度下进行。
通过将相应的式I的二甲基-[3-(羟基-苯基)-丁-3-烯基]-胺化合物的碱性盐形式(其中R4、R5和/或R6表示OH基团)与氯膦酸二芳基酯、与氯甲酸芳基酯、与异氰酸芳基酯或杂芳基酯、与氯羧酸或与芳基卤或杂芳基卤反应,可以得到式I的二甲基-(3-芳基-丁-3-烯基)-胺化合物(其中一个以上的芳香取代基R4、R5或R6表示OR8,而OR8表示磷酸酯、碳酸酯、氨基甲酸酯、羧酸酯、芳氧基基团或杂芳氧基基团)。这些反应通常在例如甲苯、二氯甲烷、乙醚和/或四氢呋喃的溶剂中,在-15-+110℃进行(Drugs ofthe Future 16,443(1991);J.Med.Chem.30,2008(1989)和32,2503(1989);J.Org.Chem.43,4797(1978);Tetrahedron Lett.1977,J.Pharm.Sci.57,774(1968))。加入铜粉和/或卤化铜(I)催化剂进行与芳基卤或杂芳基卤的反应。
通过在例如二氯甲烷溶剂中使用三乙胺和诸如氟磷酸苯并三唑-1-基-氧-三吡咯烷鏻之类的偶合试剂,将相应的式I的二甲基-[3-(羟基-苯基)-丁-3-烯基]-胺化合物(其中R4、R5和/或R6表示OH基团)与相应的2-丁氧基羰基-氨基酸反应,可以得到OR8表示α-氨基酸基团的式I的二甲基-(3-芳基-丁-3-烯基)-胺化合物。
可以将式I化合物以本领域已知的方式,用生理学相容的酸(例如盐酸、氢溴酸、硫酸、甲磺酸、甲酸、乙酸、草酸、琥珀酸、酒石酸、杏仁酸、富马酸、乳酸、柠檬酸、谷氨酸和/或天门冬氨酸)转化为其盐。盐的生成最好在溶剂例如乙醚、异丙醚、乙酸烷基酯、丙酮和/或2-丁酮中进行。而且,含三甲基氯硅的水溶液烷适用于盐酸盐的制备。
本发明化合物具有确定的镇痛作用并且为毒理学上无害的。因此它们适用作药物的有效成分。因此,本发明涉及按照权利要求1的式I的二甲基-[3-(羟基-苯基)-丁-3-烯基]-胺化合物作为药物有效成分、最好作为镇痛药物有效成分的用法。
除至少一种式I的二甲基-[3-(羟基-苯基)-丁-3-烯基]-胺化合物外,本发明的药物含有载体物质、填充剂、溶剂、稀释剂、颜料和/或粘合剂。根据药物是否用于口服、静脉内、腹膜内、真皮内、肌内、鼻内、颊、或局部应用如用于皮肤感染、粘膜或眼睛来选择这些辅料及其用量。片剂、糖衣丸、胶囊、粒剂、滴剂、汁和糖浆形式的制剂适用于口服。溶液、悬浮液、快速恢复的干制剂和喷雾剂适用于肠胃外或表面应用以及用于吸服。按照本发明作为沉淀以溶解的形式或补片、任意加入促进皮肤穿透试剂的化合物,是适宜的皮下注射形式。本发明化合物能够以延迟的方式从可口服或皮下注射的制剂形式中释放。
给予病人的有效成分的量,根据病人的体重、应用类型、适应症及疾病严重程度来改变。通常用10-500mg/kg的至少一种式I的二甲基-[3-(羟基-苯基)-丁-3-烯基]-胺化合物。
实施例
本发明化合物的制备
“醚”一词表示乙醚。
由E.Merck,Darmstadt提供的硅胶60(0.040-0.063mm)用作柱色谱的固定相。
使用由E.Merck,Darmstadt提供的预制硅胶60 F 254 HPTLC板进行薄层色谱研究。
在由Daicel Chemical Industris Ltd.提供的Chiracel OD柱上进行消旋体的分离。
所有色谱研究的流动相的混合比率是以体积/体积给出的。
实施例1
盐酸(Z)-(RS)-[3-(3-甲氧基-苯基)-2-甲基-戊-3-烯基]-二甲胺(1)
第一步:
盐酸(2RS,3RS)-1-二甲氨基-3-(3-甲氧基-苯基)-2-甲基-戊-3-醇(2)
在150ml四氢呋喃中搅拌27.0g(1.11mol)镁璇坯,滴加溶于400ml四氢呋喃中的207.6g(1.11mol)1-溴-3-甲氧基-苯。回流加热混合物1小时,随后冷却至5-10℃。在该温度下滴加溶于400ml四氢呋喃中的128.30g(0.89mol)(RS)-1-二甲氨基-2-甲基-戊3-酮。让反应混合物静置随后再冷却至5-10℃。加入300ml 20%(重量)氯化铵溶液后,混合物用400ml乙醚稀释。相分离后,用乙醚提取配合料两次,通过硫酸钠干燥,通过蒸馏除去溶剂。将得到的残留物吸收于3.2升2-丁酮中,用120.60g(1.11mol)三甲基氯硅烷和20ml水处理。得到121.5g熔点为198-199℃的盐酸盐(2)(理论值的38%)。
第二步:
盐酸(Z)-(RS)-[3-(3-甲氧基-苯基)-2-甲基-戊-3-烯基]-二甲胺(1)
将200g(0.69mol)盐酸盐(2)溶于1升浓盐酸中,让其在室温静置。真空蒸馏除去盐酸,将残留物溶于11冰水中,用10摩尔氢氧化钠溶液将pH调至13。用乙醚提取后,将有机相干燥,通过蒸馏除去溶剂,得到162g粗产物。通过重结晶纯化,得到79g(理论值的42%)熔点为169-170℃的盐酸盐(1)。
实施例2
盐酸(Z)-(RS)-3-[1-(2-二甲氨基-1-甲基-乙基)-丙烯基]-苯酚(3)
在室温将溶于360ml甲苯中的182g(Z)-(RS)-[3-(3-甲氧基-苯基)-2-甲基-戊-3-烯基]-二甲胺滴加到1.6升含20%(重量)氢化二异丁基铝的甲苯溶液中。然后将混合物回流加热11小时。冷却至0℃后,一边冷却一边滴加450ml乙醇。然后搅拌混合物15分钟,用1l甲苯稀释。之后,一边冷却一边滴加450ml乙醇/水混合物(1∶1)。在室温搅拌1小时后,抽滤出沉淀的氢氧化铝,通过蒸馏从有机相除去溶剂。得到167g(理论值的97.6%)的粗碱,将其溶于1.671丙酮中,用65ml浓盐酸处理。将152g(理论值的76%)盐酸盐(3)结晶出来,熔点为161-162℃。
实施例3
(3)的对映体:
盐酸(+)-(Z)-(S)-3-[1-(2-二甲氨基-1-甲基-乙基)-丙烯基]-苯酚(+3)
和
盐酸(-)-(Z)-(R)-3-[1-(2-二甲氨基-1-甲基-乙基)-丙烯基]-苯酚(-3)
用二氯甲烷/水合碳酸氢钠溶液,从按实施例2获得的盐酸盐(3)中释放碱。将溶液干燥后,真空馏出二氯甲烷。然后在手性HPLC柱上分离消旋体。通过在丙酮中与浓盐酸反应,从获得的对映体中分离熔点为166-167℃的盐酸盐。
(+3): 收率:理论值的42%
[α]RT D=+3.6°(c=1.04;甲醇)
(-3): 收率:理论值的44%
[α]RT D=-3.6°(c=1.04;甲醇)
实施例4
盐酸(Z)-(RS)-2-乙酸基-苯甲酸-3-[1-2-二甲氨基-1-甲基-乙基)-丙烯基]-苯基酯(4)
用二氯甲烷/水合碳酸氢钠溶液,从按实施例2制备的盐酸盐(3)中释放碱,将溶液干燥后,真空馏出二氯甲烷。将得到的0.67g(3.0mmol)碱溶于7ml干燥的二氯甲烷中,在室温用溶于3ml干燥的二氯甲烷中的0.6g(3.24mmol)2-乙酰-苯甲酰氯处理。在室温搅拌20小时后,用20ml碳酸氢钠溶液处理反应混合物,用10ml二氯甲烷提取水相两次。合并有机相并通过硫酸钠干燥。蒸馏除去溶剂后,得到1.1g粗混合物,将其导入装有硅胶的柱中。用乙醚洗脱,产生0.68g碱,从中用乙醚中的三甲基氯硅烷/水,得到0.68g(理论值的54%)熔点为86-88℃的盐酸盐(4)。
实施例5
盐酸(E)-(RS)-[3-(3-甲氧基-苯基)-2-甲基-戊-3-烯基]-二甲胺(5)
将75g实施例1(第一步)的盐酸(2RS,3RS)-1-二甲氨基-3-(3-甲氧基-苯基)-2-甲基-戊-3-醇(2)溶于1升浓盐酸中,回流加热2小时。然后用水泵真空馏出甲酸,将残留物吸收于冰水中,用氢氧化钠溶液/乙醚处理。将有机相干燥后,通过蒸馏除去溶剂,得到60g(理论值的98%)的粗碱((Z)-异构体(2):(E)-异构体(%)=6∶4)。将粗碱导入装有硅胶的柱上。用7∶1的异丙醚/甲醇洗脱,产生20g碱,由碱用2-丁酮中的三甲基氯硅烷/水,得到18.4g(理论值的26%)熔点为139-140℃的盐酸盐(5)。
实施例6
盐酸(E)-(RS)-3-[1-(2-二甲氨基-1-甲基-乙基)-丙烯基]-苯酚(6)
用二氯甲烷/氢氧化钠溶液,从按实施例5制备的(5)中释放碱,将溶液干燥后,通过蒸馏除去二氯甲烷。在实施例2给出的条件下,由获得的碱,得到盐酸盐(6),熔点为80℃,收率为理论值的73%。
实施例7
(6)的对映体:
盐酸(+)-(E)-(R)-3-[1-(2-二甲氨基-1-甲基-乙基)-丙烯基]-苯酚(+6)
和
盐酸(-)-(E)-(S)-3-[1-(2-二甲氨基-1-甲基-乙基)-丙烯基]-苯酚(-6)
用二氯甲烷/水合碳酸氢钠溶液,从按实施例6获得的盐酸盐(6)中释放碱。将溶液干燥后,真空馏出二氯甲烷。然后在手性HPLC柱上分离消旋体。通过在丙酮中与浓盐酸反应,从获得的对映体中分离熔点为154-155℃的盐酸盐。
(+6): 收率:理论值的42%
[α]RT D=+36.3°(c=0.96;甲醇)
(-6): 收率:理论值的44%
[α]RT D=-33.7°(c=1.07;甲醇)
实施例8
盐酸(Z)-(RS)-4-[1-(2-二甲氨基-1-甲基-乙基)-丙烯基]-苯酚(7)
第一步:
(Z)-(RS)-[3-(4-甲氧基-苯基)-2-甲基-戊-3-烯基]-二甲胺(8)
由(RS)-1-二甲氨基-2-甲基-戊-3-酮和1-溴-4-甲氧基-苯开始,在实施例1(第一步)给出的条件下,得到盐酸(2RS,3RS)-1-二甲氨基-3-(4-甲氧基-苯基)-2-甲基-戊-3-醇,收率为44%,熔点为188-189℃。在实施例1(第二步)给出的条件下,用浓盐酸将其转化为(Z)-(RS)-[3-(4-甲氧基-苯基)-2-甲基-戊-3-烯基]-二甲胺(8)。得到的化合物(8)为淡黄色油,收率为46%。
第二步:
盐酸(Z)-(RS)-4-[1-(2-二甲氨基-1-甲基-乙基)-丙烯基]-苯酚(7)
在实施例2给出的条件下,由第一步获得的碱得到盐酸盐(7),收率为理论值的79%,熔点为203℃。
实施例9
盐酸(Z)-(RS)-二甲基-(2-甲基-3-邻甲苯基-戊-3-烯基)胺(9)
由(RS)-1-二甲氨基-2-甲基-戊-3-酮和3-溴-甲苯开始,在实施例1(第一步)给出的条件下,得到盐酸(2RS,3RS)-1-二甲氨基-2-甲基-3-(邻甲苯基)-戊-3-醇,收率为24%,熔点为154-155℃。在实施例1(第二步)给出的条件下,用浓盐酸将其转化为盐酸(Z)-(RS)-二甲基-(2-甲基-3-邻甲苯基-戊-3-烯基)胺(9)。得到的化合物(9)收率为36%(相对于所用的醇),熔点为172℃。
实施例10
盐酸(E)-(RS)-二甲基-(2-甲基-3-邻甲苯基-戊-3-烯基)胺(10)
由按实施例9获得的盐酸(2RS,3RS)-1-二甲氨基-2-甲基-3-(邻甲苯基)-戊-3-醇开始,在实施例5给出的条件下,得到盐酸盐(10),收率为36%,熔点为153℃。
实施例11
盐酸(Z)-(RS)-[3-(3-二氟甲基-苯基)-2-甲基-戊-3-烯基]-二甲胺(11)
第一步:
盐酸(2RS,3RS)-3-(3-二氟甲基-苯基)-1-二甲氨基-2-甲基-戊-3-醇(12)
将7.0g(34mmol)由3-溴苯甲醛和三氟二乙氨基硫按Org.React.35,514(1988)描述制备的1-溴-3-二氟甲苯溶于110ml干燥的四氢呋喃中,冷却至-75℃。加入34mmol1.6摩尔正丁基锂的己烷溶液后,在-75℃搅拌混合物1小时。然后滴加溶于15ml干燥的四氢呋喃的4.8g(34mmol)(2RS)-1-二甲氨基-2-甲基-戊-3-酮。将反应混合物温热至室温2.5小时以上。对处理来说,一边冰浴冷却,一边滴加65ml 5%盐酸,使得内部温度不超过15℃。相分离后,用40ml 5%盐酸提取有机相。合并的水相用50ml乙醚洗涤两次。为了释放碱,用浓氢氧化钠溶液处理配合料,并用二氯甲烷提取。这样,得到7.8g粗产物,将其导入装有硅胶的柱上。用1∶1的乙酸乙酯/甲醇洗脱,产生4.89g碱,由碱用2-丁酮中的三甲基氯硅烷/水,得到4.6g(理论值的44%)熔点为194-195℃的盐酸盐(12)。
第二步:
盐酸(Z)-(RS)-[3-(3-二氟甲基-苯基)-2-甲基-戊-3-烯基]-二甲胺(11)
将第一步的10g(32mmol)盐酸(2RS,3RS)-3-(3-二氟甲基-苯基)-1-二甲氨基-2-甲基-戊-3-醇(12)溶于150ml浓甲酸中,回流加热2小时。然后用水泵真空馏出甲酸,将残留物吸收于冰水中,用氢氧化钠溶液/乙醚处理。将有机相干燥后,通过蒸馏除去溶剂,得到9.1g(理论值的97%)粗碱,将其导入装有硅胶的柱上。用7∶1的异丙醚/甲醇洗脱,产生3.0g碱,由碱用2-丁酮中的三甲基氯硅烷/水,得到2.3g(理论值的24%)熔点为160-161℃的盐酸盐(11)。
实施例12
盐酸(z)-(RS)-6-[1-(2-二甲氨基-1-甲基-乙基)-丙烯基]-萘-2-醇(13)
在实施例1(第二步)给出的条件下,由按Chirality,6,389(1984)的描述制备的盐酸(1RS,2RS)-6-(3-二甲氨基-1-乙基-1-羟基-2-甲基-丙基)-萘-2-醇,得到盐酸盐(13),收率为理论值的39%,熔点为207-208℃。
实施例13
盐酸(E)-(RS)-[3-(3-甲氧基-苯基)-2-甲基-己-3-烯基]-二甲胺(14)
和
盐酸(Z)-(RS)-[3-(3-甲氧基-苯基)-2-甲基-己-3-烯基]-二甲胺(15)
由盐酸(2RS)-3-二甲胺基-1-(3-甲氧基-苯基)-2-甲基-戊-1-酮和1-溴丙烷开始,在实施例1(第一步)给出的条件下,用乙醚作为溶剂,得到盐酸(2RS,3RS)-1-二甲胺基-3-(3-甲氧基-苯基)-2-甲基-己-3-醇(16),收率为81%,熔点为131-132℃。将30g(0.1mol)化合物(16)与450ml浓甲酸按实施例5反应。将这样得到的含有(Z)-异构体和(E)-异构体的混合物导入装有硅胶的柱上。用7∶1的异丙醚/甲醇洗脱,产生7g(E)化合物(14)的碱和17g(Z)化合物(15)的碱。在2-丁酮中用三甲基氯硅烷/水,将其转化为盐酸盐。
(14): 收率:5.9g(理论值的21%)
熔点:154℃
(15): 收率:15.8g(理论值的56%)
熔点:110-112℃
实施例14
盐酸(E)-(RS)-3-[1-(2-二甲氨基-1-甲基-乙基)-丁-1-烯基]-苯酚(17)
用二氯甲烷/氢氧化钠溶液,从按实施例13制备的(14)中释放碱,将溶液干燥后,通过蒸馏除去二氯甲烷。在实施例2给出的条件下,由得到的碱,得到盐酸盐(17),收率为理论值的86%,熔点为214℃。
实施例15
盐酸(Z)-(RS)-3-[1-(2-二甲氨基-1-甲基-乙基)-丁-1-烯基]-苯酚(18)
用二氯甲烷/氢氧化钠溶液,从按实施例13制备的(15)中释放碱,将溶液干燥后,通过蒸馏除去二氯甲烷。在实施例2给出的条件下,由得到的碱,得到盐酸盐(18),收率为理论值的86%,熔点为120-121℃。
实施例16
盐酸(RS)-[3-(3-甲氧基-苯基)-2-丙基-丁-3-烯基]-二甲胺(19)
由(RS)-2-二甲胺基甲基-1-(3-甲氧基-苯基)-戊-1-酮和甲基碘开始,在实施例1(第一步)给出的条件下,用乙醚作为溶剂,得到盐酸(2RS,3RS)-3-二甲氨基甲基-2-(3-甲氧基-苯基)-己-2-醇(20),收率为76%,熔点为137-138℃。将30g(0.1mol)化合物(20)与300ml浓甲酸按实施例5反应。将得到的粗碱导入装有硅胶的柱上。用7∶1的异丙醚/甲醇洗脱,产生24g碱,由碱用2-丁酮中的三甲基氯硅烷/水得到23.1g(理论值的74%)盐酸盐(19),熔点为120-121℃。
实施例17
盐酸(RS)-3-[1-(2-二甲氨基-1-甲基-乙基)-乙烯基]-苯酚(21)
第一步:
盐酸(1RS,2RS)-3-(3-二甲氨基-1-羟基-1,2-二甲基-丙基)-苯酚(22)
由盐酸(RS)-3-二甲胺基-1-(3-甲氧基-苯基)-2-甲基-丙-1-酮和甲基碘开始,在实施例1(第一步)给出的条件下,用乙醚作为溶剂,得到盐酸(2RS,3RS)-4-二甲胺基-2-(3-甲氧基-苯基)-3-甲基-丁-2-醇(23),收率为46%,熔点为178-179℃。用二氯甲烷/氢氧化钠溶液,从(23)中释放碱,将溶液干燥后,真空馏出二氯甲烷。将23.7g(0.1mol)碱与氢化二异丁基铝按实施例2反应。这样得到18.5g(理论值的71%)盐酸盐(22),熔点为183-184℃。
第二步:
盐酸(RS)-3-[1-(2-二甲氨基-1-甲基-乙基)-乙烯基]-苯酚(21)
将第一步的10g(37mmol)盐酸盐(22)溶于150ml浓甲酸中,回流加热2小时。然后用水泵真空馏出甲酸,将残留物吸收于冰水中,用氢氧化钠溶液/乙醚处理。将有机相干燥后,通过蒸馏除去溶剂,得到9.1g粗碱,由粗碱在丙酮中用浓盐酸,得到7.5g(理论值的83%)熔点为228-230℃的盐酸盐(21)。
实施例18
盐酸(RS)-3-[1-(2-二甲氨基-1-甲基-乙基)-2-甲基-丙烯基]-苯酚(24)
第一步:
(RS)-[3-(3-甲氧基-苯基)-2,4-二甲基-戊-3-烯基]-二甲胺(25)
由(RS)-1-二甲氨基-2,4-二甲基-戊-3-酮和1-溴-3-甲氧基苯开始,在实施例1(第一步)给出的条件下,得到盐酸(2RS,3RS)-1-二甲氨基-3-(3-甲氧基-苯基)-2,4-二甲基-戊-3-醇(26),收率为44%,熔点为180-181℃。将30g(0.1mol)化合物(26)与450ml浓甲酸按实施例5反应。将得到的粗碱导入装有硅胶的柱上。用7∶1的异丙醚/甲醇洗脱,产生的19g(理论值的77%)碱为淡黄色粘性油。
第二步:
盐酸(RS)-3-[1-(2-二甲氨基-1-甲基-乙基)-2-甲基-丙烯基]-苯酚(24)
由第一步获得的碱,在实施例2给出的条件下,得到盐酸盐(24),收率为理论值的84%,熔点为176-177℃。
实施例19
盐酸(RS)-二甲基-[2-(4-三氟甲基-苯基)-环戊-2-烯基甲基]-胺(27)
在实施例1(第一步)给出的条件下,将(RS)-2-二甲氨基甲基-环戊酮和1-溴-4-三氟甲基-苯反应。将得到的30g粗产物导入装有硅胶的柱上。用5∶1的乙酸乙酯/甲醇洗脱,产生11.6g碱,在2-丁酮中用三甲基氯硅烷/水,将其转化为12.0g(理论值的21%)熔点为213-214℃的盐酸(1RS,2RS)-2-二甲氨基甲基-1-(4-三氟甲基-苯基)-环戊醇(28)。将32.4g(0.1mol)盐酸盐(28)与450ml浓甲酸按实施例5反应。将得到的粗碱导入装有硅胶的柱上。用7∶1的异丙醚/甲醇洗脱,产生9.6g碱,在2-丁酮中用三甲基氯硅烷/水,将其转化为8.9g(理论值的29%)熔点为219-220℃的盐酸盐(27)。
实施例20
(27)的对映体:
盐酸(+)-(S)-二甲基-[2-(4-三氟甲基-苯基)-环戊-2-烯基甲基]-胺(+27)
和
盐酸(-)-(R)-二甲基-[2-(4-三氟甲基-苯基)-环戊-2-烯基甲基]-胺(-27)
用二氯甲烷/氢氧化钠溶液,从(27)中释放碱。将溶液干燥后,真空馏出二氯甲烷。然后在手性HPLC柱上分离消旋体。通过在丙酮中与浓盐酸反应,由获得的对映体制备熔点为244-246℃的盐酸盐。
(+27): 收率:理论值的42%
[α]RT D=+33.8°(c=1.00;甲醇)
(-27): 收率:理论值的44%
[α]RT D=-34.3°(c=1.06;甲醇)
实施例21
盐酸(RS)-2-(6-二甲氨基甲基)-环己-1-烯基)-苯酚(29)
由(RS)-2-二甲氨基甲基-环己酮和1-溴-2-甲氧基-苯开始,在实施例1(第一步)给出的条件下,用乙醚作为溶剂得到盐酸(1RS,2RS)-2-二甲氨基甲基-1-(2-甲氧基-苯基)-环己醇(30),收率为47%。用二氯甲烷/氢氧化钠溶液,从(30)中释放碱。将溶液干燥后,真空馏出二氯甲烷。将30.0g(0.1mol)碱与二异丁基铝按实施例2反应。将得到的22.7g(理论值的78%)熔点为168-170℃的盐酸(1RS,2RS)-2-(2-二甲氨基甲基-1-羟基-环己基-苯酚(31)。将28.6g(0.1mol)化合物(31)与450ml浓甲酸按实施例5反应。将得到的粗碱导入装有硅胶的柱上,用7∶1的异丙醚/甲醇洗脱。由得到的21g碱在2-丁酮中用三甲基氯硅烷/水,得到18.6g(理论值的69%)盐酸盐(29),熔点为168℃。
实施例22
(29)的对映体:
盐酸(-)-(R)-2-(6-二甲氨基甲基)-环己-1-烯基)-苯酚(-29)
和
盐酸(+)-(S)-2-(6-二甲氨基甲基)-环己-1-烯基)-苯酚(+29)
用二氯甲烷/水合碳酸氢钠溶液,从(29)中释放碱。将溶液干燥后,真空馏出二氯甲烷。然后在手性HPLC柱上分离消旋体。通过在丙酮中与浓盐酸反应,从获得的对映体分离熔点为271-272℃的盐酸盐。
(+29): 收率:理论值的43%
[α]RT D=+24.1°(c=0.96;甲醇)
(-29): 收率:理论值的44%
[α]RT D=-23.5°(c=0.94;甲醇)
实施例23
盐酸(RS)-二甲基-[2-(4-三氟甲基-苯基)-环己-2-烯基甲基]-胺(32)
在实施例1(第一步)给出的条件下,将(RS)-2-二甲氨基甲基-环己酮和1-溴-4-三氟甲基-苯反应。将得到的30g粗产物导入装有硅胶的柱上。用5∶1的乙酸乙酯/甲醇洗脱,产生18.9g碱,在2-丁酮中用三甲基氯硅烷/水,将其转化为16.4g(理论值的37%)熔点为234℃的盐酸(1RS,2RS)-2-二甲氨基甲基-1-(4-三氟甲基-苯基)-环己醇(33)。将33.7g(0.1mol)盐酸盐(33)与450ml浓甲酸按实施例5反应。将得到的粗碱导入装有硅胶的柱上。用7∶1的异丙醚/甲醇洗脱,得到12.3g碱,在2-丁酮中用三甲基氯硅烷/水,将其转化为10.4g(理论值的32.5%)熔点为205-206℃的盐酸盐(32)。
实施例24
盐酸(RS)-二甲基-[2-(2-甲基-苯并[b]噻吩-4-基]-环己-2-烯基甲基]-胺(34)
在实施例1(第一步)给出的条件下,用乙醚作溶剂,1,2-二溴乙烷作载体试剂,将(RS)-2-二甲氨基甲基-环己酮和4-溴-2-二甲基苯并[b]噻吩反应。将25g粗产物导入装有硅胶的柱上。用1∶1的乙酸乙酯/甲醇洗脱,产生12.6g碱,在2-丁酮中用三甲基氯硅烷/水,将其转化为10.4g(理论值的29%)熔点为204℃的盐酸(1RS,2RS)-2-二甲氨基甲基-1-(2-甲基-苯并[b]噻吩-4-基)-环己醇(35)。将34.0g(0.1mol)盐酸盐(35)与450ml浓甲酸按实施例5反应。将这样得到的粗碱导入装有硅胶的柱上。用乙醚洗脱,产生17.5g碱,在2-丁酮中用三甲基氯硅烷/水,将其转化为15.2g(理论值的54.8%)熔点为179-182℃的盐酸盐(34)。
实施例25
盐酸(-)-(3S,6R)-3-(6-二甲氨基甲基-3-甲基-环己-1-烯基)-苯酚(-36)
和
盐酸(+)-(3R,6S)-3-(6-二甲氨基甲基-3-甲基-环己-1-烯基)-苯酚(+36)
第一步:
盐酸(1RS,2RS,5RS)-2-二甲氨基甲基-1-(3-甲氧基-苯基)-5-甲基-环己醇(37)
将95ml(75mmol)1-溴-3-甲氧基苯溶于425ml干燥的四氢呋喃中,冷却至-75℃。加入含750mmol 1.6摩尔正丁基锂的己烷溶液后,在-75℃搅拌混合物1小时。然后滴加在冰醋酸中由3-甲基环己酮、盐酸二甲胺和低聚甲醛制备的、并溶于120ml干燥的四氢呋喃的82g(484mmol)(2RS,5RS)-2-二甲氨基甲基-5-甲基-环己酮。将反应混合物温热至室温2.5小时以上。对处理来说,一边冰浴冷却,一边滴加200ml水,使得内部温度不超过15℃。相分离后,水相用50ml乙酸乙酯提取三次。合并的有机相通过硫酸钠干燥。通过蒸馏除去溶剂后,将残留物溶于700ml丙酮中,用三甲基氯硅烷/水处理。在4-5℃将67g(理论值的48%)熔点为173-175℃的盐酸盐(37)结晶出来。
第二步:
(37)的对映体:
盐酸(+)-(1R,2R,5S)-2-二甲氨基甲基-1-(3-甲氧基-苯基)-5-甲基-环己醇(+37)
和
盐酸(-)-(1S,2S,5R)-2-二甲氨基甲基-1-(3-甲氧基-苯基)-5-甲基-环己醇(-37)
用二氯甲烷/氢氧化钠溶液,从(37)中释放碱。将溶液干燥后,真空馏出二氯甲烷。然后在手性HPLC柱上分离消旋体。通过在丙酮中与三甲基氯硅烷/水反应,从获得的对映体分离熔点为151-153℃的盐酸盐。
(+37): 收率:理论值的43%
[α]RT D=+36.4°(c=1.01;甲醇)
(-37): 收率:理论值的44%
[α]RT D=-37.7°(c=1.01;甲醇)
第三步:
盐酸(-)-(1R,4S)-[2-(3-甲氧基-苯基)-4-甲基-环己-2-烯基甲基]-二甲胺(-38)
和
盐酸(+)-(1S,4R)-[2-(3-甲氧基-苯基)-4-甲基-环己-2-烯基甲基]-二甲胺(+38)
在实施例5给出的条件下,将第二步的甲氧基化合物(-37)和(+37)转化为盐酸盐(+38)和(-38),收率为理论值的87%,熔点为122-123℃。
第四步:
盐酸(-)-(3S,6R)-3-(6-二甲氨基甲基-3-甲基-环己-1-烯基)-苯酚(-36)
和
盐酸(+)-(3R,6S)-3-(6-二甲氨基甲基-3-甲基-环己-1-烯基)-苯酚(+36)
在实施例2给出的条件下,由第三步获得的碱,通过与氢化二异丁基铝反应,随后在2-丁酮中用三甲基氯硅烷/水沉淀盐酸盐,得到盐酸盐(-36)和(+36),收率为理论值的79%,熔点为131-133℃。
(-36): [α]RT D=-75.5°(c=0.96;甲醇)
(+36): [α]RT D=+77.7°(c=1.08;甲醇)
实施例26
盐酸(-)-(R)-3-(6-二甲氨基甲基-环己-1-烯基)-苯酚(-39)
将28.8g(0-1mol)盐酸(+)-(1R,2R)-3-(2-二甲氨基甲基-1-羟基-环己基)-苯酚溶于450ml浓甲酸中,回流加热2小时。然后用水泵真空馏出甲酸,用二氯甲烷/水合碳酸钠溶液从残留物中释放碱。在丙酮中用浓盐酸处理,由碱得到21.8g(理论值的81.4%)熔点为216-217℃的盐酸盐(-39)。
(-39): [α]RT D=-96.6°(c=1.04;甲醇)
实施例27
盐酸(+)-(S)-3-(6-二甲氨基甲基-环己-1-烯基)-苯酚(+39)
在实施例26给出的条件下,由28.8g(0.1mol)盐酸(-)-(1S,2S)-3-(2-二甲氨基甲基-1-羟基-环己基)-苯酚得到21.8g(理论值的81.4%)、熔点为216-217℃的盐酸盐(+39)。
(+39): [α]RT D=+89.9°(c=0.99;甲醇)药理学研究用小鼠扭体实验进行的镇痛试验
镇痛效力的试验用苯醌诱导的小鼠扭体实验来进行(按照I.C.Hendershot,J.Forsaith,J.Pharmacol.Exp.Ther.125,237-240(1959)修改的方法)。体重为25-30g的NMRI雄鼠用于该试验。每10只为一组静脉注射一个剂量的本发明化合物,注射后10分钟,每只小鼠接受0.3ml的0.02%苯醌水溶液(苯基苯醌:由Sigma,Deisenhofen生产的;加入5%乙醇制备的、在45℃水浴保温的溶液)。将动物单独放在观察笼中,在注射苯醌之后5-20分钟,用按钮计数器来计算诱导疼痛的扭体运动(所谓的扭体反应=伸张躯干与后肢)的次数。
用消退分析(由Martens EDV Service,Eckental提供的评价程序),与平行实验组及未注射本发明化合物的组进行比较,从依赖于剂量的扭体反应的减少来计算ED50值。
所有试验的本发明化合物都表现出确定的镇痛效果,与曲马多相比效果增强。
结果总结于下表。
表:用小鼠扭体实验进行的镇痛试验
按实施例制备的本发明化合物 | ED50(mg/kg) |
23(+)-对映体3(-)-对映体41213151820(+)-对映体20(-)-对映体2425(-)-对映体26(-)-对映体27(+)-对映体比较:曲马多 | 1.372.250.981.640.972.961.332.071.402.121.350.901.041.603.68 |
Claims (8)
其中R1是C1-5烷基,而R2表示H或C1-5烷基,或R1和R2一起表示-(CH2)2-4-、-(CH2)2-CHR7或-CH2-CHR7-CH2-,
R3表示H或C1-5烷基,
R4表示H、OH、C1-4烷基、O-C1-4烷基、O-苄基、CF3、O-CF3、C1、F或OR8,
R5表示H、OH、C1-4烷基、O-C1-4烷基、O-苄基、CHF2、CF3、O-CF3、Cl、F或OR8,和
R6表示H、OH、C1-4烷基、O-C1-4烷基、O-苄基、CF3、O-CF3、Cl、F或OR8,条件是R4、R5和R6中的两个基团是H,或
R4和R5一起表示-CH=C(R9)-O-或-CH=C(R9)-S-,条件是R6是H,或
R5和R6一起表示-CH=CH-C(OR10)=CH-,条件是R4是H,
R7表示C1-8烷基、C3-8环烷基、O-C1-4烷基、O-苄基、CF3、Cl或F,
R8表示CO-C1-5烷基、PO(O-C1-4烷基)2、CO-C6H4-R11、CO(O-C1-5烷基)、CO-CHR12-NHR13、CO-NH-C6H3-(R14)2或未取代或取代的吡啶基、噻吩基、噻唑基或苯基基团,
R9表示H或C1-4烷基,
R10表示H或C1-3烷基,
R11表示邻位的OC(O)-C1-3烷基或间位或对位的CH2-N-(R15)2,其中R15表示C1-4烷基或两个基团R15与N一起表示4-吗啉基基团,
R12和R1相同或不同,表示H或C1-6烷基或C3-8环烷基,或R12和R13一起表示-(CH2)3-8-,
R14表示H、OH、C1-7烷基、O-C1-7烷基、苯基、O-芳基、CF3、Cl或F,条件是两个基团R14相同或不同,
作为对映体或消旋体,只是要排除其中R1和R2一起是-(CH2)3-,R3、R4和R6表示H,而R5是OCH3的式I化合物的消旋体。
2.按照权利要求1的二甲基-(3-芳基-丁-3-烯基)-胺化合物,其特征在于,
R1是C1-3烷基而R2是H或C1-3烷基,或R1和R2一起表示-(CH2)2-4-或-(CH2)2-CHR7,
R3表示H或C1-3烷基,
R4表示H、OH、CF3、Cl、F或OR8,
R5表示H、OH、C1-4烷基、O-C1-4烷基、O-苄基、CHF2、CF3、Cl、F或OR8,
R6表示H、OH、O-C1-4烷基、O-苄基、CF3、Cl、F或OR8,条件是R4、R5和R6中的两个基团是H,或
R4和R5一起表示-CH=C(R9)-O-或-CH=C(R9)-S-,条件是R6是H,或
R5和R6一起表示-CH=CH-C(OR10)=CH-,条件是R4是H,
R7表示C1-4烷基、CF3、Cl或F。
3.按照权利要求1或权利要求2的二甲基-(3-芳基-丁-3-烯基)-胺化合物,其特征在于,
R1表示CH3或C3H7,而R2表示H、CH3或CH2CH3,或R1和R2一起表示-(CH2)2-3-或-(CH2)2-CHR7,
R3表示H或CH3或CH2CH3,
R4表示H或OH,R5表示H、OH、OCH3、CHF2或OR8,而R6表示H、OH或CF3,条件是R4、R5和R6中的两个基团是H,或
R4和R5一起表示-CH=C(CH3)-S-,条件是R6是H,或
R5和R6一起表示-CH=CH-C(OH)=CH-,条件是R4是H,
R8表示CO-C6H4-R11,其中R11表示邻位的OC(O)-C1-3烷基。
4.按照权利要求1-3中一项或多项权利要求的二甲基-(3-芳基-丁-3-烯基)-胺化合物,其特征在于,
R1表示CH3,而R2表示H或CH3,或R1和R2一起表示-(CH2)2-3-或-(CH2)2-CH(CH3)-,
R3表示H或CH3,
R4表示H,R5表示OH或OR8,R6是H,而R8表示CO-C6H4-R11,其中R11表示邻位的OC(O)-CH3。
5.式I的二甲基-(3-芳基-丁-3-烯基)-胺化合物的制备方法
其中R1是C1-5烷基而R2表示H或C1-5烷基,或R1和R2一起表示-(CH2)2-4-、-(CH2)2-CHR7或-CH2-CHR7-CH2-,
R3表示H或C1-5烷基,
R4表示H、C1-4烷基、O-C1-4烷基、O-苄基、CF3、O-CF3、Cl或F,
R5表示H、C1-4烷基、O-C1-4烷基、O-苄基、CHF2、CF3、O-CF3、Cl或F,而
R6表示H、C1-4烷基、O-C1-4烷基、O-苄基、CF3、O-CF3、Cl或F,
条件是R4、R5和R6中的两个基团是H,或
R4和R5一起表示-CH=C(R9)-O-或-CH=C(R9)-S-,条件是R6是H,或
R5和R6一起表示-CH=CH-C(OR10)=CH-,条件是R4是H,
R7表示C1-8烷基、C3-8环烷基、O-C1-4烷基、O-苄基、CF3、Cl或F,
R9表示H或C1-4烷基,R10表示H或C1-3烷基,其中排除其中R1和R2一起表示-(CH2)3-,R3、R4和R6表示H,而R5是OCH3的式I化合物,其特征在于,
其中R1是C1-5烷基而R2表示H或C1-5烷基,或R1和R2一起表示-(CH2)2-4-、-(CH2)2-CHR7或-CH2-CHR7-CH2-,
R3表示H或C1-5烷基,
R4、R5和R6中的一个基团表示OH,而其余两个基团是H,
R7表示C1-8烷基、C3-8环烷基、O-C1-4烷基、O-苄基、CF3、Cl或F,
其特征在于,将式I化合物(其中R4、R5和R6中的一个基团表示O-CH3、而其余两个基团是H)与氢化二异丁基铝反应,或将式I的化合物(R4、R5和R6中的一个基团表示O-苄基,而其余两个基团是H)还原性去苄基。
7.按照权利要求1的式I的二甲基-(3-芳基-丁-3-烯基)-胺化合物作为药物有效成分的用法。
8.按照权利要求7的用法,其特征在于该药物是镇痛药物。
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DE19609847A DE19609847A1 (de) | 1996-03-13 | 1996-03-13 | Dimethyl-(3-aryl-but-3-enyl)-aminverbindungen als pharmazeutische Wirkstoffe |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1809527B (zh) * | 2003-06-23 | 2010-05-26 | 格吕伦塔尔有限公司 | 取代4-二甲基氨基-2-芳基-丁-2-醇化合物脱水的方法和通过多相催化制备取代二甲基-(3-芳基-丁基)-胺化合物的方法 |
CN101948397A (zh) * | 2010-09-07 | 2011-01-19 | 天津泰普药品科技发展有限公司 | 镇痛药他喷他多重要中间体的制备方法 |
CN101384563B (zh) * | 2005-12-22 | 2012-06-27 | 格吕伦塔尔有限公司 | 具有止痛作用的取代*唑衍生物 |
CN1829681B (zh) * | 2003-06-06 | 2013-02-06 | 格吕伦塔尔有限公司 | 取代的3-芳基-丁基-胺化合物的制备方法 |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4426245A1 (de) * | 1994-07-23 | 1996-02-22 | Gruenenthal Gmbh | 1-Phenyl-3-dimethylamino-propanverbindungen mit pharmakologischer Wirkung |
DE19732928C2 (de) * | 1997-07-31 | 2000-05-18 | Gruenenthal Gmbh | Verwendung substituierter Imidazolidin-2,4-dion-Verbindungen als Schmerzmittel |
DE19830105C1 (de) | 1998-07-06 | 2000-02-17 | Gruenenthal Gmbh | Acridinderivate |
ES2141688B1 (es) * | 1998-11-06 | 2001-02-01 | Vita Invest Sa | Nuevos esteres derivados de compuestos fenil-ciclohexil sustituidos. |
DE10000311A1 (de) * | 2000-01-05 | 2001-07-12 | Gruenenthal Gmbh | Aminomethyl-Phonyl-Cyclohexanonderivate |
DE10025948A1 (de) * | 2000-05-26 | 2001-11-29 | Gruenenthal Gmbh | Wirkstoffkombination |
DE10049481A1 (de) * | 2000-09-29 | 2002-05-02 | Gruenenthal Gmbh | Substituierte C-Cyclohexylmethylamin-Derivate |
DE10049483A1 (de) † | 2000-09-29 | 2002-05-02 | Gruenenthal Gmbh | Substituierte 1-Aminobutan-3-ol-Derivate |
DE10059413A1 (de) * | 2000-11-30 | 2002-06-20 | Gruenenthal Gmbh | Verwendung von substituierten 6-Dimethylaminomethyl-1-phenyl-cyclohexanverbindungen zur Therapie der Harninkontinenz |
US20050176790A1 (en) | 2001-02-28 | 2005-08-11 | Johannes Bartholomaus | Pharmaceutical salts |
WO2002074241A2 (en) * | 2001-03-16 | 2002-09-26 | Dmi Biosciences Inc. | Method of delaying ejaculation |
DE10132747A1 (de) * | 2001-07-05 | 2003-01-23 | Gruenenthal Gmbh | Substituierte 1-Aryl-but-3-enylamin- und 1-Aryl-but-2-enylaminverbindungen |
DE10146275A1 (de) * | 2001-09-18 | 2003-04-24 | Gruenenthal Gmbh | Kombination ausgewählter Opioide mit Muscarin-Antagonisten zur Therapie der Harninkontinenz |
PE20030527A1 (es) | 2001-10-24 | 2003-07-26 | Gruenenthal Chemie | Formulacion farmaceutica con liberacion retardada que contiene 3-(3-dimetilamino-1-etil-2-metil-propil) fenol o una sal farmaceuticamente aceptable del mismo y tabletas para administracion oral que la contienen |
DE10224624A1 (de) * | 2002-05-30 | 2003-12-11 | Gruenenthal Gmbh | Metabolite und Prodrugs von 1-Dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol |
DE10225315A1 (de) * | 2002-06-06 | 2003-12-24 | Gruenenthal Gmbh | Wirkstoffsalze und Ester von 1-Dimethylamino-3-(3-methoxy-phenyl)-2-methyl- pentan-3-ol und 3-(3-Dimethylamino-1-ethyl-1-hydroxy-2-methyl- propyl)-phenol |
DE10261091A1 (de) | 2002-12-20 | 2004-07-01 | Grünenthal GmbH | Gesättigte und ungesättigte Heteroarylcycloalkylmethyl-Amine |
DE102004034619A1 (de) * | 2004-07-16 | 2006-02-23 | Grünenthal GmbH | Substituierte Aminoverbindungen als 5-HT/NA Uptakehemmer |
DE102005033732B4 (de) | 2005-05-27 | 2014-02-13 | Grünenthal GmbH | Trennung stereoisomerer N,N-Dialkylamino-2-alkyl-3-hydroxy-3-phenyl-alkane |
DE102005052588A1 (de) | 2005-11-02 | 2007-05-10 | Grünenthal GmbH | Verfahren zur Herstellung substituierter Dimethyl-(3-aryl-butyl)-amin-Verbindungen mittels homogener Katalyse |
TWI448447B (zh) * | 2006-07-24 | 2014-08-11 | Gruenenthal Chemie | 製備(1r,2r)-3-(3-二甲胺基-1-乙基-2-甲基-丙基)-酚之方法 |
DK2046726T3 (da) * | 2006-07-24 | 2010-05-10 | Janssen Pharmaceutica Nv | Fremstilling af (2R,3R)-3-3-methoxyphenyl)-N,N, 2-trimethylpentanamin |
EP2619174A4 (en) | 2010-09-20 | 2014-05-14 | Ind Swift Lab Ltd | PROCESS FOR THE PREPARATION OF L-PHENYL-3-DIMETHYLAMINOPROPANE DERIVATIVES |
EP2674414A1 (en) | 2012-06-15 | 2013-12-18 | Siegfried AG | Method for the preparation of 1-aryl-1-alkyl-3-dialkylaminopropane compounds |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1518663A1 (de) * | 1965-08-02 | 1969-12-18 | Gruenenthal Chemie | Basisch substituierte Cycloalken-derivate und Verfahren zu ihrer Herstellung |
US3652589A (en) * | 1967-07-27 | 1972-03-28 | Gruenenthal Chemie | 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols |
US3978129A (en) * | 1972-01-28 | 1976-08-31 | A. H. Robins Company, Incorporated | Alkenyl- and alkanylamines |
DE2409990C2 (de) * | 1974-02-27 | 1982-11-25 | Siemens AG, 1000 Berlin und 8000 München | Meßwandler für Hochspannungsschaltanlagen mit Metallkapselung |
GB1502635A (en) * | 1974-02-27 | 1978-03-01 | Schering Ag | Process for splitting steroid ethers |
JPS598259B2 (ja) * | 1976-01-01 | 1984-02-23 | 武田薬品工業株式会社 | 新規シクロヘキセン誘導体 |
US4173649A (en) * | 1978-02-27 | 1979-11-06 | E. R. Squibb & Sons, Inc. | 5-Phenyl-2,4-pentadien-1-amines and method for inhibiting prostaglandin dehydrogenase |
FR2559765B1 (fr) * | 1984-02-16 | 1986-06-13 | Rhone Poulenc Sante | Nouveaux derives de la phenyl-3 propene-2 amine, leur preparation et les medicaments qui les contiennent |
IT1213219B (it) * | 1984-09-28 | 1989-12-14 | Consiglio Nazionale Ricerche | Derivati amminoalchilnaftalenici ad attivita' farmacologica. |
US5430044A (en) * | 1987-02-06 | 1995-07-04 | Fisons Corporation | Arylalkyl-amines and -amides having anticonvulsant and neuroprotective properties |
SE9202218D0 (sv) * | 1992-07-22 | 1992-07-22 | Kabi Pharmacia Ab | Pharmacologically active alfa-(tertiary-aminomethyl)-benzenemethanol derivatives, pharmaceutical composition containing them, therapeutical use thereof and processes for their preparation |
DE4426245A1 (de) * | 1994-07-23 | 1996-02-22 | Gruenenthal Gmbh | 1-Phenyl-3-dimethylamino-propanverbindungen mit pharmakologischer Wirkung |
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CN101948397A (zh) * | 2010-09-07 | 2011-01-19 | 天津泰普药品科技发展有限公司 | 镇痛药他喷他多重要中间体的制备方法 |
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