CN1023010C - 4-杂五环-4-[n-(苯基)酰氨基]哌啶衍生物的制备方法 - Google Patents
4-杂五环-4-[n-(苯基)酰氨基]哌啶衍生物的制备方法 Download PDFInfo
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- CN1023010C CN1023010C CN89100056A CN89100056A CN1023010C CN 1023010 C CN1023010 C CN 1023010C CN 89100056 A CN89100056 A CN 89100056A CN 89100056 A CN89100056 A CN 89100056A CN 1023010 C CN1023010 C CN 1023010C
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- Prior art keywords
- ethyl
- phenyl
- mmoles
- compound
- benzyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 58
- 238000000034 method Methods 0.000 title claims description 12
- 150000003053 piperidines Chemical class 0.000 title description 28
- 239000008194 pharmaceutical composition Substances 0.000 title description 5
- 125000003368 amide group Chemical group 0.000 title description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 21
- -1 2-(1H-pyrazol-1-yl) ethyl Chemical group 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000003814 drug Chemical class 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 55
- 125000003545 alkoxy group Chemical group 0.000 abstract description 19
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 36
- 239000002585 base Substances 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 27
- VXWFEQQIKVSOMK-UHFFFAOYSA-N oxalic acid;pyridine Chemical compound C1=CC=NC=C1.OC(=O)C(O)=O VXWFEQQIKVSOMK-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
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- 239000000047 product Substances 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 239000002253 acid Substances 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- 238000004587 chromatography analysis Methods 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- 238000002329 infrared spectrum Methods 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
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- 239000010410 layer Substances 0.000 description 9
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 9
- 229910004298 SiO 2 Inorganic materials 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 125000001425 triazolyl group Chemical group 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
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- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 5
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- 125000000335 thiazolyl group Chemical group 0.000 description 5
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- 239000003513 alkali Substances 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229940057995 liquid paraffin Drugs 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 3
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
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- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000007864 aqueous solution 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
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000008227 sterile water for injection Substances 0.000 description 3
- WRFDXBMXHLRNLO-UHFFFAOYSA-N 1-benzyl-n-phenyl-4-(2h-tetrazol-5-yl)piperidin-4-amine Chemical class C=1C=CC=CC=1CN(CC1)CCC1(C=1NN=NN=1)NC1=CC=CC=C1 WRFDXBMXHLRNLO-UHFFFAOYSA-N 0.000 description 2
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 2
- 125000004345 1-phenyl-2-propyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
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- 206010002091 Anaesthesia Diseases 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- 238000004458 analytical method Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- 238000000605 extraction Methods 0.000 description 2
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 2
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- 125000000524 functional group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
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- 238000002844 melting Methods 0.000 description 2
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Classifications
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- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
本发明涉及式(I)化合物的制备方法[式中R1是4-甲基噻唑-2-基;R2是苯基;R3是乙基;L是2-(1H-吡唑-1-基)乙基;通过酰化反应或取代反应可制得本发明的式(I)化合物。
Description
本发明涉及4-杂环-4-〔N-(苯基)酰氨基〕哌啶衍生物及其制备方法以及采用这种化合物的组合物及其制备方法。特别地,这些化合物的新种类已被发现具有合乎需要的止痛和麻醉特性。
许多专利揭示了某些有止痛活性的N-苯基-N-(4-哌啶基)酰胺。例如,美国专利3,164,600和3,998,834揭示了一些这种化合物。美国专利3,164,600所揭示的这种化合物在其哌啶环的4位上被低级烷基所取代。
根据S·Me Elvain等人的报告,JACS,卷80(1958),在哌啶4位上某些取代基团的改变通常导致止痛活性的降低或消失。例如,Me Ehain等人指出从甲基至丁基进行改变对止痛力无明显效应,用4-苯基取代后,缺乏任何显著的效应。
本发明的化合物具有有效的止痛和麻醉特性。当哺乳动物应用本发明的优选化合物时可以有包括肌肉协调性早期恢复在内的快速恢复。与通常所知的诸如芬太尼(fentanyl)的静注麻醉药相比在使用期间呼吸的抑制相对地低些。心率的降低和动脉血压的下降也较少。本化合物因而较安全,尤其是对冠状病人。
现发现非常合乎需要的激动剂可由下式化合物。它们的旋光活性的异构体形式和/或其药学上可接受的酸加成盐来提供。
上面通式(Ⅰ)中,R1是有5个原子的不饱和杂环系统,环上五个原子包括1至4个氮原子和0至1个硫原子或氧原子,所说的杂环系统可以是未取代的或者被1个或更多的低级烷基、低级烷氧基、或低级烷氧基低级烷基基团或为兼备这些基团所取代;R2是取代或非取代的苯基,其中的取代基是一个或更多的卤素原子;R3是低级烷基或低级烷氧基低级烷基;L可以是广泛的各种基团包括低级烷基、低级烷氧基、噻吩基低级烷基、4位上用低级烷基取代的噻唑基低级烷基;4位上可用低级烷基取代的(4,5-二氢-5-氧代-1H-四唑基)低级烷基;吡唑基低级烷基、吡啶基低级烷基、氧代苯基低级烷基、N-苯二甲酰亚氨基低级烷基、3位用低级烷基双取代的2,4-(1H,3H)-吡啶二酮基;非取代或取代的苯基低级烷基其中取代基可选自包括低级烷基、低级烷氧基、卤原子、三卤低级烷基或兼备这些基团所取代。
在本发明的范围内一种优选的化合物是通式为
其旋光活性的异构体形式,和/或它们的药学上可接受的酸加成盐。式中:R1是从包括噁二唑基、咪唑基、三唑基、四唑基及噻唑基一组
中选择出来的取代基,所有这些基团可以是非取代的或用低级烷氧基、低级烷氧基低级烷基、低级烷基或兼有这些基团所取代;X是卤素或氢基团;R3是低级烷基或有2-6个碳原子的低级烷氧基烷基;L是取代或非取代苯基低级烷基、噻唑基低级烷基、4位上用低级烷基取代的4,5-二氢-5-氧代-1H-四唑-1-基;以及噻吩基低级烷基。
正如上面提到的,本发明的化合物具有通式:
其中R1是有5个原子的不饱和杂环,环上的5个原子中包括1至4个氮原子和0到1个硫原子或氧原子;所说的杂环系统可为非取代或者被低级烷基、低级烷氧基、低级烷氧基低级烷基或兼有这些基团所取代;R2是取代或非取代苯基;R3是低级烷基或低级烷氧基低级烷基;L是低级烷基、低级烷氧基、噻吩基低级烷基、4位可用低级烷基取代的噻唑基低级烷基、4位可用低级烷基取代的(4,5-二氢-5-氧代-1H-四唑-1-基)低级烷基、吡唑基低级烷基、吡啶基低级烷基、氧代苯基低级烷基、N-苯二甲酰亚氨基低级烷基、3位用低级烷基双取代的2,4-(1H,3H)-吡啶二酮基;非取代和取代苯基低级烷基其中的取代基从包括低级烷基、低级烷氧基、卤素、低级卤烷基(较好为三氟烷基)中选出或兼有这些基团所取代。化合物可呈药学上可接受的酸加成盐形式、旋光活性异构体和/或顺/反异构体。
上面通式Ⅰ中R1基团是含有1至4个氮原子和0至1个氧原子或硫原子的5个原子的杂环系统。优选的杂环从包括噁二唑基、咪唑基、三唑基、噻唑基和四唑基的一组中选出来。前述的环可以被取代或非
取代的,其中的取代基可选自低级烷基、低级烷氧基、低级烷氧基低级烷基或兼有这些基团所取代。
合适的R1基团包括1-吡咯基、1,2,4-三唑-4-基、1-甲基咪唑-2-基、1-甲基-1,2,4-三唑-5-基、1-甲基-1H-四唑-5-基、2-甲基-2H-四唑-5-基、甲基乙基-1,3,4-噁二唑基、甲氧基甲基1,3,4-噁二唑基、以及4-甲基-噻唑-2-基。
优选的L基团为取代或非取代的苯基低级烷基、噻吩基低级烷基、四唑基低级烷基和噻吩基低级烷基。
优选的R2基团是2-氟苯基和苯基。
上面通式Ⅰ中的R3基团是低级烷基或低级烷氧基低级烷基。合适的R3基团例子包括甲氧基甲基、乙氧基甲基、1-丙氧基甲基、2-丙氧基甲基、1-丁氧基甲基、1-戊氧基甲基、1-己氧基甲基、1-庚氧基甲基、1-甲氧基乙基、1-乙氧基-1-乙基、1-丁氧基-1-乙基、甲基、乙基、丙基、丁基、戊基或己基。优选的R3基团是甲基、乙基、甲氧基或乙氧基。
合适的L基团包括2-苯基乙基、1-苯基-2-丙基和2-苯基-1-丙基、在4位上用乙基取代的(4,5-二氢-5-氧代-1H-四唑-1-基)乙基、噻唑基乙基、苄基、2-(2-噻吩基)乙基、2-(3-噻吩基)乙基、2-(1-吡唑基)乙基、2-(2-吡啶基)乙基、2-甲基-丁基、乙基-1,3,4-噁二唑基、2-(2-吡啶基)乙基、2-乙氧基乙基、2-氧代-2-苯基乙基、2-(4-三氟甲基)苯乙基、2-(4-氟代苯基)乙基2-(2-氟代苯基)乙基、2-(N-苯二甲酰亚氨基)乙基、2-甲基丁基、2-甲基丙基、2-(4-甲基噻唑-5-基)乙基以及3,3-二乙基-2,4-(1H,3H)-吡噻二酮-1-基)乙基。
低级烷基或低级烷氧基基团表示含有1至6个碳原子并且较好为1至4个碳原子的支链基或非支链基。
本发明的化合物可以以游离碱或治疗上或药学上可接受的酸加成盐形式存在,此酸加成盐是通过用适当的酸处理得到,适当的酸为诸如无机酸,如,盐酸、溴氢酸、硫酸、硝酸、磷酸等;或为诸如乙酸、三氟乙酸、丙酸、羟基乙酸、甲氧基乙酸、苯甲酸、枸橼酸、草酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、琥珀酸、酒石酸等有机酸。优选的酸加成盐是盐酸盐、草酸盐或枸橼酸盐。这些酸加成盐可通过常规的方法,例如,用适当的酸进行处理来制备。
本发明的化合物中具有至少一个不对称碳原子它可以以旋光活性异构体的形式存在。例如,在L是1-苯基-2-丙基的化合物中,邻接在哌啶基氮原子的碳原子是不对称碳原子,这种化合物因而以旋光活性异构体(对映体)的形式存在。用该技术领域中熟知的技术可把这种异构体形式从外消旋混合物中分离出来。
本发明的化合物。制备成游离碱,可与药学上可接受的载体相结合提供出一个药物组合物。对于游离碱合适的载体包括丙二醇-乙醇-水、等渗水、美国药典的注射用灭菌水、爱莫尔夫TM乳化剂(emulphorTM)-乙醇-水、cremophor-ELTM或该域所知的其它载体。
制备成药学上可接受酸加成盐的本发明化合物也可与药学上可接受的载体结合得到一种药物组合物。对于酸加成盐的合适载体包括等渗水溶液、美国药典的注射用灭菌水、单用或该灭菌水与其它增溶剂诸如乙醇、丙二醇或该技术领域所知的其它常规增溶剂相结合使用。当然,正如该技术领域中的常规依据药物组合物所需的给药形式其载体可以改变。优选的载体是等渗水溶液,它至少含有一种本发明的化合物从0.0001mg/ml至0.5mg/ml,它依赖于用于配方中的个体化合物的药理学性质所决定。
本发明的化合物可以以提供所需治疗效果的有效量给哺乳动物,
如,动物和人使用。这些化合物在前面所述的载体中可以静脉注射、肌肉注射或皮下注射。这些化合物也可以采用在该技术领域中常规的使用形式的合适的药学上可接受载体来口服、舌下给药、直肠给药或皮内给药。
正如上面提到的,采用有效量的本发明化合物获得所需的治疗效果。由于化合物的活性和所需治疗效果的深度不同,所用的化合物的剂量浓度也需变动。实际的使用剂量由诸如病人的体重或特定病人的异性这类通常可被认清的因素所决定。因此,对于一个特定病人(男性)的单位剂量可低至(0.00005毫克/千克)在此剂量时医生可推测至所需的效果。
可以用下面所示已知的哌啶酮开始制备本发明的化合物:
例如,根据A·H·Becket、A·F·Casey和G·Kirk在J·Med Pharm.Chem.卷1,37(1959)中公布的方法可以制备1-苯乙基-4-哌啶酮。用C·R·Ganellin和R·G·Spickch在J·Med.Chem卷8,619(1965)或P·M·Carabateas和L·Grumbach在J·Med·Pharm.Chem.卷5,913(1962)中所述工艺的相似方法可以制备1-苄基-4-哌啶酮。如同美国专利4,583,303和1987年2月2日申请的07/009,857(收编在此供作参考)所揭示的可以制备带有其他L基团的化合物。
在本发明的方法一例中,L-哌啶酮可以与苯胺反应并且所生成的席夫碱可进一步与,例如,杂环锂剂,反应给出4-杂环-氨基哌啶
或者如果采用取代的杂环胺可给出相应的取代杂环化合物。
下列反应式阐述了这样一个方法;其中R1代表本发明的杂环基团:
后者化合物可与适当的酸卤化物,如R3(COCl)或酸酐(R3CO)O反应后在下面的氨基氮原子上引入适当的R3-CO-基团。
L最初可以为苯甲基并且在最终产物中L不是苯甲基时,制备本发明化合物的一个方法是随后裂解下苄基并用所需的L基团取代。例如,当以1-(2-苯甲基)-4-哌啶酮为起始时,通过下列反应式可制得不含硫杂环化合物的本发明化合物。
替代L基团的一个补充的方法包括用α-氯代-氯甲酸乙酯进行脱苄基作用,然后进行甲酸分解作用。
通被后者化合物与适当的反应活性分子LX反应可把相应的L基团随后引入,其中X是,例如,诸如氯、溴或碘的卤素,如下所述。
LX的反应可在惰性有机溶剂中进行,例如,N,N-二甲基甲酰胺(DMF)乙腈在有诸如碱金属羰酸盐的适当碱的存在下进行反应。
由下列反应式通过一种腈中间体也可以制备本发明的化合物:
余下的步骤可如上面所示的进行。
除了杂环R1是噻唑基、咪唑基或三唑基基团的化合物外本发明化合物的另一条合成路线是通过在哌啶环上的4-氰基取代基的官能团转变。用4-氰基中间体开始,加入叠氮盐产生官能团转变成4-杂环化合物。通过适当的反应,四唑基或者噁二唑基基团可得到并且可选择R、R′和L基团。反应如下所示。
其中在上述反应式中L、R3和X可与上述的定义相同,R1可从低级烷基、低级烷氧基或低级烷氧基低级烷基中选出。
下面的实施例代表说明的目的,但不限制本发明的化合物或给合物。
实施例1
在一良好通风的通风橱内室温(RT)下搅拌氰化钾(110.5克,1.69摩尔)溶于680毫升去离子水的溶液。在该溶液中加入苯胺(157.6克1.69摩尔)溶于甲醇320毫升的溶液。所得的溶液在冰/水浴中冷却并在冷却下向内滴加12N盐酸(140毫升,1.68摩尔)(当心氰化氢)。冷却下慢慢加入N-苄基-4-哌啶酮(320克,1.69摩尔),然后将反应混合物温热至室温。反应混合物在室温下搅拌8天。搅拌停止时反应混合物分成两层。上层甲醇水倾去,留下胶状固体。把异丙醇200毫升加至胶将残余物中并且将混合物剧烈搅拌45分钟。形成了一种细碎的固体。将该固体过滤,用异丙醇洗涤并在50℃以上干燥,得到所需的α-氨基腈的白色粉末288.2克(58.5%)。
实施例2
1-苄基-4-(4-甲基噻唑-2-基)-4-(N-苯基)哌啶
在氩气氛下将2.5M丁基锂己烷溶液(103毫升,257.5毫摩尔,Aldrih)加到无水THF150毫升中,溶液冷却至-78℃。将4-甲基噻唑(25毫升,274毫摩尔,Aldrich98%)通过注射器滴加到冷丁基锂溶液中。溶液变成深橙色并且5分钟后在-78℃下通过套管迅速加
入实施例1制得的腈(38.54克,132毫摩尔)溶于350毫升THF的溶液中。反应在-78℃下搅拌5分钟,然后在水/冰浴中加温至0℃。在0℃下通过慢慢滴加入50毫升水并搅拌0.5小时反应可被终止。分离有机层,用Na2SO4干燥并浓缩给出黑色油状的粗二元胺化合物。此油通过硅胶60色谱层析(230-400目)用乙酸乙酯/己烷1∶2洗脱得到淡黄色油状物经热己烷结晶得到纯的二元胺化合物40.4克(84%)。
NMR:7.50-6.40(m,11H),4.25(br s 1H),3.50(s,2H)
2.45(s,3H),2.90-1.90(复峰,8H)
实施例3
1-苄基-4-(4-甲基-噻唑-2-基)-4-(N-苯丙酰胺基)哌啶
实施例2的二胺(6.97克,19.17毫摩尔)溶于无水氯仿150毫升中并加入过量的丙酰氯。将反应混合物加热回流5天,通过薄层层析检测无起始的二胺存在之后。将反应液冷却并滴加到氢氧化钾(25克)溶于水500毫升的冷溶液(0℃)中并搅拌2小时。分离有机层,用过量的Na2SO4干燥并真空浓缩得到所需酰胺(如琥珀玻璃)(7.63克,95%)。
NMR:7.50(s,5H),7.35(s,5H),6.85(s,1H),3.40(s,5H),2.85-1.50(复峰,10H),2.40(s,3H),0.80(t,3H)
实施例4
将实施例3所得的酰胺(9.78克,22.35毫摩尔)溶于250毫升1,2-二氯乙烷并在冰浴中冷至0℃,然后加入1-氯代氯甲酸乙酯(3.53克,24.63毫摩尔)。将溶液温热至室温并加热回流。回流2.5小时后真空蒸去二氯甲烷,橙色残余物再溶于200毫升甲醇中。甲醇溶液回流5小时,冷却并真空浓缩。将残留物溶于0.5N盐酸400毫升中并用200毫升一份的乙醚提取两次。水层用25% NaOH水溶液碱化并用氯仿提取。分离氯仿层,用Na2SO4干燥并浓缩,得到油状的去甲化合物(7.84克,96%)。
实施例5
实施例4的去甲化合物(1.06克,3.22毫摩尔)溶于乙腈40毫升中。搅拌溶液并加入K2CO3(1.8克)和苯乙基溴(0.90克,4.86毫摩尔)。反应加热并回流2天,此后反应液冷却过滤并真空浓缩。残余物在硅胶60(230-400目)上色谱层析,用乙酸乙酯/己烷1∶1洗
脱,得到浅黄色油状的化合物(1.33克,95%)。
实施例6
1-[2-(1H-吡唑-1-基)乙基]-4-(4-甲基-噻唑-2-基)-4-(N-苯基丙酰胺基)哌啶
实施例4的去甲化合物溶于乙腈45毫升中。将该溶液搅拌并加入K2CO3(1.35克)和2-(1H-吡唑-1-基)乙基对甲苯磺酸酯(0.93克,3.4毫摩尔)。加热反应回流3天,此后将反应液冷却,过滤,并真空浓缩。残余物进行硅胶60(230-400目)色谱层析,用5%甲醇的乙酯乙酯溶液洗脱得到所需的琥珀油状产物(1.21克,92%)。
草酸盐的CHN%分析 熔点:185-87℃
分析值% C(58.46) H(6.08) N(13.64)
计算值% C(58.19) H(6.05) N(13.46)
核磁共振谱 7.35(s,5H),6.09(s,1H),4.25(m,2H),2.90-2.10(复峰,13H),0.90(t,3H)
实施例7
1-苄基-4-(1-甲基-1,2,4-三唑-5-基)-4-苯胺基-哌啶
用N-苄基哌啶酮(22.72克,120毫摩尔)、苯胺(11.17克,120毫摩尔)、对-甲苯磺酸(200毫克)及甲苯(250毫升)放入500毫升圆底烧瓶。混合物回流3小时同时通过Dean-Stark汽水阀分离掉水。将所得的红褐色溶液冷却至0℃。
把1-甲基-1,2,4-三唑(13,28克,160毫摩尔)和无水THF(400ml)置于1000毫升的圆底烧瓶中。在氮气氛-78℃下向此THF溶液加入正-丁基锂(100毫升,1.6M的己烷溶液)。所得的乳状混合物在-78℃下搅拌2小时。在-78℃下通过注射针把上述的甲苯溶液加至锂混合物中。加入后,所得的混合物在-78℃下搅拌30分钟,逐渐温热至室温并在室温下搅拌30分钟。用水(300毫升)终止此反应。分离有机层,Na2SO4干燥并真空浓缩。所得的残余物进行色谱层析得到琥珀色粘滞的油状产物(20.53克,59毫摩尔):红外光谱(纯净物):3400cm;NMR(60MHz,CDCl3)3.53(S,2H,苄甲基CH2),3.93(S,3H,三唑基CH3),6.2到7.5(m′s,10H,苯基上的H),7.86(S,1H,三唑基的H)。
实施例8
1-苄基-4-(1-甲基-1,2,4-三唑-5-基)-4-(N-苯丙酰胺基)哌啶
将1-苄基-4-(1-甲基-1,2,4-三唑-5-基)-4-苯胺基哌啶(11.45克,33毫摩尔)和丙酸酐(40毫升)的混合物在140℃搅拌70小时。
然后真空浓缩。粗制品溶于CH2Cl2,用5%Na2CO3洗涤,用Na2SO4干燥并真空浓缩。残余物进行色谱层析(SiO2,乙酸乙酯)得到产物(8.59克,21毫摩尔);为一琥珀色的粘滞状油:红外光谱(纯净物):1660cm;NMR(60MHz,CDCl3)δ0.86(t,3H,CH3CH2CON),1.5-3.0(复峰,10H),3,35(s,2H,苄基的CH2),4.23(s,5H,三唑基的CH),7.23和7.40(2bs,10H,苯基的H),7.83(s,1H,三唑基的H)。
实施例9
1-苄基-4-(1H-三唑-5-基)-4-苯胺基哌啶
将叠氮钠(5.85克,90毫摩尔)和1-苄基-4-氰基-4-苯胺基哌啶(2.91克,10毫摩尔)慢慢地加至AlCl3(2.67克,20毫摩尔)的无水THF(100毫升)溶液中。所得的混合物回流过夜。用水(50毫升)终止反应。分离出THF层后,水层用外加的THF(4×50毫升)提取。合并THF层,用MgSO4干燥并真空浓缩。所得的固体溶于1N盐酸中。用1N NaOH溶液调节pH至6.0。所得的混合物静置过夜并过滤给出白色结晶的固体产物(1.58克,4.7毫摩尔):熔点:205-206℃(分解点);红外光谱(液状石蜡):3300cm;NMR(270MHz,DMSO-d6)δ2.2至2.7(m,8H,哌啶的CH2),3.53(s,2H,苄基上的CH2),6.35、6.63和7.01(3m,5H,苯胺基苯基的H),7.25(m,5H,苄基苯基的H)。C19H22
N6的分析计算值:C,68.24:H,6.63;N,25.13。测定值:C,68.79;H6.76;N,24.81。
实施例10
1-苄基-4-(1H-四唑-5-基)-4-(2-氟代苯胺基)哌啶
在0℃氮气氛下在500毫升圆底烧瓶中搅拌250毫升无水THF,并向内每次少量地加入AlCl3(23.0克,172毫摩尔)。相继地加入NaN3(47.4克,729毫摩尔)和1-苄基-4-氰基-4-(2-氟代苯胺基)哌啶(21.8克,70毫摩尔)。所得的混合物回流20小时。冷至室温并倾入正在搅拌的水中(300ml)。分离出THF层,水层用外加THF(5×500毫升)提取。合并的THF层用MgSO4干燥并过滤。滤液在0℃保温15小时。过滤后可得所需化合物,为白色粉末:熔点:195-198℃;红外光谱(液状石蜡):3360cm-1;NMR(270MHz,DMSO-d6):δ2.29,2.46和2.67(3m,8H,哌啶的CH2),3.53(s,2H,苄基CH2),6.12,6.61,6.72和6.98(4m,4H,苯胺基的苯基的H),7.2-7.4(m,5H,苄基的苯基的H)。C19H21FN6的分析计算值:C,64.75;H,6.01;N,23.85。测定值:C,64.52;H5.94;N,23.56。
实施例11
1-苄基-4-(1H-四唑-5-基)-4-(N-苯丙酰胺基)基啶鎓丙酸盐。
将1-苄基-4-(1H-四唑-5-基)-4-苯胺基哌啶(17.7克,53毫摩尔)和丙酸酐(95ml)置于250毫升圆底烧瓶中。所得的混合物在70-75℃搅拌6小时。然后,真空浓缩,粗制品进行色谱层析(SiO2,5-20%MeOH/CH2Cl2)给出白色粉末的所需化合物(14.7克,32毫摩尔):熔点:226-228℃;红外光谱(液状石蜡):1660cm-1;NMR(270MHz,CDCl3)δ0.864(t,3H,CH3CH2CON),1.175(t,3H,CH3CH2CO2H),1.883(q,2H,CH3CH2CO2H),2.113(m,4H),2.395(q,2H,CH3CH2CO2H),2.8-3.1(m,4H),3.464(s,2H,苄基的CH2),7.1到7.5(复峰,10H,苯基的H)。C22H26N6O的分析:计算值:C,64.64;H6.94;N,18.09。测定值:C,64.65;H7.00;N,17.89。
实施例12
1-苄基-4-(1H-四唑-5-基)-4-[N-(2-氟代苯基)丙酰氨基]哌啶
将1-苄基-4-(1H-四唑-5-基)-4-(2-氟代苯胺基)哌啶(20.6克,58毫摩尔)和丙酸酐(100毫升)置于250毫升圆底烧瓶中。所得的混合物在70-75℃下搅拌24小时。进行真空浓缩,残余物进行色谱层析得到白色粉末的产物(8.6克,20毫摩尔):熔点:155-160℃,红外光谱(液状石蜡):1660cm-1;NMR(270MHz,CDCl3)δ0.848(t,3H,CH3CH2CON),1.88(m,CH3CH2CO),3.488(s,2H,苄基的CH),到7.5(m,9H,苯基的H)。C22H26FN6O·0.75H2O的分析计算值:C,62.61;H6.33;N,19.91。测定值:C,62.33;H,6.17;N19.88。
实施例13
1-苄基-4-(甲基-1,3,4-噁二唑基)-4-(N-苯乙酰胺基)哌啶。
1-苄基-4-(1H-四唑-5-基)-4-苯胺基哌啶(592克,1.77毫摩尔)和乙酸酐(10ml)置于25毫升圆底烧瓶中。所得的混合物回流2小时并真空浓缩。所得的残余物溶于CH2Cl2(50ml),用5%NaHCO3和水洗涤。Na2SO4干燥并真空浓缩。残余物进行色谱层析(SiO2,乙酸乙酯得到无色液体的产物(525毫克,1.34毫摩尔):红外光谱(纯
净物):1660cm-1;NMR(60MHz,CDCl3)δ1.67(s,3H,CHCO),2.60(s,3H,噁二唑基的CH3),3.44(s,2H,苄基的CH2),7.30和7.48(2bs,10H,苯基的H)。C23H26N4O2·C2H2O4的分析计算值:C,62.49;H5.87;N,11.66。测定值:C,62.56;H,5.95;N11.37。
实施例14
1-苄基-4-(乙基-1,3,4-噁二唑基)-4-(N-苯丙酰氨基)哌啶。
将1-苄基-4-(1H-四唑-5-基)-4-苯胺基哌啶(7.45克,22毫摩尔)和丙酸酐(100毫升)的混合物在120℃下搅拌2小时(放出氮气约需20分钟)。所得的溶液真空浓缩。粗制品溶于CH2Cl2(400毫升),用5%NaHCO3(200毫升)洗涤,用Na2SO4干燥并真空浓缩。残余物进行色谱层析(SiO2,乙酸乙酯/己烷1∶1)得到琥珀色油状的产物(8.20克,19.6毫摩尔)。红外光谱(纯净物):1670cm-1;NMR(60MHz,CDCl3)δ0.89(t,3H,CH3CH2CO),1.39(t,3H,噁二唑的CH3),3.34(s,苄基CH2).7.30和7.49(2bs,10H,苯基的H)。C25H30N4O2·C2H2O4的分析计算值:C,63.76;H6.34;N,11.02。测定值:C,63.40;H,6.26;N10.79。
实施例15
1-苄基-4-(甲基-1,3,4-噁二唑基)-4-(N-苯丙酰氨基)哌啶。
将1-苄基-4-(1H-四唑-5-基)-4-(N-苯丙酰氨基)基啶鎓丙酸盐和(6.04克13毫摩尔)和乙酸酐(50毫升)置于100毫升圆底烧瓶中。所得的混合物在110℃下搅拌2小时并且真空浓缩。粗品溶于CHCl(100毫升),用5%Na2CO3(100毫升)洗涤,用Na2SO4干燥并真空浓缩。所得的残余物进行色谱层析(SiO2,乙酸乙酯/己烷1∶1)给出粘滞的油状产物(4.20克,10.4毫摩尔):NMR(60MHz,CDCl3)δ0.90(t,3H,CH3CH2CO),2.61(s,3H,噁二唑的CH3),3.46(s,2H,苄基的CH2),7.33和7.52(2bs,10H,苯基的H)。
实施例16
1-苄基-4-(甲氧基甲基-1,3,4-噁二唑基)-4-(N-苯丙酰氨基)哌啶。
在0℃时间甲氧基乙酸(4.51克,50毫摩尔)在三丙胺(80毫升)的溶液内滴加甲氧基乙酰氯(5.80克,53毫摩尔)。所得的溶液在0℃下搅拌15分钟。随后,加入1-苄基-4-(1H-四唑-5-基)-4-N-苯基丙酰氨基)基啶鎓丙酸盐(4.42克,9.5毫摩尔)。将全部混合物在110℃下搅拌3小时然后真空浓缩。粗制品溶于乙酸乙酯(300毫升)中,用5%Na2CO3(200毫升)洗涤。用Na2SO4干燥并真空浓缩。残余物进行色谱层析(SiO2,乙酸乙酯/己烷1∶1)给出琥珀色油状产物(4.15克,9.5毫摩尔)。NMR(600MHz,CDCl3)δ0.89(t,3H,CH3CH2CO)3.46(bs,5H,CH3OCH2和phCH2),4.70(s,2H,CH3OCH2),7.27和7.47(2bs,10H,苯基上的H)。
实施例17
1-苄基-4-(乙基-1,3,4-噁二唑基)-4-[N-(2-氟代苯基)丙酰氨基)哌啶。
将1-苄基-4-(1H-四唑-5-基)-4-(2-氟代苯胺)哌啶(12.0克,34毫摩尔)和丙酸酐(80毫升)置于250ml圆底烧瓶中。
所得的混合物在160℃下搅拌48小时,然后真空浓缩。粗制品溶于CH2Cl2(200毫升)中,用5%Na2CO3(100ml)洗涤,用Na2SO4干燥并真空浓缩。所得的残余物进行色谱层析(SiO,乙酸乙酯/己烷2∶1)得到粘滞的油状产物(5.75克,13毫摩尔):NMR(60MHz,CDCl)δ0.93(t,3H,CH3CH2CO),1.40(t,3H,噁二唑CH3),3.50(s,2H,苄基的CH2),7.1-7.8(m,9H,苯基的H)。
实施例18
1-苄基-4-(1和2-甲基-1H-四唑-5-基)4-(N-苯丙酰氨基)哌啶
将1-苄基-4-(1H-四唑-5-基)-4-(N-苯丙酰氨基)基啶鎓丙酸盐(18.6克,40.7毫摩尔)和DMF(120毫升)的混合物,在搅拌下加入NaH(2.4克,100毫摩尔)。混合物在室温下搅拌30分钟。向所得的棕褐色溶液中慢慢加入碘甲烷(15克,106毫摩尔)。对其进行搅拌30分钟再倾入H2O(400毫升)中。混合物用CH2Cl2(2×250ml)提取,用Na2SO4干燥并真空浓缩。所得的残余物进行色谱层析(SiO2,1%MeOH/CH2Cl2)给出1-苄基-4-(1-甲基-1H-四唑-5-基)-4-(N-苯丙酰氨基)哌啶的无色粘状油(4.58
克,11.3毫摩尔):红外光谱(纯净物):1660cm-1。NMR(270MHz,CDCl3)δ0.834(t,3H,CH3CH2CO),1.789(q,2H,CH3CH2),3.334(s,2H,phCH2),4.435(s,3H,四唑基的CH3),7.15至7.47(m′s,10H,苯基的H),以及1-苄基-4-(2-甲基-2H-四唑-5-基)-4-(N-苯丙酰氨基)哌啶的粘状油(2.75克,6.8毫摩尔):红外光谱(纯净物):1660cm-1;NMR(270MHz,CDCl3)δ0.830(t,3H,CH3CH2CO),1.810(q,2H,CH3CH2),3.402(s,2H,phCH2),4.369(s,3H,四唑基的CH3),7.30至7.54(3m′s,10H,苯基的H)。
实施例19
4-(乙基-1,3,4-噁二唑)-4-(N-苯丙酰氨基)哌啶
将1-苄基-4-(乙基-1,3,4-噁二唑)-4-(N-苯丙酰氨基)哌啶(8.20克,19.6毫摩尔)和在甲醇(100毫升)中的10%披钯木炭的混合物在帕尔摇动器中与氢气(50磅/平方英寸)反应。24小时后,所得的混合物过滤,滤液进行真空浓缩。得到泡沫状的残余物(6.42克,19.5毫摩尔)。反应液不经进一步的纯化即被使用。
实施例20
1-(2-苯乙基)-4-(乙基-1,3,4-噁二唑基)-4-(N-苯丙酰氨基)哌啶
将4-(乙基-1,3,4-噁二唑基)-4-(N-苯丙酰氨基)哌啶(900毫克,2.74毫摩尔)、苯乙基溴(507毫克,2.74毫摩尔)、Na I(490毫克,3.3毫摩尔)和Na2CO3(2.0克)在乙腈(50毫升)中的混合物回流72小时。经过滤并真空浓缩。残余物用CH2Cl2(100毫升)处理并再过滤。将滤液真空浓缩,所得的残余物进行色谱层析(SiO2,乙酸乙酯/己烷1∶1)给出无色油状的产物(904mg,2.1毫摩尔):红外光谱(纯净物):1660cm-1;NMR(60MHz,CDCl3)δ0.87(t,3H,CH3CH2CON),1.37(t,3H,噁二唑的CH3),1.60-3.15(m,16H),7.23和7.50(2bs,10H,苯基的H)。
实施例21
1-(2-苯乙基)-4-(乙基-1,3,4-噁二唑基)-4-(N-苯丙酰氨基)基啶鎓草酸盐
向1-(2-苯乙基)-4-(乙基-1,3,4-噁二唑基)-4-(N-苯丙酰氨基)哌啶(417毫克,0.96毫摩尔)的乙酸乙酯溶液(20毫升)中滴加入草酸(87毫克,0.97毫摩尔在乙酸乙酯2ml中)。所得的混合物加热至70℃,滴加入甲醇直到溶液澄清。溶液静置2小时冷却至室温。过滤后得到结晶化合物的产物,熔点:159-161℃。C26H32N4O2·C2H2O4·1/4H2O的分析计算值:C,63.80;H,6.60;N,10.63。测定值:C,63.93;H,6.65;N10.75。
实施例22
1-[2-(2-噻吩基)乙基-4-(乙基-1,3,4-噁二唑)-4-(N-苯丙酰氨基)哌啶
将4-(乙基-1,3,4-噁二唑基)-4-(N-苯丙酰氨基)哌啶(880毫克,2.68毫摩尔)、2-(2-噻吩基)乙基氯化物(385毫克,2.63毫摩尔)、Na I(470毫克,3.1毫摩尔)和Na2CO3(2.0克)在乙腈
(50毫升)中的混合物回流72小时。冷至室温后过滤。真空浓缩滤液,残余物用CH2Cl2(100毫升)处理。将所得的混合物过滤,真空浓缩滤液。残余物进行色谱层析给出琥珀色的油状产物(940mg,2.14毫摩尔):红外光谱(纯净物):1660cm;NMR(60MHz,CDCl3)δ0.88(t,3H,CH3CH2CO),1.39(t,3H,噁二唑基的CH3),1.60到3.20(m,16H),6.70到7.40(m,3H,噻吩基的H),7.44(s,5H,苯基的H)。
实施例23
1-[2-(2-噻吩基)乙基]-4-(乙基-1,3,4-噁二唑基)-4-(N-苯丙酰氨)基啶鎓草酸盐。
向1-[2-(2-噻吩基)乙基]-4-(乙基-1,3,4-噁二唑基)-4-(N-苯丙酰氨基)哌啶(660毫克,1.50毫摩尔)的乙酸乙酯溶液(20ml)中滴加入草酸(136毫克,1.51毫摩尔,在30毫升乙酸乙酯中)。所得的混合物加热至70℃,滴加甲醇至溶液呈澄清。此溶液静置2小时冷至室温。滤出沉淀得到白色结晶化合物的产物(630毫克,1.19毫摩尔),熔点:160-162℃。C24H30N4O2S·C2H2O4的分析:计算值:C,59.07;H,6.10;N10.60。测定值:C,59.08;H6.26;N,10.45。
本发明的许多化合物对其止痛性和逆转特性进行了试验。特别地,本发明试制的酸加成草酸盐化合物溶于美国药典的注射用灭菌水,形成浓度变化范围从0.00001mg/ml至5mg/ml的溶液。该溶液对小鼠的尾静脉进行静注。
从Domer,Floyd R.在Animal Experimemts in Pharmacological Ananlysis,Charles C.Thomas,Springfield,1971,283ff中所述的小鼠热板止痛试验(58℃)可获得半数有效量(ED)。列于下面表1的化合物进行该过程试验,发现具有止痛活性的列于下面表Ⅰ、Ⅱ和Ⅲ。
表Ⅲ
止痛活性
化合物 熔点℃ (ED50)mg/kg小鼠
1.1-(2-苯乙基)-4-(4-甲基- 203.5-204.5 0.022
噻唑-2-基)-4-[N-氟代苯基)
丙酰氨基]基啶鎓草酸盐
2.1-[2-(4-乙基-4,5-二氢-5-氧代-1H- 154-55 0.264
四唑-1-基)-乙基]-4-(4-甲基、噻唑-2-基)
-4-(苯丙酰氨基)基啶鎓草酸盐
3.1-[2-(4-乙基-4,5-二氢-5-氧代-1H- 144-46 0.179
四唑-1-基)-乙基]-4-(4-甲基噻唑-2-基)
-4-[N-(2-氟代苯基)丙酰氨基]基啶鎓草酸盐
4.1-[2-(1H-吡唑-1-基)乙基]-4- 185-87 0.064
(4-甲基噻唑-2-基)-4-(N-
苯丙酰氨基)基啶鎓草酸盐
5.1-[2-(1H-吡唑-1-基)乙基]-4- 185-87 0.047
(4-甲基噻唑-2-基)-4-(N-(2-氟代苯基)
丙酰氨基]基啶鎓草酸盐
6.1-[2-(2-噻吩基)乙基]-4-(4- 198-200 0.012
甲基噻唑-2-基)-4-(N-(2-氟代苯基)
丙酰氨基]基啶鎓草酸盐
7.1-[2-(3-噻吩基)乙基]-4- 202-204 0.0054
(4-甲基噻唑-2-基)-4-(N-
(2-氟代苯基)丙酰氨基)基啶鎓草酸盐
8.1-(2-苯乙基)-4-(2-噻唑基)-4- 193-94 0.0047
(N-苯丙酰氨基)基啶鎓草酸盐
9.1-(2-苯乙基)-4-(2-噻唑基)-4- 202-203 0.0034
(N-(2-氟代苯基)丙酰氨基]基啶鎓草酸盐
10.1-[2-(4-乙基-4,5-二氢-5-氧代 169-70 0.212
-1H-四唑-1-基)乙基]-4-(2-噻唑基)
-4-[N-苯丙酰氨基)基啶鎓草酸盐
11.1-[2-(4-乙基-4,5-二氢-5-氧代 177-78 0.057
-1H-四唑-1-基)乙基]-4-(2-噻唑基)-4-
[N-(2-氟代苯基)丙酰氨基]基啶鎓草酸盐
表Ⅲ续
止痛活性
化合物 熔点℃. (ED50)mg/kg 小鼠
12.1-(2-苯乙基)-4-(4,5-二甲基- 191-192 >5.0
噻唑-2-基)-4-(N-苯丙酰氨基)
基啶鎓草酸盐
13.1-[2-(3-噻吩基)乙基]-4- 201-202 0.525
(4,5-二甲基-噻唑-2-基)-4-
(N-苯丙酰氨基)基啶鎓草酸盐
14.1-[2-(4-乙基-4,5-二氢-5-氧代-1H- 194-95 N/A
四唑-1-基)乙基]4-(4,5-二甲噻唑基-2-
基)-4-(N-苯丙酰氨基)基啶鎓草酸盐
15.1-(2-苯乙基)-4-(4-甲基噻唑 204 0.072
-2-基)-4-(N-苯丙酰氨基)
基啶鎓草酸盐
16.1-[2-(2-噻吩基)乙基]-4- - 181 0.01
(4-甲基噻唑-2-基)-4-(N-
苯丙酰氨基)基啶鎓草酸盐
17.1-[2-(3-噻吩基)乙基]-4- - 202-204 0.0059
(4-甲基噻唑-2-基)-4-(N-
苯丙酰氨基)基啶鎓草酸盐
18.1-[2-(4-甲基噻唑-5-基]乙基]-4- 225 0.017
(4-甲基噻唑-2-基)-4-(N-(2-氟代苯基)
丙酰氨基]基啶鎓草酸盐
应当了解这里所述的实施例仅是例证的,该技术领域人员在不背离本发明的构思和范围内可作出许多变动和改进。这些变动和改进被包括在权利要求所定义的范围内。
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US07/139,899 | 1987-12-31 | ||
US139,899 | 1987-12-31 | ||
US07/139,899 US4791120A (en) | 1987-12-31 | 1987-12-31 | 4-heteropentacyclic-4-[N-(phenyl)amino] piperidine derivatives and pharmaceutical compositions and method employing such compounds |
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CN (1) | CN1023010C (zh) |
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US4871749A (en) * | 1987-12-31 | 1989-10-03 | Boc, Inc. | 4-heteropentacyclic-4-(N-(phenyl)amido) piperidine derivatives and pharamaceutical compositions and method employing such compounds |
USRE34201E (en) * | 1989-04-20 | 1993-03-23 | Anaquest, Inc. | N-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides and pharmaceutical compositions and methods employing such compounds |
US5145967A (en) * | 1989-04-20 | 1992-09-08 | Anaquest, Inc. | Method for preparing 4-alkoxyalkyl-4-phenylaminopiperdines and derivatives thereof |
US5053411A (en) * | 1989-04-20 | 1991-10-01 | Anaquest, Inc. | N-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides and pharmaceutical compositions and methods employing such compounds |
FR2725986B1 (fr) * | 1994-10-21 | 1996-11-29 | Adir | Nouveaux derives de piperidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US7361666B2 (en) * | 1999-05-25 | 2008-04-22 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US6635661B2 (en) | 2000-05-25 | 2003-10-21 | Sepracor Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US6677332B1 (en) * | 1999-05-25 | 2004-01-13 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US6693099B2 (en) * | 2000-10-17 | 2004-02-17 | The Procter & Gamble Company | Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance |
US6376514B1 (en) * | 2000-10-17 | 2002-04-23 | The Procter & Gamble Co. | Substituted six-membered heterocyclic compounds useful for treating multidrug resistance and compositions and methods thereof |
US20060252797A1 (en) * | 2002-11-06 | 2006-11-09 | Masahiro Kajino | Receptor regulator |
US20080319196A1 (en) * | 2005-11-17 | 2008-12-25 | Cheng Brian K | Process for Synthesizing Remifentanil |
RU2612970C1 (ru) * | 2015-10-05 | 2017-03-14 | Федеральное государственное казённое военное образовательное учреждение высшего профессионального образования "Военная академия радиационной, химической и биологической защиты имени Маршала Советского Союза С.К. Тимошенко" г. Кострома Министерства обороны Российской Федерации | Способ получения 1-бензил-4-пропиоанилидо-4-пиперидинкарбонитрила |
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US4584303A (en) * | 1984-04-09 | 1986-04-22 | The Boc Group, Inc. | N-aryl-N-(4-piperidinyl)amides and pharmaceutical compositions and method employing such compounds |
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KR890009921A (ko) | 1989-08-04 |
FI886057A (fi) | 1989-07-01 |
FI92065B (fi) | 1994-06-15 |
NO885463L (no) | 1989-07-03 |
CN1035285A (zh) | 1989-09-06 |
NO174553C (no) | 1994-05-25 |
US4791120A (en) | 1988-12-13 |
NZ227172A (en) | 1990-06-26 |
JPH01213278A (ja) | 1989-08-28 |
NO174553B (no) | 1994-02-14 |
DK732888D0 (da) | 1988-12-30 |
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