CN1016691B - 抑制精神的2-(4-丁基哌嗪-1-基)吡啶类环状亚胺衍生物的制备方法 - Google Patents
抑制精神的2-(4-丁基哌嗪-1-基)吡啶类环状亚胺衍生物的制备方法Info
- Publication number
- CN1016691B CN1016691B CN86100224A CN86100224A CN1016691B CN 1016691 B CN1016691 B CN 1016691B CN 86100224 A CN86100224 A CN 86100224A CN 86100224 A CN86100224 A CN 86100224A CN 1016691 B CN1016691 B CN 1016691B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- hydrogen
- pyridine
- azaspiro
- 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.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 57
- 230000008569 process Effects 0.000 title claims description 9
- 230000000561 anti-psychotic effect Effects 0.000 title abstract description 4
- -1 cyclic imide Chemical class 0.000 title description 16
- 238000002360 preparation method Methods 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 230000002152 alkylating effect Effects 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical class COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 229940123464 Thiazolidinedione Drugs 0.000 abstract description 6
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 abstract description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 abstract description 3
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 abstract description 2
- IJSMDZFKMKEIRX-UHFFFAOYSA-N morpholine-2,6-dione Chemical compound O=C1CNCC(=O)O1 IJSMDZFKMKEIRX-UHFFFAOYSA-N 0.000 abstract 1
- 230000000506 psychotropic effect Effects 0.000 abstract 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 22
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- 239000012141 concentrate Substances 0.000 description 15
- 235000008504 concentrate Nutrition 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
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- 239000007787 solid Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- 208000009132 Catalepsy Diseases 0.000 description 8
- 206010047853 Waxy flexibility Diseases 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 208000028017 Psychotic disease Diseases 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- CCVNZKGBNUPYPG-UHFFFAOYSA-N 2-chloro-3-methoxypyridine Chemical compound COC1=CC=CN=C1Cl CCVNZKGBNUPYPG-UHFFFAOYSA-N 0.000 description 5
- 150000001540 azides Chemical class 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 125000005594 diketone group Chemical group 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 102000015554 Dopamine receptor Human genes 0.000 description 3
- 108050004812 Dopamine receptor Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229940037003 alum Drugs 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
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- 238000000605 extraction Methods 0.000 description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical group C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 3
- 229950001675 spiperone Drugs 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- GUIPMNNQJZQJFU-UHFFFAOYSA-N 2-chloro-3-phenylpyridine Chemical class ClC1=NC=CC=C1C1=CC=CC=C1 GUIPMNNQJZQJFU-UHFFFAOYSA-N 0.000 description 2
- 150000005759 2-chloropyridine Chemical class 0.000 description 2
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 description 2
- HJKGBRPNSJADMB-UHFFFAOYSA-N 3-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CN=C1 HJKGBRPNSJADMB-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
- C07D413/12—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 linked by a chain containing hetero atoms as chain links
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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
- C07D413/14—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
- C07D417/12—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 linked by a chain containing hetero atoms as chain links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
公开了取代的N,N-哌嗪基衍生物的制备方法,其中一个取代基是取代的吡啶-2-基环,第二个取代基是连接到环状亚胺杂环上的丁二烯链,例如连接到氮杂螺[4,5]癸二酮、二烷基戊二酰亚胺、噻唑烷二酮,螺环戊基噻唑烷二酮或者吗啉-2,6-二酮等上的丁二烯链。这些化合物具有抗精神活动的性质,而且2-[4-[4-(2,4-二氧-1-硫-3-氮杂螺[4,5]壬-3-基)丁基]-1-哌嗪基]-吡啶-3-甲醛是具有选择性抗精神活动活性的典型实例。
Description
披露了一些双取代的N,N-哌嗪基衍生物,其中一个取代基是取代的吡啶-2-基环,另一个取代基是连接到环状亚胺杂环上的丁二烯链,例如连接到氮杂螺[4,5]癸二酮、二烷基戊二酰亚胺、噻唑烷二酮、螺环戊基噻唑烷二酮或吗啉-2,6-二酮上的丁二烯链。这些化合物具有影响精神的性质,而且2-[4-[4-(2,4-二氧-1-硫-3-氮杂螺[4,5]壬-3-基)丁基]-1-哌嗪基]-吡啶-3-甲醛是具有选择性抑制精神活性的典型实例。
一般来讲本发明是关于具有药物性质和生物影响性质的杂环的碳化合物及其制备和应用。具体来说,本发明涉及1,4-二取代的哌嗪衍生物,其中一个取代基是通常在环的3位上具有取代基的取代的吡啶-2-基环,另一个取代基是在其端部带有环状亚胺部分的丁烯链。这些环状亚胺杂环类的实例如下:
“杂氮螺[4,5]癸二酮”
“二烷基戊二酰亚胺”
“噻唑烷二酮”
“螺环戊基-2,4-噻唑烷二酮”
“吗啉-2,6-二酮”
在过去10年之中,积累了许多相关的现有技术文献。借助于下列的一般结构式(1),可以评论更确切的相关现有技术:
其中alk是连接在哌嗪环和环状亚胺基团上的亚烷基链B是带任意取代基的杂环。
吴等人的美国专利3,717,634和3,907,801以及相应的出版物“医药化学杂志”(J·Med·Chem.)15,447-479(1972),介绍了各种氮杂螺[4,5]癸二酮影响精神的化合物,其中B表示各种杂环,例如吡啶、嘧啶或者三嗪,它们都带有任意的取代基。B尤其可以是:
其中W和Y之一是CH,另一个是氮;R1和R2是独立地由氢、C1-C6的低级烷基或者低级烷氧基中选择出来的。正如可以看到的那样,和在本发明中的情况相同,B不能是3-取代的吡啶-2-基部分。
特姆帕(Temple)等人在美国专利4,305,944和4,361,565中披露和请求保护一些氮杂螺[4,5]癸二酮和二烷基戊二酰亚胺镇定化合物,其中B是3-氰基吡啶-2-基部分(美国专利4,305,944)或者在吡啶环上带有卤素或者三氟甲基作为第二个取代基的3-氰基吡啶-2-基环(美国专利4,361,565)。Temple等人的这些化合
物,在吡啶环部分上均含有3-氰基取代基。
Temple和Yeager在美国专利4,367,335和4,456,756中,公开了这样一些噻唑烷二酮类和螺噻唑烷二酮类,其中B是未取代的或者是含有一个氰基取代基的一个2-吡啶原子团。
这一系列化合物中,优选的化合物为MJ13980,其结构式(2)为:
但是在临床试验之前发现此化合物有毒理方面的问题。尤其是肾上腺肥大变化与长期使用MJ13980有关。MJ13980的分子结构试验表明,氰基吡啶部分似乎推测是引起这种不希望有的毒理作用的药效基团。
虽然上面所罗列的影响精神的化合物,总地说来与本发明的化合物有关,但是可以从中区别出在特定结构以及药理原因上存在着差别。现有技术中的化合物,B基本上是未取代的或者通常在3-位上带有一个氰基。这一点区别于通常在3-位上取代的并且没有氰基的本发明的化合物。
广义地讲,本发明是关于具有神经安定(抑制精神)性质的、以Ⅰ式化合物及其药物上可接受的酸加成盐为特征的哌嗪基衍生物:
在Ⅰ式中,Z代表的原子团有:
其中,n为3至6的整数;R3和R4分别是1至4个碳原子的低级烷基;而且R5和R6选自氢、1至4个碳原子的低级烷基或苯基;另外,A是一个氧或硫原子。R1选自氢、低级烷基低级烷氧基、甲酰基、烷氧羰基、卤素、硝基、苯基或者
,其中R7是低级烷基。R2选自氢、卤素、低级烷基、低级烷氧基,但R1和R2不可同时是氢。
在这里使用的“低级烷基”这个术语,是指1至4个碳原子(1和4个碳原子包括在内)的直链或者支链碳原子团。这些原子团的是这样一些碳链,例如可以是甲基、乙基、丙基、异丙基、1-丁基、1-甲基丙基和2-甲基丙基。
有两类优选的化合物。第一类化合物中,R2是氢,而且R1是上述定义的氢之外的基团,Z与上面规定的相同。在第二类化合物中,R2不是氢,R1定义如上,而且Z是上述定义的(a)之外的基团。最优选的化合物包括Z如上述定义,R1选自甲酰基烷氧羰基和硝基,而且R2是氢的那些化合物。
本发明的药学上可接受的酸加成盐是这样一些物质,即其中阴离子对盐的毒性或药理活性无明显影响,而其本身只不过是Ⅰ式碱的药理学上的等效物。这些盐通常优先用作药物。在某些情况下,这些盐具有一些使之更适于制备药物制剂的物理性质,例如溶解度,无吸湿性、制片剂的压缩性以及与可以用于药物用途的物质等其它成分之间的相容性。这些盐是按常规方法制备的,即使用Ⅰ式碱与所选出酸的混合物,最好是使采用过量的通常采用的惰性溶剂(例如水、醚、苯、乙醇、乙酸乙酯和乙腈等)的两种溶液接触的方法制备。也可以按照所属技术领域中普通技术人员可以获得的文献中记载的其它标准方法制备这种盐。可以使用的有机酸有,例如:马来酸、乙酸、酒石酸、丙酸、富马酸、羟乙磺酸、丁二酸、双羟苯酸、环己氨基磺酸、新戊酸等羧酸;可以使用的无机酸有HCl、HBr和HI等,氢卤酸、硫酸类和磷酸等。
这应当理解到,本发明包括当Z是(b)或(c)时可能得到的任何立体异构体。利用所属技术领域中普通技术人员公知的各种方法,可以完成单个主体异构体的分离工作。
本发明的化合物是具有影响精神作用的有用的药剂。就此而言,它们在无毒剂量下表现出选择性中枢神经系统活性,因而作为神经安定(抑制精
神)剂具有特殊意义。正如其它已知的精神抑制药那样,对Ⅰ式化合物按照标准的体内和体外药理试验系统进行研究时,Ⅰ式化合物能引起某些应答,这些应答已知与减轻人体急性和慢性精神病症状有密切关系。
表明本发明化合物影响精神活性和特异性时,可以采用现有技术中体外中枢神经系统受体结合法。对于优先结合到与影响精神活性或者副作用潜力有关的脑组织中那些特殊高亲和力部位上的某些化合物(一般叫作配位体),做了识别试验。结合到这种特别高亲和力部位上放射性标记配位体的抑制作用,据认为是该化合物影响相应中枢神经系统功能或者在体内引起副作用能力上的一种度量。在测量抑制[3H]螺环哌啶酮结合的试验中采用了这个原理,试验表明了显著的多巴胺受体结合活性[参见:Burt等人,“分子药理学”Molecular Pharmacology,12800(1976);“科学”Science,196,326(1977);Creese等人,“科学”Science,192,481(1976)]。
下列的体内试验体系用于说明影响精神活动剂分类以及在区别它与非特效中枢神经系统抑制剂时常用试验的例证,这些体系也决定着潜在的副作用倾向,例如僵住病的活性。
表1 用于评价Ⅰ式化合物
的体内试验
1、条件无效应答(CAR)-药物镇定作用的度量,按照经训练的禁食大鼠对电冲击无效应答的减弱测定药物镇定作用。参见:Albert,“药理学家”Pharmacologist,4,152(1962);吴等人,“医药化学杂志”J·Med·Chem.,12,876-881,(1969)。
2、阿朴吗啉诱发的(APO)刻板动作症的抑制-按照由多巴胺主动肌引起的行为综合症的减弱,测得多巴胺活性阻断的评定,阿朴吗啉。参见Janssen等人,Arzneimittel·Forsch·,17,8841(1966)。
3、僵住症-药物诱发大鼠的僵住症是人潜在锥体束外症状(EPS)的特征。参见:Costall等人,“精神药理学”,Psychopharma-Cologia,34,233-241(1974);Berkson,“美国统计协会志”,J·Amer·Stast·Assoc·,48,565-599(1953)。
4、僵住症回复-测量使大鼠神经安定药诱发的僵住症回复的药物能力。
按照由上述试验确定的药理学情况,本发明的Ⅰ式化合物具有抑制精神的潜在作用能力,因为在条件无效应答(CAR)试验中,口服半数有效量ED50值小于100毫克/公斤体重,在[3H]螺环哌啶酮多巴胺受体结合试验中IC50值小于1000毫微摩尔,因而这些化合物是相当有潜力的。在条件无效应答试验和螺环哌啶酮试验中的活性,据认为是人体抑制精神潜力的特征。关于选择性抗精神活动作用,优选的本发明化合物有显著多巴胺受体结合活性并且使大鼠的条件无效应答抑制在僵住症剂量之下。关于副作用倾向,本发明化合物在诱发僵住症方面相当迟钝,而且本发明的优选化合物在给定口服ED50值小于20mg/kg的条件下,甚至于更明显地显示出具有使神经安定药诱发的僵住症回复的能力。假如考虑到作为一类物质来说,抑制精神剂已知能产生镇静作用和锥体束外反应的话,那么本发明化合物对于僵住症诱发和回复作用的显著性,就值得更好地加以评价。这些锥体束外反应是由急性应变性肌张力障碍、静坐恐布、帕金森神经机能障碍、迟发性运动障碍和自主性神经系统作用所组成。
纵观上述讨论可知,本发明的化合物具有影响精神的性质,特别适合于用作神经安定(抗精神活动)药剂。因此,本发明的另一方面涉及改善需要这种治疗的哺乳动物精神病状态的方法,其中包括给这种哺乳动物系统投药有效剂量的Ⅰ式化合物或者其药学上可接受的酸加成盐。
Ⅰ式化合物的投药制度和剂量制度,据认为与参照化合物氯氮平相同(参见The Merck Index,第10版,(1983),344页,及其中文献)。虽然剂量和剂量制度必须按照每个病例仔细调剂,按照医生的可靠判断,同时还得考虑受药者的年龄、体重和身体状况,以及投药途径和病人的病情和严重程度;但是当非肠道投药时,日剂量通常在大约0.05至大约10mg/kg之间,最好在0.1至2mg/kg之间;口服时从大约1至大约50mg/kg之间,最好为2至30mg/kg之间。在某些情况下,在较低的剂量下就能获得足够的治疗效果,而在其它情况下需要较大的剂量。在这里所用的“系统投药”这个术语,是指口服、直肠投药和非肠道
投药,即肌肉内、静脉内和皮下投药。一般情况下将会发现,口服本发明化合物时(这是优选的投药方式),为产生相同的效果需要较大量的此活性成分,而非肠道投药量则较小。根据良好的临床实践,优选本发明化合物的投药浓度,将产生有效的神经安定(抗精神活动)作用,而不引起任何有害或者不适当的副作用。
在治疗上,本发明化合物通常是以药物组合物形式使用的,这种组合物由有效抗精神活性量的Ⅰ式化合物或其药学上可接受的酸加成盐,以及药学上可接受的载体所组成。实现这种治疗的药物组合物,含有大量或者少量的(例如从95%至0.5%)至少一种本发明化合物,同时还含有一种药物载体;所说的载体包括一种或多种固体、半固体或者液体稀释剂、添加剂和配方佐剂,它们是无毒、惰性和药学上可接受的。这些药物组合物优先选用剂量单位的形式,即含有预定量药物的物质上不连续的单位,其中所含的药量相当经计算产生所需治疗效应之剂量的分数或者倍数。这些剂量单位可以含有1、2、3、4或者更多的单剂,也可以含1/2、1/3或者1/4单剂。一个单剂中所含的药量,最好在按照下述方式投药时足以产生所需的疗效,即按照预定的剂量制度,一次使用一个或者多个剂量单位的方式投药,对于1、1/2、1/3或者1/4日剂量来说,通常每日分别投药一、二、三或者四次。也可以存在其它治疗剂。优先选用每个单位剂量含有从大约1至500mg活性成分的药物组合物,而且通常将其制成片剂、锭剂、胶囊、粉剂、水剂、悬浮剂、糖浆、驰剂和水溶液。优选的口服组合物制成片剂或者胶囊,其中可以含有常规的赋形剂,例如糖浆、阿拉伯胶、明胶、山梨糖醇、西黄著胶或者聚乙烯吡咯酮等粘合剂,例如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨糖醇或者甘氨酸等添加剂,例如硬质酸镁、滑石、聚乙二醇或者氧化硅等润滑剂,例如淀粉等崩解剂以及十二烷基硫酸钠之类的湿润剂等。为了制备静脉注射用水溶液或者肌肉内注射用油悬浮液等非肠道用组合物,采用含有传统药物赋形药的Ⅰ式化合物的溶液或者悬浮液。通过将0.1%至10%(重量)的此活性化合物,溶于水或者溶于由诸如丙三醇、丙二醇和聚乙二醇或者混合物组成的赋形药中的方法,制得适于非肠道使用之所需清晰度、稳定性和适应性的这种组合物。此聚乙二醇类由不挥发性而且通常是液体的、可溶于水和有机液体以及分子量为大约200至1500的聚乙二醇类的混合物所组成。
其中Z是二价原子团(a-e)的本发明的Ⅰ式化合物,是用包括使哌嗪基或者“亚胺”中间体烷基化的方法制得的,所用的方法与吴等人在上述专利以及Temple等人的上述专利中所介绍的方法类似,详述参见上述文献。结合这些方法为一单元方法,用于制备Ⅰ式化合物。这些方法可以加以改变,以便生产本发明包括但是却未专门介绍的其它化合物。此外,为生产稍有不同的同类化合物而对这些方法加以更改,对于所属技术领域中普通技术人员来说,也将是显而易见的。为了作出特别说明,将举出一些实施例。
单元方法
符号“X”叫作适宜的替代基,例如氯化物、溴化物、碘化物、硫酸酯、磷酸酯、甲苯磺酸酯或者甲磺酸酯。
方法A
方法A中的缩合过程,是用在例如吡啶或二甲苯等干燥、惰性的反应介质中使反应物回流的方法进行的。对于方法B和C而言,过程是在适于用仲胺类烷基化的方法制备叔胺类的反应条件下进行的。在酸结合剂存在下,于大约60°至大约150℃温度下,在适当的有机液体中加热这些反应物。苯、二甲基甲酰胺、乙醇、乙腈、甲苯和正丁醇,是一些优选的有机液体反应介质的实例。优选的酸结合剂是磷酸钾,但是也可以使用其它无机碱和有机叔胺碱,其中包括其它碱金属和碱土金属碳酸盐、酸式碳酸盐或者氢化物,以及叔胺类。这三个方法均在前面提到的专利参考文献中做了适当描述。对于本发明的化合物来说,方法C是优选的合成方法。所需的ⅡC中间体是按照上述的那些专利参考文献中介绍的方法合成的。
作为生产此同类化合物中稍有区别的化合物的一个方法变更的实例,可以使N-取代的[4-(1-哌嗪基)-丁基]环状亚胺(Ⅳ)与适当的吡啶体系(Ⅴ)反应,以生产Ⅰ式产品,例如:
此外,Ⅰ式化合物可以进一步对其R1基团作化学改变(例如将甲酰基转变为肟或者相关化合物),以便生产不同的Ⅰ式产品。
Ⅱ式或Ⅳ式的中间体环状亚胺化合物,在上面引证的专利参考文献中有适当的介绍,现在可从市场上买到几种Ⅱ式化合物。Ⅲ式吡啶基哌嗪中间体化合物以及原料吡啶类,不是可以在市场上买到(据化学文献记载),就是本文已介绍了的。合成Ⅲ式中间体所用的方法,在示意图1中加以说明。
示意图1
吡啶中间体的合成
正如示意图1所表明的那样,在乙酸酐中通过用过氧化氢处理此N-氧化物(Ⅹ),可以将吡啶类(Ⅺ)转变为相应的2(1H)-吡啶酮(Ⅷ)。在某些情况下,由相应的酰基叠氮(Ⅸ)经库尔提斯重排(Curtius rearrangement)而形成的脂环异氰酸酯前体,再经过亲电子闭环作用,也可以形成吡啶酮类(Ⅷ)。用磷酰氯处理通过两个途径形成的吡啶酮类,也以提供相应的2-氯吡啶类(Ⅵ)。这些氯代吡啶类,也可以由结构(Ⅶ)的氯代吡啶类开始,其中适当改变Y基团以便得到所需的R1基团。可能的实例是:在室温下于二甲基亚矾中用碘代甲烷处理2-氯-3-吡啶醇(Y=OH)的钠盐;在-70℃下,用DIBAL-H还原2-氯-3-氧基吡啶(Y=CN),然后酸解得到2-氯吡啶-3-甲醛;用重氮甲烷使2-氯代烟酸(Y=COOH)酯化,得到甲氧甲酰(Ⅵ)中间体。
在回流的异丙醇中,使这些取代的2-氯吡啶类(Ⅵ)与五倍过量的哌嗪反应可变的一段时间,或者在密封弹中使之在120℃下净反应24小时,将生成的可以进一步加以转化的ⅢC中间体,例如可以用1,4-二溴丁烷处理使之转变成Ⅲb,或者用3-溴丁腈处理生成可以进一步还原为Ⅲa的Ⅻ。
研究下列实施例之后,构成本发明的化合物及其制备方法将更加清楚,这些实施例是只为说明本发明而提出的,不得视为对本发明范围的限制。如果未特别指明,全部温度均视为摄氏温度。核磁共振(NMR)谱特性是指相对于用作参考标准的四甲基硅烷,以每百万份中的份数(ppm)表示的化学位置(δ)。对于质子核磁共振谱数据的各种位移而报导的相对面积,相当于该分子中特定功能类型氢原子的数目。关于多重性位移的本质,记作宽峰(bs)、单峰(S)、多重峰(m)、双峰(d)、二重双峰(dd)、三重峰(t)或者四重峰(q)。所采用的缩写有:DMSO-d。(全氘二甲基亚砜)、CDCl3(氘氯仿),其它的略语与常规相同。红外光谱(IR)的描述只包括具有官能团识别价值的吸收波数(cm-1)。采用溴化钾作稀释剂进行红外光谱测定。全部化合物均做了满意的元素分析。
ⅢC式中间体的合成
下列实施例详细说明关键中间体ⅢC的合成,利用在引证的专利文献中记载的已知反应,可以将中间体ⅢC进一步转变成其它合成的中间体。
实施例1
1-(3-苯基-2-吡啶基)哌嗪
在室温下,用30%的过氧化氢(65ml)逐滴处理3-苯基吡啶(Ⅺ,100.0克,0.64摩尔)和冰乙酸(400ml)混合物。将此溶液逐渐加热至75℃达1.5小时,然后再加过氧化氢(75ml)处理。在真空中浓缩此反应混合物,库氏蒸馏(Kugelrohr distillation,145-160°/0.1乇)后定量产生110克油状物(Ⅹ)。将此N-氧化物油状物(Ⅹ)溶解在乙酸酐(400ml)中,氮气氛下回流加热24小时。在真空中浓缩此反应混合物,溶解于二氯甲烷中,然后用水(4×250ml)萃取。分离有机相,干燥(Na2SO4),过滤,真空浓缩,生成固体,用乙酸乙酯使此固体重结晶后,得到60.3克(45%)3-苯基-2-(1H)-吡啶酮(Ⅷ),熔点223-229℃。
使3-苯基-2-(1H)-吡啶酮(Ⅷ,20.0克,0.12摩尔)和磷酰氯(300ml)的溶液回流6小时,然后慢慢倒在破碎的冰上(300ml)。将得到的溶液用氢氧化铵调成碱性,生成沉淀。用乙醚(3×500ml)萃取此化合物,干燥(Na2SO4)合并的有机萃取液。在真空中浓缩至得到固体,然后用乙羧乙酯使此固体重结晶,制得7.0克(31%)2-氯-3-苯基吡啶(Ⅵ),熔点52-56℃。
在密封弹中,165℃下将2-氯-3-苯基吡啶(Ⅵ,28.8克,0.15摩尔)和哌嗪(65.7克,0076摩尔)的纯净混合物加热24小时。使冷却的此混
合物分配于二氯甲烷和水之间,有机相进一步用水(3×300ml)萃取,分离,干燥(MgSO4),过滤,然后于真空中浓缩成油状物。经闪蒸色谱(flash chromatography,15%的乙醇-氯仿)处理并且对适当部分在真空中浓缩后,得到油状物,将其溶于乙醇中,用1当量的乙醇盐酸处理。冷却后沉淀出的盐酸盐19.8克(48.2%),是ⅢC中间体,为呈白色盐酸盐,熔点为185-187℃。
实施例2
1-(3-甲基-2-吡啶基)哌嗪
0℃下,逐滴用氯代甲酸乙酯(216.3克,2.0摩尔)的丙酮(500ml)混合物处理2.4-己二烯酸(190.0克,0.7摩尔)和三乙胺(202.1克,2.0摩尔)的丙酮(1.5升)溶液。0℃下将此反应混合物搅拌0.75小时,然后滴加叠氮化钠(169.0克,2.6摩尔)的水(700ml)溶液处理。0℃下搅拌1小时后,将此反应混合物倒入水(800ml)中,用二氯甲烷(3×400ml)萃取。干燥(Na2SO4)合并的有机萃取液,过滤后,于真空中浓缩制得粗品酰基叠氮(Ⅸ)。将酰基叠氮(Ⅸ)的二氯甲烷(200ml)溶液,小心地逐滴加至一个特大号三颈圆底烧瓶中,此烧瓶装有两支空气冷凝器并且含有加热至220-240℃的二苯醚。完全加入后,将反应混合物加热1小时,用库氏蒸馏法(170-180℃/0.1z)除去苯基醚。用苯使蒸馏釜内容物重结晶,得到61.2克(33%)3-甲基-2-(1H-吡啶酮,是白色晶体。
按照上面实施例1中给出的操作手续,在磷酰氯中回流3-甲基-2-(IH)-吡啶酮(Ⅷ),然后综合处理,得到2-氯-3-甲基吡啶(Ⅵ),产率达17%。
在密封弹中,再次采用上面实施例1的手续使2-氯-3-(IH)-吡啶与哌嗪反应,生成所需的ⅢC产物,产率为50%。
实施例3
2-(1-哌嗪基)吡啶-3-甲醛
在-78°下,逐滴用DABAL-H在二氯甲烷(0.03摩尔,33ml)的1M溶液,处理2-氯-3-氰基吡啶(Ⅶ,2.0克,0.01摩尔)在二氯甲烷中的溶液。滴加处理期间,溶液由无色变为亮黄橙色,在-78℃下继续搅拌3小时。用3NHCl75ml处理此混合物,反应物温度迅速温热至-10℃。滴加速度应加以控制,以便使反应温度保持在0°之下。逐滴用10%氢氧化钠溶液处理此溶液,生成亮黄色乳浊液,用烧结玻璃加以过滤。用二氯甲烷彻底洗涤所收集的铝盐,过滤,干燥(MgSO4)此滤液。在真空中浓缩此有机溶液,得到黄色固体,用库氏蒸馏(60°/0.4乇)法提纯后,得到0.46克(33%)2-氯-3-吡啶甲醛(Ⅵ),呈白色固体,熔点48°。
使2-氯-3-吡啶甲醛(Ⅵ,6.4克,0.05摩尔)和哌嗪(19.4克,0.23摩尔)溶液,在异丙醇(250ml)中回流5小时。在真空中将此反应混合物浓缩至浆状,然后使之分配于二氯甲烷和水之间。分离此有机相,用水(3×500ml)洗涤,干燥(MgSO4),过滤,在真空中浓缩成浆状,然后用闪蒸色谱法(10%甲醇-二氯甲烷)提纯。合并适当的部分,于真空中浓缩,将其溶解于乙醇中,然后用1当量乙醇盐羧处理,得到粗盐酸盐结晶8.8克(87%),为适用的ⅢC中间体。
实施例4
1-(3-甲氧基-2-吡啶基)哌嗪
用2-氯-3-吡啶醇(Ⅶ,18克,0.14摩尔)处理钠(3.2克,0.14摩尔)的甲醇(40ml)溶液,回流0.5小时。逐滴加入干燥二甲基亚矾,直到此反应混合物澄清为止,溶液于真空中浓缩。将收集的泡沫体溶解在二甲基亚矾(50ml)之中,室温下与碘代甲烷(19.9克,0.14摩尔)一起加热,导致生成沉淀。过滤收集沉淀,进行库式蒸馏(68°/0.5乇),生成白色晶体(28.5克)。将此固体分配在乙醚和水之间,分离有机相,干燥(Na2SO4),过滤,在真空中浓缩,得到4.3克(21%)白色晶状2-氯-3-甲氧基吡啶(Ⅵ)。
按照实施例3的手续,在回流的异丙醇介质中用哌嗪处理2-氯-3-甲氧基吡啶(Ⅵ),然后进行相类似的处理,得到所需的ⅢC中间体。
实施例5
2-(1-哌嗪基)吡啶-3-羧酸甲酯
在65°下,用乙醚(204ml)中的N-甲基N-亚硝基-对-甲苯磺酰胺(22.6克,0.1摩尔,Diazald Aldrich)溶液,处理搅拌下的氢氧化钾(22.6克,0.4摩尔)、乙醇(45.3ml)和水(36ml)的溶液。用乙醚重氮甲烷溶液的蒸馏速率,调节该溶液的加入速率。使用全部是磨砂玻璃
的重氮甲烷发生仪器,蒸馏乙醇的重氮甲烷溶液,馏出液收集在串联连接的两个收集容器之中,第一个接受器冷却至0°,第二个接受器冷却至-78°。在-15°下,逐滴加入2-氯代烟酸(4.7克,0.03摩尔)的甲醇溶液处理合并的重氮甲烷溶液。使此反应混合物于-15°下保持4小时,然后使之慢慢平衡至室温。在真空中浓缩此溶液成黄色固体,使之分配于碳酸钠水溶液和二氯甲烷之中,分离有机层,干燥(MgSO4)并且于真空中浓缩,制得5.2克(近似100%)2-氯烟酸甲酯(Ⅵ),是适于按照下列方法与哌嗪反应的油状物粗品。
在异丙醇中,使2-氯烟酸甲酯(Ⅵ,3.8克,0.02摩尔)和哌嗪(9.7克,0.11摩尔)回流24小时。在真空中浓缩此溶液,使之分配于二氯甲烷和水之中,分离出有机相,干燥(MgSO4),然后于真空中浓缩成金色油状物。用闪蒸色谱法(CH2Cl2-10%甲醇-1%NH4OH)提纯此油状物,合并适当的部分洗脱液,在真空中浓缩得到纯ⅢC产物,为金色油状物(1.7克,35%)。核磁共振和红外光谱数据与理论结构互相一致。
实施例6
1-(3-硝基-2-吡啶基)哌嗪
室温下,在异丙醇(100ml)中将2-氯-3-硝基吡啶(Ⅵ,2.5克,0.015摩尔)和哌嗪(6.5克,0.075摩尔)的混合物搅拌30分钟。在真空中浓缩此溶液,使其分配于二氯甲烷和水之中,分离出有机层,干燥(MgSO4),在真空中浓缩至橙色油状。将此油状物溶解在最小体积的异丙醇中,冷却后过滤生成的黄色固体ⅢC产物(3.1克,96.5%),熔点82-85℃。
C9H12N4O2的计算值:C51.91,H5.80,N26.90;
测得值:C52.21,H5.83,N26.95。
实施例7
1-[3-(5-甲基-1,3,4-噁二唑
-2-基)-2-吡啶基]哌嗪
按照实施例6的手续,用2-氯-3-(5-甲基-1,3,4-噁二唑-2-基)吡啶[按照“杂环化学杂志”J·Heferocyclic Chemisfry,17,425,(1980)中的方法制备的]和哌嗪制备这种中间体化合物。
通过选择适当的原料和采用上述实施例中概括介绍的适当方法,在化学合成领域中的普通技术人员,很容易制得所需的其它ⅢC中间体。
Ⅰ式产品的合成
前面曾经概括说明的制备Ⅰ式化合物的合成方法,在作为参考的专利文献中已有所介绍和举例。为方便起见,下面将给出采用优选的方法(方法C)的一般操作手续和一些特定实例。
实施例8
N-{4-[4-(3-取代的-2-吡啶基)-
1-哌嗪基]丁基}-环状亚胺衍生物(一般方法)
以下实验条件表示合成Ⅰ式化合物时采用的一般操作方法。在乙腈中,使适当的N-(4-溴丁基)-环状亚胺化合物(例如5-螺环戊基-2,4-噻唑烷二酮、8-螺[4,5]癸-7,9-二酮、4,4-二烷基-2,6-哌啶二酮或者N-吗啉-2,6-二酮,均带有4-溴丁基链,1当量)、1-(3-取代的-2-吡啶基)哌嗪衍生物(ⅢC,1当量)和碳酸钾(3当量)的混合物回流可变化的一段时间(4-24小时)。将此反应混合物过滤、在真空中浓缩,然后经闪蒸色谱法提纯,通常使用乙醇-氯仿混合溶剂。在真空中将适当部分的色谱洗脱液加以浓缩,溶解于有机溶剂中,然后用乙醇盐酸处理,以其盐酸盐形式分离Ⅰ式化合物。
实施例9
2-{4-[4-(3-硝基-2-吡啶基)-1
1-哌嗪基]-丁基}-1
-硫代-3-氮杂螺[4,4]壬-2,4-二酮
使3-(4-溴丁基)-5-螺环戊基)-2,4-噻唑烷二酮(ⅡC,5.5克,0.018摩尔)、1-(3-硝基-2-吡啶基)-哌嗪(ⅢC,在实施例6中制备的,3.75克,0.018摩尔)和碳酸钾(4.9克,0.036摩尔)的混合物,在乙腈(300ml)中回流24小时。过滤此溶液,在真空中浓缩,进行闪蒸色谱(CHCl3-4%乙醇)处理。得到5克(64%)橙色油状物。用乙醇盐酸处理此油状物的冷却乙腈溶液,得到黄色的二盐酸盐,熔点190-194℃。
C20H27N5O4S·2HCl的计算值:C47.44,H5.77,N13.83;
测得值:C47.69,H5.69,N14.19;
核磁共振DMSO-d6):1.75(8,m),2.23(4,m),
3.11(4,m),3.59(8,m),
7.06(1,dd,4.2,8.0Hz),8.36(1,dd,1.4,8.0Hz),8.49(1,dd,1.4,4.2Hz),11.85(1,bs),11.90(1,bs)。
红外光谱(KBr):0.45,1340,1440,1535,1595,1635,1675,1740,2430,2950。
实施例10
2-[4-[4-(2,4-二氧-1-硫-3-
氮杂螺[4,4]壬-3-基)
-丁基]-1-哌嗪基]吡啶-3-甲醛盐酸盐
使3-(4-溴丁基)-5-螺环戊基)-2,4-噻唑烷二酮(ⅡC,5.5克,0.018摩尔)、2-(1-哌嗪基)-吡啶-3-甲醛(ⅢC,在实施例3中制备的,3.4克,0.018摩尔)和碳酸钾(4.9克,0.036摩尔)的混合物在乙腈(100ml)中回流24小时。过滤此溶液,在真空中浓缩,作闪蒸色谱处理(CH2Cl2-5%甲醇),生成棕色油状物。将此棕色油状物溶解在热乙腈中,在乙醇盐酸存在下加热,冷却和过滤之后得到白色固体(2.8克,3.7%),熔点为187-189℃。
C21H28N4O3S·HCl的计算值:C55.68,H6.45,N12.37;
测得值:C55.96,H6.55,N12.43
核磁共振(CDCl3):2.04(2,m),3.35(6,m),3.69(2,t,6.7Hz),3.95(4,m),7.06(1,dd,4.5,7.7Hz),8.07(1,dd,1.8,7.7Hz),
8.41(1,dd,1.8,4.5Hz),10.02(1,s),11.80(1,bs)。
红外光谱(KBr):940,1350,1365,1390,1435,1580,1675,1745,2590,2950。
实施例11
2-[4-[4-(2,4-二氧-1-硫-3-
氮杂螺[4,4]壬-3-基-
丁基-1-哌嗪基]吡啶-3-羧酸甲酯二盐酸盐
使3-(4-溴丁基)-5-螺环戊基-2,4-噻唑烷二酮(ⅡC,3.5克,0.11摩尔)、2-(1-哌嗪基)-3-吡啶羧酸甲酯(ⅢC,在实施例5中制备的,2.5克,0.011摩尔)和3.1克(0.022摩尔)磷酸钾的混合物,在乙腈(300ml)中回流24小时。过滤此溶液,在真空中浓缩至深色粘稠的油状,经闪蒸色谱法(CHCl3-5%乙醇)处理后,得到金色油状物。将此油状物溶解于热乙腈中,用乙醇盐酸处理,制得盐酸盐(2.04克,40.8%),熔点195℃。
C22H30N4O4S·2HCl的计算值:C50.87,H6.21,N10.74;
测得值:C50.71,H6.37,N10.76。
核磁共振(DMSO-d6):1.76(8,m),2.20(4,m),3.10(4,m),3.55(6,m),3.83(3,S,3.90(2,m),7.00(1,dd,4.8,7.4Hz),8.11(1,dd,1.6,7.4Hz),8.16(2,bs),8.35(1,dd,1.6,4.8Hz),11.70(1,bs)。
红外光谱(KBr):770,1270,1350,1600,1670,1725,2370,2950。
按照上述合成操作手续制备Ⅰ式产物的某些其它实例,列于表2之中。
表2
表3
其它式Ⅰ化合物
实施例 Za)R1R2分子式, m.p.(℃)
12 (d) -OMe H C21H30N4O3S·C7H8SO3125-128
13 (d) -Me H C21H30N4O2S·HCl 175-182
14 (b) -Me H C21H32N4O2·1.1HCl 195-200
15 (b) -Cl H C20H29ClN4O2·1.2HCl 217-221
16 (d) -Cl H C20H27ClN4O2S·HCl 185-188
17 (d) -Ph H C26H32N4O2S·C4H4O4·0.4H2O 125-127
18 (a) -OMe H C23H34N4O3·2HCl 194-196
19 (e) -Ph H C23H28N4O3·2.1HCl·H2O 225-235(d)
20 (a) -Me H C23H34N4O2·2HCl·1.3H2O 145-147
21 (b) -Ph H C26H34N4O2·1.2HCl·0.8H2O 230-235
22 (d) H -OMe C21H30N4O3S·HCl 194-196
23 (b) H -OMe C21H32N4O3·HCl 212-214
24 (e) -Cl H C17H23ClN4O3·2HCl 217-220
25 (e) -CHO H C18H24N4O4·HCl 184-186
26 (e) -NO2H C17H23N5O5·HCl 199-203
27 (b) -CO2He H C22H32N4O4·HCl 168-171
28 (d) -CH=NOMe H C22H31N5O3S·HCl 168-170
29 (e) -CO2Me H C19H26N4O5·2HCl 185-187
30 (a)5-甲基-1,3,4,C25H34N6O3·HCl·0.5H2O 185-187
-噁二唑二基,
Claims (8)
1、一种制备Ⅰ式化合物及其药学上可接受的酸加成盐的方法,其特征在于Ⅰ式化合物为
其中R1为甲酰基或低级烷氧羰基或氢,
R2选自氢、卤素、低级烷基或者低级烷氧基,Z为
R5和R6独立地选自氢、低级烷基,
所说的方法包括使Ⅱ式中间化合物:
其中Z定义如上,而且
W可以是>NH或者>N-(CH2)4-X,而X是氯、溴或碘,
与Ⅲ式结构的化合物反应:
条件是:
既1在酸结合剂存在下,在大约60℃至大约150℃温度下,于适当的有机液体中加热反应物,以及
2)当W是>N-(CH2)4-X时,Y是H,而且反应条件适于按照上面1)中用使仲胺烷基化的方法制备叔胺的那些条件,
如需要,将得到的式Ⅰ化合物转化成药学上可接受的酸加成盐。
4、按照权利要求1的方法,其中该方法制得的化合物的R2是氢。
5、按照权利要求1的方法,其中该方法制得的化合物的R2是低级烷基或者烷氧基。
6、根据权利要求3的方法,其中该方法制得的化合物是2-[4-[4-(2,4-二氧-1-硫-3-氮杂螺[4,4]壬-3-基)-丁基]-1-哌嗪基]-吡啶-3-甲醛。
7、根据权利要求2的方法,其中该方法制得的化合物是2-[4-[4-(2,4-二氧-1-硫-3-氮杂螺[4,4]壬-3-基)-丁基]-1-哌嗪基]吡啶-3-羧酸甲酯。
8、根据权利要求3的方法,其中该方法制得的化合物是3-[4-[4-(6-甲氧基-2-吡啶基)-1-哌嗪基]丁基]-1-硫-3-氮杂螺[4,4]壬-2,4-二酮。
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN86100224A Expired CN1016691B (zh) | 1985-01-16 | 1986-01-15 | 抑制精神的2-(4-丁基哌嗪-1-基)吡啶类环状亚胺衍生物的制备方法 |
Country Status (29)
Country | Link |
---|---|
US (1) | US4619930A (zh) |
JP (1) | JPH0780873B2 (zh) |
KR (1) | KR900000366B1 (zh) |
CN (1) | CN1016691B (zh) |
AT (1) | AT391698B (zh) |
AU (1) | AU591473B2 (zh) |
BE (1) | BE904047A (zh) |
CA (1) | CA1284325C (zh) |
CH (1) | CH666269A5 (zh) |
DE (1) | DE3601143C2 (zh) |
DK (1) | DK19286A (zh) |
EG (1) | EG17759A (zh) |
ES (2) | ES8705869A1 (zh) |
FI (1) | FI90077C (zh) |
FR (1) | FR2580282B1 (zh) |
GB (1) | GB2191772B (zh) |
HU (1) | HU198202B (zh) |
IE (1) | IE58866B1 (zh) |
IL (1) | IL77577A (zh) |
IT (1) | IT1214497B (zh) |
LU (1) | LU86248A1 (zh) |
NL (1) | NL8600071A (zh) |
NZ (1) | NZ214790A (zh) |
OA (1) | OA08187A (zh) |
PT (1) | PT81843B (zh) |
SE (1) | SE466310B (zh) |
SU (1) | SU1521282A3 (zh) |
YU (1) | YU45757B (zh) |
ZA (1) | ZA859692B (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4677104A (en) * | 1985-05-06 | 1987-06-30 | Bristol-Myers Company | Antipsychotic fused-ring pyridinylpiperazine derivatives |
US4812567A (en) * | 1985-10-16 | 1989-03-14 | American Home Products Corporation | Polycyclic spiroimides with psychotropic activity |
MX174210B (es) * | 1987-02-17 | 1994-04-28 | Pfizer | Procedimiento para la preparacion de compuestos arilpiperazinil-alquilenfenil-p-heterociclicos |
US4748240A (en) * | 1987-04-03 | 1988-05-31 | American Home Products Corporation | Psychotropic bicyclic imides |
EP0316723B1 (en) * | 1987-11-20 | 1992-09-30 | Hoechst-Roussel Pharmaceuticals Incorporated | 3-[4(1-Substituted-4-piperazinyl)butyl]-4-thiazolidinones a process for their preparation and their use as medicaments |
US4880930A (en) * | 1987-11-30 | 1989-11-14 | New James S | Psychotropic acyclic amide derivatives |
US5001130A (en) * | 1988-02-18 | 1991-03-19 | Bristol-Myers Company | Psychotropic heterobicycloalkylpiperazine derivatives |
US5116970A (en) * | 1988-02-18 | 1992-05-26 | New James S | Psychotropic heterobicycloalkylpiperazine derivatives: 2. fused pyridazinones |
DK0482696T3 (da) * | 1990-10-23 | 1996-05-20 | Akzo Nobel Nv | 4-(4- eller 6-(trifluormethyl-2-pyridinyl))-1-piperazinylalkyl-substituerede lactamer |
JP6440625B2 (ja) | 2012-11-14 | 2018-12-19 | ザ・ジョンズ・ホプキンス・ユニバーシティー | 精神分裂病を処置するための方法および組成物 |
CN104230915B (zh) * | 2014-08-29 | 2016-08-17 | 南京大学 | 含噻唑烷二酮的苯基哌嗪衍生物及其制备方法与用途 |
CN104513198A (zh) * | 2014-11-29 | 2015-04-15 | 南京红太阳生物化学有限责任公司 | 一种2-氯烟酸的合成方法 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE759371A (fr) * | 1969-11-24 | 1971-05-24 | Bristol Myers Co | Azaspirodecanediones heterocycliques et procedes pour leur preparation |
US3976776A (en) * | 1972-12-06 | 1976-08-24 | Mead Johnson & Company | Tranquilizer process employing N-(heteroarcyclic)piperazinylalkylazaspiroalkanediones |
AT330777B (de) * | 1973-09-08 | 1976-07-26 | Thomae Gmbh Dr K | Verfahren zur herstellung von neuen isochinolinderivaten und deren salzen |
US4305944A (en) * | 1980-09-08 | 1981-12-15 | Mead Johnson & Company | N-[(4-[3-cyano substituted pyridyl]piperazino)alkyl]-azaspirodecanediones |
US4456756A (en) * | 1981-08-03 | 1984-06-26 | Mead Johnson & Company | Spirothiazolidinyl piperazine derivatives |
US4367335A (en) * | 1981-08-03 | 1983-01-04 | Mead Johnson & Company | Thiazolidinylalkylene piperazine derivatives |
DE3135532A1 (de) * | 1981-09-08 | 1983-03-24 | NPL po Dvigateli s Vatrešno Gorene, Varna | Brennkraftmaschine |
US4361565A (en) * | 1981-12-28 | 1982-11-30 | Mead Johnson & Company | 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyridines |
JPS5976059A (ja) * | 1982-10-21 | 1984-04-28 | Sumitomo Chem Co Ltd | 環状イミド誘導体及びその酸付加塩 |
JPS61238784A (ja) * | 1985-04-17 | 1986-10-24 | Sumitomo Seiyaku Kk | コハク酸イミド誘導体及びその酸付加塩 |
DE3529872A1 (de) * | 1985-08-21 | 1987-02-26 | Kali Chemie Pharma Gmbh | Neue tetraoxoverbindungen |
-
1985
- 1985-01-16 US US06/691,952 patent/US4619930A/en not_active Expired - Lifetime
- 1985-12-19 ZA ZA859692A patent/ZA859692B/xx unknown
- 1985-12-31 FR FR8519488A patent/FR2580282B1/fr not_active Expired - Lifetime
-
1986
- 1986-01-10 NZ NZ214790A patent/NZ214790A/xx unknown
- 1986-01-10 CA CA000499331A patent/CA1284325C/en not_active Expired - Fee Related
- 1986-01-13 FI FI860136A patent/FI90077C/fi not_active IP Right Cessation
- 1986-01-13 ES ES550829A patent/ES8705869A1/es not_active Expired
- 1986-01-13 YU YU4186A patent/YU45757B/sh unknown
- 1986-01-13 IL IL77577A patent/IL77577A/xx not_active IP Right Cessation
- 1986-01-14 JP JP61006146A patent/JPH0780873B2/ja not_active Expired - Lifetime
- 1986-01-15 IT IT8619081A patent/IT1214497B/it active
- 1986-01-15 NL NL8600071A patent/NL8600071A/nl active Search and Examination
- 1986-01-15 SU SU864011790A patent/SU1521282A3/ru active
- 1986-01-15 HU HU86207A patent/HU198202B/hu unknown
- 1986-01-15 LU LU86248A patent/LU86248A1/fr unknown
- 1986-01-15 KR KR1019860000203A patent/KR900000366B1/ko not_active IP Right Cessation
- 1986-01-15 IE IE12586A patent/IE58866B1/en not_active IP Right Cessation
- 1986-01-15 DK DK19286A patent/DK19286A/da not_active Application Discontinuation
- 1986-01-15 CH CH130/86A patent/CH666269A5/de not_active IP Right Cessation
- 1986-01-15 SE SE8600173A patent/SE466310B/sv not_active IP Right Cessation
- 1986-01-15 CN CN86100224A patent/CN1016691B/zh not_active Expired
- 1986-01-15 PT PT81843A patent/PT81843B/pt unknown
- 1986-01-15 OA OA58765A patent/OA08187A/xx unknown
- 1986-01-15 BE BE0/216140A patent/BE904047A/fr not_active IP Right Cessation
- 1986-01-16 EG EG20/86A patent/EG17759A/xx active
- 1986-01-16 DE DE3601143A patent/DE3601143C2/de not_active Expired - Lifetime
- 1986-01-16 AU AU52294/86A patent/AU591473B2/en not_active Expired
- 1986-01-16 AT AT0010086A patent/AT391698B/de not_active IP Right Cessation
- 1986-06-17 GB GB8614686A patent/GB2191772B/en not_active Expired - Lifetime
-
1987
- 1987-02-13 ES ES557390A patent/ES8801822A1/es not_active Expired
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