CN1048718C - 苯乙胺类和苯丙胺类化合物及其制备方法和其药物制剂及其应用 - Google Patents
苯乙胺类和苯丙胺类化合物及其制备方法和其药物制剂及其应用 Download PDFInfo
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- CN1048718C CN1048718C CN94190765A CN94190765A CN1048718C CN 1048718 C CN1048718 C CN 1048718C CN 94190765 A CN94190765 A CN 94190765A CN 94190765 A CN94190765 A CN 94190765A CN 1048718 C CN1048718 C CN 1048718C
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 14
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
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- 239000001257 hydrogen Substances 0.000 claims description 19
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 14
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- 125000000217 alkyl group Chemical group 0.000 description 7
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
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- CYFLXLSBHQBMFT-UHFFFAOYSA-N sulfamoxole Chemical group O1C(C)=C(C)N=C1NS(=O)(=O)C1=CC=C(N)C=C1 CYFLXLSBHQBMFT-UHFFFAOYSA-N 0.000 description 1
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- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
- C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
-
- 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
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/62—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
- C07D223/08—Oxygen atoms
- C07D223/10—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/44—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing eight carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
本发明涉及通式(Ⅰ)化合物,其中Z为饱和或不饱和的3-6碳链,m为2或3,R1为氢原子、或直链或支链C1-4烷基,R2、R3和R13选自下列基团;H、OH、OR14、卤素、CO2R9、CN、CF3、NO2、NH2、COCH3、OSO2CF3、OSO2CH3、CONR10R11和OCOR12,R为(1)、(2)、(3)或(4),其中R4、R5、R6、R7、R8、W、n3和n4具有权利要求书中所述意义,本发明还涉及所述化合物的制备方法、含有所述化合物的药物制剂以及所述化合物在治疗精神病学疾病方面的用途。
Description
本发明的领域
本发明涉及新的苯乙胺类和苯丙胺类、它们的制备方法、含有所述苯乙胺类和苯丙胺类的药物组合物、以及所述化合物在治疗中的应用。
本发明的目的是提供可用于治疗精神病学疾病,例如精神分裂症和其他精神病、焦虑症、抑郁症和躁狂一抑郁性精神病的新化合物。
先有技术
根据该专利,R1和R2是一个或多个独立地选自下列基团的基团:氢、羟烷基、卤代烷基、酰基、环烷基、环烷基烷基、卤代烷基磺酰基、烷基羰基、卤素、烷硫基、苯基烷基、苯基烷硫基、氰基、硝基、氨基、烷氨基、磺酰基(sulfono)、烷氨基磺酰基、酰氨基、烷基酰氨基、肟基、肟基烷基、羧基、羧基烷基、羧基链烯基、噻唑基、甲基噻唑基、烷氧羰基氨基、烷氨基磺酰氨基、氨基羰基亚氨基烷基、卤代烷基羰基、吗啉代烷基羰基、氨基噻唑基、吗啉代硫代羰基烷基、二氧杂环烷基烷基、环丙基羰基、四唑基烷基、亚氨基烷基和肟基烷基;其中R3至R6各自独立地选自氢、烷基、烷氧基、链烯基、羟烷基、烷氨基烷基羰基、烷氧基烷基、甘氨酰、氨基烷基、烷氨基硫代烷基、氨基烷基羰基氧基、氰基、苯基烷基、苯基烷氧基烷基、环烷基、卤代烷基、吗啉代烷基烷基、哌嗪基烷基、吖庚因基烷基、苯基烷基氨基烷基酰氨基、烷氨基羰基氧基烷基、哌啶基烷基、和哌啶基烷氨基烷基羰基;其中X选自硫、亚磺酰基和磺酰基:其中m为0或1:以及其中n为1至5的整数。所述化合物具有预防与缺氧或局部缺血症状有关的神经变性结果的作用。
在Journal of Medicinal Chemistry,1989,32,1921-1926中,Glennon和其同仁描述了某些下式化合物:其中X为氢或甲氧基,n为2或3,R′为甲基或氢,以及R为甲基或N-[4-(2-邻苯二甲酰亚氨基)丁基]。所述化合物具有-些对于5-HT1A受体的亲和力。
本发明的公开
Z为饱和的或不饱和的3-6碳链;
m为2或3;
R1为氢原子、或直链或支链C1-4烷基;
R2、R3和R13位于苯环的邻、间或对位,并且它们可相同或不同,且选自下列基团:H、OH、OR14、卤素、CO2R9、CN、CF3、NO2、NH2、COCH3、OSO2CF3、OSO2CH3、CONR10R11、OCOR12、其中R9、R12和R14为直链或支链C1-4烷基,R10和R11可相同或不同,并且代表氢、或直链或支链C1-6烷基;
R为1)其中R4和R5可相同或不同,并且当它们不同时,代表氢原子、直链或支链C1-5烷基、或取代或未取代的环烷基;而当它们相同时,代表直链或支链C1-5烷基;或者R4和R5一起为-(CH2)n1-,其中n1为3-7;或者2)其中R6为氢原子、直链或支链C1-6烷基,和R7为取代的或未取代的环烷基;或者R6和R7一起为-(CH2)n2-,其中n2为3-6;或者3)其中W为任选取代的碳环或任选取代的亚甲基,和R8为直链或支链C1-5烷基或苯基,n3为0-2;或者4)其中W为任选取代的碳环、或任选取代的亚甲基,及n4为1或2。
某些化合物还具有对5-HT1A和D2受体的亲和力。这些作用使得可以使用上述定义的化合物治疗精神紊乱,例如精神病、精神分裂症和抑郁症。
上述定义中的R2、R3和R13优选为氢、甲氧基、乙氧基、卤素、CN、CONR10R11、CF3、硝基或氨基;R10和R11优选为氢、甲基或乙基。
上述定义中的卤素优选为氟、氯或溴。
上述定义中的Z,在饱和时优选为3-6碳链,而当不饱和时为4-6碳链。
上述定义中的R4和R5优选是相同的,并为直链或支链C1-4烷基;或者R4和R5一起为-(CH2)n1,n1优选为4-6。
上述定义中的R6优选为氢原子或C1-3烷基。
上述定义中的碳环优选为具有5-10个碳原子的单环、二环或多环,例如环戊基、环己基或环庚基。
上述定义中的碳环上的取代基优选为氢原子或直链或支链C1-4烷基。
上述定义中的环烷基优选为C3-12单环、二环或多环,例如金刚烷基、环庚基、环己基、环戊基、二环辛基、二环庚基、二环壬基、二环庚烯基、二环辛烯基、二环壬烯基。
上述定义中亚甲基上的取代基优选为氢原子或C1-4烷基。
最优选的是下列化合物:
8-(4-{[2-(4-氨基-3-三氟甲基苯基)乙基]甲氨基}丁基)-8-氮杂-螺[4.5]癸烷-7,9-二酮草酸盐,
N-(4-{[2-(3,4-二甲氧基苯基)乙基]-丙氨基}丁基)-环己基甲酰胺,
N-(4-{[2-(5-溴-2-甲氧基苯基)乙基]-丙氨基}丁基)-环己基甲酰胺草酸盐,
N-(6-{[2-(4-氨基-3-三氟甲基苯基)乙基]-甲氨基}己基)-二环[2.2.2]辛基-1-甲酰胺盐酸盐,
N-(4-{异丙基-[2-(2-甲氧基苯基)乙基]氨基}丁基)-二环[2.2.2]辛基-1-甲酰胺,
N-(4-{[2-(2-甲氧基苯基)乙基]-丙氨基}丁基)-金刚烷基-1-甲酰胺草酸盐,
N-(4-{[2-(2-氯-4-甲氧基苯基)乙基]-丙氨基}丁基)-环己基甲酰胺草酸盐,
N-(4-{[2-(2,4-二甲氧基苯基)乙基]-丙氨基}丁基)-金刚烷基-1-甲酰胺草酸盐。制备
其中R、R1、R2、R3、R13、Z和m如上所定义:
A.以直接或逐步的方式,使通式II化合物与通式III化合物,在适宜溶剂(例如醇、DMF、乙腈或DMSO)中在碱(例如三乙胺、氢氧化钠、或碳酸钾)以及催化量的卤化钠或卤化钾(例如KI)存在下,在环境温度或较高温度下反应较长时间,或者在适宜还原剂(例如氰基硼氢化钠或氢化锂铝)存在下反应,
R-Z-X II
其中R1、R2、R3、R13和m如上所定义。
B.以直接或逐步的方式,使通式IV化合物与通式V化合物,在适宜溶剂(例如醇、DMF、乙腈或DMSO)中,在碱(例如三乙胺、氢氧化钠、或碳酸钾)和催化量的卤化钠或卤化钾(例如KI)存在下,在环境温度或较高温度下反应较长时间,或者在适宜还原剂(例如氰基硼氢化钠或氢化锂铝)存在下反应,
其中X、m、R2、R3和R13如上所定义。
C.以直接或逐步的方式,使通式VI化合物与通式VII化合物,在适宜溶剂(例如醇、DMF、乙腈或DMSO)中在碱(例如三乙胺、氢氧化钠、或碳酸钾)以及催化量的卤化钠或卤化钾(例如KI)存在下,在环境温度或较高温度下反应较长时间,或者在适宜还原剂(例如氰基硼氢化钠或氢化锂铝)存在下反应,
其中R、Z、m、R2、R3和R13如上所定义,
R1X VII
其中R1和X如上所定义。
其中Z、R1、R2、R3、R13和m如上所定义。
E.用适宜的还原剂(例如氢气、氢化物、硼烷、钠的氨溶液或锌)在适宜的催化剂(例如钯、铂、镍盐、铅盐、亚铜盐)存在下,在适宜溶剂(例如乙醇、THF、甲苯、HMPT)中,在环境温度或升高的温度下经较长时间,使通式XI化合物转化为通式I化合物,
其中R、R1、R2、R3、R13、Z和m如上所定义。
其中R、R1、Z和m如上所定义,和R1 2、R1 3和R1 13代表可通过适宜的反应,例如还原反应、氢化反应、水解反应、脱甲基化作用、硝化作用、酯化作用、卤化作用、乙酰化作用、羰基化作用(C=O)或脱水作用或其他适宜的反应进行修饰的取代基,
其中R、R1、R2、R3、R13、Z和m如上所定义。
其中X、Z、R1、R2、R3、R13和m如上所定义。
H.使通式XVI化合物与多聚甲醛和通式XVII化合物,在适宜溶剂(例如二噁烷、丙酮或乙醇)中,在适宜的催化剂(例如乙酸铜)的存在下,在环境温度或升高的温度下反应较长时间,
R-(CH2)pC≡CH XVI其中R如上所定义,和p为1-3,
其中R1、R2、R3、R13和m如上所定义。药物制剂
按照本发明,式I化合物通常以具有可药用剂型的药物制剂的形式经口服、直肠或经注射途径给药,所述药物制剂包含作为游离碱或可药用无毒的酸加成盐(例如盐酸盐、氢溴酸盐、乳酸盐、乙酸盐、磷酸盐、硫酸盐、氨基磺酸盐、柠檬酸盐、酒石酸盐、草酸盐等)形式的活性成分。所述剂型可以为固体制剂、半固体制剂或液体制剂。通常活性物质构成制剂的0.1-99%(重量),更具体地讲,构成注射用制剂的0.5-20%(重量),和构成适于口服的制剂的0.2-50%(重量)。
为了制备用于口服给药的、剂量单位形式的、含有式I化合物的药物制剂,可将所选择的化合物与固体赋形剂,例如乳糖、蔗糖、山梨糖醇、甘露糖醇、淀粉类(例如马铃薯淀粉、玉米淀粉或支链淀粉)、纤维素衍生物、粘台剂(例如明胶或聚乙烯吡咯烷酮)、及润滑剂(例如硬脂酸镁、硬脂酸钙、聚乙二醇、蜡类、石蜡等)混合,然后压制成片剂。如果需要包衣片剂,可将上述制备的药心用可以含有例如阿拉伯树胶、明胶、滑石、二氧化钛等的浓糖溶液包衣。此外,该片剂也可用溶于易挥发有机溶剂或有机溶剂混合物或溶于水中的、本领域中公知的聚合物包衣。可以向这些包衣物中加入染料,以便易于区分开含有不同活性物质或不同用量的活性化合物的片剂。
为了制备软明胶胶囊,可将所述活性物质与例如植物油或聚乙二醇混合,硬明胶胶囊可以含有活性物质的颗粒,使用上面对于片剂所述的赋形剂,例如蔗糖、山梨糖醇、甘露糖醇、淀粉类(例如马铃薯淀粉、玉米淀粉或支链淀粉)、纤维素衍生物或明胶。也可以将液体或半固体状的药物填装入硬明胶胶囊中。
用于直肠施用的剂量单位可以是溶液,或悬浮液,或者可以制备成包含所述活性物质及与之混合的中性脂肪基质的栓剂形式,或者包含所述活性物质以及与之混合的植物油或石蜡油的明胶直肠用胶嚢。
用于口服施用的液体制剂可以呈糖浆或悬浮液的形式,例如含有约0.2%至约20%(重量)本文所述活性物质、余量为糖和乙醇、水、甘油与丙二醇的混合物的溶液。任选地,这种液体制剂可以含有着色剂、调味剂、糖精和作为增稠剂的羧甲基纤维素或其他本领域公知的赋形剂。
用于非肠道施用的溶液可以制备成所述活性物质的水溶性可药用盐的水溶液,优选浓度为约0.5%至约10%(重量)。这些溶液也可以含有稳定剂和/或缓冲剂,并可方便地以各种剂量单位的安瓿提供。
用于人的治疗目的时,本发明化台物适宜的日剂量为50-500mg(口服),以及最高达100mg(经非肠道给药)。
实施例实施例1(方法A)
8-(4-{[2-(4-氨基-3-三氟甲基苯基)乙基]-甲氨基}丁基)-8-氮杂螺[4.5]癸烷-7,9-二酮草酸盐
将N-甲基-4-氨基-3-三氟甲基苯乙胺(520mg,2.38mmol)、N-(4-溴丁基)-8-氮杂螺[4,5]癸烷-7,9-二酮(792mg,2.6mmol)、碳酸钾(359mg,2.6mmol)和碘化钾(催化量)的混合物在DMF(25ml)中在90℃加热3小时。真空除去溶剂,将残余物溶于乙醚和水中。分离有机相,干燥并除去溶剂,得到1.11g油状物,将其经色谱法用甲醇纯化,得到460mg(1.1mmol)纯碱。将其溶于二异丙醚中,并用130mg草酸二水合物处理,将沉淀经二异丙醚/乙醇重结晶,得到362mg(0.7mmol)标题化合物。
M.p.83-86℃。
以类似的方式制备下列化合物(实施例2-34):实施例2
1-(3-{[2-(4-氨基-3-三氟甲基苯基)乙基]-丙氨基}丙基)-3-苯基吡咯烷-2,5-二酮1H NMR(CDCL3)δ7.36-7.10(m,7H),6.66(d,1H),4.00(m,1H),3.60(t,2H),3.13(dd,1H),2.80(dd,1H),2.60(s,4H),2.50(t,2H),2.43(t,2H),1.75(q,2H),1.59(q,2H),0.87(t,3H).实施例3
8-(6-{异丙基-[2-(2-甲氧基苯基)乙基]氨基}-己基)-8-氨杂-螺[4.5]癸烷-7,9-二酮草酸盐
M.p.117-119℃。实施例4
8-(4-{丙基-[3-(2-甲氧基苯基)丙基]氨基}-丁基)-8-氮杂-螺[4.5]癸烷-7,9-二酮1H NMR(CDCl3)δ7.14(m,2H),6.84(m,2H),3.82(s,3H),3.75(t,2H),2.58(s,4H),2.40(m,12H),1.70(m,4H),1.45(m,8H),0.82(t,3H).实施例5
N-(4-{[2-(3,4-二甲氧基苯基)乙基]-丙氨基}丁基)-环己基甲酰胺1H NMR(CDCl3)δ6.79(d,1H),6.72(m,2H),6.15(bs 1H),3.86(s+s,3+3 H),3.22(q,2H),2.67(bs,4H),2.46(m,4H),2.03(m,1H),1.75(m,5H),1.43(m,8H),1.23(m,3H),0.89(t,3H).实施例6
N-(4-{[2-(5-溴-2-甲氧基苯基)乙基]-丙氨基}丁基)-环己基甲酰胺草酸盐
M.p.104-106℃。实施例7
N-(4-{[2-(5-甲氧基-2-硝基苯基)乙基]-丙氨基}丁基)-金刚烷基-1-甲酰胺草酸盐(NCA 319)
M.p.144-148℃。实施例8
N-(4-{[2-(3-氯-2-甲氧基苯基)乙基]-丙氨基}丁基)-2,2,3,3-四甲基-环丙基甲酰胺草酸盐
M.p.107-113℃。实施例9
N-(4-{[2-(4-氯-3-甲氧基苯基)乙基]-丙氨基}丁基)-金刚烷基-1-甲酰胺草酸盐
M.p.163-165℃。实施例10
N-(6-{[2-(2-甲氧基苯基)乙基]-甲氨基}己基)-1-苯基-环丙基甲酰胺草酸盐
M.p.60-64℃。实施例11
N-(4-{[2-(4-氨基-3-三氟甲基苯基)乙基]-异丙氨基}丁基)-1-苯基-环丙基甲酰胺二盐酸盐
M.p.180-181℃。实施例12
N-(6-{[2-(4-氨基-3-三氟甲基苯基)乙基]-甲氨基}己基)-二环[2.2.2]辛基-1-甲酰胺盐酸盐
M.p.54-58℃。实施例13
N-(4-{[2-(2-甲氧基苯基)乙基]-甲氨基}丁基)-金刚烷基-1-甲酰胺草酸盐
M.p.78-82℃。实施例14
N-(4-{[2-(2,3-二甲氧基苯基)乙基]-丙氨基}丁基)-环己基甲酰胺草酸盐
M.p.99-101℃。实施例15
N-(4-([2(3-溴-4-甲氧基苯基)乙基]-丙氨基}丁基)-2,2,3,3-四甲基-环丙基甲酰胺草酸盐
M.p.69-73℃。实施例16
N-(4-{[2-(2-氯-4-甲氧基苯基)乙基]-丙氨基}丁基)-环己基甲酰胺草酸盐(NCA 541)
M.p.90-93℃。实施例17
N-(4-{[2-(2,5-二甲氧基苯基)乙基]-丙氨基}丁基)-2,2,3,3-四甲基-环丙基甲酰胺草酸盐
M.p.138-141℃。实施例18
N-(4-{[2-(2,4-二甲氧基苯基)乙基]-丙基氨基}-丁基)-金刚烷基-1-甲酰胺草酸盐
M.p.132-134℃。实施例19
8-(4-{异丙基-[2-(2-甲氧基苯基)乙基]氨基}-丁基)-8-氮杂-螺[4.5]癸烷-7,9-二酮1H NMR(CDCl3)δ7.14(m,2H),6.85(m,2H),3.83(s,3H),3.77(m,2H),2.97(m,1H),2.70(m,2H),2.58(m,6H),2.46(m,2H),1.70(m,4H),1.49(m,8H),0.99(d,6H).实施例20
8-(6-{[2-(3-氨基-4-氯-苯基)乙基]-丙基-氨基}-己基)-8-氮杂-螺[4.5]癸烷-7,9-二酮1H NMR(CDCl3)δ,7.11(d,1H),6.60(d,1H),6.50(dd,1H),4.02(bs,2H),3.75(t,2H),2.58(s,6H),2.42(m,8H),1.70(m,4H),1.58(m,8H),1.27(m,4H),0.86(t,3H).实施例21
N-(4-{[2-(3-甲氧基-苯基)乙基]-丙基-氨基}-丁基)-金刚烷基-1-甲酰胺草酸盐
M.p.131-135℃。实施例22
1-(4-{异丙基-[2-(2-甲氧基-苯基)乙基]-氨基}-丁基)-全氢化吖庚因-2-酮1H NMR(CDCl3)δ7.15(dd,2H),6.85(dd,2H),3.82(s,3H),3.30(m,4H),2.98(m,1H),2.70(m,4H),2.50(m,4H),1.68(m,6H),1.46(m,4H),0.98(d,6H)。实施例23
N-(5-{[2-(4-硝基苯基)乙基]-丙氨基)-戊基)-反式-4-丙基环己基甲酰胺草酸盐
M.p.101-105℃。实施例24
N-(5-{[2-(4-氨基-3,5-二溴苯基)乙基]-丙氨基}-戊基)-反式-4-丙基环己基甲酰胺草酸盐
M.p.131-135℃。实施例25
N-(5-{[2-(2-氯-4-硝基苯基)-乙基]-丙氨基}-戊基)-反式-4-丙基环己基甲酰胺
M.p.84-86℃。实施例26
N-(4-{[2-(3-氰基-4-硝基苯基)-乙基]-丙基-氨基}-丁基)-环己基甲酰胺
M.p.48-52℃。实施例27
N-(4-{[2-(4-氨基-3-三氟甲基苯基)-乙基]-丙氨基}-丁基)-环己基甲酰胺1H NMR(CDCl3)7.24(d,1H),7.14(dd,1H),6.69(d,1H),5.77(宽,1H),3.26-3.20(m,2H),2.70(s,4H),2.58-2.50(m,4H),2.07-1.99(m,1H),1.86-1.21(m,16H),0.90(t,3H).实施例28
N-(4-{[2-(4-氨基-3-三氟甲基苯基)-乙基]-丁氨基}-丁基)-环己基甲酰胺1H NMR(CDCl3)7.24(d,1H),7.12(dd,1H),6.67(d,1H),5.81(宽,1H),3.26-3.20(m,2H),2.61(s,4H),2.45(t,4H),2.07-1.99(m,1H),1.86-1.21(m,18H),0.91(t,3H).实施例29
N-(4-{N′-异丙基-2-(2-甲氧基-5-溴苯基)-乙基氨基)-丁基)-金刚烷基-1-甲酰胺草酸盐
M.p.40-50℃。实施例30
N-(4-{N′-异丙基-2-(2-甲氧基-5-氟苯基)-乙基氨基}-丁基)-金刚烷基-1-甲酰胺盐酸盐1H NMR(CDCl3),baseδ6.83(m,2H),6.75(dd,1H),5.60(br s,1H),3.78(s,3H),3.20(q,2H),2.95(m,1H),2.65(m,2H),2.57(m,2H),2.42(t,2H),2.04(br s,3H),1.84(br s,6H),1.71(m,6H),1.43(m,4H),0.97(d,6H).实施例31
N-(5-{2-(4-甲氧基苯基)-乙基氨基}-戊基)-金刚烷基-1-甲酰胺
M.p.63-64.5℃。实施例32
[3-{N-丙基-2-(2-氯-4-甲氧基苯基)-乙基氨基}-丙基]-2,3-二氢-1H-异吲哚-1,3-二酮盐酸盐
M.p.152-154.5℃。实施例33
N-(3-{N′-丙基-2-(2-氯-4-甲氧基-苯基)-乙基氨基}-丙基)-金刚烷基-1-甲酰胺1H NMR(CDCl3)7.10(d,1H),7.01(br s,1H),6.89(d,1H),6.75(dd,1H),3.76(s,3H),3.32(q,2H),2.81(m,2H),2.68(m,2H),2.60(t,2H),2.50(t,2H),2.01(br s,3H),1.83(s,6H),1.69(br s,6H),1.65(m,2H),1.53(m,2H),0.90(t,3H).实施例34(方法B)
N,N-二异丙基-6-{异丙基-[2-(2-甲氧基苯基)-乙基]-氨基}己酰胺
向6-邻苯二甲酰亚氨基己酸(7.83g,30mmol)的100ml甲苯和1ml DMF的溶液中,加入亚硫酰氯(7.2ml,160mmol),并将混合物在100℃加热1小时。蒸发后,将剩余的酰氯溶于25ml二氯甲烷中,并在0-10℃将其加入到二异丙胺(7.0g,70mmol)和100ml二氯甲烷中。将该混合物在室温下搅拌2小时,除去溶剂,残余物溶于乙醚中,并用2N HCl萃取。除去有机溶剂,残余物用二异丙醚/己烷(3∶2)重结晶,得到70% N,N-二异丙基邻苯二甲酰亚氨基己酰胺。M.p.85-86℃。将该酰胺(1.03g,3mmol)和水合肼(250mg,5.3mmol)在乙醇中在80℃加热6小时。将混合物冷却并过滤,除去溶剂,残余物溶于H2O和乙酸乙酯中。有机相产生出440mg(70%)N,N-二异丙基-6-氨基己酰胺。该化合物(440mg,2.0mmol)与丙酮(240mg,6mmol)和氰基硼氢化钠(226mg,3mmol)在甲醇(用乙酸将pH调至5-6)中在室温下反应5小时。加入2ml 2M HCl,碱化后除去溶剂,并将残余物溶于乙醚中。得到400mg(78%)N,N-二异丙基-6-异丙氨基己酰胺。将该仲酰胺(400mg,1.6mmol)、2-甲氧基苯乙基溴(从2-甲氧基苯乙醇和PBr3制得,516mg,2.4mmol)、及碳酸钾(330mg,2.4mmol)在20ml DMF中加热20小时。除去溶剂,残余物经快速色谱法用丙酮纯化。得到180mg(30%)标题化合物。1H NMR(CDCl3):7.15(m,2H),6.85(m,2H),3.97(m,1H),3.82(s,3H),3.48(宽,1H),3.00(m,1H),2.73(m,2H),2.60(m,2H),2.46(t,2H),2.28(t,2H),1.64(m,2H),1.50(m,2H),1.38(d,6H),1.35(m,2H),1.20(d,6H),1.00(d,6H).实施例35(方法B)
N-{4-[(2-苯基乙基)-丙基-氨基]丁基}环己基甲酰胺
将环己基甲酸,4-甲磺酸酯基丁基酰胺(1.38g,5mmol)、丙胺(3.0g,50mmol)、和碳酸钠(1.0g,10mmol)的混合物在乙腈(30ml)中在80℃加热2小时。除去溶剂,将残余物溶于乙醚和水中。有机相用2M HCl萃取,水相被调成碱性,产物溶于乙醚中,得到N-(4-丙氨基-丁基)环己基甲酰胺(510mg,2.1mmol)。该原料在DMF中在80℃下与2-溴乙基苯(425mg,2.3mmol)和碳酸钾(317mg,2.3mmol)一起加热3小时。除去溶剂,残余物溶于乙醚和H2O中,有机相用2M HCl萃取,将酸相调节成碱性,并用乙醚萃取,得到454mg(63%)原料,将其经快速色谱法(乙酸乙酯/三乙胺100∶4)纯化。1H NMR(CDCl3)7.30-7.16(m,5H),5.80(br s,1H),3.22(q,2H),2.70(d,4H),2.47(m,4H),2.03(m,1H),1.75(m,5H),1.42(m,8H),1.23(t,3H),0.88(t,3H).实施例36(方法C)
N-(5-{N′-丙基-2-(4-甲氧基苯基)-乙基-氨基}-戊基)-金刚烷基-1-甲酰胺草酸盐
将丙醛(416L,6.0mmol)和氰基硼氢化钠(200mg,3.0mmol)加入到N-(5-[2-(4-甲氧基苯基)乙基]氨基-戊基)-金刚烷基-1-甲酰胺的甲醇(15ml)溶液中,用乙酸将pH调至5。在室温下搅拌2小时后,除去甲醇,加入乙醚,有机层用2M NH3洗涤,并干燥。蒸发溶剂,得到630mg(95%)油状物。向580mg(1.3mmol)该碱的丙酮(10ml)溶液中加入草酸(166mg,1.3mmol),接着加入异丙醚,在蒸发掉所有溶剂,并接着用己烷洗涤后,得到569mg(85%)白色固体。1H NMR(碱,CDCl3)7.11(d,2H),6.83(d,2H),5.63(br s,1H),3.78(s,3H),3.21(q,2H),2.65(br s,4H),2.45(q,4H),2.03(br s,3H),1.84(br s,6H),1.71(m,6H),1.46(m,6H),1.31(m,2H).实施例37(方法D)
N-(4-{异丙基-[2-(2-甲氧基苯基)-乙基]-氨基}-丁基)-二环[2.2.2]辛基-1-甲酰胺
将二环[2.2.2]辛基-1-甲酸(0.53g,3.4mmol)、及亚硫酰氯(1ml,13mmol)溶于10ml甲苯中,并在80℃加热3小时。除去部分溶剂,将残余物在0℃滴加到4-{异丙基-[2-(2-甲氧基苯基)-乙基]-氨基}-丁胺(1.2g,4.5mmol)和三乙胺(3ml,20mmol)的10ml二氯甲烷溶液中,并在室温搅拌1小时。将该混合物加到硅胶柱上,用己烷/乙酸乙酯/三乙胺(16∶4∶1)洗脱,得到1.1g(86%)油状物。1H NMR(CDCl3)δ7.15(dd,2H),6.84(dd,2H),5.55(bs,1H),3.81(s,3H),3.18(1m,2H),2.98(m,1H),2.71(m,2H),2.57(m,2H),2.45(t,2H),1.67(m,6H),1.60(m,7H),1.45(m,4H),0.99(d,6H).
用类似的方式制备了下列化合物(实施例38):实施例38
N-(4-{异丙基-[2-(2-甲氧基苯基)-乙基]-氨基}-丁基)-金刚烷基-1-甲酰胺1H NMR(CDCl3)δ7.20-7.11(m,2H),6.89-6.83(m,2H),5.6(s,1H),3.82(s,3H),3.24-3.21(m,2H),2.99(七重峰,1H),2.75-2.72(m,2H),2.60-2.55(m,2H),2.48-2.43(m,2H),2.06-2.03(m,3H),1.85-1.84(m,6H),1.71-1.69(m,6H),1.48-1.45(m,4H),1.00(d,6H).实施例39(方法E)
N-(4-{异丙基-[2-(2-甲氧基苯基)-乙基]-氨基}-丁-2-烯基)-金刚烷基-1-甲酰胺
在5ml乙醇中在环境温度下将N-(4-{异丙基-[2-(2-甲氧基苯基)-乙基]-氨基}-丁-2-炔基)-金刚烷基-1-甲酰胺(90mg,0.21mmol)、氯化镍六水合物(60mg,0.25mmol)、乙二胺(0.15ml,0.25mmol)和硼氢化钠(0.25ml,1N的EtOH溶液,0.25mmol)的混合物搅拌10小时。过滤该混合物,除去溶剂,残余物溶于二氯甲烷中,并用水洗涤。蒸发溶剂得到71mg油状物。1H NMR(CDCl3)δ7.20-7.11(m,2H),6.90-6.83(m,2H),5.75-5.67(m,1H),5.70(s,1H),5.85-5.50(m,1H),3.93(dd,1H),3.82(s,3H),3.21(d,1H),3.03(七重峰1H),2.77-2.72(m,2H),2.63-2.57(m,2H),2.06-2.01(m,3H),1.84-1.83(m,6H),1.72-1.69(m,6H),1.03(d,6H).
用类似的方式制备了下列化合物(实施例40-42):实施例40
N-(4-{[2-(2,3-二甲氧基苯基)-乙基]-丙氨基}-顺式-丁-2-烯基)-环己基甲酰胺草酸盐
M.p.113-115℃。实施例41
N-丙基-N-[2-(2,3-二甲氧基苯基)-乙基]-(4-邻苯二甲酰亚氨基-顺式-丁-2-烯基)-胺1H NMR(CDCl3)7.86-7.83(m,2H),7.72-7.69(m,2H),6.97(dd,1H),6.80-6.76(m,2H),5.79-5.70(m,2H),5.65-5.57(m 2H),4.36(d,2H),3.85(s,3H),3.83(s,3H),3.42(d,2H),2.81-2.79(m,2H),2.74-2.69(m,2H),2.54-2.49(m,2H),1.57(六重峰、2H),0.90(t,3H).实施例42
N-丙基-N-[2-(4-氨基-3-三氟甲基苯基)-乙基]-(4-邻苯二甲酰亚氨基-顺式-丁-2-烯基)-胺草酸盐
M.p.136-138℃。实施例43(方法F)
8-(4-{异丙基-[2-(2-羟基苯基)-乙基]-氨基}-丁基)-8-氮杂-螺[4.5]癸烷-7,9-二酮
在氮气氛下将溶于10ml二氯甲烷中的8-(4-{异丙基-[2-(2-甲氧基苯基)-乙基]-氨基}-丁基)-8-氮杂-螺[4.5]癸烷-7,9-二酮(550mg,1.2mmol)冷却至-60℃。在20分钟内加入三溴化硼(0.28ml,2.9mmol)和3ml二氯甲烷的混合物,并在10℃将混合物搅拌过夜,并倾入到5ml冷的碳酸氢钠溶液中。水相用1M氨水处理,并用二氯甲烷萃取,蒸发溶剂得到410mg油状物。1H NMR(CDCl3)δ8.05(s,1H),7.09(t,1H),6.96(d,1H),6.84(d,1H),6.72(t,1H),3.77(m,2H),3.12(m,1H),2.77(m,2H),2.70(m,2H),2.56(5,4H),2.52(m,2H),1.69(m,4H),1.51(m,8H),1.00(d,6H).实施例44(方法F)
三氟甲磺酸2-(2-{[4-(7,9-二氧代-8-氮杂-螺[4.5]癸-8-基)-丁基]-异丙氨基}-乙基)苯基酯
在氮气氛下将实施例26的产物(224mg,0.56mmol)的二氯甲烷溶液和三乙胺(74mg,0.73mmol)冷却至-70℃。在10分钟内滴加入三氟甲磺酸酐(190mg,0.67mmol),并将混合物温热至0℃,用1M氨水洗涤。有机相用MgSO4干燥,蒸发溶剂得到200mg油状物。1H NMR(CDCl3)δ7.40-7.25(m,4H),3.75(t,2H),2.95(m,1H),2.80(m,2H),2.64(m,2H),2.58(s,4H),2.53(m,2H),1.70(m,4H),1.50(m,4H),1.38(m,4H),0.94(d,6H).实施例45(方法F)
2-(2-{[4-(7,9-二氧代-8-氮杂-螺[4.5]癸-8-基)-丁基]-异丙基氨基}-乙基)-N-甲基苯甲酰胺
在-氧化碳气氛中向实施例44的产物(360mg,0.68mmol)的8ml二噁烷溶液中,加入乙酸钯(10mg,0.04mmol)、1,3-二(二苯基膦基丙烷)(25mg,0.06mmol)和4ml甲胺与二噁烷的混合物。在80℃将该混合物加热16小时。除去溶剂,残余物溶于乙酸乙酯中,并用饱和碳酸钾溶液洗涤。干燥有机相,除去溶剂,残余物经色谱法纯化,得到260mg油状物。1H NMR(CDCl3)δ7.53(d,1H),7.31(dd,1H),7.17-7.22(m,2H),3.61(t,2H),2.97(d,3H),2.70-2.90(m,5H),2.56(s,4H),2.26(t,2H),1.67-1.72(m,4H),1.42-1.50(m,4H),1.18-1.30(m,4H),1.89(d,6H).实施例46(方法F)
N-(5-{[2-(4-氨基-2-氯苯基)-乙基]-丙氨基}-戊基)-反式-4-丙基环己基甲酰胺二盐酸盐
M.p.125-130℃。实施例47(方法F)
N-(4-([2-(4-氨基-3-氰基苯基)-乙基]-丙基-氨基}-丁基)-环己基甲酰胺1H NMR(CDCl3)7.15(m,2H),6.66(d,1H),5.75(s,1H),4.34(s,2H),3.43(t,2H),3.19(m,2H),2.56(s,4H),2.38(m,4H)1.95(m,5H),1.42(宽,6H),1.22(宽,4H),0.83(t,3H).实施例48(方法H)
N-(4-{异丙基-[2-(2-甲氧基苯基)-乙基]-氨基}-丁-2-炔基)-金刚烷基-1-甲酰胺
将多聚甲醛(72mg,2.4mmol)和N-炔丙基-金刚烷基-1-甲酰胺(440mg,2.0mmol)的3ml二噁烷溶液加热至50℃,并维持在此温度达1小时。加入催化量的乙酸铜和N-异丙基-2-甲氧基苯乙胺(390mg,2.0mmol),并将该混合物在80℃加热.3小时。冷却后,加入10ml-氯甲烷,有机相用水(2×10ml)洗涤,蒸发溶剂,残余物经色谱法(正己烷/乙酸乙酯)纯化,得到125mg由状物。1H NMR(CDCl3)δ7.19-7.13(m,2H),6.91-6.84(m,2H),5.7(s,1H),4.00-4.03(m,2H),3.83(s,3H),3.50-3.46(m,2H),3.04(七重峰,1H),2.78-2.71(m,4H),2.07-2.03(m,3H),1.84-1.83(m,6H),1.72-1.69(m,6H),1.07(d,6H).
用类似的方式制备了下列化合物(实施例49):实施例49
N-(4-{[2-(2,3-二甲氧基苯基)-乙基]-丙氨基}-丁-2-炔基)-环己基甲酰胺
M.p.69-71℃。药物制剂
下列实施例说明了用于本发明方法中的适宜的药物组合物。为了制备片剂,制备了下列组合物。组合物1
实施例1化合物 50g
乳糖 85g
马铃薯淀粉 40g
聚乙烯吡咯烷酮 5g
微晶纤维素 18g
硬脂酸镁 2g组合物2
实施例1化合物 100g
乳糖 90g
马铃薯淀粉 50g
聚乙烯吡咯烷酮 5g
微晶纤维素 23g
硬脂酸镁 2g
由上述组合物,可以制备每片分别含有50mg和100mg活性物质的1000片片剂。如果需要,所得片剂可以用例如在有机溶剂中的羟丙基甲基纤维素或用水进行薄膜包衣。药理学
普遍接受的观点是,与多巴胺D2受体结合的、并且是这些受体的拮抗剂的药物可在临床上有效地用作精神病药剂(例如用于精神分裂症中)。人们还认为,作为激动剂的5-羟色胺能(5HT1A)受体亲和力可能是一种有用的性质,它可以降低锥体束外的副作用的发生及增加所述物质在精神病方面的效力。这些物质由于具有一定比例的D2和5HT1A结合能力而在减少副作用发生和改善效力的同时,又保持了抗精神病作用。
本发明化合物具有对D3受体的亲和力。D3受体浓集在脑缘部分,这意味着对这些受体具有亲和力的药物可以具有较低的副作用。某些化合物还具有对5-HT1A和D2受体的亲和力。这些作用使得得以使用上述定义的化合物治疗精神紊乱,例如精神病、精神分裂症和抑郁症。
药理学方法描述如下。D2受体结合测定法细胞和膜的制备:
表达入D2(long)受体的小鼠成纤维细胞LTK-细胞承蒙Dr.0.Civelli(Oregon Health Sciences University)提供,并生长于在37℃下、在含5% CO2的空气中的具有通风盖(Costar)的225cm3烧瓶中的含有10mM HEPES、10%胎牛血清(FCS)的Dulbecco′s Modified Eagle′s Medium(DMEM)中。细胞用0.05%胰蛋白酶和0.02%EDTA的PBS(磷酸盐缓冲盐水)溶液移出,在300g条件下离心10分钟,在DMEM中再洗涤两次,并用Dounce均化器在pH7.4的10mM Tris-HCl和5mM MgSO4中均化。均浆在结合缓冲剂(含有1mM EDTA、5mM KCl、1.5mM CaCl2、4mM MgCl2和120mM NaCl的50mM Tris-HCl(pH7.4))中通过在43500g条件下离心10分钟洗涤两次,并以等份试样贮存于-70℃。受体结合测定:
将冷冻的细胞膜解冻,用Branson 450声破碎器均化,并悬浮于结合缓冲剂中至最终受体浓度为100pM。在室温下,将各种浓度的试验化合物、放射配体(1nM 3H-Raclopride)和细胞均浆保温60分钟。通过加入1μM(+)-Butaclamol来测定非特异性结合。通过用玻璃纤维滤器(Whatman GF/B,用0.05%聚乙烯亚胺)迅速过滤来终止上述保温过程,使用Brandel细胞捕获装置、用冷的50mMTris-HCl(pH7.4)洗涤。在加入闪烁液(Packard Ultima Gold,3ml)后,在Liquid Scintillation Analyzer(Packard 2200CA或2500TR)中以约50%的效率测定滤器(filters)的放射性。用LIGAND程序通过非线性回归分析数据,并以Ki值表示。5-HT1A受体结合测定法组织的制备:
将大鼠断头,并在冰上解剖出其海马。所述海马使用UltraTurrax在含有10mM EDTA、pH7.4的50mM Tris-HCl缓冲剂中进行均化。在4℃下在19,500rpm(43,500xg)条件下将均浆离心(使用Sorvall RC-5B)10分钟。将滤片重新悬浮于pH7.4的50mM Tris-HCl缓冲剂中,并再次离心。最终的滤片悬浮于0.32M的蔗糖中,并在-20℃冷冻直至使用为止。
在进行测定的当天,将冷冻的均浆解冻,每个试管2.5mg原始净重,并将其悬浮于结合缓冲剂(含有2mM CaCl2、1mM MgCl2的、pH7.4的50mM Tris-HCl缓冲剂)中。在37℃将均浆预培养10分钟,以便除去内源性5-羟色胺,之后,加入巴吉林至最终浓度为10μM。受体结合测定:
将各种浓度的试验化合物(在0.1%抗坏血酸中稀释)、放射配体(在结合缓冲剂中稀释的1nM 3H-8-OH-DPAT)和均浆以最终体积为0.5ml在37℃培养45分钟。按在100μM未标记的5-羟色胺存在下的结合的测定方法获得非特异性结合。通过经玻璃纤维滤器(Whatman GF/B)的迅速过滤来停止上述保温过程,随后用细胞捕获器(Brandel)、使用冷的pH 7.4的50mM Tris-HCl缓冲剂洗涤。在液体闪烁分光计(Beckman LS 5000 TD或Packard 2500 TR)中测定滤器(filters)的放射性。使用LIGAND程序、通过非线性回归分析数据,并以Ki值表示。D3受体结合测定法细胞和膜的制备:
在37℃在含有5% CO2的空气中于带有通风盖(Costar)的225cm3烧瓶中,在含有10mM HEPES、10%透析的胎牛血清(FCS)和PeSt(70μg/ml苄青霉素K和10μg/ml链霉素硫酸盐)的Dulbecco′s Modified Eagle′s Medium(DNEM)中培养购于Insern Institute,Paris,France的、表达人D3受体的中国大田鼠卵巢(CHO)细胞。细胞用0.05%胰蛋白酶和0.02%EDTA的PBS(磷酸盐缓冲盐水)溶液移出,在300g离心10分钟,在DMEM中再洗涤两次,并用Dounce均化器在pH7.4的10mM Tris-HCl和5mMMgSO4中均化。均浆在结合缓冲剂(含有1mM EDTA、5mM KCl、1.5mM CaCl2、4mM MgCl2、120mM NaCl的pH7.4的50mMTris-HCl)中通过在43500g条件下离心10分钟洗涤两次,并以等份试样在-70℃下贮存。受体结合测定:
将冷冻的细胞膜解冻,用Branson 450声破碎器均化,并悬浮于结合缓冲剂中至最终受体浓度为100PM。在室温下,将各种浓度的试验化合物、放射配体(1nM 3H-Raclopride)和细胞均浆保温60分钟。通过加入1μM(+)-Butaclamol来测定非特异性结合。通过用玻璃纤维滤器(Whatman GF/B,用0.05%聚乙烯亚胺)迅速过滤来终止上述保温过程,使用Brandel细胞捕获装置、用冷的50mMTris-HCl(pH7.4)洗涤。在加入闪烁液(Packard Ultima Gold,3ml)后,在Liquid Scintillation Analyzer(Packard 2200CA或2500TR)中以约50%的效率测定滤器(filters)的放射性。用LIGAND程序通过非线性回归分析数据,并以Ki值表示。
Claims (13)
Z为饱和的或不饱和的3-6碳链;
m为2或3;
R1为氢原子、或直链或支链C1-4烷基;
R2、R3和R13位于苯环的邻、间或对位,并且它们可相同或不同,且选自下列基团:H、OH、OR14、卤素、CO2R9、CN、CF3、NO2、NH2、COCH3、OSO2CF3、OSO2CH3、CONR10R11、OCOR12、其中R9、R12和R14为直链或支链C1-4烷基,R10和R11可相同或不同,并且代表氢、或直链或支链C1-6烷基;
2.权利要求1所述的化合物,其中在通式I中:
R为
R1为氢原子、或直链或支链C1-4烷基;
R2为氢、甲氧基、乙氧基、卤素、CN、CONR10R11、CF3、硝基或氨基;
R3为甲氧基、乙氧基、卤素、CN、CONR10R11、CF3、硝基或氨基;
R4为直链或支链C1-4烷基;
R5为直链或支链C1-4烷基,或者R4和R5一起为-(CH2)n1;
R13为氢、甲氧基、乙氧基、卤素、CN、CONR10R11、CF3、硝基或氨基;
Z在饱和时,为3-6碳链,而在不饱和时,为4-6碳链;和
m为2或3,和
R10、R11和n1如权利要求1中所定义。
6.权利要求1-5中任何一项中所述的化合物:
8-(4-{[2-(4-氨基-3-三氟甲基苯基)乙基]甲氨基}丁基)-8-氮杂-螺[4.5]癸烷-7,9-二酮草酸盐,
N-(4-{[2-(3,4-二甲氧基苯基)乙基]-丙氨基}丁基)-环己基甲酰胺,
N-(4-{[2-(5-溴-2-甲氧基苯基)乙基]-丙氨基}丁基)-环己基甲酰胺草酸盐,
N-(6-{[2-(4-氨基-3-三氟甲基苯基)乙基]-甲氨基}己基)-二环[2.2.2]辛基-1-甲酰胺盐酸盐,
N-(4-{异丙基-[2-(2-甲氧基苯基)乙基]氨基}丁基)-二环[2.2.2]辛基-1-甲酰胺,
N-(4-{[2-(3-甲氧基苯基)乙基]-丙氨基}丁基)-金刚烷基-1-甲酰胺草酸盐,
N-(4-{[2-(2-氯-4-甲氧基苯基)乙基]-丙氨基}丁基)-环己基甲酰胺草酸盐,
N-(4-{[2-(2,4-二甲氧基苯基)乙基]-丙氨基}丁基)-金刚烷基-1-甲酰胺草酸盐,
N-(4-([2-(4-氨基-3-氰基苯基)乙基]丙氨基)-丁基)-环己基甲酰胺。
7.制备如权利要求1中所定义的通式I化合物的方法,其特征在于:
A.使通式II化合物与通式III化合物反应,
R-Z-X II
其中R和Z如权利要求1中所定义,和X为离去基团、或下式基团,
其中Y为氢、羟基、卤素或烷氧基,
其中R、R1、R2、R3、R13和m如权利要求1中所定义;或者
B.使通式IV化合物与通式V化合物反应,其中R、Z和R1如权利要求1中所定义,其中X、m、R2和R3如权利要求1中及如上所定义;或者C.使通式VI化合物与通式VII化合物反应,其中R、Z、m、R2和R3如权利要求1中所定义,
R1X VII其中R1和X如权利要求1中及上述所定义;或者D.使通式VII化合物或通式IX化合物与通式X化合物反应,其中R7如权利要求1中所定义,和T代表酸衍生物基团,其中W、n3和n4如权利要求1中所定义,
其中Z、R1、R2、R3、R13和m如权利要求1中所定义;或者
E.通过使用还原剂,使通式XI化合物转化为通式I化合物,
其中R、R1、R2、R3、R13和m如权利要求1中所定义,和Z1代表不饱和的3-6碳链,
其中R、R1、R2、R3、R13、Z和m如权利要求1中所定义;或者
其中R、R1、Z和m如权利要求1中所定义,和R1 2、R1 3和R1 13代表可通过反应,例如还原反应、氢化反应、水解反应、脱甲基化作用、硝化作用、酯化作用、卤化作用、乙酰化作用、羰基化作用或脱水作用进行修饰的取代基,其中R、R1、R2、R3、R13、Z和m如权利要求1中所定义,或者
其中W、n3、n4和M如权利要求1中所定义,
其中X、Z、R1、R2、R3、R13和m如权利要求1中所定义;或者
H.使通式XVI化合物与多聚甲醛和通式XVII化合物反应,
R-(CH2)pC≡CH XVI
其中R如权利要求1中所定义,和p为1-3,
其中R1、R2、R3、R13和m如权利要求1中所定义;
之后,如果需要,将通过方法A-H中任何一种方法获得的化合物转化为其可药用盐或转化为光学活性形式。
8.权利要求7中所述的方法,其特征在于,制备权利要求2-6中任何一项所述的化合物。
9.一种用于治疗精神病学疾病的药物制剂,其中活性成分为权利要求1-5中任何一项中所述的化合物。
10.权利要求9所述的药物制剂,所述药物制剂以剂量单位形式存在。
11.权利要求9所述的药物制剂,该药物制剂包含所述活性成分以及可药用载体。
12.权利要求1-5中任何一项中所述化合物用于制备具有抗精神病学疾病作用的药物的应用。
13.治疗与D3受体表达的机能障碍有关的疾病的药物制剂,其中活性成分是按照权利要求1至5中任何一项的化合物。
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WO2003022269A1 (en) * | 2001-09-12 | 2003-03-20 | Merck Patent Gmbh | Novel use of substituted aminomethyl chromans for the treatment of movement disorders and of adverse effects induced by drugs administered to treat extrapyramidal movement disorders |
IL147953A (en) | 2002-02-01 | 2008-04-13 | Meir Bialer | Derivatives and pharmaceutical compositions of n-hydroxymethyl tetramethylcyclopropyl- |
IL157751A0 (en) | 2003-02-28 | 2004-03-28 | Yissum Res Dev Co | New amide derivatives of 2,2,3,3-tetramethylcyclopropane carboxylic acid, a method for their synthesis and pharmaceutical compositions containing them |
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FR7644E (fr) | 1903-08-11 | 1907-09-17 | Chappee Et Fils Soc | Nouveau système d'assainissement des villes |
DE1518375A1 (de) * | 1965-06-08 | 1969-08-14 | Thomae Gmbh Dr K | Verfahren zur Herstellung von neuen 2-Amino-halogenbenzylaminen |
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DE2345423A1 (de) * | 1973-09-08 | 1975-03-20 | Thomae Gmbh Dr K | Neue substituierte phenylaethylaminderivate, deren saeureadditionssalze, diese enthaltende arzneimittel sowie verfahren zu deren herstellung |
US4021558A (en) * | 1973-09-08 | 1977-05-03 | Boehringer Ingelheim Gmbh | 1,3-Dioxo-2-[(methoxyphenethyl-amino)-alkyl]-4,4-dimethyl-isoquinolines and salts thereof useful as hypotensive agents |
JPS5414956A (en) * | 1977-07-04 | 1979-02-03 | Sumitomo Chem Co Ltd | Novel 3-amino-4-homoisotwistan derivative |
DE3119874A1 (de) * | 1981-05-19 | 1982-12-09 | Dr. Karl Thomae Gmbh, 7950 Biberach | "benzazepinderivate, ihre herstellung und ihre verwendung als arzneimittel" |
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FR2608157B1 (fr) * | 1986-12-11 | 1989-09-08 | Roussel Uclaf | Nouveaux derives de l'azaspirodecane, leurs sels, procede de preparation, application a titre de medicaments et compositions les renfermant et intermediaires |
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US3948898A (en) * | 1973-09-08 | 1976-04-06 | Boehringer Ingelheim Gmbh | 1,3-Dioxo-2-aminoalkyl-4,4-dimethyl-isoquinolines and salts thereof |
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