CN1301972C - 作为毒覃碱拮抗剂的哌啶化合物 - Google Patents
作为毒覃碱拮抗剂的哌啶化合物 Download PDFInfo
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- CN1301972C CN1301972C CNB028199901A CN02819990A CN1301972C CN 1301972 C CN1301972 C CN 1301972C CN B028199901 A CNB028199901 A CN B028199901A CN 02819990 A CN02819990 A CN 02819990A CN 1301972 C CN1301972 C CN 1301972C
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- Prior art keywords
- compound
- alkyl
- solvate
- pharmaceutically acceptable
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- 239000012453 solvate Chemical class 0.000 claims description 35
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- XNERWVPQCYSMLC-UHFFFAOYSA-N phenylpropiolic acid Chemical compound OC(=O)C#CC1=CC=CC=C1 XNERWVPQCYSMLC-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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
- C07D401/06—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 carbon chain containing only aliphatic 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/24—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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Abstract
本发明公开了化合物,其为新的毒蕈碱性受体拮抗剂;还公开了制备这类化合物的方法。在另一个实施方案中,本发明公开了含有这类毒蕈碱性受体拮抗剂的药物组合物和用它们治疗认知障碍(如阿尔茨海默氏病)的方法。
Description
交叉引用至相关申请
本申请要求享受2001年10月10日提交的美国临时申请No.60/328,356的权利。
技术领域
本发明涉及用于治疗认知紊乱的化合物、含有该化合物的药物组合物、使用本发明所述化合物的治疗方法和所述化合物与胆碱乙酰化酶抑制剂结合的用途。
背景技术
阿尔茨海默氏病及其他认知紊乱近来已受到非常的重视,然而对于这些疾病的治疗尚不很成功。
根据Melchiorre等人(J.Med.Chem.(1993),36,3734-3737)所述,那些选择性对抗M2毒蕈碱性受体、特别是与M1毒蕈碱性受体相关的化合物应具有对抗认知紊乱的活性。Baumgold等人(Eur.J.ofPharmacol.,251,(1994)315-317)公开了3-α-chloroimperialine作为高度选择性的M2毒覃碱拮抗剂。
本发明在于发现了一类1,4-二取代的哌啶,其中一些具有的M2选择性甚至高于3-α-chloroimperialine。Logemann等人(Brit.J.Pharmacol.(1961),17,286-296)描述了一些二N-取代的哌嗪,但是其与本发明的化合物不同。此外,Logemann等人没有公开其化合物具有对抗认知紊乱的活性。
发明内容
在一个方面,本申请提供了一种具有下述通式I的化合物:
或该化合物的药学可接受盐或溶剂化物,
其中:
Z是N、C(H)或C-(烷基);
X是-O-、-S-、-SO-、-S(O)2-、-C(O)-、-CH2-或-C(S);
R是
R2是
R3是1至5个取代基,其可以相同或不同,各个所述的取代基是烷氧基或卤素;
R4是H或1至3个取代基,所述取代基可以相同或不同,各个所述取代基是烷基或卤代烷基;
R27是氢或1或2个取代基,所述取代基可以相同或不同,各个所述取代基独立地选自烷基、羟烷基、芳烷基、氨基烷基、卤代烷基、烷硫基、烷硫基亚烷基、羧烷基、咪唑基烷基和吲哚基烷基;
R28是氢或1或2个取代基,所述取代基可以相同或不同,各个所述取代基独立地选自烷基、羟烷基、芳烷基、氨基烷基、卤代烷基、烷硫基、烷硫基亚烷基、羧烷基、咪唑基烷基和吲哚基烷基;或R27和R28可连接在一起形成亚烷基;
R29是氢、烷基、-C(O)-烷基、-C(O)-环烷基、烷氧羰基、氨基羰基、芳氧基羰基、烷基氨基羰基、烷基磺酰基、芳基磺酰基或-SO2-NH-R35;
R31是氢或1或2个取代基,所述取代基可以相同或不同,各个所述取代基独立地选自烷基、芳基、环烷基、羟烷基、氨基烷基、羟基、-N(R35)2、-O-酰基、-N(R35)酰基、-OC(O)OR35和-OC(O)N(R35)2;
R32是氢或1或2个取代基,所述取代基可以相同或不同,各个所述取代基独立地选自烷基、芳基、环烷基、羟烷基、氨基烷基、羟基、-N(R35)2、-O-酰基、-N(R35)酰基、-OC(O)OR35和-OC(O)N(R35)2,或R31和R32可连接在一起形成基团-(CH2)r-,其中r是1、2、3、4、5或6;
R33是芳基或杂芳基,条件是当R33是杂芳基时,C(O)-R33键是R33基团中的碳原子;
和R35是氢、芳基或烷基。
式I化合物可用作M2毒覃碱受体拮抗剂,并且可用于治疗阿尔茨海默氏症和其它神经变性或认知疾病。本发明的另一个实施方案是药物组合物,其用于治疗神经变性或认知疾病。该组合物包括治疗疾病或失调量的式I化合物或该化合物药学可接受的盐和药学可接受的载体。
发明详述
在一个实施方案中,本发明提供了结构式I所示的化合物或其药学可接受的盐或溶剂化物。在式I的一个优选实施方案中,
R2是
和
X是-O-、-S-、-SO-或-S(O)2-,
或所述化合物的药学可接受盐或溶剂化物。
在式I的一个优选实施方案中,R2和X定义如下:
表1
在式I的优选实施方案中,本发明的化合物具有下式,包括其药学可接受的盐或溶剂化物:
在式I的另一个优选实施方案中,本发明的化合物具有下式,包括其药学可接受的盐或溶剂化物:
除非另有说明,下列定义用于整个说明书和权利要求。这些定义的应用与术语是否单独使用或与其它术语结合使用无关。因此,“烷基”的定义可用于“烷基”以及“烷氧基”、“卤代烷基”等的“烷基”部分。
除非是已知、说明或显示有意思相反,有多个术语的取代基(结合在一起定义一个片段的多个术语)结合到一个主体结构的结合点是通过多个术语的最后一个命名的术语。例如,“芳烷基”取代基与目标结构通过取代基的“烷基”部分结合。相反地,当取代基是“烷基芳基”时,其通过取代基的“芳基”部分与目标结构结合。类似地,环烷基烷基取代基通过取代基的“烷基”部分与目标结合(例如,结构-烷基-环烷基)。
“患者”包括人和其它哺乳动物。
“哺乳动物”表示人和其它动物。
“烷基”是指直链或支链的且链包括约1-约20个碳原子的脂族烃基。优选的烷基链含有约1-12个碳原子。更优选烷基链含有约1-6个碳原子。支链是指一个或多个低级烷基——如甲基、乙基或丙基——与直链烷基链相连。“低级烷基”表示具有约1-6个链碳原子的直链或支链的基团。术语“取代的烷基”意思是烷基可被一个或多个取代基取代,所述取代基可相同或不同,各个取代基独立地选自卤素、烷基、芳基、环烷基、氰基、羟基、烷氧基、烷硫基、氨基、-NH(烷基)、-NH(环烷基)、-N(烷基)2、羧基和-C(O)O烷基。适合的烷基的非限制性例子包括甲基、乙基、正-丙基、异丙基、正丁基、叔丁基。
“烯基”表示含有至少一个碳-碳双键的脂族烃基,其可以是直链或支链的且在链中包括约2-15个碳原子。优选的链烯基具有约2-12个链碳原子。更优选约2-6个链碳原子。支链是指一个或多个低级烷基一如甲基、乙基或丙基与一个直链烯基链相连。“低级烯基”表示具有约2-6个链碳原子,所述链可以是直链或支链。术语“取代的烯基”指烯基可被一个或多个取代基取代,所述取代基相同或不同,各个取代基独立地选自卤素、烷基、芳基、环烷基、氰基和烷氧基。合适的烯基的非限制性例子包括乙烯基、丙烯基、正丁烯基和3-甲基丁-2-烯基。
“炔基”表示含有至少一个碳-碳三键的脂族烃基,其可以是直链或支链的且在链中包括约2-15个碳原子。优选的链炔基具有约2-12个链碳原子;更优选约2-4个链碳原子。支链是指一个或多个低级烷基--如甲基、乙基或丙基--与一个直链炔基链相连。“低级炔基”表示具有约2-6个链碳原子,所述链可以是直链或支链。合适的炔基的非限制性例子包括乙炔基、丙炔基和2-丁炔基。术语“取代的炔基”指炔基可被一个或多个取代基取代,所述取代基相同或不同,各个取代基独立地选自烷基、芳基和环烷基。
“亚烷基”指从如上定义的烷基脱去一个氢原子得到的双官能基团。亚烷基的非限制性实例包括亚甲基、亚乙基和亚丙基。
“芳基”是指具有约6-14个碳原子、优选约6-10个碳原子的芳族单环或多环环系。芳基可以是未取代的或在环上被一个或多个取代基任选取代的,所述取代基可以相同或不同,各个取代基独立地选自烷基、芳基、杂芳基、芳烷基、烷基芳基、芳烯基、杂芳基烷基、烷基杂芳基、杂芳基烯基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、酰基、芳酰基、卤素、硝基、氰基、羧基、烷氧羰基、芳氧基羰基、芳烷氧基羰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、烷基亚硫酰基、芳基亚硫酰基、杂芳基亚硫酰基、烷硫基、芳硫基、杂芳基硫基、芳烷硫基、杂芳烷硫基、环烷基、环烯基、杂环基、杂环烯基、Y1Y2N-、Y1Y2N-烷基-、Y1Y2NC(O)-和Y1Y2NSO2-,其中Y1和Y2可以相同或不同,独立地选自氢、烷基和芳烷基。可取代的芳基的非限制性实例包括苯基和萘基。
“杂芳基”是含约5-14个、优选约5-10个环原子的芳族单环或多环环系,其中一个或多个环原子是除了碳以外的其它原子,例如氮、氧或硫,这些原子可单独存在或组合存在。优选的杂芳基含有约5-6个环原子。“杂芳基”可任选在环上被取代,即,由一个或多个相同或不同的取代基取代环上可被代替的氢,各个取代基独立地选自烷基、芳基、杂芳基、芳烷基、烷基芳基、芳烯基、杂芳基烷基、烷基杂芳基、杂芳基烯基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、酰基、芳酰基、卤素、硝基、氰基、羧基、烷氧羰基、芳氧基羰基、芳烷氧基羰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、烷基亚硫酰基、芳基亚硫酰基、杂芳基亚硫酰基、烷硫基、芳硫基、杂芳基硫基、芳烷硫基、杂芳烷硫基、环烷基、环烯基、杂环基、杂环烯基、Y1Y2N-、Y1Y2N-烷基-、Y1Y2NC(O)-和Y1Y2NSO2-,其中Y1和Y2可以相同或不同,分别独立地选自氢、烷基、芳基和芳烷基。在杂芳基词根前面的前缀氮杂、氧杂或硫杂表示氮、氧或硫原子分别作为环原子存在。杂芳基的氮原子可被任选氧化成相应的N-氧化物。适合的杂芳基的非限制性实例包括吡啶基、吡嗪基、呋喃基、噻吩基、嘧啶基、异唑基、异噻唑基、唑基、噻唑基、吡咯基、三唑基等。
“芳烷基”或“芳基烷基”是指芳基-烷基基团,其中芳基和烷基如上所述。优选的芳烷基包括低级烷基。适合的芳烷基的非限制性例子包括苄基、2-苯乙基和萘基甲基。通过烷基与主体部分键合。
“烷芳基”是指烷基-芳基基团,其中烷基和芳基如上所述。优选的烷芳基包括低级烷基。适合的烷芳基的非限制性例子包括间甲基苯基、对甲基苯基、二甲基苯基。通过芳基与主体部分键合。
“环烷基”是含约3-10个、优选约5-10个碳原子的非芳族单环或多环环系。优选的环烷基环含有约5-7个环原子。环烷基可任选在环上被取代,即,由一个或多个相同或不同的取代基取代环上可被代替的氢,各个取代基独立地选自烷基、芳基、杂芳基、芳烷基、烷基芳基、芳烯基、杂芳基烷基、烷基杂芳基、杂芳基烯基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、酰基、芳酰基、卤素、硝基、氰基、羧基、烷氧羰基、芳氧基羰基、芳烷氧基羰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、烷基亚硫酰基、芳基亚硫酰基、杂芳基亚硫酰基、烷硫基、芳硫基、杂芳基硫基、芳烷硫基、杂芳烷硫基、环烷基、环烯基、杂环基、杂环烯基、Y1Y2N-、Y1Y2N-烷基-、Y1Y2NC(O)-和Y1Y2NSO2-,其中Y1和Y2可以相同或不同,分别独立地选自氢、烷基、芳基和芳烷基。适合的单环环烷基的非限制性实例包括环丙基、环戊基、环己基、环庚基等。适合的多环环烷基的非限制性例子包括1-萘烷基、降冰片烷基、金刚烷基等。
“卤代”指氟代、氯代、溴代或碘代基团。优选氟代、氯代或溴代,更优选氟代和氯代。
“卤素”指氟、氯、溴或碘。优选氟、氯或溴,更优选氟和氯。
“卤代烷基”指上述定义的烷基中在烷基上的一个或多个氢原子被上述卤代基团代替。
“环烯基”是含约3-10个、优选约5-10个碳原子的非芳族单环或多环环系,其含至少一个碳-碳双键。优选的环烯基环含有约5-7个环原子。环烷烯可任选在环上被取代,即,由一个或多个相同或不同的取代基取代环上可被代替的氢,各个取代基独立地选自烷基、芳基、杂芳基、芳烷基、烷基芳基、芳烯基、杂芳基烷基、烷基杂芳基、杂芳基烯基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、酰基、芳酰基、卤素、硝基、氰基、羧基、烷氧羰基、芳氧基羰基、芳烷氧基羰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、烷基亚硫酰基、芳基亚硫酰基、杂芳基亚硫酰基、烷硫基、芳硫基、杂芳基硫基、芳烷硫基、杂芳烷硫基、环烷基、环烯基、杂环基、杂环烯基、Y1Y2N-、Y1Y2N-烷基-、Y1Y2NC(O)-和Y1Y2NSO2-,其中Y1和Y2可以相同或不同,分别独立地选自氢、烷基、芳基和芳烷基。适合的单环环烯基的非限制性实例包括环戊烯基、环己烯基、环庚烯基等。适合的多环环烷基的非限制性例子是降冰片烯基。
“杂环烯基”是含约3-10个、优选约5-10个碳原子的非芳族单环或多环环系,其中环系的一个或多个原子是除碳以外的其它原子,例如氮、氧或硫原子,它们单独存在或组合存在,并且环系含至少一个碳-碳双键或碳-氮双键。在环系中不存杂相邻的氧和/或流原子。优选的杂环烯基环含有约5-6个环原子。在杂环烯基词根之前的前缀氮杂、氧杂或硫杂分别表示至少一个氮原子、氧原子或硫原子作为环原子存杂。杂环烯基可任选在环上被取代,即,由一个或多个相同或不同的取代基取代环上可被代替的氢,各个取代基独立地选自烷基、芳基、杂芳基、芳烷基、烷基芳基、芳烯基、杂芳基烷基、烷基杂芳基、杂芳基烯基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、酰基、芳酰基、卤素、硝基、氰基、羧基、烷氧羰基、芳氧基羰基、芳烷氧基羰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、烷基亚硫酰基、芳基亚硫酰基、杂芳基亚硫酰基、烷硫基、芳硫基、杂芳基硫基、芳烷硫基、杂芳烷硫基、环烷基、环烯基、杂环基、杂环烯基、Y1Y2N-、Y1Y2N-烷基-、Y1Y2NC(O)-和Y1Y2NSO2-,其中Y1和Y2可以相同或不同,分别独立地选自氢、烷基、芳基和芳烷基。杂环烯基的氮或硫原子可任选被氧化成相应的N-氧化物、S-氧化物或S,S-二氧化物。适合的单环氮杂杂环烯基的非限制性实例包括1,2-二氢吡啶基、1,4-二氢吡啶基、1,2,3,6-四氢吡啶基等。适合的氧杂杂环烯基的非限制性实例包括3,4-三氢-2H-吡喃、二氢呋喃等。适合的多环氧杂杂环烯基的非限制性例子是7-氧杂双环[2.2.1]庚烯基。适合的单环硫杂杂环烯基环的非限制性例子是二氢噻吩基、二氢噻喃基等。
“杂环烷基”是含约3-10个、优选约5-10个碳原子的非芳族单环或多环环系,其中环系的一个或多个原子是除碳以外的其它原子,例如氮、氧或硫原子,它们单独存在或组合存在。在环系中不存杂相邻的氧和/或流原子。优选的杂环烷基环含有约5-6个环原子。在杂环烷基词根之前的前缀氮杂、氧杂或硫杂分别表示至少一个氮原子、氧原子或硫原子作为环原子存杂。杂环烷基可任选在环上被取代,即,由一个或多个相同或不同的取代基取代环上可被代替的氢,各个取代基独立地选自烷基、芳基、杂芳基、芳烷基、烷基芳基、芳烯基、杂芳基烷基、烷基杂芳基、杂芳基烯基、羟基、羟烷基、烷氧基、芳氧基、芳烷氧基、酰基、芳酰基、卤素、硝基、氰基、羧基、烷氧羰基、芳氧基羰基、芳烷氧基羰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、烷基亚硫酰基、芳基亚硫酰基、杂芳基亚硫酰基、烷硫基、芳硫基、杂芳基硫基、芳烷硫基、杂芳烷硫基、环烷基、环烯基、杂环基、杂环烯基、Y1Y2N-、Y1Y2N-烷基-、Y1Y2NC(O)-和Y1Y2NSO2-,其中Y1和Y2可以相同或不同,分别独立地选自氢、烷基、芳基和芳烷基。杂环烷基的氮或硫原子可任选被氧化成相应的N-氧化物、S-氧化物或S,S-二氧化物。适合的单环杂环烷基的非限制性实例包括哌啶基、吡咯烷基、哌嗪基、吗啉基等。
“芳烯基”指芳基-链烯基基团,其中芳基和链烯基如上所述。优选的芳烯基包括低级烯基。适合的芳烯基的非限制性例子包括2-苯乙烯基和2-萘乙烯基。通过烯基与主体部分键合。
“杂芳烷基”指杂芳基-烷基基团,其中杂芳基和烷基如上所述。优选的杂芳烷基包括低级烷基。适合的杂芳烷基的非限制性例子包括吡啶甲基、2-(呋喃-3-基)乙基和喹啉-3-基甲基。通过烷基与主体部分键合。
“杂芳烯基”指杂芳基-链烯基基团,其中杂芳基和链烯基如上所述。优选的杂芳烯基包括低级烯基。适合的杂芳烯基的非限制性例子包括2-(吡啶-3-基)乙烯基和2-(喹啉-3-基)乙烯基。通过烯基与主体部分键合。
“羟烷基”指HO-烷基基团,其中烷基如上所述。优选的羟烷基含有低级烷基。适合的羟烷基的非限制性例子包括羟甲基和2-羟乙基。
“磺酰基”表示式-S(O)2-基团。
“亚硫酰基”表示式-S(O)-基团。
“酰基”表示H-C(O)-、烷基-C(O)-、烯基-C(O)-、炔基-C(O)-、环烷基-C(O)-、环烯基-C(O)-或环炔基-C(O)-,其中各个的基团如前所述。通过羰基与主体部分键合。优选的酰基含有低级烷基。合适的酰基的非限制性实例包括甲酰基、乙酰基、丙酰基、2-甲基丙酰基和环己酰基。
“芳酰基”表示芳基-C(O)-基团,其中芳基如前所述。通过羰基与主体部分键合。合适的基团的非限制性实例包括苯甲酰基和1-萘酰基和2-萘酰基。
“烷氧基”表示烷基-O-基团,其中烷基如前所述。合适的烷氧基的非限制性实例包括甲氧基、乙氧基、异丙氧基和正丁氧基。通过醚氧基与主体部分键合。
“芳氧基”表示芳基-O-基团,其中芳基如前所述。合适的芳氧基的非限制性实例包括苯氧基和萘氧基。通过醚氧基与主体部分键合。
“烷基氨基”表示-NH2或-NH3 +基团,其中在氮上的一个或多个氢原子被如上定义的烷基代替。
“烷硫基”表示烷基-S-基团,其中烷基如前所述。合适的烷硫基的非限制性实例包括甲硫基、乙硫基、异丙硫基和庚硫基。通过硫与主体部分键合。
“烷硫基亚烷基表示烷基-S-烷基基团,其中亚烷基和烷硫基如前所述。合适的烷硫基烷基的非限制性实例包括甲硫基亚甲基和乙硫基亚乙基。通过烷基与主体部分键合。
“芳基硫”表示芳基-S-基团,其中芳基如前所述。合适的芳硫基的非限制性实例包括苯硫基和萘硫基。通过硫与主体部分键合。
“芳烷硫基”表示芳烷基-S-基,其中芳烷基如前所述。合适的芳烷硫基的非限制性实例是苯甲硫基。通过硫与主体部分键合。
“烷氧羰基”表示烷基-O-CO-基团。合适的烷氧羰基的非限制性实例包括甲氧羰基和乙氧羰基。通过羰基与主体部分键合。
“芳氧基羰基”表示芳基-O-C(O)-基团。合适的芳氧基羰基的非限制性实例包括苯氧基羰基和萘氧基羰基。通过羰基与主体部分键合。
“芳烷氧基羰基”表示芳烷基-O-C(O)-基团。合适的芳烷氧基羰基的非限制性实例是苄氧基羰基。通过羰基与主体部分键合。
“氨羰基”表示氨基-O-C(O)-基团。合适的氨羰基的非限制性实例是NH2-O-C(O)-。通过羰基与主体部分键合。
“烷基氨基羰基”表示烷基-氨羰基基团。合适的烷基氨基羰基的非限制性实例是甲基-NH-OC(O)-。通过羰基与主体部分键合。
“烷基磺酰基”表示烷基-S(O2)-基团。优选的基团是其中烷基是低级烷基的那些。通过磺酰基与主体部分键合。
“烷基亚硫酰基”表示烷基-S(O)-基团。优选的基团是其中烷基是低级烷基的那些。通过亚硫酰基与主体部分键合。
“芳基磺酰”表示芳基-S(O2)-基团。通过磺酰基与主体部分键合。
“芳基亚硫酰基”表示芳基-S(O)-基团。通过亚硫酰基与主体部分键合。
术语“任选取代的”表示被特定基团、游离基或片断任选取代。
在此使用的术语“组合物”包括一种含有特定量特定成分的产物以及任何直接或间接与特定量特定成分结合得到的产物。
在此还涉及本发明化合物的前体药物和溶剂化物。在此使用的术语“前体药物”表示一种化合物,其是一种药物前体,通过给主体给药,经代谢或化学过程进行化学转化得到式I化合物或其盐和/或溶剂化物。T.Higuchi和V.Stella在Pro-drugs as Novel DeliverySystems(1987),A.C.S.Symposium Series第14卷中和Edward B.Roche编辑的Bioreversible Carriers in DrugDesign(1987),American Pharmaceutical Association andPergamon Press中讨论了前体药物,这两篇文献均引入在此作为参考。
“溶剂化物”是指本发明的化合物与一种或多种溶剂分子的物理结合。物理结合包括各种程度的离子键和共价键键合,其中包括氢键键合。在某些情况下,溶剂化物可被分离出来,例如当一个或多个溶剂分子掺入到结晶固体的晶格中时。“溶剂化物”包括溶液-相和可分离的溶剂化物。合适的溶剂化物的非限制性实例包括乙醇化物、甲醇化物等。“水合物”是一种溶剂化物,其中溶剂分子是H2O。通常,对于本发明的目的,含药学可接受的溶剂——如水、乙醇等——的溶剂化物形式与非溶剂化物形式等价。
“有效量”或“治疗有效量”用以描述本发明化合物与毒蕈碱性受体亚型结合并因此生产期望的治疗效果的量。
在此还涉及本发明化合物的前体药物和溶剂化物。在此使用的术语“前体药物”表示一种化合物,其为一种药物前体,通过给主体给药,经代谢或化学过程进行化学转化得到式I化合物或那些盐和/或溶剂化物。T.Higuchi和V.Stella在Pro-drugs as Novel DeliverySystems(1987),A.C.S.Symposium Series第14卷中和Edward B.Roche编辑的Bioreversible Carriers in Drug Design(1987),American Pharmaceutical Association and Pergamon Press中讨论了前体药物,这两篇文献均引入在此作为参考。
式I化合物形成的盐也包括在本发明的范围内。除非另有所述,认为在此提及的式I化合物包括了其盐。在此使用的术语“盐”表示用无机和/或有机酸形成的酸式盐以及用无机和/或有机碱形成的碱式盐。另外,当式I化合物含有两个碱性片断——诸如(但不限于)吡啶或咪唑——和一个酸性片断——诸如(但不限于)羧酸,可形成两性离子(“内盐”),其包括在在此使用的术语“盐”中。药学上可接受的(即,无毒的、生理学可接受的)盐是优选,虽然其它盐也可使用。式I的化合物的盐可例如通过式I化合物与适量酸或碱(如等量)在一种介质中反应形成,所述介质诸如是盐在其中沉淀的,或是含水介质,然后进行冷冻干燥。
典型的酸加成盐包括乙酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙炔酸盐(cyclopentanepropionates)、二葡萄糖酸盐、十二烷基磺酸盐、乙烷磺酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢磺酸盐、2-羟基乙烷磺酸盐、乳酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乙二酸盐、果胶酸盐、过硫酸盐、3-苯基丙炔酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸酯、磺酸盐(如那些在此所述的)、酒石酸盐、硫氰酸盐、甲苯磺酸盐(亦称甲苯磺酸盐)、十一烷酸盐等。另外,讨论了通常考虑适用于与碱性药用化合物形成药学有用的盐的酸,例如,S.Berge等人的Journal of PharmaceuticalSciences(1977)66(1)1-19;P.Gould,International J.ofPharmaceutics(1986)33 201-217;Anderson等人的The Practiceof Medicinal Chemistry(1996),Academic Press,New York;以及在The Orange Book(Food & Drug Administration,Washington,D.C.on their website)中。这些公开引入在此作为参考。
典型的碱式盐包括铵盐、碱金属盐--如钠、锂和钾盐、碱土金属盐--如钙和镁盐、与有机碱(例如有机胺)形成的盐--如苄星青霉素、二环己基胺、hydrabamines(N,N-二(脱氢松香基)乙二胺)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁胺形成的盐和与氨基酸(如精氨酸、赖氨酸等)形成的盐。碱性含氮基可用低级卤代烃(例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物)、二烷基硫酸盐(例如二甲基、二乙基、二丁基和二戊基硫酸盐)、长链卤化物(例如癸基、月桂基、肉豆蔻基和硬脂酰氯化物、溴化物和碘化物)、芳烷基卤化物(例如苄基溴和苯乙基溴)等季化。
定义所有这些酸式盐和碱式盐是本发明范围内的药学可接受盐,对于本发明的目的,认为所有的酸盐和碱盐等价于相应化合物的游离态。
式I化合物和其盐、溶剂化物和前体药物可以它们的互变异构形式存在(例如作为一种酰胺或亚氨醚)。所有这些互变异构形式在此也作为本发明的一部分。
本发明化合物(包括所述化合物的盐、溶剂化物和前体药物以及前体药物的盐和溶剂化物)的全部立体异构体(例如几何异构体、旋光异构体等),诸如那些可由于在各个取代基上的不对称碳而形成的,包括对映异构形式(其可以甚至在没有不对称碳的情况下存在)、几何异构体形式、阻转异构体和非对映形,也在本发明范围内。本发明化合物的各个立体异构体可以例如实质上不含其它异构体,或可以是混合的,例如作为外消旋物或与所有其它的或其它被选择的立体异构体混合。本发明的手性中心可具有如IUPAC 1974 Recommendations定义的S或R构型。术语“盐”、“溶剂化物”、“前体药物”等的使用,同样适用于本发明化合物的对映异构体、立体异构体、旋转异构体、互变异构体、外消旋物或前体药物的盐、溶剂化物和前体药物。
当在结构式中不止一次出现变量时,例如,当X是-C(OR5)2-时的R5,不止一次出现的各个变量的含义可独立选自这些变量的定义。
单一的异构体可用常规的拆分方法制备,例如,用合适的旋光活性酸处理,分离非对映体,然后回收期望的异构体。另外,单一的旋光异构体可通过不对称合成制备。
另外,在酸(-COOH)或醇基存在的情况下,可使用药学上可接受的酯,如甲基、乙基、丁基、乙酸酯、马来酸酯、特戊酰氧甲基等;以及本领域已知的用于改进溶解度或水解特性的酯,它们用于持续释放或前体药物配方。
在一个实施方案中,本发明提供一种药物组合物,其包括结构式I的化合物,其与药学可接受的载体结合。
在另一个实施方案中,本发明提供一种生产药物组合物的方法,包括将式I化合物与药物可接受的载体混合。
本发明的另一个方面涉及一种治疗认知或神经变性疾病的方法,包括给予患有所述疾病的患者有效量的式I化合物。
本发明的另一个方面涉及治疗认知或神经变性疾病的方法,包括给所述疾病的患者有效量的与乙酰胆碱酯酶抑制剂联合使用的式I化合物。
本发明的另一个方面涉及一种试剂盒,其用于治疗认知或神经变性的疾病,试剂盒包括独立的容器,在一个单独的包装中有用于组合使用的药物化合物,在一个容器有式I乙酰胆碱释放提高化合物,在另一个容器中有乙酰胆碱酶抑制剂,所述化合物和抑制剂分别在药物可接受的载体中,它们结合使用的量是有效量。
式I化合物显示出选择性M2和/或M4毒覃碱拮抗活性,其与治疗认知障碍(诸如阿尔茨海默氏病和老年性痴呆)的药物活性相关。
为了用一种以上活性剂组合治疗,其中活性剂以单独的剂量配方,所述活性剂可以分别给药或组合给药。另外,一种成分可以在另一种药剂给药之前、期间或之后给药。
为了制备药物组合物,将一或多种活性化合物与药学上可接受的惰性载体混合。活性化合物非限制性地包括本发明的化合物、能够提高ACh释放的化合物和ACh酶抑制剂。药学上可接受的载体可以是固体或液体。
固体形式的制剂包括粉末、片剂、可分散的颗粒、胶囊、扁囊剂和栓剂。固体载体可以是一或多种物质,其还可作为稀释剂、增香剂、增溶剂、润滑剂、助悬剂、粘合剂或片剂分裂剂;其还可以是一种包封材料。液体形式的制剂包括溶液、悬浮液和乳状液。例如可以是水或水-丙二醇溶液,其用于胃肠外注射。
含有活性成分的药物组合物可以是适合口服应用的形式,例如片剂、锭剂、糖锭、含水或油性悬浮液、可分散性粉剂或颗粒、乳状液、硬或软胶囊或糖浆剂或酏剂。用于口服的组合物可根据本领域已知的用于生产药物组合物的任一方法制备,这类组合物可含有一种或多种选自甜味剂、增香剂、着色剂和防腐剂的药剂以提供药学上美观且适口的制剂。片剂含有活性成分,其与非毒性药学可接受的适合生产片剂的赋形剂混合。这些赋形剂可以是例如惰性稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;成粒和分裂剂,例如玉米淀粉或藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶,以及润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是无涂层的,或它们可以通过已知的方法涂覆以延迟崩解和在胃肠道中的吸收,从而在较长的时间内提供持续作用。例如,可使用延时材料,如单硬脂酸甘油酯或甘油基二硬脂酸酯。它们也可以通过在US4,256,108、US4,166,452和US4,265,874中所述的方法涂覆,形成控制释放的渗透治疗片剂。
用于口服的配方还可以是硬胶囊,其中活性成分与一种惰性固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合;或是软胶囊,其中活性成分与水或一种油介质(例如花生油、液体石蜡或橄榄油)混合。
水悬浮液含有与适合生产水悬浮液的赋形剂混合的活性物质。这类赋形剂是助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基-纤维素、海藻酸钠、聚乙烯-吡咯烷酮、黄蓍树胶和阿拉伯胶;分散或润湿剂可以是天然存在的磷脂,例如卵磷脂;或烯氧化物与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯;或环氧乙烷与长链脂族醇的缩合产物,例如十七碳烯-鲸蜡醇;或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,如聚氧乙烯山梨糖醇一油酸;或环氧乙烷与衍生自脂肪酸和己糖醇酸酐的偏酯的缩合产物,例如聚乙烯单油酸山梨醇酐酯。水悬浮液还可含有一或多种防腐剂,例如乙基、或正-丙基、对-羟基苯酸酯,一种或多种着色剂,一或多种增香剂,以及一种或多种甜味剂、如蔗糖、糖精或甜味素。
油性悬浮液可通过将活性成分悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(如液体石蜡)中配制。油性悬浮液可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可加入如上所述的甜味剂和增香剂以提供适口的口服制剂。这些组合物可通过加入抗氧化剂(如抗坏血酸)防腐。可分散性粉剂和颗粒适于通过加入水制备水悬浮液,其通过活性成分与分散或润湿剂、助悬剂和一个或多种防腐剂混合制备。合适的分散或润湿剂和助悬剂已举例说明如上。可也存在其它的赋形剂,例如甜味剂、矫味剂和着色剂。
本发明的药物组合物也可以是水包油乳化剂。油相可以是植物油(例如橄榄油或花生油)或矿物油(例如液体石蜡)或它们的混合物。合适的乳化剂可以是天然存在的磷脂,例如大豆磷酯、卵磷脂;衍生自脂肪酸和己糖醇酸酐的酯或偏酯,例如单油酸山梨醇酐酯;和所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨醇单酯。乳状液还可含有甜味剂和调味剂。
糖浆和酏剂可用甜味剂配制,例如甘油、丙二醇、山梨糖醇或蔗糖。这种配方还可含有缓和剂、防腐剂和矫味着色剂。
本发明的化合物或其药物组合物可以是无菌可注射的水或油悬浮液形式。
这种悬浮液可根据已知技术用上述适合的分散或润湿剂和助悬剂配制。无菌的可注射制剂还可以是在无毒药学可接受稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为在1,3-丁烷二醇中的溶液。在可使用的可接受赋形剂和溶剂中,有水、生理盐水和等渗氯化钠溶液。另外,无菌的固定油类通常用作溶剂或悬浮介质。对于该用途,可使用任何无味的固定油,包括合成的单或二酸甘油酯添加剂,脂肪酸(如油酸)可用于可注射制剂中。
本发明的化合物或其药物组合物还可以用于直肠给药的栓剂形式给药。这些组合物可通过将药物与合适的无刺激性的赋形剂混合制备,所述赋形剂在常温下是固体,但在直肠温度是液体,并因此在直肠中融化从而释放药物。
这类材料是可可脂和聚乙二醇。
对于局部应用,可使用含有式I化合物的霜剂、软膏、凝胶、溶液或悬浮液等。(对于这种应用,局部施用应包括洗口药和含嗽液)本发明的化合物或其药物组合物可以通过合适的鼻内赋形剂经鼻内给药局部应用,或通过透皮途径使用本领域普通技术人员公知的透皮贴片给药。通过透皮给药体系给药,在整个给药方案中,给药的剂量当然是连续的而不是间歇的。
本发明的化合物或其药物组合物还可作为栓剂引入,所述栓剂使用的基质例如是可可脂、甘油胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇脂肪酸酯的混合物。
优选药物制剂是单位剂型。在这种形式中,制剂再分成含有适量活性组分的单位剂量。单位剂量可以是包装的药剂,所述包装包括不连续的多个药剂,如在小瓶或安瓿中包装的片剂、胶囊和粉末。单位剂型还可以是胶囊剂、扁囊剂或片剂本身,或可以是适当数量的任何这些剂型在一个包装中的形式。
应用本发明化合物的给药方案根据各种要素选择,包括患者的类型、人种、年龄、体重、性别和体格条件;被处理病症的严重程度;给药途径;患者的肾和肝脏功能;和所使用的特定化合物。普通技能的内科医师或兽医可以容易地确定和处方预防、对抗、抑制或逆转的病症进程所需药物的有效量。使药物最精确地达到在产生疗效而不产生毒性的范围内的浓度,需要一种基于药物达到靶位的动力学的方法。这包括药物的分布、饱和和消除因素。在单位剂量制备中,活性化合物的量可根据特定的应用和活性成分的效价以及要进行的治疗在1mg至100mg改变或调节。这相当于一次剂量为约0.001-约20mg/kg,其可以分为每天1至3次给药。如果希望,该组合物还可含有其它的治疗剂。
本发明的活性剂可有利地以单日剂量给药,或将总日剂量分成每天两次、三次或四次给药。
那些可与载体结合生产单剂型的活性成分的量可根据治疗主体和给药的特定模式改变。
但是,应当认为对于任何特定的患者,具体的剂量浓度取决于各种要素,包括年龄、体重、全身健康条件、性别、饮食、给药时间、给药途径、排泄速度和进行治疗的特定疾病的严重程度。
当式I化合物或能够提高ACh释放的化合物与乙酰胆碱酯酶抑制剂结合使用治疗认知障碍时,这两种活性组分可以同时或相继共同给药,或可以使用单一的药物组合物,该组合物包括在药学可接受的载体中的式I化合物或能够提高ACh释放以及乙酰胆碱酯酶抑制剂。该组合物的成分可以在任何常规的口服或胃肠外剂型中分别或一起给药,所述的剂型例如是胶囊剂、片剂、粉末、扁囊剂、悬浮液、溶液、栓剂、鼻喷剂等。乙酰胆碱酯酶的抑制剂的剂量可以是0.001-100mg/kg体重。
本发明的另一个方面涉及一种治疗认知或神经变性疾病的方法,包括给予患有所述疾病的患者有效量的式I化合物。
本发明的另一个方面涉及治疗认知或神经变性疾病的方法,包括给所述疾病的患者有效量的与乙酰胆碱酯酶抑制剂联合使用的本发明化合物。
本发明的另一个方面涉及治疗认知或神经变性疾病的方法,包括给所述疾病的患者有效量的与乙酰胆碱酯酶抑制剂联合使用的提高乙酰胆碱释放的化合物。乙酰胆碱酯酶抑制剂优选是M2或M4选择性的毒覃碱拮抗剂。
本发明的另一个方面涉及一种用于治疗认知或神经变性疾病的试剂盒。该试剂盒包括独立的容器,其中配置了它们的内容物,其中一个容器装有提高乙酰胆碱释放的化合物,一个单独的容器装有乙酰胆碱酯酶抑制剂。化合物和抑制剂分别处于药学可接受的载体中,它们的配置量是有效量。提高乙酰胆碱释放的化合物优选是M2或M4选择性的毒覃碱拮抗剂。
在此,通过下述制剂和实施例举例说明本发明,它们不应被视为对公开范围的限制。
可供选择的机械途径和类似结构对于本领域技术人员而言是显而易见的。
实施例1:合成化合物No41、47、48、61和62
步骤A:市售的4(4-氟代苄基)哌啶盐酸盐(25g,0.1026mol)溶解并混入含有10%二乙醚(126ml)和10%NaOH(126mol)的溶液中。混合物冷却到0℃,然后滴加二叔丁基重碳酸盐(26.88g,0.1231mol)在Et2O(50ml)中的溶液。混合物在室温搅拌过夜,然后用Et2O(3×200ml)萃取。合并有机层,用MgSO4干燥,然后蒸发至干燥,得到化合物B(30.7g,97%)。
步骤B:氢化钠(4.92g,0.123mol,60%油分散液)悬浮在DMF(50ml)中,随后在0℃在N2下添加2-丙硫醇(9.06ml,0.0976mol)。反应混合物在室温搅拌5分钟后,分批加入化合物B(15g,0.0488mol)。反应混合物加热至65℃6小时,然后冷却到室温。在将200mol的1N NaOH溶液加入混合物中后,搅拌3天让过量的2-丙硫醇氧化。反应混合物然后用Et2O(3×300ml)萃取。合并Et2O相,用NaHCO3干燥,然后蒸发。用Et2O重结晶化合物C(15.8g,89%)。
步骤C:化合物C(15g,04126mol)溶于THF(80ml)。溶液冷却到-78℃后,滴加甲基锂溶液(在乙醚中1.5M,41.26ml,0.0619mol)。反应混合物在室温在N2下搅拌1小时。将饱和NaHCO3溶液(200ml)加入反应混合物,然后用CH2Cl2(3×200ml)萃取。合并有机相,用MgSO4干燥,然后蒸发。得到化合物D(15g,95%)。
步骤D:化合物D(8.0g,0.0211mol)溶解在CH2Cl2(25mol)中,然后加入三氟乙酸(25ml)。反应混合物回流过夜,然后冷却至室温。反应混合物然后用1N NaOH溶液(100ml)稀释。混合物用CH2Cl2(2×100ml)萃取。合并有机相,用NaHCO3干燥,然后蒸发。得到化合物E(5.33g,96%)。
步骤E:将三乙酰氧基硼氢化钠(12.98g,0061mol)加入到化合物E(5.33g,0.02mol)和0.03mol合适的酮在二氯乙烷(100ml)中的溶液中。用于合成化合物41、47、48、61和62的酮分别是环己酮、4-N-丙基环己酮、4-三氟甲基环己酮,3-甲基环己酮用于合成化合物61然后62。这些酮加合到化合物E上,生成化合物F的R2基团。R2具有上述表1所述的含义。反应混合物在N2下在室温搅拌过夜,然后用1N NaOH溶液(200ml)猝灭。反应混合物用CH2Cl2(3×200ml)萃取。合并有机相,用NaHCO3干燥,然后蒸发。用闪蒸塔色谱法(20%EtOAc在己烷中)提纯残留物,得到化合物F(9.22g)。
实施例2:合成化合物No.41、47、48、61和62
使用与实施例1所述相同的方法,除了在步骤B中用2-丙醇代替2-丙硫醇。在步骤E中用于制备化合物No.40和60的酮分别是环己酮和3-甲基环己酮。
实施例3:合成化合物No.7
用与实施例1所述相同的方法进行步骤A-E,其中在步骤E中所用的酮是N-叔丁氧基羰基-4-哌啶酮。然后进行步骤F制备化合物G。
步骤F:化合物F(0.87g,1.956mol)溶于CH2Cl2(5ml),然后加入TFA(5ml)。混合物在室温搅拌1小时,然后蒸发。残留物溶于CH2Cl2(100ml),用1N NaOH溶液洗涤,用NaHCO3干燥,然后蒸发得到化合物G(0.667g,98%)。
实施例4:合成的化合物No.8
使用与实施例3所述相同的方法,除了在步骤B中用2-丙醇代替2-丙硫醇。
实施例5:合成化合物No.3、4、6、11、12、16、17、23、24、27、28、37和49
用与实施例3所述相同的方法进行步骤A-F。然后进行步骤G制备化合物H。
步骤G:一般过程:化合物G(100mg,0.29mmol)溶于CH2Cl2(5ml)后,加入相应的酸(1.5当量)、EDCl(200mg,1毫摩尔)、DMAP(5mg)。反应混合物在室温在N2下搅拌过夜。产物酰胺(化合物H)通过制备薄层色谱法(7%MeOH在CH2Cl2中)。
实施例6:合成化合物No.1、2、10、42、43、44和63
使用与实施例5所述相同的方法,除了在步骤B中用2-丙醇代替2-丙硫醇。
实施例7:合成化合物No.5、13-15、18-22、25-26、29-36、38、39、54、55、58、59和64
用与实施例5所述相同的方法进行步骤A-G。然后进行步骤H制备化合物I。
步骤H:在步骤G中制备的酰胺(100mg,0.207mol)溶于乙酸(4ml),随后添加过硼酸钠四水合物(70mg,0.456mol,2.2当量)。反应混合物在室温搅拌过夜,然后用1N NaOH溶液(50ml)猝灭。反应混合物用CH2Cl2(2×50ml)萃取。合并有机相,用NaHCO3干燥,然后蒸发。
亚砜和砜通过制备薄层色谱法(7%甲醇在CH2Cl2中)分离。
实施例8:合成化合物No.45-46、50-53、56、57、63、66、67和68
用与实施例1和3所述相同的方法进行步骤A-F。然后按实施例7所述进行步骤H制备化合物J。用于制备化合物No.45-46;50-51;52-53、63和66-68;和56-57的酮分别是环己醇、4-甲基环己醇;3-甲基环己醇;和4-异丙基环己醇。
实施例9:合成化合物No.69-70
按实施例8所述相同的方法制备化合物J,除了在步骤B中用4-甲氧基苯硫醇代替2-丙硫醇。用于在步骤E制备化合物No.69-70的酮是3-甲基环己醇。
实施例10:合成化合物No.71
按实施例8所述相同的方法制备化合物J,除了在步骤B中用3-甲氧基苯硫醇代替2-丙硫醇。用于在步骤E制备化合物No.69-70的酮是3-甲基环己醇。
如有必要或需要,可在上述反应后进行一个或多个下列步骤;(a)从这样生产的化合物除去任何保护基;(b)将这样生成的化合物转化为药学可接受的盐、酯和/或溶剂化物;(c)将这样生成的式I化合物转化为另一种式I化合物和(d)分离式I化合物,包括分离式1的立体异构体。
基于上述反应过程,本领域技术人员能够选择生产任何式I化合物所需的起始原料。
在上述过程中,在反应期间有时需要和/或必须保护某些基团。可使用常规的本领域技术人员所熟知的保护基。在反应后,保护基可用标准方法除去。
在上述方法或这些方法的改进中使用的合适原料是本领域技术人员熟知的,可制备下述化合物表格中所列的化合物。
化合物表
在所设计的用于显示M1和M2毒覃碱拮抗剂活性的测试过程中,式I化合物显示出药理活性。在药学治疗剂量,该化合物是无毒的。下温描述测试过程。
毒覃碱结合活性
测试所研究化合物抑制与细胞株人M1、M2、M3、M4和M5毒蕈碱性受体亚型结合的能力。在这些研究中,受体的来源是稳定转染CHO细胞系的膜,该所述细胞系表达了各个受体亚型。在培养后,将细胞粒化,随后用Poltron将其在50体积冷10mM钠/K磷酸盐缓冲液、pH7.4(缓冲剂B)中均化。在4℃以40,000Xg离心均化物20分钟。清除得到的上层清液,将颗粒再悬浮在缓冲剂B中,最终浓度为20mg湿组织/ml。这些膜在-80℃储存,直到在下式结合试验中使用。
用3H-奎宁环基二乙醇酸酯(QNB)与细胞株人毒蕈碱性受体进行结合(Watson等人,1986)。简而言之,膜(对于含M1、M2和M4的膜分别为约8、20和14pg蛋白质样品)用3H-QNB(100-200pM最后浓度)培养,在2ml的最终体积中在25℃提高未标记药物的浓度90分钟。在1uM阿托品存在下检验非特异性的结合。通过在GF/B玻璃纤维过滤器上使用Skatron过滤装置真空过滤结束培养,过滤物用冷的10mM Na/K磷酸盐缓冲剂(pH 7.4)洗涤。将闪烁剂加入到过滤物中,小瓶培养培养过夜。在液体闪烁计数器(50%效率)中测定结合放射性配体。用EBDA计算机程序(McPherson,1985)分析所得数据的IC50值(即,50%抑制结合所需的化合物浓度)。然后用下式(Cheng and Prusoff,1973)确定亲合值(Ki);
因此,Kj值越低,显示结合亲合性越大。
为了确定化合物结合特定毒蕈碱性受体的选择性,用第一种毒蕈碱性受体的Ki值除以另一种毒蕈碱性受体的Kj值。例如,当M1受体的Ki值除以M2受体的Kj值时,越高的比例显示出对M2毒蕈碱性受体结合的选择性越大。
对于化合物表格中的化合物,对于M2受体,毒覃碱拮抗活性的范围在约0.295-168.15nM。
虽然已经结合上述具体实施方案描述了本发明,但是对于对本领域普通技术人员而言,它们的许多替代、改进或其它变化是显而易见的。所有这些替代、改进和变化也属于本发明的精神和范围。
Claims (17)
1.一种具有下述通式I的化合物:
或该化合物的药学可接受盐或溶剂化物,其中:
Z是N;
X是-O-、-S-、-SO-或-S(O)2-;
R是
R2是
R3是1至5个取代基,其可以相同或不同,各个所述的取代基是烷氧基或卤素;
R4是H或1至3个取代基,所述取代基可以相同或不同,各个所述取代基是烷基或卤代烷基;
R27是氢或1或2个烷基;
R28是氢或1或2个烷基;
R29是氢、烷基、-C(O)-烷基、-C(O)-环烷基、烷氧羰基、氨基羰基、芳氧基羰基、烷基氨基羰基、烷基磺酰基、芳基磺酰基或-SO2-NH-R35;
R31是氢或1或2个烷基;
R32是氢或1或2个烷基;
R33是芳基或杂芳基,条件是当R33是杂芳基时,C(O)-R33键是R33基团中的碳原子;
和R35是氢、芳基或烷基,
其中烷基是直链或支链的且链包括1-6个碳原子的脂族烃基;
其中芳基是具有6-10个碳原子的芳族单环或多环环系。
3.根据权利要求2的化合物或所述化合物的药学可接受盐或溶剂化物,其具有下式:
6.根据权利要求2的化合物或所述化合物的药学可接受盐或溶剂化物,其具有下式:
8.根据权利要求2的化合物或所述化合物的药学可接受盐或溶剂化物,其具有下式:
10.根据权利要求2的化合物或所述化合物的药学可接受盐或溶剂化物,其具有下式:
14.一种药物组合物,其包括与药学可接受的载体结合的权利要求1定义的化合物。
15.制备药物组合物的方法,包括将权利要求1化合物与药物可接受的载体混合。
16.权利要求1的化合物在制备治疗认知或神经变性疾病的药物中的用途。
17.一种试剂盒,其用于治疗认知或神经变性的疾病,试剂盒包括独立的容器,在一个容器中有根据权利要求1的化合物,所述化合物在药物可接受的载体中。
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US7700603B2 (en) | 2003-12-15 | 2010-04-20 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
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