CN1183129C - 作为加压素激动剂的稠合氮杂� - Google Patents
作为加压素激动剂的稠合氮杂� Download PDFInfo
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- CN1183129C CN1183129C CNB018031323A CN01803132A CN1183129C CN 1183129 C CN1183129 C CN 1183129C CN B018031323 A CNB018031323 A CN B018031323A CN 01803132 A CN01803132 A CN 01803132A CN 1183129 C CN1183129 C CN 1183129C
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- Prior art keywords
- compound
- pharmaceutically useful
- useful salt
- methyl
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- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- 238000006482 condensation reaction Methods 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
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- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- YNKFCNRZZPFMEX-XHPDKPNGSA-N desmopressin acetate trihydrate Chemical compound O.O.O.CC(O)=O.C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 YNKFCNRZZPFMEX-XHPDKPNGSA-N 0.000 description 1
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 1
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- 238000010790 dilution Methods 0.000 description 1
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- 239000000284 extract Substances 0.000 description 1
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- 230000002349 favourable effect Effects 0.000 description 1
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- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
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- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
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- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- XTZCVWDSGCVDFI-UHFFFAOYSA-N methyl 4-(bromomethyl)-3-chlorobenzoate Chemical compound COC(=O)C1=CC=C(CBr)C(Cl)=C1 XTZCVWDSGCVDFI-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229940028441 minirin Drugs 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 101150078860 pho gene Proteins 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- 239000000047 product Substances 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- 230000001718 repressive effect Effects 0.000 description 1
- 231100000817 safety factor Toxicity 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明提供了如通式(1)的新型化合物,其中A是二环或三环氮杂䓬衍生物,V<sup>1</sup>和V<sup>2</sup>都是H、OMe或F,或V<sup>1</sup>和V<sup>2</sup>中的一个是Br、Cl、F、OH、OMe、OBn、OPh、O-酰基、N<sub>3</sub>、NH<sub>2</sub>、NHBn或NH-酰基,另一个是H,或V<sup>1</sup>和V<sup>2</sup>一起是=O、-O(CH<sub>2</sub>)<sub>p</sub>O-或-S(CH<sub>2</sub>)<sub>p</sub>S-;W<sup>1</sup>是O或S;X<sup>1</sup>和X<sup>2</sup>都是H,或一起是=O或=S;Y是OR<sup>5</sup>或NR<sup>6</sup>R<sup>7</sup>;R<sup>1</sup>、R<sup>2</sup>、R<sup>3</sup>和R<sup>4</sup>分别选自H、低级烷基、低级烷氧基、F、Cl和Br;R<sup>5</sup>选自H和低级烷基;R<sup>6</sup>和R<sup>7</sup>独立地选自H和低级烷基,或一起是-(CH<sub>2</sub>)<sub>n</sub>-;n=3、4、5、6;以及p是2或3。该化合物是加压素V<sup>2</sup>受体激动剂,可被用作抗利尿剂和前凝血质。本发明进一步包含混有这些加压素激动剂的药物组合物,该组合物在治疗中枢性尿崩症、夜间遗尿和夜尿症中尤其有用。∴
Description
本发明的技术领域
本发明涉及一种作为肽激素加压素的新的化学实体。它们可以减少肾的排尿量,因此它们可用于治疗以多尿症为特征的某些人类疾病。它们也可以用于控制小便失禁和出血机能紊乱。
本发明的背景技术
加压素是一种由垂体后叶腺分泌的肽激素。它作用于肾以增加水潴留,因此可以减少排尿量。因此,加压素又被称为“抗利尿激素”。它还作用于脉管系统,在该系统中产生高血压作用。控制这两种作用的细胞受体各有特性,是不相同的。抗利尿作用是通过一般被称为V2受体的2型加压素受体来实现的。能与V2受体相互作用,且以与加压素相同的方式作用于V2受体的物质被称为V2受体激动剂(或简称为V2激动剂)。这种物质也会有抗利尿作用。如果这些物质选择性的与V2受体作用而不与其它的加压素受体亚型相互作用,那么它们就不会有加压素的高血压作用。这将是一个重要的安全因素,正是这一点使得该类物质在治疗以多尿症(这里指的是形成过多的尿)为特征的人类疾病中很有吸引力。
加压素
实际上,该类物质已经用于人类治疗。去氨加压素(或[1-脱氨基(desamino),D-Arg8]加压素,MinirinTM,DDAVPTM)是一种加压素的肽类似物,它是一种选择性的V2受体激动剂。它被用于治疗中枢性尿崩症,它是由于加压素分泌不足而导致的一种疾病。它也被用于控制夜间遗尿,还可以用于控制夜尿症。但是,去氨加压素并不是在所有的情况中都是一种理想的物质。即使其目前最优的合成方法也很冗长,并且去氨加压素不适用于最方便的纯化技术如结晶。因此,去氨加压素相对较为昂贵。它的口服生物利用度很低,且该参数有一定的可变性。
总而言之,需要一种易于制备和纯化的选择性加压素V2受体激动剂,且该物质具有较高且可以预知的口服生物利用度。该性质是非肽化合物最希望获得的。这一考虑因素导致其它的研究小组对非肽加压素V2激动剂进行研究,这些研究成果被公开于例如国际专利申请WO97/22591、WO99/06403、WO99/06409、WO00/46224、WO00/46225、WO00/46227和WO00/46228中。但是在这些文献中公开的化合物都不太理想。尤其是它们的口服生物利用度都很低,这可能部分地是由于它们的低水溶性。本发明提供了具有改善的溶解度和生物利用度的化合物。
除了其抗利尿作用外,去氨加压素还被用于增加血中被称为因子VIII和冯威勒布兰特(von Willebrand)因子的凝固蛋白的浓度。在临床上,该种作用使得去氨加压素可用于治疗A型血友病和冯威勒布兰特疾病。本发明的非肽激动剂也具有类似的应用。
本发明的概述
正如这里所公开的,本发明涉及一系列加压素的非肽激动剂化合物,该类化合物选择性的作用于V2受体亚型。该类化合物可以用通式1表示
其中:
A是选自通式2至7的二环或三环氮杂衍生物
A1、A4、A7和A10分别独立地选自CH2、O和NR8;
A2、A3、A9、A11、A13、A14和A15分别独立地选自CH和N;
A5是共价键且A6是S,或A5是N=CH且A6是共价键;
A8和A12分别独立地选自NH和S;
A16和A17都是CH2,或A16和A17中一个是CH2,另一个选自O、SOx、以及NR8,
V1和V2都是H、OMe或F,或V1和V2中的一个是Br、Cl、F、OH、OMe、OBn、OPh、O-酰基、N3、NH2、NHBn或NH-酰基,另一个是H,或V1和V2一起是=O、-O(CH2)PO-或-S(CH2)pS-;
W1是O或S;
X1和X2都是H,或一起是=O或=S;
Y是OR5或NR6R7;
Z是S或-CH=CH-;
R1、R2、R3和R4独立地选自H、低级烷基、低级烷氧基、F、Cl和Br;
R5选自H和低级烷基;
R6和R7独立地选自H和低级烷基,或一起是-(CH2)n-;
R8是H或低级烷基;
n=3、4、5或6;
p是2或3;和
x是0、1或2。
本发明进一步包含混有这些加压素激动剂的药物组合物,该组合物在中枢性尿崩症、夜间遗尿以及夜尿症的治疗中特别有用。
本发明的详细描述
本发明包含如通式1所定义的N-苄基氨基甲酰吡咯烷衍生物。
在该分子式中,A代表通式2-7中之一的二环或三环氮杂基团。
A1、A4、A7和A10代表选自亚甲基(-CH2-)、氧(-O-)和被取代的氮(-NR8-)的二价基团。A2、A3、A9、A11、A13、A14和A15代表N原子(-N=)或次甲基(-CH=)。A5可以代表一个共价键,在这种情况下A6代表一个硫原子(-S-),包含这样两个基团的环是一个噻吩环。另外一种情况是A5可以代表-N=CH-基团,A6代表一个共价键,包含这样两个基团的环是一个吡啶环。A8和A12代表-NH-或硫原子(-S-)。A16和A17代表二价基团。二者可以都是亚甲基(-CH2-)或一个是亚甲基而另一个选自羟基亚甲基(-CH(OH)-)、二氟亚甲基(-CF2-)、氧(-O-)、取代的(-NR8-)和硫或氧化硫(-S-、-SO-、或-SO2-)。
V1和V2可以都是氢、甲氧基或氟,或假如一个为氢时,另一个选自溴、氯、氟、羟基、低级烷氧基、苄氧基、苯氧基、酰氧基、叠氮基、氨基、苄氨基和酰胺基(Br、Cl、F、OH、O-低级烷基、OBn、OPh、O-酰基、NH2、NHBn和NH-酰基),或V1和V2一起可以代表一个氧原子,这样的片段CV1V2是一个羰基(C=O)。V1和V2也可以是亚乙基或亚丙基二氧或二硫链(-O(CH2)2O-,-O(CH2)3O-,-S(CH2)2S-,-S(CH2)3S-),这样的CV1V2是1,3-二氧戊环、1,3-二噁烷、1,3-二硫戊环或1,3-二噻烷环(dithiane ring)。
W1是氧或硫原子。
X1和X2都是氢,或者一起代表一个氧或硫原子,这样的片段CX1X2是羰基或硫代羰基(C=O或C=S)。
Y是基团-OR5或基团-NR6R7。
Z代表硫原子或基团-CH=CH-,代表硫原子时包含该原子的环为噻吩环,代表-CH=CH-时包含该原子的环为苯环。
R1、R2、R3和R4分别独立地选自氢、低级烷基、低级烷基氧和卤素氟、氯以及溴。
R5可以是氢原子或低级烷基。
R6和R7可以分别独立地是氢原子或低级烷基,或它们一起可以形成一个有3到6个亚甲基的链,该链与和它们相连的氮原子相结合,形成氮杂环丁烷、吡咯烷,哌啶或全氢化氮杂环。
R8可以是氢或低级烷基。
在本公开文本中,术语“低级烷基”指的是有1至6个碳原子的直链和支链烷基以及环烷基。例如甲基、乙基、异丙基、叔丁基、新戊基和环己基都在术语低级烷基的范围之内。术语“酰基”指的是低级烷基羰基,如乙酰基、新戊酰基、环丙基羰基等。甲酰基也被认为是一种酰基基团。
通式1中的某些化合物可以与酸或碱形成盐。例如包含一个或多个氮原子的化合物可以与无机酸和有机酸如盐酸、硫酸、磷酸、醋酸、三氟醋酸、甲磺酸、柠檬酸以及苯甲酸形成加合盐(addition salts)。含有酸性基团的化合物可以与碱形成盐。该种盐的例子包括钠盐、钾盐、钙盐、三乙铵盐以及四乙铵盐。此外,同时拥有酸性基团和碱性基团的化合物可以形成内盐(两性离子(zwiterions))。这些盐都是可药用盐,它们都包括在本发明的范围之内。
通式1的化合物都有至少一个立体中心(一个四面体碳原子有四个不同的取代基),因此可以以光学异构体如对映异构体以及非对映异构体的形式存在。这样的异构体及其混合物都在本发明的范围之内。
在本发明的优选实施方案中,A是如通式2所示的基团。在本发明的另一个优选的实施方案中,A是如通式3所示的基团。在本发明的另外一个优选的实施方案中,A是如通式4所示的基团。在本发明的另外一个优选的实施方案中,A是如通式5所示的基团。在本发明的另外一个优选的实施方案中,A是如通式6所示的基团。
在本发明的另外一个优选的实施方案中,A是如通式7所示的基团。在更优选的实施方案中,A是四氢-1-苯并氮杂-1-基基团,即如通式7所示的基团,其中Z是-CH=CH-,且A16和A17都是亚甲基。
在另外一个优选的实施方案中,R1和R2中的一个是氯或甲基,另外一个是氢,R3和R4也都是氢。
在另外一个优选的实施方案中,V1和V2中的一个是甲氧基或苄氧基,另外一个是氢。
在又一个优选的实施方案中,X1和X2一起代表一个氧原子,且Y是-NR6R7。
本发明尤其优选的实施方案是这些结合了两个或更多个上述优选特征的方案。
本发明仍然更优选的实施方案是如通式8所示的化合物。
在通式8中,W1、R5和R6的定义同通式1中的定义相同。Ra和Rb中的一个是氢,另一个是氯或甲基。Rc是甲基或苄基。
本发明仍然更优选的实施方案是如通式8A所示的化合物,其中表明了其立体化学。
本发明另一个优选的实施方案是如通式1所示的化合物,其中V1和V2都是氢。在更优选的实施方案中,X1和X2一起是氧原子且Y是NR6R7。仍然是更优选的实施方案的是如通式9所示的化合物。
在通式9中,W1、R5和R6的定义同通式1中的定义相同。Ra和Rb中的一个是氢,另一个是氯或甲基。
甚至更优选的是如通式9A的化合物,其中表明了其立体化学。
本发明中个别优选的化合物包括(但不限于)如下的化合物:
1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-L-脯氨酸-N,N-二甲基酰胺,
(4R)-4-羟基-1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-L-脯氨酸-N,N-二甲基酰胺,
(4R)-1-(3-氯-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-4-甲氧基-L-脯氨酸-N,N-二甲基酰胺,
(4R)-1-(2-氯-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-4-甲氧基-L-脯氨酸-N,N-二甲基酰胺,
(4R)-4-苄氧基-1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基-氨基甲酰氨基)-L-脯氨酸-N,N-二甲基酰胺,
(4R)-4-甲氧基-1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-L-脯氨酸-N,N-二甲基酰胺,
(4R)-4-甲氧基-1-(3-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-L-脯氨酸-N,N-二甲基酰胺,
(4R)-1-(2-氯-4-(5,6,7,8-四氢-4H-噻吩并[3,2-b]氮杂-4-基羰基)苄基氨基甲酰基)-4-甲氧基-L-脯氨酸-N,N-二甲基酰胺,
(4R)-1-(4-(10,11-二氢-5H-吡咯并[2,1-c](1,4)苯并二氮杂-10-基羰基)-2-甲基苄基氨基甲酰基)-4-甲氧基-L-脯氨酸-N,N-二甲基酰胺,
(4R)-1-(2-氯-4-(10,11-二氢-5H-吡咯并[2,1-c](1,4)苯并二氮杂-10-基羰基)-苄基氨基甲酰基)-4-甲氧基-L-脯氨酸-N,N-二甲基酰胺,和
(4R)-1-(4-(10,11-二氢-5H-吡咯并[2,1-c](1,4)苯并二氮杂-10-基羰基)-2-甲基-苄基氨基甲酰基)-4-甲氧基-L-脯氨酸-N,N-二甲基硫酰胺。
本发明的化合物可以用现有技术中已知的一般方法来进行制备。通式1的化合物可以被认为是由三个相连接的片段(A-C)所组成。
这三个片段一般是分别制备,然后在后面的合成步骤中结合在一起。各种基团(R1-R4、V1、V2、X1、X2等等)的一些例子可能在该组合中不能互容,因此需要使用保护基团。
保护基团的使用在现有技术中是公知的(见例如“有机合成中的保护基团”,T.W.Greene,Wiley-Interscience,1981)。需要保护的特定基团有胺(酰胺或氨基甲酸酯保护)、醇(以酯或醚保护)以及羧酸(以酯保护)。以便于讨论的观点而言,可以假定这些保护基团是按需要设置的了。
片段A、B和C可经过两种策略结合在一起以给出分子式1的化合物。在第一种策略中,片段A和B相互连接给出相应的片断AB,然后将该片段与片段C相结合。在第二种策略中,片段B和C相互连接给出相应的BC,然后该片段再与片段A相结合。在片段A与片段B以及片段B与片段C缩合过程中包含的化学过程在任何一个策略中都是相同的。我们发现当用于小规模生产和制备有选择的化合物时,第一种策略更为灵活。虽然如此,在大规模制备所选择的化合物时第二种策略可能更为有利。
片段AB的形成
在这里,{A}和{B}分别代表了片段A和B的部分结构。通过羧酸与胺的缩合反应形成酰胺是众所周知的。一般而言是在存在缩合剂的条件下,将酸和胺在非质子溶剂中混合,其中所说的非质子溶剂如二氯甲烷或二甲基甲酰胺,其中所说的缩合剂如碳二亚胺(例如“水溶性碳二亚胺”,它是N-乙基-N-(3-二甲基氨基丙基)碳二亚胺)或活性的磷衍生物(例如“BOP”,它是(苯并三唑-1-基氧)三(二甲基氨基)鏻六氟磷酸盐)。该反应可以任选地被叔胺如三乙胺或4-二甲基氨基吡啶所催化。除此之外的另一种方法是,羧酸可以被转换成一种更具反应活性的衍生物,如酰氯。然后用该种衍生物与如上所描述的胺反应,但并不需要缩合剂。
片段BC的形成
在片段B和C之间形成脲或硫脲键可以通过将与片段B相对应的伯胺与碳酸衍生物反应形成氨基甲酸衍生物中间体而很容易地完成,其中所说的碳酸衍生物如phogene(其中上述LG是氯)或羰基二咪唑(其中LG是1-咪唑基)。当W1是硫而不是氧时,使用二氯硫化碳或硫代羰基二咪唑。该反应一般在存在叔胺如三乙胺或N,N-二异丙基乙胺的情况下在非质子溶剂中进行,其中所说的非质子溶剂如二氯甲烷或二甲基甲酰胺。在经过足够的时间形成中间体后,向反应混合物中加入与片段C相应的仲胺。不需要将氨基甲酸酯衍生物中间体分离出来。
作为该过程的一种变化形式,可以将与片段B和C相应的胺的加入顺序颠倒过来,这样就由仲胺形成了氨基甲酸酯衍生物,随后再加入伯胺。
总的来说,合成本发明的化合物需要下述中间体
i)对于片段A
这些通式中的稠合氮杂可以用以下文献中所报道的方法来进行制备:Aranapakam等,Bioorg.Med.Chem.Lett.1993,1733;Artico等,Farmaco.Ed.Sci.24,1969,276;Artico等,Farmaco.Ed.Sci.32,1977,339;Chakrabarti等,J.Med.Chem.23,1980,878;Chakrabarti等,J.Med.Chem.23,1980,884;Chakrabarti等,J.Med.Chem.32,1989,2573;Chimirri等,Heterocycles 36,1993,601;Grunewald等,J.Med.Chem.39,1996,3539;Klunder等,J.Med.Chem.35,1992,1887;Liegéois等,J.Med.Chem.37,1994,519;Olagbemiro等,J.Het.Chem.19,1982,1501;Wright等,J.Med.Chem.23,1980,462;Yamamoto等,Tet.Lett.24,1983,4711;和公开号为WO99/06403的国际专利申请。
它们中的一些已经商品化。
ii)对于片段B
由于伯胺和羧酸基团不相容,所以它们必须被分别形成并被保护起来。取代的苯甲酸是众所周知的,羧酸一般用其甲基醚的形式来进行保护。伯胺可以用相应的腈(通过还原)和醇(通过用氮亲核试剂取代)来加工获得。最好的方法视取代基R1-R4的性质而定。
iii)对于片段C
这种类型的吡咯烷衍生物是根据文献中所描述的方法进行制备的。例如参见Dugave等,Tet.Lett.39,1998,1169;Petrillo等,J.Med.Chem.31,1988,1148;和Smith等,J.Med.Chem.31,1988,875。
所定义的立体化学的脯氨酸和羟脯氨酸衍生物是商业化的物质,且是方便的起始材料。
本发明进一步包含药物组合物,该组合物包括至少一种上述化合物作为活性组分。该组合物也可以包含如解痉剂或钾通道阻滞剂之类的第二种药理学物质,在现有技术中已知这些物质可以改善膀胱功能紊乱。优选地,该组合物仅仅包括一种活性组分。该组合物可以包括选自粘合剂、填充剂、分散剂、溶剂、稳定剂等的赋形剂,这些赋形剂在现有技术中都是已知的。
使用的赋形剂取决于想要得到的制剂的性质,该制剂的性质又取决于想要给药的途径。可以口服给药、经粘膜给药(transmucosal)(如舌下给药、颊给药、鼻内给药、阴道给药以及直肠给药)、经皮给药或注射给药(如皮下注射、肌肉注射和静脉注射)。一般优选口服给药。对口服给药而言,制剂应当是片剂或胶囊剂。其它的制剂包括干粉末剂、溶液剂、混悬剂、栓剂等等。
另一方面,本发明是一种治疗或控制某种人类生理功能紊乱的方法。该方法包括给需要这种治疗的病人使用有效剂量的药物组合物,该组合物包含如前所述的化合物作为活性组分。该化合物可以通过减少尿的产生量而起作用,所以本发明的方法可用于尿量增加是疾病主要因素的所有情况中。该化合物也可以增加被称为因子VIII和冯威勒布兰特因子的血凝固蛋白的生成量,因此可用于治疗出血紊乱。
在优选的实施方案中,被治疗的疾病是尿崩症。这是一种由于机体不能产生和分泌生理活性加压素,从而导致水的重新摄取被大量减少而尿量大量增加而引起的疾病。
在另一个优选的实施方案中,被治疗的疾病是夜间遗尿。该疾病被定义为当病人睡觉时膀胱排空。该种情况主要影响儿童,包含了大量的病原学因素。
在另外一个优选的实施方案中,被治疗的疾病是夜尿症。该疾病被定义为在夜间有丰富的尿产生需要病人起床排空膀胱。该种情况也是大量因素作用的结果。
在另一个优选的实施方案中,被治疗的疾病是失禁。该种情况部分地是以减少膀胱容量和控制能力为特征,且除非频繁排空膀胱,否则会出现无意识的排尿行为。失禁被分为两种情况,压迫性(stress)失禁和驱动性失禁(urge incontinence)。认为该种疾病包含了大量的病原学因素。为了使失禁的病人保持几个小时的干燥(如多至四个小时),本发明的治疗在延迟膀胱排空(“排泄延迟”)(“voiding postponement”)的需要方面尤其有用。这种排空延迟也可以用于非失禁群体,例如对于被迫留在延长时间的会议上的人。
在另一个优选的实施方案中,被治疗的疾病是A型血友病或冯威勒布兰特疾病。在该种疾病中因子VIII或冯威勒布兰特因子的产生被减少,病人遭受持续的出血。
在另一个优选的实施方案中,该组合物在外科手术(包括牙科外科手术)前被给药以增加血液的凝固性,从而减少周围操作(peri-operative)的血液损失。
本发明组合物的给药一般在医师的控制下使用。医师会考虑病人的身体状况和治疗目标而决定该组合物的给药剂量和服用方案。对于成年尿崩症病人而言,典型的剂量可为每天50mg到1g的活性化合物,可视为一天一片或最多至四片药物片剂。对于除口服给药之外的其它给药途径而言,由于非口服途径可能是治疗物质进入循环系统的更为有效的途径,所以化合物的数量将被减少。例如治疗A型血友病和冯威勒布兰特疾病的化合物的量可能高于治疗尿崩症所需的化合物的量。
现在用一些非限制性的实施例对上面的概述进行进一步的阐述。
实施例
缩写
本文使用如下的缩写。
Ac 乙酰基
AIBN 偶氮-二-(异丁腈)
Bn 苄基
BOC 叔丁氧基羰基(Butyloxycarbonyl)
(BOC)2O 二碳酸二叔丁酯(Di-tert-butyl dicarbonate)
DMF 二甲基甲酰胺
Et 乙基
EtOAc 乙酸乙酯
IPA 异丙醇
iPr 异丙基
M.S. 质谱
Me 甲基
NBS N-溴代丁二酰亚胺
pet.ether 石油醚,沸点在60-80℃的馏分
Ph 苯基
tBu 叔丁基
THF 四氢呋喃
WSCDI 水溶性碳二亚胺
中间体的制备
与片段A和C相应的反应物可以从商业上获得或用除在特定实施例中详细描述的方法之外的已公开的方法进行制备。
与片段B相关的反应物的制备如下所述。
实施例A
3-氯-4-(叔丁氧基羰基氨基甲基)苯甲酸
A1.3-氯-4-溴甲基苯甲酸甲酯
向3-氯-4-甲基苯甲酸甲酯(5.0g,27.1mmol)在四氯化碳(50ml)的溶液中加入NBS(5.8g,32.0mol)和AIBN(0.442g,2.70mmol)。将混合物搅拌下回流18小时。将混合物冷却到室温,然后真空浓缩。将残余物在硅胶上(洗脱剂EtOAc∶pet.ether 0∶100至5∶95)用快速柱层析法进行纯化;收率5.96g(84%)。
A2.3-氯-4-(叔丁氧基羰基氨基甲基)-苯甲酸
向氨水在乙醇(170ml)中的饱和溶液中加入由实施例A1获得的3-氯-4-溴甲基苯甲酸甲酯(5.5g,20.9mmol)。将混合物在室温下搅拌1小时,然后在真空下浓缩。将残余物用乙醚研制,然后将白色结晶生成物过滤,用更多的乙醚洗涤。向该固体的水溶液(100ml)中加入(BOC)2O(5.0g,23.0mmol)的二噁烷溶液(100ml)和氢氧化钠(1.86g,46.0mmol)的水溶液(100ml)。将该混合物在室温下搅拌18小时,然后在真空下浓缩。将水性残余物用柠檬酸酸化,然后用氯仿/IPA萃取。将有机层用水洗涤,用MgSO4干燥,然后真空浓缩得到白色固体;收率2.8g(67%)。
实施例B
3-甲基-4-氰基苯甲酸
在-78℃,氮气环境下向2-甲基-4-溴苄腈(2.0g,10.2mmol)在THF(100ml)中的溶液中滴加2.5M的正丁基锂(4.48ml,11.2mmol)溶液。将混合物在-78℃下搅拌1小时,然后倾倒入在THF(50ml)中的固体二氧化碳(5g)中。使混合物升温到室温。向其中加入水(200ml),然后用乙醚对混合物进行萃取(3次)。向水层中加入浓盐酸进行酸化然后用氯仿进行萃取(3次)。将合并的氯仿萃取物用水洗涤,用MgSO4干燥,然后真空浓缩,得到白色固体;收率1.2g(73%)。
实施例C
2-甲基-4-氰基苯甲酸
3-甲基-4-溴苄腈(2.0g,10.2mmol)根据实施例B的方法反应得到黄色固体,该固体用己烷研制,然后过滤;收率0.96g(59%)。
将与片段A、B和C相关的试剂结合,给出如下详细描述的特定实施例。
实施例1
1-(2-甲基-4-(2,3,45-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-L-脯
氨酸-N,N-二甲基酰胺
1A.2-甲基-4-((2,3,4,5-四氢-1H-苯并[b]氮杂)-1-羰基)苄腈
向2,3,4,5-四氢-1H-苯并[b]氮杂(0.80g,5.44mmol)在二氯甲烷(50ml)中的溶液中加入3-甲基-4-氰基苯甲酸(0.96g,5.95mmol)、三乙胺(0.60g,5.95mmol)、4-(二甲基氨基)吡啶(0.73g,5.95mmol)和WSCDI(1.24g,6.48mmol)。将混合物在回流下搅拌18小时,然后冷却,在真空下蒸发干燥将残余物在EtOAc和1MKHSO4中进行分配。将有机层用饱和碳酸氢钠溶液和盐水洗涤,用MgSO4干燥,然后在真空下浓缩。在硅胶上对粗品用快速柱层析进行纯化(洗脱剂EtOAc∶pet.ether 30∶70);收率1.10g(70%)。
1B.1-(4-(氨基甲基)-3-甲基苯甲酰基)-2,3,4,5-四氢-1H-苯并[b]氮杂盐
酸盐
向实施例1A的氰基苯并氮杂(1.10g,3.79mmol)在甲醇(50m1)中的脱气溶液中加入浓盐酸(0.98ml,11.3mmol)和10%碳钯(palladiumon carbon)(0.80g)。通过在室温下搅拌5小时脱氢气。用才利特(celite)衬垫过滤除去催化剂,将滤液蒸发;收率1.23g(98%)。
1C.1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰
基)-L-脯氨酸-N,N-二甲基酰胺
在氮气氛围下,向实施例1B的胺(0.10g,0.302mmol)在DMF(10ml)中的溶液加入N,N-二异丙基乙胺(43mg,0.332mmol)和羰基二咪唑(0.074g,0.453mmol)。混合物在室温下搅拌40分钟。向其中加入脯氨酸-N,N-二甲基酰胺(0.107g,0.756mmol)在DMF(1ml)中的溶液。混合物在室温下再搅拌16小时。真空下将溶剂除去,在硅胶上对粗品用快速柱层析进行纯化(洗脱剂甲醇∶二氯甲烷5∶95);收率0.115g(82%)。
1H NMR(CDCl3):δ1.35-1.55(1H,m),1.74-2.10(3H,m),2.11(3H,s),2.17-2.35(1H,m),2.60-2.82(2H,m),2.86(3H,s),2.90-3.14(2H,m),3.05(3H,s),3.26(1H,dd,J=14.9 & 7.2Hz),3.40-3.53(1H,m),3.64-3.84(1H,m),4.03-4.19(1H,m),4.29-4.42(1H,m),4.55-4.68(1H,m),4.74-4.81(1H,m),4.85-4.98(1H,m),6.58(1H,d,J=7.7Hz),6.75-6.89(2H,m),6.91-7.06(3H,m),7.16(1H,d,J=6.5Hz),7.93-8.03(1H,m)ppm。
M.S.:计算值m/e=462.26;实测值[M+H]+=463.2
实施例2
(4R)-4-羟基-1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基
甲酰基)-L-脯氨酸-N,N-二甲基酰胺
2A.L-反式-4-羟基脯氨酸-N,N-二甲基酰胺盐酸盐
向BOC-羟脯氨酸(2.99g,13.89mmol)在二氯甲烷(100ml)中的溶液加入N,N-二异丙基乙基胺(3.7ml,21.24mmol)、4-(二甲基氨基)吡啶(1.74g,14.24mmol)、盐酸二甲胺(1.72g,21.09mmol)和WSCDI(3.17g,16.68mmol)。将混合物在室温下搅拌30小时。将混合物用二氯甲烷(100ml)稀释,然后用0.3的MKHSO4、饱和碳酸氢钠溶液和盐水洗涤,然后用MgSO4干燥,在真空下浓缩得到无色的胶状物。将粗品重新溶解于4N的HCl/二噁烷(50ml)中,室温下搅拌1小时,然后在真空下浓缩。残余物与甲苯和乙醚共沸得到白色固体;收率0.45g(17%)。
2B.(4R)-4-羟基-1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨
基甲酰基)-L-脯氨酸-N,N-二甲基酰胺
将实施例1B的胺(0.10g,0.302mmol)与实施例2A的胺(0.153mg,0.785mmol)按照实施例1C的方法进行反应。在硅胶上对产物用快速柱层析进行纯化(洗脱剂:氯仿∶甲醇∶醋酸95∶4∶1);收率0.95g(66%)。
1H NMR(CDCl3):δ1.65-1.80(2H,m),1.85-2.00(3H,m),2.05-2.25(1H,m),2.10(3H,s),2.80-3.10(3H,m),2.85(3H,s),3.00(3H,s),3.40-3.30(1H,m),3.45-3.55(1H,m),3.65-3.95(1H,m),4.00-4.10(1H,m),4.30-4.55(1H,m),4.91(1H,t,J=7.7Hz),5.15-5.30(1H,m),6.10-6.20(1H,m),6.55-6.65(1H,m),6.85-7.50(5H,m)ppm。
M.S.:计算值m/e=478.26;实测值[M+H]+=479.2
实施例3-116
用类似的方法制备下表所列的其它实施例。
实施例编号 | R/S | V2 | X | Y | [M+H]+ |
3 | S | H | H2 | OMe | 436.4 |
4 | R | H | H2 | OMe | 436.2 |
5 | R/S | OPh | O | OH | 528.3 |
6 | R/S | OPh | O | NMe2 | 555.3 |
实施例编号 | R1 | R2 | V1 | V2 | X | Y | [M+H]+ |
7 | H | Me | H | H | O | OtBu | 492.5 |
8 | H | Me | H | H | O | OH | 436.3 |
9 | H | Me | H | OH | O | OMe | 466.0 |
10 | H | Me | H | OAc | O | NMe2 | 521.0 |
11 | H | Me | =O | O | NMe2 | 477.3 | |
12 | H | Me | H | OH | O | OEt | 480.2 |
13 | H | Me | H | OCOcC3H5 | O | NMe2 | 547.3 |
14 | H | Me | H | OMe | O | NMe2 | 493.5 |
15 | H | Cl | H | H | O | NMe2 | 483.4 |
16 | H | Me | H | H | S | NMe2 | 479.2 |
实施例编号 | R1 | R2 | V1 | V2 | X | Y | [M+H]+ |
17 | H | Me | H | H | O | NMeEt | 477.2 |
18 | H | OMe | H | H | O | NMe2 | 479.2 |
19 | H | Me | H | OMe | O | OMe | 480.2 |
20 | H | Me | H | H | O | OiPr | 478.2 |
21 | H | Me | H | OH | O | OH | 452.1 |
22 | H | Me | H | OBn | O | OiPr | 584.2 |
23 | H | Me | H | OH | O | OiPr | 494.1 |
24 | H | Me | H | OBn | O | NMe2 | 569.2 |
25 | Me | H | H | H | O | NMe2 | 463.2 |
26 | H | Me | H | OMe | O | OH | 466.2 |
27 | Cl | H | H | H | O | NMe2 | 483.1 |
28 | H | Et | H | H | O | NMe2 | 477.3 |
29 | H | Cl | H | H | S | NMe2 | 499.2 |
30 | H | Cl | H | OBn | O | NMe2 | 589.2 |
31 | H | Cl | H | OH | O | NMe2 | 499.2 |
32 | H | Me | H | OEt | O | NMe2 | 507.3 |
33 | H | Me | Br | H | O | NMe2 | 541.1 |
34 | H | Me | H | Cl | O | OMe | 484.1 |
35 | H | Me | F | F | O | NMe2 | 499.2 |
36 | H | Me | H | Cl | O | OH | 470.1 |
37 | H | Me | H | N3 | O | NMe2 | 504.3 |
38 | H | Me | H | Cl | O | NMe2 | 497.2 |
39 | H | Me | H | OtBu | O | NMe2 | 535.3 |
40 | H | Me | Cl | H | O | NMe2 | 497.2 |
41 | H | Me | H | OPh | O | OMe | 542.3 |
42 | H | Me | H | F | O | OMe | 468.3 |
43 | H | Me | H | F | O | OH | 454.4 |
44 | H | Me | H | F | O | NMe2 | 481.3 |
实施例编号 | R1 | R2 | V1 | V2 | X | Y | [M+H]+ |
45 | H | Me | H | NHBn | O | NMe2 | 568.0 |
46 | H | Me | OMe | OMe | O | OMe | 510.3 |
47 | H | Me | OMe | OMe | O | OH | 496.2 |
48 | H | Me | OMe | OMe | O | NMe2 | 523.3 |
实施例编号 | R2 | V2 | X | [M+H]+ |
49 | Cl | H | O | 489.1 |
50 | Me | H | O | 469.2 |
51 | Me | OH | O | 485.0 |
52 | Cl | OMe | O | 519.3 |
53 | Me | OMe | O | 499.3 |
54 | Cl | OMe | S | 535.1 |
实施例编号 | R3 | V2 | W1 | X | [M+H]+ |
55 | H | H | S | O | 479.4 |
56 | H | OH | S | O | 495.0 |
57 | H | H | S | S | 495.1 |
实施例编号 | R3 | V2 | W1 | X | [M+H]+ |
58 | Me | H | O | O | 477.2 |
59 | H | OBn | S | O | 585.2 |
60 | H | OBn | O | S | 585.0 |
实施例编号 | A16 | A17 | R2 | V2 | [M+H]+ |
61 | NEt | CH2 | Me | OMe | 522.4 |
62 | NH | CH2 | Me | OMe | 494.3 |
63 | CH2 | NiPr | Me | OMe | 536.4 |
64 | CH2 | NH | Me | OMe | 494.5 |
65 | O | CH2 | Cl | OMe | 515.2 |
66 | CH(OH) | CH2 | Me | H | 479.2 |
实施例编号 | V1 | V2 | X | Y | [M+H]+ |
87 | H | H | S | NMe2 | 516.2 |
88 | H | OBn | O | NMe2 | 606.3 |
89 | H | OH | O | NMe2 | 507.3 |
90 | H | OMe | O | NMe2 | 530.3 |
91 | -OCH2CH2O- | O | OMe | 545.3 | |
92 | OMe | OMe | O | OMe | 547.3 |
93 | -OCH2CH2O- | O | NMe2 | 558.3 | |
94 | -SCH2CH2S- | O | NMe2 | 590.2 |
实施例编号 | A10 | R2 | V2 | X | [M+H]+ |
105 | O | Me | H | O | 519.3 |
106 | NMe | Me | H | O | 532.3 |
107 | NMe | Me | OH | O | 548.1 |
108 | NMe | Me | OBn | O | 638.2 |
109 | NMe | Me | OMe | O | 562.3 |
110 | O | Me | OMe | O | 549.2 |
111 | NMe | Me | Cl | O | 566.2 |
112 | NMe | Me | OMe | S | 578.2 |
113 | O | Cl | OMe | O | 569.1 |
实施例编号 | A10 | R2 | V2 | X | [M+H]+ |
114 | O | Me | OMe | S | 565.2 |
115 | O | Cl | OMe | S | 585.1 |
116 | NH | Me | OMe | O | 548.2 |
实施例117
体外生物学特性
本发明的化合物是选择性V2受体激动剂。在标准放射性配体置换试验中,所有化合物对V2受体的K1值都低于10μM。
实施例118
体内生物学特性
Brattleboro大鼠是被认可的加压素缺陷模型(见综述FD Grant,“加压素缺陷的生殖模型”,
Exp.Physiol.85,203S-209S,2000)。该动物不分泌加压素,所以产生大量的稀释尿。用本发明的化合物对Brattleboro大鼠进行给药(在甲基纤维素中0.1-10mg/kg p.o.)。收集每小时的尿,将其容积与对照动物进行比较。在实验过程中动物自由进食进水。有代表性的结果见下表。用去氨加压素的结果作为对照。
实施例的化合物 | 剂量 | 尿产生量抑制%(在1小时) |
1 | 1mg/kg | 82 |
14 | 1mg/kg | 84 |
52 | 1mg/kg | 90 |
54 | 1mg/kg | 68 |
85 | 1mg/kg | 63 |
90 | 1mg/kg | 60 |
101 | 1mg/kg | 74 |
104 | 1mg/kg | 81 |
109 | 1mg/kg | 73 |
110 | 1mg/kg | 80 |
112 | 1mg/kg | 75 |
114 | 1mg/kg | 85 |
115 | 1mg/kg | 88 |
去氨加压素 | 0.1mg/kg | 37 |
1mg/kg | 100 | |
10mg/kg | 100 |
实施例119
用于片剂的药物组合物
用如下的方法制备含有100mg作为活性成分的实施例1的化合物的片剂:
实施例1的化合物 200.0g
玉米淀粉 71.0g
羟丙基纤维素 18.0g
羧甲基纤维素钙 13.0g
硬脂酸镁 3.0g
乳糖 195.0g
总重 500.0g
将上述物质混合,压片,得到2000片片重为250mg的片剂,每片包含100mg实施例5的化合物。
前面的实施例表明落在本发明范围内的化合物易于使用标准的化学技术来进行制备,且这些化合物有所预期的V2受体激动剂的生物学性质。更特别的是,该化合物在加压素缺陷的动物模型中是强效的抗利尿剂。因此,很显然它们可以用于治疗目前能用去氨加压素治疗的人类疾病,如中枢性尿崩症、夜间遗尿和夜尿症。这进一步表明抗利尿剂去氨加压素可以用于某种类型的小便失禁。这些论据也适用于本发明的化合物。
去氨加压素也可用于治疗某些凝血功能紊乱。有很好的证据表明该作用也是通过V2受体而实现的(参见例如JE Kaufmann等,“涉及V2受体和cAMP的加压素诱导的冯威勒布兰特因子从内皮细胞的分泌”,
J. Clin.Invest.106,107-116,2000;A Bernat等,“在有意识的狗体内的DDAVP诱导的止血因子的释放的V2受体拮抗作用”,
J.Pharmacol.Exp. Ther.282,597-602,1997),因此,可以预期本发明的化合物是一种有用的前凝血质。
本发明的范围用下面的权利要求进一步的进行限定。
Claims (23)
1.一种通式1的化合物或其可药用的盐,
其中:
A是选自通式2至7的二环或三环氮杂衍生物
A1、A4、A7和A10分别独立地选自CH2、O和NR8;
A2、A3、A9、A11、A13、A14和A15分别独立地选自CH和N;
A5是共价键且A6是S,或A5是N=CH且A6是共价键;
A8和A12分别独立地选自NH和S;
A16和A17都是CH2,或A16和A17中一个是CH2,另一个选自CH(OH)、
CF2、O、SOx、以及NR8,
V1和V2都是H、OMe或F,或V1和V2中的一个是OH、OMe、OBn、
OPh、O-酰基、Br、Cl、F、N3、NH2、NHBn或NH-酰基,另一个是H,
或V1和V2一起是=O、-S(CH2)pS-或-O(CH2)PO-;
W1是O或S;
X1和X2都是H,或一起是=O或=S;
Y是OR5或NR6R7;
Z是S或-CH=CH-;
R1、R2、R3和R4独立地选自H、低级烷基、低级烷氧基、F、Cl和Br;
R5选自H和低级烷基;
R6和R7独立地选自H和低级烷基,或一起是-(CH2)n-;
R8是H或低级烷基;
n=3、4、5或6;
p是2或3;和
x是0、1或2;其中“低级烷基”是指具有1至6个碳原子的直链或支链烷基或环烷基,“低级烷氧基”是指具有1至6个碳原子的直链或支链烷氧基或环烷氧基,“酰基”是指具有1至6个碳原子的直链或支链烷基羰基或环烷基羰基。
2.一种如权利要求1所述的化合物或其可药用的盐,其中A是如通式2所示的基团。
3.一种如权利要求1所述的化合物或其可药用的盐,其中A是如通式3所示的基团。
4.一种如权利要求1所述的化合物或其可药用的盐,其中A是如通式4所示的基团。
5.一种如权利要求1所述的化合物或其可药用的盐,其中A是如通式5所示的基团。
6.一种如权利要求1所述的化合物或其可药用的盐,其中A是如通式6所示的基团。
7.一种如权利要求1所述的化合物或其可药用的盐,其中A是如通式7所示的基团。
8.一种如权利要求1或权利要求7所述的化合物或其可药用的盐,其中A是如通式7所示的基团,Z是-CH=CH-且A16和A17都是-CH2-。
9.一种如权利要求1所述的化合物或其可药用的盐,其中R1和R2中一个是Cl或Me,另一个是H,且R3和R4都是H。
10.一种如权利要求1所述的化合物或其可药用的盐,其中V1和V2中的一个是OMe或OBn,另一个是H。
11.一种如权利要求1所述的化合物或其可药用的盐,其中X1和X2一起是=O,且Y是NR6R7。
13.一种如权利要求1所述的化合物或其可药用的盐,它是
其中
W1是O或S;
Ra和Rb中的一个是Cl或甲基,另一个是H;
Rc是甲基或苄基;
R6和R7独立地选自H和具有1至6个碳原子的直链或支链烷基或环烷基,或一起是-(CH2)n-;和n是3、4、5或6。
14.一种如权利要求1的化合物或其可药用的盐,其中V1和V2都是H。
15.一种如权利要求14所述的化合物或其可药用的盐,其中X1和X2一起是=O且Y是NR6R7。
16.一种如权利要求1所述的化合物或其可药用的盐,它是
其中
W1是O或S;
R4和Rb中的一个是Cl或甲基,另一个是H;
R6和R7独立地选自H和具有1至6个碳原子的直链或支链烷基或环烷基,或一起是-(CH2)n-;和n是3、4、5或6。
17.一种如权利要求1所述的化合物或其可药用的盐,它是
其中
W1是O或S;
Ra和Rb中的一个是Cl或甲基,另一个是H;
R6和R7独立地选自H和具有1至6个碳原子的直链或支链烷基或环烷基,或一起是-(CH2)n-;和n是3、4、5或6。
18.一种如权利要求1所述的化合物或其可药用的盐,该化合物选自
1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-L-脯氨酸-N,N-二甲基酰胺,
(4R)-4-羟基-1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-L-脯氨酸-N,N-二甲基酰胺,
(4R)-4-苄氧基-1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-L-脯氨酸-N,N-二甲基酰胺,
(4R)-4-甲氧基-1-(2-甲基-4-(2,3,4,5-四氢-1-苯并氮杂-1-基羰基)苄基氨基甲酰基)-L-脯氨酸-N,N-二甲基酰胺,
(4R)-1-(2-氯-4-(5,6,7,8-四氢-4H-噻吩并[3,2-b]氮杂-4-基羰基)苄基氨基甲酰基)-4-甲氧基-L-脯氨酸-N,N-二甲基酰胺,
(4R)-1-(4-(10,11-二氢-5H-吡咯并[2,1-c](1,4)苯并二氮杂-10-基羰基)-2-甲基苄基氨基甲酰基)-4-甲氧基-L-脯氨酸-N,N-二甲基酰胺,和
(4R)-1-(4-(10,11-二氢-5H-吡咯并[2,1-c](1,4)苯并二氮杂-10-基羰基)-2-甲基苄基氨基甲酰基)-4-甲氧基-L-脯氨酸-N,N-二甲基硫酰胺。
19.一种如权利要求1至18中任一项所述的化合物或其可药用的盐在制备药物组合物中的应用。
20.一种如权利要求1至18中任一项所述的化合物或其可药用的盐在制备用于治疗夜间遗尿、夜尿症、多尿症、小便失禁以及出血紊乱中的一种或多种的治疗剂中的应用。
21.一种药物组合物,该组合物包含作为活性成分的选自如权利要求1至18中任一项所述的化合物或其可药用的盐,和赋形剂。
22.一种如权利要求21所述的药物组合物,其中该组合物是用于多尿症、夜间遗尿、夜尿症、中枢性尿崩症、出血紊乱和小便失禁中的一种或多种的治疗或控制的组合物。
23.一种如权利要求22所述的药物组合物,其中该组合物是对小便失禁的治疗导致排空延迟的组合物。
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