CN1775767A - 新的苯并噻二嗪化合物及其制备方法和含有它们的药物组合物 - Google Patents
新的苯并噻二嗪化合物及其制备方法和含有它们的药物组合物 Download PDFInfo
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- CN1775767A CN1775767A CNA2005101316002A CN200510131600A CN1775767A CN 1775767 A CN1775767 A CN 1775767A CN A2005101316002 A CNA2005101316002 A CN A2005101316002A CN 200510131600 A CN200510131600 A CN 200510131600A CN 1775767 A CN1775767 A CN 1775767A
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- 238000002360 preparation method Methods 0.000 title claims description 33
- 238000000034 method Methods 0.000 title claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- 150000007658 benzothiadiazines Chemical class 0.000 title description 6
- 230000008569 process Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 125000005843 halogen group Chemical group 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 239000001301 oxygen Substances 0.000 claims description 26
- 239000002585 base Substances 0.000 claims description 24
- 229910052719 titanium Inorganic materials 0.000 claims description 21
- 239000010936 titanium Substances 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- RCFKEIREOSXLET-UHFFFAOYSA-N disulfamide Chemical compound CC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O RCFKEIREOSXLET-UHFFFAOYSA-N 0.000 claims description 15
- 239000000460 chlorine Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
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- 230000005494 condensation Effects 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
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- 230000000996 additive effect Effects 0.000 claims description 5
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000001335 demethylating effect Effects 0.000 claims description 2
- 238000010520 demethylation reaction Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
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- 150000002431 hydrogen Chemical group 0.000 abstract 1
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- 238000004452 microanalysis Methods 0.000 description 17
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- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 6
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- 108020004999 messenger RNA Proteins 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- RJCQBQGAPKAMLL-UHFFFAOYSA-N bromotrifluoromethane Chemical compound FC(F)(F)Br RJCQBQGAPKAMLL-UHFFFAOYSA-N 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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Abstract
式(I)化合物及药物,其中:R1代表被一个或多个卤素原子取代的烷基;R2代表氢原子,卤素或者OH;R3代表取代或未取代的烷基,其异构体和加成盐。
Description
技术领域
本发明涉及新的苯并噻二嗪化合物、其制备方法和含有它们的药物组合物。
背景技术
现在已经认识到:兴奋性氨基酸,非常特别是谷氨酸在神经可塑性的生理学过程以及在学习和记忆的机理中起着重要的作用。病理生理学研究已清楚表明,谷氨酸能神经传递的缺陷与阿尔茨海默氏症的发展有着紧密关系(Neuroscience and Biobehavioral Reviews,1992,
16,13-24;Progress inNeurobiology,1992,
39,517-545)。
此外,近年来的大量工作已经证明:存在兴奋性氨基酸受体的亚型以及它们的功能性相互作用(Molecular Neuropharmacology,1992,
2,15-31)。
在这些受体中,AMPA(α-氨基-3-羟基-5-甲基-4-异噁唑-丙酸)受体似乎在很大程度上与生理学神经元兴奋性现象有关,特别是与记忆过程中的那些现象有关。例如,已经表明,学习与海马区AMPA与其受体结合的增加有关,而海马区是大脑中对于记忆和认知过程所必需的区域之一。类似地,在最近已经将益智剂如茴拉西坦描述为以正向方式调节神经元细胞的AMPA受体(Journal of Neurochemistry,1992,58,1199-1204)。
在文献中已报道了具有苯甲酰胺结构的化合物具有这种相同的作用机理,并可改善记忆行为(Synapse,1993,
15,326-329)。特别是化合物BA74是这些新的药理学试剂中最具活性的化合物。
最后,欧洲专利说明书EP 692484描述了一种对AMPA电流有促进活性的苯并噻二嗪化合物,专利申请WO 99/42456尤其描述了某些作为AMPA受体调节剂的苯并噻二嗪化合物。
发明内容
本发明所涉及的苯并噻二嗪化合物除了是新的以外,而且还令人惊奇地表现出对AMPA电流具有特别有价值的药理学活性。它们可作为AMPA调节剂来治疗或预防与下述因素相关的记忆和认知紊乱:年龄、焦虑或抑郁综合征、进行性神经变性疾病、阿尔茨海默氏病、皮克氏病、亨廷顿舞蹈病、精神分裂症、急性神经变性疾病后遗症、缺血后遗症和癫痫后遗症。
更具体而言,本发明涉及式(I)化合物、它们的对映异构体和非对映异构体,以及它们与可药用酸或碱的加成盐,
其中:
R1代表被一个或多个卤素原子取代的直链或支链(C1-C6)烷基,
R2代表氢原子、卤素原子或羟基,
R3代表未取代的芳基或者被一个或多个相同或不同的基团取代的芳基,所述基团选自:
直链或支链(C1-C6)烷基;直链或支链(C1-C6)烷氧基;直链或支链(C1-C6)多卤代烷基;卤素原子;直链或支链(C1-C6)烷氧羰基;直链或支链(C1-C6)烷硫基;羧基;直链或支链(C1-C6)酰基;直链或支链(C1-C6)多卤代烷氧基;羟基;氰基;硝基;脒基(任选被一个或两个相同或不同的选自直链或支链(C1-C6)烷基、羟基、直链或支链(C1-C6)烷氧基和
的基团取代);氨基(任选被一个或两个直链或支链(C1-C6)烷基取代);氨羰基(任选被一个或两个直链或支链(C1-C6)烷基取代);苄氧基;(C1-C6)烷基磺酰氨基(任选在N原子上被直链或支链(C1-C6)烷基取代);(三氟甲磺酰基)氨基;杂环基团;以及直链或支链(C1-C6)烷基,其一端被一个或多个相同或不同的选自氢、卤素原子和直链或支链(C1-C6)烷基的基团取代,另一端被选自NR4R5、S(O)nR6、OR7、脒基(任选被一个或两个相同或不同的选自直链或支链(C1-C6)烷基、羟基、直链或支链(C1-C6)烷氧基和
的基团取代)和杂环基团的基团取代,其中:
R4代表氢原子或者直链或支链(C1-C6)烷基、S(O)pR8、COR9或P(O)(OR10)(OR11)基团,
R5代表氢原子或者直链或支链(C1-C6)烷基,
或者R4和R5与带有它们的氮原子共同构成杂环基团,
R6、R8、R9、R10、R11和R12可以相同或不同,各自代表氢原子或者任选被一个或多个卤素原子取代的直链或支链(C1-C6)烷基;芳基-(C1-C6)烷基,其中烷基部分是直链或支链的;或者芳基,
R7代表直链或支链(C1-C6)烷基或者直链或支链(C1-C6)酰基,
n和p可以相同或不同,各自代表0、1或2。
可以理解:
◆杂环基团指含有一至四个相同或不同的选自氮、氧和硫的杂原子的单环或双环的芳香或非芳香基团,任选被一个或多个相同或不同的选自下述的基团取代:卤素、直链或支链(C1-C6)烷基、直链或支链(C1-C6)烷氧基、直链或支链(C1-C6)多卤代烷基、直链或支链(C1-C6)烷氧羰基、氧代、硫代、羧基、直链或支链(C1-C6)酰基、直链或支链(C1-C6)多卤代烷氧基、羟基、氰基、硝基、氨基(任选被一个或多个直链或支链(C1-C6)烷基取代)、氨基磺酰基(任选被一个或多个直链或支链(C1-C6)烷基取代)和(C1-C6)烷基磺酰基氨基,
◆芳基指单环芳香基团或其中至少一个环是芳香环的二环基团,任选被一个或多个相同或不同的选自下述的基团取代:卤素、直链或支链(C1-C6)烷基(任选被一个或多个羟基取代)、直链或支链(C1-C6)烷氧基、直链或支链(C1-C6)多卤代烷基、直链或支链(C1-C6)烷氧羰基、氧代、硫代、直链或支链(C1-C6)烷硫基、羧基、直链或支链(C1-C6)酰基、直链或支链(C1-C6)多卤代烷氧基、羟基、氰基、硝基、氨基(任选被一个或多个直链或支链(C1-C6)烷基或者直链或支链(C1-C6)酰基取代)、氨羰基(任选被一个或多个直链或支链(C1-C6)烷基取代)、氨基磺酰基(任选被一个或多个直链或支链(C1-C6)烷基取代)、单-或二-((C1-C6)烷基磺酰基)氨基、单-或二-(三氟甲磺酰基)氨基、PO(ORa)(ORb)(其中Ra和Rb可以相同或不同,各自代表氢原子或者直链或支链(C1-C6)烷基)、苄氧基和苯基(任选被一个或多个相同或不同的选自卤素,直链或支链(C1-C6)烷基,直链或支链(C1-C6)全卤代烷基、羟基、直链或支链(C1-C6)烷氧基的基团取代)。
在可药用酸中,可不加任何限制被提及的是盐酸、氢溴酸、硫酸、膦酸、乙酸、三氟乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、酒石酸、马来酸、柠檬酸、抗坏血酸、甲磺酸和樟脑酸等。
在可药用碱中,可不加任何限制被提及的是氢氧化钠、氢氧化钾、三乙胺和叔丁胺等。
R1基团优选为卤代乙基,如氟乙基、氯乙基或溴乙基,更优选为氟-或氯-乙基。
R2优选表示氢原子。
R3基团优选为苯基或被取代的苯基,更特别是被下列基团取代的苯基:
-脒基,
-羟脒基,
-烷氧基,
-任选在氮原子上被烷基取代的烷基磺酰氨基,
-或者被脒基、羟脒基、OR7、NHS(O)pR8或NHCOR9基团取代的烷基。
本发明甚至更特别涉及如下的式(I)化合物:
·N-(4-{[4-(2-溴乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)甲磺酰胺,
·N-(4-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)甲磺酰胺,
·N-(4-{[4-(2-氯乙基]-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)甲磺酰胺,
·N-(3-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苯基)甲磺酰胺,
·N-(4-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苯基)甲磺酰胺,
·4-(2-氟乙基)-7-(3-甲氧基苯氧基)-3,4-二氢-2H-1,2,4-苯并噻二嗪1,1-二氧化物,
·N-(3-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)乙酰胺,
·N-(3-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基]苄基)甲磺酰胺,
·N-(4-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)-N-甲基甲磺酰胺,
·4-(2-氟乙基)-7-苯氧基-3,4-二氢-2H-1,2,4-苯并噻二嗪1,1-二氧化物,
·3-{[4-(2-氟乙基)-1,1-二氧化物-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}-N′-羟基苯甲脒,和
·3-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}-N-甲基苯甲酰胺。
本发明还涉及式(I)化合物的制备方法,该方法的特征在于使用式(II)化合物为原料,其中R2如式(I)中定义,
式(II)化合物在碱性介质中与带有羟基的直链或支链(C1-C6)卤代烷基缩合,然后转化为相应的卤化化合物,得到式(III)化合物,其中R1和R2如式(I)中定义:
式(IV)化合物在Cu(OAc)2存在下与式(V)硼酸化合物缩合,其中R3如式(I)中定义,
R3-B(OH)2 (V)
得到式(VI)化合物,其中R1、R2和R3如前文定义:
式(VI)化合物用例如NaBH4进行还原反应,得到式(I)化合物,其中R1、R2和R3如前文定义:
或者式(III)化合物在如NaBH4存在下进行还原反应,得到式(VII)化合物,其中R1和R2如前文定义,
式(VII)化合物在例如BBr3或BF3存在下进行脱甲基化反应,得到式(VIII)化合物,
其中R1和R2如前文定义,
式(VIII)化合物在Cu(OAc)2存在下与前文定义的式(V)硼酸化合物缩合,得到式(I)化合物,
将式(I)化合物根据需要采用常规纯化技术进行纯化,酌情采用常规分离技术分离为它们的异构体,并且根据需要转化为它们与可药用酸或碱的加成盐。
本发明还涉及如前文所定义的式(VIII)化合物:
它可用作合成式(I)化合物的合成中间体和用作AMPA受体调节剂,
更尤其是涉及式(IX)化合物,它是式(VIII)化合物的一个具体实例:
其中X代表氟、氯、溴或碘原子,它可用作合成式(I)化合物的合成中间体和用作AMPA受体调节剂。
本发明还涉及包含作为活性成分的式(I)或(IX)化合物以及一种或多种适宜的惰性无毒赋形剂的药物组合物。在本发明的药物组合物中,可被提及的更尤其是适于口服、胃肠道外(静脉内或皮下)或经鼻给药的那些,如片剂或糖衣丸、舌下片、明胶胶囊、锭剂、栓剂、霜剂、软膏剂、皮肤凝胶、注射剂和可饮用混悬液等。
有用剂量可根据疾病的性质和严重程度、给药途径以及患者的年龄和体重而改变,为每天1至500mg,单次或多次给药。
具体实施方式
下述制备例和实施例用于解释本发明,但不以任何方式限制本发明。
所用原料均为公知产品或可按公知的操作步骤制得。
在实施例中所描述的化合物结构通过常规的分光光度技术(红外、NMR、质谱等)测定。
制备例1:4-(2-溴乙基)-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-酚1,1-二氧化物
步骤A:2-(7-甲氧基-1,1-二氧化-4H-1,2,4-苯并噻二嗪-4-基)乙醇
向7-甲氧基-4H-1,2,4-苯并噻二嗪1,1-二氧化物(4.0g,18.8mmol)在30mlDMF和30ml CH3CN的混合物中的溶液中加入8.6g(56.6mmol)CsF和1.47ml(18.8mmol)2-溴乙醇。于75℃搅拌2小时,加入1.47ml(18.8mmol)2-溴乙醇。在75℃下再过6小时后,再次加入1.47ml(18.8mmol)2-溴乙醇,然后加入2.8g(18.8mmol)CsF,于75℃持续搅拌过夜。在环境温度下滤出盐,用CH3CN冲洗;蒸干滤液。将残余物置于CH2Cl2中,有机相用饱和NaCl溶液洗涤并干燥(MgSO4)。蒸发后,将粘稠残余物溶于乙醚/CH2Cl2的混合物中。研磨胶状物直至得到固体,经滤出得到标题化合物。
熔点:160-162℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 46.8746.99 | 4.724.96 | 10.9310.34 | 12.5112.51 |
步骤B:4-(2-氟乙基)-7-甲氧基-4H-1,2,4-苯并噻二嗪1,1-二氧化物
向在冰浴中冷却的3.85g(15.02mmol)前述步骤的化合物在100mlCH2Cl2中的溶液中逐滴加入用20ml CH2Cl2稀释的3.97ml(30.0mmol)DAST。然后使反应溶液在约1小时内恢复至环境温度;然后倒入100ml饱和NaCl溶液,倒出有机相,干燥(MgSO4)并真空蒸发。残余物在乙醚/CH2Cl2的混合物中研磨至得到固体,经滤出得到标题化合物。
熔点:123-128℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 46.5045.88 | 4.294.41 | 10.8510.46 | 12.4212.61 |
步骤C:4-(2-氟乙基)-7-甲氧基-3,4-二氢-2H-1,2,4-苯并噻二嗪1,1-二氧化物
将454mg(12.0mmol)的NaBH4分小批量加入2.77g(10.7mmol)前述步骤的化合物在25ml乙醇中的混悬液中。于环境温度搅拌2小时后,逐滴加入1N HCl直至生成白色沉淀,滤出沉淀以回收标题化合物。
熔点:91-93℃
步骤D:4-(2-溴乙基)-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-酚1,1-二氧化物
将17.6ml(17.6mmol)的1M BBr3的CH2Cl2溶液逐滴加入1.53g(5.88mmol)前述步骤的化合物在70ml CH2Cl2的溶液中,冰浴冷却。搅拌混合物过夜,同时使温度返回到环境温度。反应混悬液在冰浴中冷却,逐滴加入50ml水。搅拌30分钟后,滤出沉淀,用水冲洗并真空干燥。由此得到所需化合物,为浅褐色粉末状。
熔点:144-148℃
制备例2:4-(2-氟乙基)-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-酚1,1-二氧化物
步骤A:4-(2-氟乙基)-4H-1,2,4-苯并噻二嗪-7-酚1,1-二氧化物
将100ml(950mmol)的BF3-Me3S复合物加入用氮净化过的双颈烧瓶中,该烧瓶与装有次氯酸钠的阱通过套管相连,并加以氮压。然后在搅拌和通轻微氮气流的同时,迅速小批量加入5.63g(21.8mmol)制备例1步骤B的化合物在75ml CH2Cl2中的混悬液。停止氮气流,反应混悬液于环境温度搅拌过夜。冰浴冷却反应混合物,并加入冰水。混悬液搅拌30分钟,滤出沉淀,用水和庚烷冲洗。干燥固体,从水中重结晶,得到标题化合物。
熔点:230-235℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 44.2644.55 | 3.714.18 | 11.4711.34 | 13.1313.59 |
步骤B:4-(2-氟乙基)-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-酚1,1-二氧化物
方法如制备例1步骤C,以上述步骤A所得化合物为原料,除了标题化合物在加入1N HCl后不沉淀,但可用CH2Cl2萃取。
熔点:178-180℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 43.9043.73 | 4.504.37 | 11.3811.10 | 13.0212.80 |
制备例3:4-(2-氯乙基)-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-酚1,1-二氧化物
步骤A:4-(2-氯乙基)-7-甲氧基-4H-1,2,4-苯并噻二嗪-1,1-二氧化物
在环境温度下,向1.0g(3.90mmol)制备例1步骤A的化合物在20mlCH2Cl2中的混悬液中加入0.1ml DMF,然后逐滴加入1.42ml(19.5mmol)SOCl2在5ml CH2Cl2中的溶液。加完后,得到溶液,在CH2Cl2回流下搅拌2小时。真空蒸去CH2Cl2,将残余物溶于5%NaHCO3溶液中。研磨残余物后,得到固体,将固体滤出,用水冲洗并干燥,得到标题化合物。
熔点:126-130℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 43.7243.79 | 4.044.06 | 10.209.84 | 11.6712.01 |
步骤B:4-(2-氯乙基)-7-甲氧基-3,4-二氢-2H-1,2,4-苯并噻二嗪1,1-二氧化物
条件和处理方法与制备例1的步骤C相同。
熔点:139-143℃
元素微量分析:
C | H | N | S | Cl | |
理论值%实测值% | 43.4043.73 | 4.735.05 | 10.129.89 | 11.5911.07 | 12.8113.30 |
步骤C:4-(2-氯乙基)-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-酚1,1-二氧化物条件和处理方法与制备例1的步骤D相同。
熔点:171-173℃
实施例1-12化合物可以通O-芳基化反应制得,该反应采用制备例1、2或3中描述的中间体和适宜硼酸通过下文实施例1中所述的反应和处理条件进行。
实施例1:N-(4-{[4-(2-溴乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)甲磺酰胺
将80ml CH2Cl2、548μl(6.79mmol)吡啶、700mg(2.29mmol)制备例1的化合物、8g 4分子筛、786mg(3.43mmol)4-{[(甲磺酰基)-氨基]甲基苯基}溴酸和623mg(3.43mmol)Cu(OAc)2置于100ml锥形瓶中。室温下剧烈搅拌溶液,锥形瓶保持敞口。4小时30分钟后,将反应混合物用另外的50ml CH2Cl2稀释,过滤混悬液。蒸发滤液至干,残余物用硅胶柱进行色谱法两次,第一次色谱法用CH2Cl2/MeOH(98/2)连续洗脱,第二次用CH2Cl2/丙酮(95/5)连续洗脱,得到标题化合物。
熔点:182-184℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 41.6442.05 | 4.113.76 | 8.578.29 | 13.0813.09 |
实施例2:N-(4-{[4-(2-氟乙基)-1,1-二氧代-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)甲磺酰胺
工艺同实施例1,原料为制备例2所得的化合物和4-{[(甲磺酰基)氨基]甲基}苯基硼酸。
熔点:100-102℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 47.5447.14 | 4.694.97 | 9.789.56 | 14.9314.99 |
实施例3:N-(4-{[4-(2-氯乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)甲磺酰胺
方法如实施例1,以制备例3所得的化合物和4-{[(甲磺酰基)氨基]甲基}苯基硼酸开始制备。
熔点:172-175℃
元素微量分析:
C | H | N | S | Cl | |
理论值%实测值% | 45.7945.55 | 4.524.84 | 9.429.24 | 14.3814.69 | 7.958.41 |
实施例4:N-(3-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苯基)甲磺酰胺,
方法如实施例1,由制备例2所得的化合物和3-{[(甲磺酰基)氨基]}苯基硼酸开始制备。
熔点:131-134℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 46.2646.09 | 4.374.35 | 10.119.91 | 15.4415.85 |
实施例5:N-(4-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苯基)甲磺酰胺
方法如实施例1,由制备例2所得的化合物和4-{[(甲磺酰基)氨基]}苯基硼酸开始制备。
熔点:151-152℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 46.2645.71 | 4.374.78 | 10.119.90 | 15.4415.65 |
实施例6:4-(2-氟乙基)-7-(3-甲氧苯氧基)-3,4-二氢-2H-1,2,4-苯并噻二嗪1,1-二氧化物
方法如实施例1,由制备例2所得的化合物和3-甲氧基苯基硼酸开始制备。
熔点:101-102℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 54.5454.50 | 4.864.85 | 7.957.77 | 9.108.91 |
实施例7:N-(3-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)乙酰胺
方法如实施例1,由制备例2所得的化合物和3-[(乙酰氨基)甲基]苯基硼酸开始制备。
熔点:129-131℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 54.9555.03 | 5.125.18 | 10.6810.35 | 8.158.22 |
实施例8:N-(3-{[4-(2-氟乙基)-1,1-二氧-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)甲磺酰胺
方法如实施例1,由制备例2所得的化合物和3-{[(甲磺酰基)氨基]甲基}苯基硼酸开始制备。
熔点:110-112℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 45.5447.26 | 4.694.86 | 9.789.45 | 14.9315.01 |
实施例9:N-(4-{[4-(2-氟乙基)-1,1-二氧-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)-N-甲基甲磺酰胺
方法如实施例1,由制备例2所得的化合物和4-{[甲基(甲磺酰基)氨基]甲基}苯基)硼酸开始制备。
熔点:59℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 48.7548.53 | 5.005.16 | 9.479.06 | 14.4614.41 |
实施例10:4-(2-氟乙基)-7-苯氧基-3,4-二氢-2H-1,2,4-苯并噻二嗪1,1-二氧化物
方法如实施例1,由制备例2所得的化合物和苯基硼酸开始制备。
熔点:145℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 55.8955.70 | 4.694.81 | 8.698.48 | 9.959.89 |
实施例11:3-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}-N′-羟基苯甲脒
步骤A:3-{[4-(2-氟乙基)-1,1-二氧化-4H-1,2,4-苯并噻二嗪-7-基]氧基}氰苯
方法如实施例1,从制备例2中步骤A所得的化合物和3-氰基苯基硼酸开始制备,反应时间延长到48小时。
熔点:202-208℃
步骤B:3-{[4-(2-氟乙基)-1,1-二氧化-4H-1,2,4-苯并噻二嗪-7-基]氧基}-N′-羟基苯甲脒
将770μL(5.52mmol)三乙胺加入盐酸羟胺(384mg,5.52mmol)在1.8mlDMSO中的溶液中,混悬液于室温搅拌20分钟。滤出沉淀,滤液真空浓缩。向所得滤液中加入225mg(0.921mmol)上述步骤A的化合物,溶液于75℃搅拌4小时。反应混合物冷却至室温,并将反应混合物从水中沉淀。通过简单滗析,从水相中分离出白色不可过滤的粘性糊状物。将该粘性物在乙醇中研磨至出现结晶。滤出固体,得到标题化合物。
熔点:181-183℃
步骤C:3-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}-N′-羟基苯甲脒
将10mg(0.258mmol)NaBH4加入步骤B所得的化合物(75mg,0.198mmol)在1ml乙醇中的混悬液中。将混悬液于室温搅拌30分钟,然后冰浴冷却。加入1NHCl中和反应混合物,并用乙酸乙酯萃取。有机相用饱和NaCl溶液洗涤,干燥(MgSO4),并真空蒸发。蒸发残余物用CH2Cl2重结晶。过滤回收所需化合物。
熔点:160-163℃
实施例12:3-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}-N-甲基苯甲酰胺
方法如实施例1,从制备例2所得的化合物和3-[(甲氨基)羰基]苯基硼酸开始制备。
熔点194-196℃
元素微量分析:
C | H | N | S | |
理论值%实测值% | 53.8253.53 | 4.784.98 | 11.0810.87 | 8.458.42 |
本发明化合物的药理学研究
爪蟾卵母细胞中由AMPA诱导的兴奋电流的研究
a-
方法:
用胍鎓硫氰酸盐(guanidinium thiocyanate)/苯酚/氯仿法由雄性Wistar大鼠的大脑皮层制备mRNA’s。通过寡脱氧胸苷酸纤维素层析法分离出聚(A+)mRNA’s,以50ng/卵母细胞的用量注射。将卵母细胞于18℃孵育2-3天以允许受体表达,然后在8-10℃下储存。
于20-24℃和OR2介质中,在Plexiglass室(J.Exp.Zool.,1973,
184,321-334)中采用2-电极“电压钳”法记录电生理信号,第3个电极置于浴中作为参考。
所有化合物均通过孵育培养基应用,在应用期结束时测定电流。所用AMPA的浓度为10μM。对于所研究的每个化合物,测定两倍(EC2X)或五倍(EC5X)于由AMPA单独诱导的电流强度(5到50nA)时的浓度。
b-
结果:
本发明的化合物以相当大的程度加强了AMPA的兴奋作用,它们的活性非常明显地高于参比化合物的活性。
举例来说,实施例1的化合物的EC2X值为0.04μM。
药物组合物
制备1000片片剂的处方,每片含有100mg N-(4-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-并噻二嗪-7-基]氧基}苄基)甲磺酰胺(实施例2)
实施例2的化合物 ……………………………………………………100g
羟丙基纤维素…………………………………………………………2g
小麦淀粉………………………………………………………………10g
乳糖……………………………………………………………………100g
硬脂酸镁………………………………………………………………3g
滑石粉…………………………………………………………………3g
Claims (11)
1、式(I)化合物、它们的对映异构体和非对映异构体,以及它们与可药用酸或碱的加成盐,
其中:
R1代表被一个或多个卤素原子取代的直链或支链(C1-C6)烷基,
R2代表氢原子、卤素原子或羟基,
R3代表未取代的芳基或者被一个或多个相同或不同的基团取代的芳基,所述基团选自:
直链或支链(C1-C6)烷基;直链或支链(C1-C6)烷氧基;直链或支链(C1-C6)多卤代烷基;卤素原子;直链或支链(C1-C6)烷氧羰基;直链或支链(C1-C6)烷硫基;羧基;直链或支链(C1-C6)酰基;直链或支链(C1-C6)多卤代烷氧基;羟基;氰基;硝基;脒基(任选被一个或两个相同或不同的选自直链或支链(C1-C6)烷基、羟基、直链或支链(C1-C6)烷氧基和
的基团取代);氨基(任选被一个或两个直链或支链(C1-C6)烷基取代);氨羰基(任选被一个或两个直链或支链(C1-C6)烷基取代);苄氧基;(C1-C6)烷基磺酰氨基(任选在N原子上被直链或支链(C1-C6)烷基取代);(三氟甲磺酰基)氨基;杂环基团;以及直链或支链(C1-C6)烷基,其一端被一个或多个相同或不同的选自氢、卤素原子和直链或支链(C1-C6)烷基的基团取代,另一端被选自NR4R5、S(O)nR6、OR7、脒基(任选被一个或两个相同或不同的选自直链或支链(C1-C6)烷基、羟基、直链或支链(C1-C6)烷氧基和
的基团取代)和杂环基团的基团取代,其中:
R4代表氢原子或者直链或支链(C1-C6)烷基、S(O)pR8、COR9或P(O)(OR10)(OR11)基团,
R5代表氢原子或者直链或支链(C1-C6)烷基,
或者R4和R5与带有它们的氮原子共同构成杂环基团,
R6、R8、R9、R10、R11和R12可以相同或不同,各自代表氢原子或者任选被一个或多个卤素原子取代的直链或支链(C1-C6)烷基;芳基-(C1-C6)烷基,其中烷基部分是直链或支链的;或者芳基,
R7代表直链或支链(C1-C6)烷基或者直链或支链(C1-C6)酰基,
n和p可以相同或不同,各自代表0、1或2。
2.根据权利要求1的式(I)化合物,其中R1代表卤代乙基。
3.根据权利要求1的式(I)化合物,其中R2代表氢原子。
4.根据权利要求1的式(I)化合物,其中R3代表未取代的苯基。
5.根据权利要求1的式(I)化合物,其中R3代表如下基团取代的苯基:脒基、羟脒基、烷氧基、烷基磺酰氨基(任选在N原子上被烷基取代),或者被脒基、羟脒基、OR7、NHS(O)pR8或NHCOR9基团取代的烷基。
6.根据权利要求1的式(I)化合物,为:
●N-(4-{[4-(2-氟乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)甲磺酰胺,和
●N-(4-{[4-(2-氯乙基)-1,1-二氧化-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-基]氧基}苄基)甲磺酰胺,
以及它们与可药用酸或碱的加成盐。
7、制备权利要求1的式(I)化合物的方法,其特征在于使用式(II)化合物为原料,其中R2如式(I)中定义,
式(II)化合物在碱性介质中与带有羟基的直链或支链(C1-C6)卤代烷基缩合,然后转化为相应的卤化化合物,得到式(III)化合物,其中R1和R2如式(I)中定义:
式(IV)化合物在Cu(OAc)2存在下与式(V)硼酸化合物缩合,其中R3如式(I)中定义,
R3-B(OH)2 (V)
得到式(VI)化合物,其中R1、R2和R3如前文定义:
式(VI)化合物用例如NaBH4进行还原反应,得到式(I)化合物,其中R1、R2和R3如前文定义:
或者式(II)化合物在如NaBH4存在下进行还原反应,得到式(VII)化合物,其中R1和R2如前文定义,
式(VII)化合物在例如BBr3或BF3存在下进行脱甲基化反应,得到式(VII)化合物,其中R1和R2如前文定义,
式(VIII)化合物在Cu(OAc)2存在下与前文定义的式(V)硼酸化合物缩合,得到式(I)化合物,
将式(I)化合物根据需要采用常规纯化技术进行纯化,酌情采用常规分离技术分离为它们的异构体,并且根据需要转化为它们与可药用酸或碱的加成盐。
10、药物组合物,包含作为活性成分的权利要求1-6、8和9中任一项的化合物以及一种或多种惰性无毒的可药用赋形剂或载体。
11、根据权利要求10的药物组合物,包含作为活性成分的权利要求1-6、8和9中任一项的化合物,用作AMPA调节剂药物。
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ES (1) | ES2298970T3 (zh) |
FR (1) | FR2877338B1 (zh) |
GE (1) | GEP20074256B (zh) |
HR (1) | HRP20080119T5 (zh) |
MA (1) | MA27917A1 (zh) |
MX (1) | MXPA05011820A (zh) |
NO (1) | NO20055167L (zh) |
NZ (1) | NZ543358A (zh) |
PL (1) | PL1655030T3 (zh) |
PT (1) | PT1655030E (zh) |
SG (1) | SG121999A1 (zh) |
SI (1) | SI1655030T1 (zh) |
ZA (1) | ZA200508911B (zh) |
Families Citing this family (8)
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EP2404605B1 (en) * | 2004-08-25 | 2015-04-22 | Essentialis, Inc. | Pharmaceutical formulations of potassium ATP channel openers and uses thereof |
EP2404604B1 (en) | 2006-01-05 | 2019-02-06 | Essentialis, Inc. | Salts of potassium ATP channel openers and uses thereof |
WO2009006483A1 (en) * | 2007-07-02 | 2009-01-08 | Essentialis, Inc. | Salts of potassium atp channel openers and uses thereof |
US8124793B2 (en) * | 2007-11-27 | 2012-02-28 | Gail Marie Cronyn, legal representative | Derivatives of ethylene methanedisulfonate as cancer chemotherapeutic agents |
FR2943342B1 (fr) * | 2009-03-20 | 2011-03-04 | Servier Lab | Nouveaux derives de benzothiadiazepines,leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
WO2010111518A1 (en) * | 2009-03-27 | 2010-09-30 | Yale University | Treatment and prevention of white matter injury with katp channel activators |
FR2955106B1 (fr) * | 2010-01-08 | 2011-12-23 | Servier Lab | Nouveaux derives de benzothiadiazines cyclopropylees, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
KR101633632B1 (ko) | 2015-09-30 | 2016-06-27 | 김동용 | 방사능 차폐재 |
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FR2722502B1 (fr) | 1994-07-12 | 1996-08-23 | Adir | Nouveau derive de benzothiadiazine, son procede depreparation et les compositions pharmaceutiques qui le contiennent |
WO1998012185A1 (en) * | 1996-09-17 | 1998-03-26 | The Regents Of The University Of California | Benzothiadiazide derivatives and their use as allosteric up-modulators of the ampa receptor |
HUP0101280A3 (en) | 1998-02-18 | 2003-02-28 | Neurosearch As | Positive ampa receptor modulator compounds and their use |
FR2801587B1 (fr) * | 1999-11-30 | 2002-01-11 | Adir | Nouveaux derives de benzothiadiazines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR2833950B1 (fr) * | 2001-12-21 | 2005-12-16 | Servier Lab | Nouveaux derives de benzothiazine et de benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR2833956B1 (fr) * | 2001-12-21 | 2004-01-30 | Servier Lab | Nouveaux derives de benzothiazine et de benzothiadiazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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