CN1128757A - 1，4-二氢吡啶-3，5-二羧酸酯作为药物的用途 - Google Patents
1，4-二氢吡啶-3，5-二羧酸酯作为药物的用途 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- 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
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- C07D211/84—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 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及通式(I)的1，4-二氢吡啶-3，5-二羧酸酯(其中一些是已知的)(其中A和R1-R3具有说明书中所给定义)作为药物的应用，特别是用于治疗中枢神经系统疾病，以及本发明涉及新的经选择的活性化合物。
Description
本发明涉及1，4-二氢吡啶-3，5-二羧酸酯(其中一些是已知的)作为药物的用途，特别是用于治疗中枢神经系统疾病，以及本发明涉及新的经选择的活性化合物。
具有流变学活性的1-烷基-和1-环烷基-(1，4-二氢吡啶)-3，5-二羧酸酯已由DOS 40 11 695为人所知。具有冠状循环作用的1-N-取代的二氢吡啶类化合物，其对血管循环有影响，也已由DOS 1 813 436和DOS 1 923 990为人所知。特定的二氢吡啶尼莫地平(nimopidine)对大脑的作用已公开在DOS 2 815 578中。
现已发现通式(I)的1，4-二氢吡啶-3，5-二羧酸酯及其盐：
其中：
A代表6至10个碳原子的芳基或吡啶基，它们可以相同或不同方式被硝基、氰基、卤素、三氟甲基或被具有至多6个碳原子的直链或支链烷硫基任选取代至多3次，
R1和R2可相同或不同，且代表3至6个碳原子的环烷基或代表具有至多8个碳原子的直链或支链烷基，其可以相同或不同方式被具有至多4个碳原子的直链或支链烷氧基、卤素或被式-NR4R5的基团任选取代至多2次，
其中：R4和R5可相同或不同，且表示氢、苄基、苯基或具有至多4个碳原子的直链或支链烷基，和
R3代表3至6个碳原子的环烷基或代表具有至多6个碳原子的直链或支链烷基，其被羟基、苯基或被各自至多具有6个碳原子的直链或支链烷氧基或烷氧羰基任选取代，令人吃惊地对具有高传导性的钙依赖性钾通道具有选择性调节作用，因此适宜用于治疗中枢神经系统疾病，特别用于治疗神经元的疾病和用于治疗痴呆和抑郁症。
本发明优选涉及式(I)的这些二氢吡啶类化合物的用途，其实际上以通常剂量没有相应的钙激动作用或钙拮抗作用，但对钾通道有特殊的调节作用。
具有选择性商值Qse1至少为10的化合物被特别选出。该选择性商值被定义为按试验1所得的钾通道作用的数值和按试验2所得的钙通道作用的数值之间的商。
试验1(钾通道作用)：
从C6-BU1神经胶质瘤细胞中流出的86铷流量
该试验按Tas等人描述的方法(Neurosi.Lett.94，279-284，(1988))进行，略有变化。大鼠C6-BU1神经胶质瘤细胞培养物被用于这些试验。由数据计算出由伊屋诺霉素引起的86Rb流量超出基本流量的增加并设为100％，那么在试验物质存在下的刺激作用以此值为基础。
试验2(钙通道作用)：
该试验按D.J.Triggle方法(Molecular Pharmacol.35，541-52(1989))进行，略有差异。这里通过对在大鼠大脑膜均浆上的放射性标记的3(+)-PN-200-110的取代来测定物质对L-Ca通道的结合。结果用Ki值表示。
生理上可接受的盐一般为本发明化合物与无机或有机酸形成的盐。优选的盐为与无机酸形成的盐，所述无机酸为例如：盐酸、氢溴酸、磷酸或硫酸，或与有机羧酸或磺酸形成的盐，所述有机羧酸或磺酸为如乙酸、马来酸、富马酸、苹果酸、柠檬酸、酒石酸、乳酸或苯甲酸、或甲磺酸、乙磺酸、苯磺酸、甲苯磺酸或萘二磺酸。
本发明的化合物可以以立体异构体形式存在，其表现为镜像(对映体)或不表现为镜像(非对映体)。本发明涉及对映体和外消旋体形式，以及非对映体混合物。外消旋体形式，象非对映体一样，可以按已知方法被分成立体异构均一的成分。
优选使用的通式(I)的化合物为以下定义的化合物及其盐：其中：
A代表苯基、萘基或吡啶基，其可以相同或不同方式被硝基、氰基、氟、氯、溴、碘、三氟甲基或被具有至多4个碳原子的直链或支链烷硫基任选取代至多3次，
R1和R2可相同或不同，且代表环丙基、环戊基或环己基，或代表具有至多7个碳原子的直链或支链烷基，其可以相同或不同方式被具有至多3个碳原子的直链或支链烷氧基、氟、氯、溴或被式-NR4R5基团任选取代至多2次，
其中：
R4和R5可相同或不同，且代表氢、苄基、苯基或具有至多3个碳原子的直链或支链烷基，和
R3代表环丙基、环戊基或环己基，或代表具有至多5个碳原子的直链或支链烷基，其可被羟基、苯基或被各自具有至多5个碳原子的直链或支链烷氧基或烷氧羰基任选取代。
特别优选用于治疗大脑疾病的通式(I)化合物是以下定义的化合物及其盐：
其中：
A代表苯基、萘基或吡啶基，其可以相同或不同方式被硝基、氰基、氟、氯、溴、三氟甲基或被甲硫基任选取代至多2次，
R1和R2可相同或不同，且代表环丙基、环戊基或环己基，或代表具有至多6个碳原子的直链或支链烷基，其可以相同或不同方式被甲氧基、氟、氯、溴或被式-NR4R5基团任选取代至多2次，
其中：
R4和R5可相同或不同，且代表氢、苄基、苯基、甲基或乙基，和
R3代表环丙基、环戊基或环己基，或代表具有至多5个碳原子的直链或支链烷基，其被羟基、苯基、或各自具有至多3个碳原子的直链或支链烷氧基或烷氧羰基任选取代。
本发明还涉及新的被选择的通式(I)化合物和其盐，它们具有下表所示的取代基定义： R2 R1 R33-NO2，2-H -CH3 -CH3 -CH33-NO2，2-H -CH3 -CH3 -C2H53-NO2，2-H -C5H9 -CH3 -CH34-CF3，2-H -CH3 -CH3 -i-C4H94-CF3，2-H -CH(CH2F)2 -CH3 -CH34-CF3，2-H -CH3 -CH3 n-C4H94-CF3，2-H -CH3 -CH3 -(CH2)3COOCH34-CF3，2-H -CH3 -CH3 -CH2OCH2CH34-CF3，2-H s-C4H9 -CH3 -CH34-Cl，2-H -CH3 -CH3 CH2C6H54-Cl，2-H -CH3 -CH3
2-Cl，3-Cl -CH3 -CH3
4-F，3-H -CH3 -CH3 -CH2CH(CH3)24-CF3，3-Cl -CH3 -CH3 -CH34-CF3，3-Cl -CH3 -CH3
4-CF3，3-Cl -CH3 -CH3 -CH2CH2CH33-CF3，4-Cl -CH3 -CH3 -CH2CH2CH3H，H -CH3 -C2H5 -CH34-Cl，3-CF3 -CH3 -CH3
4-CF3，2-H -CH3 -CH3 -CH34-CF3，2-H -CH3 -CH3 -n-C3H7
通式(I)的化合物可用常规方法，例如用DOS 40 11 695中描述的方法制备。
本发明通式(I)的已知的和新的化合物表现出不可预见的作用谱。
它们是特别被选择的对高传导性的钙依赖性钾通道(BK(Ca)通道)，尤其是对中枢神经系统的钙依赖性钾通道具有选择性的通道调节剂。
基于它们的药理学性质，它们可用于制备用于治疗中枢变性疾病的药物，如痴呆的发作(多发梗塞性痴呆(MID)，原发性变性痴呆(PDD)，早老性和老年性阿尔茨海默氏病，HIV痴呆和其它形式的痴呆)，帕金森病或肌萎缩性测索硬化以及多发性硬化。
此外，所述活性化合物适于治疗与年龄相关的大脑性能障碍、器质性脑病综合症(OBS)和与年龄相关的记忆缺损(AAMI)。
它们适用于预防和治疗、和用于抗大脑循环障碍引起的后遗症，如大脑缺血、中风、颅脑损伤和蛛网膜下的出血。
它们可用于治疗抑郁症和精神病，例如精神分裂症。它们还适宜治疗神经内分泌失调和神经递质分泌失调，以及在健康方面的相关的失调，如躁狂、酒精中毒、药物滥用，瘾癖或病态饮食行为。其它应用领域是治疗偏头痛、睡眠失调和神经病。它们还适宜作为止痛药。
另外，这些活性化合物适宜治疗免疫系统失调，尤其是T细胞增殖。
本发明也涉及药物制剂，其除了惰性、无毒的药物上适宜的辅助剂和赋形剂外，还包括一种或多种通式(I)化合物，或者由一种或多种式(I)活性化合物组成，本发明还涉及制备这些制剂的方法。
式(I)的活性化合物按总混合物重量计，应以0.1-99.5％(重量)，优选0.5-95％(重量)的浓度存在于所述制剂中。
除了式(I)的活性化合物外，该药物制剂也可包括其它药物活性化合物。
上述药物制剂可用常规方式，按已知方法例如使用助剂或赋形剂来制备。
通常，已证明了为了得到所需结果，每24小时以总量约0.01至约100mg/kg，优选以总量约1mg/kg至50mg/kg体重给药式(I)活性化合物是有益的，如果必要的话可以几种单独剂量的形式。
然而，如果必要的话，偏离上述剂量也是有益的，尤其是取决于受治疗者的性质和体重、个体对药物的行为、疾病的性质和严重性、制剂的性质和给药的性质，以及给药的时间或间隔。
制备实施例：
按类似于DOS40 11 695中的方法制备实施例1-18的新化合物。表1：
Claims (6)
1.通式(I)的1，4-二氢吡啶-3，5-二羧酸酯和其盐作为对高传导性的钙依赖性钾通道具有选择性调节作用的药物的用途：
其中：
A代表6至10个碳原子的芳基或吡啶基，它们可以相同或不同方式被硝基、氰基、卤素、三氟甲基或被具有至多6个碳原子的直链或支链烷硫基任选取代至多3次，
R1和R2可相同或不同，且代表3至6个碳原子的环烷基或代表具有至多8个碳原子的直链或支链烷基，其可以相同或不同方式被具有至多4个碳原子的直链或支链烷氧基、卤素或被式-NR4R5的基团任选取代至多2次。
其中：R4和R5可相同或不同，且表示氢、苄基、苯基或具有至多4个碳原子的直链或支链烷基，和
R3代表3至6个碳原子的环烷基或代表具有至多6个碳原子的直链或支链烷基，其被羟基、苯基或被各自至多具有6个碳原子的直链或支链烷氧基或烷氧羰基任选取代。
2.根据权利要求1的通式(I)化合物在制备用于治疗中枢神经系统疾病的药物方面的用途。
3.具有选择性商值Qse1至少为10的根据权利要求1的通式(I)化合物用于治疗中枢神经系统疾病的用途。
4.选自实施例1至18的根据权利要求1的通式(I)新化合物。
5.具有对钾通道选择性调节作用的药物，其含有至少一种根据权利要求1的通式(I)的二氢吡啶。
6.具有对钾通道选择性调节作用的用于治疗中枢神经系统疾病的药物的制备方法，其特征在于至少一种根据权利要求1的通式(I)的化合物被转化为适宜的给药形式，如果必要的话可使用常规助剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4430094.8 | 1994-08-25 | ||
| DE4430094A DE4430094A1 (de) | 1994-08-25 | 1994-08-25 | Verwendung von 3,5-Dicarbonsäureester-1,4-Dihydropyridinen als Arzneimittel |
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| Publication Number | Publication Date |
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| CN1128757A true CN1128757A (zh) | 1996-08-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95116647A Pending CN1128757A (zh) | 1994-08-25 | 1995-08-24 | 1，4-二氢吡啶-3，5-二羧酸酯作为药物的用途 |
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| Country | Link |
|---|---|
| US (2) | US5665741A (zh) |
| EP (1) | EP0705819A1 (zh) |
| JP (1) | JPH0859468A (zh) |
| KR (1) | KR960007563A (zh) |
| CN (1) | CN1128757A (zh) |
| AU (1) | AU3011295A (zh) |
| CA (1) | CA2156673A1 (zh) |
| DE (1) | DE4430094A1 (zh) |
| EE (1) | EE9500055A (zh) |
| FI (1) | FI953957A (zh) |
| HU (1) | HUT74617A (zh) |
| IL (1) | IL115030A0 (zh) |
| NO (1) | NO953322L (zh) |
| PL (1) | PL310146A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103998038A (zh) * | 2011-11-24 | 2014-08-20 | 里皮达特发展研究及咨询公司 | 具有hsp调节活性的1,4-二氢吡啶衍生物 |
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| EP1191021A4 (en) * | 1999-06-23 | 2002-08-07 | Ajinomoto Kk | Dihydropyridine derivative |
| KR100875362B1 (ko) * | 2002-02-05 | 2008-12-22 | 아스텔라스세이야쿠 가부시키가이샤 | 2,4,6-트리아미노-1,3,5-트리아진 유도체 |
| US20050075359A1 (en) * | 2003-03-14 | 2005-04-07 | Rikako Kono | Large conductance calcium-activated K channel opener |
| CN104710441B (zh) * | 2014-12-18 | 2017-01-18 | 苏州科技学院 | 吡啶五甲酸二钾化合物及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE1813436C3 (de) * | 1968-12-07 | 1979-01-11 | Bayer Ag, 5090 Leverkusen | N-Substituierte 2,6-Dimethyl-l,4dihydropyridine |
| US3883543A (en) * | 1969-05-10 | 1975-05-13 | Bayer Ag | N-alkyl-1,4-dihydropyridines |
| DE1923990C3 (de) | 1969-05-10 | 1978-11-23 | Bayer Ag | Verfahren zur Herstellung von N-substituierten M-Dihydropyridin-S.S-dicarbonsäureestern |
| JPS4899181A (zh) * | 1972-04-04 | 1973-12-15 | ||
| DE2815578C2 (de) * | 1978-04-11 | 1986-01-16 | Bayer Ag, 5090 Leverkusen | Neue pharmazeutische Verwendung von Nimodipin |
| DE3809912A1 (de) * | 1987-03-27 | 1988-10-27 | Byk Gulden Lomberg Chem Fab | Neue zwischenprodukte zur herstellung von 1,4-dihydropyridin-3,5-dicarbonsaeurederivaten |
| DE4011695A1 (de) | 1990-04-11 | 1991-10-17 | Bayer Ag | Verwendung von n-alkylierten 1,4-dihydropyridindicarbonsaeureestern als arzneimittel, neue verbindungen und verfahren zu ihrer herstellung |
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1994
- 1994-08-25 DE DE4430094A patent/DE4430094A1/de not_active Withdrawn
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1995
- 1995-08-14 EP EP95112766A patent/EP0705819A1/de not_active Withdrawn
- 1995-08-17 AU AU30112/95A patent/AU3011295A/en not_active Abandoned
- 1995-08-18 US US08/516,668 patent/US5665741A/en not_active Expired - Fee Related
- 1995-08-18 JP JP7232035A patent/JPH0859468A/ja active Pending
- 1995-08-22 CA CA002156673A patent/CA2156673A1/en not_active Abandoned
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- 1995-08-24 EE EE9500055A patent/EE9500055A/xx unknown
- 1995-08-24 KR KR1019950026301A patent/KR960007563A/ko not_active Application Discontinuation
- 1995-08-24 CN CN95116647A patent/CN1128757A/zh active Pending
- 1995-08-24 NO NO953322A patent/NO953322L/no unknown
- 1995-08-25 HU HU9502509A patent/HUT74617A/hu unknown
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103998038A (zh) * | 2011-11-24 | 2014-08-20 | 里皮达特发展研究及咨询公司 | 具有hsp调节活性的1,4-二氢吡啶衍生物 |
| CN110606822A (zh) * | 2011-11-24 | 2019-12-24 | 里克特吉迪翁公司 | 具有hsp调节活性的1,4-二氢吡啶衍生物 |
Also Published As
| Publication number | Publication date |
|---|---|
| HUT74617A (en) | 1997-01-28 |
| CA2156673A1 (en) | 1996-02-26 |
| KR960007563A (ko) | 1996-03-22 |
| JPH0859468A (ja) | 1996-03-05 |
| PL310146A1 (en) | 1996-03-04 |
| FI953957A (fi) | 1996-02-26 |
| FI953957A0 (fi) | 1995-08-23 |
| EP0705819A1 (de) | 1996-04-10 |
| DE4430094A1 (de) | 1996-02-29 |
| IL115030A0 (en) | 1995-12-08 |
| NO953322L (no) | 1996-02-26 |
| US5955482A (en) | 1999-09-21 |
| AU3011295A (en) | 1996-03-07 |
| EE9500055A (et) | 1996-04-15 |
| US5665741A (en) | 1997-09-09 |
| NO953322D0 (no) | 1995-08-24 |
| HU9502509D0 (en) | 1995-10-30 |
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