CN1599604A - 4-氧代丁酸衍生物在治疗炎症中的用途 - Google Patents
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Abstract
本发明涉及4-氧代丁酸衍生物用于制备治疗炎症的药物组合物的用途。
Description
本发明涉及4-氧代丁酸衍生物用于制备治疗炎症的药物组合物的用途。
在专利申请WO 98/07681中描述了用作抗糖尿病药、尤其是用于治疗非胰岛素依赖型糖尿病的4-氧代丁酸衍生物。
因此,本专利申请首先涉及通式(I)的至少一种4-氧代丁酸衍生物用于制备治疗炎症的药物的用途。
式(I)化合物的定义如下:
其中基团A和B彼此独立地选自:
-含有6至14个碳原子的单-、双-或三环芳基;
-选自吡啶基、嘧啶基、吡咯基、呋喃基和噻吩基的杂芳基;
-含有1至14个碳原子的烷基;
-含有5至8个碳原子的环烷基;
-选自四氢呋喃基、四氢吡喃基、哌啶基和吡咯烷基的饱和杂环基;
其中基团A和B可以带有1至3个选自以下的取代基:C1-C6烷基、C1-C6烷氧基、C6-C14芳基、选自吡啶基、嘧啶基、吡咯基、呋喃基和噻吩基的杂芳基、(C6-C14)芳基(C1-C6)烷基、(C6-C14)芳基(C1-C6)烷基(C6-C14)芳基、卤素或三氟甲基、三氟甲氧基、氰基、羟基、硝基、氨基、羧基、(C1-C6)烷氧基羰基、氨基甲酰基、(C1-C6)烷基磺酰基、磺氨基、(C1-C6)烷基磺酰氨基、氨磺酰基或(C1-C6)烷基羰基氨基;
或取代基中的两个取代基形成亚甲二氧基,其溶剂合物或该酸的盐。
在本发明的优选实施方案中,4-氧代丁酸是那些其中的A和B选自芳基的式(I)化合物。
可提及的芳基的例子包括苯基、α-萘基、β-萘基和芴基。
C1-C6烷基可以是直链或支链的。可提及的例子包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基和戊基。
C1-C6烷氧基也可以是直链或支链的。
可提及的例子包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基和异丁氧基。
卤素可选自氟、氯、溴和碘。
本发明还包括通式(I)化合物的互变异构体形式、这些化合物的对映异构体、非对映异构体和差向异构体,以及其溶剂合物。
通式(I)化合物的盐的例子包括药理学可接受的盐,如钠盐、钾盐、镁盐、钙盐、胺盐和其它同类型(铝、铁、铋等)的盐。
在优选的实施方案中,4-氧代丁酸选自:
-2-苄基-4-(4-甲氧基苯)-4-氧代丁酸
-2-苄基-4-(4-氟苯基)-4-氧代丁酸
-2-环己基甲基-4-(4-甲氧基苯基)-4-氧代丁酸
-2-苄基-4-苯基-4-氧代丁酸
-2-(β-萘基甲基)-4-苯基-4-氧代丁酸
-2-苄基-4-(β-萘基)-4-氧代丁酸
-2-[(4-氯苯基)甲基]-4-(4-甲氧基苯基)-4-氧代丁酸
-2-苄基-4-(4-甲基苯基)-4-氧代丁酸
-4-(4-氟苯基)-2-[(4-甲氧基苯基)甲基]-4-氧代丁酸
-2-苄基-4-(3,4-亚甲二氧基苯基)-4-氧代丁酸
-2-苄基-4-环己基-4-氧代丁酸
-4-苯基-2-[(四氢呋喃-2-基)甲基]-4-氧代丁酸,
-这些酸的溶剂合物、对映异构体和盐。
优选地,4-氧代丁酸衍生物选自:
-(-)-2-苄基-4-(4-甲氧基苯基)-4-氧代丁酸
-(+)-2-苄基-4-(4-甲氧基苯基)-4-氧代丁酸
-(-)-2-苄基-4-(4-氟苯基)-4-氧代丁酸
-(+)-2-苄基-4-(4-氟苯基)-4-氧代丁酸,
-这些酸的溶剂合物和盐。
最为优选的化合物是2-苄基-4-(4-氟苯基)-4-氧代丁酸、其溶剂合物、其对映异构体和其盐。
将式(I)的化合物进行生物学试验以证实它们的抗炎活性。用大鼠的炎症实验模型研究了式(I)化合物的体内活性。通过在大鼠的后足皮内注射角叉菜胶(1%V/V)诱发大鼠足的炎性水肿。根据Winter C.A.等(Proc.Soc.Exp.Biol.Med.;(1962);
111;544-547)的方法,用器官充满度测量法测量上述水肿。具有抗炎作用的物质使如此造成的水肿减轻。在试验中以吲哚美辛作为抗炎参比物。
结果表明式(I)的化合物具有体内抗炎特性。可以预防性地或治愈性地进行炎症治疗。
因此,就此而言,它们可用于轻微至中等强度的疼痛病症和/或发热病症的症状治疗,更具体而言,可用于治疗糖尿病性神经病、多关节炎、关节病、腰痛、创伤性疼痛和ORL炎症。
根据本发明,所治疗的炎症可以与胰岛素抵抗代谢综合征的病理学、与糖尿病引起的病理学有关,例如视网膜病、肾病、神经病、微血管病和大血管病、高血压或动脉粥样硬化。具体而言,血糖控制差的糖尿病患者易于罹患与炎性过程相关的动脉粥样斑感染[Endocr.;2000,6(3),272-276]。所述炎症也可以与中枢起源的病理学有关,例如神经变性疾病如尤其是阿尔茨海默病或帕金森病[Lancet;2001,8月11日,358(9280),436、J.Neuropathol.Exp.Neurol.2001;10月;60(10);923]。
本发明的化合物可以与任何适合的赋形剂组合、以任何适于经肠(更具体而言是口服)或经胃肠外施用的形式,例如以片剂、软胶囊剂、散剂、糖衣片或口服液或注射液形式存在。这些适合的形式和适合的赋形剂如申请人提交的专利申请WO 98/7681中所定义。
式(I)的化合物可以向成年人以约1至400mg的日剂量口服施用或以0.1至200mg的日剂量经胃肠外施用。
以下实施例阐述了本发明,但不限制本发明。
实施例
·实验资料:
动物模型:Wistar种大鼠
抗炎参比物:Sigma公司的吲哚美辛
对照物:0.5%甲基纤维素水凝胶。
禁食一天后,测量右后足体积[V足]。以10ml/kg的量口服施用受试化合物、参比物和对照物。施用1小时后,通过在右后足足底内(intraplantar)注射50微升角叉菜胶(1%,V/V)水凝胶诱发水肿。诱发水肿后3小时测量该足体积。用注射角叉菜胶之前和之后3小时的该足的体积之差评价水肿强度[V水肿]。
在下表中对结果进行了比较:
角叉菜胶诱发的炎性水肿试验
V足(ml) | V水肿(ml) | 水肿减轻(%) | |
对照物 | 1.65 | 0.62 | -- |
吲哚美辛 | 1.65 | 0.20 | -67 |
P(30mg) | 1.57 | 0.42 | -32 |
P(100mg) | 1.67 | 0.11 | -83 |
P(300mg) | 1.71 | 0.17 | -73 |
P相当于(-)-2-苄基-4-(4-氟苯基)4-氧代丁酸。
实验结果证明了通式(I)化合物的抗炎作用。
Claims (8)
1.式(I)的至少一种4-氧代丁酸衍生物用于制备治疗炎症的药物的用途,式(I)的定义如下:
其中基团A和B彼此独立地选自:
-含有6至14个碳原子的单-、双-或三环芳基;
-选自吡啶基、嘧啶基、吡咯基、呋喃基和噻吩基的杂芳基;
-含有1至14个碳原子的烷基;
-含有5至8个碳原子的环烷基;
-选自四氢呋喃基、四氢吡喃基、哌啶基和吡咯烷基的饱和杂环基;
其中基团A和B可以带有1至3个选自以下的取代基:C1-C6烷基、C1-C6烷氧基、C6-C14芳基、选自吡啶基、嘧啶基、吡咯基、呋喃基和噻吩基的杂芳基、(C6-C14)芳基(C1-C6)烷基、(C6-C14)芳基(C1-C6)烷基(C6-C14)芳基、卤素或三氟甲基、三氟甲氧基、氰基、羟基、硝基、氨基、羧基、(C1-C6)烷氧基羰基、氨基甲酰基、(C1-C6)烷基磺酰基、磺氨基、(C1-C6)烷基磺酰氨基、氨磺酰基或(C1-C6)烷基羰基氨基;
或取代基中的两个取代基形成亚甲二氧基,其溶剂合物或该酸的盐。
2.权利要求1的用途,其特征在于4-氧代丁酸衍生物选自:
-2-苄基-4-(4-甲氧基苯基)-4-氧代丁酸
-2-苄基-4-(4-氟苯基)-4-氧代丁酸
-2-环己基甲基-4-(4-甲氧基苯基)-4-氧代丁酸
-2-苄基-4-苯基-4-氧代丁酸
-2-(β-萘基甲基)-4-苯基-4-氧代丁酸
-2-苄基-4-(β-萘基)-4-氧代丁酸
-2-[(4-氯苯基)甲基]-4-(4-甲氧基苯基)-4-氧代丁酸
-2-苄基-4-(4-甲基苯基)-4-氧代丁酸
-4-(4-氟苯基)-2-[(4-甲氧基苯基)甲基]-4-氧代丁酸
-2-苄基-4-(3,4-亚甲二氧基苯基)-4-氧代丁酸
-2-苄基-4-环己基-4-氧代丁酸
-4-苯基-2-[(四氢呋喃-2-基)甲基]-4-氧代丁酸,
-这些酸的溶剂合物、对映异构体和盐。
3-权利要求1或2的用途,其特征在于式(I)的化合物选自:
-(-)-2-苄基-4-(4-甲氧基苯基)-4-氧代丁酸
-(+)-2-苄基-4-(4-甲氧基苯基)-4-氧代丁酸
-(-)-2-苄基-4-(4-氟苯基)-4-氧代丁酸
-(+)-2-苄基-4-(4-氟苯基)-4-氧代丁酸,
-这些酸的溶剂合物和盐。
4.以上权利要求之一的用途,其特征在于所述药物旨在用于轻微至中等强度的疼痛病症和/或发热病症的症状治疗。
5.权利要求1至3之一的用途,其特征在于所述药物旨在用于治疗糖尿病性神经病、多关节炎、关节病、腰痛、创伤性疼痛或ORL炎症。
6.权利要求1至3之一的用途,其特征在于所述药物旨在用于治疗与胰岛素抵抗代谢综合征的病理学相关的炎症。
7.权利要求1至3中任意一项的用途,其特征在于所述药物旨在用于治疗与糖尿病引起的病理学、特别是选自视网膜病、肾病、神经病、微血管病或大血管病、高血压和动脉粥样硬化的疾病相关的炎症。
8.权利要求1至3中任意一项的用途,其特征在于所述药物旨在用于治疗与中枢起源的病理学、特别是选自神经变性疾病的病症相关的炎症。
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Application Number | Priority Date | Filing Date | Title |
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FR01/15601 | 2001-12-03 | ||
FR0115601A FR2832925B1 (fr) | 2001-12-03 | 2001-12-03 | Utilisation de derives de l'acide 4-oxobutanoique dans le traitement de l'inflammation |
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US (1) | US7897644B2 (zh) |
EP (1) | EP1450780B1 (zh) |
JP (1) | JP2005511654A (zh) |
KR (1) | KR20050043728A (zh) |
CN (1) | CN1599604A (zh) |
AT (1) | ATE355834T1 (zh) |
AU (1) | AU2002342883B2 (zh) |
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CA (1) | CA2468910C (zh) |
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PL (1) | PL369845A1 (zh) |
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ES2368692T3 (es) | 2007-12-03 | 2011-11-21 | Merck Patent Gmbh | Utilización de derivados del ácido 4-oxobutanoico en el tratamiento de patologías asociadas con trastornos inmunológicos. |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
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US3784701A (en) * | 1970-09-21 | 1974-01-08 | American Cyanamid Co | Compositions containing substituted benzoylpropionic acids and method of use to treat inflammation and pain |
JPS59144717A (ja) * | 1983-02-07 | 1984-08-18 | Microbial Chem Res Found | 鎮痛剤 |
US5789434A (en) * | 1994-11-15 | 1998-08-04 | Bayer Corporation | Derivatives of substituted 4-biarylbutyric acid as matrix metalloprotease inhibitors |
GB9522615D0 (en) * | 1995-11-03 | 1996-01-03 | Pharmacia Spa | 4-Phenyl-4-oxo-butanoic acid derivatives with kynurenine-3-hydroxylase inhibiting activity |
CO5011113A1 (es) * | 1996-05-15 | 2001-02-28 | Bayer Corp | Derivados de acido 3-arilbutirico sustituido como inhibidores de la metaloproteasa de matriz y composiciones farmaceuticas que los contienen |
FR2752422B1 (fr) * | 1996-08-16 | 1998-11-06 | Lipha | Composition pharmaceutique contenant des acides 4-oxo-butanoiques |
FR2777566B1 (fr) | 1998-04-15 | 2003-02-21 | Synthelabo | Derives d'azacycloalcanes, leur preparation et leur application en therapeutique |
US6060250A (en) * | 1998-06-30 | 2000-05-09 | Incyte Pharmaceuticals, Inc. | Human transferases |
AU4229499A (en) * | 1998-07-30 | 2000-02-21 | Warner-Lambert Company | Tricyclic heteroaromatics and their derivatives as inhibitors of matrix metalloproteinases |
FR2793411B1 (fr) * | 1999-05-11 | 2001-06-29 | Synthelabo | Utilisation de derives de l'acide succinique pour obtenir un medicament destine au traitement de l'inflammation |
EP1295609A4 (en) * | 2000-02-24 | 2004-11-03 | Takeda Chemical Industries Ltd | DRUGS CONTAINING COMBINED ACTIVE INGREDIENTS |
-
2001
- 2001-12-03 FR FR0115601A patent/FR2832925B1/fr not_active Expired - Fee Related
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2002
- 2002-11-06 US US10/497,491 patent/US7897644B2/en not_active Expired - Fee Related
- 2002-11-06 PL PL02369845A patent/PL369845A1/xx unknown
- 2002-11-06 KR KR1020047006346A patent/KR20050043728A/ko not_active Application Discontinuation
- 2002-11-06 MX MXPA04005265A patent/MXPA04005265A/es unknown
- 2002-11-06 WO PCT/EP2002/012357 patent/WO2003047561A1/en active IP Right Grant
- 2002-11-06 CN CNA028241045A patent/CN1599604A/zh active Pending
- 2002-11-06 EP EP02779532A patent/EP1450780B1/en not_active Expired - Lifetime
- 2002-11-06 ES ES02779532T patent/ES2280589T3/es not_active Expired - Lifetime
- 2002-11-06 AT AT02779532T patent/ATE355834T1/de not_active IP Right Cessation
- 2002-11-06 BR BR0214644-4A patent/BR0214644A/pt not_active IP Right Cessation
- 2002-11-06 HU HU0402242A patent/HUP0402242A3/hu unknown
- 2002-11-06 JP JP2003548817A patent/JP2005511654A/ja not_active Ceased
- 2002-11-06 AU AU2002342883A patent/AU2002342883B2/en not_active Ceased
- 2002-11-06 CA CA2468910A patent/CA2468910C/en not_active Expired - Fee Related
- 2002-11-06 DE DE60218726T patent/DE60218726T2/de not_active Expired - Lifetime
- 2002-11-06 RU RU2004120557/15A patent/RU2004120557A/ru not_active Application Discontinuation
- 2002-11-29 TW TW091134839A patent/TW200300670A/zh unknown
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2004
- 2004-07-01 ZA ZA200405246A patent/ZA200405246B/en unknown
Also Published As
Publication number | Publication date |
---|---|
TW200300670A (en) | 2003-06-16 |
FR2832925A1 (fr) | 2003-06-06 |
EP1450780A1 (en) | 2004-09-01 |
HUP0402242A3 (en) | 2006-01-30 |
EP1450780B1 (en) | 2007-03-07 |
DE60218726D1 (de) | 2007-04-19 |
AU2002342883B2 (en) | 2007-11-29 |
FR2832925B1 (fr) | 2006-07-14 |
ZA200405246B (en) | 2005-06-24 |
AU2002342883A1 (en) | 2003-06-17 |
KR20050043728A (ko) | 2005-05-11 |
US20050014768A1 (en) | 2005-01-20 |
MXPA04005265A (es) | 2004-10-11 |
JP2005511654A (ja) | 2005-04-28 |
PL369845A1 (en) | 2005-05-02 |
CA2468910C (en) | 2012-01-03 |
US7897644B2 (en) | 2011-03-01 |
WO2003047561A1 (en) | 2003-06-12 |
HUP0402242A2 (hu) | 2005-02-28 |
ATE355834T1 (de) | 2007-03-15 |
CA2468910A1 (en) | 2003-06-12 |
BR0214644A (pt) | 2004-11-03 |
DE60218726T2 (de) | 2007-11-15 |
ES2280589T3 (es) | 2007-09-16 |
RU2004120557A (ru) | 2005-05-10 |
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