CN1270713C - 一种用于预防或治疗糖尿病的协同药物组合物 - Google Patents
一种用于预防或治疗糖尿病的协同药物组合物 Download PDFInfo
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- CN1270713C CN1270713C CNB02814340XA CN02814340A CN1270713C CN 1270713 C CN1270713 C CN 1270713C CN B02814340X A CNB02814340X A CN B02814340XA CN 02814340 A CN02814340 A CN 02814340A CN 1270713 C CN1270713 C CN 1270713C
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- addition salts
- acid
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- diabetes
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Abstract
本发明涉及一种协同药物组合物,包括(a)第一药物组合物,它含有抗糖尿病或抗高血脂活性剂或者和一种或多种常规载体,和(b)第二药物组合物,它含有式(I)的羟肟酸衍生物和一种或多种常规载体。该药物组合物尤其适用于预防或治疗糖尿病。
Description
本发明涉及一种适用于预防或治疗前驱糖尿病状态、代谢X-综合征或糖尿病以及与上面所列状态有关的紊乱,即内源代谢紊乱、胰岛素抗性、血脂异常、脱发、弥漫性脱发和/或以产生雄性征优势为基础的女性内分泌紊乱的协同药物组合物。
在工业发达国家,越来越多的人患有糖尿病。例如,因产生和使用胰岛素的缺陷促进了2型糖尿病(即非胰岛素依赖性糖尿病,NIDDM)出现。遗传和环境因素同等地导致了这种广泛分布的严重疾病的形成,并伴随着显著的死亡率。事实上,用胰岛素或另一抗糖尿病或抗高血脂药物治疗的患者仅获得减轻的治疗,其提高了生命质量,然而不可避免地出现糖尿病所伴随的并发症。
本发明的目的是提供一种药物组合物,它适用于预防糖尿病的产生或者至少糖尿病所伴随的并发症,或者,如果这种预防不再可能时,用于有效治疗所述并发症。
发现上述目的是通过一种包括如下组合物的协同药物组合物实现的:
(a)第一药物组合物,它含有一种抗糖尿病或抗高血脂活性剂和一种或多种常规载体,和
(b)第二药物组合物,它含有下式的羟肟酸衍生物或其药用合适的酸加成盐以及一种或多种常规载体,
其中
R1代表氢原子或C1-5烷基,
R2代表氢原子、C1-5烷基、C3-8环烷基或任选被羟基或苯基取代的苯基,或者
R1和R2与和它们相连的氮原子一起形成5-至8-元环,这些环任选含有一种或多种另外的氮、氧或硫原子,并且所述环可以与另一脂族环或杂环缩合,所述另一环优选苯环、萘环、喹啉环、异喹啉环、吡啶环或吡唑啉环,而且任选所述氮和/或硫杂原子以氧化物或二氧化物的形式存在,
R3代表氢原子、苯基、萘基或吡啶基,其中所述基团可以被一个或多个卤原子或C1-4烷氧基取代,
Y是氢原子、羟基、任选被氨基取代的C1-24烷氧基、含有1-6个双键的C2-24聚链烯氧基、C1-25烷酰基、C3-9链烯酰基(alkenoyl)或R7-COO-的基团,其中R7代表含有1-6个双键的C2-30聚链烯基,
X代表卤原子、氨基、C1-4烷氧基或者
X与B形成一个氧原子,或者
X和Y与和它们相连的碳原子以及在所述碳原子之间的-NR-O-CH2-基团一起形成下式的环
其中
Z代表氧原子或者式-N=或-NH-的基团,
R代表氢原子或者
R与B形成一化学键,
A是C1-4亚烷基或一化学键或者下式的基团:
其中
R4代表氢原子、C1-5烷基、C3-8环烷基或任选被卤原子、C1-4烷氧基或C1-5烷基取代的苯基,
R5代表氢原子、C1-4烷基或苯基,
m具有值0、1或2,
n具有值0、1或2。
本发明以式I的羟肟酸衍生物增强胰岛素的敏感性的认识为基础。因此,在有式I的羟肟酸衍生物或其药用合适的酸加成盐的存在下,用于治疗该病理状态的抗糖尿病或抗高血脂活性剂可以相当低的剂量给予以获得目标效果,由此降低或消除了传统治疗伴随的副作用。
从美国专利4,308,399和EP 417 210得知式I的羟肟酸衍生物。根据这些文献,这些化合物可用于治疗糖尿病血管病,并且它们中间一部分具有选择性β-阻断效果。
根据以编号T/66350公布的匈牙利专利申请号2385/92,式I范围内的某些羟肟酸衍生物可用于治疗因糖尿病引起的血管并发症。
式I的羟肟酸衍生物的各种其它生物效应也为已知,其中尤其是其用于预防和治疗线粒体源的疾病(WO 97/13504),用于增强细胞的应力蛋白质水平(WO 97/16439),用于延迟皮肤老化进程(WO 97/23198),抗自身免疫疾病(WO 00/07580)等。
说明书和权利要求书中所用的术语的定义:
药物组合物是两种药用活性剂的结合,其中
1)使用一种或多种常规载体以及任意常规的制药方法将每一种活性剂一个接一个地转化为单独的药物组合物,并且在这种情况下所得两类药物组合物同时给予患者或者先给予其中一个,间隔一定时间后再给予另一个;
2)或者两种活性剂已转化成单一的药物组合物,可以将该组合物给予需要它的患者。在后一情况下,药物组合物可以含有两种活性剂的混合物、或者每一种活性剂可以存在于药物组合物的不同部位,例如它们其一在片剂核芯,另一个在片剂核芯的涂层中。当然,使用一种或多种常规载体和任意常规的制药方法制备该单一药物组合物。
抗糖尿病活性剂是指常用于治疗糖尿病的任何药用活性剂。它们主要是以下物质:
-胰岛素,
-胰岛素增敏活性剂(Sensitizing active agent),
-提高胰岛素产生的活性剂,
-磺胺类,
-双胍衍生物和
-α-葡糖苷酶抑制剂。
作为胰岛素,首先,使用通过重组技术制得的人胰岛素,一般来说将其经非肠道给药。
胰岛素增敏活性剂提高胰岛素的效果。它们中间最重要的类型是PPAR(过氧物酶体增殖剂-活化受体)γ-激动剂,例如噻唑烷二酮衍生物,诸如吡格列酮[(±)-5-[[4-[2-(5-乙基-2-吡啶基)乙氧基]苯基]甲基]-2,4-噻唑烷二酮]、曲格列酮[(±)-5-[[4-[(3,4-二氢-6-羟基-2,5,7,8-四甲基-2H-1-苯并吡喃-2-基)甲氧基]-苯基]甲基]-2,4-噻唑烷二酮]、环格列酮[5-[[4-[(1-甲基环己基)甲氧基]苯基]甲基]-2,4-噻唑烷二酮、罗格列酮(rosiglitazone)[(±)-5-[4-[2-[N-甲基-N-(2-吡啶基)氨基]-乙氧基]苄基]-2,4-噻唑烷二酮]和其它2,4-噻唑烷二酮衍生物及其药用合适的酸加成盐。
提高胰岛素产生的活性剂如下:米格列萘(mitiglinide)[(αS,3αR,7aS)-八氢-γ-氧代-α-(苯基甲基)-2H-异吲哚-2-丁酸]、瑞格列奈[(S)-2-乙氧基-4-[2-[[3-甲基-1-[2-(1-哌啶基)苯基]丁基]氨基]-2-氧代乙基]苯甲酸]、司格列奈(senaglinide)(即nateglinide)[N-[[(反-4-(1-甲基乙基)-环己基]羰基]-D-苯基丙氨酸]或药用合适的酸加成盐或其药用合适的盐。
磺胺类中,最重要的是磺酰脲衍生物,例如甲苯磺丁脲[N-[(丁基氨基)-羰基]-4-甲基苯磺酰胺]、氯磺丙脲[4-氯-N-[(丙基氨基)羰基]苯磺酰胺]、妥拉磺脲[N-[[(六氢-1H-吖庚因-1-基)氨基]羰基]-4-甲基苯磺酰胺]、醋磺己脲[4-乙酰基-N-[(环己基氨基)羰基]苯磺酰胺]等等作为第一代磺酰脲类,或者例如格列本脲[5-氯-N-[2-[4-[[[(环己基氨基)羰基]氨基]磺酰基]苯基]乙基]-2-甲氧基苯甲酰胺]、格列吡嗪[N-[2-[4-[[[(环己基氨基)羰基]氨基]磺酰基]苯基]乙基]-5-甲基吡嗪甲酰胺]、格列齐特[N-[[(六氢环戊[c]吡咯-2(1H)-基)氨基]羰基]-4-甲基苯磺酰胺]、格列美脲[反-3-乙基-2,5-二氢-4-甲基-N-[2-[4-[[[[(4-甲基环己基)氨基]羰基]氨基]磺酰基]苯基]乙基]-2-氧代-1H-吡咯-1-甲酰胺]、格列喹酮[N-[(环己基-氨基)羰基]-4-[2-(3,4-二氢-7-甲氧基-4,4-二甲基-1,3-二氧代-2(1H)-异喹啉基)乙基]苯磺酰胺]、格列波脲[N-[[(3-羟基-4,7,7-三甲基双环[2.2.1]庚-2-基)氨基]羰基]-4-甲基苯磺酰胺]、格列派特[N-[2-[4-[[[[(六氢-1H-吖庚因-1-基)氨基]羰基]氨基]-磺酰基]苯基]乙基]-5-甲基-3-异噁唑甲酰胺]、格列本脲[5-氯-N-[2-[4-[[[(环己基氨基)羰基]-氨基]磺酰基]苯基]乙基]-2-甲氧基苯甲酰胺]、格列生脲[N-[2-[4-[[[(环戊基氨基)羰基]氨基]磺酰基]苯基]乙基]-2-甲氧基苯甲酰胺]、格列索脲[N-[2-[4[[[(环己基氨基)羰基]氨基]磺酰基]苯基]乙基]-5-甲基-3-异噁唑甲酰胺]、格列丁唑[N-[5-(1,1-二甲基乙基)-1,3,4-噻二唑-2-基]苯磺酰胺]、格列吡脲[4-氯-N-[(1-吡咯烷基氨基)羰基]苯磺酰胺]等等作为第二代磺酰脲类及其药用合适的酸加成盐。
最重要的双胍衍生物可以通过下式表征:
其中
R8、R9、R10和R11独立地代表氢原子、C1-10烷基、萘基、苯基或苯基(C1-4烷基)基团,其中在前面两种情况下苯基任选被1-3个取代基取代,这些取代基可以独立地是卤原子、C1-4烷基或C1-4烷氧基,条件是R8、R9、R10和R11之一不是氢原子,或者
R8和R9与相邻氮原子一起和/或R10和R11与相邻氮原子一起形成一5-或6-元、饱和、不饱和或芳族环,这些环可以与另一5-或6-元饱和、不饱和或芳族环(任选也含有一个氮原子)稠合。
特别优选的双胍衍生物是甲福明[N,N-二甲基亚氨基甲亚氨基二酰胺]、丁福明[N-丁基亚氨基二碳亚氨基二酰胺]和苯乙福明[N-(2-苯基乙基)亚氨基二碳亚氨基二酰胺]。
α-葡糖苷酶抑制剂抑制酶α-葡糖苷酶。其重要的代表是例如米格列醇[1,5-二脱氧-1,5-[(2-羟基乙基)亚氨基]-D-葡萄糖醇]、阿卡糖[O-4,6-二脱氧-4-[[[1S-(1α,4α,5β,6α)]-4,5,6-三羟基-(3-羟基甲基)-2-环己烯-1-基]氨基]-α-D-吡喃葡萄糖基-(1→4)-O-α-D-吡喃葡萄糖基-(1→4)-D-葡萄糖]、伏格列波糖[3,4-二脱氧-4-[[2-羟基-1-(羟基甲基)乙基]氨基]-2-C-(羟基甲基)-D-表肌醇]等等。
抗高血脂活性剂是指常用于治疗高血脂水平的任何药用活性剂。它们是可以分类成如下的化合物:
芳氧基链烷酸衍生物,
HMG辅酶还原酶抑制剂,
烟酸衍生物,
用于胆汁酸的抗酸剂。
在芳氧基链烷酸衍生物中,优选的活性剂是例如氯贝特[2-(4-氯苯氧基)-2-甲基-丙酸乙酯]、吉非贝齐[5-(2,5-二甲基-苯氧基)-2,2-二甲基戊酸]、双贝特[2-(4-氯-苯氧基)-2-甲基丙酸1,3-丙二酯]、依托贝特[3-吡啶甲酸2-[2-(4-氯苯氧基)-2-甲基-1-氧代丙氧基]乙酯]、环丙贝特[2-[4-(2,2-二氯环丙基)苯氧基]-2-甲基丙酸]、氯烟贝特[3-吡啶甲酸3-[2-(4-氯苯氧基)-2-甲基-1-氧代丙氧基]丙酯]等等。
在HMG辅酶还原酶抑制剂中,最重要的活性剂如下:洛伐他汀[[1S-[1α(R*),3α,7β,8β(2S*,4S*),8αβ]]-2-甲基丁酸1,2,3,7,8,8α-六氢-3,7-二甲基-8-[2-(四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1-萘酯]、氟伐他汀[[R*,S*-(E)]-(±)-7-[3-(4-氟苯基)-1-(1-甲基-乙基)-1H-吲哚-2-基]-3,5-二羟基-6-庚酸]、普伐他汀[[1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-1,2,6,7,8,8a-六氢-β,δ,6-三羟基-2-甲基-8-(2-甲基-1-氧代丁氧基)-1-萘庚酸一钠盐]、辛伐他汀[[1S-[1α,3α,7β,8β(2S*,4S*),8αβ]]-2,2-二甲基丁酸1,2,3,7,8,8a-六氢-3,7-二甲基-8-[2-(四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1-萘酯]、阿托伐他汀[[R-(R*,R*)]-2-(4-氟苯基)-β,δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸]等等。
在烟酸衍生物中,例如使用以下的:阿昔莫司[5-甲基吡嗪甲酸4-氧化物]、戊四烟酯[3-吡啶甲酸2,2-双[[(3-吡啶基羰基)氧基]甲基]-1,3-丙二酯]、尼可莫尔[3-吡啶甲酸(2-羟基-1,3-环己二亚基)-四(亚甲基)酯]、尼可氯酯[3-吡啶甲酸1-(4-氯苯基)-2-甲基丙酯]等等。
在结合胆汁酸的抗酸剂中,重要的是如下:考来替泊[一种碱性阴离子交换树脂:带有(氯甲基)环氧乙烷的N-(2-氨基乙基)-N’-[2-[(2-氨基乙基)氨基]-乙基]-1,2-乙二胺聚合物]、考来烯胺[一种合成的强碱性阴离子交换树脂,含有与苯乙烯-二乙烯基苯共聚物相连的季铵官能团]、polidexide[一种阴离子交换树脂,含有结合肠内胆汁酸的季铵基团]等等。
抗糖尿病和抗高血脂活性剂从文献中可以了解到。如果需要并且化学上可能的话,这些活性剂可以其药用合适的酸加成盐的形式或者以与药用合适的碱形成的盐的形式使用。
在本说明书和权利要求书中,C1-4烷基是甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基。
除了上面所列的之外,C1-5烷基还可以是例如正戊基。
C1-4烷氧基例如可以是甲氧基、乙氧基、正丙氧基或正丁氧基。
卤原子例如是氟、氯、溴或碘原子。
C3-8环烷基例如代表环丙基、环戊基、环己基、环庚基或环辛基。
含有氮原子以及可以含有另一杂原子的5-至8-元环例如是吡咯、吡唑、咪唑、噁唑、噻唑、吡啶、哒嗪、嘧啶、哌嗪、吗啉、吲哚、喹啉环等等。
除了上面所列的烷氧基之外,C1-24烷氧基还可以是例如正戊氧基、癸氧基、十二烷基氧基、十八烷基氧基等。
C1-25链烷酰基例如是甲酰基、乙酰基、丙酰基、丁酰基、己酰基、棕榈酰基、硬脂酰基等。
C3-9链烯酰基例如是丙烯酰基、戊烯酰基、己烯酰基、庚烯酰基、辛烯酰基等。
当Y代表式R1-COO-的基团时,它例如可以是亚麻酰基、亚油酰基、二十二碳六烯酰基、二十碳五烯酰基、花生四烯酰基等。
当R3代表吡啶基时,如果需要的话,其氮原子可以是N-氧化物的形式。同样,当R1和R2与相邻氮原子形成5-至8-元环时,例如哌啶基环,如果需要的话,其氮原子也可以N-氧化物的形式存在。
药用合适的酸加成盐是指与药用合适的无机酸如盐酸或硫酸等,或者与药用合适的有机酸如乙酸、富马酸、乳酸等形成的酸加成盐。
当抗糖尿病或抗高血脂活性剂具有可以与碱形成盐的化学结构时,也可以使用与药用合适的无机或有机碱形成的活性剂的盐。当所述活性剂可以与酸形成酸加成盐时,也可以使用该活性剂的药用合适的酸加成盐。
在式I的羟肟酸衍生物中,优选的亚类由下式的羟肟酸衍生物及其药用合适的酸加成盐组成
其中R1、R2、R3、R4、R5、m和n与式I中的定义相同,X代表卤原子或氨基,Y代表羟基。
特别优选式II的羟肟酸衍生物及其药用合适的酸加成盐,其中R1和R2与相邻氮原子一起形成哌啶子基,R3是吡啶基,m和n都为0,X定义如上。其中,特别优选O-(3-哌啶子基-2-羟基-1-丙基)烟酰偕胺肟(nicotinic amidoxime)和药用合适的酸加成盐,特别优选其一盐酸盐或二盐酸盐。
式I的羟肟酸衍生物的另一有利的亚类由下式的化合物及其药用合适的酸加成盐组成
其中R1、R2、R3和A定义与式I中的相同。
式I的羟肟酸衍生物的另一优选亚类由下式的环状化合物及其药用合适的酸加成盐组成
其中R1、R2、R3和A定义与式I中的相同,Z代表氧原子或式-N=或-NH-的基团。
式I的羟肟酸衍生物的进一步的优选亚类由下式的化合物及其药用合适的酸加成盐组成
其中R1、R2、R3和A定义与式I中的相同,R6代表C1-4烷基。
式I的化合物可以使用从美国专利4,308,399、EP 417 210和匈牙利专利申请公开号T/66350已知的方法制得。
在本发明的协同药物组合物中,(a)抗糖尿病或抗高血脂活性剂或者(如果需要和化学可能的话)其药用合适的酸加成盐或与药用合适的碱形成的盐与(b)式I的羟肟酸衍生物或其药用合适的酸加成盐的质量(或重量)比通常是(1-100):(100-1)。该药用组合的一种或两种药物组合物适合经口或非肠道给药并且为固体或液体组合物。合适的剂量形式及其加工以及有用的载体可以从文献中得知,例如Remington’s Pharmaceutical Sciences,Mack Publishing Co.,Easton、USA。
优选地,本发明的协同药物组合物包括(a)式II的羟肟酸衍生物或其药用合适的酸加成盐和(b)抗糖尿病或抗高血脂活性剂或者(如果需要和化学可能的话)其药用合适的酸加成盐或与药用合适的碱形成的盐,其中这些活性剂存在于分别的药物组合物中或者存在于单一常规药物组合物中。该抗糖尿病或抗高血脂活性剂例如可以是上面所列的物质之一。因此,本发明的优选协同药物组合物可以含有(a)式II的羟肟酸衍生物,例如O-(3-哌啶子基-2-羟基-1-丙基)烟酰偕胺肟或其药用合适的酸加成盐如二盐酸盐或一盐酸盐以及(b1)抗糖尿病活性剂如胰岛素、或胰岛素增敏活性剂如噻唑烷二酮衍生物,例如吡格列酮、曲格列酮、环格列酮、罗格列酮、或提高胰岛素产生的活性剂如米格列奈、瑞格列奈、司格列奈、或一种磺胺如甲苯磺丁脲、氯磺丙脲、妥拉磺脲、醋磺己脲、格列本脲、格列吡嗪、格列齐特、格列美脲、格列喹酮、格列波脲、格列派特、格列本脲、格列生脲、格列索脲、格列丁唑、格列吡脲、或式VI的双胍衍生物,优选甲福明、丁福明、苯乙福明、或α-葡糖苷酶抑制剂如米格列醇、阿卡糖或伏格列波糖,或(b2)抗高血脂活性剂如芳氧基链烷酸衍生物,诸如氯贝特、吉非贝齐、双贝特、依托贝特、环丙贝特、氯烟贝特、或HMG辅酶还原酶抑制剂,诸如洛伐他汀、氟伐他汀、普伐他汀、辛伐他汀、阿托伐他汀、或烟酸衍生物,诸如阿昔莫司、戊四烟酯、尼可莫尔、尼可氯酯、或胆汁酸的抗酸剂,诸如考来替泊、考来烯胺、polidexide、或者(如果需要和化学可能的话)其药用合适的酸加成盐或与以(b1)和(b2)给出的物质的药用合适的碱形成的盐。
本发明的另一优选药物组合物包括(a)式III、IV或V的化合物或其药用合适的酸加成盐、以及(b1)抗糖尿病活性剂如胰岛素、或胰岛素增敏活性剂如噻唑烷二酮衍生物,例如吡格列酮、曲格列酮、环格列酮、罗格列酮、或提高胰岛素生产的活性剂如米格列奈、瑞格列奈、司格列奈、或磺胺如甲苯磺丁脲、氯磺丙脲、妥拉磺脲、醋磺己脲、格列本脲、格列吡嗪、格列齐特、格列美脲、格列喹酮、格列波脲、格列派特、格列本脲、格列生脲、格列索脲、格列丁唑、格列吡脲、或式VI的双胍衍生物,优选甲福明、丁福明、苯乙福明,或α-葡糖苷酶抑制剂如米格列醇、阿卡糖或伏格列波糖,或(b2)抗高血脂活性剂,例如芳氧基链烷酸衍生物如氯贝特、吉非贝齐、双贝特、依托贝特、环丙贝特、氯烟贝特,或HMG辅酶还原酶抑制剂如洛伐他汀、氟伐他汀、普伐他汀、辛伐他汀、阿托伐他汀,或烟酸衍生物如阿昔莫司、戊四烟酯、尼可莫尔、尼可氯酯,或胆汁酸的抗酸剂如考来替泊、考来烯胺、polidexide、或者(如果需要和化学可能的话)其药用合适的酸加成盐或以(b1)和(b2)给出的与药用合适的碱形成的盐。
使用以下试验研究本发明的组合物对葡萄糖敏感性的影响。进行的所有试验符合护理和使用试验动物的欧共体指导原则。
成年新西兰白兔,重3-3.2kg,圈养于动物室(一天12-小时光/暗周期,温度为22-25℃,相对湿度为50-70%),每个围栏中有一个动物,随意喂饲商购实验室饲料和自来水,自始至终使用这些动物。这些动物在适应两周之后进行手术。
在无菌条件下进行手术。用10mg/kg地西泮(Sigma,St.Louis,MO,USA)和5mg/kg氯胺酮(EGIS Pharmaceuticals Ltd.,Budapest,Hungary)的静脉内大剂量推注将兔麻醉。如Szilvassy Z.等人,Br.J.Pharmacol.,
112,999-1001(1994)所述,皮下给予利多卡因(EGISPharmaceuticals Ltd.,Budapest,Hungary)以缓解局部疼痛。将聚乙烯导管插入到颈静脉和左颈动脉的两个主要支管内。这些导管经颈背外置。这些管线保持开放以填充肝素钠溶液(100lU/ml)。
高胰岛素血euglycaemic葡萄糖夹研究
在120分钟内经这些静脉管之一以恒定速率(13mU/kg,NOVONordisk,Copenhagen)注入人常规胰岛素。该胰岛素注入以稳定状态产生100±5μU/ml的血浆胰岛素免疫反应性。该值相当于正常上限值的5倍。以10分钟间隔从动脉管取出血样(0.3ml)用于血液葡萄糖浓度。经第二个静脉管通过可变葡萄糖注入速度将血液葡萄糖浓度保持恒定(5.5±0.5mmol/l)。当血液葡萄糖稳定至少30分钟时,我们定义这种条件为稳定状态。在该稳定状态下,以10分钟间隔取出另外血样(0.5ml)以测定血浆胰岛素。将稳定状态期间的葡萄糖注入速度(mg/kg/min)用于表征胰岛素敏感性[DeFronzo R.A.等人,Am.J.OfPhysio.,
237,E214-223(1979)]。将受试化合物分别经口以单剂量每天给予健康且高胆固醇血的动物,持续5天,并在有6个动物组成的每一试验组中将第6天测定的葡萄糖注入速度平均。使用一组健康和一组高胆固醇血的动物作为对照。所得结果显示在表1和2中。
表1
通过稳定状态期间的葡萄糖注入速度(mg/kg/min)表征的胰岛素敏感
性
动物组 | 对照 | BGP-1530mg/kg每日剂量p.o. | 甲福明100mg/kg每日剂量p.o. | BGP-15(30mg/kg)+甲福明(100mg/kg) |
正常HC | 14.6±1.039.7±1.0 | 15.9+1.8213.4+1.11 | 15.8±0.8311.7±0.87 | 18.1+0.9215.8+0.75 |
正常=将健康动物用于该试验;
HC=将高胆固醇血动物用于该试验;
BGP-15=O-(3-哌啶子基-2-羟基-1-丙基)烟酰偕胺肟盐酸盐。
表2
通过稳定状态期间的葡萄糖注入速度(mg/kg/min)表征的胰岛素敏感
性
动物组 | 对照 | BGP-1530mg/kg每日剂量p.o. | 曲格列酮75mg/kg每日剂量p.o. | BGP-15(30mg/kg)+曲格列酮(75mg/kg) |
正常HC | 13.9+1.229.0+0.84 | 15.4+1.2613.8+1.29 | 14.3±0.0814.1±1.33 | 16.9+1.0416.07+0.84 |
正常=将健康动物用于该试验;
HC=将高胆固醇血动物用于该试验;
BGP-15=O-(3-哌啶子基-2-羟基-1-丙基)烟酰偕胺肟盐酸盐。
事实上,已在上面的试验中测定了获得恒定血液葡萄糖水平所注入的葡萄糖的量。在指示胰岛素效果提高的给定血液葡萄糖水平下应需要较高量的葡萄糖是有利的。因此,测定的葡萄糖注入速度越高,受试化合物获得的效率越高。
正如表1中看到的,当然在健康动物内获得的值比高胆固醇血动物的值要高。在对照组中,葡萄糖注入速度要比用BGP-15或甲福明处理的组中的低。总之,在健康和胆固醇血动物中,当动物用BGP-15和甲福明处理时,明显比仅给予一种受试化合物的葡萄糖注入速度要高。因此,观察到BGP-15和甲福明之间的协同作用。
如表2所示,用BGP-15和曲格列酮的情形相同。
本发明还包括一种治疗或预防前驱糖尿病状态、代谢X-综合征或糖尿病以及与上面状态有关的紊乱的方法,这些紊乱即内源代谢紊乱、胰岛素抗性、血脂异常和/或以产生雄性征优势为基础的女性内分泌紊乱,其中患有或者预示所示状态的患者一方面用治疗有效量的抗糖尿病或抗血脂活性剂、或者(如果需要和化学可能的话)其药用合适的酸加成盐或与药用合适的碱形成的盐治疗,另一方面,用式I的羟肟酸衍生物或其药用合适的酸加成盐治疗。
该抗糖尿病或抗高血脂活性剂和式I的羟肟酸衍生物可以同时给予,或者可以先给予其中一个,间隔短时间后如几秒钟或几分钟或者持续更长间隔如10-30分钟给予另一个。
由于式I的羟肟酸衍生物协同地增强抗糖尿病或抗高血脂活性剂的治疗效果,因此在本发明的方法中,抗糖尿病或抗高血脂剂的每日剂量比不给予式I的羟肟酸衍生物时常规治疗中所用的常规每日剂量要低。
使用本发明的方法,可以预防特别是以下临床症状的发展,或者当一旦发展时,它们可以有益地受到影响:
-前驱糖尿病状态,例如葡萄糖耐受性或胰岛素抗性,
-代谢X-综合征,
-两种类型的糖尿病(IDDM和NIDDM),
-糖尿病并发症,具体有视网膜病、神经病、肾病、多囊卵巢综合征(PCOS)、妊娠糖尿病(GDM)、动脉压力过高、血脂异常、动脉硬化、肥胖、与糖尿病有关的贲门局部缺血等等。
因此,本发明包括式I的羟肟酸衍生物或其药用合适的酸加成盐用于制备一种用于预防或治疗前驱糖尿病状态、代谢X-综合征或糖尿病以及与上面的状态有关的紊乱,即内源代谢紊乱、胰岛素抗性、血脂异常、脱发、弥漫性脱发和/或以产生雄性征优势为基础的女性内分泌紊乱药物组合物的用途,所述药物组合物协同地增强活性剂、特别是抗糖尿病或抗高血脂活性剂的效果。因此,含有式I的羟肟酸衍生物或其药用合适的酸加成盐作为活性剂的该药物组合物可以给予正在接受抗糖尿病或抗高血脂活性剂治疗的患者以便预防或治疗前驱糖尿病状态、代谢X-综合征或糖尿病以及与上面状态有关的紊乱,即内源代谢紊乱、胰岛素抗性、血脂异常、脱发、弥漫性脱发和/或以产生雄性征优势为基础的女性内分泌紊乱。给予含有式I的羟肟酸衍生物或其药用合适的酸加成盐作为活性剂的药物组合物使得抗糖尿病或抗高血脂活性剂的剂量降低。当含有式I的羟肟酸衍生物或其药用合适的酸加成盐,例如O-(3-哌啶子基-2羟基-1-丙基)烟酰偕胺肟或其药用合适的酸加成盐如其二盐酸盐或一盐酸盐作为活性剂的药物组合物给予患有糖尿病并获得规则胰岛素治疗的患者时,可以降低每日胰岛素剂量,从而避免胰岛素抗性的进展。
Claims (3)
1.一种用于预防或治疗前驱糖尿病状态、代谢X-综合征或糖尿病以及内源性代谢紊乱、胰岛素抗性、血脂异常、脱发和/或弥漫性脱发的协同药物组合物,包括
(a)第一药物组合物,它含有选自过氧化物酶体增生物-激活受体γ-激动剂和双胍衍生物或其药用合适的酸加成盐或与药用合适的碱形成的盐的抗糖尿病活性剂和一种或多种常规载体,以及
(b)第二药物组合物,它含有O-(3-哌啶子基-2-羟基-1-丙基)烟酰偕胺肟或其药用合适的酸加成盐以及一种或多种常规载体其中,活性剂与O-(3-哌啶子基-2-羟基-1-丙基)烟酰偕胺肟的重量比为(1-100)∶(100-1)。
2.权利要求1的药物组合物,其中包含甲福明或其药用合适的酸加成盐作为抗糖尿病活性剂。
3.O-(3-哌啶子基-2-羟基-1-丙基)烟酰偕胺肟或其药用合适的酸加成盐用于制备药物组合物的用途,所述的药物组合物协同地增强选自过氧化物酶体增生物-激活受体γ-激动剂和双胍衍生物的抗糖尿病活性剂的作用,所述的药物组合物用于预防或治疗前驱糖尿病状态、代谢X综合征或糖尿病以及内源性代谢紊乱、胰岛素抗性、血脂异常、脱发和/或弥漫性脱发。
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US20080108602A1 (en) * | 2006-11-02 | 2008-05-08 | N-Gene Research Laboratories, Inc. | Prevention of obesity in antipsychotic, antidepressant and antiepileptic medication |
ZA200902761B (en) * | 2006-11-02 | 2010-07-28 | N Gene Res Lab Inc | A pharmaceutical composition having antipsychotic, antidepressant or antiepileptic activity with reduced side effect |
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US7763601B2 (en) | 2006-11-02 | 2010-07-27 | N-Gene Research Laboratories, Inc. | Prevention and treatment of obesity |
US20080208328A1 (en) * | 2007-02-23 | 2008-08-28 | Endovalve, Inc. | Systems and Methods For Placement of Valve Prosthesis System |
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US20090281143A1 (en) * | 2007-12-10 | 2009-11-12 | N-Gene Research Laboratories, Inc. | Dose Reduction of a Cannabinoid CB1 Receptor Antagonist in the Treatment of Overweight or Obesity |
CN103547588B (zh) | 2011-04-13 | 2016-06-29 | Isis制药公司 | Ptp1b表达的反义调节 |
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