CN1288458A - 三氮杂䓬酮类化合物、其制备方法及其治疗用途 - Google Patents
三氮杂䓬酮类化合物、其制备方法及其治疗用途 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/02—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及通式(Ⅰ)所示化合物,发现该化合物在糖尿病治疗中的应用。
Description
本发明涉及新的三氮杂衍生物、其制备方法和含有它们的药物组合物。
本发明更具体地涉及在治疗中用于有效抑制葡萄糖或其氧化产物(α-二羰基衍生物如乙二醛或甲基乙二醛)与蛋白质的胺基之间的反应的三氮杂衍生物，并且因此发现了它们在糖尿病及其并发症中的治疗用途。
所以，本发明的主题是以下通式所示的化合物及其与药学上可接受的酸形成的盐：其中：-R选自氢原子、甲基和下式所示基团：
和-R1、R2、R3和R4分别独立地选自：
a)氢原子，
b)C1-C8烷基、环(C3-C8)烷基、环(C3-C8)烷基(C1-C8)烷基、环(C3-C8)烷氧基(C1-C8)烷基、环(C3-C8)烷基(C1-C8)烷氧基(C1-C8)烷基、(C1-C8)烷氧基(C1-C8)烷基、(C1-C8)羟基烷基、(C6-C14)芳基、(C6-C14)杂芳基、杂(C6-C14)芳基(C1-C8)烷基、(C6-C14)芳基(C1-C8)烷基、(C6-C14)芳基(C1-C8)烷基(C6-C14)芳基、(C6-C14)芳氧基(C1-C8)烷基或(C6-C14)芳基(C1-C8)烷氧基(C1-C8)烷基，
不同的芳基、环烷基和杂芳基本身可能被1-3个取代基取代，所述取代基选自：(C1-C8)烷基，C1-C8烷氧基，选自氟、氯、溴和碘的卤素；和三氟甲氧基、羟基、氰基、硝基、氨基、氨基甲酰基、C1-C8烷基氨基、(C1-C8)烷基硫代(C1-C8)烷基亚磺酰基、C1-C8烷基磺酰基、磺酰氨基或氨磺酰基(C1-C8)烷基羰基氨基，这些基团中的两个基团可能形成亚甲基二氧基；-R1和R2以及R3和R4可以与其所连接的氮一起形成以下通式的基团：
其中n表示1-4的数字并且X选自-CH2-、-O-、-S-、-NH-和-NR’-、R’具有b)中R1的含义；
c)下式的基团
其中Q表示直链或支链的C2-C14亚烷基；R5和R6彼此独立地选自氢原子和b)中所述基团；R5和R6也可能与其所连接的氮共同构成通式(1)所示的基团：
d)稠合或桥连型的双环胺残基。
所述C1-C8烷基可以直链或支链。值得提及的例如是甲基、乙基、异丙基、丁基、异丁基、叔丁基和戊基。
同样地，所述C1-C8烷氧基可以是直链或支链。值得提及的例子是甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基和戊氧基。
术语“芳基”应被理解为是指含有6-14个碳原子的单环、双环或三环基团。所述芳基的例子可以是苯基、α-萘基、β-萘基和芴基。
所述杂芳基可以尤其选自吡啶基、嘧啶基、吡咯基、呋喃基、噻吩基、喹啉基、吲哚基、苯并噻吩基、苯并呋喃基、苯并吡喃基、苯并噻喃基、氧芴基(dibenzofuryl)、咔唑基和苯并噻嗪基。
所谓的稠合或桥连型的的双环胺残基代表以下类型的残基：
通式(Ⅰ)的化合物含有碱性氮原子并且可以和无机酸或有机酸生成盐。通式(Ⅰ)的化合物与酸生成的盐的实例包括药学可接受盐，例如但不限于，盐酸盐、氢溴酸盐、硫酸盐、琥珀酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐和磺酸盐，如甲磺酸盐、苯磺酸盐和甲苯磺酸盐。
式Ⅰ的化合物的制备可以通过将以下通式的α-酮醛类化合物：
与以下通式的双胍类化合物反应：
式(Ⅲ)的双胍类化合物特别公开在US-A-2 455 896、FR-A-2 085665、FR-A-1 518 398、FR-A-2 230 347和US-A-2 961 377中。
该反应是在低分子量的醇(例如甲醇)中或更适宜在水中进行。
通过1H、15N和13C光谱分析证实了所得化合物的结构。
下列实施例举例说明式(Ⅰ)化合物的制备。实施例1
2-氨基-4-二甲基氨基-7-甲基-5,7-二氢(1,3,5)三氮杂-6-酮(triazepin-6-one)(和盐酸盐)的制备
将25.8g(0.2mol)的碱N,N-二甲基双胍(二甲双胍)和100ml水加入到250ml三颈烧瓶中；当溶解完全后，将溶液冷却，在维持内部温度为0-+5℃的条件下加入34ml(0.210mol)40％的甲基乙二醛(丙酮醛)水溶液。
在+5℃下将该混合物搅拌1小时。生成晶状沉淀。继续在+20℃下将该混合物搅拌4小时。在烧结漏斗上过滤出产物，用水洗涤且在真空下干燥。得到18.2g(收率：50％)浅乳白色产物并且其熔点为264-266℃(Kofler bank)。由二甲基甲酰胺中重结晶。制备盐酸盐，并且其盐酸盐的熔点为260-262℃(Kofler bank)。
本发明的化合物可应用于糖尿病及其并发症的治疗。
糖尿病的慢性并发症是由于生成了高级糖基化终产物(称作AGE’s)，高级糖基化终产物衍生自葡萄糖、其氧化衍生物和蛋白质的氨基官能团之间发生的糖氧化(glycoxidation)反应，其中包括，例如，称作乙二醛糖化的美拉德反应。
双胍型的化合物如二甲双胍通过在蛋白质的氨基与葡萄糖的α-二糖基衍生物，特别是甲基乙二醛，的反应中起干扰作用，从而抑制这些反应。
如今，在糖尿病并发症的致病机理中，糖氧化原理包括数个代谢途径：
由此可以看出，体内50％的AGE产物衍生自涉及乙二醛的反应，这些产物引起糖尿病的慢性并发症。
式(Ⅰ)的化合物的价值在于能够通过对α-二糖基衍生物如乙二醛的“清除”作用的方式来抑制所述美拉德反应，因此这些化合物具有抗糖化作用。
已通过在本发明所述化合物存在或不存在的条件下测定用甲基乙二醛温育白蛋白期间所生成的氯胺酮(“果糖胺”)对本发明所述化合物的这种抑制美拉德反应的作用进行了体外研究。
在浓度为1mM的2-氨基-4-二甲基氨基-7-甲基-5,7-二氢(1,3,5)三氮杂-6-酮存在或不存在的条件下，将6.6mg/ml牛白蛋白在0.2M pH7.4的磷酸盐缓冲液中的溶液和1mM甲基乙二醛一起温育。温育是在37℃的无菌条件下进行6天。当温育时间结束时，按照制造商提供的说明书，用市售的果糖胺分析试剂盒(即“FRA”试剂盒，产品编号：0757055,Prodiuts Roche S.A.)来测定氯胺酮的含量。在上述试验条件下观察到，在2-氨基-4-二甲基氨基-7-甲基-5,7-二氢(1,3,5)三氮杂-6-酮的存在下白蛋白和甲基乙二醛一起温育后的果糖胺水平比该三氮杂酮(triazepinone)不存在下用甲基乙二醛温育白蛋白时测定的的果糖胺水平低31％。
所以，本发明的主题是含有本发明所述化合物作为活性组分的药物组合物。
本发明所述药物组合物可以以适用于非肠道、口服、直肠、经粘膜或经皮给药的形式提供。
所以，它们可以采取用于注射或多剂量瓶的溶液或悬浮液形式，普通片剂、包衣片、糖衣片剂、糯米纸囊剂、明胶胶囊、丸剂、扁囊剂、粉剂、栓剂或直肠用胶囊的形式，或经皮使用的在极性溶剂中的溶液或悬浮液，或用于经粘膜给药的溶液或悬浮液。
对于固体剂型，适合这种给药的赋形剂是纤维素或微晶纤维素的衍生物、碱土金属的碳酸盐、磷酸镁、淀粉、改性淀粉和乳糖。
对于直肠给药用的赋形剂，优选可可脂或聚乙二醇硬脂酸酯。
对于非肠道给药，最方便使用的载体是水、水溶液、生理盐水和等渗溶液。
给药剂量可以在宽范围内变化，这取决于治疗适应征和给药途径，以及个体的年龄和体重。
Claims (4)
1．下列通式所示的化合物：及其与药学上可接受的酸形成的盐：
其中：-R选自氢原子、甲基和下式所示基团：和-R1、R2、R3和R4分别独立地选自：
a)氢原子，
b)C1-C8烷基、环(C3-C8)烷基、环(C3-C8)烷基(C1-C8)烷基、环(C3-C8)烷氧基(C1-C8)烷基、环(C3-C8)烷基(C1-C8)烷氧基(C1-C8)烷基、(C1-C8)烷氧基(C1-C8)烷基、(C1-C8)羟基烷基、(C6-C14)芳基、(C6-C14)杂芳基、杂(C6-C14)芳基(C1-C8)烷基、(C6-C14)芳基(C1-C8)烷基、(C6-C14)芳基(C1-C8)烷基(C6-C14)芳基、(C6-C14)芳氧基(C1-C8)烷基或(C6-C14)芳基(C1-C8)烷氧基(C1-C8)烷基，
不同的芳基、环烷基和杂芳基本身可能被1-3个取代基取代，所述取代基选自：(C1-C8)烷基，C1-C8烷氧基，选自氟、氯、溴和碘的卤素；和三氟甲氧基、羟基、氰基、硝基、氨基、氨基甲酰基、(C1-C8)烷基，C1-C8烷基氨基、(C1-C8)烷基硫代(C1-C8)烷基亚磺酰基、C1-C8烷基磺酰基、磺酰氨基或氨磺酰基(C1-C8)烷基羰基氨基，这些基团中的两个基团可能形成亚甲基二氧基；-R1和R2以及R3和R4可以与其所连接的氮一起形成以下通式所示基团：其中n表示1-4的数字并且X选自-CH2-,-O-,-S-,-NH-和-NR’-,R，具有b)中R1的含义；
c)下式的基团：
其中Q表示直链或支链的C2-C14亚烷基；-R5和R6彼此独立地选自氢原子和b)中所述基团；-R5和R6可能与其所连接的氮共同构成式(1)所示的基团：
d)稠合或桥连型的双环胺残基。
2．如权利要求1所述的化合物，其中是2-氨基-4-二甲基氨基-7-甲基-5,7-二氢(1,3,5)-三氮杂-6-酮，或其与药学可接受酸形成的盐。
3．一种用于制备如权利要求1所述化合物的方法，其中将下式的化合物：
与下式的双胍反应：
R、R1、R2、R3和R4具有权利要求1所述定义。
4．药物组合物，含有如权利要求1或2所述的化合物作为活性组分。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9800321A FR2773560B1 (fr) | 1998-01-14 | 1998-01-14 | Triazepinones, leur procede de preparation et leur application en therapeutique |
| FR98/00321 | 1998-01-14 |
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| CN1140503C CN1140503C (zh) | 2004-03-03 |
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| US5955617A (en) * | 1996-05-21 | 1999-09-21 | Pharmacia & Upjohn Company | Aminoguanidine carboxylate lactams for the treatment of non-insulin-dependent diabetes mellitus |
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| CN113072269A (zh) * | 2021-03-25 | 2021-07-06 | 北京建筑大学 | 一种处理污泥中重金属的方法 |
| CN113072269B (zh) * | 2021-03-25 | 2022-07-22 | 北京建筑大学 | 一种处理污泥中重金属的方法 |
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