WO2013086980A1

WO2013086980A1 - Sulfonylurea guanidine, preparation method and use thereof

Info

Publication number: WO2013086980A1
Application number: PCT/CN2012/086431
Authority: WO
Inventors: 柏俊; 孙备; 胡士高; 程杰; 田磊
Original assignee: 安徽贝克联合制药有限公司
Priority date: 2011-12-14
Filing date: 2012-12-12
Publication date: 2013-06-20
Also published as: CN103159651A; CN103159651B

Abstract

Provided is a compound as represented by formula (I). Compared to prior art, the compound of the present invention has a dual structure of sulfonylurea and aminoguanidine; the sulfonylurea can reduce blood sugar level by enhancing the secretion of endogenous insulin, and the aminoguanidine structure has significant prevention and treatment effects for various complications of diabetic patients. Each substituent of X, R₁, R₂, R₃ and R₄ is as defined in the specification.

Description

磺酰脲胍及其制备方法和用途技术领域 Sulfonylurea and preparation method and use thereof

本发明涉及有机合成技术领域，具体涉及橫酰脲胍化合物及其制备方法和用途。背景技术 The present invention relates to the field of organic synthesis technology, and in particular to a transverse ureide guanidine compound, a preparation method and use thereof. Background technique

糖尿病是一种基因性疾病、与感染、肥胖等基因促发有关，其病理生理基础是由于胰岛素的分泌不足和利用障碍导致的代谢紊乱而出现高血糖问题。糖尿病病人易发生失明、冠心病、肾衰等并发症和相关疾病。据统计，糖尿病所致死亡率仅次于心血管疾病和肿瘤，因此开发出具有治疗糖尿病的高效、低毒、经济的药物具有较大的社会和经济效益。 Diabetes is a genetic disease that is associated with genes such as infections and obesity. Its pathological basis is due to hyperglycemia due to insufficient insulin secretion and metabolic disorders caused by the use of disorders. Diabetic patients are prone to complications such as blindness, coronary heart disease, renal failure and related diseases. According to statistics, the mortality caused by diabetes is second only to cardiovascular diseases and tumors. Therefore, the development of effective, low-toxic, and economical drugs for treating diabetes has great social and economic benefits.

现有技术中，口服降糖药主要有酰脲类和双胍类两种，该两种药物单独使用时均可以用于控制血糖，但均存在不同的副作用，如酰脲类的药物具有低血糖危险、肾毒性、视网膜病变等副作用，而二曱双胍具有乳酸性酸中毒、视网膜病变等副作用。除上述两种口服降糖药以外，还有胰岛素降糖药，但胰岛素类降糖药价格吊贵，而且会使病人体重增加。 In the prior art, oral hypoglycemic agents mainly include ureide and biguanide. Both drugs can be used to control blood sugar when used alone, but all have different side effects, such as ureide drugs having hypoglycemia. Dangerous, nephrotoxicity, retinopathy and other side effects, while diterpene has side effects such as lactic acidosis and retinopathy. In addition to the above two oral hypoglycemic agents, there are insulin hypoglycemic agents, but the price of insulin-based hypoglycemic agents is expensive and will increase the weight of patients.

考虑到现有技术存在上述缺点，本发明人考虑设计具有磺酰脲和氨基胍双重结构的新化合物，这样不但可以利用橫酰脲结构增强内源性胰岛素的分泌而达到降低血糖的目的，而且可以利用氨基胍结构对糖尿病患者的多种并发症产生防治作用。发明内容 In view of the above disadvantages of the prior art, the present inventors considered designing a novel compound having a double structure of a sulfonylurea and an aminoguanidine, so that not only the use of the acid ureide structure enhances the secretion of endogenous insulin, but also achieves the purpose of lowering blood sugar, and The aminoguanidine structure can be used to prevent and treat various complications of diabetic patients. Summary of the invention

本发明解决的问题在于提供一种化合物，本发明所述化合物具有磺酰脲和氨基胍的双重结构，两种结构在人体代谢过程中分别与不同靶点起作用；该化合物中的橫酰脲结构可以增强内源性胰岛素的分泌，达到降低血糖的效果，该化合物中的氨基胍结构可以对糖尿病并发症产生防治作用。 The problem to be solved by the present invention is to provide a compound having the dual structure of a sulfonylurea and an aminoguanidine, the two structures acting separately with different targets in the metabolism of the human body; The structure can enhance the secretion of endogenous insulin and achieve the effect of lowering blood sugar. The aminoguanidine structure in the compound can prevent and treat diabetic complications.

为了解决以上技术问题，本发明提供一种化合物或其药学上可接受的盐，具有式（ I ) 所示的结构：

In order to solve the above technical problems, the present invention provides a compound or a pharmaceutically acceptable salt thereof having the structure represented by the formula (I):

其中， X选自 0或 s ; Wherein X is selected from 0 or s;

选自 H、 C_1-12烷基、 C_1-12烷氧基、 C_2-8烯基、 C_2-8炔基、卤素、羟基、氨基、硝基、氰基、羧基、 d_₁₂烷氧基羰基、 d_₁₂烷基羰氧基，其中，所述烷基或烷氧基中的一个或多个氢原子任选被素、羟基、氨基、硝基、氰基或羧基取代； Selected from H, C _1-12 alkyl, C _1-12 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, halogen, hydroxy, amino, nitro, cyano, carboxy, d- ₁₂ alkane An oxycarbonyl group, a d- ₁₂ alkylcarbonyloxy group, wherein one or more hydrogen atoms of the alkyl group or alkoxy group are optionally substituted by a phenol, a hydroxyl group, an amino group, a nitro group, a cyano group or a carboxyl group;

R₂选自 H、 Cw₂烷基、。环烷基、氰基，其中，所述烷基或环烷基中的一个或多个氢原子任选被卤素、羟基、氨基或羧基取代； R _{2 is} selected from the group consisting of H, Cw ₂ alkyl, and. a cycloalkyl group, a cyano group, wherein one or more hydrogen atoms in the alkyl group or cycloalkyl group are optionally substituted by a halogen, a hydroxyl group, an amino group or a carboxyl group;

R₃和 R₄各自独立地选自 H、 Cw₂烷基，其中，所述烷基中的一个或多个氢原子任选被卤素、羟基、氨基、羧基、。环烷基或苯基取代；或者， R₃和 R₄、或 R₂和 R₄与其所连的氮原子共同构成五元、六元或七元饱和或不饱和杂环。 R ₃ and R ₄ are each independently selected from H, Cw ₂ alkyl, wherein one or more hydrogen atoms in the alkyl group are optionally halogen, hydroxy, amino, carboxy. A cycloalkyl or phenyl group; or, R ₃ and R ₄ , or R ₂ and R ₄ together with the nitrogen atom to which they are attached constitute a five-, six- or seven-membered saturated or unsaturated heterocyclic ring.

根据本发明的药学上可接受的盐可以是无机酸盐或有机酸盐，如果存在酸性基团，也可以与碱成盐。 The pharmaceutically acceptable salt according to the present invention may be a mineral acid salt or an organic acid salt, and if an acidic group is present, it may also form a salt with a base.

本发明还提供一种式（ I )化合物或其药学上可接受的盐的制备方法，包括（A )将式（ II ) 所示的氨基胍

The present invention also provides a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises (A) an aminoguanidine represented by the formula (II)

与式（ III ) 所示的异氰酸酯进行反应,

Reacting with an isocyanate represented by formula (III),

得到式（ I )化合物，并任选将其转化为药学上可接受的盐; Obtaining a compound of formula (I), and optionally converting it to a pharmaceutically acceptable salt;

II ) 所示的氨基胍

II) shown as aminoguanidine

与式（IV ) 所示的酰卤进行反应，

Reacting with an acid halide represented by formula (IV),

得到式（ I )化合物，并任选将其转化为药学上可接受的盐；其中，丫是素， X、 Ri、 R₂、 R₃和 R₄的定义如前所述。 The compound of formula (I) is obtained and optionally converted into a pharmaceutically acceptable salt; wherein, hydrazine is a compound, and X, Ri, R ₂ , R ₃ and R ₄ are as defined above.

式（ I )所示化合物或其药学上可接受的盐的制备方法，其具体步骤包括： A method for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof, the specific steps of which comprise:

( i )提供式（ II ) 所示氨基胍或其盐酸盐的有机溶液； (i) providing an organic solution of aminoguanidine or its hydrochloride as shown in formula (II);

( ii )在所述氨基胍（盐酸盐）的有机溶液中加入碱，得到第一混合 (ii) adding a base to the organic solution of the aminoguanidine (hydrochloride) to obtain a first mixture

( iii ) 向所述第一混合液中加入式（ III ) 所示异氰酸酯或式（ IV ) 所示的酰得到第二混合液； (iii) adding an isocyanate represented by the formula (III) or an acyl group represented by the formula (IV) to the first mixed solution to obtain a second mixed liquid;

( iv )将所述第二混合液加热至回流状态反应，冷却得到式（ I )化合物； (iv) heating the second mixture to a reflux state, and cooling to obtain a compound of the formula (I);

( V )根据需要，将式（ I )化合物转化为相应的药学上可接受的盐。本发明还提供一种药物组合物，包括式（ I )化合物作为活性成分，以及可药用载体。 (V) converting a compound of formula (I) to the corresponding pharmaceutically acceptable salt, as needed. The present invention also provides a pharmaceutical composition comprising the compound of the formula (I) as an active ingredient, and a pharmaceutically acceptable carrier.

本发明还提供了式（ I )化合物在制备治疗糖尿病药物中的应用。本发明还提供一种治疗糖尿病的方法，所述方法包括给有此需要的患者施用治疗有效量的式（ I )化合物或其药学上可接受的盐和 /或包含式 ( I )化合物的药物组合物。 The invention also provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of diabetes. The invention also provides a method of treating diabetes, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and/or a medicament comprising a compound of formula (I) combination.

与现有技术相比，本发明提供的化合物具有磺酰脲和氨基胍的双重结构，磺酰脲可以增强内源性胰岛素的分泌而降低血糖；氨基胍类结构对糖尿病患者的多种并发症具有显著的防治作用。具体实施方式 Compared with the prior art, the compound provided by the invention has the dual structure of sulfonylurea and aminoguanidine, and the sulfonylurea can enhance the secretion of endogenous insulin and lower blood sugar; the aminoguanidine structure has various complications for diabetic patients. Has a significant preventive effect. detailed description

示的化合物或其药学上可接受的盐，

( I ) a compound or a pharmaceutically acceptable salt thereof,

(I)

X、 R₂、和 R₄的定义如前所述。所述 Ci_₁₂烷基为直链或支链，优选碳原子数为 1-8 , 更优选 1-6, 特别优选曱基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。 The definitions of X, R ₂ , and R ₄ are as described above. The Ci ₁₂ alkyl group is linear or branched, preferably having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and particularly preferably an anthracenyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or an isobutyl group. Base, sec-butyl, tert-butyl.

所述 d_₁₂烷氧基中的烷基同 d_₁₂烷基的定义。 The alkyl group in the d- ₁₂ alkoxy group is the same as the d- ₁₂ alkyl group.

所述 C₂_₈烯基和 C₂_₈炔基为直链或支链，具有一个或多个不饱和键，优选碳原子数为 2-6, 更优选 2-4。 The C ₂ _-8 alkenyl group and the C ₂ _-8 alkynyl group are linear or branched and have one or more unsaturated bonds, preferably having 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms.

所述 Cwo环烷基为单环或稠环结构，优选碳原子数为 3-8 ,更优选 3-6。本发明中所述卤素优选氟、氯、溴、碘。 The Cwo cycloalkyl group is a monocyclic or fused ring structure, preferably having 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. The halogen in the present invention is preferably fluorine, chlorine, bromine or iodine.

在一个优选的实施方式中， R 于磺酰胺基的邻位或对位，优选为对位。 In a preferred embodiment, R is ortho or para to the sulfonamide group, preferably in the para position.

在另一个优选的实施方式中， R₃和 R₄与其所连的氮原子共同构成二氢咪唑、四氢咪唑、二氢嘧 ¹定、四氢嘧¹¹定等杂环。 In another preferred embodiment, R ₃ and R ₄ with the nitrogen atom to which they are attached together form dihydro-imidazole, imidazolidine, dihydro-pyrimidine ¹ set, ^{11-tetrahydro-pyrimidin-set} of heterocyclic.

在又一个优选的实施方式中，选自 H、 C_1-6烷基； R₂选自 H、 Ci_-6 烷基，优选地， R₂为 H; R₃和 R₄各自独立地选自 H、 C^₆烷基，优选地， R₃和 R₄均为 H。 In still another preferred embodiment, selected from H, C _1-6 alkyl; R _{2 is} selected from H, Ci- ₆ alkyl, preferably, R ₂ is H; and R ₃ and R ₄ are each independently selected from H, C^ ₆ alkyl, preferably, R ₃ and R ₄ are both H.

所述的药学上可接受的盐可以是无机酸盐或有机酸盐，例如盐酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、曱酸盐、草酸盐、琥珀酸盐、富马酸盐、马来酸盐、柠檬酸盐、苹果酸盐，但不限于此。特别地，当式（ I ) 化合物的结构中存在酸性基团时，还可以与碱成盐，具体例子可以为碱金属盐，例如钠盐、钾盐，碱土金属盐，例如镁盐、钙盐，以及铵盐或有机季铵盐，但不限于此。 The pharmaceutically acceptable salt may be a mineral acid salt or an organic acid salt such as a hydrochloride, a sulfate, a nitrate, a phosphate, an acetate, a citrate, an oxalate, a succinate, or a rich Horse salt, maleate salt, citrate, malate, but not limited to this. In particular, when an acidic group is present in the structure of the compound of the formula (I), it may also form a salt with a base, and specific examples may be an alkali metal salt such as a sodium salt, a potassium salt, an alkaline earth metal salt such as a magnesium salt or a calcium salt. And an ammonium salt or an organic quaternary ammonium salt, but is not limited thereto.

在根据本发明的式（ I )化合物的制备方法中，取式（ II )所示氨基胍或其盐酸盐溶于有机溶剂中得到式（ II ) 的氨基胍（盐酸盐）的有机溶液，所述有机溶剂选自醇类有机溶剂、代烃类有机溶剂、醚类有机溶剂、酮类有机溶剂、酯类有机溶剂。所述醇类有机溶剂的具体例子可以为曱醇、乙醇、异丙醇、正丙醇、正丁醇、叔丁醇，但不限于此。所述卤代烃类有机溶剂的具体例子可以为二氯曱烷、氯仿、 1 , 2-二氯乙烷，但不限于此。所述醚类有机溶剂的具体例子可以为四氢呋喃、 ***、异丙醚、苯曱醚、曱基叔丁基醚，但不限于此。所述酮类有机溶剂的具体例子可以为丙酮、曱基异丁基酮、丁酮、曱基丁基酮，但不限于此。所述酯类有机溶剂的具体例子可以为乙酸乙酯、乙酸异丁酯、乙酸丁酯、乙酸异丙酯，但不限于此。有机溶剂对于反应物应是惰性的，本领域的技术人员有能力根据不同反应物的类型选择合适的溶剂。优选地，所述的有机溶剂为丙酮，对于氨基胍（盐酸盐）有机溶液的浓度，优选为 0.5~2mol/L , 更优选为 0.7 ~1.5mol/L, 特别优选为 0.9 ~l . lmol/L。 In the preparation method of the compound of the formula (I) according to the present invention, the aminoguanidine or its hydrochloride salt of the formula (II) is dissolved in an organic solvent to obtain an organic solution of the aminoguanidine (hydrochloride) of the formula (II). The organic solvent is selected from the group consisting of an alcohol organic solvent, a hydrocarbon-based organic solvent, an ether organic solvent, a ketone organic solvent, and an ester organic solvent. Specific examples of the alcohol organic solvent may be decyl alcohol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol, but are not limited thereto. Specific examples of the halogenated hydrocarbon organic solvent may be dichlorosilane, chloroform or 1,2-dichloroethane, but are not limited thereto. Specific examples of the ether organic solvent may be tetrahydrofuran, diethyl ether, isopropyl ether, benzoin ether, decyl tert-butyl ether, but are not limited thereto. Specific examples of the ketone organic solvent may be acetone, decyl isobutyl ketone, butanone, decyl butyl ketone, but are not limited thereto. Specific examples of the ester organic solvent may be ethyl acetate, isobutyl acetate, butyl acetate, or isopropyl acetate, but are not limited thereto. The organic solvent should be inert to the reactants, and those skilled in the art have the ability to vary The type of reactant is selected as a suitable solvent. Preferably, the organic solvent is acetone, and the concentration of the aminoguanidine (hydrochloride) organic solution is preferably 0.5 to 2 mol/L, more preferably 0.7 to 1.5 mol/L, and particularly preferably 0.9 to 1. /L.

还可以在所述氨基胍（盐酸盐）的有机溶液中加入碱，所述碱为有机碱或无机碱，例如三乙胺、吡啶、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾，但不限于此。优选地，所述碱为三乙胺。碱与氨基胍的物质的量之比为 1 ： 2-2： 1 , 优选为 1 ： 1.5~1.5 ： 1 , 更优选为 1 : 1。 It is also possible to add a base to the organic solution of the aminoguanidine (hydrochloride), which is an organic base or an inorganic base such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, But it is not limited to this. Preferably, the base is triethylamine. The ratio of the amount of the base to the aminoguanidine is from 1:2 to 2:1, preferably from 1:1.5 to 1.5:1, more preferably from 1:1.

配制所述氨基胍（盐酸盐）的有机溶液时，优选在保护气氛下，向有机溶剂中加入氨基胍（盐酸盐）搅拌均勾，保护气氛可以为氮气、氩气等；对于搅拌方式，本发明并无特别限制，优选使用本领域技术人员熟知的机械搅拌方式。配制完氨基胍（盐酸盐）的有机溶液后，向所述有机溶液中加入碱，优选三乙胺，搅拌均勾得到第一混合液。 When preparing the organic solution of the aminoguanidine (hydrochloride), it is preferred to add an aminoguanidine (hydrochloride) to the organic solvent under a protective atmosphere, and the protective atmosphere may be nitrogen, argon, etc.; The present invention is not particularly limited, and a mechanical stirring method well known to those skilled in the art is preferably used. After the organic solution of aminoguanidine (hydrochloride) is prepared, a base, preferably triethylamine, is added to the organic solution, and the first mixture is obtained by stirring.

室温下，向所述第一混合液中加入式（ III ) 所示异氰酸酯或式（ IV ) 所示的酰 , 得到第二混合液。所述异氰酸酯或酰与氨基胍的物质的量之比为 1 ： 2~2： 1 , 优选为 1 ： 1.5~1.5 ： 1 , 更优选为 1 : 1。然后将第二混合溶液升温至回流状态反应，反应时间为至少 1小时，优选为 3小时，更优选为 4小时，特别优选 5小时，得到式（ I )所示的化合物。然后，将反应后的混合液冷却、过滤、重结晶。对于过滤和重结晶，本发明并无特别限制，可以按照本领域技术人员熟知的方式进行。 To the first mixed solution, an isocyanate represented by the formula (III) or an acyl group represented by the formula (IV) is added to the first mixed solution to obtain a second mixed solution. The ratio of the amount of the isocyanate or acyl group to the aminoguanidine is from 1:2 to 2:1, preferably from 1:1.5 to 1.5:1, more preferably from 1:1. Then, the second mixed solution is heated to a reflux state for a reaction time of at least 1 hour, preferably 3 hours, more preferably 4 hours, particularly preferably 5 hours, to obtain a compound represented by the formula (I). Then, the reaction mixture was cooled, filtered, and recrystallized. The present invention is not particularly limited for filtration and recrystallization, and can be carried out in a manner well known to those skilled in the art.

根据本发明，还可以进一步利用式（ I )所示的化合物制备其药学上可接受的盐。特别地，在制备盐酸盐时，优选按照如下方法： According to the present invention, a compound represented by the formula (I) can be further used to prepare a pharmaceutically acceptable salt thereof. In particular, in the preparation of the hydrochloride, it is preferred to follow the following method:

室温下，将式（ I )化合物加入到有机溶剂中，所述有机溶剂选自醇类有机溶剂、代烃类有机溶剂、醚类有机溶剂、酮类有机溶剂、酯类有机溶剂。所述醇类有机溶剂的具体例子可以为曱醇、乙醇、异丙醇、正丙醇、正丁醇、叔丁醇，但不限于此。所述代烃类有机溶剂的具体例子可以为二氯曱烷、氯仿、 1 , 2-二氯乙烷，但不限于此。所述醚类有机溶剂的具体例子可以为四氢呋喃、 ***、异丙醚、苯曱醚、曱基叔丁基醚，但不限于此。所述酮类有机溶剂的具体例子可以为丙酮、曱基异丁基酮、丁酮、曱基丁基酮，但不限于此。所述酯类有机溶剂的具体例子可以为乙酸乙酯、乙酸异丁酯、乙酸丁酯、乙酸异丙酯，但不限于此；优选为曱醇。 The compound of the formula (I) is added to an organic solvent selected from the group consisting of an alcohol organic solvent, a hydrocarbon-based organic solvent, an ether organic solvent, a ketone organic solvent, and an ester organic solvent at room temperature. Specific examples of the alcohol-based organic solvent may be decyl alcohol, ethanol, isopropanol, n-propanol, n-butanol or t-butanol, but are not limited thereto. Specific examples of the hydrocarbon-derived organic solvent may be dichlorosilane, chloroform or 1,2-dichloroethane, but are not limited thereto. Specific examples of the ether organic solvent may be, but are not limited to, tetrahydrofuran, diethyl ether, diisopropyl ether, benzoin ether, and mercapto tert-butyl ether. Specific examples of the ketone organic solvent may be acetone, decyl isobutyl ketone, butanone, decyl butyl ketone, but are not limited thereto. Specific examples of the ester organic solvent may be ethyl acetate, isobutyl acetate, butyl acetate or isopropyl acetate, but are not limited thereto; preferably, decyl alcohol.

所述式（ I )化合物与所述有机溶剂的摩尔体积比为 0.5~2mol/L, 优选为 0.7~1.5mol/L, 更优选为 0.9~l.lmol/L。在搅拌的状态下通入干燥的The molar volume ratio of the compound of the formula (I) to the organic solvent is 0.5 to 2 mol/L, which is excellent It is selected to be 0.7 to 1.5 mol/L, more preferably 0.9 to 1.1 mol/L. Passing dry under agitation

HC1气体搅拌均勾至式（ I )化合物全部溶解得到其盐酸盐，然后可以过滤和浓缩。对于得到的盐酸盐，可以加入到丙酮中冷藏，然后再进行过滤，干燥提纯。 The HC1 gas is stirred until the compound of formula (I) is completely dissolved to obtain its hydrochloride salt, which can then be filtered and concentrated. The obtained hydrochloride salt can be added to acetone for refrigeration, and then filtered, dried and purified.

根据本发明的药物组合物，包括式（ I )化合物作为活性成分。药物组合物可以制成片剂、丸剂、散剂、颗粒剂、胶嚢剂、糖浆剂、乳剂等本领域技术人员熟知的药物制剂。药物组合物中还可以包括本领域技术人员熟知的药用载体，如本领域技术人员熟知的赋形剂、粘合剂、崩解剂、矫味剂、矫臭剂、乳化剂、稀释剂、助溶剂等，对此本发明并无特别限制。 The pharmaceutical composition according to the present invention comprises a compound of the formula (I) as an active ingredient. The pharmaceutical composition can be formulated into pharmaceutical preparations well known to those skilled in the art such as tablets, pills, powders, granules, capsules, syrups, emulsions and the like. Pharmaceutically acceptable carriers well known to those skilled in the art may also be included in the pharmaceutical compositions, such as excipients, binders, disintegrating agents, flavoring agents, flavoring agents, emulsifiers, diluents, well known to those skilled in the art. A cosolvent or the like is not particularly limited in the present invention.

本发明化合物能够增强内源性胰岛素的分泌，从而实现降低血糖的效果，而且可以对糖尿病患者的多种并发症（如肾毒性、眼病、动脉硬化等）产生防治作用。 The compound of the present invention can enhance the secretion of endogenous insulin, thereby achieving the effect of lowering blood sugar, and can prevent and treat various complications of diabetic patients (such as nephrotoxicity, eye disease, arteriosclerosis, etc.).

为了进一步说明本发明，下面结合实施例对本发明优选的实施方案进行描述，但是应当理解，以下具体实施例和药理实验描述只是为进一步说明本发明的特征和优点，而不是对本发明保护范围的限制。制备例 In order to further illustrate the invention, the preferred embodiments of the present invention are described in the preferred embodiments of the present invention. . Preparation example

实施例 1 Example 1

( a )对曱基苯石黄胺酰基氨胍（化合物 1 ) 的制备 (a) Preparation of p-nonyl phenylphosphonium alanine amide (Compound 1)

室温 N₂保护下，机械搅拌，向 400 mL丙酮溶解的 44.0 g ( 0.4 mol ) 氨基胍盐酸盐中滴加 56 mL ( 0.4 mol ) 三乙胺，搅拌均匀。然后滴加 80.0 g ( 0.4 mol )对曱苯蹟酰异氰酸酯，加完后升温回流 4h, 冷却、过滤，重结晶得到 98.5 g白色固体状对曱苯橫胺酰基氨胍，收率为 93%。 ESI-MS: m/z = 271.9(M⁺)。 Under a N ₂ protection at room temperature, mechanically stir, add 56 mL (0.4 mol) of triethylamine to 44.0 g (0.4 mol) of aminoguanidine hydrochloride dissolved in 400 mL of acetone, and mix well. Then, 80.0 g (0.4 mol) of p-benzoyl isocyanate was added dropwise, and after heating, the mixture was heated to reflux for 4 h, cooled, filtered, and then recrystallized to give 98.5 g of yt. ESI-MS: m/z = 271.9 (M ⁺ ).

( b )对曱基苯橫胺酰基氨胍盐酸盐（化合物 2 ) 的制备 (b) Preparation of p-nonylbenzene cross-aminoacylamine hydrochloride (Compound 2)

室温下，取 60.0 g已制备的对曱苯橫胺酰基氨胍加入到 240 mL曱醇中，然后搅拌并通入干燥的 HC1气体至固体全部溶解，过滤，浓缩，加入 90ml丙酮在 4°C冷藏 4小时后，过滤，干燥，得到 64.7 g白色晶体，收率为 95%,纯度 > 99.5% ¾ NMR (300MHz, D₂0), δ: 2.24 (s, 3H), 7.28 (d, 2H, J = 7.8 Hz), 7.67 (d, 2H, J = 8.4 Hz)。 At room temperature, 60.0 g of the prepared p-toluene cross-aminoacylamine was added to 240 mL of methanol, then stirred and passed through a dry HCl gas to dissolve all solids, filtered, concentrated, and added to 90 ml of acetone at 4 ° C. After chilling for 4 hours, it was filtered and dried to give 64.7 g of white crystals, yield: 95%, purity > 99.5% 3⁄4 NMR (300 MHz, D ₂ 0), δ: 2.24 (s, 3H), 7.28 (d, 2H, J = 7.8 Hz), 7.67 (d, 2H, J = 8.4 Hz).

实施例 1的反应路线如下：

实施例 2 The reaction route of Example 1 is as follows:

Example 2

(a)对乙基苯石黄胺酰基氨胍（ 3) 的制备 (a) Preparation of p-ethyl phenylphosphonium alanine (3)

室温 N₂保护下，机械搅拌，向 200 mL丙酮溶解的 22.0 g ( 0.2 mol ) 氨基胍盐酸盐中滴加 28 mL ( 0.2 mol )三乙胺，搅拌均匀，室温下滴加 40.5 g ( 0.2 mol )对乙基苯蹟酰异氰酸酯，加完后升温回流 4h, 冷却、过滤，重结晶得 50.0 g白色固体状对乙基苯橫胺酰基氨胍，收率为 94%。 ESI-MS: m/z = 285.3(M⁺)。 Under the protection of N ₂ under room temperature, mechanically stir, add 28 mL (0.2 mol) of triethylamine to 22.0 g (0.2 mol) of aminoguanidine hydrochloride dissolved in 200 mL of acetone, stir evenly, and add 40.5 g (0.2) at room temperature. Methyl) p-ethyl phenyl amide isocyanate, after heating, refluxing for 4 h, cooled, filtered, and recrystallized to give 50.0 g of p-ethyl-phenyl-s-amino-amino-amino hydrazide as a white solid with a yield of 94%. ESI-MS: m/z = 285.3 (M ⁺ ).

(b)对乙基苯橫胺酰基氨胍盐酸盐（化合物 4) 的制备 (b) Preparation of p-ethylphenylheptylaminoguanidine hydrochloride (Compound 4)

室温下， 120 mL曱醇加入到 30.0 g对乙基苯橫胺酰基氨胍中，搅拌并通入干燥的 HC1气体至固体全部溶解，过滤、浓缩，加入 50 mL丙酮冷藏，过滤、干燥，得 33.1 g白色结晶，得率 95% ,纯度 >98%。 ^ NMR (300MHz D₂0), δ: 1.40 (t, 3Η, J= 3.4 Hz), 2.65 (m, 2H), 7.28 (d, 2H, J= 7.8 Hz), 7.67 (d, 2 ,J= 8.4 Hz)。 At room temperature, 120 mL of sterol was added to 30.0 g of p-ethylphenylheptylaminoguanidine, stirred and passed through dry HCl gas to dissolve all solids, filtered, concentrated, added to 50 mL of acetone, filtered, and dried. 33.1 g of white crystals with a yield of 95% and a purity of >98%. ^ NMR (300MHz D ₂ 0), δ: 1.40 (t, 3Η, J = 3.4 Hz), 2.65 (m, 2H), 7.28 (d, 2H, J = 7.8 Hz), 7.67 (d, 2, J= 8.4 Hz).

实施例 2的反应路线如下： The reaction route of Example 2 is as follows:

实施例 3 Example 3

(a) 4-(N-对曱基苯橫胺酰基) -1-(N-乙基) -氨胍（化合物 5) 的制备室温 N₂保护下，机械搅拌，向 400 mL丙酮溶解的 45.0 g ( 0.32 mol ) 1-N-乙基氨基胍盐酸盐中滴加 56 mL ( 0.4 mol ) 三乙胺，搅拌均匀。然后滴加 80.0 g ( 0.4 mol )对曱苯蹟酰异氰酸酯，加完后升温回流 4h, 冷却、过滤，重结晶得到 95.8 g白色固体状对曱苯橫胺酰基氨胍，收率为 90%。 ESI-MS: m/z = 299.2(M⁺)。 (a) Preparation of 4-(N-p-nonylphenyleminoamido)-1-(N-ethyl)-aminoindole (Compound 5) Under a N ₂ protection at room temperature, mechanically stir, add 56 mL (0.4 mol) of triethylamine to 45.0 g (0.32 mol) of 1-N-ethylaminoguanidine hydrochloride dissolved in 400 mL of acetone, and mix well. Then, 80.0 g (0.4 mol) of p-benzoyl isocyanate was added dropwise, and after heating, the mixture was heated to reflux for 4 hours, cooled, filtered, and recrystallized to give 95.8 g of a white solid, p-phthalic acid, in a yield of 90%. ESI-MS: m/z = 299.2 (M ⁺ ).

( b ) 4-(N-对曱基苯橫胺酰基) -1-(N-乙基) -氨胍盐酸盐（化合物 6 ) 的制备 (b) Preparation of 4-(N-p-nonylphenyleminoamido)-1-(N-ethyl)-aminoguanidine hydrochloride (Compound 6)

室温下，取 60.0 g已制备的 4-(N-对曱基苯橫胺酰基) -1-(N-乙基) -氨胍加入到 250 mL曱醇中，然后搅拌并通入干燥的 HC1气体至固体全部溶解，过滤，浓缩，加入 lOOmL丙酮在 0°C冷藏 4小时后，过滤，干燥，得到 65.3 g白色晶体，收率为 95%,纯度〉 99.5%。 ^ NMR (300MHz, D₂0), δ: 1.02(t, 3Η, J = 2.6 Hz), 2.27 (s, 3H), 3.15(m, 2H), 7.28 (d, 2H, J = 7.9 Hz), 7.67 (d, 2H, /= 8.4 Hz)。 60.0 g of prepared 4-(N-p-nonylphenyleminoamido)-1-(N-ethyl)-amidoxime was added to 250 mL of sterol at room temperature, then stirred and passed to dry HC1. The gas was completely dissolved in the solid, filtered, concentrated, and added to 100 mL of acetone at 0 ° C for 4 hours, filtered, and dried to obtain 65.3 g of white crystals, yield 95%, purity > 99.5%. ^ NMR (300MHz, D ₂ 0), δ: 1.02(t, 3Η, J = 2.6 Hz), 2.27 (s, 3H), 3.15(m, 2H), 7.28 (d, 2H, J = 7.9 Hz), 7.67 (d, 2H, /= 8.4 Hz).

实施例 3的反应路线如下： The reaction route of Example 3 is as follows:

HCIHCI

实施例 4

Example 4

( a ) 4-(N-对乙基苯橫胺酰基) -1-(N-乙基) -3-(N-曱基) -氨胍（化合物 7 ) 的制备 Preparation of (a) 4-(N-p-ethylphenylheptylamino)-1-(N-ethyl)-3-(N-fluorenyl)-aminoindole (Compound 7)

室温 N₂保护下，机械搅拌，向 240 mL丙酮溶解的 23.0 g ( 0.15 mol ) 1-N-乙基 -3-N-曱基-氨基胍盐酸盐中滴加 25 mL ( 0.18 mol ) 三乙胺，搅拌均匀，室温下滴加 36.5 g ( 0.18 mol )对曱苯蹟酰异氰酸酯，加完后升温回流 4h, 冷却、过滤，重结晶得 51.7 g白色固体状对乙基苯橫胺酰基氨胍，收率为 94%。 ESI-MS: m/z = 314.3 [(M+H) +]。 ( b ) 4-(N-对乙基苯橫胺酰基) -1-(N-乙基) -3-(N-曱基) -氨胍盐酸盐（化合物 8 ) 的制备 Under the protection of N ₂ under room temperature, mechanically stir, add 25 mL ( 0.18 mol ) to 23.0 g ( 0.15 mol ) of 1-N-ethyl-3-N-indenyl-aminoguanidine hydrochloride dissolved in 240 mL of acetone. Ethylamine, stir well, add 36.5 g (0.18 mol) of p-nonylbenzene isocyanate at room temperature, and then heat up and reflux for 4 h, cool, filter and recrystallize to give 51.7 g of white solid.胍, the yield was 94%. ESI-MS: m/z = 314.3 [(M+H) +]. Preparation of (b) 4-(N-p-ethylphenylheptylamino)-1-(N-ethyl)-3-(N-fluorenyl)-aminoguanidine hydrochloride (Compound 8)

室温下， 120 mL曱醇加入到 30.0 g对乙基苯橫胺酰基氨胍中，搅拌并通入干燥的 HC1气体至固体全部溶解，过滤、浓缩，加入 50 mL丙酮冷藏，过滤、干燥，得 35.8 g白色结晶，得率 96%,纯度 >98%。 ^ NMR (300MHz D₂0), δ: 1.10 (t, 3H, J= 2.4 Hz), 2.32 (s, 3H), 2.74 (s, 3H), 2.92(m, 2H), 7.28 (d, 2H, J= 7.9 Hz), 7.67 (d, 2H, J= 8.4 Hz)。 At room temperature, 120 mL of sterol was added to 30.0 g of p-ethylphenylheptylaminoguanidine, stirred and passed through dry HCl gas to dissolve all solids, filtered, concentrated, added to 50 mL of acetone, filtered, and dried. 35.8 g of white crystals with a yield of 96% and a purity of >98%. ^ NMR (300MHz D ₂ 0), δ: 1.10 (t, 3H, J = 2.4 Hz), 2.32 (s, 3H), 2.74 (s, 3H), 2.92 (m, 2H), 7.28 (d, 2H, J = 7.9 Hz), 7.67 (d, 2H, J = 8.4 Hz).

实施例 4的反应路线如下： The reaction route of Example 4 is as follows:

实施例

Example

( a ) 4-(N-对乙基苯橫胺硫代酰基) -1-(N-异丙基 )-3-(N-曱基) -氨胍（化合物 9 ) 的制备 Preparation of (a) 4-(N-p-ethylphenylhengthoylthioacyl)-1-(N-isopropyl)-3-(N-fluorenyl)-aminopurine (Compound 9)

室温 N₂保护下，机械搅拌，向 240 mL丙酮溶解的 23.0 g ( 0.15 mol ) 1-N-异丙基 -3-N-曱基-氨基胍盐酸盐中滴加 28 mL ( 0.20 mol ) 三乙胺，搅拌均匀，室温下滴加 42.5 g ( 0.20 mol )对曱苯蹟酰石克代异氰酸酯，加完后升温回流 4h, 冷却、过滤，重结晶得 54.3 g白色固体状对乙基苯横胺酰基氨胍，收率为 91%。 ESI-MS: m/z = 343.1 (M+)。 Under the protection of N ₂ under room temperature, mechanically stir, add 28 mL (0.20 mol) to 23.0 g (0.15 mol) of 1-N-isopropyl-3-N-indenyl-aminoguanidine hydrochloride dissolved in 240 mL of acetone. Triethylamine, stir well, add 42.5 g (0.20 mol) of p-benzoyl ketone isocyanate at room temperature. After heating, reflux and reflux for 4 h, cool, filter and recrystallize to obtain 54.3 g of p-ethylbenzene as white solid. The transverse amino amide was found to have a yield of 91%. ESI-MS: m/z = 343.1 (M+).

( b )4-(N-对乙基苯橫胺硫代酰基) -1-(N-异丙基 )-3-(N-曱基) -氨胍盐酸盐（化合物 10 ) 的制备 (b) Preparation of 4-(N-p-ethylphenylphosphazene thio)-1-(N-isopropyl)-3-(N-fluorenyl)-aminoguanidine hydrochloride (Compound 10)

室温下， 130 mL曱醇加入到 30.0 g对乙基苯橫胺酰基氨胍中，搅拌并通入干燥的 HC1气体至固体全部溶解，过滤、浓缩，加入 60 mL丙酮冷藏，过滤、干燥，得 30.8 g白色结晶，得率 93%,纯度 >98%。 ^ NMR (300MHz_: D₂0), δ: 1.06 (m, 6H), 2.38 (s, 3H), 2.71 (s, 3H), 3.42(m, 1H), 7.25 (d, 2H, J = 8.0 Hz), 7.70 (d, 2H, J = 8.4 Hz)' At room temperature, 130 mL of sterol was added to 30.0 g of p-ethylphenylheptylaminoguanidine, stirred and passed through dry HCl gas to dissolve all solids, filtered, concentrated, added to 60 mL of acetone, filtered, and dried. 30.8 g of white crystals with a yield of 93% and a purity of >98%. ^ NMR (300MHz _: D ₂ 0), δ: 1.06 (m, 6H), 2.38 (s, 3H), 2.71 (s, 3H), 3.42 (m, 1H), 7.25 (d, 2H, J = 8.0 Hz), 7.70 (d, 2H, J = 8.4 Hz)'

实施例 5的反应路线如下： The reaction route of Example 5 is as follows:

实施例 6 使用化合物 1制备的薄膜衣片

Example 6 Film-coated tablets prepared using Compound 1

原料为 50.0mg的化合物 1 (由实施例 1制备）、 70.5mg的 D-甘露醇、 16.0mg的玉米淀粉、 15.0mg的碳酸氢钠、 3. Omg的羟丙基曱基纤维素、 5.0mg的滑石、 0.5mg的硬脂酸镁。 The starting material was 50.0 mg of Compound 1 (prepared from Example 1), 70.5 mg of D-mannitol, 16.0 mg of corn starch, 15.0 mg of sodium hydrogencarbonate, 3. Omg of hydroxypropyl decyl cellulose, 5.0 mg. Talc, 0.5 mg of magnesium stearate.

将化合物 1、 D-甘露醇、玉米淀粉以及碳酸氢钠混合，并用羟丙基曱基纤维素水溶液喷雾流动制粒，制粒物过 24目筛后加滑石和硬脂酸镁并用旋转式打片机按每片 160mg打片。实施例 7 使用化合物 2制备细颗粒剂 Compound 1, D-mannitol, corn starch and sodium hydrogencarbonate were mixed and spray granulated with aqueous solution of hydroxypropyl decyl cellulose. The granules were passed through a 24 mesh sieve, then talc and magnesium stearate were added and rotated. The tablet is shot at 160mg per piece. Example 7 Preparation of Fine Granules Using Compound 2

原料为 10%重量的化合物 2 (由实施例 1制备）、 89.5%重量的 D-甘露醇、 0.5%重量的羟丙基曱基纤维素。 The starting material was 10% by weight of Compound 2 (prepared from Example 1), 89.5% by weight of D-mannitol, and 0.5% by weight of hydroxypropyl decyl cellulose.

将化合物 2和 D-甘露醇混合后加羟丙基曱基纤维素水溶液粘合、制粒并在 50°C下干燥，制粒物过 32目筛做成细粒剂。实施例 8使用化合物 3制备片剂 Compound 2 and D-mannitol were mixed, and then an aqueous solution of hydroxypropyl fluorenyl cellulose was added, granulated, and dried at 50 ° C, and the granules were sieved through a 32 mesh sieve to prepare a fine granule. Example 8 Preparation of a Tablet Using Compound 3

原料为 50.0mg的化合物 3 (由实施例 2制备）、 30.0mg的 D-甘露醇、 19.0mg的玉米淀粉、 15. Omg的碳酸氢钠、 1.5mg的羟丙基曱基纤维素、 4.0mg的滑石、 0.5mg的硬脂酸镁。 The starting material was 50.0 mg of Compound 3 (prepared from Example 2), 30.0 mg of D-mannitol, 19.0 mg of corn starch, 15. Omg of sodium bicarbonate, 1.5 mg of hydroxypropyl decyl cellulose, 4.0 mg. Talc, 0.5 mg of magnesium stearate.

将化合物 3、 D-甘露醇、玉米淀粉以及碳酸氢钠混合、并用羟丙基曱基纤维素水溶液喷雾流动制粒，制粒物过 24目筛后加滑石和硬脂酸镁并用旋转式打片机按每片 120mg打片。药理实验 Compound 3, D-mannitol, corn starch and sodium hydrogencarbonate were mixed and sprayed and granulated with an aqueous solution of hydroxypropyl decyl cellulose. The granules were passed through a 24 mesh sieve and then talc and magnesium stearate were added. Each tablet was punched with 120 mg using a rotary tableting machine. Pharmacological experiment

实验 1 急性毒性预试实验 Experiment 1 Acute toxicity pre-test

使用昆明小鼠，用实施例 1制备的对曱苯橫胺酰基胺胍（化合物 1 ) 进行实验， 5g/kg剂量， 0.5%CMC (羟曱基纤维素钠）配置未见死亡，可以免做急性毒性实验；用实施例 1制备的对曱苯橫胺酰基胺胍盐酸盐（化合物 2 ) 进行实验， lg/kg剂量， 0.5%CMC配置未见小鼠死亡； 10g/kg剂量， 0.5CMC%配置时 100%死亡率， LD₅。 (半数致死量 )在 3~5g/kg范围内。实验 2 正常小鼠的降糖作用 Using Kunming mice, the experiment was carried out using the p-phthalic acid amide amide amide (Compound 1) prepared in Example 1. The dose of 5 g/kg, 0.5% CMC (sodium hydroxydecyl cellulose) was not dead, and it could be avoided. Acute toxicity test; experiment with the indole phenyleminoamidamine hydrochloride (Compound 2) prepared in Example 1, no death was observed in the lg/kg dose, 0.5% CMC configuration; 10 g/kg dose, 0.5 CMC 100% mortality at % configuration, LD ₅ . (half the lethal dose) is in the range of 3 to 5 g/kg. Experiment 2 Hypoglycemic effect in normal mice

使用昆明小鼠，降糖作用及效果见表 1： Using Kunming mice, hypoglycemic effect and effect are shown in Table 1:

表 1 本发明化合物对正常小鼠的降糖作用效果 Table 1 Effect of the compound of the present invention on hypoglycemic effect in normal mice

化合物 2 剂量 12.86mg/kg 51.4mg/kg Compound 2 dose 12.86mg/kg 51.4mg/kg

(由实施例 1 (by embodiment 1

降糖量 12.0% 13.0% Sugar reduction 12.0% 13.0%

制备） Preparation)

化合物 1 剂量 43 mg/kg 21.5 mg/kg 10.75 mg/kg Compound 1 dose 43 mg/kg 21.5 mg/kg 10.75 mg/kg

(由实施例 1 (by embodiment 1

降糖量 16.3% 13.9% 11.6% 制备）实验 3 II型糖尿病 db小鼠血糖 Hypoglycemic rate 16.3% 13.9% 11.6% Preparation) Experiment 3 Type II diabetes db mouse blood glucose

使用 II型糖尿病 db小鼠，使用实施例 1制备的化合物 1和化合物 2, 按格列奇特人用量 200mg/kg换算， 0.5%CMC配置。其中，格列奇特有效功能基团和实施例 1制备的化合物基团等摩尔。小鼠血糖浓度（mmol/1 ) 在每次给药后 3h检测，检测血糖前动物禁 8h, 结果如表 2所示： Using Type II diabetic db mice, Compound 1 and Compound 2 prepared in Example 1 were used in a 0.5% CMC configuration in terms of a Glickey amount of 200 mg/kg. Among them, the Grignard effective functional group and the compound group prepared in Example 1 were equimolar. The blood glucose concentration (mmol/1) of the mice was detected 3 hours after each administration, and the animals were banned for 8 hours before the blood glucose was detected. The results are shown in Table 2:

表 2本发明化合物对 II型糖尿病 db小鼠血糖的影响 Table 2 Effect of the compound of the present invention on blood glucose of Type II diabetic db mice

动物剂量给药 18 给药 21 给药 28 给药 35 Animal dose administration 18 administration 21 administration 28 administration 35

给药 42天数 (只） (/kg) 天天天天 Dosing 42 days (only) (/kg) days and days

等量溶 Isometric

模型组 8 23.3+3.50 26.1+3.46 25.8±1.78 27.1±1.36 24.1+3.10 媒格列奇 20.1±4.03 21.6±3.27 22.4+2.22 22.9+2.63 20.9±2.52Model group 8 23.3+3.50 26.1+3.46 25.8±1.78 27.1±1.36 24.1+3.10 Media Gleich 20.1±4.03 21.6±3.27 22.4+2.22 22.9+2.63 20.9±2.52

8 36mg 大剂量 19.0±1.28 21.8+2.20 22.3+3.10 25.0+2.64 17.3±1.93 8 36mg high dose 19.0±1.28 21.8+2.20 22.3+3.10 25.0+2.64 17.3±1.93

8 50.8mg 8 50.8mg

化合物 2 * * Compound 2 * *

小剂量 18.8±3.47 20.5±3.01 23.8±2.74 18.8+2.52 Small dose 18.8±3.47 20.5±3.01 23.8±2.74 18.8+2.52

8 25.4mg 21.9±2.53 8 25.4mg 21.9±2.53

化合物 2 * Compound 2 *

大剂量 18.9±1.26 21.3±2.20 21.5±2.21 24.5±2.35 18.4±2.23 Large dose 18.9±1.26 21.3±2.20 21.5±2.21 24.5±2.35 18.4±2.23

8 43.0mg 8 43.0mg

化合物 i * * Compound i * *

小剂量 19.1±2.54 21.2±2.91 22.7+2.63 19.3+2.47 Small dose 19.1±2.54 21.2±2.91 22.7+2.63 19.3+2.47

8 29.5mg 21.2±2.32 8 29.5mg 21.2±2.32

化合物 i * Compound i *

注：与模型组相比较 *P<0.05, **P<0.01 实验 4 Note: Compared with the model group *P<0.05, **P<0.01 Experiment 4

5周龄的雄性 SD大鼠静脉给予链脲霉素（ 65mg/kg )诱发糖尿病。从糖尿病发病 9周以后开始每天经口给药一次含本发明化合物 1 (由实施例 1制备）的 0.5%重量羟丙曱基纤维素悬浮液或含本发明化合物 2 (由实施例 1制备）的 0.5%重量羟丙基曱基纤维素悬浮液。 Male 5-day-old SD rats were given intravenous streptozotocin (65 mg/kg) to induce diabetes. A suspension containing 0.5% by weight of hydroxypropyl hydrazine cellulose containing Compound 1 of the present invention (prepared by Example 1) or containing Compound 2 of the present invention (prepared by Example 1) was orally administered once a day after the onset of diabetes for 9 weeks. A 0.5% by weight suspension of hydroxypropyl fluorenyl cellulose.

给药 9周以后，为了测定肾小球的损伤程度，取出肾用 10%中性福尔马林緩沖液固定。组织切片进行苏木精 /伊红染色，根据肾小球的阻塞程度分为 5个阶段评价（0: 无阻塞， 1 : ~25%阻塞， 2: ~50%阻塞， 3：〜 75% 阻塞， 4：〜 100%阻塞）。每个标本评价 50个肾小球，将级数的合计作为肾小球阻塞度的指标，上述操作在单盲的条件下进行，结果见表 3 : After 9 weeks of administration, in order to measure the degree of glomerular damage, the kidneys were removed and fixed with 10% neutral formalin buffer. Tissue sections were stained with hematoxylin/eosin and divided into 5 stages according to the degree of glomerular obstruction (0: no obstruction, 1 : ~25% obstruction, 2: ~50% obstruction, 3: ~ 75% obstruction) , 4: ~ 100% blocked). Each specimen was evaluated for 50 glomeruli, and the total number of stages was used as an indicator of glomerular obstruction. The above operation was performed under single-blind conditions. The results are shown in Table 3:

表 3 本发明制备化合物的肾小球损伤实验结果 Table 3 Results of glomerular injury test of the compound prepared by the present invention

给药量肾小球阻塞程度组另 ij 例数 Dosage amount glomerular obstruction group another ij case

mg/kg/天级数 Mg/kg/day

糖尿病组 0 8 90.1±6.8 化合物 1给药组 8.0 7 90.2±9.8 化合物 1给药组 17.0 6 64.2±11.8 化合物 1给药组 34.0 5 54.8±7.8* 化合物 2给药组 10.0 7 91.2±9.4 化合物 2给药组 20.0 6 63.1±10.8 化合物 2给药组 40.0 5 53.5±8.9* 注：与模型组相比较 *P<0.05 Diabetes group 0 8 90.1±6.8 Compound 1 administration group 8.0 7 90.2±9.8 Compound 1 administration group 17.0 6 64.2±11.8 Compound 1 administration group 34.0 5 54.8±7.8* Compound 2 administration group 10.0 7 91.2±9.4 Compound 2 Administration group 20.0 6 63.1±10.8 Compound 2 administration group 40.0 5 53.5±8.9* Note: Compared with the model group *P<0.05

表 3的结果表明，本发明制备的化合物 1、 2剂量可以抑制糖尿病引起的肾小球损伤。实验 5 化合物 1、化合物 2对糖尿病大鼠视网膜病变及动脉粥样硬化的保护作用 The results in Table 3 indicate that the dose of Compounds 1 and 2 prepared by the present invention can inhibit glomerular injury caused by diabetes. Experiment 5 The protective effect of compound 1 and compound 2 on retinopathy and atherosclerosis in diabetic rats

90只 SD大鼠（雄性，体质量 180 ~ 210 g )。对照组 10只予普通饲料喂养；其余 80只随机分为治疗组及模型组各 10只，均采用一次性腹腔注射链脲佐菌素 60mg/kg诱发糖尿病模型（ 72 h后尾血血糖》 90 SD rats (male, body mass 180-210 g). Ten rats in the control group were fed with normal diets; the other 80 were randomly divided into the treatment group and the model group, each of which was induced by a single intraperitoneal injection of streptozotocin 60 mg/kg (72 h after tail blood glucose).

16.7mmol/L ), 高脂饲料喂养（常规饲料 20%蔗糖、 10%猪油、 2.5%胆固醇）， 3个月后治疗组给予化合物 1 (由实施例 1制备）、化合物 2 (由实施例 1制备）灌胃给药， 1次 /d, 治疗 2个月。结果显示： 16.7 mmol/L), fed with high fat diet (conventional feed 20% sucrose, 10% lard, 2.5% cholesterol), 3 months later, the treatment group was given Compound 1 (prepared from Example 1), Compound 2 (by example) 1 Preparation) Oral administration, 1 time / d, treatment for 2 months. The results show:

( 1 )视网膜消化铺片内皮细胞 (E)、周细胞 (P)计数及 E/P比较结果如表 4所示。 (1) Retinal digested patch endothelial cells (E), pericytes (P) counts and E/P comparison results are shown in Table 4.

表 4 各组间内皮细胞 (E), 周细胞 (P)计数及 E/P比较 (^ 士 s, n=4) 剂量 Table 4 Endothelial cells (E), pericytes (P) counts and E/P comparisons between groups (^ s, n=4)

组别内皮细胞 /个周细胞 /个 Group endothelial cells / pericytes /

/mg.kg-1 /mg.kg-1

正常 754.11±18.74 274.25±18.14 Normal 754.11±18.74 274.25±18.14

模型 972.18±21.53 ^Δ 71.33±17.61 ^{Δ Δ} Model 972.18±21.53 ^Δ 71.33±17.61 ^{Δ Δ}

羟苯磺酸钙 150 818.57±19.21 * 214.45±14.59** Calcium hydroxybenzenesulfonate 150 818.57±19.21 * 214.45±14.59**

化合物 1小 Compound 1 small

8.8 904.21±22.47 126.28±21.89* 8.8 904.21±22.47 126.28±21.89*

剂量 Dose

化合物 1中 Compound 1

17.0 802.34±20.15* 203.19±18.51 ** 17.0 802.34±20.15* 203.19±18.51 **

剂量 Dose

化合物 1 大 Compound 1 large

34.0 797.47±18.63* 254.20±19.74** 34.0 797.47±18.63* 254.20±19.74**

剂量 Dose

化合物 2小 Compound 2 small

10.0 891.26±22.31 * 134.21±19.99* 10.0 891.26±22.31 * 134.21±19.99*

剂量 Dose

化合物 2中 Compound 2

20.0 793.28±19.77* 217.18±17.24** 20.0 793.28±19.77* 217.18±17.24**

剂量化合物 2 大 Dose Compound 2 large

40.0 785.46±23.44* 267.24±22.74** 40.0 785.46±23.44* 267.24±22.74**

剂量 Dose

注：与正常组比较， ^ <ο.θ5, ^ΔΔΡ<0.01 ; 与模型组比较， *Ρ<0.05, **Ρ<0.01 Note: Compared with the normal group, ^ <ο.θ5, ^ΔΔ Ρ<0.01; compared with the model group, *Ρ<0.05, **Ρ<0.01

表 4显示模型组较正常组内皮细胞增生明显，周细胞明显减少。而化合物 1、化合物 2组同模型组比这种改变明显减轻（Ρ<0.05 )。 Table 4 shows that the endothelial cells proliferated significantly in the model group compared with the normal group, and the pericytes were significantly reduced. Compound 1 and Compound 2 were significantly less than this model group (Ρ<0.05).

( 2 )视网膜微血管超微结构 (2) Retinal microvascular ultrastructure

模型组大鼠视网膜毛细血管内皮细胞胞质内吞饮小泡数量增多，线粒体水肿，部分线粒体的嵴和膜融合消失，基底膜增厚，治疗组化合物 1、化合物 2视网膜毛细血管管腔规则，内皮细胞核形态完整，胞质内部分线粒体水肿，基底膜正常。 In the model group, the number of cytoplasmic vesicles in the retinal capillary endothelial cells increased, mitochondrial edema, partial mitochondrial sputum and membrane fusion disappeared, basement membrane thickened, treatment group compound 1, compound 2 retinal capillary lumen regulation, The nucleus of endothelial cells is intact, some mitochondrial edema in the cytoplasm, and the basement membrane is normal.

( 3 )血脂测定 (3) Determination of blood lipids

结果如表 5所示。表 5 化合物 1、 2对糖尿病大鼠动脉粥样硬化的保护作用 ( ^x土 s, n=10) The results are shown in Table 5. Table 5 Protective effects of Compounds 1 and 2 on atherosclerosis in diabetic rats ( ^x soil s, n=10)

剂量 TC LDL Dose TC LDL

组别 Group

/mg.kg- ¹ mmol/1 mmol/1 /mg.kg- ¹ mmol/1 mmol/1

正常 0.93±0.02 0.23±0.01 模型 6.14±1.75^{Δ Δ} 0.54±0.14^{Δ Δ} Normal 0.93±0.02 0.23±0.01 Model 6.14±1.75 ^{Δ Δ} 0.54±0.14 ^{Δ Δ}

化合物 1小 Compound 1 small

8.8 4.73±1.54 0.400±0.12* 8.8 4.73±1.54 0.400±0.12*

剂量 Dose

化合物 1中 Compound 1

17.0 3.16±0.89* 0.307±0.14* 17.0 3.16±0.89* 0.307±0.14*

剂量 Dose

化合物 1 大 Compound 1 large

34.0 0.97±0.01 ** 0.24±0.01 ** 34.0 0.97±0.01 ** 0.24±0.01 **

剂量 Dose

化合物 2小 Compound 2 small

10.0 4.96±1.67 0.409±0.19 10.0 4.96±1.67 0.409±0.19

剂量 Dose

化合物 2中 Compound 2

20.0 3.24±0.77* 0.314±0.11 * 20.0 3.24±0.77* 0.314±0.11 *

剂量 Dose

化合物 2 大 40.0 1.07±0.02* 0.29±0.01 剂量 Compound 2 is 40.0 1.07±0.02* 0.29±0.01 dose

注：与正常组比较， ^ΔΡ<0.05, ^ΔΔΡ<0.01 ; 与模型组比较， *Ρ<0.05, **Ρ<0.01 Note: Compared with the normal group, ^Δ Ρ<0.05, ^ΔΔ Ρ<0.01; compared with the model group, *Ρ<0.05, **Ρ<0.01

表 5显示，与正常组比较，模型组的总胆固醇 (TC)和低密度脂蛋白胆固醇 (LDL)均明显增高，与模型组比较，各用药组明显好转。 Table 5 shows that the total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) of the model group were significantly higher than those of the normal group, and the medication groups were significantly improved compared with the model group.

结果表明，本发明制备的化合物 1、 2对眼病、动脉硬化具有治疗作用，而且作用在极低的用量时也可以持续。以上对本发明所提供的对曱苯磺胺酰基氨胍及其盐酸盐进行了详细上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。 The results show that the compounds 1 and 2 prepared by the present invention have therapeutic effects on ocular diseases and arteriosclerosis, and can also be sustained at a very low dosage. The above description of the indole sulfonamide and its hydrochloride provided by the present invention has been described in detail in the above examples only to assist in understanding the method of the present invention and its core idea. It is to be understood that those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the invention.

Claims

权利要求或其药学上可接受的盐:

( 工）其中， X选自 0或 s ; The claim or a pharmaceutically acceptable salt thereof:

(工) where X is selected from 0 or s;

选自 H、 C_1-12烷基、 C_1-12烷氧基、 C_2-8婦基、 C_2-8炔基、素、羟基、氨基、硝基、氰基、羧基、 C_1-12烷氧基羰基、 C_1-12烷基羰氧基，其中，所述烷基或烷氧基中的一个或多个氢原子任选被卤素、羟基、氨基、硝基、氰基或羧基取代； Selected from H, C _1-12 alkyl, C _1-12 alkoxy, C _2-8 , C _2-8 alkynyl, hydroxy, amino, nitro, cyano, carboxy, C _{1- a 12} alkoxycarbonyl group, a C _1-12 alkylcarbonyloxy group, wherein one or more hydrogen atoms of the alkyl group or alkoxy group are optionally halogen, hydroxy, amino, nitro, cyano or carboxy Replace

R₂选自 H、 C_1-12烷基、 C_3-10环烷基、氰基，其中，所述烷基或环烷基中的一个或多个氢原子任选被卤素、羟基、氨基或羧基取代； R _{2 is} selected from H, C _1-12 alkyl, C _3-10 cycloalkyl, cyano, wherein one or more hydrogen atoms in the alkyl or cycloalkyl group are optionally halogen, hydroxy, amino Or a carboxyl group;

R₃和 R₄各自独立地选自 H、 C_M2烷基，其中，所述烷基中的一个或多个氢原子任选被卤素、羟基、氨基、羧基、。环烷基或苯基取代； R ₃ and R ₄ are each independently selected from H, C _M2 alkyl, wherein one or more hydrogen atoms in the alkyl group are optionally halogen, hydroxy, amino, carboxy. Cycloalkyl or phenyl substituted;

或者， R₃和 R₄、或 R₂和 R₄与其所连的氮原子共同构成五元、六元或七元饱和或不饱和杂环。 Alternatively, R ₃ and R ₄ , or R ₂ and R ₄ together with the nitrogen atom to which they are attached form a five-, six- or seven-membered saturated or unsaturated heterocyclic ring.

2、权利要求 1 所述的化合物或其药学上可接受的盐，其特征在于，位于磺酰胺基的邻位或对位，优选为对位。 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized by being in the ortho or para position of the sulfonamide group, preferably in the para position.

3、权利要求 1或 2所述的化合物或其药学上可接受的盐，其特征在于， Ri选自 H、 C_1-8烷基、 C_1-8烷氧基、 C_2-6烯基、 C_2-6炔基、卤素、羟基、氨基、硝基、氰基、羧基、烷氧基羰基、（^₈烷基羰氧基，其中，所述烷基或烷氧基中的一个或多个氢原子任选被卤素、羟基、氨基、硝基、氰基或 « 取代； The compound according to claim 1 or 2, wherein Ri is selected from the group consisting of H, C _1-8 alkyl, C _1-8 alkoxy, C _2-6 alkenyl, or a pharmaceutically acceptable salt thereof , C _2-6 alkynyl, halogen, hydroxy, amino, nitro, cyano, carboxy, alkoxycarbonyl, ₍₈ ^ alkylcarbonyloxy, wherein said alkyl or alkoxy group or a a plurality of hydrogen atoms optionally substituted by halogen, hydroxy, amino, nitro, cyano or «;

R₂选自 H、 C^₈烷基、 C_3-8环烷基、氰基，其中，所述烷基或环烷基中的一个或多个氢原子任选被卤素、羟基、氨基或羧基取代； R _{2 is} selected from the group consisting of H, C ₈ alkyl, C _3-8 cycloalkyl, cyano, wherein one or more hydrogen atoms in the alkyl or cycloalkyl group are optionally halogen, hydroxy, amino or Carboxyl substitution;

R₃和 R₄各自独立地选自 H、烷基，其中，所述烷基中的一个或多个氢原子任选被卤素、羟基、氨基、 «、环烷基或苯基取代。 R ₃ and R ₄ are each independently selected from H, alkyl, wherein one or more hydrogen atoms in the alkyl group are optionally substituted by halogen, hydroxy, amino, «, cycloalkyl or phenyl.

4、权利要求 1或 2所述的化合物或其药学上可接受的盐，其特征在于， Ri选自 H、 C_1-6烷基、 C_1-6烷氧基、 C_2-4烯基、 C_2-4炔基、卤素、羟基、氨基、硝基、氰基、羧基、 C^₆烷氧基羰基、 C^₆烷基羰氧基，其中，所述烷基或烷氧基中的一个或多个氢原子任选被卤素、羟基、氨基、硝基、氰基或 « 取代； The compound according to claim 1 or 2, wherein Ri is selected from the group consisting of H, C _1-6 alkyl, C _1-6 alkoxy, C _2-4 alkenyl, or a pharmaceutically acceptable salt thereof , C _2-4 alkynyl, halogen, hydroxy, amino, nitro, cyano, carboxy, C ₆ alkoxycarbonyl, C ₆ alkylcarbonyloxy, wherein said alkyl or One or more hydrogen atoms in the alkoxy group are optionally substituted by halogen, hydroxy, amino, nitro, cyano or «;

R₂选自 H、 C_1-6烷基、 C_3-8环烷基、氰基，其中，所述烷基或环烷基中的一个或多个氢原子任选被卤素、羟基、氨基或羧基取代； R _{2 is} selected from the group consisting of H, C _1-6 alkyl, C _3-8 cycloalkyl, cyano, wherein one or more hydrogen atoms in the alkyl or cycloalkyl group are optionally halogen, hydroxy, amino Or a carboxyl group;

5、权利要求 1或 2所述的化合物或其药学上可接受的盐，其特征在于， Ri选自 H、 C_1-6烷基、 C_1-6烷氧基、氟、氯、溴、碘、羟基、氨基、羧基、 C^₆烷氧基羰基、（^₆烷基羰氧基，其中，所述烷基或烷氧基中的一个或多个氢原子任选被氟、氯、溴、碘、羟基、氨基或羧基取代，优选地，选自 H、 C_1-6烷基； The compound according to claim 1 or 2, wherein Ri is selected from the group consisting of H, C _1-6 alkyl, C _1-6 alkoxy, fluorine, chlorine, bromine, or a pharmaceutically acceptable salt thereof. Iodine, hydroxy, amino, carboxy, C^ ₆ alkoxycarbonyl, ( _{6 6} alkylcarbonyloxy, wherein one or more hydrogen atoms of the alkyl or alkoxy group are optionally fluorine, chlorine, Substituted by bromine, iodine, hydroxy, amino or carboxy, preferably selected from H, C _1-6 alkyl;

R₂选自 H、 C_1-6烷基、 C_3-6环烷基、氰基，其中，所述烷基或环烷基中的一个或多个氢原子任选被氟、氯、溴、碘、羟基、氨基或羧基取代，优选地， R₂选自 H、 C_1-6烷基，更优选地， R₂为 H; R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, cyano, wherein one or more hydrogen atoms in the alkyl or cycloalkyl group are optionally selected from fluorine, chlorine, bromine Substituting iodine, hydroxy, amino or carboxy, preferably, R _{2 is} selected from H, C _1-6 alkyl, more preferably, R ₂ is H;

R₃和 R₄各自独立地选自 H、烷基，其中，所述烷基中的一个或多个氢原子任选被氟、氯、溴、碘、羟基、氨基、羧基、 C₃_₆环烷基或苯基取代，优选地， R₃和 R₄各自独立地选自 H、 Ci_-6烷基，更优选地， R₃和 R₄均为 H。 R ₃ and R ₄ are each independently selected from H, alkyl, wherein one or more hydrogen atoms in the alkyl group are optionally fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, C ₃ _-6 Substituted by a cycloalkyl group or a phenyl group, preferably, R ₃ and R ₄ are each independently selected from H, Ci _-6 alkyl group, and more preferably, both R ₃ and R ₄ are H.

6、权利要求 1或 2所述的化合物或其药学上可接受的盐，其特征在于， R₃和 R₄与其所连的氮原子共同构成二氢咪唑、四氢咪唑、二氢嘧啶、四氢嘧¹¹定。 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₃ and R ₄ together with the nitrogen atom to which they are attached constitute a dihydroimidazole, a tetrahydroimidazole, a dihydropyrimidine, or a tetra Hydrogen pyrimidine ¹¹ fixed.

7、权利要求 1或 2所述的化合物或其药学上可接受的盐，其特征在于，所述药学上可接受的盐是无机酸盐或有机酸盐，例如盐酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、曱酸盐、草酸盐、琥珀酸盐、富马酸盐、马来酸盐、柠檬酸盐、苹果酸盐；优选地，当式（ I )化合物的结构中存在酸性基团时，与碱成盐，具体例子为碱金属盐，例如钠盐、钾盐；碱土金属盐，例如镁盐、钙盐；以及铵盐或有机季铵盐。 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a mineral acid salt or an organic acid salt such as a hydrochloride salt, a sulfate salt, or a nitric acid salt. Salt, phosphate, acetate, citrate, oxalate, succinate, fumarate, maleate, citrate, malate; preferably, when the structure of the compound of formula (I) In the presence of an acidic group, a salt is formed with a base, and specific examples are alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts or organic quaternary ammonium salts.

8、权利要求 1或 2所述的化合物或其药学上可接受的盐，选自以下：对曱基苯磺胺酰基氨胍， The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: p-nonylbenzenesulfonamide aminoguanidine,

对曱基苯磺胺酰基氨胍盐酸盐， p-Mercaptophenylsulfonylaminoguanidine hydrochloride,

对乙基苯磺胺酰基氨胍， P-ethylbenzenesulfonyl amidohydrazide,

对乙基苯磺胺酰基氨胍盐酸盐， 4— (N-对曱基苯磺胺酰基) -1-(N-乙基) -氨胍， P-ethylbenzenesulfonylaminoguanidine hydrochloride, 4-(N-p-nonylbenzenesulfonyl)-1-(N-ethyl)-ammonium,

4-(N-对曱基苯磺胺酰基) -1-(N-乙基) -氨胍盐酸盐， 4-(N-p-nonylbenzenesulfonyl)-1-(N-ethyl)-aminoguanidine hydrochloride,

4-(N-对乙基苯橫胺酰基)- 1 -(N-乙基) -3 -(N-甲基) -氨胍， 4-(N-p-ethylphenylheptylamino)-1 -(N-ethyl)-3-(N-methyl)-ammonium,

4-(N-对乙基苯橫胺酰基) -1-(N-乙基) -3-(N-曱基) -氨胍盐酸盐， 4-(N-p-ethylphenylheptylamino)-1-(N-ethyl)-3-(N-indenyl)-aminoguanidine hydrochloride,

4-(N-对乙基苯横胺硫代酰基) -1-(N-异丙基 )-3-(N-曱基) -氨胍， 4-(N-p-ethylphenylheptylamine thioyl)-1-(N-isopropyl)-3-(N-fluorenyl)-ammonium,

4-(N-对乙基苯磅胺硫代酰基) -1-(N-异丙基 )-3-(N-曱基) -氨胍盐酸盐。 4-(N-p-Ethylphenylamine amine thioyl)-1-(N-isopropyl)-3-(N-indenyl)-aminoguanidine hydrochloride.

9、权利要求 1所述的化合物或其药学上可接受的盐的制备方法，包括: 9. A process for the preparation of a compound of claim 1 or a pharmaceutically acceptable salt thereof, comprising:

II )所示的氨基胍

II)

与式（ III )所示的异氰酸酯进行反应,

Reacting with an isocyanate represented by formula (III),

得到式（ I )化合物，并任选将其转化为药学上可接受的盐 A compound of formula (I) is obtained, and optionally converted to a pharmaceutically acceptable salt

或者（B )将式（ II )所示的氨基胍 Or (B) an aminoguanidine represented by formula (II)

N N

Η₂Ν、_ΝΛ ₄ Η ₂ Ν, _Ν Λ ₄

R₃ ^Η ( II ) R ₃ ^Η ( II )

与式（IV )所示的酰卤进行反应， Reacting with the acid halide represented by the formula (IV),

α χ χ χ

// //

HN-C HN-C

, Υ , Υ

0^/ 0 ( IV ) 0 ^/ 0 ( IV )

得到式（ I )化合物，并任选将其转化为药学上可接受的盐； Obtaining a compound of formula (I), and optionally converting it to a pharmaceutically acceptable salt;

其中， Υ是卤素， X、 Ri、 R₂、 R₃和 R₄的定义如权利要求 1中所述。 Wherein Υ is halogen, and X, Ri, R ₂ , R ₃ and R ₄ are as defined in claim 1.

10、权利要求 9所述的制备方法，其特征在于，所述化合物的制备方法包括如下步骤： The method according to claim 9, wherein the method for preparing the compound comprises the steps of:

( 1 )取式（ II )所示氨基胍或其盐酸盐溶于有机溶剂中，得到式（ II ) 的氨基胍（盐酸盐）的有机溶液； (1) The aminoguanidine or its hydrochloride salt of the formula (II) is dissolved in an organic solvent to obtain an organic solution of the aminoguanidine (hydrochloride) of the formula (II);

(2)向步骤（1 )得到的有机溶液中加入碱，搅拌均匀，得到第一混合 (2) adding a base to the organic solution obtained in the step (1), stirring uniformly to obtain a first mixture

(3) 室温下，向步骤（2)得到的第一混合液中加入式（III )所示异氰酸酯或式（IV)所示得到第二混合液；

(3) adding the isocyanate of the formula (III) or the second mixture as shown in the formula (IV) to the first mixture obtained in the step (2) at room temperature;

(4)将步骤（3)得到的第二混合溶液升温至回流状态反应，冷却，即得式（I)所示的化合物； (4) The second mixed solution obtained in the step (3) is heated to a reflux state to be reacted, and cooled to obtain a compound represented by the formula (I);

(5)根据需要，将式（ I )化合物转化为相应的药学上可接受的盐；其中， Y是卤素， X、 Ri、 R₂、 R₃和 R₄的定义如权利要求 1中所述。 (5) converting a compound of the formula (I) into a corresponding pharmaceutically acceptable salt, as required; wherein Y is a halogen, and X, Ri, R ₂ , R ₃ and R ₄ are as defined in claim 1. .

11、权利要求 10所述的制备方法，其特征在于，在步骤（1 ) 中，所述有机溶剂选自醇类有机溶剂、代烃类有机溶剂、醚类有机溶剂、酮类有机溶剂、酯类有机溶剂；所述醇类有机溶剂选自曱醇、乙醇、异丙醇、正丙醇、正丁醇、叔丁醇；所述代烃类有机溶剂选自二氯曱烷、氯仿、 1, 2-二氯乙烷；所述醚类有机溶剂选自四氢呋喃、 ***、异丙醚、苯曱醚、曱基叔丁基醚；所述酮类有机溶剂选自丙酮、曱基异丁基酮、丁酮、曱基丁基酮；所述酯类有机溶剂选自乙酸乙酯、乙酸异丁酯、乙酸丁酯、乙酸异丙酯；优选地，所述的有机溶剂为丙酮。 The method according to claim 10, wherein in the step (1), the organic solvent is selected from the group consisting of an alcohol organic solvent, a hydrocarbon-based organic solvent, an ether organic solvent, a ketone organic solvent, and an ester. The organic solvent is selected from the group consisting of decyl alcohol, ethanol, isopropanol, n-propanol, n-butanol, and tert-butanol; and the hydrocarbon-based organic solvent is selected from the group consisting of dichlorosilane, chloroform, and , 2-dichloroethane; the ether organic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, diisopropyl ether, phenyl ether, decyl tert-butyl ether; the ketone organic solvent is selected from the group consisting of acetone and decyl isobutyl Ketone, butanone, mercaptobutyl ketone; the ester organic solvent is selected from the group consisting of ethyl acetate, isobutyl acetate, butyl acetate, and isopropyl acetate; preferably, the organic solvent is acetone.

12、权利要求 10或 11所述的制备方法，其特征在于，在步骤（ 1 ) 中，所述氨基胍（盐酸盐 )有机溶液的浓度为 0.5~2mol/L,优选为 0.7 ~1.5mol/L, 更优选为 0.9~l.lmol/L。 The preparation method according to claim 10 or 11, wherein in the step (1), the concentration of the aminoguanidine (hydrochloride) organic solution is 0.5 to 2 mol/L, preferably 0.7 to 1.5 mol. /L, more preferably 0.9 to 1.lmol/L.

13、权利要求 10或 11所述的制备方法，其特征在于，在步骤（2) 中，所述碱为有机碱或无机碱；优选为三乙胺。 The process according to claim 10 or 11, wherein in the step (2), the base is an organic base or an inorganic base; preferably triethylamine.

14、权利要求 10或 11所述的制备方法，其特征在于，在步骤（2) 中，加入的碱与氨基胍的物质的量之比为 1 ： 2~2： 1, 优选为 1： 1.5~1.5： 1, 更优选为 1 : 1。 The preparation method according to claim 10 or 11, wherein in the step (2), the ratio of the amount of the base added to the aminoguanidine is 1: 2 to 2: 1, preferably 1: 1.5. ~1.5: 1, more preferably 1:1.

15、权利要求 10或 11所述的制备方法，其特征在于，在步骤（3) 中，加入的式（ III )所示异氰酸酯或式（ IV )所示的酰卤与氨基胍的物质的量之比为 1： 2~2： 1 , 优选为 1： 1.5~1.5： 1 , 更优选为 1 : 1。 The preparation method according to claim 10 or 11, wherein in the step (3), The ratio of the amount of the isocyanate represented by the formula (III) or the acid halide represented by the formula (IV) to the aminoguanidine is 1:2 to 2:1, preferably 1:1.5 to 1.5:1, more preferably 1 : 1.

16、权利要求 10或 11所述的制备方法，其特征在于，在步骤（4 ) 中，反应时间为至少 1小时，优选为 3小时，更优选为 4小时，特别优选为 5小时。 The process according to claim 10 or 11, wherein in the step (4), the reaction time is at least 1 hour, preferably 3 hours, more preferably 4 hours, and particularly preferably 5 hours.

17、药物组合物，包括权利要求 1至 8中任一项所述的化合物或其药学上可接受的盐和载体。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof and a carrier.

18、权利要求 1至 8 中任一项所述的化合物或其药学上可接受的盐和 / 或权利要求 17所述的药物组合物在制备治疗糖尿病药物中的应用。 Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and/or a pharmaceutical composition according to claim 17 for the preparation of a medicament for the treatment of diabetes.

19、一种治疗糖尿病的方法，其特征在于，所述方法包括给有此需要的患者施用治疗有效量的权利要求 1至 8中任一项所述的化合物或其药学上可接受的盐和 /或权利要求 17所述的药物组合物。 A method of treating diabetes, which comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a patient in need thereof. / or the pharmaceutical composition of claim 17.