TW200300682A - Pharmaceutical composition comprising an α - glucosidase inhibitor and a thiazolidinedione derivative, and use thereof for the preparation of medicaments for treating diabetes - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising, as active principles, a derivative of 5-phenoxyalkyl-2, 4-thiazolidinedione type and an α-glucosidase inhibitor, in combination with one or more pharmaceutically acceptable excipients. These compositions are particularly suitable for treating diabetes.

Description

200300682 A7 B7 V. Description of the Invention (Technical Field) The present invention relates to a pharmaceutical composition comprising, as an active ingredient, a phenoxyalkylthiazolidinedione derivative and α-sugar as described in WO 97 / 476l2. This invention also relates to 5-phenoxyalkyl_2,4_thiazolidinedione derivatives and α-glucosidase inhibitors for the preparation for reducing hyperglycemia, and more particularly non-insulin. Use of drugs for dependent diabetic hyperglycemia. Many thiazolidine-2,4-dione derivatives have been described in the prior art as antihyperglycemic agents and hypolipidemic agents, so they are described as antidiabetic (Takeda, EP 1 93 25 6 and Sankyo EP 2 07 5 8 1). These compounds are activators of peroxisome proliferator-activated receptor-r (ppar r). Α-Sugar Glucosidase inhibitors are described as antihyperglycemic agents and are often used to treat type 2 diabetes (NIDDM). Special mention may be made of glucoamylase inhibitors including acarbose, rice Miglitol and voglibose. Mixtures of certain thiazolidinedione derivatives, such as Activators of PPAR r, such as pioglitazone and troglitazone, in combination with α-glucosidase inhibitors have been described for the treatment of diabetes (SmithKline Beecham, patent application WO 98/5763 5). Diabetes is a chronic disease with multiple pathological phenomena . It will be accompanied by fat and sugar metabolism disorders and circulatory disorders. In many cases, diabetes often progresses to multiple pathological outbreaks. Therefore, find out that the Chinese national standard (CNS) A4 specification applicable to this paper standard ( 210x 297 mm) (Please read the notes on the back before filling out this page)

11, 11 Printed by the Ministry of Economic Affairs, Intellectual Property, and Industrial Cooperatives -5- 200300682 Α7 Β7 5. Invention Description (3 The treatment of individual diabetic patients is necessary. Α · Glycosidase inhibitors and PPAR r conversion Specific combinations of inactive 5-phenoxyalkyl-2,4-thiazolidinediones have not been mentioned, and offer some special advantages, especially without adding weight and / or causing blood thinning. Accordingly, it is an object of the present invention to provide a composition which can significantly improve the use of glucose. Another object of the present invention is to provide a composition which is suitable for treating by exhibiting a significant effect on the metabolic syndrome of insulin resistance Diabetes. Finally, the object of the present invention is to propose a composition particularly suitable for treating various stages of diabetes. These and other objectives are achieved by the present invention with regard to a pharmaceutical composition including at least as an active ingredient An α-sugarase inhibitor and at least one compound of formula (I), in combination with one or more pharmaceutically acceptable excipients. . In the treatment of diabetes, particularly for non-insulin dependent diabetes which is particularly suitable for reducing non-insulin dependent diabetes is hyperglycemia defined compound of formula (I) as follows:

This paper size applies to China National Standard (CNS) A4 specification (2 丨 0X 297 mm) (Please read the notes on the back before filling this page), 11 Intellectual Property Bureau of the Ministry of Economic Affairs (printed by the Industrial and Consumer Cooperatives -6 _ 200300682 Α7 Β7 V. Description of the invention (i Wherein, A represents a saturated or unsaturated, linear or branched hydrocarbon group containing 2 to 16 carbon atoms. D represents a substrate with the same carbon or heterocarbon, single Aromatic structures which are cyclic, bicyclic or tricyclic, and may contain one or more heteroatoms. X represents an aromatic structure substituent, and the selection range includes hydrogen, an alkyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms. Carbon atom alkoxy, alkoxyalkyl, wherein the alkoxy and alkyl are defined as above, and aryl is defined as an aromatic containing one or two rings, and optionally one or two heteroatoms in the ring Cyclic structure, such as phenyl or α- or Θ-naphthyl; aralkyl, where alkyl is as defined above, and aryl is as defined above and optionally includes one or more substituents; aralkylaryl Group, where the aralkyl and aryl portions are as defined above ; Halogen, trifluoromethyl, cyano, hydroxy, nitrogen, amine, carboxyl, alkoxycarbonyl, carboxyamido, sulfoamido, wind, sulfoamido, aminosulfoamido, alkylsulfo Fluorenylamino, fluorenylamino or trifluoromethoxy, η is an integer from 1 to 3. In the above, in the aromatic group D, the structures based on the same carbon include phenyl, α-naphthalene Radicals, Θ-naphthyl, onionyl and alkynyl. Among the heterocyclic aromatic radicals, mention may be made of pyridyl and quinolinyl or carbazolyl. D is preferably phenyl or naphthalene Among the alkyl groups containing 1 to 6 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, third butyl, pentyl, and hexyl groups may be particularly mentioned. In the alkoxy group containing 1 to 6 carbon atoms, the paper size can be adapted to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page ) Yi. Order printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200300682 A7 B7 V. Description of the invention (4 Do not mention methoxy, ethoxy, propoxy, isopropoxy, Oxygen and isobutoxy. Among the halogens that may be mentioned are fluorine, chlorine, bromine and iodine. The A chain is a linear or branched hydrocarbon-based chain containing 2 to 16 carbon atoms, which is saturated Or one or more vinyl groups, optionally containing at least one hydroxy or phenyl substituent. Examples of linear radicals that may be specifically mentioned include divalent ethyl, propyl, butyl, pentyl, hexyl, Octyl, nonyl, decyl, dodecyl, hexadecyl. Branched alkane chains that may be mentioned in particular are divalent 2-ethylhexyl, 2-methylbutyl, 2-methylpentyl , 1-methylhexyl, and 3-methylheptyl. Preferred monohydroxyalkyl chains are those containing 2 or 3 carbon atoms, such as 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxy. Propyl. Preferred polyhydroxyalkyl chains are groups containing 3 to 6 carbon atoms and 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, or 2,3, 4,5-tetrahydroxypentyl or pentaerythritol residues. Among hydrocarbon-based chains containing 2 to 16 carbon atoms and one or more vinyl groups, a divalent allyl group may be particularly mentioned. Preferred is divalent ethyl or propyl. The present invention also relates to tautomeric forms of the compounds of the general formula (I), mirror image isomers, non-image isomers and epimers, etc. of these compounds, and their solvates. The keto functions carried in the thiazolidinedione ring can be enolized into mono-enols. The thiazolidinedione derivative may be salted and may be in the form of a basic salt. Examples of the basic salts of the compound of the general formula (I) include pharmaceutically acceptable salts, such as sodium, potassium, magnesium, calcium, amine, and other salts of the same type (aluminum, iron, bismuth, etc.) ). Pharmacologically unacceptable amine salts can be used as the size of the paper. The national standard (CNS) A4 specification (210X 297 mm) is applicable (please read the precautions on the back before filling this page). Order-^ 1. Economy Printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau-8- 200300682 Α7 Β7 V. Description of Invention (5) Tools for identification, purification, or disassembly. Among the compounds of general formula (I) of the present invention, the following are more specifically mentioned as the presently preferred compounds: (Please read the precautions on the back before filling this page} -5- [3- (4-fluorophenoxy ) Propyl] thiazolium-2,4-dione-5- (2-phenoxyethyl) thiazolidine-2,4-dione-5- [2_ (4-fluorophenoxy) ethyl] Thiazolium-2, 'dione-5-{[1-hydroxy-2- (4-fluorophenoxy) ethyl]} thiazolidine-2,4-dione-5-{[2-hydroxy -3- (4-fluorophenoxy) propyl]} thiazolidine-2,4-dione-5- [1-methyl-2-phenoxyethyl] thiazolidine-2,4-dione -5- [2- (4-cyanophenoxy) ethyl] thiazolidine-2,4-dione-5- [2- (2-fluorophenoxy) ethyl] thiazolidine-2,4 -Diketone-5- [2- (2-naphthyloxy) ethyl] thiazolidine-2,4-dione and their pharmaceutically acceptable salts. These compounds are in patent application W097 / 476 12 It has been described in the above. The preferred one is 5- [2- (4-cyanophenoxy) ethyl] thiazolidine-2,4-dione. It is printed by the Industrial and Commercial Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs as an anti- Alpha-glucosidase inhibitors for hyperglycemic agents are particularly selected from the group consisting of sugar lozenges, miglitol, peixin, and arthritis Emiglit ate 〇 The composition of the present invention contains a therapeutically effective amount of various active ingredients. The ratio of the amount of the α-glucosidase inhibitor to the amount of the compound of the formula (I) is therefore variable. Preferably, α-sugar The weight ratio of the glycosidase inhibitor to the compound of the formula (I) ranges from 10-3 to 40, preferably from IV3 to, and more preferably to 5 ° This paper standard applies Chinese National Standard (CNS) Α4 Specifications (210 × 297 mm), 200300682 A7 B7 V. Description of the invention (3 The composition of the present invention is best administered orally parenterally or better, but it does not exclude other routes of administration such as rectum If the oral method is desired, the composition of the present invention can be made into capsules, effervescent lozenges, coated or uncoated lozenges, medicine packs, sugar-coated lozenges, ready-to-use potions or solutions, granules, or Sustained-release form. If parenteral administration is desired, the composition of the present invention can be in the form of injection solutions and suspensions, and filled in vials or bottles for slow intravenous infusion. The preparation of drugs by oral means Substances and various excipients or vehicles For example, tincture filling, disintegrant (or disintegrating agent), binder, colorant, taste enhancer and other similar substances, etc., and then shape the mixture. The colorant can be any colorant for pharmaceutical use. Examples of taste enhancers include cocoa powder, mint, borneol, cinnamon powder, etc. Examples of binders that can be mentioned include polyvinylpyrrolidone, hydroxypropylmethyl cellulose, alginic acid, carbomer, carboxymethyl cellulose , Dextrin, ethylcellulose, starch, sodium alginate, polymethacrylate, malt lake essence, liquid glucose, aluminum magnesium silicate, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose , Methyl cellulose and bitter gum. Can use alginic acid, carboxymethyl cellulose, colloidal silica, cross-linked residual cellulose cellulose, parent-linked polyethylenylsulfonate, bitter gum, aluminum magnesium magnesium oxalate, methyl fiber As disintegrants, cellulose, microcrystalline cellulose, cellulose powder, pre-added gelatin starch, sodium alginate or sodium starch glycolate are used.塡 Fillers are, for example, cellulose, lactose, dibasic calcium phosphate, or microcrystalline fiber. The size of the paper is applicable to Chinese National Standard (CNS) A4 (210X297 mm). Ϋ ^ ιΒΙ m ^ in ^ — ^ ϋ— · * n ^ ii Hi · Hi (Please read the notes on the back before filling out this page)

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 1T-10 200300682 A7 B7 V. Description of the invention (, voxel. Lozenges can be prepared by the traditional method of compressing particles with one or more lubricants. Suitable lubricants include hard Calcium stearate, glyceryl monostearate, glyceryl palmitate, hydrogenated ramie oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, Sodium stearate, stearic acid, talc and zinc stearate. These lozenges can then be carried out in polymers such as hydroxypropyl methyl cellulose or ethyl cellulose equal to a solution or suspension Surface coating. Granules used for this purpose are, for example, wet granulation procedures, using a mixture of the active ingredient with one or more excipients, such as binders, disintegrating agents (or disintegrating agents), and concrete fillings. To obtain hard capsules, fill the empty capsule with a mixture of the active ingredient and a suitable tincture (such as lactose), and if necessary, contain a lubricant such as magnesium stearate, stearic acid, and talc Or zinc stearate, etc. Gelatin capsules or soft capsules are prepared by dissolving the active ingredient substance in a suitable solvent (such as polyethylene glycol), and then filling the soft capsule. The parenteral administration form is by mixing the active ingredient with a buffer, Stabilizers, preservatives, solubilizers, tonicity agents, and suspending agents are obtained in a conventional manner. According to known techniques, these mixtures are subsequently sterilized and then packaged into an intravenous form. For buffers, add The skilled artisan can use organic phosphate-based buffers. Examples of suspending agents include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, gelatin, and sodium carboxymethyl cellulose. This paper is suitable for this paper China National Standard (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

Printed by 1T Intellectual Property of the Ministry of Economic Affairs and Consumer Cooperatives of the People's Republic of China-200300682 A7 B7 V. Description of the invention (3 Examples of dissolving agents include castor oil solidified with polyethylene oxide, polysorbate 80, nicotinamide, and macrogol (polyethylene glycol) In addition, the stabilizers that can be used in the present invention are sodium sulfite and sodium metabisulfite, and preservatives that can be mentioned include sodium para-hydroxybenzoate, sorbic acid, cresol and chlorocresol. Preparation of oral solutions Or suspension, the active ingredients and dispersants, wetting agents, suspending agents (such as polyvinylpyrrolidone), preservatives (such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate), taste Enhancers or colorants, etc. are dissolved or suspended in a suitable vehicle. Suppositories are prepared by mixing the active ingredient in a manner known per se with a suitable base composition, such as polyethylene glycol or a semi-synthetic glycerol fatty acid ester. Capsules Is prepared by combining the active ingredient with a suitable diluent, a suitable stabilizer, a medicament that promotes the sustained release of the active substance, or any other type of additive to formulate a center The core, which is then coated with a suitable polymer (such as a water-soluble resin or a water-insoluble resin). This technique can be accomplished using techniques well known to those skilled in the art. The microcapsules thus produced can be used as required Formulated into appropriate dosage units. A subject of the present invention is also a combination of an alpha-glucosidase inhibitor and a compound of formula (I) as defined above for the preparation of a pharmaceutical composition for the treatment of diabetes, particularly non-insulin-dependent diabetes. Use. According to another aspect, the present invention relates to the use of a combination of glitazone and the compound of formula (I) for the preparation of a pharmaceutical composition for reducing hyperglycemia in non-insulin-dependent diabetes. The present invention Also related to the treatment of a kind of diabetes, especially mammals, the paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇297 mm) (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperative of the Property Bureau-12- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200300682 Α7 Β7 V. Description of the Invention 3 A method for insulin-dependent diabetes mellitus, comprising administering the composition of the present invention to the mammal. If a glucosidase inhibitor and a compound of formula (I) are incorporated into the same unit dose, the unit dose It may include 0.1 mg to 400 mg of ^ -glucosidase inhibitor (dose depends on the activator to be considered). If the α-glucosidase inhibitor is selected from the group consisting of migiitol and glyceroscopy , The unit dose preferably includes 10 mg to 400 mg of α-glucosidase inhibitor. If the α-glucosidase inhibitor is Peixin, the unit dose preferably includes 0.1 mg to 1 mg of Peixin. The unit dose in this case is advantageously comprised of 12.5 to 200 mg of a compound of formula (I) (the dose depends particularly on the active agent under consideration). Of course, the dose depends on the active agent under consideration, the mode of administration, the symptoms of treatment, and the age and condition of the patient. A specific range of dosage per day is between 0.1 mg to 1 mg of an α-glucosidase inhibitor, and 25 to 200 mg of a compound of formula (I). So far, specific but non-limiting embodiments of the present invention have been proposed. Unless otherwise stated, percentages are given on a weight basis. Embodiment 1 Example 1: This paper size applies to China National Standard (CNS) Α4 size (210X297 mm) (Please read the precautions on the back before filling this page)

-13- 200300682 ΚΊ B7 V. Description of the invention (Preparing lozenges with the following composition: 4- [2- (2,4-diketothiazolidin-5-yl) ethoxy] benzonitrile * 50 mg 19.5% Tanglo 150 mg 58.4% Fine lactose powder 30 mg 11.7% Hydroxypropyl cellulose 1 2 mg 4.7% Croscarmellose sodium 12 mg 4.7% Magnesium stearate 3 mg 1.2% Also known as 5 -[2- (4-Cyanophenoxy) ethyl] thiazolidine-2,4-dione Example 2 (Please read the notes on the back before filling this page) Prepare a lozenge with the following composition: -, 1T Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 4- [2- (2,4-diketothiazolidin-5-yl) ethoxy] benzonitrile * 50 mg 11.4 ¾ Sugar Lupin 3 50 mg 68.2% fine lactose powder 45 mg 10.2% hydroxypropyl cellulose 20 mg 4.5% croscarmellose sodium 20 mg 4.5% magnesium stearate 5 mg 1.1% This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) -14-200300682 A7 B7 V. Description of the invention (Example 3 Preparation of a tablet having the following composition 4- [2- (2,4-diketothiazolidine-5- ) Ethoxylate 100 mg 3 1.3% based] Benzonitrile saccharose 150 mg 46.9% Fine lactose powder 36 mg 11.3% Hydroxypropyl cellulose 15 mg 4.7% Croscarmellose sodium 15 mg 4.7% Stearin Magnesium acid 4 mg 1.3% (Please read the precautions on the back before filling out this page} Printed by the Intellectual Property of the Ministry of Economic Affairs and the Consumer Cooperative Society Example 4: Preparation of tablets with the following composition: 4- [2- (2, 4-diketothiazolidin-5-yl) ethoxy] benzonitrile * 100 mg 20.4% Sugarlod tablet 3 00 mg 61.2% Fine lactose powder 44 mg 9% Hydroxypropyl cellulose 20 mg 4.1¾ Crosslinked carboxyl Sodium methylcellulose 21mg 4.3% Magnesium stearate 5mg 1% The size of this paper applies to Chinese National Standard (CNS) A4 (210X 297 mm) -15- 200300682 A7 B7 V. Description of the invention (eg Example 5 Preparation of a lozenge 4- [2- (2,4-diketothiazolidinyl) ethoxy] benzonitrile * with the following composition * 200 mg 46.0% Tanglo 150 mg 3 4.5% fine lactose powder 42 mg 9.7 % Hydroxypropyl cellulose 18 mg 4.1% croscarmellose sodium 20 mg 4.6% Magnesium stearate 5 mg 1.1% (Please read the notes on the back before filling out this page) Printed by Example 6 of the Intellectual Property of the Ministry of Economic Affairs / Employee Consumption Cooperative. Preparation of tablets with the following composition: 4- [2- (2, 4-Diketothiazolidinyl) ethoxy] benzonitrile * 200 mg 33.3% Tangluo tablets 3 00 mg 50.0% Fine lactose powder 45 mg 7.5% Hydroxypropyl cellulose 24 mg 4.0% Cross-linked carboxymethyl fiber Sodium 25 mg 4.2% Magnesium stearate 6 mg 1.0% Pharmacological study 4- [2- (2,4-diketothiazolidin-5-yl) ethoxy] benzonitrile (Compound A) * and The anti-diabetic effect of the combination of Tanglu tablets was investigated in n5 STZ mice, an experimental model of non-insulin-dependent diabetes. This model is based on Chinese paper standard (CNS) A4 (210X297 mm) -16- 200300682 A7 B7 V. Description of the invention (such as by intraperitoneal injection of 80 mg / kg streptomycin after the fifth day of birth (steptozocin) (STZ). (Please read the precautions on the back before filling out this page) The characteristics of this model are: Basic hypoglycemia with moderate hypoglycemia Glucose intolerance insulin resistance * Compound A also Called -5- [2- (4-cyanophenoxy) ethyl] thiazolidine-2,4-dione. Experimental procedure After the rats were fasted for two hours, basic screening was performed for the hyperglycemia to make the Each group was homogenized, and 48 male n5STZ experimental mice were used. They were divided into seven groups: n5STZ control group "normal" mouse control group Intellectual Property of the Ministry of Economic Affairs 笱 Employee Cooperative Cooperative printed 100 mg / kg Tanglu tablets The treatment group was orally administered with 400 mg / kg Tanglu tablets. The treatment group was orally administered with 12.5 mg / kg Compound Lu. The treatment group was administered with 100 mg / kg Tanglu tablets and 12.5 mg / kg Compound A orally. 12.5 mg / The products of the treatment group of Compound A were taken orally between 8 am and 9 am. Four paper sizes were applied to the Chinese National Standard (CNS) A4 specification (21〇χ: Z97 mm) -17- 200300682 A7 _ B7 V. Description of the invention (days. (Read the precautions on the back and then fill out this page). On the fourth day of treatment, a food test is performed. This test includes oral Eoprotine at a rate of 10 kcal / kg-rat weight. (Milk powder, Milupa). This food test was performed two hours after the last dose of the drug. Blood glucose and blood insulin were 10, 20, 30, 45, 60, 90, and 12 before taking Proprotine and after forced feeding, respectively. Minute measurement. Blood samples were obtained from awake rat tails. Results Printed by the Consumer Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs. Table 1: Blood glucose (millimolars / liter) 0 minutes 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes H5STZ control group 9.87 soil 15, 2¾ 18.24 soil 19.5 soil 19.63 soil 18.66 soil 16.44 soil 12.36 soil 0.35 0.4 0.76 0.91 1.2 1.4 1.6 1.7 Compound A 12.5 mm 9.37 soil 16.17 soil 19.26 soil 20.6 5 soil 20.87 soil 20.72 soil 20.42 soil 17.34 soil g / kg 0.72 1 1.1 1.5 2.2 2.4 2.7 2.7 Tangluo 100 mg / 9.17 soil 14,70 soil 16.82 soil 17.50 soil 17.94 soil 18.22 soil 17.01 soil 15.22 soil kg 0.28 0.7 0.91 1.2 1.3 1.4 1.5 1.6 Tanglo tablets 400 mg / 8.9 soil 13.65 soil 14.84 soil 17.89 soil 18.65 soil 18.61 soil 16.83 soil 14.67 soil kg 0.92 0.4 1.14 0.84 1 0.7 1.1 1.7 Compound A 12.5 milligram 8.89 soil 13.12 soil 14.97 soil 16.38 soil 17.21 soil 18.04 Soil 16.98 soil 14.7 soil g / kg + sugar lozenge mg 0.27 0.5 0.81 0.87 1.3 1.5 2.3 2.2 Compound A 12.5 milligrams 8.8 soil 12.45 soil R15 soil 14.88 soil 15.85 soil 15.91 soil 14.16 soil 13.00 soil g / kg + sugar granule mg / Kg 0.45 0.5 0.92 1.05 1.5 1.5 1.2 1.2 This paper size is applicable to Chinese National Standard (CNS) A4 specification (21〇χ 297 mm) -18- 200300682 A7 ______B7 V. Description of the invention (such as ΆΛ_LAM island element ) 0 minutes 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes n5STZ control 223 soil 482 soil 503 soil 56½ 433 soil 349 soil 274 soil 301 soil 48 91 76 64 81 49 35 23 Compound A 12.5 mg / kg 199 soil 3 72 soil 501 soil 427 soil 368 soil 324 soil 307 soil 270 soil 49 93 138 88 51 56 39 40 sugar lozenge 100 mg / kg 188 soil 392 soil 493 Soil 387 soil 343 soil 324 soil 256 soil 239 soil 25 53 92 73 58 67 68 64 sugar lozenge 400 mg / kg 201 soil 309 soil 325 soil 371 soil 3 64 soil 353 soil 241 soil 220 soil 32 36 47 51 56 57 41 49 Compound A 12.5 mg / kg 186 soil 355 soil 3 89 soil 317 soil 281 soil 312 soil 270 soil 284 soil + sugar lozenge 100 mg 32 49 43 36 61 33 33 42 Compound A 12.5 mg / kg 168 soil 295 soil 329 soil 287 soil 251 soil 270 soil 264 soil 236 soil + sugar bark 400 mg / kg 26 28 53 48 61 39 38 58 (Please read the precautions on the back before filling out this page) Comment on the Ministry of Economic Affairs Intellectual Property Gou Employee Consumer Cooperative After four days of printing, the basic blood glucose level of the n5 STZ laboratory mice did not improve, whether it was a single drug or a combination of drugs. Regarding the disappearance kinetics of hyperglycemia induced by food tests, this study showed that: Compound A treatment: Compound A does not change the disappearance kinetics of glucose at low doses (Figure 1). In fact, the area under the curve (AUC) of the glucose level of blood glucose is applicable to the Chinese national standard (CNs) A4 specification (210X 297 mm) at this paper scale. -19- 200300682 A7 B7_ V. Description of the invention (feature increased slightly after treatment ( + 1 5%). Regarding the insulin response to glucose, after taking Compound A, its AUC (-8%) slightly decreased. However, no result was significant. Treatment with sugar tablets ... At the lowest dose, oral administration of 1000 mg / kg Tanglu tablets does not change the disappearance kinetics of glucose. At the highest dose, that is, oral 400 mg / kg Tanglu tablets, food test for ten minutes and twenty Significantly reduced hyperglycemia after 5 minutes (Figure 4). Overall, the area under the curve (AUC) of glycemic disease did not improve after treatment (-2%). Regarding insulin response to glucose, AUC after taking sugar tablets There is a decrease (-20%). However, no result is significant (Figures 5 and 6). Treatment with Compound A and Sugar Lozenge Combination: 400 mg / kg of Sugar Loose and 12.5 mg / kg of Compound A Induced hyperglycemia in combination with food test Significant reduction in radon. Compound A / sugar tablets significantly improved carbohydrate tolerance during the initial absorption phase. At the same time, it also had a significant effect of reducing insulin secretion (Figures 8 and 9). Conclusion: Tanglu tablets are a kind of inhibitor Alpha-glucosidase enzyme compounds and compounds that reduce postprandial glucose increase. In experimental models of insulin-resistant diabetic rats, Tangluo tablets only mildly improve postprandial hyperglycemia. In contrast, Tangluo tablets and novel anti-diabetics The combination of the drug '4- [2- (2,4-diketothiazolidin-5-yl) ethoxy] benzonitrile (compound A), was unexpectedly induced by a food test on high blood sugar. Zhang scale applies Chinese National Standard (C1SS) Α4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -20- 200300682 A7 B7 V. Description of the invention (1) 7 A synergistic effect of the reduction of peaks. This beneficial effect is also accompanied by a significant reduction in insulin secretion. (Please read the precautions on the back before filling out this page) Brief description of the diagrams Figure 1: Food test-Compound A (12.5 mg / kg) after four days of treatment. Figure 2: Blood glucose AUC (compound A alone) after food test. Figure 3: Blood insulin AUC after consumption test (compound A only). Figure 4: Food test-Effect of treating male n5-STZ mice with Tangluo tablets (400 mg / kg) for four days. Figure 5: Glucose AUC (glucose tablets only) after a food test. Figure 6: Blood insulin AUC after food test (sugar tablets only). Figure 7: Effect of food test-Compound A (12.5 mg / kg) and Tanglurui (400 mg / kg) on male n5-STZ experimental mice after four days of treatment. Figure 8: Blood glucose after food test (Compound A + Sugar Lozenge combination). Printed by the Intellectual Property of the Ministry of Economic Affairs and the Consumers' Cooperatives Figure 9 · Blood insulin AUC (compound A + sugar lozenge combination) after food test. This paper size applies to China National Standards (CNs) Λ4 specification (210X 297 mm) -21-

Claims (1)

200300682 AB-CD VI. Patent application scope 1 1. A pharmaceutical composition comprising the following active main ingredients containing (i) at least one α-glucosidase inhibitor and (ii) at least one compound of formula (I), combining one Or more pharmaceutically acceptable excipients, the compound of formula (I) is defined as follows: Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, where A represents a group containing 2 to 16 carbon atoms and is mainly a saturated or unsaturated, linear or branched hydrocarbon group, and D represents a homogeneous carbon or heterogeneous group. Heterocarbon is a monocyclic, bicyclic or tricyclic aromatic structure. The aromatic structure may contain one or more heteroatoms. X represents a substituent of the aromatic structure. It is selected from hydrogen and an alkane containing 1 to 6 carbon atoms. Alkoxy, alkoxyalkyl containing 1 to 6 carbon atoms, wherein the alkoxy and alkyl are as defined above, and aryl is defined as an aromatic cyclic structure containing one or two rings, The ring optionally includes one or two heteroatoms, such as phenyl or α- or / 3-naphthyl; aralkyl, where alkyl is as defined above, and aryl is as defined above, and optionally includes one or more Substituents; aralkylaryl, where aralkyl and aryl are as defined above; halogen, trifluoromethyl, cyano, hydroxyl, 'nitro, amine, carboxy, alkoxycarbonyl, Carboxamido, sulfoamido, wind, sulfoamido, aminosulfoamido, alkylsulfo Group, acyl group or trifluoromethoxy group, [eta] is an integer of 1 to 3. 2 · If the pharmaceutical composition in the scope of patent application No. 1 is used (please read the precautions on the back before filling this page) Binding · The size of the paper is applicable to the Chinese National Standard (CNS) Α4 specification (210X 297) (Centi) -22- 200300682 Α8 B8 C8 D8 6. Application for patent scope 1 Treatment of diabetes. 3. If the pharmaceutical composition in the scope of patent application No. 1 or 2 is applied, (please read the precautions on the back before filling this page) for non-insulin-dependent diabetes. 4. The pharmaceutical composition according to item 1 or 2 of the patent application range, characterized in that the weight ratio of the α-glucosidase inhibitor to the compound of formula (I) is in the range of 10-3 to 40, preferably 1-10. 3 to 10, and more preferably 10_3 to 5. 5. The pharmaceutical composition according to item 1 or 2 of the patent application scope, characterized in that the α-glucosidase inhibitor is selected from the group consisting of acarbose, miglitol, and voglibose ) And emiglitate. 6. The pharmaceutical composition according to item 1 or 2 of the scope of patent application, characterized in that the compound of formula (I) is selected from the following: printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -5- [3_ (4 _Fluorophenoxy) propyl] thiazolidine-2,4-dione-5- (2-phenoxyethyl) thiazolidine-2,4-dione-5- [2- (4-fluorobenzene (Oxy) ethyl] thiazolidine-2,4 · dione-5-{[1-hydroxy-2- (4-fluorophenoxy) ethyl]} thiazolidine-2,4-dione-5- {[2-hydroxy-3- (4-fluorophenoxy)] propyl} thiazolidine-2,4-difluorene-5- [1-methyl-2-phenoxyethyl] thiazolidine-2 , 4-dione • 5- [2- (4-cyanophenoxy) ethyl)] thiazolidine-2,4-dione-5- [2- (2-fluorophenoxy) ethyl] Thiazolidine-2,4-dione-5- [2- (2-naphthyloxy) ethyl] thiazolidine-2,4-dione and its pharmaceutically acceptable salts. 7. The pharmaceutical composition according to item 6 of the patent application, characterized in that the compound of formula (I) is 5- [2- (4-cyanophenoxy) ethyl] thiazolidine-2,4-dibenzyl Paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) -23 200300682 Printed by A8, B8, C8, D8, Consumer Cooperatives of Intellectual Property Bureau of the Ministry of Economic Affairs. 6. Scope of patent application. 8. The pharmaceutical composition according to claim 1 or 2, which is suitable for oral administration. 9 · The pharmaceutical composition according to item 1 of the scope of patent application, which is used to prepare a pharmaceutical composition for treating diabetes. 10. The pharmaceutical composition according to item 9 of the scope of patent application, which is used to prepare a pharmaceutical composition for treating non-insulin-dependent diabetes mellitus. 1 1. The pharmaceutical composition according to claim 9 or 10, wherein the α-glucosidase inhibitor is selected from the group consisting of acarbosej, miglitol, and voglibose. And emiglitate. 1 2 · The pharmaceutical composition of claim 9 or 10, characterized in that the compound of formula (I) is selected from the following: -5- [3- (4-fluorobenzene (Oxy) propyl] thiazolidine-2,4-dione-5- (2-phenoxyethyl) thiazolidine-2,4-dione-5- [2- (4-fluorophenoxy) Ethyl] thiazolidine-2,4-dione-5-{[1-hydroxy-2- (4-fluorophenoxy) ethyl]} thiazolidine-2,4-dione-5-{[2 -Hydroxy-3- (4-fluorophenoxy) propyl]} thiazolidine-2,4-dione-5- [1-methyl-2-phenoxyethyl] thiazolidine-2,4- Dione-5- [2 · (4-cyanophenoxy) ethyl] thiazolidine-2,4-dione-5- [2- (2-fluorophenoxy) ethyl] thiazolidine-2 1,4-dione-5- [2- (2-naphthyloxy) ethyl] thiazolidine-2,4-dione and its pharmaceutically acceptable salts. 1 3 · As claimed in the patent application No. 9 or 1 The pharmaceutical composition of item 0, characterized in that the pharmaceutical composition contains an α-glucosidase inhibitor and a formula of formula (I) The Zhang scale is applicable to the Chinese National Standard (CNS) Α4 specification (210 × 297 & ^ Γ) " a-24- (Please read the precautions on the back before filling this page) 200300682 8 8 8 8 ABCD Six, patent application scope 4 A unit dosage form of a drug. 1 4 · The pharmaceutical composition according to claim 9 or 10, characterized in that the unit dose includes 0.1 mg to 400 mg of an α-glucosidase inhibitor and 12.5 to 200 mg of Formula ⑴ compound. (Please read the precautions on the back before filling out this page} Binding /-Order printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Employee Consumer Cooperatives This paper is printed in accordance with the Chinese National Standard (CNS) Α4 specification (21〇 × 297 mm) -25-