TW201105338A - Medicine derived from a combination of SGLT1-inhibitor and DPP-IV inhibitor - Google Patents

Abstract

A medicine for treating diseases derived from hyperglycemia is provided by combining 3-(3-{4-[3-(β -D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)-2, 2-dimethylpropionamide or a pharmacologically acceptable salt thereof having SGLT1 (sodium-dependent glucose cotransporter 1)-inhibiting activity with a DPP-IV inhibitor.

Description

201105338 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a medicine comprising a combination of an SGLT1 inhibitor and a DPP-IV inhibitor. In more detail, 'is related to a 3-(3-{4-[3-(β-D-. ratio. sulphate)-5-isopropyl-1 Η-~-pyrazol-4-yl fluorenyl group ]-3-methylphenoxy}propylamino)-2,2-dimethylpropanamide (hereinafter also referred to as "Compound 1") or its pharmacologically acceptable salt and DPP -IV A combination of drugs that hinder the drug. [Prior Art] Diabetes is a group of metabolic diseases in which the state of glucose concentration (blood sugar level) in chronic blood is increased due to insufficient insulin action. The treatment of diabetes is usually performed by diet therapy or exercise therapy, and when it is impossible to achieve the target blood sugar control, a drug therapy using an oral hypoglycemic agent or an insulin preparation is performed. As an oral hypoglycemic agent, according to the patient's condition, the use of sulfonylurea (SU, sulf〇nylurea), fast-acting insulin secretion promoting drug, α-glucosidase inhibitor, tetrahydrothiazole drug and other anti-islet health improvement Medicine, biguanide drugs, etc. However, in the case of using these drugs alone, in addition to the case where satisfactory blood sugar control cannot be obtained, various by-products corresponding to the respective (four) substances are also reported. For example, the drug report ^ hypoglycemia or (four) system caused by 2 invalid, α • (4) glycocalyx smear drugs reported diarrhea, etc., anti-insulin improvement drugs reported weight gain "sub-swelling, etc." Lactic acidosis, etc. #, Although the mechanism of action of diabetes is not proposed or practical, but the disease or symptoms of diabetic patients are more complicated 'so it is not easy to choose the most suitable for each patient 149395.doc 201105338. When a single dose of oral hypoglycemic agents is administered, it is necessary for you to set up a follow-up, or the blood sugar control of the -Bei, or -Teng!: hypoglycemic agents, or take the combination of insulin and the combination of Tengdaosu. In terms of sex or safety, it is required to provide a combination of highly useful agents. It does not increase the appearance of hypoglycemia. From the moon, it can be used as soon as possible. A combination therapy that exhibits an effective combination of excellent effects. Recently, it has been reported that ash can be absorbed by blocking the nano-dependent glucose co-transport carrier (the sputum, which hinders or delays the absorption of sugar in the small intestine). Sugar value The compound which inhibits the action of the growth is expected to be a preventive and therapeutic drug for diabetes or the like which utilizes a novel mechanism of action (for example, Japanese Patent Laid-Open Publication No. Hei. No. 4 to 4). ): [Chemical 1]

Compound 1 (chemical name: 3_(Μ4_[3·(Μ)_πpyranosyloxy)-5-isopropyl-1Η-pyrazol-4-ylmethyl]-3-methylphenoxy Various of propylamino)-2,2-dimethylpropionamide. Sitting on a derivative than 0. Further, it is known that Glucagon-like peptide 1 (GLP-1, a glycopeptide-like peptide) is a kind of incretin (149395.doc 201105338 digestive S hormone which promotes insulin secretion during food intake), and is strong. The insulin secretion enhancing substance is X-resolved by dipeptidyl peptidase-IV (DPP-IV, dipeptidyl-peptidaSe-IV) (Non-Patent Documents 1 and 2). A DPP-IV blocker has been developed which inhibits the action time of GLP-1 by inhibiting the depletion of GLP-1 caused by Dpp_iv, and adjusts the blood glucose level of diabetes or glucose intolerance. For example, 'sitagliptin is a DPP-IV inhibitor which is represented by the following formula (Π), has an action of increasing active GLP-丨, and is commercially available as a therapeutic drug for type 2 diabetes. [Chemical 2]

Also, the formula (III) is known: [Chemical 3] (II)

F~0~CI 0anX>vJ> (10)

a compound represented by I ch3 (chemical name: 6_[(3r)_3_aminopiperidinyl]-5-(2-chloro·5-fluorobenzyl)_ι,3·dimethyl·1H_pyrrolo[ 3,2_d] Pyrimidine-2,4(3H,5H)-dione (compound 3)) (Patent Document 5). Regarding these new diabetes treatments, it is also relevant to other diabetes treatments.

149395.doc 201105338 A variety of studies have been conducted in combination, for example, a combination of a DPP-IV inhibitory drug and a diterpene bismuth as a biguanide or a combination of alogliptin as a PPARy agonist (for example, refer to Non-Patent Document 1) And 3). Further, in the above-mentioned SGLT1 inhibitory drug, Patent Document 1 generally describes a combination of various antidiabetic agents containing a DPP-IV inhibitor, and the like, and the combined effects have not been reported so far. In any of the above documents, there is no description or suggestion that the combination of the SGLT1 inhibitory drug such as the compound 1 or its pharmacologically acceptable salt and the DPP-IV inhibitory drug has a significant blood glucose increase inhibitory effect or GLP- 1 The effect of increasing the concentration and its persistence effect make it extremely useful for the treatment of diseases caused by hyperglycemia. [PRIOR ART DOCUMENT] [Patent Document 1] International Publication No. 2004/01 8491 Handbook [Patent Document 2] International Publication No. 02/098893 Handbook [Patent Document 3] International Publication No. 2004/014932 Manual [ Patent Document 4] International Publication No. 2004/019958 Manual [Patent Document 5] International Publication No. 2006/068 163 Manual [Non-Patent Document] [Non-Patent Document 1] Bo Ahren, Best Practice & Research Clinical Endocrinology & Metabolism , 2007, Vol. 21, No. 4, p. 517-533 [Non-Patent Document 2] Carolyn F. Deacon, Diabetes, September 2004, Volume 53, p.2181-2189 149395.doc 201105338 [Non Patent Document 3] Bo Ahren, Vascular Health and Risk

Management '2008, Vol. 4, No. 2, p. 383-394 [Non-Patent Document 4] Diabetes Care. 2009; 32: 193-203 [Summary of the Invention] [Problems to be Solved by the Invention] The present invention provides A medicine for treating a compound caused by hyperglycemia or the like, and combining the compound 1 or a pharmacologically acceptable salt thereof with a Dpp-iv inhibitor. [Means for Solving the Problem] The inventors of the present invention have diligently studied in view of the above problems, and as a result, have found for the first time that the compound 2 (the azelaic acid salt of the compound 1) which is an inhibitor of SGLT1 is As a Dpp_IV inhibitor drug, sitagliptin or Compound X (one of the compounds 3 hydrochloride 1/2 hydrate) is used in combination, and the blood sugar rise is markedly suppressed and the effect of 1 is enhanced as compared with the case of using the Dpp_IV inhibitor alone. this invention. That is, the present invention relates to: Item 1 '· A medicine in which an SGLT1 inhibitor and a DPP_IV inhibitor are combined, and the above SGLT1 inhibitor S3_(3_{4_[3_(p_D_D-pyranoseoxy)-5-isopropyl) -1H-pyrazole-4-ylmethyl]_3_methylphenoxy}propylamino)·2,2-dimethylpropionamide or a pharmacologically acceptable salt thereof, DPP-IV above The obstructive drug system is selected from the group consisting of sitagliptin, vildagliptin, alogliptin, saponin, dystopol, and dysinoside (1) ut〇gHptin, piroximate, ceramide (Carmegliptin), and linali Ting and 6 [(3R)_3·Aminopiperidinyl]-5-(2-chloro-5-qijiejib·················· 149395.doc 201105338 2,4(3H,5H)-dione and a group consisting of the pharmacologically acceptable salts; Item 2: The medicine of item 1, wherein the DPP-IV inhibitor is sitac Tet or 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-a-5-fluorobenzyl)-1,3-dimethyl-1H-. 3, 2, d] pyrimidine-2,4(3H,5H)-dione, or a pharmacologically acceptable salt thereof; Item 3: The medicine according to Item 1 or 2, wherein the DPP-IV inhibitory drug is cisplatin Lenin or its pharmacology Item 4: The medicine according to Item 1 or 2, wherein the DPP-IV inhibitor is 6-[(3R)-3-aminospin-1-yl]_5_(2_chloro-5-fluorobenzyl) Base)_13_ dimethyl_1H_„ 咯 并 [3,24] sputum _2,4(311,511)-dione or its pharmacologically acceptable salt; Item 5. Items 1 to 4 Any of the medicines used in the treatment of diseases caused by high blood stasis; Item 6 of the medicine according to item 5, wherein the disease caused by high glycemic disease is selected from glucose K disease, glucose intolerance, fasting blood glucose A disease in a group consisting of an impaired fasting glucose, a diabetic complication, an obesity, and a hyperinsulinemia; Item 7: The medicine according to any one of items 1 to 4, which is a postprandial hyperglycemia improving drug Item 8. The medicine according to any one of item 4 to 4, which is an action enhancing drug, etc. μ Further, as a seed type, the present invention relates to a medicine or the like, which is to be compounded. The salt allowed in combination with the DPP_IV inhibitory drug can be used for the treatment of patients with adequate glycemic control due to the administration of SGLTm or Dpp]v inhibitors. Treatment of diseases It is used for post-prandial hyperglycemia or for enhanced use of GLP_I#. [Effect of the invention] ' ° The medicine of the present invention has a strong blood sugar rise inhibiting effect and GLp-l enhancing effect, and is extremely useful for treating hyperglycemia. The disease. This medicine achieves an excellent post-meal sugar-improving effect for treating diabetes or inhibiting the development of diabetes into diabetic complications (such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, arteriosclerosis). In addition, compared with the case where the SGLT1 inhibitor or the DPP_IV inhibitor is used alone, it has an excellent effect of enhancing blood sugar rise inhibition, increasing the activity (10), and reducing excessive secretion of insulin. Further, by appropriately selecting the contents of the two doses, the administration method, the administration amount, and the like, it is used for the stabilization of blood sugar increase and the reduction of side effects for long-term drug administration. In addition, compared with the Dpp_IV inhibitory drug alone, the concentration of active GLP-1 in the pulp increased and persisted, showing the effect of inhibiting the increase of insulin ^ = so far, while reducing the secretion of insulin. Excellent physiological effects of GLP-1 (eg appetite = effect, pancreatic beta cell protection). Therefore, it is also used in various conditions related to excessive secretion of 姨 素 (eg vascular complications, hypoglycemia, arteriosclerosis, obesity). [Embodiment] Hereinafter, the present invention will be described in detail. Preferred examples of the "SGLT1 inhibitory drug" in the present invention include the compound 1 or a pharmacologically acceptable salt thereof. 149395.doc 201105338 Compound 1 or a pharmacologically acceptable salt thereof can be produced by a method described in the literature or by a method described in the above methods or reference examples (for example, refer to Patent Document 1). Examples of the "pharmacologically acceptable salt of the compound" include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and formic acid, acetic acid, and methylation. Acid, stupid sulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, anti-butyric acid, butyric acid, oxalic acid, malonic acid, cis-succinic acid, milk Sjl, Acid addition salts of organic acids such as fruit acid, carbonic acid, facial acid, aspartic acid, azelaic acid, and inorganic salts such as sodium salts and potassium salts, and N-methyl-D-reduced glucose a preferred addition salt of an organic base such as an amine, hydrazine, Ν'-dibenzylethylenediamine, 2-aminoethanol, tris(hydroxymethyl)aminodecane, arginine or lysine; An acid addition salt with a counter-butanic acid or a succinic acid (sebacic acid), more preferably an acid addition salt with azelaic acid. The compound 1 or a pharmacologically acceptable salt thereof also contains a hydrate thereof or a solvate of a pharmacologically acceptable solvent (e.g., ethanol or the like). As the "pharmacologically acceptable salt of Compound 1," it is preferred that "3 _ (3-{4-[3-(p-D_o than nassolicoxy)-5-isopropyl-iH-n Ratio. sit _4-ylmethyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropanamine·1/2 fumarate dihydrate) Or "bis[3-(3-{4-[3-(β-Γ)-glucopyranosyloxy)-5-isopropyl-1Η-.boxazol-4-ylmethyl]-3-quinone Phenyloxy}propylamino)-2,2-dimethylpropionamide]•monosebacate (hereinafter sometimes referred to as "compound 2")", more preferably compound 2. As the SGLT1 inhibitory drug, in addition to "Compound 1 or a pharmacologically acceptable salt thereof", a compound which inhibits SGLT1 and has a property of inhibiting 149395.doc •10·201105338, pp-sodium-dependent glucose may be selectively used. Transporter 2 (SGLT2) blocks compounds that are more active against SGLT1 than the active phase & πt beans. Specific examples thereof include, for example, International Publication WO 2007/129668, Sakamoto Yoshiyuki*, 々 ( (7) Special Table 2008-501745, 'International Publication No. 〇07/126117, etc. The compound described or a pharmacologically acceptable salt thereof, etc., as a compound described in the handbook of International Publication No. 2007/129668, for example, 4_{4-[2-(benzyloxy)ethoxy] 2-mercaptobenzyl bromide 5-Isopropyl-111-pyrazolyl-5-thio-β-D-glucoside (Example 1); 4_[4_(2-hydroxyethoxy)-2_ Nonylbenzyl]-5-isopropyl-1H-pyrazol-3-yl 5-thio-β-D-glucoside (Example 2); 4_[4_(2_Aminoethoxy)_2 _Methylbenzyl]-5-isopropyl]H_Dbiazole-3-yl 5thio-p_D glucoside (Example 3); [Imino group ({2_[4_({5_isopropyl_3_) [(5"^R_p_D·glucopyranosyl)oxy]-1Η-carbazole-4-yl}methyl)-3-methylphenoxy]ethyl}amino)indolyl]benzyl carbamate Ester (Example 4); N-{2-[4-({5-isopropyl-3-[(5-thio-β-D-^b-glucopyranosyl))oxy]_iH-n ratio Azole-4-yl}indolyl-3-methylphenoxy]ethyl}anthracene (Example 5); 4_ {4-[2-(N-Amino-mercaptodecylamino)ethoxy]-2-indolyl}-5-isopropyl- lH-nitD sitting-3_yl 5-thio-β -D-glucoside (Example 6); N-(2-yl-1,1-didecylethyl)_N - {2-[4-({5-isopropyl-3-(5) - thio-β-D-indolepyranosyl)oxy]-1Η-.bazol-4-yl}methyl)-3-indolylphenoxy]ethyl}urea (Example 7); 4-[4-(2-{bis[2-(benzyloxy)ethyl]amino}ethoxy)_2-mercaptobenzyl]-5-isopropyl-lH-o than sal-3- 5-thio-β-D-glucoside (real 149395.doc 201105338 Example 8); N-[2-hydroxy-1-(hydroxyindenyl)-bu methylethyl]_N,-{2_[4· ({5-Isopropyl-3-[(5-thio-β-Dnpyranosyl)oxy]-1Η-indol-4-yl}indenyl)-3-methylphenoxy]B Base I urea (Example 9); 4-(4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]ethoxy b-2-methylbenzyl)_ 5- Isopropyl-1H-pyrazol-3-yl 5-thio-β-D-glucoside (Example 10); N-[4-({5-isopropyl-3-[(5-thio) -β-D-glucopyranosyl)oxy]-lH-ηpyrazol-4-yl}methyl)phenyl]urea (Example u); n-[4-({5-isopropyl- 3-[(5-thio-β-D-吼 葡萄糖 葡萄糖 ) ) 氧基 氧基 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 葡萄糖 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 2_Hydroxyl-1,1-dimethylethyl)-4-[4-({5-isopropyl}-3-[(5-thio-β-D-0)pyranosyl)oxy] · 1Η-η than salivyl-4-yl}methyl)phenyl]butanyl-3-indolylamine (Example 13); (3Ε)-Ν-(2-amino-indole, ΐ-dimethyl_ 2_oxoethyl)_ 4-[4-({5-isopropyl}-3-[(5-thio-β-D-»pyranosyl)oxy]_ 1Η-° ratio 4-yl}mercapto)phenyl]buty-3-endecylamine (Example μ); Ν-(2-Rotigen-1,1-dimethylethyl)-4-[4-({5 -isopropyl_3-[(5-thio-β-D-°pyranosyl)oxy]-1Η-»bazole-3-yl}methyl)phenyl]butanamine (Example 15) ; Ν-(2-amino-1,1-diindolyl-2-oxoethyl)_4_[4_({5_isopropyl-3-[(5-thio--0-〇-) ° 喃 glucosyloxy) 丑 丑 〇 〇 〇 _ _ _ _ _ _ _ _ _ _ _ _ _ _ 酿 酿 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (Methyl) 4-[4-({5-isopropyl-3-[(5-thio-β-〇-.比glycosyl)oxy]-1Η-pyrazol-4-yl}fluorenyl)phenyl]butanamine (Example n); N_fl ^ Dimethyl-2-(4-methyl well-1- ))-2-oxoethyl]_4-{4-({5-isopropyl-3-[(5-thio-β-D-11 ratio. glucosyl)oxy] 4_基} A 149395. doc -12- 201105338 phenyl) butanamine (Example 18) and the like. The compound described in the following table, for example, may be mentioned as a compound described in JP-A-2008-501745. [Chemical 4]

149395.doc -13- 201105338

I < 149395.doc 1 〇〇oooooo 〇8 σ o CJ 〇oo 〇o 〇o 〇oooo -ch=chch2- 1 Ol a: ΓΕ g 1 -ch=chch2- 1 CM g CM rc rc 1 u az 4 , g 1 -ch2ch2ch2- 1 ra nc SL g ί 1 C4 hj 4, 0 1 I zc rc o -ch2chzch2- 1 a: 4, e °NO 1 l C4 °N 0 1 1 94 3: 〇〇>« 4, ffi 〇1 1 C4 33 X 0 1 gc«a 3 1 u 3C e>4 X 1 as 4, 3 1 1 NX 〇) l | (N s ca Π2 〇1 -ch=ch2- X 1 1 1 1 1 1 1 1 1 1 1 1 1 1 i 1 1 1 1 1 ca 03 CvJ ac C>3 SC CO 33 U 32 CJ C4 Π3 〇CM tr; CvJ ffl 〇Γ4 a: o 5 ca as aa: Cs» Rc a 04 31 u 02 ca 〇g e4 X o C4 so 3C << 〇oo 〇oo 〇oo 〇oooo 〇ooo 〇〇05 CKi CO 05 ch2ch2nhch2ch2 ;CH2CH2CH2CHs 03 S3 gg ac o ;ch2ch2conh2 ac § m zc § π cc o ;CH2CH2C0NH2 ;ch2conh2 ;CH[CFi20H]C0NH2 ;CH[CH20H]C0NH2 ch2ch2n[ch2ch2oh] ch,ch2 cc C3 o 5G z« Π5 5 ch2ch2ch2ch2ch2 ch2ch2ch2ch2ch2ch2 g C4 g ch2ch2nhch2ch2 g aa D: ;c[ch3]2ch2oh ;C[CH3]2CH20H o K o ίχί wu: W ra as tn ac ac Π3 tc ΪΖ: 02 id I X! s az u: 2C 2C 03 <〇ίϋ !Z3 DC Π: rx: ZE :c X PC 33 X cc 33 X ΪΧ! Μ rx: :xi a: tz: CC IX: ac pc 22 S3 m iC PCJ S inch Μ XX X 22 Ξ: ΠΠ 2G SG K CO Οί i-Pr i-Pr I cx • c-1 i-Pr ά 1 «ι-Ι o a. ώ 1 »— •H Λ 〇CO S *ri | i-Pr 丨έι 1 •M 卞•ii [i-Pr | i-Pr I i-Pr i~Pr P-( •rH (N Ci fX iX (X< iX Cx. Cju Uh tx. A Pu u. CL( IX 3: rri 5C 2C ac ac w K nc 33 re |Example) — 03 CO ιο to 00 CJ5 o iH (N CO LO CO 00 〇) § -14- 201105338 [CN- Id >1 o υ ooo 〇〇〇〇〇u 〇〇oo NHCO 1 1 NHCO NHCO u 1 N oo 5 3: 3: o '« s 0 1 *NX 32 〇C4 X 1 s, su NX 1 -ch2chzch2 - 2: 3: s 1 N SN S3 CM K 0W ac 0 1 f N 3: mm 1 NN nc corpse 〒 -NHCHjT i eg w 0 1 -nhch2- 1 03 a: HOI 3Γ H, x 4, O 1 X 1 1 1 \ 1 1 1 1 1 i Ο ooo U 1 1 CQ N ac o 32 〇〇esj X s CJ oa ac o N 3: 〇N nc ¢4 3 3C sc a nc N as u N 3C o □3 U rr u S3 〇co 〇o 〇o O 〇oo 〇o ο oooo 〇σ> Cti 00 〇£5 CO Γ—Ί 3: C4 5 ch2ch2ch2nh2 fQ OH , γ^〇Η °Y^0H ch2〇h CH2CH2N[S0jH]CH2CH2 CO re X re o N ; CH2CH20S03H ; C[CH3] 2C1120S03H CH2CH20CH2CHz PO tE C4 w 33 〇I—J 〇;ch2ch2ch3 2: w ffi cc ac rn r> δ 5 5: H; C[CH3]2CH20H ! rn i rn EE Ac 2C 02 tn SC ffi sc 3: 3: κ 3: 3: 03 a: a: 3 IX: 3: 3: 3: XK to X 5C K m nc as re Π2 tc n: 3: 33 3: rr lO CEi αα 3: oc SC 2C Λ aa 3C 3: Π3 3: inch Ρ Λ id id 3C 33 X cn rx: 33 WW ac ί: re 33 CO Pi i-Pr | i-Pr | | i-Pr 1 1 ά 1 U-Pr 1 h-Pr | 十•|H al 1 •rH i-Pr ! | i-Pr s i-Pr , •rH r> AO δ i-Pr | i-Pr 1 (N Pi tL. Tu IX. Cl, tL, (JU Uh PL. tlr tL·· U-. tL·, tu ϋ-< vu rc X 3ί 35 SC 2C n: O: X 3; :cw Example CnJ Csl csi CO C&gt ;3 π (N UD C>3 CD CM r^* (N 00 Cn3 cn o CO CO CO CO 守CO 1C CO CD C〇卜 C〇-15- 149395.doc 201105338 as International Publication WO 2007/126 Examples of the compound described in the manual No. 117 include compounds shown in the following tables. [Chemical 5]

149395.doc •16- 201105338 [I-<N<]

' ^tr-NHCONHs tn o Π2 g 〇Ϊ ogu N oc go N g PC t CM °. on 03 o S g ◦ M 5 O ko C4 g 04 /*vn K ^CJ o B g 33 CJ 5 〇t £ i天I/ ΓΖ fco 6. Γ9 32 § °N td nc § o 0□ g It a: uk CO ο 1 0 Z 1 »wo °N uo ffi § 2C X: U 5 X e>4 SNXU /- ^S. <〇CJ s § o N k /)-CH2CH2CH2CONHC (CH3)2CHz0H <〇on π: F? 3: 〇nngr» 〇Γ3 X o § oo PC ogo 〇ggo - - CO OJ inch Ι Ω &lt ; M o 00 (N 03⁄4 CSi o CO CO /t-NHC0NHCH2CH20H CO CM 32 〇〇2; k /7-NHC0NHC(CH3)2CH20H p-NHC0NHCH2C0NH2 p-NHCONHCH2CH2CONH2 „ X £〇°4-i 〇乂2乂〇 1 £ woo 〒 Π p-NHCONH(i-Pr) j /7-NHC0N(CH5)2 /T-NHCONH (n-Hex) n 33 〇m 〇C5 ac o 3? Λ sd go rt SC o tn o p -^ Pi g >-^1 o 03 〇〇ο ooo D: 〇00 to 00 03 o T»K 149395.doc -17- 201105338 [<N-(N<] N p-CHaCH2CH2CONHC (CH3) 2€0NH2 p-CH=CHCUz ( 〇) SC g C4 3 g § sc« X Ϊ o ;H:H2CH2CH2NHC (=NH) NH2 j^-CH2CHzCH2C0NHC (CH3) 2CONHCH2CHaOH 〇〇gn: X J7-CH2C H2CH2C0NHC (ch3) 2conhch2conh2 —N N-GH3 p-CH2CH2CH2C0NHC(CH3)2C0 (N~~) J^^ N N-COOCHg jd-CH2CH2CH2CONHC(CH3)2CO ( v_/ ) ~N N-CH2CH2OH, vd- CH2CH2CH2CONHC (ch3) 3C0 ( \_/ ) P2 na «*> nc Π3 〇g" c* ac nr or*> nc ci gogg tongue oggg 53⁄4 CSI oo CO inch CO ΙΛ CO ¢0 CO 00 CO C5S CO CO p-NHCONH(c-Hex) p-NHC0NH2 p-NHS02Ph p-NHS0NH2 /r-NHC (=NH)NH2 /zrNHCONHjj p-NHC0NH2 p-NHC0NH2 p-NHC0NH2 /3-NHC0NH2 p-NHC0NH2 CM Pi n 〇〇X CJ n 〇CO X r> n ΪΧ: az DC - Pi 〇〇〇a: 〇gg 5 och3 r> gi-1 p-4 C<3 CO 2 LO to 00 Oi ca 149395.doc -18- 201105338 Py means pyridyl, n-Hex means hexyl, c_Hex means cyclohexyl, and the double bond of "CH=CH" in the substituent Z of the compound of No. 23, 25-29, 33, 34 means Trans-body. The "DPP-IV inhibitory drug" in the present invention may be selected from the group consisting of sitagliptin, vildagliptin, alogliptin, saxagliptin, Dutogliptin >, Dutogliptin, Melogliptin, Carmegliptin, Teneligliptin, Lili, Linagliptin and 6-[(3R )-3-aminopiperidine·1-yl]-5-(2-chloro-5-fluoro)-1,3-dimethyl-1Η-pyrrolo[3,2-d]pyrimidine-2, 4 (3Η,5Η)-dione, and DPP-IV inhibitors in the group consisting of these pharmacologically acceptable salts. Preferably, it is selected from the group consisting of sitagliptin and 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chloro-5-fluorobenzyl)-1,3-dioxene A DPP-IV inhibitory drug in the group consisting of keto-1H-pyrrolo[3,2-d]pyrimidin-2,4(3H,5H)-dione, and such pharmacologically acceptable salts. Examples of such pharmacologically acceptable salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroquinone, sulfuric acid, nitric acid, and phosphoric acid, and formic acid, acetic acid, and methanesulfonic acid. Benzoic acid, p-toluene acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamine Acidic addition salts of organic acids such as acid and aspartic acid, organic salts such as diethanolamine salt, ethylenediamine salt and N-methyl reduced glucosamine salt, and salt, magnesium salt, sodium salt and potassium salt A salt of an inorganic base. The above DPP-IV inhibitors also include hydrates or solvates of pharmacologically acceptable solvents (e.g., ethanol, etc.). 149395.doc •19· 201105338 The above-mentioned DPP-IV inhibitors can also be produced by the methods described in the literature or by the methods described above (for example, refer to International Publication WO 2004/085378, International Publication No. 2004/085661 Handbook, International Publication No. 2006/033848, International Publication No. 00/34241, etc.). "Compound 3 or a pharmacologically acceptable salt thereof" can be easily produced by the method described in the literature or by the methods described above (for example, refer to Patent Document 5). The compound 3 or a pharmacologically acceptable salt thereof also contains a hydrate thereof or a solvate of a pharmacologically acceptable solvent (e.g., ethanol or the like). As the compound 3 or a pharmacologically acceptable salt thereof, a hydrochloride thereof (Compound 4: 6-[(3R)-3-aminopiperidin-1-yl]_5_(2_chloro_5_) is preferred. Fluorinyl)-1,3-indolyl-1H-indole is more than [3,2-d] sneezing - 2,4(3H,5H)-diindole monohydrochloride)' is better 1/2 hydrate of compound 4 (compound X: 6_[(3R)-3-aminopiperidinyl)]_5_(2_gas_5_fluorobenzyl)_13_dimethyl_1H_ 0 ratio Each is [3,2-d]pyrimidine·2,4(3Η,5Η)-dione•monohydrochloride 1/2 hydrate). As the pharmacologically acceptable salt of sitagliptin, phosphate or a hydrate thereof is preferred. As the pharmacologically acceptable salt of vildagliptin, a hydrochloride is preferred. As the pharmacologically acceptable salt of alogliptin, a benzoate is preferred. The "combined medicine" (hereinafter, also referred to as the medicine of the present invention) in the present invention is a compound which is a compound or a pharmacologically acceptable salt thereof, and is selected from the group consisting of sitagliptin and vildagliptin. DPP in a group consisting of alogliptin, saxagliptin, dutoglipin, merostatin, cumulus, linagliptin, and compound X, and the pharmacologically acceptable salts of these -IV Obstruction Group 149395.doc •20- 201105338 Co-author. These components may be combined at the time of administration, or may be combined in an organism after administration. Specifically, t may be a pharmaceutical composition containing the two active ingredients (sometimes also referred to as a pharmaceutical composition of the present invention), or may be formed by separating the two active ingredients at a certain time. A form that is administered or combined at the same time. The other aspect of the medicine of the present invention may be a compound selected from the compound ι, the compound described in the handbook of International Publication WO 2007/129668, the compound described in Japanese Patent Laid-Open Publication No. 2008-501745, and the International Publication WO 2007/ A pharmaceutical composition comprising a compound described in the 126117 manual and a SGLT1 inhibitory drug in the group consisting of the pharmacologically acceptable salts, and a compound 3 or a pharmacologically acceptable inhibitor thereof. The pharmaceutical composition of the present invention also comprises a single preparation (mixture) containing two active ingredients, and each of the preparations of the respective combination of users (combination kits, etc.) is contained at the same time or at intervals, and is administered in the same manner. Morphological or different forms of administration. In the case of the medicine of the present invention, when the number of the two active ingredients is different on the one day, the simultaneous administration and the single dose administration are mixed in one day. Examples of the "disease caused by hyperglycemia" in the present invention include type 1 and type 2 diabetes, glucose intolerance, abnormal fasting blood glucose, and diabetic complications (for example, retinopathy, neurological disorders, kidney diseases, ulcers, Large blood disease), obesity, insulinism, hyperlipidemia, hypercholesterolemia, triglycerideemia, abnormal lipid metabolism, atherosclerosis, hypertension, septic heart failure , edema, hyperuricemia, gout 149395.doc • 21 · 201105338 and so on. Further, it can be expected that the medical treatment of the present invention can enhance the secretion of pancreatic ghrelin, inhibit the secretion of ^ ^ ^ sputum, and the differentiation and proliferation of pancreatic β cells. And cell death, inhibition, vomiting, ... * system, improvement of myocardial and endothelial function, inhibition of niacin and pancreatic juice secretion, diet, weight loss, insulin sensitivity, inhibition of glucose synthesis by muscle and adipose tissue, The movement of the stomach ", hoarding a few times, reducing the liver in the liver ^ exercise inhibition, after meals • fasting blood sugar drop, ~ drop, fructamine (fruct. protection, heart protection, etc., especially 1 "b month & god ^ ^ — 兀 /, 疋 is extremely useful for the treatment of type 1 and 2 diabetes, glucose intolerance, fasting blood " obesity, sputum sputum, etc., book urinary tract complications, in the present invention Among the diseases caused by hyperglycemia, it is obtained by correcting hyperglycemia, preventing glucose, and developing H to prevent diabetes (prophylactic treatment), etc. or fasting blood glucose is different in the present invention. Medicine" (10)_] Degree increase and persistence;: two to make an intrinsic active agent. The action of GLP] is used in the medicine of the present invention for practical treatment. * Various dosage forms of preparation V are used, according to drugs or agents, granules, The fine granules and the dry _ ^ j may be exemplified by powders, liquids, etc., which are administered orally or parenterally: capsules, injections of the active ingredients are simultaneously or separately formulated, and the agents can be administered by injection. In the case of the two, the dosage forms of the two may be the same or the separate preparations which can be separately obtained in the form of a solid preparation. Moreover, the medicine of the present invention can also be used according to the dosage form of the 10,000 clothes according to the dosage form, 149395 .doc •22- 201105338 The method used in the formulation, and, Zhou Tianzhi excipients, disintegrants, knots σ, full slip agent, thinner, buffer _ ^ 巧 剜, Preservative, wetting agent = emulsifier, dispersing agent, stabilizer, dissolving aid # Drug additives are mixed or diluted and dissolved, and adjusted according to the usual method. For example, the key agent can be (4) the method described in the literature or the method according to the method. It is easy to manufacture. The tablet can also be coated as needed. A film-forming tablet, a sugar-coated tablet, an enteric-coated skin tablet, etc. The capsule may be added to an appropriate component, if necessary, by adding an appropriate excipient, a (four) agent, etc., and then filling it into a suitable capsule to form a capsule. It can also be filled into granules or fine granules by a conventional method. When the medicine of the present invention is used for actual treatment, the dosage of each active ingredient is based on the age, sex, weight, disease and degree of treatment of the patient, and the medicinal agent. The dosage form, the administration method, the combination of the medicines, etc. are appropriately determined. In the case of oral administration, the adult is approximately 000H000 mg per day, and in the case of non-oral administration, every adult is 1 曰. A SGLT1 inhibitory drug such as Compound 1 or a pharmacologically acceptable salt thereof may be appropriately administered once or several times in a range of approximately 1 to 3 mg. In the case of oral administration, DPP-IV inhibitory drugs may be administered once or several times a day in the range of approximately 0.01 to 3000 mg per adult, for example, one dose or one dose may be administered. / 曰西西列〉丁' can be administered in 1 a or fractions of 1 to 100 mg / day of vildagliptin, 1 or 400 mg / day of alogliptin can be administered once or in fractions. The saxagliptin and the like may be administered once or in portions of 1 to 4 Q〇mg/day. [Examples] The contents of the present invention are described in more detail with reference to the following Reference Examples, Test Examples and Examples, but the present invention is not limited thereto. Reference Example 1: Bis[3-(3-{4-[3-(pD-indolyl glucooxy)-5-isopropyl-1H-indazole-4-ylmethyl]-3-methylbenzene Oxy}propylamino)-2,2-dimethylpropionamine]·monosebacate 3-(3-{4-[3-(β-ϋ-η 鸣 葡萄糖 glucooxy) -5-isopropyl-1H-0 is 0--4-methyl>-3-mercaptophenoxy}propylamino)-2,2-dimethylpropanamide (1.00 g) Sebacic acid (0.18 g) was suspended in ethanol (10 mL) and dissolved by heating at 7 ° C for 5 minutes. Add two isopropyl mystery (5 mL) at 70 ° C and mix at room temperature for 1 hour. After the precipitate was taken, it was 5 Torr under reduced pressure. Drying was carried out to give the title compound (1.05 g). Further, the compound was heated to reflux and dissolved in ethanol (10 mL), and then diisopropyl ether (5 mL) was added, and the mixture was cooled to room temperature and stirred overnight. The crystals thus precipitated were collected by filtration, and dried under reduced pressure at 50 ° C to afford crystals of the title compound (0.96 g). JH-NMR (DMSO-d6) (δ (ppm)): 1.00-1.10 (12H, m), 1.24 (4H, s), 1.40-1.50 (2H, m), 1.70-1.90 (2H, m), 2.17 (2H, t, J-7.0 Hz), 2.26 (3H, s), 2.64 (2H, t, J=6.5 Hz), 2.70-2.80 (1H, m), 3.00-3.20 (4H, m), 3.40- 3.50 (3H, m), 3.62 (1H, d, J=ll.5 Hz), 3.93 (2H, t, J=6.〇Hz), 4.20-4.80 (1H, br), 5-18 (1H, d, J = 8.0 Hz), 6.60 (ih, d, J = 8.0 Hz), 6.69 (2H, s), 6.82 (1H, d, J = 8.5 Hz), 7.47 (1H, s) 〇 Reference Example 2: 3-(3_{4-[3-(pD-glucopyranosyloxy)_5_isopropyl_1H pyrazole_4_ 149395.doc •24· 201105338 methyl]-3-methylphenoxy} Propylamino)-2,2-dimercaptopropionamide · 1/2 fumarate dihydrate 3-(3-{4-[3-(0-〇-°-pyranose) Oxy)_5-isopropyl-1-only-'1 than sino-4-ylmethyl]-3-methylphenoxy}propylamino)_2,2-dimethylpropanamide (17 g) Dissolved in ethanol (150 mL) at 40 ° C, and added 1/2 equivalent of fumaric acid (1.75 g) and ethanol (105 mL), and stirred under heating at 7 °t. After cooling until after, mix for 2 hours. The precipitate was taken and dried under reduced pressure at 70 for 12 hours, whereby crystals of 1/2 fumarate ethanolate (18.5 g) were obtained. The crystal of 1/2 fumarate ethanolate (6 4 g) was dissolved in a mixed solvent of ethanol (64 mL) and water (3.2 mL) under heating. After filtration, the filtrate was stirred at room temperature for 15 hours. The precipitated crystals were collected by filtration and dried under reduced pressure at 50 ° C. The obtained crystals were allowed to stand at 25 ° t / 6 〇 % relative humidity for 2 days, and further The crystal of 1/2 fumarate dihydrate (5 3 g) was obtained by standing at 4 ° C / 75% relative humidity. H-NMR (DMSO-d6) (δ (ppm) ): 1.00-1.10 (12H, m), 1 88 (2H, t, J=6.5 Hz), 2.26 (3H, s), 2.64 (2H, s), 2.70-2.80 (3H, m), 3.10-3.30 (4H, m), 3.40-3.60 (3H, m), 3.62 (1H, d5 1=11.0 Hz), 3.95 (2H, t, J=6.0 Hz), 4.40-4.60 (1H, br), 5.18 (1H , d, J=7.5 Hz), 6.47 (1H, s), 6.61 (1H, d, J=7.5 Hz), 6.70 (1H, s), 6.82 (1H, d, J=8.5 Hz), 6.89 (1H , s), 7.50 (iH, s), 11.00-12.00 (1H, br). Reference Example 3: 6-[(3R)-3-Amino-based α-small base]_5_(2-Gas_5•Fluorine Section base ^, ^ two 149395.doc • 25- 201105338 monohydrochloride 1/2 base_1H_° piroxi[3,2.d] feeding cough-2,4(3H,5H)_ diketone water Compound [Chemical 6]

(1) 6-[(3R)-3-Aminopiperidinyl]•5_(2_chloro-5 fluorobenzyl)13-dimercapto-1H-pyrrolo[3,2-d]pyrimidine_2, The 4(3H,5H)-dione can be synthesized by the method described in the International Publication WO 2006/068163. (2) 6-[(3R)-3-Aminopiperidinyl]-yl]_5_(2_chloro-5-fluorobenzyl y, % dimethyl-1H-pyrrolo[3,2-d 1 n Hydrochloric acid (2.67 kg) was added dropwise to a mixture of pyrimidine-2,4(3H,5H)-dione (1·〇2 kg) and water (7.80 kg), and mixed at room temperature. After 1 hour Toluene was added and concentrated under reduced pressure three times. To the obtained residue, isopropyl alcohol (4.49 kg) containing 15% of water was added, and the mixture was heated to 8 Torr. (: After a homogeneous solution, ethyl acetate was added dropwise. (1 6.64 kg). After slowly recovering to the temperature, mix in an ice bath for 1 hour. The solid formed is recovered by "drying with acetic acid" and then dried under reduced pressure. The title compound (72 1.8 g) was crystallized. NMR (400 MHz, DMSO) δ 8.12 (brs, 3H), 7.53-7.56 (m, 1H), 7.13-7.18 (m, 1H), 6.10-6.15 (m, 2H ), 5.39-5.50 (m, 2H), 3.39 (s, 3H), 3.22-3.27 (m, 2H), 3.13 (s, 3H), 2.82-2.88 (m, 2H), 2.66-2.71 (m, 1H) ), 1.83-1.92 (m, 1H), 1.71-1.78 (m, 1H), 1.40-1.52 (m, 2H). 149395.doc •26· 201105338

MS (ESI+) 420 (M++l, loo%). Mp 205 to 208 〇 C Test Example 1: Blood sugar rise suppressing effect Test Example 1A: ZF rats (丨〇 weeks old, male, Japanese SLC) as a type 2 diabetes model were used. The anti-diabetic effect obtained by combining the compound 2 and the compound was studied by using the inhibitory effect of blood glucose rise after the mixed carbohydrate load as an index. ZF rats were divided into 4 groups (8 each). After fasting overnight, only one group was orally administered with a solvent, and 2 groups were orally administered with 0.03 mg/kg of Compound 2 as Compound 1 (solvent: distilled water). ) 'Forcibly oral administration of 0.3 mg/kg of compound χ (solvent: 5%. 5% methylcellulose solution) to 3 groups was administered orally to 4 groups as compound iio 〇 3 mg/kg of compound 2 and 0 • 3 mg/kg of compound hydrazine (Table 3). Carbohydrate loading is mandatory for oral administration of 2 g/kg of mixed carbohydrates (soluble starch·sucrose: lactose monohydrate = 6 : 3 : 1). Compound X is applied to a mixed carbohydrate load of 3 knives, and the compound 2 is administered before the carbohydrate load is to be mixed. The blood collection system was performed from the tail vein over time, and EDTA (Ethyiene Diamine Tetraacetic Acid' Ethylenediaminetetraacetic acid) was added as an anticoagulant at a final concentration of 1 mg/mL, and ι/1 () D DPP was added. -IV inhibitory drug (Millipore p was used to centrifuge the plasma, and the glucose concentration was measured using a commercially available kit (Glucose CII-Test Wako, Wako Pure Chemical Industries, Ltd.). The average of each group (N=8) ± The standard error indicates the blood glucose level (glucose concentration in plasma) at each time point (Table 4). The trapezoidal method was used to calculate the load of the mixed water-breaking compound and then simmered for 1 hour and 〇 to 2 hours. 149395.doc •27·201105338 Blood glucose increase curve The area under the ground (△AUC〇.丨心 and AAUC〇_2 hr). The results of each group are expressed by the average soil standard error, and the student t test is performed and shown in (Table 5). Also, the significance level is less than 5%. Significantly set. [Table 3] Group dosage of pharmaceutical administration 1 Solvent 8 2 Compound 2 0.03 mg/kg 8 3 Compound X 03 mg/kg 8 4 Compound 2 0.03 mg/kg 8 Compound X 0.3 mg/kg [Table 4] Group administration of pharmaceutical mixed carbohydrates Blood glucose level after loading (mK/dL) -30 min 0 min 15 min 30 min 60 min 90 min 120 min 1 Solvent 107 ± 5 110 ± 5 158 ± 4 161 ± 7 136 ± 7 123 ± 5 122 ± 4 2 Compound 2 111±5 117±5 153 ±5 139±5 143 ±3 141 Earth 5 136 Earth 5 化合物 Compound X 113±4 115 Earth 3 158 ± 6 127 ± 4 128 ± 6 126 ± 5 128 ± 4 4 Compound 2 + Compound X 115±4 120 Soil 4 147±4 114±5 128±5 131±6 133 Soil 5 [Table 5] Blood glucose level AAUCfmg.hr/dL·) after administration of the agent mixed with water-breaking compound load 0~ 1 hour load guess 0~2 hours 1 Solvent 37.9±5.4 54.0±7.9 2 Compound 2 24.0 士3.3* 47 7土 5 7 3 Compound X 18.7±2.1** 31.] ±4.0* 4 Compound 2 + Compound X 6.4± 3.0***## $ $ 17.2±7.7**## ~Comparative lions are shown in Table 4, Table 5 and Figure ,, as a compound of SGLT1 inhibitor 2 and a compound as a DPP-IV inhibitor. Compared with the solvent group, the individual administration group was compared with the solvent group, and the blood sugar rise after the mixed carbohydrate load was inhibited by 37% and 50%, respectively, and the blood sugar increase was 83% when the two compounds were used together. Significantly inhibited. That is, in the case of the combined use of I49395.doc -28 * 201105338, there is a significant difference compared with the solvent or separately. Further, it was also administered separately in 0 to 2 hours, and 12% and 42% were inhibited, and when used in combination, 68% was further suppressed. According to the above, it is clear that by using two doses in combination, it is shown that a very strong blood sugar level increase inhibitory effect is exhibited in comparison with the separate administration. Test Example 1B: It was used as a normal mouse iC57BL/6J mouse (9 weeks old, male, 曰本柯末亚). The anti-diabetic effect obtained by the combination of Compound 2 and sitagliptin phosphate was studied by the inhibition of blood glucose rise after glucose loading as a finger. The C57BL/6J mice were divided into 4 groups (3_4 each). After fasting overnight, only the oral administration of the solvent to the sputum group was carried out, and the two groups were orally administered as the compound 丨mg/kg of the compound 2 (solvent). : Distilled water) For 3 groups, 1 mg/kg of sitagliptin phosphate (solvent: 0.25% methylcellulose solution) was orally administered, and two groups were orally administered with two compounds (Table 6). The glucose load was forced to orally administered a 5 mL/kg 2 g/mL glucose solution. Sitagliptin phosphate was administered 30 minutes before the glucose load, and Chemical & 2 was administered prior to the glucose load. The blood collection system was performed from the tail vein over time, and the glucose concentration (mg/dL) in the plasma was measured using an electrode-type blood glucose measuring device Antosence 11. Use the trapezoidal method to calculate the area under the curve of blood glucose (glucose/agriculture in plasma) from 0 to 1 hour after glucose loading (Auc.·&quot; j (mg · hr/dL) and increase part of AUC (AAUCq-i hr) (mg · h/dL). The results of each group are expressed as mean ± standard error, and the student's t-test is performed and shown in Table 6. Further, the significance level is less than 5 ° / is set to be significant. S- 149395.doc -29- 201105338 [9&lt;1 AUC(mg-hr/dL) △AUC〇-i hr 189.0 ± 14.6 153.5 ±4.5* 138.1 ±8.8* 81.9±8.3**###$$ AUC〇,i |lr 337.3 ±9.0 275.5 ± 15.9* 264.6 Soil 9.7** 220.9 ±7.5***#$ Blood glucose (mg/dL) TH 399.7 ±3.7 345.0 ±7.3** 278.8 ±26.5* 240.3 ± 4.2***娜0.5 hr 400.7 ± 8.5 317.5 ±22.3* 326.5 ±9.6** 252.3 ± 14.5***#$$ OJ 〇, 148.3 ±21.9 122.0 ± 12.8 126.5 ±2.6 139.0 ±7.4 dosage (mg/kg) Compound 2 Ο τ-( Ο 1 —&lt; sitagliptin phosphate ο rr ^^ (Ν cn 寸.^驾三琳嫦%^二馨^》狳卜&lt;瓦^昭韹穿铼) 10.0&gt;&$200&gt;&; :^w 敬(N#&lt;°qr-铼)looo&gt;d### &lt;so&gt;d# :(洞玉W 軚蘅姨朱)I0oo&gt;di = „ &lt;Ι0Ό&gt;&lt;ίί - sovd* 149395.doc ·30· 201105338 As shown in Table (10) 'Compound 2 and Qianxi _, and sputum group (dissolved in 0~1 hours after glucose load, the blood sugar rise is inhibited, respectively) When the two compounds were used in combination, the inhibitory effect was 57% more strongly. Because &amp; 'is compared with the separate administration alone, the blood glucose increase inhibition effect was obtained by obtaining the apparent glucose load by using the two compounds in combination. As a result of the example 1, it is understood that the medicine of the present invention does not induce side effects such as hypoglycemia, enhances the blood sugar rise suppressing action of the Dpp_IV inhibitor, and is extremely useful for treating diseases caused by hyperglycemia. 5 Example 2 GLP-1 Effect Enhancement Effect Test Example 2 A: Blood sulphate obtained by the mixed carbohydrate load test shown in Test Example 1A was measured using a commercially available kit GLP-1 (7-36) ActiVe ELISA Kit (Millip0re). Type glp] concentration. The active GLP-I concentration at each time point was expressed by the average soil standard error of each group (1^=8) (Table 7). The active GLP-1 concentrations ΔΑυΟίΜ hr and AAUC0.2 hr were calculated by the trapezoidal method after the mixed carbohydrate loading for ~1 hour and 〇~2 hours. The results of each group are indicated by the average soil standard error, and the student t test is performed and shown in (Table 8). Also, the significance level is less than 5%. [Table 7] The concentration of active GLP-1 in plasma after administration of a mixture of carbohydrates (pM) -30 min 0 min 15 min 30 min 60 min 90 min 120 min 1 Solvent 4.2 ± 0.5 3.9 ± 0.7 8.6 Earth 1.8 4.6 ±1.1 4.0 ± U 3.5 ±1.2 3.5 ± 1.6 2 Compound 2 6.7 ± 0.7 3.9 ± 0.8 8 · 2 ± 2 · 4 7.6 ± 1.5 5.2 ± 1.3 4.9 ± 1.2 3.2 ± 1.0 3 Compound X 6.2 Soil 0.8 7.3 ± 1.2 17.0 士2.3 12·7 士1·9 6.9 ±0.6 6.3 ± 1.5 6.8 ± 0.7 4 Compound 2 + Compound X 9.7 Soil 1·9 10.7 ±2.4 23.8 ±4.8 18.6 ±U 14.9 ±2,8 11.8±2.3 10.0± 1.8 149395.doc -31- 201105338 [Table 8] Group of active GLP-1 concentrations after solvent-mixed carbohydrate loading AAUC (pM'hr) After loading ~] hour load 〇~2 hours 1 Solvent 1,51 Soil 0.60 1.27 ±0.90 2 Compound 2 2.83 ± 1.14 3.52 ± 2.13 3 Compound X 4.36 ± 1.61 3.66 ± 2_82 4 Compound 2 + Compound X 7.27 Soil 1.78** 8.67 ± 2.77* *Ρ&lt;0·05,**Ρ&lt;0 · 01 (compared with the solvent group), the student t test. As shown in Table 7, Table 8, and Figure 2, the individual administration groups of Compound 2 and Compound X increased the concentration of active GLP-1 AAUC by 1.32, respectively, compared with the solvent group, 0 to 1 hour after the mixed carbohydrate loading. (pM · hr) and 2.85 (pM • hr). In the case of the combination of Compound 2 and Compound X, it is more powerful and exhibits a significant increase of 5.77 (ρΜ · hr). In addition, 2 to 25 (ρΜ · hr) and 2·39 (ρΜ · hr) were added for 0 to 2 hours after the mixed carbohydrate load, and when combined, 74.0 (ρΜ · hr) was further exhibited. Significant and significant increase. The concentration of active GLP-1 in the plasma after the mixed carbohydrate was loaded was increased by the administration of the compound X. In the administration of Compound 2, the maximum value of the increase in the concentration of active GLP-1 in plasma was the same as that of the solvent group, and was different from the compound X administration group until the mixed carbohydrate load was higher than the control group 90 minutes after the mixed carbohydrate load. value. Further, by the simultaneous administration of the two drugs, the maximum value of the increase portion of the active GLP-1 concentration in the plasma was increased while the compound X was administered alone, and the duration of the concentration was extended to 90 minutes. This condition is also understood to be due to the 0-2 hour ΔΑυ of the active GLP-1 concentration in plasma (: a high value that is apparent in the combined administration group. 149395.doc •32·201105338 Test Example 2B: Normal Wistar rats were divided into 4 groups (5 each). After fasting overnight, only one group was orally administered with a solvent, and 2 groups were orally administered with 0.03 mg/kg of Compound 2 as Compound 1 (solvent: steaming hall) Water), 30 groups of orally administered 30 mg/kg of sitagliptin phosphate (solvent: 0.25% thioglycolate solution), and forced administration of two compounds to 4 groups. Glucose load is mandatory oral administration 5 mL/kg of 0.4 g/mL glucose solution was given. Sisalite phosphate &gt; 'Ding was administered 30 minutes before the glucose load, and Compound 2 was administered before the glucose load was applied. One hour after the glucose administration, The laparotomy was performed under diethyl ether anesthesia, and blood was collected from the P vein. The concentration of the active GLP-1 in the portal vein plasma was measured using a commercially available kit GLP-1 (7-36) Active ELISA Kit (Millipore). Soil standard error indicates the results of each group, and students are checked Further, it is shown in (Table 9). Further, the significance level is less than 5%. [Table 9] Amount of administration (mg/kg) GLP-1 concentration (pmol/L) Group of sitagliptin phosphate 2 1 hr difference 1 0 0 5.3 ± 1.5 - 2 0 0.03 14.1 ±2.6* 8.8 3 30 0 10.5 ±2.1 5.2 4 30 0.03 35.3 ± 5.4***##$$ 30.0 *Ρ&lt;0·05,*** Ρ &lt;0·001 (comparison with solvent group); ##P&lt;0.01 (comparison with compound 2 group); $$P&lt;0.01 (comparison with sitagliptin phosphate group), all for student t-test. As shown in Table 9, Compound 2 and sitagliptin phosphate were compared with the solvent group, and the concentration of active GLP-1 was increased by 8.8 pmol/L and 5.2 pmol/L, respectively, 1 hour after glucose loading. In the case of Love, Pierre ij is more 149395.doc •33·201105338 Strong 'shows a significant increase of 30.0 pmol/L. From the results of Test Examples 2Α and 2Β, it was found that by using SGLT 丨 barrier drug and DPP-IV together The drug was inhibited, and the concentration of the active form was synergistically increased. Test Example 3: Insulin concentration inhibition effect The blood collection obtained by the mixed carbohydrate load test shown in Test Example 1A was used as a commercially available set. Insulin concentrations were determined (Lbis rats with insulin, SHIBAYAGI Ltd.). The insulin concentration at each time point was expressed as the mean standard error of each group (N=8) (Table 丨0) ^The trapezoidal method was used to calculate the insulin concentration after 混合~1 hour and 〇~2 hours after mixed carbohydrate loading △ AUCo] Hr and ΔΑυ (: 0_2 hr. The results of each group are expressed by the average soil standard error, and the student t test is performed and shown in (Table 11). Further, the significance level is less than 5%. [Table 1〇] Group administered with mixed carbon; 1 血浆 compound loaded plasma insulin concentration (ng/mL) -30 min 0 min 15 min 30 min 60 min 90 min 120 min 1 solvent 5·6 ± 0.9 5.9 ± 0·4 18.6 Soil 1·2 9.7 Soil 1·2 4.7 ± 0.5 3.4 ± 0.8 4.0 ± 0.4 2 Compound 2 5.0 ± 1.0 5.6 ± 0.7 14.0± ί.9 8.0 ± 1.4 6.5 ± 0.7 4.6 ± 0.9 4.7 ± 0.9 3 Compound X 4.9 士士0.5 6.0 ± 0.6 21·0±2.4 11_9± 1.6 5·5 Soil 0·6 4.4 ±0.8 4.6 ±0.9 4 Compound 2 + Compound X 5.0 Soil 0.7 5.6 ±0.2 19.6 ±2_4 7*7 Soil 1·3 6.6 ±0.8 5.1 ± 1.2 5.6 ±0.6 [Table 11] Insulin concentration after group-administered drug mixed carbohydrate load AAUC (ng.hr/mL) 0-1 small after loading 0-2 hours after loading 1 Solvent 4.34 ± 0.76 2.36 ± 1.12 2 Compound 2 3.21 ± 0.66 2.65 ± 0.97 3 Compound X 5.86 ± 0-81 4.62 ± 1.04 4 Compound 2 + Compound X 4.55 ± 09.6 ± 1.63 Not significant Difference, Student's t-test. As shown in Table 10, Table 11, and Figure 3, the AAUC of the insulin concentration in the compound X administered to the group increased slightly, but decreased in the compound 2 administration group, and was administered -34-149395.doc The 201105338 group showed a decrease compared with the compound X administration group, and the compound 2 showed an increase compared with the group, and the results showed an area under the curve of the insulin concentration increase curve which was approximately the same as the control group. In combination with administration, it is possible to control blood glucose by less than the amount of insulin secreted by Compound X alone. The synergistic decrease in blood glucose level when SGLT1 inhibitor and DPP-IV inhibitor are combined, and the compound 2 as an SGLT1 inhibitor The inhibition of blood glucose rise by the DPP-IV inhibitory drug was significantly enhanced (Test Example 1). This effect was not caused by the secretion of insulin secretion (Test Example 3). In addition, the concentration of the active GLP-1, such as the protective action of the known pancreatic β-cells, was increased by the administration of the two drugs in combination, and the increase was sustained (Test Example 2). In other words, it was confirmed that the compound 2 which is an inhibitor of SGLT1 supplements the effect of the DPP-IV inhibitor on blood sugar level in a form independent of insulin secretion, and exhibits a concentration of GLP-1 which enhances the protective action of known pancreatic β cells. And use the effect. Examples 1 to 3: According to the formulations of Formulation Examples 1 to 3, the following components 1 to 6 were mixed, granulated, and tableted to obtain a 300 mg bond. [Formula 12] Formulation Example 1: Content of tablet ingredient containing Compound 2 and sitagliptin phosphate hydrate (mg/per 1 ingot) 1 Compound 2 60 2 Sitagliptin phosphate hydrate 60 3 Mannitol 112 4 Crystalline cellulose 50 5 Cross-linked carboxymethyl cellulose sodium 15 6 Magnesium stearate 3 149395.doc -35· 201105338 [Table 13] Formulation Example 2: Content of the tablet component containing Compound 2 and Vigregli Mg/per 1 ingot) 1 compound 2 60 2 vildagliptin 30 3 mannitol 142 4 crystalline cellulose 50 5 croscarmellose sodium _ 15 6 stearic acid town 3 [Table 14] Formulation Example 3: Content of the suspect component containing compound 2 and alogliptin benzoate (me per 1 suspect) 1 Compound 2 60 2 Alogliptin benzoate 15 3 Mannitol ~~- 157 4 Crystalline fiber ~ 50 5 Cross-linked carboxymethyl cellulose stone ~~ 15 6 Stearic acid town ' 3 Example 4 : According to the formulation of Formulation Example 4, the following ingredients 1 - 5 were mixed, and wet granulation was carried out using the aqueous solution of ingredient 6 And mixed with ingredient 7. The obtained mixture was subjected to tableting to obtain a tablet of 300 mg. [Formula 15] Formulation Example 4: Tablets containing Compound 2 and Compound X ______ Content (mg/head 1 bond) 1 Compound 2 60 _ 2 Compound X 15 _-3 Lactose ' 157.5__ 4 Corn starch 60___ 5 Carboxy Sulfhydryl cellulose Yao 5_______ 6 Hydroxypropyl cellulose (HPC-L) 2 _- 7 Magnesium stearate 0.5 ______________ 149395.doc -36- 201105338 [Industrial availability] The medicine of the present invention has powerful blood sugar Ascending inhibition and Glp·1 enhancement are extremely useful for the treatment of diseases caused by hyperglycemia. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a forced oral administration of Compound 2, Compound X and the two agents to Zucker-fa/fa rats (ZF rats). The graph on the left side of Figure 1 shows the change in blood glucose level (mean ± SE) of the oral mixed carbohydrate loading test performed after 30 minutes of drug administration. ♦ indicates solvent, indicating that compound 2 (0.03 mg/kg)' ▲ indicates compound x (〇 3 mg/kg), and · indicates compound 2 (〇 3 mg/kg) + compound χ (〇. 3 mg/kg). The graph on the right shows the area under the increased blood glucose curve (mean SE) of the oral mixed carbohydrate test. *Ρ&lt;0·05,**p<〇.〇i,***p&lt;〇〇〇1 (comparison with solvent group); ##P&lt;0_01 (compared with compound 2 to the group); $ $p&lt;〇〇1 (comparison with compound X administered group)' is all for student t-test. Figure 2 is a forced oral administration of Compound 2, Compound X and the two agents to ZF rats. The graph on the left side of Fig. 2 shows the change in the concentration of active GLp-1 in plasma (mean ± SE) of the oral mixed carbohydrate loading test performed 3 minutes after the administration of the drug. ♦ indicates solvent, indicating compound 2 (〇〇3 mg/kg), ▲ indicates compound χ (〇3 mg/kg), · indicates compound 2 (〇〇3 mg/kg) + compound χ (〇.3 mg/kg) ). The graph on the right shows the increase in the concentration of the active glp-1 concentration in the plasma (mean ± SE) in the oral mixed carbohydrate test. **P&lt;0_01 (compared to solvent group), Student 1 check. Figure 3 is a forced oral administration of Compound 2, Compound χ and the two doses of 149395.doc, 201105338, etc. to ZF rats. The graph on the left side of Fig. 3 shows the change in plasma insulin concentration (average value of £8) in the oral mixed carbohydrate loading test performed 30 minutes after the administration of the drug. Life means solvent, _ means compound 2 (0.03 11^/]^), win means compound 乂(〇.3 111吕/1&lt;^), spring means compound 2(0.03 111吕/1&lt;;旦)+compound X (0.3 mg/kg). The graph on the right shows the area under the increase in plasma insulin concentration curve for the oral mixed carbohydrate loading test (mean SE). 149395.doc -38·

Claims (1)

201105338 VII. Patent application scope: 1. A medicine consisting of SGLT1 inhibitor and Dpp-blocking drug. The above SGLT1 hinders the drug line 3-(3-{4-[3-(PD-.pyranoseoxy) -5-isopropyl-1H-indole. Sodium-4-ylindenyl]-3-mercaptophenoxy}propylamino)_2,2_-methylpropanolamine or its pharmacologically acceptable The salt, the above 〇ρρ_ιν barrier drug is selected from the group consisting of sitagliptin, vildhiline, diced, alogliptin, sagridin gt; Ding, Dutogliptin, merostatin, coughmei Carmegliptin, linagliptin and 6_[(3r)_3_aminopiperidine-indenyl]-5_(2-a-5-fluorobenzyl)-13-diindolyl-1H-pyrrolo[ 3,2_d]pyrimidine _ 2,4(3H,5H)-dione and a group consisting of such pharmacologically acceptable salts. 2. As requested! The medicine 'where Dpp-jv inhibitor is sitagliptin or 6_[(3R)-3-aminopiperidinyl + yl]_5_(2_chloro-5-fluoro]pyrene) 4} dimethyl _ 1H- . Bilo[3,2-d]pyrimidine-2,4(3H,1H)-dione or a pharmacologically acceptable salt thereof. 3. The medicament of claim 1 or 2 wherein the dpp-IV inhibitor is sitagliptin or a pharmacologically acceptable salt thereof. 4. The medicament according to claim 1 or 2, wherein the DPP-IV inhibitor is 6-[(3R)-3-amino group. Ding-1-yl]-5-(2-a-5-fluorobenzyl)-i,3-dimercapto-ih-pyrrolo[3,2-d]pyrimidine_2,4(3H,5H) a diketone or a pharmacologically acceptable salt thereof. 149395.doc 1 The medicine of any one of claims 1 to 4 for use in the treatment of a disease caused by hyperglycemia. The disease of the month of the 5th disease, in which the disease caused by hyperglycemia is the disease in the group consisting of 201105338 free diabetes, glucose intolerance, abnormal fasting blood glucose, diabetic complications, obesity and hyperinsulinemia . 7. The medicine according to any one of items 1 to 4, which is a postprandial blood sugar improving medicine. 8. If requested! To any of the medicines of 4, which is a GW·1 action enhancing drug 0 149395.doc