CN101267838B

CN101267838B - Use of a DPP-IV inhibitor to reduce hypoglycemic events

Info

Publication number: CN101267838B
Application number: CN200680034365XA
Authority: CN
Inventors: B·巴尔康; D·G·霍姆斯; T·E·休斯; E·B·维尔豪尔
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2005-09-20
Filing date: 2006-09-18
Publication date: 2012-09-05
Anticipated expiration: 2026-09-18
Also published as: CN101267838A; ES2369046T3

Abstract

The invention relates to a method to reduce the hypoglycemic events, especially sever hypoglycemic events resulting from insulin treatment, wherein the patient is treated with a Dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor) or a pharmaceutically acceptable salt thereof.

Description

The purposes of DPP-IV inhibitor to reduce hypoglycemic events

The present invention relates to reduce because the antidiabetic compound hypoglycemia incident, the particularly method of severe hypoglycemia incident that cause of insulinize particularly, wherein the patient is to use inhibitors of dipeptidyl IV (DPP-IV inhibitor) or the treatment of its officinal salt.

The patient who is treated preferably suffers from hyperglycemia such as diabetes, is preferably non-insulin-dependent diabetes mellitus or impaired glucose metabolism (IGM), preferred impaired glucose tolerance (IGT).

Diabetes are common relatively obstacle (estimating 1% sickness rate of about total population), it is characterized by hyperglycemia.The diabetes that three kinds of fundamental types are arranged, I type or insulin dependent diabetes mellitus (IDDM) (IDDM), I1 type or non-insulin-dependent diabetes mellitus (NIDDM) and A type insulin resistant type.There is the patient of I type or I1 type diabetes to become to the effect of exogenous insulin insensitive (" insulin resistant ") through number of mechanisms.A type insulin resistance is because site defective behind the variation of insulin receptor gene or the receptor that glucose metabolism is played a crucial role.General through administration of exogenous insulin (particularly in type i diabetes), diet control and exercise (particularly in I1 type diabetes) or both control of diabetes.

Impaired glucose metabolism (IGM) is defined as blood glucose levels and is higher than normal range but is not high enough to the diagnostic criteria of satisfying type 2 diabetes mellitus.Different between the sickness rate country variant of IGM, but usually than the frequent 2-3 of obvious diabetes doubly.Up to date, the IGM individuality is considered to prediabetes, but the individuality that the contention of several epidemiological study data has IGM risk aspect diabetes and cardiovascular morbidity and mortality rate is different.The data prompting has those people of individuality, the especially IGT of IGM always not develop into diabetes, but no matter whether they are diabetes, and their cardiovascular morbidity is all high with dead risk.In the IGM individuality, about 58% has impaired glucose tolerance (IGT), and in addition 29% has fasting glucose impaired (IFG), and 13% have two kinds unusual (IFG/IGT).As above discuss, the IGT hyperglycemia that (food back) raises with after the meal is a characteristic, and IFG is defined based on fasting blood sugar by ADA (seeing the following form).

1997 ADA (ADA) defined glucose tolerance normal (NGT), IGM and type 2 diabetes mellitus.

IGT in non-diabetic and diabetes as one independently risk factor this fact proved that from diabetes, separating it as new indication is reasonably, is beneficial to prevent and treat the morbidity and the death of cardiovascular and cancer.In addition; Stage in the blood glucose amount between the normal and type ii diabetes; Particularly rise the insulin stage; Become main focus, and strongly need to suppress or postpone type 2 diabetes mellitus and many cardiovascular and blood capillary disease and disease and the method for the cancer progression that is associated with IGM and particularly IFG and/or IGT.

Type ii diabetes is a PD, although and may command blood glucose when monotherapy is initial in some patients, itself and high secondary mortality interrelate.This high treatment mortality is the main contribution factor of a high proportion of long-term hyperglycemia related complication among the type ii diabetes patient.The treatment of single component possibly be overcome for the restriction of keeping glycemic control, at least in some patients, and at limited time phase, reduces with untenable blood glucose during the single component treatment to be implemented in for a long time through combining multiple oral medicine.Obtainable data are supported oral monotherapy failure among most of type 2 diabetes mellitus patients and are needed the conclusion of multiple Drug therapy.

But, because type ii diabetes is a PD, even there is the patient of good initial communication need increase dosage or further insulinize the most at last to conjoint therapy, because being difficult in, blood sugar level keeps stable for a long time.

Although conjoint therapy has the potentiality of improving glycemic control, it is not restriction.Many results show that hypoglycemic danger possibly increase with therapeutic alliance, and the needs of multiple medicine possibly reduce patient's compliance.In addition, take the interactional potential probability of pharmacokinetics that multiple hyperglycemia medicine has increased the other drug that possibly take with the patient.

The reasonable use of oral combination therapy maybe temporary delay the needs of injection of insulin repeatedly, promoted temporarily to keep hypoglycemia level or low GH (HbA1c) level and helped temporary transient prevention vascular complication.

The applicant find uncannily the DPP-IV inhibitor particularly LAF237 can be used for uniting use with antidiabetic compound; Particularly unite use with insulinize, to reduce because the antidiabetic compound serious hypoglycemia incident that causes of insulinize particularly.In addition, the long-term treatment of using this combination is for example made up than other, and combination of insulin dative row ketone has less significantly inconvenience.

Insulin is the known chemical compound that is used for the processing of treating diabetes property by FDA's approval.

Term " insulin " also refers to comprise described in any form such as the United States Patent (USP) 6620780 of insulin or derivatives thereof in this article.

The human islets of langerhans have three primary amino radical groups: the N-end group and the LysB of A-chain and B-chain ²⁹The epsilon-amino group.Substituted several insulin derivates are well known in the art in one or more groups of these groups.Therefore, United States Patent (USP) 3,528,960 (EIi Lilly) relate to N-carboxy arene acyl group insulin, and wherein one of insulin molecule, two or three primary amino radical groups have the carboxy arene acyl group.No specific N ^{ε B29}-substituted insulin is disclosed.

According to GB patent 1.492.997 (Nat.Res.Dev.Corp.), find at N ^{ε B29}Have the blood sugar reducing function characteristic of improvement by the substituted islets of langerhans of carbamoyl.

(Kodama Co. Ltd.) discloses wherein fatty acid and Phe to P publication application No.1-254699 ^B1Amino group or and Lys ^B29Epsilon-amino group or the two bonded insulin.The purpose of the derivatization of statement is to obtain acceptable, stable insulin preparation on the pharmacology.

Insulin, its B30 position have and can be described among the Japanese publication application 57-067548 (Shionogi) with the aminoacid of at least 5 carbon atoms of nucleotide triplet coding.Insulin analog requires to be used for diabetes, particularly owing to produce patient's the right of treatment of the insulin resistance of cattle or Iletin II (Lilly) antibody.

United States Patent (USP) 5; 359; 030 (Ekwuribe, Protein Delivery Inc.) have described and combine stable peptide composition to be used to comprise the oral or parenteral administration with the polypeptide of the polymer covalent coupling that comprises straight chain polyalkylene part and lipophilic portion; Said part is arranged relative to each other, and polypeptide has resistance in the body of improvement to enzymatic degradation.

It is the protein derivatives of formula [protein] [Z] n that EP 511600 A2 relate to, wherein [protein] expression have n amino residue each can be through remove an one of which hydrogen atom rather than amino group from amino deutero-protein.[Z] is the residue of being represented by formula-CO-W-COOH, and wherein W is a bivalence long chain hydrocarbon groups group, and it also can comprise some hetero atom, and n represents the average of amido link quantity between [Z] and [protein].Mentioned that the deutero-protein original shape of protein derivatives of the present invention and its compares quite long serum half-life is arranged, and it shows no antigen.Also should mention; Insulin is one of protein of the derivant that can prepare according to the present invention; But it is open in EP511600 not have concrete insulin derivates, and the preferred positions of also not having in preferred [Z] or [Z] should be introduced into so that obtain any sign of useful insulin derivates.

In this manual, whenever the term insulin is to use plural form, or in general sense, its objective is to comprise naturally occurring insulin and insulin analog and derivant thereof." insulin derivates " that this paper uses is meant the comprise Cys similar with human insulin ^A7And Cys ^B7And Cys ^A20And Cys ^B19Between disulfide bridge bond and Cys ^A6And Cys ^A11Between the polypeptide of inside disulfide bridge bond molecular structure, and insulin active is arranged.

Preferably, insulin is the solution that comprises from about 30nmol/ml to about 3000nmol/ml, or the form of the pharmaceutical composition of the about 600nmol/ml insulin solutions of 120nmol/ml to 1200nmol/ml.

The instance of insulin is:

NovoLog ([rDNA source] insulin aspart injection) is the human insulin analogue of quick acting, the outer blood glucose depressant of intestinal.The dosage of NovoLog should individuation and based on doctor's suggestion, confirm according to patient's needs.Total daily individual insulin requirement is usually at 0.5-1.0 unit/kg/ between day.When being used for the subcutaneous injection therapeutic scheme of meals-relevant, total insulin requirement of 50-70% can be provided by NovoLog, and is remainingly provided by middle effect or protamine zine insulin.Insulin glulisineAPIDRA ^TM(paddy relies insulin [rDNA source]) is the human insulin analog, and it is quick-acting, parenteral blood glucose depressant.Paddy relies insulin to use non-pathogenic laboratory strains escherichia coli (K12) preparation by recombinant DNA technology.Paddy relies that insulin is different with human insulin to be, replaced by lysine at the asparagine aminoacid of B3 position, and the lysine of B29 position is replaced by glutamic acid.Chemically, 3 ^B-lysine-29 ^B-glutamic acid-insulin human, empirical formula C ₂₅₈H ₃₈₄N ₆₄O ₇₈S ₆, molecular weight 5823.There is following packing in APIDRA 100 units/ml (U-100): 10mL bottle NDC0088-2500-33.The dosage of APIDRA should individuation and based on doctor's suggestion, confirm according to patient's needs.APIDRA should use in the therapeutic scheme that comprises protamine zine insulin or basal insulin analog usually.

Humalog (lispro, rDNA source) is the human insulin analogue of quick acting, the outer blood glucose depressant of intestinal.Chemically, it is Lys (B28), Pro (B29) human insulin analog, produces when putting upside down with 29 amino acids when 28 on insulin B-chain.

LANTUS

(insulin Glargine [rDNA source] injection) is the sterile solution that insulin Glargine is used as injection.Insulin Glargine is recombinant human insulin's analog (seeing clinical pharmacology) of long-acting (effect continues to reach 24-hour), parenteral blood glucose depressant.LANTUS uses non-pathogenic laboratory strains escherichia coli (K12) as producing the organism preparation by recombinant DNA technology.The asparagine aminoacid of the different A21 of being with insulin human of insulin Glargine position is replaced by glycine, and two arginine to be added in the C-of B-chain terminal.In the clinical research with the type 2 diabetes mellitus patient of oral antidiabetic thing treatment of not using insulin, LANTUS begins with 10IU mean dose once-a-day, and then according to patient's needs be adjusted to every day total dose range from 2 to 100IU.

Exubera is the short-acting insulin preparation that sucks; Indication is 1 type and type 2 diabetes mellitus patient's treatment, by Pfizer exploitation (insulin human [rDNA source]) inhalant powder).Exubera

is before being at table; Use palm Exubera

inhaler oral to be sucked into the quick-acting of pulmonary; The dry powder insulin human.

Term " DPP-IV inhibitor " is intended to refer to that the enzymatic activity to DPP-IV and function relevant enzyme shows for example 1-100% inhibition and keeps the molecule of substrate molecule effect especially, includes but not limited to glucagon-like-peptide-1, gastric inhibitory polypeptide, histidine MET peptides, P material, neuropeptide tyrosine and general at aminoterminal second molecule that comprises alanine or proline residue.Treat the persistent period that has prolonged the peptide substrates effect and improved its level complete, that do not degrade form with the DPP-IV inhibitor, cause the relevant BA of a series of and disclosed the present invention.

Because the substrate of DPP-IV comprises insulinotropic glucagon-like-peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), so DPP-IV can be used for controlling glucose metabolism.GLP-1 and GIP only just have activity when its complete form; Remove then inactivation of two aminoacid of its N-end.Use synthetic property DPP-IV inhibitor in the body and stop the N-end degraded of GLP-1 and GIP, cause the PC of these hormones higher, insulin secretion increases and so improve glucose tolerance.For this purpose, tested the ability of the CD26/DPP-IV enzymatic activity of chemical compound inhibition purification.In brief, measure its activity through the ability of the synthetic property substrate Gly-Pro-paranitroanilinum (Gly-Pro-pNA) of CD26/DPP-IV cutting at external (in vitro).DPP-IV is to the cutting releasing product paranitroanilinum (pNA) of Gly-Pro-pNA, and it speed occurs and is directly proportional with enzymatic activity.Through specific enzyme inhibitor inhibitory enzyme activity, the generation that slows down pNA.Between inhibitor and the enzyme effect strong more, the generation speed of pNA is slow more.Therefore the inhibition degree to the pNA accumulation rate is the direct tolerance of enzyme inhibition strength.Accumulation with spectrophotometer measurement PNA.Enzyme and the inhibitor of several kinds of variable concentrations and the inhibition constant K i that the substrate incubation is measured each chemical compound through fixed amount.

In context of the present invention, " DPP-IV inhibitor " also comprises its active metabolite and prodrug, like the active metabolite and the prodrug of DPP-IV inhibitor." metabolite " is the reactive derivative of the DPP-IV inhibitor that produces during by metabolism when the DPP-IV inhibitor." prodrug " is the chemical compound that is metabolised to the DPP-IV inhibitor or is metabolised to the metabolite identical with the DPP-IV inhibitor.In context of the present invention, " DPP-IV inhibitor " also comprises its officinal salt.

The DPP-IV inhibitor is known in the prior art.In following list of references, enumerated representational DPP-IV inhibitor.

The DPP-IV inhibitor usually and is particularly disclosed in following each document: for example in WO98/19998, DE19616 486 A1, WO 00/34241, WO 95/15309, WO 01/72290, WO 01/52825, WO 03/002553, WO 9310127, WO 99/61431, WO 9925719, WO 9938501, WO 9946272, WO 9967278 and WO 9967279.

In 33 below the patent applications preferred DPP-IV inhibitor is described; WO 02053548, particularly chemical compound 1001 to 1293 and embodiment 1 to 124; WO 02067918, particularly chemical compound 1000 to 1278 and 2001 to 2159; WO 02066627, particularly described embodiment; WO 02/068420, particularly all chemical compounds listed especially in the LXIII of example I and the analog of described correspondence, even describe in the preferred chemical compound table that is report IC50 2 (28), 2 (88), 2 (119), 2 (136); WO 02083128, such as in claim 1 to 5, and the chemical compound described of embodiment 1 to 13 and claim 6 to 10 particularly; US 2003096846, particularly specifically described chemical compound; WO 2004/037181, and particularly embodiment 1 to 33; WO0168603, the particularly chemical compound of embodiment 1 to 109; EP1258480, the particularly chemical compound of embodiment 1 to 60; WO 0181337, and particularly embodiment 1 to 118; WO 02083109, and particularly embodiment 1A is to 1D; WO 030003250, the chemical compound of embodiment 1 to 166 particularly, most preferably 1 to 8; WO 03035067, the chemical compound of particularly describing among the embodiment; The chemical compound that WO03/035057 particularly describes among the embodiment; US2003216450, particularly embodiment 1 to 450; WO 99/46272, particularly the chemical compound in the claim 12,14,15 and 17; WO 0197808, particularly the chemical compound of claim 2; WO 03002553, particularly the chemical compound of embodiment 1 to 33; WO 01/34594, the chemical compound of particularly describing among the embodiment 1 to 4; WO 02051836, and particularly embodiment 1 to 712; EP1245568, particularly embodiment 1 to 7; EP1258476, particularly embodiment 1 to 32; US 2003087950, particularly described embodiment; WO 02/076450, and particularly embodiment 1 to 128; WO 03000180, and particularly embodiment 1 to 162; WO 03000181, and particularly embodiment 1 to 66; WO 03004498, and particularly embodiment 1 to 33; WO 0302942, and particularly embodiment 1 to 68; US 6482844, particularly described embodiment; WO 0155105, the chemical compound of particularly listing among the embodiment 1 and 2; WO 0202560, and particularly embodiment 1 to 166; WO 03004496, and particularly embodiment 1 to 103; WO 03/024965, and particularly embodiment 1 to 54; WO 0303727, and particularly embodiment 1 to 209; WO 0368757, and particularly embodiment 1 to 88; WO 03074500, particularly embodiment 1 to 72, embodiment 4.1 to 4.23, embodiment 5.1 to 5.10, embodiment 6.1 to 6.30, embodiment 7.1 to 7.23, embodiment 8.1 to 8.10, embodiment 9.1 to 9.30; WO 02038541, and particularly embodiment 1 to 53; WO 02062764, and particularly embodiment 1 to 293, the chemical compound of preferred embodiment 95 (2-{{3-(amino methyl)-4-butoxy-2-neopentyl-1-oxo-1,2 dihydro-6-isoquinolyl } the oxygen base } acetamide hydrochloride); WO 0230890; Particularly 90 pages embodiment 1-1 to 1-109, embodiment 2-1 to 2-9, embodiment 3, embodiment 4-1 to 4-19, embodiment 5-1 to 5-39, embodiment 6-1 to 6-4, embodiment 7-1 to 7-10, embodiment 8-1 to 8-8, embodiment 7-1 to 7-7,91 to 95 pages embodiment 8-1 to 8-59, embodiment 9-1 to 9-33, embodiment 10-1 to 10-20; US 2003225102; The chemical compound of chemical compound 1 to 115, embodiment 1 to 121 particularly; Preferred compound is a) to z), aa) to az), ba) to bz), ca) to cz) and da) to dk), WO0214271, particularly embodiment 1 to 320; US 2003096857, the U.S. application serial no 09/788 that submit to February 16 calendar year 2001; The embodiment that 173 (agent's file LA50) particularly describe, embodiment that the embodiment that WO99/38501 particularly describes, WO99/46272 particularly describe and DE19616 486 A1 are val-pyr, val-Thiazolidine particularly; Isoleucine-Thiazolidine, the fumarate of isoleucine-pyrrolidine and isoleucine-Thiazolidine and isoleucine-pyrrolidine.

Preferred DPP-IV inhibitor comprises United States Patent (USP) 6124305 and US 6107317, international patent application, publication number WO 9819998, WO 9515309 and WO 9818763 disclosed specific embodiments; Such as 1 [2-[(5 cyanopyridines-2-yl) aminoethylamino] acetyl group-2-cyanic acid-(S)-pyrrolidine with (2S)-1-[(2S)-2 amino-3,3-dimethyl butyrate acyl group]-2-pyrrolidine nitrile.

In a more preferred embodiment, the DPP-IV inhibitor is N-peptidyl-O-aroyl-azanol or its officinal salt.Aroyl, for example, naphthyl carbonyl; Or it is unsubstituted or for example by lower alkoxy, low alkyl group, halogen or nitro list-or dibasic benzoyl preferably.The peptide base section preferably comprises two a-amino acids, for example glycine, alanine, leucine, phenylalanine, lysine or proline, the preferably proline that wherein directly is connected with the azanol nitrogen-atoms.

In various situation, particularly under the situation of end-product of compound claim and work embodiment, the subject content of end-product, pharmaceutical preparation and claim in these publications is incorporated herein the application as a reference.

WO 9819998 discloses N-(N '-substituted glycyl)-2-Cyanopyrolidine, particularly 1-[2-[5-cyanopyridine-2-yl] amino]-ethylamino] acetyl group-2-cyanic acid-(S)-pyrrolidine.

Preferred compound described in the WO03/002553 is listed on the 9th to 11 page, is introduced among the application as a reference.

DE19616 486 A1 disclose the fumarate (fumar salt) of val-pyr, val-Thiazolidine, isoleucyl--Thiazolidine, isoleucyl--pyrrolidine and isoleucyl--Thiazolidine and isoleucyl--pyrrolidine.

WO 0034241 and US 6110949 disclose the substituted adamantyl-amino of N--acetyl group-2-Cyanopyrolidine and W (substituted glycyl)-4-Cyanopyrolidine respectively.Interested DPP-IV inhibitor is cited those in the claim 1 to 4 particularly.

WO 9515309 discloses the aminoacid 2-Cyanopyrolidine amide substance as the DPP-IV inhibitor, and WO 9529691 discloses the peptide radical derivative of alpha-aminoalkyl phosphonic acid diester, particularly has those of proline or dependency structure.Interested DPP-IV inhibitor is table 1 cited those in 8 especially.

In WO 01/72290, interested DPP-IV inhibitor is cited those in embodiment 1 and claim 1,4 and 6 especially.

WO 01/52825 especially discloses (S)-1-{2-[5-cyanopyridine-2 base] amino } ethyl-glycyl }-2-cyanic acid-pyrrolidine or (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine (LAF237).

WO 9310127 discloses the borate proline as the DPP-IV inhibitor.Interested DPP-IV inhibitor is cited those in embodiment 1 to 19 especially.

Disclosed patent application WO 9925719 disclose sulphostin-a kind of through to streptomyces microorganism cultivate the DPP-IV inhibitor that makes.

WO 9938501 discloses the substituted 4-to 8-of N-unit heterocycle.Interested DPP-IV inhibitor is cited those in the claim 15 to 20 especially.

WO 9946272 discloses the phosphorus-containing compound as the DPP-IV inhibitor.Interested DPP-IV inhibitor is cited those in the claim 1 to 23 especially.

Other preferred DPP-IV inhibitor has the chemical compound of disclosed formula I, II or III among the 14th to 27 page of the patent application WO 03/057200.Most preferred DPP-IV inhibitor is at the 28th and 29 page of specifically described chemical compound.

Disclosed patent application WO 9967278 and WO 9967279 disclose the inhibitor of DPP-IV prodrug and A-B-C form, and wherein C is stable or unsettled DPP-IV inhibitor.

Preferably, N-peptidyl-O-aroyl azanol is the chemical compound of formula VII

Wherein

J is 0,1 or 2;

R _{ε 1}Expression natural amino acid side chain; With

R _{ε 2}Expression lower alkoxy, low alkyl group, halogen or nitro;

Or its officinal salt.

In a highly preferred embodiment of the present invention, N-peptidyl-O-aroyl azanol is the chemical compound of formula VIIa

Or its officinal salt.

People such as H.U.Demuth are at J.Enzyme Inhibition 1988, the 2 volume, the 129-142 page or leaf, and especially for example formula VII or VIIa and preparation thereof are described to N-peptidyl-O-aroyl azanol at the 130-132 page or leaf.

Preferred DPP-IV inhibitor is people such as Mona Patel (Expert Opinion InvestigDrugs.2003 April; 12 (4): 623-33) the 5th section, especially P32/98 described those, K-364, FE-999011, BDPX, NVP-DDP-728 etc., this publication is introduced into as a reference at this, especially described DPP-IV inhibitor.

The No.815541 (T 6666) that another preferred DPP-IV inhibitor is Tanabe.

Preferred DPP-IV inhibitor also is described in patent application WO 02/083128, the chemical compound of particularly describing among the embodiment 1 to 13, and US 6; 395; 767 embodiment 1 to 109 and WO03/033671, all specifically described chemical compounds are the chemical compound of chemical compound 1 to 393, the 67-70 page or leaf for example.

In the 14th page of patent application WO 95/15309, described FE-999011, its compound number is 18.

Another kind of preferred inhibitors is disclosed compd B MS-477118 (chemical compound of embodiment 60) in WO 2001068603 or United States Patent(USP) No. 6,395,767, its also be called as (1S, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxyl three ring [3.3.1.1 ^3,7] last of the ten Heavenly stems-the 1-yl)-the 1-oxoethyl]-2-azabicyclic [3.1.0] hexane-3-nitrile; Benzoate (1: 1) (shown in the formula M of patent application WO 2004/052850 page 2); With corresponding free alkali (1S, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxyl-three ring [3.3.1.1 ^3,7] last of the ten Heavenly stems-the 1-yl)-the 1-oxoethyl]-2-azabicyclic-[3.1.0] hexane-3-nitrile (M ') and monohydrate (M ") (shown in the formula M of patent application WO 2004/052850 page 3) thereof.Described compd B MS-477118 also is called as saxagliptin.

Another kind of preferred inhibitors is disclosed chemical compound GSK23A in WO 03/002531 (embodiment 9), also be called as (2S, 4S)-1-((2R)-2-amino-3-[(4-methoxy-benzyl) sulfonyl]-3-methylbutyryl base)-4-fluoropyrrolidine-2-nitrile hydrochlorate.

P32/98 (CAS number: 251572-86-8) also be called as 3-[(2S; 3S)-and 2-amino-3-methyl isophthalic acid-oxo amyl group] Thiazolidine; Can with 3-as follows [(2S, 3S)-2-amino-3-methyl isophthalic acid-oxo amyl group] Thiazolidine with (2E)-form of 2-butylene diacid salt/ester (2: 1) mixture is used

And in WO 99/61431,, be described by identical company with the title of Probiodrug and with the title of Compound P 93/01 among the 1253-1258 also at Diabetes 1998,47.

Other DPP-IV inhibitor very preferably has disclosed chemical compound in patent application WO 02/083128, the chemical compound described in claim 1 to 5.Most preferred DPP-IV inhibitor is a specifically described chemical compound in embodiment 1 to 13 and the claim 6 to 10.

Other DPP-IV inhibitor very preferably are such as Saxagliptin (BMS477118) by the disclosed chemical compound of Bristol-Myers Squibb.

In International Patent Application WO 02/076450 (especially embodiment 1 to 128) and Wallace T.Ashton (Bioorganic & Medicinal Chemistry Letters 14 (2004) 859-863), other DPP-IV inhibitor very preferably of the present invention is described, especially chemical compound 1 and in table 1 and 2 listed chemical compound.Preferred chemical compound is the chemical compound 21e (table 1) of following formula

In patent application WO 2004/037169 (especially embodiment 1 to 48) and WO 02/062764 (especially embodiment 1 to 293), other preferred DPP-IV inhibitor is described; Chemical compound 3-(amino methyl)-2-isobutyl group (isobuthyl)-1-oxo-4-phenyl-1 of more preferably in the 7th page, describing; 2-dihydro-6-isoquinolin Methanamide and 2-{ [3-(amino methyl)-2-isobutyl group-4-phenyl-1-oxo-1; 2-dihydro-6-isoquinolyl] the oxygen base } acetamide, in patent application WO2004/024184 (especially the reference implementation example 1 to 4), description is arranged also.

In patent application WO 03/004498 (especially embodiment 1 to 33), other preferred DPP-IV inhibitor is described the chemical compound of most preferred embodiment 7 described following formulas

It also is called as MK-0431 or sitagliptin MK-0431.Preferred day application dosage of sitagliptin 25 and 100mg between.

In patent application WO 2004/037181 (especially embodiment 1 to 33), also preferred DPP-IV inhibitor is described, most preferably at the chemical compound described in its claim 3 to 5.

Preferred DPP-IV inhibitor has the substituted adamantyl-amino of N--acetyl group-2-Cyanopyrolidine; N (substituted glycyl)-4-Cyanopyrolidine; N-(N '-substituted glycyl)-the 2-Cyanopyrolidine; N-aminoacyl Thiazolidine; N-aminoacyl pyrrolidine; L-not-the isoleucyl-Thiazolidine; L-Soviet Union-isoleucyl-pyrrolidine and L-not-the isoleucyl-pyrrolidine; 1-[2-[(5-cyanopyridine-2-yl) amino] ethylamino] acetyl group-2-cyanic acid-(S)-pyrrolidine; MK-431 and their officinal salt.Aforesaid P32/98), MK-0431,3-(aminomethyl)-2-isobutyl group-1-oxo-4-phenyl-1 most preferred DPP-IV inhibitor is selected from [S]-1-[2-(5-cyanic acid-2-pyridine amino) ethylamino] acetyl group-2-pyrrolidine nitrile mono-hydrochloric salts, (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine and L-threo form isoleucyl-thiazolidine (according to the chemical compound code of Probiodrug:; 2-dihydro-6-isoquinolin carboxylic acid amides and 2-{ [3-(aminomethyl)-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxygen base } acetamide and its optional pharmaceutical salts.

[S]-1-[2-(5-cyanic acid-2-pyridinylamino)-ethylamino] acetyl group-2-pyrrolidine nitrile mono-hydrochloric salts with (S)-1-[(3-hydroxyl-1-adamantyl)-amino] acetyl group-2-cyanic acid-pyrrolidine is respectively specifically disclosed among the embodiment 1 of embodiment 3 and WO 00/34241 of WO98/19998.DPP-IV inhibitor P32/98 (seeing above) is Diabetes 1998,47, and is specifically described among the 1253-1258.Can be made into preparation described in [S]-1-[2-(5-cyanic acid-2-pyridinylamino)-ethylamino] acetyl group-2-pyrrolidine nitrile mono-hydrochloric salts and (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine such as WO98/19998 the 20th page or the WO 00/34241.

Especially preferred is 1-{2-[(5-cyanopyridine-2-yl) amino] ethylamino of following formula } acetyl group-2 (S)-cyanic acid-pyrrolidine (being also referred to as [S]-1-[2-(5-itrile group-2-pyridinylamino) ethylamino] acetyl group-2-pyrrolidine nitrile mono-hydrochloric salts),

Especially (the S)-1-of its dihydrochloride and mono-hydrochloric salts and following formula [(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine (being also referred to as (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine, LAF237 or row spit of fland, Victor)

And L-Soviet Union-isoleucyl-Thiazolidine (as stated; Chemical compound code according to Probiodrug: P32/98), sitagliptin, GSK23A, saxagliptin, 3-(amino methyl)-2-isobutyl group-1-oxo-4-phenyl-1; 2-dihydro-6-isoquinolin Methanamide and 2-{ [3-(amino methyl)-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] oxygen base } acetamide and its pharmaceutical salts in any situation randomly.DPP728 and LAF237 respectively in the embodiment 1 of the embodiment of WO 98,/19,998 3 and WO 00/34241 by concrete open.At Diabetes 1998,47, among the 1253-1258 DPP-IV inhibitor P32/98 (on seeing) is specifically described.DPP728 and LAF237 can prepare as described in the 20th page of WO98/19998 or WO 00/34241 or the international patent application No.EP2005/000400 (application number).

Being introduced in the above-mentioned patent document as a reference disclosed any material at this all is considered to can be used as the DPP-IV inhibitor and comes embodiment of the present invention.

The DPP-IV inhibitor that the present invention uses separately can use with carrier.

Carrier among this paper is a kind of instrument (natural, synthetic, the peptide class peptide class, non-), for example transports predetermined substance and passes the protein that it is embedded in cell membrane wherein and gets into cell.Need to transport different materials with different carrier (natural, synthetic, the peptide class peptide class, non-), this is only to be used to discern perhaps material like the category of a kind of material because it is designed separately.

Can detect combining of DPP-IV and carrier with any detection means well known by persons skilled in the art, for example through labeled vector is detected.

Described DPP-IV inhibitor can be the peptide class or be preferably non-peptide class DPP-IV inhibitor.

Most preferably orally active DPP-IV inhibitor and pharmaceutical salts thereof.

Active component of the present invention (DPP-IV inhibitor) or its officinal salt can also be used with the form of solvate, like hydrate or comprise the solvate that is used for crystalline other solvent.

Find uncannily DPP-IV inhibitor or its salt, particularly LAF237 can be used for at least a antidiabetic compound (for example one or both antidiabetic compounds) particularly insulin combination use the severe hypoglycemia incident that causes with the treatment that reduces by antidiabetic compound particularly because the serious hypoglycemia incident that insulinize causes.Therefore in first embodiment; The invention provides the method that is used to reduce the severe hypoglycemia incident; Comprise particularly DPP-IV inhibitor or its salt of patient's administering therapeutic effective dose of insulinize to the patient who uses at least a antidiabetic compound (for example, one or both antidiabetic compounds) treatment.

Perhaps be used for reducing owing to use at least a antidiabetic compound (promptly; One or both antidiabetic compounds), comprise to the patient who uses the antidiabetic drug treatment particularly with DPP-IV inhibitor or its salt of patient's administering therapeutic effective dose of insulinize particularly because the hypoglycemia incident that causes of insulinize or the method for severe hypoglycemia incident.

Perhaps DPP-IV inhibitor or its salt and at least a antidiabetic compound (for example, one or both antidiabetic compounds) particularly insulin combination be used to produce the purposes of the medicine that reduces hypoglycemia incident or severe hypoglycemia incident.

Perhaps DPP-IV inhibitor or its salt are used for produce to reduce using the patient of at least a antidiabetic compound (for example one or both antidiabetic compounds) treatment particularly to make the patient's of insulinize the purposes of medicine of hypoglycemia incident or severe hypoglycemia incident.

Purposes as described herein, wherein hypoglycemia incident or severe hypoglycemia incident be owing to insulinize causes, i.e. the result of insulinize.

Purposes as described herein, wherein hypoglycemia incident or severe hypoglycemia incident be because treatment is promptly for example a kind of with antidiabetic compound, two or three be selected from metformin, Nateglinide, glitazone (preferably pioglitazone or rosiglitazone), sulfonylurea, GLP-1 or GLP-1 analog (preferably exendin-4), Cannabined receptor-1 (CB1) antagonist (preferably Rimonabant) and insulinize the result.When the patient treated with two kinds of antidiabetic compounds, combination can be; Metformin+sulfonylurea, metformin+lattice row ketone, metformin+GLP-1 analog, metformin+CB1 antagonist; Lattice row ketone+sulfonylureas, metformin+insulin, lattice row ketone+insulin; GLP-1 analog+sulfonylureas, sulfonylureas+insulin, or GLP-1 analog+insulin.

Term " hypoglycemia incident " " or " hypoglycemic episodes " be well known to those skilled in the art.Hypoglycemia is defined as the symptom that prompting confirms the low blood glucose of SMBG＜3.1mmol/L plasma glucose equivalent.Severe hypoglycemia is defined as any outbreak (low plasma glucose value＜3.1mmol/L is only if the seriousness of incident can not be carried out glucose assays) that needs the opposing party to assist.Therefore according to the present invention, term " severe hypoglycemia incident " is preferably to be defined as low plasma glucose value＜3.8mmol/L, preferably＜and the outbreak of 3.1mmol/L.

Preferably, the DPP-IV inhibitor be formula (I) (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine (LAF237 or row spit of fland, Victor)

Or its officinal salt.

In the present invention, term " (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine " or " LAF237 " or row spit of fland, Victor also refer to comprise its any salt or crystal form.

Preferred antidiabetic compound is selected from insulin signaling pathway regulator; The chemical compound that produces of the liver glucose of Protein-tyrosine-phosphatase (PTPases) inhibitor, non-micromolecule simulated compound and glutamine-D-fructose-6-phosphoric acid amide transferase (GFAT) inhibitor, influence imbalance for example; For example G-6-Pase (G6Pase) inhibitor, fructose-1; 6-diphosphatase (F-1,6-BPase) inhibitor, glycogen phosphorylase (GP) inhibitor, glucagon receptor antagonist and phosphoenolpy ruvate carboxy kinase (PEPCK) inhibitor, pyruvic dehydrogenase kinase (PDHK) inhibitor, insulin sensitivity reinforcing agent, insulin secretion stimulators, Alpha-glucosidase inhibitor, gastric emptying inhibitor, insulin and α ₂-1 adrenergic antagonists or CB1 cannabinoid receptor antagonists.

Used term " insulin sensitivity reinforcing agent " is meant and can strengthens the various pharmacologically active chemical compounds of tissue to the sensitivity of insulin among this paper.The insulin sensitivity reinforcing agent comprises for example inhibitor, retinoid-like X receptor (RXR) agonist, β-3AR agonist, UCP agonist, diabetes thiazolidinediones (glitazone (glitazone)), non-glitazone type PPAR gamma agonist, dual PPAR γ/PPAR alfa agonists, diabetes vanadium-containing compound and biguanide, the for example metformin of GSK-3.

The insulin sensitivity reinforcing agent is preferably selected from diabetes thiazolidinediones, diabetes vanadium-containing compound and metformin.

In a preferred embodiment, the insulin sensitivity reinforcing agent is a metformin.

Metformin extensively be used for reducing by writing out a prescription among the NIDDM patient blood glucose and with 500,750,850 and 1000mg specification listing.Yet because it is fugitive medicine, metformin needs twice of every day or three administrations every day (500-850mg tablet 2-3/ days or 1000mg took with meals in each two days).U.S. Patent number 3,174, in 901 disclosed biguanide antihyperglycemic metformin current in the U.S. with its hydrochlorate (Glucophage), Bristol-Myers SquibbCompany) the form listing.The preparation of metformin (dimethyl biguanide) and its hydrochlorate is a prior art and first by Emil A.Werner and James Bell, J.Chem.Soc.121, and 1922,1790-1794 is open.Metformin can be for example, with as with the administered of trade mark GLUCOPHAGE listing.

Mefformin increases in host's the peripheral tissues sensitivity to insulin.Mefformin also participates in suppressing glucose absorption, the inhibition glycogen heteroplasia from intestinal and suppressing fatty acid oxidation.The proper dosage scheme of Mefformin comprises the 500mg UD, every day 2 to 3 times, and can even be increased to every day 5 times or 850mg, every day 1 time or twice.[Martindale，TheComplete?Drug?Reference]。

Use some controlled release or the slow releasing preparation of antihyperglycemic example hydrochloric acid metformin to be confined to use foaming agent or gellant to control the release of medicine from dosage form.The instance of this research is instruction and the GLUCOPHAGE XR product insert of WO96/08243, and it is from the available controlled release metformin of Bristol-Myers Squibb product through commercial sources.GLUCOPHAGE (metformin hydrochloride tablet agent) should take with meals with broken dose, and GLUCOPHAGE XR (metformin hydrochloride prolongation release tablet) will be generally once a day, along with tuxedo is used.Metformin is preferably the form of metformin hydrochloride.

The term " metformin " that this paper uses refers to metformin or its pharmaceutically useful salt; Example hydrochloric acid salt, metformin (2: 1) fumarate; Other known melbine salts with disclosed metformin (2: 1) succinate, hydrobromate, right-chlorobenzene ethoxyacetic acid salt or embonate and single and two alkali carboxylic acids in the US application serial No. 09/262,526 of applying on March 4th, 1999; Comprise U.S. Patent number 3; Those disclosed in 174,901 all is called metformin together with all salt.The metformin that preferred this paper uses is Metformin, that is, and and with the Metformin (trade mark of Bristol-Myers SquibbCompany) of GLUCOPHAGE-D or GLUCOPHAGE XR listing.

In this context; " DPP-IV inhibitor ", " metformin ", " lattice row ketone " or any particular bin row ketone are intended to comprise its any pharmaceutically useful salt, crystal form, hydrate, solvate, diastereomer or enantiomer as " pioglitazone ", " rosiglitazone ".

Antidiabetic thiazolidinedione (lattice row ketone) is for for example; (S)-((3; 4-dihydro-2-(phenyl-methyl)-2H-1-.alpha.-5:6-benzopyran-6-yl) methyl-thiazolidine-2; 4-diketone (englitazone), 5-{ [4-(3-(5-methyl-2-phenyl-4-

azoles base)-1-oxopropyl)-phenyl]-methyl }-thiazolidine-2; 4-diketone (darglitazone), 5-{ [4-(1-methyl-cyclohexyl base) methoxyl group]-phenyl } methyl)-thiazolidine-2; 4-diketone (ciglitazone), 5-{ [4-(2-(1-indyl) ethyoxyl) phenyl] methyl }-thiazolidine-2; 4-diketone (DRF2189), 5-{4-[2-(5-methyl-2-phenyl-4-

azoles base)-ethyoxyl] } benzyl)-thiazolidine-2; 4-diketone (BM-13.1246), 5-(2-naphthyl sulfonyl)-thiazolidine-2; 4-diketone (AY-31637), two { 4-[(2; 4-dioxo-5-thiazolidinyl) methyl] phenyl } methane (YM268), 5-{4-[2-(5-methyl-2-phenyl-4- azoles base)-2-hydroxyl-oxethyl] benzyl }-thiazolidine-2; 4-diketone (AD-5075), 5-[4-(1-phenyl-1-cyclopropane carbonyl is amino)-benzyl]-thiazolidine-2; 4-diketone (DN-108), 5-{ [4-(2-(2,3-indoline-1-yl) ethyoxyl) phenyl methyl]-thiazolidine-2,4-diketone, 5-[3-(4-chloro-phenyl)]-2-propynyl }-the 5-phenyl sulfonyl } thiazolidine-2; 4-diketone, 5-[3-(4-chlorophenyl)]-2-propynyl)-5-(4-fluoro phenyl-sulfonyl) thiazolidine-2; 4-diketone, 5-{ [4-(2-(methyl-2-pyridine radicals-amino)-ethyoxyl) phenyl] methyl }-thiazolidine-2,4-diketone (rosiglitazone), 5-{ [4-(2-(5-ethyl-2-pyridine radicals) ethyoxyl) phenyl]-methyl } thiazolidine-2, [4-((3 for 4-diketone (pioglitazone), 5-{; 4-dihydro-6-hydroxyl-2; 5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-2-yl) methoxyl group)-phenyl]-methyl }-thiazolidine-2; 4-diketone (troglitazone), 5-[6-(2-fluoro-benzyloxy) naphthalene-2-ylmethyl]-thiazolidine-2; 4-diketone (MCC555), 5-{ [2-(2-naphthyl)-benzo

azoles-5-yl]-methyl } thiazolidine-2,4-diketone (T-174) and 5-(2,4-dioxo Thiazolidine-5-ylmethyl)-2-methoxyl group-N-(4-trifluoro acute pyogenic infection of nails base-benzyl) Benzoylamide (KRP297).

Specific lattice row ketone picture " pioglitazone ", " rosiglitazone " also are intended to comprise its any officinal salt, crystal form, hydrate, solvate, diastereomer or its enantiomer.

For with the PPAR antidiabetic, special lattice row ketone be applied to the maturity-onset diabetes patient (body weight: 50kg), for example, every day, dosage was generally 0.01 to 1000mg, preferred 0.1 to 500mg.This dosage can be used once and arrive several times every day.Especially, when pioglitazone hydrochloride was used as insulin sensitizers, every day, the dosage of pioglitazone hydrochloride normally 7.5 arrived 60mg, preferred 15 to 45mg.When troglitazone was used as insulin sensitizers, every day, the dosage of troglitazone was generally 100 to 1000mg, and preferred 200 to 600mg.When rosiglitazone (perhaps its maleate) was used as insulin sensitizers, every day, the dosage of rosiglitazone was generally 1 to 12mg, and preferred 2 to 12mg.

Lattice row ketone is preferably pioglitazone, pioglitazone hydrochloride, troglitazone or rosiglitazone (perhaps its maleate), preferred especially pioglitazone hydrochloride.

Monotherapy or with sulfonylureas, metformin or insulin combination treatment in; The dosage of ACTOS

(pioglitazone) will be no more than 45mg, once a day.The combination of ACTOS and metformin can be with 15mg or 30mg, begin once a day.Current metformin dosage can continue when initial ACTOS treats.The dosage of metformin can not since with the combination treatment of ACTOS in hypoglycemia and will need adjustment.ACTOS can obtain with the tablet of 15mg, 30mg and 45mg.

AVANDIA

(rosiglitazone) can be used as the single daily dose and uses or portioning and using with evening in the morning with the 4mg initial dose.For the patient who replys deficiency (like what measure through the minimizing of FPG) after 8 to 12 weeks of treatment, dosage can be used as monotherapy or is increased to 8mg every day with the metformin combination.The dosage of AVANDIA should be no more than 8mg every day, as single dose or be divided into twice of every day.AVANDIA can obtain with 2mg, 4mg and 8mg tablet.

Can also the combination that comprise the listing of metformin and thiazolidine diketone derivative used according to the invention.Particularly, can be with the administered rosiglitazone of for example pressing trade mark AVANDAMET

listing and the combination of metformin.Use the dosage of the anti-diabetic therapy of AVANDAMET and to be no more than 8mg/2, the maximum recommended daily dose of 000mg based on effectiveness and resistant individualsization.AVANDAMET

provide different types of tablet.Each tablet contains following rosiglitazone and metformin hydrochloride as maleate: 1mg/500mg, 2mg/500mg, 4mg/500mg, 2mg/1,000mg, 4mg/1,000mg.

Fei Gelie ketone type PPAR gamma agonist is N-(2-benzoyl phenyl)-L-tyrosine analog particularly, for example, and GI-262570 and JTT501.

Insulin secretion stimulators is the pharmacologically active chemical compounds with the characteristic that promotes pancreas beta cell excreting insulin.The instance of insulin secretion stimulators comprises glucagon receptor antagonist (on seeing), sulfonylurea derivant, incretin hormone, particularly glucagon class peptide-1 (GLP-1) or GLP-1 agonist, β cell imidazoline receptor antagonist and short-acting insulin succagoga; For example diabetes phenylacetic acid derivatives, diabetes D-phenylalanine derivative and T.Page etc. are in " Britain pharmacology journal (Br.J.Pharmacol.) 1997; 122, the BTS67582 described in the 1464-1468.

The sulfonylurea derivant is for example glisoxepide, glibenclamide, glibenclamide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, Phenbutamide or metahexamide; Preferred glimepiride or gliclazide.Tolbutamide, glibenclamide, gliclazide, glibornuride, gliquidone, glisoxepide and glimepiride respectively can its with trade mark RASTINON HOECHST ^TM, AZUGLUCON ^TM, DIAMICRON ^TM, GLUBORID ^TM, GLURENORM ^TM, PRO-DIABAN ^TMAnd AMARYL ^TMThe administered of selling.

GLP-1 is a kind of pancreotropic hormone protein, and it for example is recorded in W.E.Schmidt etc., " diabetes are of science " (Diabetologia) 28,1985,704-707 and US 5,705,483.Term " GLP-1 agonist " used among this paper is meant GLP-1 (7-36) NH ₂Variant and analog, it specifically is disclosed in US 5,120,712, US 5,118666, US 5,512,549, WO 91/11457 and C.Orskov etc., J.Biol.Chem.264 (1989) 12826.Term " GLP-1 agonist " is particularly including chemical compound GLP-1 (7-37) for example, in this chemical compound, and Arg ³⁶Carboxyl-terminal amide functional group by GLP-1 (7-36) NH ₂The Gly that molecule is the 37th replaces, and its variant and analog comprise GLN ⁹-GLP-1 (7-37), D-GLN ⁹-GLP-1 (7-37), acetyl group LYS ⁹-GLP-1 (7-37), LYS ¹⁸-GLP-1 (7-37) and especially GLP-1 (7-37) OH, VAL ⁸-GLP-1 (7-37), GLY ⁸-GLP-1 (7-37), THR ⁸-GLP-1 (7-37), MET ⁸-GLP-1 (7-37) and 4-imidazoles propiono-GLP-1.Also people such as preferred especially Greig is recorded in Diabetologia 1999,42, the GLP agonist analog exendin-4 among the 45-50.BYETTA (exendin-4) is first of new classification that is used for treating the type ii diabetes medicine; Be called the incretin analogies; And show many effects identical and at United States Patent (USP) 5,424 with human body incretin hormone glucagon-like-peptide-1 (GLP-1), require its right in 286.BYETTA is made into preparation and is used for using with fixed dosage oneself, and subcutaneous injection gives before breakfast and dinner.BYETTA will make the preparatory filling pen injector device of each dosage 5-mg and two kinds of each dosage 10-mg.

The antagonist of CB1 Cannabined receptor is such chemical compound, and its bind receptor but self lack the how primary ability of activated receptor.Therefore, antagonist can prevent or reduce the functional activation of receptor or must be stepped by agonist such as Annan and occupy (under there is situation in agonist).In some embodiments, the IC of antagonist ₅₀For about 1 μ M to about 1nM.In other embodiment, the IC of antagonist ₅₀Be about 0.1 μ M to 0.01 μ M, 1.0 μ M to 0.1 μ M or 0.01 μ M to 1nM.In some embodiments, the shared binding site on the competition of antagonist and agonist and the receptor combines.

First group of suitable cannabinoid CB 1 receptor antagonist is pyrazole derivatives.Patent application EP-A-576 357 and EP-A-658 546 have described the exemplary pyrazole derivatives that Cannabined receptor is had affinity.More particularly; Patent application EP-A-656354 discloses exemplary pyrazole derivatives and has required protection N-piperidino-5-(4-chlorphenyl)-1-(2; The 4-Dichlorobenzene base)-and 4-methylpyrazole-3-Methanamide or SR 141716 and officinal salt thereof, they have good affinity to the Cannabined receptor of maincenter.Exemplary CB1 receptor antagonist in addition is disclosed in U.S. Patent number 5,596,106, aryl benzo [b] thiophene and benzo [b] furan compound that it discloses blocking-up or has suppressed the mammal Cannabined receptor.Preferably, this cannabinoid antagonist has selectivity to the CB1 receptor, and it is to the IC of CB1 receptor ₅₀Be to the CB2 receptor 1/4th or lower, perhaps more preferably be IC to the CB2 receptor ₅₀1/10th, perhaps even more preferably be IC to the CB2 receptor ₅₀One of percentage.Each above-mentioned document all is incorporated herein by reference at this.

Be used for selectivity CB of the present invention ₁The other instance of antagonist compound includes, but is not limited to:

1) disclosed by Sanofi as selectivity CB ₁The diaryl pyrazole azole of receptor antagonist, representative example are for example at EP 0969835 or EP 1150961 (Central mediation of thecannabinoid cue:activity of a selective CB ₁Antagonist; SR 141716A PerioA; Rinaldi-Carmona M, Maruani J Behavioural Pharmacology 1996,7:1 (65-71)) in disclosed compound S R-141716A, SR-147778, SR-140098 and Rimonabant and related compound thereof; By the disclosed WIN-54461 of Sanofi-Winthrop (Cannabinoid receptor ligands:Clinical andneuropharmacological considerations relevant to future drug discoveryand development.Pertwee R G; Expert Opinion on Investigational Drugs1996,5:10 (1245-1253)).N-piperidino-5-(4-chlorphenyl)-1-(2, the 4-Dichlorobenzene base)-4-methylpyrazole-3-Methanamide of being used to prepare the medicine of treating dysorexia has been described (SR 141616-CAS number: 168273-06-1), its officinal salt and solvate thereof.SR 141616, (pINN: Rimonabant) be expressed from the next:

Rimonabant be described in especially among the EP-B-656354 or people's such as M.Rinaldi-Carmona article in (FEBS Lett., 1994,350,240-244).EP1446384 A1 has described the new polymorph of Rimonabant, and the preparation that comprises Rimonabant is described among the WO2003082256, and the purposes of Rimonabant in dysorexia is described among the WO99/00119.

2) as CB ₁The disclosed amino alkyl indole class of receptor antagonist, representational embodiment such as compound I odopravadoline (AM-630),

3) by Eli Lilly describe as selectivity CB ₁The substituted benzofuran of the aryl-aroyl of receptor antagonist; LY-320135 (Cannabinoid receptor ligands:Clinical andneuropharmacological considerations relevant to future drug discoveryand development.Pertwee R G for example; Expert Opinion on Investigational Drugs1996; 5:10 (1245-1253))

4) chemical compound of describing by Merck&Co; For example AM 251 and AM 281 (meeting: 31stAnnual Meeting of the Society for Neuroscience; San Diego, USA, 10-15.11.2001); And in for example U.S.2003-114495 or WO 03/007887 disclosed substituted imidazole radical derivative

5) by Aventis Pharma disclosed azetidine derivatives in for example WO 02/28346 or EP 1328269,

6) from CP-55940 (Comparison of the pharmacology andsignal transduction of the human cannabinoid CB1 and CB2 receptors, Felder C C, Joyce K E, the Briley E M of Pfizer Inc.; Mansouri J, Mackie K, Blond O; Lai Y, Ma A L, Mitchell R L; Molecular Pharmacology 1995,48:3 (443))

6 ') at patent application EP1622876, EP1622902, EP1622903, EP162290, EP1622909, EP1638570, EP1594872, EP1592691, EP1558615, EP1556373, EP1572662; The Pfizer chemical compound, particularly CP-945598 described in the specific embodiment of particularly wherein describing.

7) diaryl-pyrazine from Astra Zeneca-amide derivatives of in WO 03/051851 for example, describing,

8) from the ACPA and ACEA (" the Effects ofAM 251&AM 281 of Medical College of Wisconsin (Aberdeen); cannabinoid CB1 antagonists; on palatable food intakein lewis rats " J.Pharmacol.Exp.Ther.289, No 3,1427-33; 1999)

9) pyrazole derivatives of describing in WO 01/29007 for example by University of Connecticut,

10) from HU-210 (international pain EASD-the 9th boundary's international conference (part ii), Austria Vienna, the Dickenson A H of the Yissum R&D Co of Jerusalem Hebrew university; Carpenter K, Suzuki R, IDDB meeting report; 22-27 day in August, 1999) and HU-243 (Cannabinoid receptor agonists and antagonists, Barth F, CurrentOpinion in Therapeutic Patents 1998; 8:3 (301-313))

11) from O-823 (Drug development pipeline:O-585, O-823, O-689, O-1072, nonamines, Orgaix, Altropane Organix Inc, corporate communication, on August 10th, 1999 of Organix Inc.; The IDDb data base) with from O-2093 (" the A structure/activity relationship study on arvanil of Consiglio Nazionale delleRicerche, endocannabinoid and vanilloid hybrid. ", Marzo DV; Griffin G, PetrocellisL, Brandi I; Bisogno T; Journal of Pharmacology and ExperimentalTherapeutics 2002,300:3 (984-991))

12) the 3-alkyl of describing as cannabinoid receptor ligand-5,5 '-diphenyl-imidazole alkane diketone,

13) the current CB that is developing of Bayer AG ₁Antagonist compound (IDDb data base: corporate communication, on February 28th, 2002).

14) the CB1 receptor antagonist is according to U.S. Patent number 6,028, the pyrazole derivatives of 084 formula (I), and the document all is incorporated herein by reference at this.

15) U.S. Patent number 6,017, and 919 disclose and are used for another kind of suitable cannabinoid receptor antagonists of the present invention.These antagonisies have following general formula:

Wherein substituent group is as at U.S. Patent number 6,017, in 919 define, the document all is incorporated herein by reference at this.

16) CB1 cannabinoid antagonist is at U.S. Patent number 5,747,524 and in the calendar year 2001 Patent Application No. 2001/0053788A1 that announces of December 20 days, instruct have 4,5 of CB1-antagonist activities, a dihydro-1 h-pyrazole derivatives.

17) the CB1 receptor antagonist be in Patent Application No. 2001/0053788A1, instruct have 4,5 of a CB1-antagonist activities, dihydro-1 h-pyrazole derivatives, and be disclosed in formula (I) wherein especially.Patent Application No. 2001/0053788A1 is published in calendar year 2001 December 20 days and all be incorporated herein by reference at this.

18) be described in the CB1 receptor antagonist, the particularly chemical compound of embodiment 1-8 of WO2005049615.

19) be described in CB1 receptor antagonist, the particularly chemical compound of embodiment 1-99 among the WO2005047285.

20) CB1 receptor antagonist (the 4R)-3-(4-chlorphenyl)-4 of Solvay company exploitation, 5-dihydro-N-methyl-4-phenyl-N '-[[4-(trifluoromethyl) phenyl] sulfonyl]-1H-pyrazoles-1-carboximidamide (SLV 326-34 ^ThNeuroscience, Abs in October, 1009.4,2004) (WO0170700 A1):

Solvay CB1 receptor antagonist is described among the embodiment of patent application WO2005040130 A1, WO2005028456 A1, WO2005020988 A1, WO2004026301 A1, WO2003078413 A1, WO2003027076 A2, WO2003026648 A1, WO2003026647 A1, WO2002076949 A1, WO0170700 A1.

Required Rimonabant daily dose can depend on that for example mode of administration changes with treating sanatory seriousness in the embodiment of the present invention method.For Orally administered, the daily dose scope of pointed activating agent is about 1 to about 100mg, and for example 5 to 50mg or 5 to 20mg, easily applied once or use with the dosage that separates.

Preferably the patient of treatment suffers from hyperglycemia according to the present invention.

More preferably described patient suffers from the disease of the diabetes of being selected from, I type or insulin dependent diabetes mellitus (IDDM) (IDDM), II type or non-insulin-dependent diabetes mellitus (NIDDM), A type insulin resistant type, carbohydrate metabolism impaired (IGM), IFG (IFG) or impaired glucose tolerance (IGT).In preferred embodiments, described patient suffers from type ii diabetes or IGT.

In most preferred embodiment, DPP-IV inhibitor or its salt are added to patient's standard treating diabetes, and disease of patient is that diabetes can not fully be controlled with insulin or by a kind of, two or three antidiabetic compound by coverlet.It is well known to those skilled in the art estimating suitable disease control criterion, and is described in the document, for example annual by ADA (diabetic medicine treatment standard 2006-29:S4-42S) in the summary of treating diabetes.

This method or purposes are to be used in particular for preventing or to delay disease, the particularly cardiovascular relevant with type ii diabetes or IGT and the progress of blood capillary disease.

The invention still further relates to DPP-IV inhibitor or its salt be used for producing the patient be reduced in the patient that treats with at least a antidiabetic compound (for example, one or both antidiabetic compounds) or insulinize, particularly use at least a antidiabetic compound (for example one or both antidiabetic compounds) or only insulinize can not fully control (for example I1 diabetes mellitus type) promptly by the purposes of the medicine of hypoglycemia incident among at least a antidiabetic compound or the patient that only can not fully control with the insulin glucose level or severe hypoglycemia incident.

Preferably the present invention relates to DPP-IV inhibitor or its salt with at least a antidiabetic compound (a kind of, two or three antidiabetic compound) or insulin combination, be used for produce reducing with one or more antidiabetic compounds or only promptly do not used the purposes of the medicine of at least a antidiabetic compound (a kind of, two or three antidiabetic compound) or patient's (for example I1 diabetes mellitus type) the hypoglycemia incident only fully do not controlled with insulin diabetes or glucose level or severe hypoglycemia incident by abundant control with insulin.

Method as herein described or purposes, wherein 25 and 150mg between, preferably row spit of fland, Victor or its salt of 50mg or 100mg will be used, preferred every day (dosage every day).

In addition, as used herein, " dosage every day " meaning is the dosage that gives in during 24 hours.

Term " prevention " refers to use said combination to prevent the outburst of the disease that this paper mentions to healthy patients is preventative.In addition, term " prevention " refers to treat the patient in the early stage that is in this disease of treatment and uses this combination.

The patient that the term " delaying of progress " that this paper uses refers to treat the early stage that is in this disease of treatment uses combination, and like combination preparation or pharmaceutical composition, in said patient, the form in early stage of corresponding disease obtains diagnosis.

Term " treatment " is understood that to handle and look after the patient, and purpose is to struggle with disease, disease or obstacle.

As used herein, term " patient " is meant the animal that suffers from hyperglycemia or diabetes or IGM.Preferred animal is a mammal, such as Canis familiaris L., cat, horse, cattle and the mankind.Preferred patient is human.

Preferred in the art patient crowd is more than 45 years old at the age, most preferably more than 60 years old.

Can select correlation test model and scheme to confirm beneficial effect of the present invention fully those skilled in the relevant art.

The supervision of blood sugar condition like what implemented by patient and medical worker, is to know in this area, such as " blood sugar test in the diabetes---ADA " 200326:S106-108 that in treating diabetes, reports and hereinafter described.This publication is introduced this paper as a reference in full.

The technology summary that should consult ADA is to obtain further information (for example, Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan D, PetersonCM: the blood sugar test in the diabetes (technology summary).Treating diabetes 18:896-909,1995).

In in recent years, by the patient blood glucose being carried out oneself's supervision (SMBG) has revolutionary effect to diabetes.Use SMBG, have the patient of diabetes can work to realize and to keep specific blood glucose target.

The theme of SMBG is extensively discussed by the common recognition meeting of two ADAs; It provides the exhaustive overview (ADA: the self-monitoring of blood glucose (common recognition is discussed) of this theme; DiabetesCare 17:81-86; 1994-and-ADA: the self-monitoring of blood glucose (common recognition is discussed), Diabetes Care 10:93-99,1987).

For Most patients, SMBG has replaced glucose in urine and has detected.Patient's glucose in urine at home detects is by draining based on single, and the semiquantitative determination composition of the fixed quantity " piece " of 4-24h is collected in perhaps not too frequent pass through.Principle is that urine sugar value has reflected the average blood sugar during urine is collected.

Blood detects the useful information that diabetes treatments every day are provided with urine glucose detection and urine ketone.

But these tests can not in the time that continues, offer the patient and the medical worker is quantitative and blood sugar measured reliably.Glycosylated protein, mainly be the measurement of hemoglobin and serum albumin, increased the new yardstick that is used to estimate blood glucose.Use single measurement, each of these tests be the average blood sugar of several weeks and several months quantitatively, with the detection of this additional every day.

GH (GHb) detects:

GHb also refers to glycohemoglobin, GH, HbA _1c, or HbA ₁, be to be used to describe term from the stable minor hemoglobinin componentin normal human adults series of hemoglobin and the slow and non-enzymolysis formation of glucose.The GHb formation rate is with concentration of glucose is directly proportional on every side.Because erythrocyte can freely see through glucose, the GHb level in the blood sample provides 120 days the blood glucose in front of mean corpuscular vital stage historical.GHb has most accurately reflected front 2-3 month glycemic control situation.

Can there be many dissimilar GHb assay methods to be used for routine clinical laboratory, for example HbA _1cCan use ion exchange on Bio-Rad Diamat analyser, to measure through HPLC (HPLC).Use auxiliary affine method if observe haemoglobin variant or hemoglobin degrading peak.

For glycosylation composition, interference and the non-diabetic scope measured, method is significantly different.GH often is reported as hemoglobin A _1cHbA _1cBecome the preferred standard that is used to estimate glycemic control.In this test, " A1C detection " will use a technical term.

A1C detects and should in all diabeticss, routine carry out, and record controlling degree of blood sugar when initial evaluation at first is then as the part of continued treatment.Because A1C detects the average blood sugar level reflected during preceding 2-3 month, need to measure in per approximately 3 months once to confirm that patient's metabolism is controlled and whether reached and maintain in the target scope.

A1C detects the danger shown the development that is used for predicting the many chronic complicating diseases of diabetics, and uses the dangerous similar of the sick development of cholesterol determination predicting cardiovascular.

Glycosylation serum albumin (GSP)

Because (erythrocyte life cycle 120 days) much shorter is compared in Albumin's turnover (half-life 14-20 days) with hemoglobin; The glycosylation degree of serum albumin (mainly being albumin) provides the glycemic index shorter than the hemoglobin glycosylation time cycle; The measured value of total GSP and glycosylation serum albumin (GSA) is relative to each other well, and relevant good with the measured value of GH (A1C check).Can not carry out maybe can not using under the situation of (for example hemolytic anemia) in the A1C detection, GSP analyzes maybe be valuable in the evaluation of therapeutic scheme.The quantitatively total GSP of several method or total GSA have been described.One of the most widely used fructosamine that is called is measured.The numerical value of GSP changes along with the synthetic of the serum albumin that possibly take place in acute systemic disease or hepatopathy or the variation of removing.In addition, whether for fructosamine is measured to proofread and correct serum albumin or seralbumin concentration lasting dispute is arranged.

The blood sugar condition index in 1-2 week before the unitary determination of GSP provides, single A1C measures individual month the blood sugar condition index of time period, 2-3 that provides longer significantly simultaneously.

No matter specific analytical method, GSP mensuration not will be understood that with A1C and detect quite, because it only shows the glycemic control of short time period.Therefore, GSP measures and must carry out in every month to collect and the identical information of three to four times A1C mensuration in every year.Measure unlike A1C, it is relevant with the danger of the generation of chronic complicating diseases of diabetes and progress that GSP shows as yet.

It is that the doctor knows that the glucose level progress detects (for example, GSP analysis, A1C, insulin), and is for example reported by ADA in the art.

The present invention also relates to and is used for the for example therapeutic scheme of type ii diabetes of treating diabetes, wherein

1. the patient who selects insulinize and only fully do not control with insulin,

25 and 150mg between, (S)-1-of 50mg or 100mg [(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine or its salt preferably, quilt is applied to said patient every day with insulin combination.

The present invention also relates to and is used for the for example therapeutic scheme of the treatment of type ii diabetes of treating diabetes, wherein

1. select to use at least a antidiabetic compound (for example, a kind of, two or three) and only with the insulin abundant patient of control not,

In above-described therapeutic scheme; Term " every day "; Administration of insulin with (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine (Victor La Ting) or only use (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine (Victor La Ting), for example when the insulin pump of sending insulin dose every day or any relevant apparatus are housed in patient's body.

The present invention also relates to and is used for the for example therapeutic scheme of type 2 diabetes mellitus treatment of diabetes, wherein:

1) patient who selects to make insulinize and show the preferred severe hypoglycemia incident of hypoglycemic episodes,

2) 25 and 150mg between, (S)-1-of 50mg or 100mg [(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine preferably, quilt is applied to said patient every day with insulin combination.

1) select to use at least a antidiabetic compound (for example, a kind of, two or three) treatment and show the patient of the preferred severe hypoglycemia incident of hypoglycemic episodes,

2) DPP-4 inhibitor or its salt quilt are applied to said patient every day with insulin combination.

The present invention also relates to and is used for the for example therapeutic scheme of type 2 diabetes mellitus treatment of diabetes, wherein,

I) select to use at least a antidiabetic compound (for example, a kind of, two or three) treatment and show the patient of the preferred severe hypoglycemia incident of hypoglycemic episodes,

Ii) DPP-4 inhibitor or its salt quilt and at least a antidiabetic i) associating is applied to said patient every day.

I) patient who selects to use at least a antidiabetic compound treatment and show the preferred severe hypoglycemia incident of hypoglycemic episodes,

Ii) DPP-4 inhibitor or its salt quilt and at least a antidiabetic i) associating uses to said patient every day.

Iii) at least a antidiabetic compound i) dosage or daily dosage reduce until reaching required glucose level gradually.

2) 25 and 150mg between, (S)-1-of 50mg or 100mg [(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine or its salt preferably, quilt is applied to said patient every day with insulin combination.

3) dosage of insulin or daily dosage reduce the required glucose level that for example passes through the analysis of blood HbA1c level until reaching, i.e. blood sugar level gradually.

Ii) 25 and 150mg between, (S)-1-of 50mg or 100mg [(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine or its salt preferably, quilt and at least a antidiabetic compound i) associating is applied to said patient every day.

Iii) at least a antidiabetic compound i) it is blood sugar level that dosage or daily dosage reduce until the required glucose level that for example reaches the analysis through blood HbA1c level gradually.

Insulin, according to its delivery form for example twice of every day, once a day, per 2 or 3 days using regularly once by the sky.

According to " at least a antidiabetic compound " of the present invention for example twice of every day, once a day, per 2 or 3 days using regularly once by the sky.

2) 25 and 150mg between, (S)-1-of 50mg or 100mg [(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine or its salt preferably, quilt is applied to said patient every day with the insulin combination that reduces dosage.

Ii) DPP-4 inhibitor or its salt quilt and reduce at least a antidiabetic compound i of dosage) associating is applied to said patient every day.

Ii) 25 and 150mg between, (S)-1-of 50mg or 100mg [(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine or its salt preferably, quilt and reduce at least a antidiabetic compound i of dosage) associating is applied to said patient every day.

Therapeutic scheme described herein, wherein (S)-1-[(3-hydroxyl-1-adamantyl) amino] acetyl group-2-cyanic acid-pyrrolidine can be by those replacements particularly described herein of any other DPP-4 inhibitor, and the dosage concrete DPP-4 inhibitor that is suitable for selecting.

Therapeutic scheme described herein, method or purposes, wherein the DPP-4 inhibitor between 25mg and 200mg or its salt are applied to the patient who is treated by every day.Be applied in the every day of preferred sitagliptin 25 and 100mg between.

Therapeutic scheme described herein, method or purposes, wherein the DPP-4 inhibitor can be co-administered with other antidiabetic compound such as metformin, lattice row ketone (for example pioglitazone or rosiglitazone) or sulfonylureas.

Therapeutic scheme described herein, method or purposes, the patient who is wherein treated suffers from insulin dependent diabetes mellitus (IDDM) (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) or A type insulin resistant.

Therapeutic scheme described herein, method or purposes, wherein the DPP-4 inhibitor can with insulin or other antidiabetic compound such as a kind of, two or three be selected from metformin, Nateglinide, glitazone (preferably pioglitazone or rosiglitazone), sulfonylurea, GLP-1 or GLP-1 analog (preferably exendin-4), Cannabined receptor-1 (CB1) antagonist (preferably Rimonabant) antidiabetic compound and insulin combination and use.When the patient treated with two kinds of antidiabetic compounds, combination can be; Metformin+sulfonylurea, metformin+lattice row ketone, metformin+GLP-1 analog, metformin+CB1 antagonist, lattice row ketone+sulfonylureas, metformin+insulin, lattice row ketone+insulin, GLP-1 analog+sulfonylureas, sulfonylureas+insulin.

Incident serious hypoglycemia incident after insulin administration for example when the patient who preferably treats at the method or the quilt in the purposes of above description is suffering hyperglycemia and hypoglycemia.Most preferably suffer the patient of hyperglycemia to suffer from the disease of the diabetes of being selected from, type i diabetes or insulin dependent diabetes mellitus (IDDM) (IDDM), type ii diabetes or non-insulin-dependent diabetes mellitus (NIDDM), A type insulin resistant, IGM, IFG or IGT.In preferred embodiments, the patient suffers from type ii diabetes or IGT.In another preferred embodiment, by the patient that treated be disease for example hyperglycemia or glucose level only with insulin not by the patient of abundant control.In another preferred embodiment, be the for example patient that fully do not control with at least a antidiabetic compound of hyperglycemia or glucose level of disease by the patient that treated.

Do not comprise the DPP-4 inhibitor according to term of the present invention " at least a antidiabetic compound ".

The structure of the activating agent through code, common name or trade (brand) name sign can obtain from the manual of standards " Merck index (The Merck Index) " of current edition or obtain from data base such as PatentsInternational (for example IMS World Publications).Its corresponding contents is hereby incorporated by.Any technical staff in this area fully can the identified activity agent, and based on these with reference to making these activating agents and testing drug indication and characteristic in the standard testing model in vitro and in vivo.

Pharmaceutical preparation as herein described can be applied to Homoiotherm through intestinal (for example oral); All right per rectum or parenteral administration are in Homoiotherm, and wherein said pharmaceutical preparation only comprises medicine activity component or comprises medicine activity component and conventional medicine auxiliary substance.For example, pharmaceutical preparation is formed to about 80% reactive compound by about 0.1% to 90%, preferably approximately 1%.Be used for through intestinal or parenteral and can be unit dosage form for example, such as coated tablet, tablet, capsule or suppository and ampulla through the pharmaceutical preparation that eye is used.They can prepare in a manner known way, for example use conventional mixing, granulation, coating, solubilising or step of freeze drying.Therefore, the pharmaceutical preparation that is used to orally use can be through mixing reactive compound and solid excipient, with resulting granulating mixture (if necessary) and after adding suitable auxiliary substance mixture or granule being processed into tablet or coated cores (if desired or essential).

The dosage of reactive compound depends on multiple factor, such as mode of administration, Homoiotherm kind, age and/or individual state.

The preferred dose that the commerce of the active component of drug regimen can get according to the present invention is particularly treated the dosage that effective commerce can get.

The dosage of reactive compound depends on multiple factor, such as mode of administration, Homoiotherm species, age and/or individual state.

Corresponding active component or its officinal salt can also use the form of its hydrate or comprise and be used for crystalline other solvents.

Definite dosage will change with chemical compound, method of application and the needed treatment used natch.Chemical compound can any conventional approach, non-oral or preferred oral is used.

Usually, when the DPP-IV inhibitor particularly LAF237 can obtain satisfied result when using from about 0.01 to 50mg/kg daily dosage, more preferred dose scope from 0.1 to 50mg/kg.

Well describe with insulin or with the treatment of at least a antidiabetic compound is existing in the art.

For bigger animal, be from about scope of 0.01 to 100mg/kg, with every day 2 to 4 times, for example comprise from the unit dosage forms of the chemical compound of about 0.1 to about 50mg slow release form and use easily at chemical compound like pointed total daily dosage.

Preferably for the DPP-IV inhibitor particularly total daily dosage range of pointing out of LAF237 be 1 and 500mg between scope in, particularly 10 and 200mg between active component.

Another preferred DPP-IV inhibitor particularly LAF237 day oral dose be 1 and 100mg between preferably 10 and 100mg between 10mg for example, most preferably 25 and 100mg between for example 25mg or 30 or 40 or 50,61,70,90,100,150mg.LAF237 day oral dose very preferably is between 50mg and 100mg.

Be used for Orally administered suitable UD and comprise for example about 25, or about 25 to about 100mg DPP-IV inhibitor LAF237 particularly, such as preferably 25,50 or 100mg to about 200.Be used for the suitable dosage that intestinal uses outward and comprise for example about chemical compound of 1 to about 100mg, for example from 10 to 50mg.

But the DPP-IV inhibitor is every day or only per two days or administered twice weekly also.

Chemical compound can the mode similar with known standard be used, to be implemented in the purposes in these application.The suitable daily dosage of individual compound will rely on many factors such as its active relative intensity.Those skilled in the relevant art can confirm to treat effective dose fully.

Chemical compound of the present invention can free alkali or the administered of pharmaceutically acceptable acid addition or quaternary ammonium salt.These salt can prepare in a conventional manner and present the activity of same levels with free form.If these chemical compounds have for example at least a basic center, it can form acid-addition salts.Corresponding acid-addition salts can also be formed with other basic center if desired.There is the chemical compound (for example COOH) of acidic-group also can form salt with alkali.For example, bonded chemical compound can be rendered as sodium salt, maleate or dihydrochloride.Active component or its officinal salt can also hydrate form or the form that comprises other solvents that crystallization uses use.

Simultaneously, separately or the DPP-IV inhibitor that comprises free form or pharmaceutical acceptable salt that uses in regular turn and insulin or at least a (a kind of, two or three) antidiabetic compound with optional at least a, be one or more for example the combination preparation of two kinds of pharmaceutically suitable carrier be special " complete medicine box " in a sense; The DPP-IV inhibitor of component free form or pharmaceutical acceptable salt and insulin or at least a antidiabetic compound can be independently or the different preparations of the component through using distinguishing amount, i.e. different time points or administration simultaneously.The component of complete medicine box can be for example to the different piece of complete medicine box simultaneously or time interleaving ground, use with equal or different time intervals at different time point.Preferably, selection time makes the disease of treatment or the effect of disease at interval, and the each several part combination is used than only using the effect of any one acquisition in the component bigger.

The treatment effective dose of every kind of composition of combination of the present invention can simultaneously or be used in regular turn and with any order, and component can be used individually or with fixed combination.

Can mode known per se prepare according to pharmaceutical composition of the present invention; And be to be suitable for enteral, to be applied to mammal (homoiothermic animal) outward, to comprise the people such as oral or rectum and intestinal; It comprises the pharmaceutically active compounds of treating effective dose, particularly is suitable for pharmaceutically suitable carrier combination that enteral or intestinal are used outward individually or with one or more pharmaceutically suitable carrier.

In order further to illustrate the present invention, but not, following clinical research is provided with the mode of restriction.

Below through having described the present invention with reference to preferred embodiment, but be possible for one skilled in the art should appreciate that many interpolations, delete and changing, all are all in the scope of following claim.

This description is intactly quoted all patents and list of references as a reference.Under inconsistent situation, will comprise definition and explain preferentially with this description.

Embodiment 1

Clinical research

Use insulin to comprise the representative of hypoglycemia incident as antidiabetic compound.

Equivalence research can use other antidiabetic compounds (for example a kind of, two or three) to carry out to show the unexpected advantage of DPP-4 inhibitor requirement.

The testing program summary

Research topic

Multicenter, double blinding, at random, the 24 weeks treatment of parallel-group research LAF237 50 mg bid and placebo is as adding the effect of treatment in making the type ii diabetes patient of insulinize.

The research purpose:

This research design is used for confirming adding effectiveness and the safety of treatment the type 2 diabetes mellitus patient who makes insulinize with LAF237 50 mg bid.This research supports LAF237 conduct in the type 2 diabetes mellitus patient to ratify with the global registration of insulin combination treatment.

Purpose:

Main purpose: the HbAlc that treats after 24 weeks through check LAF237 50 mg bid reduces the hypothesis that surpasses placebo, confirms to add the effectiveness of treatment in the type ii diabetes patient of use insulin with LAF237 50 mg bid.

Secondary objective: key variables 1-reduces the hypothesis that fasting glucose (FPG) surpasses placebo through check with LAF237 50 mg bid 24 week back, confirms that LAF237 adds the effectiveness of treatment in making the type 2 diabetes mellitus patient of insulinize.

2-relatively has similar adverse events incident through showing after LAF237 50 mg bid add 24 weeks of treatment with placebo, confirms the safety of LAF237 in making the type 2 diabetes mellitus patient of insulinize.

3-through showing insulin dose every day average reduction and with LAF237 50 mg bid unite use every day injection of insulin quantity to be reduced in 24 weeks treatments back bigger than placebo, confirm to add the effectiveness of treatment in making the type 2 diabetes mellitus patient of insulinize with LAF237.

4-is bigger than placebo after the treatment of 24 weeks through the responsiveness that shows LAF237 50 mg bid, confirms that LAF237 adds the effectiveness of treatment in making the type 2 diabetes mellitus patient of insulinize.

5-is using insulin to stride across the inferior effectiveness of organizing among the type 2 diabetes mellitus patient who treats of baseline HbAlc in order to confirm that the LAF237 interpolation is treated, and whether after the treatment of 24 weeks, (use 50 mg bid to compare the reduction of HbAlc with placebo) with evaluation LAF237 better than low baseline patient (＜9%) therapeutic effect in high baseline HbAlc (＞9%) patient.

The exploration variable

1-improves beta cell function (with empty stomach proinsulin concentration, on an empty stomach proinsulin/insulin ratio and HPMA B is index) and the hypothesis that reduce insulin resistance (with FPI concentration and HOMA IR is index) in 24 weeks treatments back with respect to placebo through check LAF237 50mg bid, explores the mechanism of action of in making the type ii diabetes patient of insulinize, treating with the LAF237 interpolation.

2-through check LAF23750mg bid in 24 weeks treatments back with respect to placebo to fasting plasma lipid curve and body weight-neutral beneficial effect, explore LAF237 and add the auxiliary clinical benefit of treatment in the type 2 diabetes mellitus patient of use insulin.

3-treats the back with respect to the favourable influence of placebo to quality of life, patient satisfaction and work efficiency through showing LAF237 50mg bid in 24 weeks, explores LAF237 and adds the auxiliary clinical benefit of treatment in the type ii diabetes patient of use insulin.

The crowd: the type 2 diabetes mellitus patient that insulin is not fully controlled can be benefited from the reinforcement of its insulin administration scheme or through adding oral antidiabetic.In this research, before visit for the first time, in minimum 4 weeks of 0 unit of Insulin 3 every day, will be eligible for this research.

The crowd forms (infertile or use the birth control method of medical science authentication can not be conceived), HbA1c7.5-11% by the age 18 to 80 years old masculinity and femininity patient.

This is out-patient's multicenter study of carrying out at about 80 centers of US and European.To screen about 384 patients so that dissolve 192 patients at random.

Selected/exclusion standard

Inclusion criteria: masculinity and femininity (infertile or use the birth control method of medical science authentication can not the be conceived) patient of type 2 diabetes mellitus is arranged, front insulinize at least 3 months, the age 18 is to 80 years old, Body Mass Index 22-45kg/m ², HbA1c 7.5-11% (comprising), FPG_270mg/dL (15mmol/L) also agrees to keep current diet and exercise.

Exclusion standard: the women of pregnancy or suckling; The type i diabetes history, the acute metabolic diabetic syndrome in diabetes that the pancreatic injury causes or diabetes secondary form, in the past 6 months; The evidence of remarkable diabetic syndrome; In nearest 4 weeks, possibly influence the actute infection of glycemic control; The property reversed chamber speed, ventricular tachycardia, ventricular fibrillation; Percutaneous coronary in 3 months is got involved in the past; Myocardial infarction in 6 months, coronary bypass in the past, or unstable angina pectoris; Congestive heart failure NYHA level III or IV; 2 degree AV blocks (Mobitz1 and 2), 3 degree AV blocks, QTc prolongs; In nearest 5 years, comprise leukemia and lymphadenomatous cancerating; Hepatic disease; Acromegaly or growth hormone therapy; In nearest 3 months, use the treatment of any oral antidiabetic thing; The treatment of insulin pump; Long-term oral or parenteral corticosteroid treatment in nearest 8 weeks; Ia, Ib, Ic or the treatment of III class antiarrhythmic; Significant lab testing is unusual.Research and reference therapy:

Except insulinize, the patient is assigned in the double-blind treatment of LAF237 50mg bid or placebo in 1: 1 ratio.

Research design:

This be multicenter, at random, the research of double blinding, placebo control.At least 3 months the patient that type 2 diabetes mellitus is arranged of insulinize (HbA1C 7.5-11%) is eligible for test.Titular patient equally arrives LAF237 50mg bid group or placebo group at random except continuing it the insulinize.This insulin dose should be no more than 25% of baseline insulin dose with can adjusting but adjusting upward of clinical demonstration downwards.

Each patient participates in the screening visit (the-4 week) of once estimating selected/exclusion standard.Qualified patient accomplishes 5 further visits at the 2nd visit randomization (baseline, the 1st day) and during the treatment that LAF237 or the placebo in 24 weeks adds insulin then.

Efficiency evaluation:

Main efficiency evaluation: HbA1c; Less important efficiency evaluation: fasting plasma glucose; Empty stomach lipid (triglyceride; T-CHOL; The LDL that calculates, HDL, the non-HDL of calculating, the VLDL of calculating), body weight, beta cell function (proinsulin, proinsulin/insulin ratio, HOMA B) on an empty stomach on an empty stomach, insulin resistance (FPI, HOMA IR), average every day insulin dose, average every day injection of insulin number of times and responsiveness, made at least 3 months type ii diabetes patient of insulinize.

Other evaluations:

Safety evaluatio comprises adverse events, vital sign, physical examination laboratory evaluation (hematology, biochemistry and urinalysis) and electrocardiogram.Other evaluations comprise the quality of life application form.

Data analysis:

Be used to the hypothesis of checking LAF23750mg bid more superior than placebo, LAF237 and placebo combine with insulin, and the effect that is used to reduce HbA1c will be H ₀: δ _{LAF50mg bid}=δ _PlaceboTo Ha: δ _{LAF50mg bid}With δ _PlaceboDifference, wherein δ is the mean change of the baseline of the treatment group represented from subscript.Match variance analysis (ANCOVA) model comprises term, baseline HbA1c and the zone that is used to treat.For of the variation of each treatment group least square average (" adjustment average ") from baseline; In the difference of least square mean change between (LAF237 50mg bid-placebo) between two treatment groups, and bilateral 95% confidence interval of difference and obtain and demonstration from main analytical model for treatment p value relatively.Use the less important effectiveness variable of similar model evaluation.

Instruct the patient when any suspection hypoglycemia and the blood sugar detection of early implementing self-monitoring before the meal, at least 3 times weekly.Hypoglycemia is defined as the hypoglycemic symptom of being confirmed by SMBG＜3.1mmol/L plasma glucose equivalent of prompting.Serious hypoglycemia is defined as needs the auxiliary any outbreak of other party (low plasma glucose value＜3.1mmol/L is only if the seriousness of incident can not be carried out glucose assays).

Therefore according to the present invention, term " severe hypoglycemia " is preferably to define low plasma glucose value＜3.8mmol/L, preferably＜and the outbreak of 3.1mmol/L.

All laboratory evaluations are undertaken by central laboratory.HbA _1cWith the HPLC method with reference to (NGSP) 1 grade of certificate laboratory (bioanalysis research company [BARC]-EU of national glycolated hemoglobin standardized program (NGSP); Ghent; Belgium or Covance-US, Indianapolis is IN) or at NGSP network laboratories (diabetes diagnosis laboratory; Columbia, DCCT standard quantitative MO).Every other laboratory evaluation be by BARC-US (Lake Success, NY) or BARC-EU carry out.Analysis be according to standardization and through the program of checking according to the good laboratory enforcement of regulations.

The result:

Data acknowledgement LAF237 is associated with less severe hypoglycemia outbreak when adding to insulin.Only the patient of insulinize shows the particularly serious hypoglycemic episodes (1) of hypoglycemic episodes of remarkable high quantity.Patient with insulin and LAF237 treatment does not show any serious hypoglycemic episodes (1).

(1) 2 grade of hypoglycemia incident: blood glucose＜3.1 and symptom prompting hypoglycemia.

As if row spit of fland, Victor (LAF237) have protective effect to insulin-induced hypoglycemia.

Table 1 is presented at patient's quantity (A group) of experience one or many outbreak among the patient that row spit of fland, randomization Victor 50mg bid or placebo add insulin, the quantity (C group) that sum of outbreak (B group) and severe hypoglycemia are shown effect.In the group of row spit of fland, Victor, 33 patient reported amount to 113 incidents, wherein do not have the serious incident that promptly needs other party to help.In placebo group, 45 patient reported amount to 185 incidents, wherein 6 times is serious.Both hypoglycemia incident quantity and matters of aggravation quantity statistics the row spit of fland group lower (based on the X 2 test of two Poisson probability, being respectively P＜0.001 and P=0.032) in the Victor with learning remarkable meaning.

Group	Victor row spit of fland+insulin, patient's quantity	Placebo+insulin, patient's quantity
			A	?33	?45
B	?113	?185
			C	?0	?6

Table 1: in the quantity of reporting the patient of any hypoglycemic episodes (A group) with row spit of fland, Victor 50mg bid (n=144) or during placebo (n=152) 24 weeks of treatment, the quantity (C group) of report hypoglycemic episodes sum (B group) and severe hypoglycemia outbreak is compared with placebo ^*P＜0.05), ^{* *}P＜0.001.

In addition, insulin dose can reduce in the patient who uses the LAF237 treatment.

Claims

1.DPP-IV inhibitor or its salt are used for producing, and hyperglycemia, diabetes, insulin dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus, A type insulin resistant, carbohydrate metabolism are impaired suffering from of treating with insulin, the patient of IFG or impaired glucose tolerance reduces the purposes of the medicine of hypoglycemia incident or severe hypoglycemia incident, wherein the DPP-IV inhibitor is row spit of fland, Victor or its salt.

2. according to the purposes of claim 1, row spit of fland, wherein said Victor and insulin are simultaneously or use in regular turn and with any order.

3. according to the purposes of claim 1, wherein the amount used every day of Victor row spit of fland 25 and 150mg between.

4. according to the purposes of claim 1, wherein said patient treats with other a kind of, two or three antidiabetic compound.

5. according to the purposes of claim 4, wherein said other antidiabetic compound is selected from metformin, Nateglinide, glitazone, sulfonylurea, GLP-1 or Exendin-4 and Cannabined receptor-1 antagonist.

6. according to the purposes of claim 4; Wherein said patient is with being selected from metformin and sulfonylurea; Metformin and Ge Lie ketone, metformin and Exendin-4, metformin and CB1 antagonist; Lattice row ketone and sulfonylureas, and other two kinds of antidiabetic compounds treatment of Exendin-4 and sulfonylureas.

7. according to the purposes of claim 1, wherein said hypoglycemia incident or severe hypoglycemia incident are caused by insulinize.

8. according to the purposes of claim 1, wherein said hypoglycemia incident or severe hypoglycemia incident are caused by at least a antidiabetic compound treatment.

9. according to the purposes of claim 5, wherein said lattice row ketone is pioglitazone or rosiglitazone.