CN101195613A

CN101195613A - Compound with substituted tetratomic ring structure and medicine use thereof

Info

Publication number: CN101195613A
Application number: CNA2006101191092A
Authority: CN
Inventors: 王明伟; 陈德溯; 李娜; 刘青; 廖嘉渝
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2006-12-05
Filing date: 2006-12-05
Publication date: 2008-06-11
Anticipated expiration: 2026-12-05
Also published as: WO2008067711A1; CN101195613B

Abstract

The invention provides a compound with a substituted four-membered ring structure represented as formula I or II, relative pharmacy acceptable salt, ester, solvent and metal complex, or prodrug with same pharmacologia function, and ra elative application of being glucagon-like peptide-1 receptor modulator to prevent and/or treat metabolic disorder (as diabetes, insulin resistance and obesity or the like), cardiovascular disease and neurodegenerative disease (as Alzheimer's) or the like.

Description

One class has compound and the medical usage thereof that replaces the tetra-atomic ring structure

Technical field

The present invention relates to a class has the compound that replaces the tetra-atomic ring structure (Glucagon like peptide-1 receptor, GLP-1R) conditioning agent is at the medical usage that prevents and/or treats metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc. as pancreas hyperglycemia sample peptide-1 receptor.

Background technology

Carbohydrate metabolism disturbance, particularly diabetes have become the principal disease of modern society's serious threat human health and life.It is predicted that whole world diabetic subject just with the speed increase in every year 6%, has 3.2 hundred million patients (China is 6,000 ten thousand people, occupies second) to the year ends 2006.Diabetes are one group of clinical syndromes that caused by the h and E factor interaction, mainly be divided into 1 type and 2 types, wherein the basic pathology physiology of type 1 diabetes is the absoluteness hypoinsulinism, and clinical treatment is based on supplementation with insulin, so be called insulin-dependent diabetes mellitus again.Diabetes B accounts for more than 95% of ill colony, clinical study finds that most diabetes B patients can synthesize normal even excessive Regular Insulin, but because of the susceptibility reduction (also claim " insulin resistant ") of target cell to Regular Insulin, cause the Regular Insulin relative deficiency, be called non insulin dependent diabetes again.Insulin resistant is the key factor in diabetes B generation and the evolution.The medicine of diabetes B comprises sulfourea, biguanides, other euglycemic agents and assist measure etc.After the receptors bind of sulfonylureas drugs for diabetes thing and pancreatic beta cell film, close potassium-channel, the blocking-up efflux of K+ ions causes the cytolemma depolarize, impels Ca ²⁺Channel opener causes the outer flow of calcium ions of born of the same parents, after intracellular free calcium level increases, triggers the release of Regular Insulin.Be divided into for two generations by its priority of coming out, the first-generation such as toluene sulphur third urea, the s-generation comprises Glyburide (glyburide), gliclazide (diamicron), Glipizide (minidiab) and gliquidone (Glurenor) etc.Biguanide antidiabetic medicament energy depress appetite, increase Regular Insulin combines with acceptor, promotes the anaerobic glycolysis of cell to glucose, suppresses tissue respiration, suppresses the liver glycogen heteroplasia.Mainly contain N1,N1-Dimethylbiguanide, phenformin and buformin etc.Other antidiabetic drugs comprise that mainly thiazolidinediones (Thiazolidinediones) medicine (for example troglitazone, rosiglitazone, pioglitazone etc.), β 3-adrenoceptor conditioning agent, glucagon receptor antagonist, fatty acid metabolism disturb medicine, alpha-glycosidase Depressant (for example acarbose, voglibose, miglitol etc.) and aldose reductase inhibitor etc.

Glucagon-like peptide-1 receptor (Glucagon like peptide-1receptor, GLP-1R) belong to the category-B type g protein coupled receptor (G protein-coupled receptor, GPCR).When body is taken in nutritive substance, intestines peptide hormone-glucagon-like-peptide-1 (Glucagon like peptide-1 that enteroendocrine cell discharges, GLP-1), by with the GLP-1R high degree of specificity combine and make its activation, stimulate insulin secretion, the generation of glucagon suppression makes the postprandial blood sugar reduction and maintains constant level.Under the physiological condition, the effect that GLP-1 stimulates insulin secretion depends on blood sugar concentration, can hypoglycemia not take place because of continuous release.GLP-1 also has propagation and the differentiation that promotes the β cell, and dysfunction of nervous regulation, postpones stomach emptying, reduces appetite.External, and the class β cell that GLP-1 can promote embryonic stem cell to be divided into to have insulin secretion function (J Endocrinol.2005,186:343-52).GLP-1 acts on maincenter and can promote cell survival and reduce apoptosis, reduce the neural poison of beta amyloid peptide, suppress the process of nerve retrograde affection and promote learning and memory, so the someone proposes GLP-1 is used for treatment (the Ann N Y Acad Sci of Alzheimer ' s disease recently, 2004,1035:290-315; Nat Med, 2003,9:1173-1179; Curr Alzheimer Res, 2005,2:377-385; J Pharmacol Exp Ther, 2002,302:881-888).In addition, GLP-1 also plays an important role in cardiovascular systems.It has the effect that brings high blood pressure down with vasodilation, and acute injection GLP-1 can improve the contractile function of left ventricle in the myocardial hypertrophy experiment.It can also alleviate myocardial cell's damage (J.Hypertens, 2003,21:1125-1135 under dabbling again situation behind the myocardial ischemia; Am J Physiol Endocrinol Metab, 2004,287:E 1209-E 1215; Circulation, 2004,110:955-961; Diabetes, 2005,54:146-151).Because above-mentioned clear and definite physiological effect, since the mid-80 was found this target spot, the small molecules agonist of seeking GLP-1R was the research focus of international many new drug development mechanism.

All at exploitation GLP-1 class original new drug, (commodity are called Liraglutide to the GLP-1 derivative of developing as Denmark NovoNordisk company to internationally famous transnational pharmaceuticals of many families; Enter phase iii clinical trial) and GLP-1 analogue Exendin-4 (the trade(brand)name Exenatide that develops jointly of U.S. Amylin pharmaceuticals and Li Lai company; In last Apr approval listing, this year, sales volume was estimated to exceed 1,000,000,000 dollars).Except GLP-1 and polypeptide analog thereof, still there is not the report that any relevant non-peptide micromolecular GLP-1R agonist is succeedd and developed at present.Because polypeptide drugs inconvenience is oral, seek non-peptide class GLP-1R conditioning agent, the antidiabetic thing that exploitation has independent intellectual property right is the direction of the common concern of present many new drug research institutes of mechanism.

Summary of the invention

Compound that a class replaces the tetra-atomic ring structure by having of representing of following general formula I or II and pharmaceutically acceptable salt, ester, solvate, metal complexes or have the prodrug of identical pharmacological action have been the object of the present invention is to provide;

Another object of the present invention is to provide a kind of pharmaceutically pharmaceutical composition of acceptable salt, ester, solvate or metal complexes of the compound represented by following general formula I or II or its that contains;

Another purpose of the present invention be to provide the compound represented by following general formula I or II or its pharmaceutically acceptable salt, ester, solvate or metal complexes as pancreas hyperglycemia sample peptide-1 receptor regulator at the medical usage that prevents and/or treats metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc.

The invention provides pancreas hyperglycemia sample peptide-1 receptor regulator, increased the member who prevents and/or treats metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases medicines such as (as Alzheimer ' s diseases).The present invention relates to have a compound that replaces the tetra-atomic ring structure by what following general formula I or II represented, or acceptable salt, ester, solvate, metal complexes or have the prodrug of identical pharmacological action on its pharmacology:

Or

Described compound comprises solid and the optical isomer that they are all.

Wherein X and Y are respectively (CH ₂) _n, n is 0-2; O; S or NH.

R wherein ₁, R ₂Be following any one substituting group independently of one another: hydrogen; Halogen; Alkyl; Cycloalkyl; Hydroxyl; Nitro; Carboxyl; Aldehyde radical; Alkoxyl group; Amido; The amine alkyl; Amide group; Carbonamido; Sulfydryl; Alkylthio; Ether; Thioether; Replace or unsubstituted aryl; Replace or the unsubstituted pyridine base; Replace or unsubstituted furyl; Replace or unsubstituted pyranyl; Replace or unsubstituted thienyl; Perhaps, replacement or unsubstituted pyrryl.

R ₃, R ₄Be following any one substituting group independently of one another: hydrogen; Alkyl; Cycloalkyl; Alkoxyl group; Amido; The amine alkyl; Amide group; Carbonamido; Alkylthio; Replace or unsubstituted aryl; Replace or the unsubstituted pyridine base; Replace or unsubstituted furyl; Replace or unsubstituted pyranyl; Replace or unsubstituted thienyl; Replace or unsubstituted pyrryl.

Preferably, the compound for above-mentioned general formula I or II is characterized in that: X, Y are respectively (CH ₂) _n, n is 0-2; O; S or NH, R ₁, R ₂Independently be separately respectively:

R wherein ₅Be following any one substituting group: H; C ₁-C ₆Alkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyl; C ₂-C ₆Thiazolinyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Thiazolinyl; C ₂-C ₆Alkynyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Alkynyl; C ₃-C ₆Cycloalkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C ₁-C ₆Alkyloyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyloyl; C ₂-C ₆Enoyl-; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Enoyl-; C ₂-C ₆The alkynes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆The alkynes acyl group; C ₃-C ₆The cycloalkanes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X ₁Be (CH ₂) _n, n is 0-2; O; When S or NH;

R ₃, R ₄Be respectively:

R wherein ₆Be following any one substituting group: H; C ₁-C ₆Alkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyl; C ₂-C ₆Thiazolinyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Thiazolinyl; C ₂-C ₆Alkynyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Alkynyl; C ₃-C ₆Cycloalkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C ₁-C ₆Alkyloyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyloyl; C ₂-C ₆Enoyl-; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Enoyl-; C ₂-C ₆The alkynes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆The alkynes acyl group; C ₃-C ₆The cycloalkanes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X ₂Be (CH ₂) _n, n is 0-2; O; S or NH;

Perhaps R ₃, R ₄Be respectively:

R wherein ₇, R ₈Independent separately is following any one substituting group: H; C ₁-C ₆Alkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyl; C ₂-C ₆Thiazolinyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Thiazolinyl; C ₂-C ₆Alkynyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Alkynyl; C ₃-C ₆Cycloalkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C ₁-C ₆Alkyloyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyloyl; C ₂-C ₆Enoyl-; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Enoyl-; C ₂-C ₆The alkynes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆The alkynes acyl group; C ₃-C ₆The cycloalkanes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X ₁Be (CH ₂) _n, n is 0-2; O; S or NH; X ₂Be (CH ₂) _n, n is 0-2; O; S or NH;

Perhaps R ₃, R ₄Be respectively:

R wherein ₉Be following any one substituting group: H; C ₁-C ₆Alkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyl; C ₂-C ₆Thiazolinyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Thiazolinyl; C ₂-C ₆Alkynyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Alkynyl; C ₃-C ₆Cycloalkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C ₁-C ₆Alkyloyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyloyl; C ₂-C ₆Enoyl-; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Enoyl-; C ₂-C ₆The alkynes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆The alkynes acyl group; C ₃-C ₆The cycloalkanes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X ₂Be (CH ₂) _n, n is 0-2; O; S or NH;

Perhaps R ₃, R ₄Be respectively:

R wherein ₁₀, R ₁₁Independent separately is following any one substituting group: H; C ₁-C ₆Alkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyl; C ₂-C ₆Thiazolinyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Thiazolinyl; C ₂-C ₆Alkynyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Alkynyl; C ₃-C ₆Cycloalkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C ₁-C ₆Alkyloyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyloyl; C ₂-C ₆Enoyl-; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Enoyl-; C ₂-C ₆The alkynes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆The alkynes acyl group; C ₃-C ₆The cycloalkanes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X ₁Be (CH ₂) _n, n is 0-2; O; S or NH; X ₂Be (CH ₂) _n, n is 0-2; O; S or NH.

Perhaps, work as R ₁, R ₂Independently be separately respectively:

R wherein ₁₂, R ₁₃Independent separately is following any one substituting group: H; C ₁-C ₆Alkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyl; C ₂-C ₆Thiazolinyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Thiazolinyl; C ₂-C ₆Alkynyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Alkynyl; C ₃-C ₆Cycloalkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C ₁-C ₆Alkyloyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyloyl; C ₂-C ₆Enoyl-; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Enoyl-; C ₂-C ₆The alkynes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆The alkynes acyl group; C ₃-C ₆The cycloalkanes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X ₁Be (CH ₂) _n, n is 0-2; O; S or NH; X ₂Be (CH ₂) _n, n is 0-2; O; When S or NH;

R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

In addition more preferably, work as R ₁, R ₂Independently be separately respectively:

R wherein ₁₄Be following any one substituting group: H; C ₁-C ₆Alkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyl; C ₂-C ₆Thiazolinyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Thiazolinyl; C ₂-C ₆Alkynyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Alkynyl; C ₃-C ₆Cycloalkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C ₁-C ₆Alkyloyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyloyl; C ₂-C ₆Enoyl-; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Enoyl-; C ₂-C ₆The alkynes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆The alkynes acyl group; C ₃-C ₆The cycloalkanes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X ₁Be (CH ₂) _n, n is 0-2; O; When S or NH;

R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Work as R ₁, R ₂Independently be separately respectively:

R wherein ₁₅, R ₁₆Independent separately is following any one substituting group: H; C ₁-C ₆Alkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyl; C ₂-C ₆Thiazolinyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Thiazolinyl; C ₂-C ₆Alkynyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Alkynyl; C ₃-C ₆Cycloalkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C ₁-C ₆Alkyloyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyloyl; C ₂-C ₆Enoyl-; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Enoyl-; C ₂-C ₆The alkynes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆The alkynes acyl group; C ₃-C ₆The cycloalkanes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X ₁Be (CH ₂) _n, n is 0-2; O; S or NH; X ₂Be (CH ₂) _n, n is 0-2; O; When S or NH,

R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

In addition preferably, this compounds or its acceptable salt on pharmacology is the form with pharmaceutical composition, or separately, or with pharmacology on acceptable carrier or vehicle unite and provide.The present invention also provides the medicine that comprises above-claimed cpd, is used to prevent and/or treat metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc.

Again on the one hand, the present invention relates to prevent and/or treat the method for metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc.This method comprises needs or is ready the object of receiving treatment or preventing, give significant quantity, optionally regulate acceptable salt on the compound of glucagon-like peptide-1 receptor or its pharmacology, with prevention or treat above-mentioned disease or symptom.Preferably, above-mentioned metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc. by giving significant quantity the compound that replaces the tetra-atomic ring structure by having of representing of following general formula I or II or its pharmacology on acceptable salt, ester, solvate, metal complexes or have the prodrug of identical pharmacological action:

Or

Described compound comprises solid and the optical isomer that they are all.

Wherein X and Y are respectively (CH ₂) _n, n is 0-2; O; S or NH.

On the other hand, the present invention relates to combined preparation, this combined preparation comprises a kind of selectivity adjusting glucagon-like peptide-1 receptor that has, especially activate the compound of this receptor function, or acceptable salt on its pharmacology, or separately, or with pharmacology on acceptable carrier or excipient composition exist.This compound has the structure of following general formula I or II:

Or

And all solids and optical isomer, perhaps have prodrug, its ester, its solvate or its metal complexes of identical pharmacological action with it.

Wherein X and Y are respectively (CH ₂) _n, n is 0-2; O; S or NH.

The invention provides the medicine box that comprises above-mentioned combined preparation.The present invention also further provides the above-mentioned combined preparation of application to be used to prevent and/or treat metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc., reach the optionally drug effect of exciting glucagon-like peptide-1 receptor, improve patient's symptom and quality of life.

In order to illustrate summary of the invention and not limited to by it, invention is divided into following trifle is described in detail.

The A definition

Unless otherwise defined, technology that the present invention is used and scientific term have same meaning with the general understanding of the current techique in field under the present invention.All patents that derive from gene pool and other databases that this place mentions, application, the application of announcement and other publications and sequence are quoted as a reference by comprehensive income.If all patents that derive from gene pool and other databases of definition that this section is illustrated and this patent ginseng usefulness, application, the definition that the application of announcing and other publications and sequence are taken in and quoted is set forth opposite, or when inconsistent, the definition of illustrating with this section is as the criterion.

Used herein, " one " or " one " refers to " at least one " or " one or more ".

Used herein, " metabolism disorder disease " means metabolism such as sugar, fat or the protein imbalance that is caused by a variety of causes and related symptoms and/or the disease that causes.

Used herein, " diabetes " refer to a kind of metabolic disease of multi-pathogenesis, and characteristics are chronic hyperglycemias, follow because of insulin secretion and/or effect the defective sugar, fat and the protein metabolism disorder that cause.Along with the fall ill prolongation of time of diabetes, the intravital metabolism disorder of body is controlled well as can not get, the chronic complicating diseases that can cause organs such as tissue such as eye, kidney, nerve, blood vessel and heart, so that final take place blind, lower limb are gangrenous, uremia, cerebral apoplexy or myocardial infarction, even threat to life.

Used herein, " insulin resistant " is meant that surrounding tissue is to the susceptibility reduction of Regular Insulin in the body, and target tissues such as muscle, fat promote the effect of glucose uptake that opposing has taken place to Regular Insulin.Insulin resistant is prevalent in the diabetes B, almost accounts for more than 90%, is one of morbidity principal element of diabetes B.

Used herein, " obesity " is meant that the amount of body fat is too much, and 25% or the woman's body weight that man's body weight surpasses ideal body weight surpasses 30% phenomenon of ideal body weight.Inherited genetic factors, hypothalamus sufferer, endocrine regulation, hyperalimentation and activity all are the reason that produces obesity very little.

Used herein, " alzheimer's disease (Alzheimer ' s Disease; AD claims presenile dementia Alzheimer ' s dementia again) is a kind of neural carrying out property transformation disease, and the chronic weakening and the chronic of memory that show as intellectual level are clinically lost.

Used herein, " cardiovascular disorder " comprises heart trouble, pulmonary heart disease, hypertension and hyperlipidaemia etc.Characteristics with " sickness rate height, mortality ratio height, disability rate height, recurrence rate height " and " complication is many ".

" significant quantity " that is used for the treatment of the compound of a certain specified disease used herein refers to enough improve or alleviate to a certain extent the amount of the sick symptom that accompanies therewith.This dosage can the single dose administration, also can be according to the treatment plan administration.But this dosage cure diseases, but be typically administration in order to improve this symptom.May need for improving the symptom repeat administration.

Used herein, " acceptable salt, ester or other derivatives on the pharmacology " comprises any salt, ester or derivative that those skilled in the art are easy to prepare with currently known methods.The compound of deriving like this and generating can not have toxic action to animal and human's administration.This compound or have pharmaceutical activity, or prodrug.

Used herein, " treatment " refers to that disease and symptom are improved in any way, or other useful changes.Treatment also comprises the application of The compounds of this invention on medicine.

Used herein, the symptom that gives a certain specified disease of a certain certain drug composition " improvement " is meant any alleviating, and is no matter permanent, interim, of short duration over a long time, can both owing to or relevant with using of this pharmaceutical composition.

Used herein, " pure basically " is meant enough even, can not survey impurity by those skilled in the art for the standard method of analysis of estimating purity and using, described standard method of analysis is just like thin layer chromatography (TLC), gel electrophoresis and high performance liquid chromatography (HPLC).Even perhaps enough pure also refer to be further purified can not change the observable physicochemical property of this material, for example enzymic activity and biological activity.Being used for purifying compounds and making chemical pure basically method, is known in those skilled in the art.Yet chemical pure basically compound can be the mixture of steric isomer or isomers.In this case, be further purified the specific activity that perhaps can increase compound.

Used herein, " prodrug " is meant a kind of compound of vivo medicine-feeding, and this compound can be by metabolism, or be converted into biologically, on the pharmacology or the activity form on the therapeutics.In order to make prodrug, pharmaceutical active compounds will be modified, and this active compound is produced by metabolic process again.Prodrug can be designed to change its metabolic stability, or the precursor of transportation characterization, to cover its side effect or toxicity, improves the sense of taste of medicine, or changes other characteristics.Rely on the knowledge of pharmacokinetics and medicine internal metabolism, in case active compound is known on the pharmacology, those skilled in the art just can design the prodrug of this compound.[referring to Medicinal Chemistry A BiochemicalApproach, Oxford University Press, New York, 1985, pages 388-392].

Term " basically " is identical even or similar, can change to some extent in context the understanding of correlation technique according to those skilled in the art, and be generally at least 70%, is preferably at least 80%, more excellently be at least 90%, and optimum is identical at least 95%.

Here used " composition " refers to any mixture.Can be solution, suspension, liquid, powder, ointment, water-based, nonaqueous or their any combination.

Here used " associating " refers to any associating between two or more.

Term used herein " object " comprises humans and animals, for example, and dog, cat, ox, pig, rodent etc.Experienced implementer should understand object and for being suitable for and being ready metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc. be treated and prevented.

Any protectiveness group used herein, the abbreviation of amino acid and other compounds, consistent with their abbreviations general, that generally acknowledge or the biochemical name of IUPAC-IUB council promulgation, unless stated otherwise.

B glucagon-like peptide-1 receptor conditioning agent

The invention provides the conditioning agent of glucagon-like peptide-1 receptor function, increased the member who prevents and/or treats metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases medicines such as (as Alzheimer ' s diseases).The present invention relates to have a compound that replaces the tetra-atomic ring structure by what following general formula I or II represented, or acceptable salt, ester, solvate, metal complexes or have the prodrug of identical pharmacological action on its pharmacology:

Or

Described compound comprises solid and the optical isomer that they are all.

Wherein X and Y are respectively (CH ₂) _n, n is 0-2; O; S or NH.

Compound of the present invention can be a specific steric isomer, for example R-or S-configuration, or their mixture, for example, racemic mixture.Here the compound of Kao Lving comprises that all have the classes of compounds of pharmaceutical activity, or its solution or mixture.Also comprise its hydration type, the aqueous solution of these compounds for example, hydrolysate or ionization product; And these compounds can contain the bound water molecule of different quantities.

Compound of the present invention can prepare or synthesize according to any suitable method.Preferably, prepare this compound in order to the synthesis method of quoting as proof in the following F joint.

In addition preferably, acceptable salt provides with the form of pharmaceutical composition on this compound or its pharmacology, and is perhaps independent, perhaps combines with acceptable carrier or vehicle on a kind of pharmacology.

Compound of the present invention can prepare with the form of any suitable acid with acceptable salt on its pharmacology.For example, mineral acid example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc.; Organic acid such as formic acid, acetate, propionic acid, phenylformic acid, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid etc.; Alkylsulphonic acid such as methylsulphonic acid, ethylsulfonic acid etc.; Aryl sulfonic acid such as Phenylsulfonic acid, tosic acid etc. all can use.

C treatment and prevention method

The present invention relates to be used to prevent and/or treat the method for metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc.This method comprises needs or is ready the object of receiving treatment or preventing, give significant quantity, optionally above-mentioned disease or symptom are treated or prevented to acceptable salt on the compound of exciting glucagon-like peptide-1 receptor or its pharmacology.

Preferably, above-mentioned disease by giving significant quantity the compound that replaces the tetra-atomic ring structure by having of representing of following general formula I or II or its pharmacology on acceptable salt, ester, solvate, metal complexes or prodrug with identical pharmacological action treat or prevent:

Or

Described compound comprises solid and the optical isomer that they are all.

Wherein X and Y are respectively (CH ₂) _n, n is 0-2; O; S or NH.

Can prevent and treat any object with present method, preferred mammal, more preferably people.

Present method can be used to prevent and treat metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc.Preferred disease or symptom are any disease or symptoms that is caused or followed by insulin secretion and/or dysfunction.

When preventing and/or treating metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), can use separately or comprise with other Remedies for diabetes that maybe will go on the market of having gone on the market that euglycemic agent is united and use compound of the present invention.Any suitable metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity) medicine all can be united use with compound of the present invention.Wherein, typical euglycemic agent comprises rosiglitazone and pioglitazone etc.

Do not give above-mentioned euglycemic agent when in a preferred embodiment of the invention, using The compounds of this invention.More preferably, with compounds for treating of the present invention or the prevention because of using the above-mentioned Remedies for diabetes (comprising euglycemic agent) that maybe will go on the market that gone on the market to develop immunity to drugs or caused disease of toxic side effects or symptom.

Can be by any suitable method separately with compound administration of the present invention, or comprise that with other suitable Remedies for diabetes euglycemic agent unites use.For example, can pass through intracavitary administration, subcutaneous injection, intravenous injection, intramuscularly, the intradermal injection, oral or local with compound administration of the present invention, or with acceptable salt administration on its pharmacology.

In specific embodiments, present method further comprises the disease of administration object or symptom is diagnosed and prognosis evaluation.Can use any suitable method to be used for diagnosis and assessment relative disease or symptom and prognosis thereof.Diagnosis and prognosis can be based on the substance in vivo that detects and/or identify any or all, for example glycolated hemoglobin, enzyme, antigen, antibody, nucleic acid or other pathologic and clinical marker thing etc. and related symptoms.For example, the diagnosis or the method for prognosis that can use international monopoly WO 01/44815 and United States Patent (USP) 5,571,674 to disclose.

The D combined preparation, the method for medicine box and drug combination

On the other hand, the present invention also relates to combined preparation, this associating comprises that a kind of selectivity regulates the compound of glucagon-like peptide-1 receptor function, or acceptable salt and one or more metabolism disorder disease therapeutic medicines comprise euglycemic agent on its pharmacology.

Preferably, this drug combination comprises that acceptable salt comprises euglycemic agent with one or more metabolism disorder disease therapeutic medicines on The compounds of this invention or its pharmacology, and this compound is represented by following general formula I or II:

Or

Wherein X and Y are respectively (CH ₂) _n, n is 0-2; O; S or NH.

In combined preparation of the present invention, can use any suitable Remedies for diabetes to comprise euglycemic agent.In a particular, be used for combined preparation of the present invention and can comprise that above-mentioned Remedies for diabetes comprises one or more in the euglycemic agent.

In another particular, the disease that provides a kind of treatment or prevention to cause or followed or the method for symptom by insulin secretion and/or dysfunction, this method comprises needs and is ready to receive treatment or the object that prevents gives the above-mentioned combined preparation of significant quantity, or acceptable salt on its pharmacology, thereby treat or prevent above-mentioned disease or symptom.

In another particular, a medicine box is provided, comprising acceptable salt on compound of the present invention or its pharmacology and use above-claimed cpd or its pharmacology on acceptable salt prevent and treat by insulin secretion and/or dysfunction and cause or the disease followed or the operation instruction of symptom.

In a further embodiment, provide a medicine box, comprised above-mentioned combined preparation and use treatment of described combined preparation or prevention to cause or the disease followed or the operation instruction of symptom by insulin secretion and/or dysfunction.

E prescription and dosage

According to the present invention, compound of the present invention, separately or with other medicament, carrier or vehicle associating, for any suitable route of administration is formulated preparation, for example intracavitary administration, subcutaneous injection, intravenous injection, intramuscularly, intradermal are injected, oral or local application.Present method can be used injecting and administering preparations, with the form of single dose at ampoule, or in the multi-dose container with the buffer reagent drug administration by injection that adds.Preparation can be taked following form such as suspension, solution or the emulsion in oiliness or aqueous media.Preparation can contain prescription reagent such as suspensoid, stablizer and/or dispersion agent.In addition, before the use, activeconstituents can powder type and suitable carriers, aseptic no heat source water or other solvents formation formulation.Local application of the present invention can adopt foam, gel, and ointment, ointment changes leather diaphragm, or paste.

Operable medicinal compositions and the method that is used for administration includes, but are not limited among the present invention, United States Patent (USP) 5,736,154,6,197,801B1,5,741,511,5,886,039,5,941,868,6,258,374B1 and 5,686,102 contents of being set forth.

The dosage size of treatment or prevention is the seriousness of feelings and route of administration and change to some extent due to illness.Dosage can react different because of age, body weight, healthy state and individual patient with the medication frequency.

It is to be noted (the diagnosis and treatment doctor also should know), according to toxicity and side reaction, the termination of must taking the necessary measures, interruption or reduction therapeutic dose.On the contrary, if clinical response not obvious (getting rid of toxicity and side reaction), the doctor should suitably adjust treatment plan, improves dosage.

Any suitable route of administration all may be utilized.Formulation comprises tablet, lozenge, beans shape capsule, dispersion agent, suspension agent, solution, capsule, diaphragm and analogue etc.

In actual applications, compound of the present invention is united separately or with other preparations, can be according to general pharmacology hybrid technology and pharmaceutical carrier or vehicle, and for example beta-cyclodextrin and 2-hydroxyl-propyl group-beta-cyclodextrin are closely mixed.According to the needs of dispensing, can adopt the special carrier of universal support, part or parenteral route.Prepare non-parenteral dosage forms, for example intravenous injection or the composition inculcated can adopt similar medicine medium, water known in those skilled in the art, ethylene glycol, oil, buffer reagent, sugar, sanitas, liposome etc.The example of this non-enteron aisle composition comprises, but is not restricted to dextrose, physiological saline or other solution of 5%W/V.The total dose of compound of the present invention, separately or and other preparation Combined Preparation, the administration of available bottle intravenous fluid, volume is approximately from 1 milliliter to 2000 milliliters.According to the total dose of administration, the dilution liquid measure also can be different.

The present invention also provides the medicine box of realizing treatment plan.This medicine box is united the The compounds of this invention of effective dose separately or with other reagent with acceptable form on the pharmacology, is included in one or more containers.Preferably medicament forms is and Sterile Saline, dextrose solution, and buffered soln, or other drug is learned upward, and acceptable sterile liquid share.Perhaps, composition can be by freeze-drying or drying; In this case, medicine box is randomly further with acceptable solution on a kind of pharmacology, and preferred aseptic solution is included in the container, is formed for injecting the solution of purpose to reformulate mixture.Acceptable solution is physiological saline and dextrose solution on the typical pharmacology.

In another embodiment, medicine box of the present invention further comprises and is used for the preferred with the pin of sterile form packing or the alcohol pads of syringe and/or packing of injectable composition.Can randomly comprise specification sheets for doctor or patient's use.

The F preparation method

The compound that general formula I of the present invention or II represent method preparation as described below, wherein raw materials used (application number: the synthetic method 200310109331.0) is synthetic with reference to Chinese patent application.The compounds process for production thereof that general formula I of the present invention or II represent is as follows:

Compound 1 and compound 2 are dissolved in the mixed solvent of an amount of methylene dichloride, water, ethylene dichloride, DMSO, dioxane or above-mentioned solvent, the optional benzophenone that adds catalytic amount, temperature of reaction is controlled between 0 ℃～60 ℃, placed under 150W high voltage mercury lamp or the natural light illumination 1 day to 2 months, detect with HPLC during this time and follow the tracks of reaction, lyophilize removes and desolvates, and residuum obtains compound of the present invention with the reversed-phase silica gel column chromatography separation.

Description of drawings

Fig. 1 illustrates that the external results of pharmacodynamic test a. of compound S 4P and Boc5 induces HEK293/GLP1R+Luc with GLP-1, S4P and the Boc5 of different concns respectively, relative (100%, the GLP-1 of 10nM) agonist activity of expression assessment compound by detecting the luciferase reporter gene that CRE drives.Compound S 4P and Boc5 are to the equal tool dose-dependently of the agonist activity of GLP-1R, and both EC ₅₀Numerical value close (S4P is 1.2 μ M, and Boc5 is 3.1 μ M), but the response intensity of S4P when 10 μ M is 37.3% of GLP-1 (10nM), and Boc5 is the full agonist of GLP-1R.B. use the receptor-specific of Exendin (9-39) checking compound to the GLP-1R agonist activity.When adding 0.05nM GLP-1,10 μ M S4P and Boc5 respectively, Exendin (9-39) but equal its inductive reporter gene expression of dose-dependently ground inhibition, IC ₅₀Value is respectively 68.22,14.69 and 33.38nM, shows that the biological activity of S4P and Boc5 is the same with GLP-1, mediates by GLP-1R.C. with ¹²⁵The GLP-1 of I mark is as aglucon, by the avidity of CBA method detection compound to acceptor.When GLP-1, the S4P of different concns gradient and Boc5 and ¹²⁵I mark GLP-1 and when the GLP1R of HEK293/GLP1R+Luc cell extraction is hatched jointly, S4P and Boc5 all can be specifically with ¹²⁵The competitive combination of I mark GLP-1, its inhibiting rate when 30 μ M reaches 80.6% and 63.7% respectively, both IC ₅₀Value is respectively 286.6nM and 1.5 μ M.Under the same experiment condition, the IC of GLP-1 ₅₀Value is 0.66nM.

Fig. 2 illustrates that the inhibition test result that ingests of compd B oc5 uses the C57BL/6 mouse, fasting pneumoretroperitoneum injection Boc5 solution overnight and positive control (perhaps antagonist), every interval 15-30 minute observation food ration.A.Boc5 abdominal injection dosage relies on the ground depress appetite, and under the dosage of Boc52mg/20g body weight, 12 hours the inhibiting rate of ingesting is 54 ± 13% (P=0.0034).B. the ED of abdominal injection Boc5 depress appetite ₅₀Value be 1.57 ± 0.09mg (～80mg/kg).The appetite inhibiting effect that the c.Boc5 intraperitoneal injection produces can be by preventative abdominal injection exendin (9-39) institute antagonism.D. compare with the blank group, during oral administration 1ml/20g body weight, 2 hours the restraining effect of ingesting has dose-dependently, and the prompting oral administration can produce biological activity.The e.Boc5 oral administration produces the inhibiting ED that ingests ₅₀Value is 0.53 ± 0.08mg.The appetite inhibiting effect that the f.Boc5 oral administration produces can be by preventative abdominal injection exendin (9-39) institute antagonism.

Fig. 3 illustrates that Boc5 after the normal C57BL/6 mouse peritoneal injection of the pharmacokinetic parameter analysis Boc52mg/20g of normal C57BL/6 mouse body weight (3 of every time points), uses the HPLC detection method and carries out the pharmacokinetic parameter analysis.The final elimination transformation period is 7.5 ± 1.2 hours.

Fig. 4 illustrates that the long-term pharmacodynamic study a. of compound S 4P and Boc5 is divided into blank group, S4P treatment group and wild-type control group with each group mouse at random according to the HbA1c level, and after the result showed the S4P administration, HbA1c obviously reduced; B. each group mouse is divided into the control group of freely ingesting at random, ingests and limit control group, Boc51mg group, Boc52mg group and wild-type control group according to the HbA1c level.The HbA1c of the diabetic mice of abdominal injection Boc51mg or 2mg reduces gradually, and 4-6 reaches normal level during week in treatment, with the wild-type mice there was no significant difference, but significantly is lower than freely the ingest control group and the restriction control group of ingesting; C. the fasting plasma glucose of mouse changes instability, but reaction tendency of each group is consistent with HbA1c; D. the control group mice food ration of freely ingesting increases by 23%, and mean body weight has increased 12g; The body weight change and the wild-type mice there was no significant difference of restriction control group, Boc51mg and the 2mg treatment group of ingesting, weight increase all is starkly lower than the control group of freely ingesting; When e.6 the treatment in week finishes, each is organized mouse and randomly draws half and carry out abdominal injection carbohydrate tolerance test (IPGTT), the result shows, the area under curve (AUC) of Boc52mg treatment group significantly is lower than freely the ingest control group and the restriction control group (P=0.0006 and P=0.0006) of ingesting, and compare there was no significant difference with wild-type mice, the sugar tolerance of prompting Boc52mg treatment group has recovered normal; F. the control group and the fasting insulin level that limits control group of ingesting of freely ingesting is significantly higher than wild-type mice, pointed out the reduction of insulin sensitivity, compares with the restriction control group of ingesting, and Boc51mg and 2mg treatment group have down regulation trend to a certain degree.

Embodiment

Laboratory apparatus and reagent

The HP1100HPLC system possesses binary gradient pump, online vacuum degassing machine, automatic sampler, column oven and photodiode array detector.Chromatographic column is ZORBAX SB-C18 (2.1 * 150mm, 3.5 μ m), and moving phase is acetonitrile/water 65: 35, and flow velocity is 0.2ml/min, and the detection wavelength is 254nm.Fusing point adopts IA6304 type fusing point instrument to measure; NMR is recorded by Varian Mercury-300 and VarianMercury Plus 400 type nuclear magnetic resonance analyser that (solvent is CDCl ₃, CD ₃OD or DMSO-d ₆); ESI-MS is recorded by AB Mariner type mass spectrograph, and EI is recorded by Finnigan MAT95 type mass spectrograph.Raw materials usedly in synthetic except that specializing the source, be the commercially available prod.

The present invention is further elaborated for following specific embodiment, but do not limit the present invention.

Embodiment 1: the preparation of compound S 4P

NMR calibration: δ H/C 7.26/77.0ppm (CDCl ₃); δ H/C 2.50/39.51ppm (DMSO-d ₆).

Compound Wang516 (1g) is dissolved among an amount of DMSO, places under the 150W high voltage mercury lamp irradiation 3 days, add 1ml water, continue irradiation 7-10 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, cold doing except that desolvating, and residuum uses column chromatography.Obtain light yellow powdery solid chemical compound S4P.

¹HNMR(300MHz，DMSO-d ₆)10.053(2H，br.s)，8.630(2H，br.s)，8.090(2H，dd，J ₁＝4.8Hz，J ₂＝1.2Hz)，8.029(2H，dd，J ₁＝3.6Hz，J ₂＝1.2Hz)，7.605(4H，d，J＝8.4Hz)，7.395(4H，d，J＝8.1Hz)，7.31(2H，m)，7.280(2H，br.s)，7.260(2H，m)，7.206(2H，br.d，J＝8.1Hz)，4.987(2H，br.s)，3.244(6H，s)，2.740(2H，m)，1.815(4H，m)，1.703(4H，m)，1.652(4H，m)，1.526(4H，m)。

¹³CNMR(75MHz，DMSO-d ₆)174.7，172.8，166.8，159.4，150.1，142.1，137.7，135.2，133.6，131.6，129.1，128.7，128.1，122.5，122.1，118.1，112.5，63.2，54.9，48.4，45.3，30.0，25.7。

Embodiment 2: the preparation of compound S 4P and isomer thereof

Compound Wang516 (10g) is dissolved among an amount of DMSO, places under the room temperature natural light and shone 30-90 days, cold doing except that desolvating, residuum separates with HPLC, can seldom be measured regional isomer and the S4P of light yellow powdery solid chemical compound S4P.

¹HNMR(300MHz，DMSO-d ₆)10.125(2H，br.s)，8.025(2H，d，J＝4.8Hz)，7.921(2H，d，J＝2.9Hz)，7.667(4H，br.s)，7.251(2H，m)，7.220(2H，br.s)，6.983(2H，d，J＝7.7Hz)，6.908(2H，d，J＝7.7Hz)，5.269(2H，br.s)，3.335(6H，s)，2.779(2H，m)，1.832(4H，m)，1.715(4H，m)，1.677(4H，m)，1.527(4H，m)。

¹³CNMR(75MHz，DMSO-d ₆)174.8，174.7，164.7，159.5，149.9，142.1，136.5，135.0，131.7，129.3，128.7，127.6，121.8，120.1，118.4，112.0，64.7，55.1，51.8，45.3，30.1，25.7。

The nuclear magnetic resonance data of S4P is with example 1.

Embodiment 3: the preparation of compound S 4P under the situation of applications catalyst

Compound Wang516 (20mg) is dissolved among an amount of DMSO, adds the 25mg benzophenone, place under the 150w high voltage mercury lamp and shone 1 day, cold doing except that desolvating, residuum separates with the post layer, obtains light yellow powdery solid chemical compound S4P.

Embodiment 4: the preparation of compd B oc5

Compound Wang520 (10g) is dissolved among an amount of DMSO, places under the 150W high voltage mercury lamp irradiation 3 days, add 1ml water, continue irradiation 25-30 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, cold doing except that desolvating, and residuum uses column chromatography.Obtain light yellow powdery solid chemical compound Boc5.

¹HNMR(300MHz，DMSO-d ₆)9.571(2H，br.s)，8.607(2H，br.s)，8.078(2H，d，J＝4.8Hz)，8.035(2H，d，J＝3.3Hz)，7.464(4H，d，J＝8.4Hz)，7.363(4H，d，J＝8.1Hz)，7.31(2H，m)，7.30(2H，m)，7.260(2H，m)，7.216(2H，br.d，J＝8.1Hz)，4.991(2H，br.s)，3.270(6H，s)，1.444(18H，s)。

¹³CNMR(75MHz，DMSO-d ₆)172.8，166.9，159.5，152.6，150.2，142.4，137.8，135.2，133.6，131.7，128.8，128.4，128.2，122，117.1，112，79.6，63.2，54.9，48，28.1。

Embodiment 5: external pharmacodynamics test

1. reporter gene expression detects

GLP-1R is a g protein coupled receptor, when GLP-1R with after agonist combines, the proteic G alpha subunit of G is activated, and stimulates adenylate cyclase, causes that the cAMP level raises in the cell.Because of there is the cAMP response element in the promoter region of proinsulin gene, cAMP starts the proinsulin gene transcription with after this response element combines, thus stimulate the expression of Regular Insulin and secretion (Diabetes, 2000, Vol.49:1156-1164).This experimental technique adopts stable transfection GLP-1R acceptor gene expression vector and is subjected to the human embryonic kidney cell line (HEK 293) of the luciferase reporter gene expression vector of cAMP response element adjusting, detect its reaction (Cell Biology to test compound, 1992, Vol.89:8641-8645; Proc.Natl.Acad.Sci.U.S.A.1987, Vol.84:3434-3438).When compound is screened, but the sample of the plain enzyme reporter gene expression of induced fluorescence is considered as having the GLP-1R agonist activity.

1.1 test materials and instrument

The HEK 293/GLP-1R+Luc cell strain (The National Center for Drug Screening is self-built) of cell strain: GLP-1R and luciferase stably express

Foetal calf serum (GIBCO company)

DMEM substratum (GIBCO company)

Steady-GloTM luciferase analytical system (Promega company)

GLP-1 standard substance (Sigma company)

G418 (Invitrogen company)

Forma CO2gas incubator (Forma company);

Victor2 plate reading machine (Wallac company);

Testing compound: S4P, Boc5

1.2 test method

The HEK293/GLP1R+Luc cell inserts 96 well culture plates with 20,000/100 μ l/ holes, cultivates based on 37 ℃ of overnight incubation with the DMEM that contains 10% foetal calf serum and 500 μ g/ml G418.GLP-1 standard substance and testing compound S4P and Boc5 are diluted to the finite concentration gradient respectively, add in the above-mentioned 96 hole microtest plates with 1 μ l/ hole then.At 37 ℃, cultivated 6 hours under the 5%CO2 condition.Press the explanation of Steady-GloTM luciferase analytical system test kit and detect uciferase activity, the Victor2 plate reading machine carries out reading.

1.3 test-results

Result of study shows that (table 1, Fig. 1 a) are induced the expression of luciferase in the HEK293/GLP1R+Luc cell compound S 4P and the equal dose-dependently of Boc5.Both EC ₅₀Numerical value close (S4P is 1.2 μ M, and Boc5 is 3.1 μ M), but the response intensity of S4P when 10 μ M is 37.3% of GLP-1 (10nM), and Boc5 is the full agonist of GLP-1R.

The relative reactivity of table 1. reporter gene expression detection compound

(% reaction is 100% with the reaction of 10nM GLP-1)

2.Exendin (9-39) antagonistic effect

For the conclusive evidence active compound has receptor-specific to the activation of reporter gene, we adopt specific antagonists Exendin (9-39) (Eur.J.Pharmacol.1994, the 269:183-191 of GLP-1R; Metabolism 2004,53:252-259.) verify its can the above-mentioned representative compounds of antagonism to the agonist activity of GLP-1R.

2.1 test materials and instrument:

Foetal calf serum (GIBCO company)

DMEM substratum (GIBCO company)

Exendin (9-39) (AnaSpec company)

Steady-GloTM luciferase analytical system (Promega company)

G418 (Invitrogen company)

Forma CO2gas incubator (Forma company);

Victor2 plate reading machine (Wallac company);

Testing compound: S4P, Boc5

2.2 test method

The HEK293/GLP1R+Luc cell inserts 96 well culture plates with 20,000/100 μ l/ holes, cultivates based on 37 ℃ of overnight incubation with the DMEM that contains 10% foetal calf serum and 500 μ g/ml G418.Exendin (9-39) is diluted to certain concentration gradient, adds in the above-mentioned 96 hole microtest plates, with 1 μ l/ hole then at 37 ℃, hatched under the 5%CO2 condition 10 minutes, add 10 μ M S4P, Boc5 and 0.05nMGLP-1 then respectively,, cultivated 6 hours under the 5%CO2 condition at 37 ℃.Press the explanation of Steady-GloTM luciferase analytical system test kit and detect uciferase activity, the Victor2 plate reading machine carries out reading.

2.3 test-results

Exendin (9-39) can suppress by GLP-1, S4P and Boc5 inductive reporter gene expression (table 2, Fig. 1 b), its IC on dose-dependently ground ₅₀Value is respectively 68.22,14.69 and 33.38nM, shows that the biological activity of S4P and Boc5 mediates by GLP-1R.

Table 2.Exendin (9-39) is to the antagonistic action of GLP-1, S4P and Boc5

(% reaction is 100% with the reaction of 0.05nM GLP-1)

3. receptors bind vigor test

For determining the binding ability of active compound to acceptor, prepare the cell of great expression GLP-1R, with ¹²⁵The GLP-1 of I mark adds compound to be detected simultaneously as aglucon.When testing compound with ¹²⁵Being at war with property of I mark GLP-1 in conjunction with the time, the isotopic labeling on the cytolemma reduces.Can assess in view of the above compound to acceptor avidity (J Mol Endocrinol.2000Vol.25:321-35; J BiomolScreen.2000Vol.5:377-84).

3.1 test materials and instrument:

HEK 293/GLP1R+Luc cell strain (The National Center for Drug Screening is self-built)

Tagged compound: ¹²⁵The GLP-1 of I mark (Amersham Biosciences company)

Wallac MicroBata workstation (Perkin Elmer company)

TomTech cell harvestor (TomTec company)

Scintillation solution (Wallac company)

Testing compound: S4P, Boc5

3.2 test method

Get 10 ⁵The HEK 293/GLP1R+Luc cell of logarithmic phase, under 25 ℃ of conditions, in the 200 μ l assay buffer, with ¹²⁵The I mark positive peptide of GLP-1 (final concentration 40pM) was hatched 4 hours altogether, added the positive peptide of non-marked simultaneously or treated screening of medicaments.Use cell harvestor, use washing soln washed cell three times.Add scintillation solution, on the Microbata counter, read every hole reading.

3.3 test-results

Compound S 4P and Boc5 can be specifically with ¹²⁵I mark GLP-1 is competitive in conjunction with (table 3, Fig. 1 c.Under 30 μ M concentration, the inhibiting rate of S4P and Boc5 reaches 80.6% and 63.7% respectively, both IC ₅₀Value is respectively 286.6nM and 1.5 μ M.Under the same experiment condition, the IC of GLP-1 ₅₀Value is 0.66nM.

Table 3.S4P and Boc5 are right ¹²⁵I mark GLP-1 tests in conjunction with vigor

Embodiment 6: pharmacodynamics test in the body

1. acute in vivo test

Acute injection GLP-1 analogue can produce suppress to ingest, to postpone stomach emptying, stimulate insulin secretion, glucagon suppression secretion excretory effect mutually when repairing Regular Insulin the first (Regul Pept, 2004, Vol.117:77-88).The C57BL/6 mouse is used in this test, and fasting pneumoretroperitoneum injection Boc5 solution overnight is observed the restraining effect of the acute administration of compound to appetite.

1.1 test materials and instrument

The C57BL/6 mouse: female, in 6 ages in week, 18-20g is available from Shanghai Slac Experimental Animal Co., Ltd.

Exendin-4 (Sigma company)

HPLC (Agilent company)

Testing compound: the Boc5 of various dose gradient all is dissolved in the physiological saline (intraperitoneal injection test) of 1%DMSO and 20%PEG400 or the physiological saline of 2%DMSO and 20%PEG400 (oral administration test)

1.2 test method

Mouse is after fasting overnight, and single cage is raised, and is divided into blank group, exendin-41 μ g group, Boc50.1mg group, Boc50.3mg group, Boc51mg group and Boc52mg group immediately, and administering mode is an abdominal injection.Each is organized mouse and freely ingests, and observes residual feed in every interval 15-30 minute before the administration and after the administration, and continuous 12 hours observations is used for calculating the accumulation food ration.In oral test, blank group, Boc50.3mg group, Boc51mg group, Boc53mg group and Boc510mg group are set, irritate that body of stomach is long-pending to be 1ml, the observation cycle is 6 hours.

1.3 test-results

Result of study shows that Boc5 dosage relies on the ground depress appetite, reaches more than 12 hours action time.Compare with the blank mouse, under the dosage of Boc52mG/20g body weight, 12 hours the inhibiting rate of ingesting is 54 ± 13% (P=0.0034), ED ₅₀Be 1.57 ± 0.09mg (～80mg/kg) (Fig. 2 a, 2b).Compare with the blank group, during oral administration 1ml/20g body weight, 2 hours the restraining effect of ingesting has dose-dependently, and the prompting oral administration can produce biological activity (Fig. 2 d), ED ₅₀Be 0.53 ± 0.08mg (Fig. 2 e).The appetite inhibiting effect that intraperitoneal injection and oral administration produce all can by preventative abdominal injection exendin (9-39) institute antagonism (Fig. 2 c, 2f).

After the normal C57BL/6 mouse peritoneal injection Boc52mg/20g body weight (3 of every time points), use the HPLC detection method and carry out the pharmacokinetic parameter analysis.The final elimination transformation period is 7.5 ± 1.2 hours (Fig. 3).The biological activity of Boc510mg/20g body weight oral administration is analyzed through HPLC and is found that tangible blood medicine peak obtains confirming.

2. long-term in vivo test

The long-term peripherally administered body weight that can alleviate the obesity animal model of GLP-1R agonist, the increment and differentiation (the Regul Pept that can reduce HbA1c and blood fat, recovery β cell function, improve insulin sensitivity and induce the β cell at the diabetes B animal model, 2004, Vol.117:77-88).Application diabetes B MODEL C 57BL/6J-m+ /+Lepr ^Db(db/db) mouse has been carried out the pharmacodynamic study of abdominal injection Boc5 and S4P.

2.1 test materials and instrument

C57BL/6J-m+ /+Lepr ^Db(db/db) mouse: age in male and female half and half, 8 week, available from Nanjing University model animal research centre (confirming to meet the diabetes B pathogeneticing characteristic) through this center.

DS 1Glycosal HbA1c Analyzer (Drew Scientific company)

Glycosal HbA1c kit (Provalis Diagnostics company)

Freestyle Mini ^TMAutomatic blood glucose meter/test paper (TheraSense company)

D-glucose (Sigma company)

Total cholesterol, triglyceride level, high-density lipoprotein (HDL), low-density lipoprotein, gpt and glutamic-oxal(o)acetic transaminase are measured test kit (Roche company)

Automatic clinical chemistry analyzer 7060 (Hitachi company)

Testing compound: the Boc5 of various dose gradient or S4P all are dissolved in the physiological saline of 1%DMSO and 20%PEG400

2.2 test method

Each is organized mouse and is divided into 4 groups (14-15/group) at random according to the HbA1c level, and administering mode is an abdominal injection.Except the control group of freely ingesting, Boc5 1mg group and Boc5 2mg group, the restriction control group of ingesting is set, day food ration of this group equals the Boc5 2mg group of proxima luce (prox. luc), with the detection blood sugar characteristic change that inhibition causes of ingesting.One group of wild-type non-diabetic C57BL/6 mouse is set in addition, in order to observe the range of normal value of every index.Observation index is as follows: HbA1c is weekly, fasting plasma glucose weekly twice, and body weight and food ration are observed once every day.After treating for 6 weeks, every group is extracted half (7-8 only) fasting overnight, detect the fasting insulin level, carry out the carbohydrate tolerance test of 2g kg-1D-glucose abdominal injection, put to death animal, blood sample collection detects total cholesterol, triglyceride level, high density lipoprotein cholesterol, low density lipoprotein cholesterol, gpt and glutamic-oxal(o)acetic transaminase.Each group residue mouse after the drug withdrawal continues to observe for 6 weeks.

2.3 test-results

After the S4P administration, HbA1c obviously reduces (Fig. 4 a), therefore with the main evaluation index of HbA1c as the Boc5 correlative study.According to the HbA1c value, the db/db mouse is carried out random packet.Before the administration, each HbA1c that organizes the db/db mouse is significantly higher than wild-type mice, and the latter all keeps the HbA1c of lower level in whole experiment process.Experimental result shows that the HbA1c of freely the ingest control group and the restriction control group db/db mouse that ingests all continues higher.By contrast, the HbA1c of the diabetic mice of abdominal injection Boc5 1mg or 2mg reduces gradually, 4-6 reaches normal level during week in treatment, with the wild-type mice there was no significant difference, but significantly is lower than freely the ingest control group and restriction control group db/db mouse (P＜0.0001 of ingesting; The Tukey-Kramer check).In 6 weeks of drug withdrawal, the HbA1c of two treatment groups still remains on normal level (Fig. 4 b).

With HbA1c Comparatively speaking, the fasting plasma glucose of mouse changes unstable, but reaction tendency consistent with HbA1c (Fig. 4 c) of each group.Blood glucose condition all reaches normal range at Boc5 1mg and 2mg treatment group in the body that fasting plasma glucose and HbA1c are reflected.

In phase, the body weight change of wild-type mice is very little at the medicine-feeding test in 6 weeks, and by comparison, the control group mice of freely ingesting food ration increases by 23%, and mean body weight has increased 12g (Fig. 4 d); The body weight change and the wild-type mice there was no significant difference of restriction control group, Boc5 1mg and the 2mg treatment group of ingesting.Weight increase all is starkly lower than the control group of freely ingesting (P＜0.0001).

When the treatment in 6 weeks finished, each was organized mouse and randomly draws half and carry out abdominal injection carbohydrate tolerance test (IPGTT), and the remaining mouse of each group has also carried out the IPGTT test after drug withdrawal observed for 15 weeks.The blood glucose response of mouse with the glucose load of 2g/kg after area under curve (AUC) in 120 minutes weigh (Fig. 4 e).After 6 weeks of treatment, the AUC of freely the ingest control group and the restriction control group of ingesting is significantly higher than wild-type mice (P=0.0075 and P=0.0043).The AUC of Boc5 2mg treatment group significantly is lower than freely the ingest control group and the restriction control group (P=0.0006 and P=0.0006) of ingesting, and compares there was no significant difference (P=0.64) with wild-type mice.Therefore, the sugar tolerance of Boc5 2mg treatment group has recovered normal.The sugar tolerance of Boc5 1mg treatment group obtains part to be improved.After drug withdrawal observed for 15 weeks, the sugar tolerance bounce-back of treatment group mouse, the feasible sugar tolerance situation there was no significant difference (P＞0.05) of respectively organizing diabetic mice, (control group P=0.0026 freely ingests all to be significantly higher than wild-type mice, restriction control group P=0.0153 ingests, Boc5 2mg P=0.0072, Boc5 1mg P=0.0052).

The control group and the fasting insulin level that limits control group of ingesting of freely ingesting is significantly higher than wild-type mice (P＜0.0001), pointed out the reduction of insulin sensitivity.Compare with the restriction control group of ingesting, Boc5 1mg and 2mg treatment group have down regulation trend (P=0.0054 and P=0.0653) (Fig. 4 f) to a certain degree.

When 6 weeks, treatment finished, the triglyceride level of Boc5 treatment group has downtrending, (P=0.0054 compares with the restriction control group of ingesting and total cholesterol significantly reduces, P=0.0002 compares with the control group of freely ingesting), owing to the slight reduction (P=0.0045) of low density lipoprotein cholesterol and the downward modulation significantly (P=0.0005) of high density lipoprotein cholesterol.

Claims

1. acceptable salt on the class compound that replaces the tetra-atomic ring structure by having of representing of following general formula I or II or its pharmacology, ester, solvate, metal complexes or have the prodrug of identical pharmacological action with it:

Or

Wherein X and Y are respectively (CH ₂) _n, n is 0-2; O; S or NH;

R wherein ₁, R ₂Be following any one substituting group independently of one another: hydrogen; Halogen; Alkyl; Cycloalkyl; Hydroxyl; Nitro; Carboxyl; Aldehyde radical; Alkoxyl group; Amido; The amine alkyl; Amide group; Carbonamido; Sulfydryl; Alkylthio; Ether; Thioether; Replace or unsubstituted aryl; Replace or the unsubstituted pyridine base; Replace or unsubstituted furyl; Replace or unsubstituted pyranyl; Replace or unsubstituted thienyl; Perhaps, replacement or unsubstituted pyrryl;

2. according to claim 1 have acceptable salt on the compound that replaces the tetra-atomic ring structure or its pharmacology, ester, solvate, metal complexes or with its prodrug with identical pharmacological action, it is characterized in that:

X, Y are respectively (CH ₂) _n, n is 0-2; O; When S or NH; R ₁, R ₂Independently be separately respectively:

R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

R wherein ₁₀, R ₁₁Independent separately is following any one substituting group: H; C ₁-C ₆Alkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyl; C ₂-C ₆Thiazolinyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Thiazolinyl; C ₂-C ₆Alkynyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Alkynyl; C ₃-C ₆Cycloalkyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C ₁-C ₄Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C ₁-C ₆Alkyloyl; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₁-C ₆Alkyloyl; C ₂-C ₆Enoyl-; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆Enoyl-; C ₂-C ₆The alkynes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₂-C ₆The alkynes acyl group; C ₃-C ₆The cycloalkanes acyl group; Contain and comprise halogen atom, C ₁-C ₆Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements ₃-C ₆The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X ₁Be (CH ₂) _n, n is 0-2; O; S or NH; X ₂Be (CH ₂) _n, n is 0-2; O; S or NH;

Perhaps, work as R ₁, R ₂Independently be separately respectively:

R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps, work as R ₁, R ₂Independently be separately respectively:

R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps, work as R ₁, R ₂Independently be separately respectively:

R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

Perhaps R ₃, R ₄Be respectively:

3. describedly have acceptable salt on the compound that replaces the tetra-atomic ring structure or its pharmacology, ester, solvate, metal complexes or have the prodrug of identical pharmacological action according to any one of claim 1 to 2 with it, it is characterized in that, when having geometrical isomer in the molecule, described compound is various independent geometrical isomers or its mixture.

4. describedly have acceptable salt on the compound that replaces the tetra-atomic ring structure or its pharmacology, ester, solvate, metal complexes or have the prodrug of identical pharmacological action according to any one of claim 1 to 3 with it, it is characterized in that, when having chiral carbon in the molecule, described compound is raceme or optically active body.

According in the claim 1 to 4 any one describedly have acceptable salt on the compound that replaces the tetra-atomic ring structure or its pharmacology, ester, solvate, metal complexes or be used for the purposes that preparation prevents and/or treats metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) with its prodrug with identical pharmacological action.

6. pharmaceutical composition that is used to prevent and/or treat metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc., said composition contain as each described compound and this compounds in the claim 1 to 4 of activeconstituents in treatment acceptable salt and with the concatenator of other molecule or carrier.

7. pharmaceutical composition according to claim 6 is characterized in that further containing acceptable carrier and vehicle on the pharmacology.

8. pharmaceutical composition according to claim 6 is characterized in that described disease or symptom can be because of causing medicine generation resistance or the toxic side effects that has gone on the market.

9. combined preparation comprises as acceptable salt and other treatment medicine on compound as described in the claim 1 to 4 any or its pharmacology.

10. medicine box, it comprises in the claim 1 to 4 acceptable salt on any described compound or its pharmacology, and uses acceptable salt on described compound or its pharmacology to prevent and/or treat the explanation of metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease).

11. medicine box, it comprises the described combined preparation of claim 9 and uses described combined preparation to prevent and/or treat the explanation of metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease).