CN101195584A - Compound with substituted cyclopropane structure, production method and medicine use thereof - Google Patents

Compound with substituted cyclopropane structure, production method and medicine use thereof Download PDF

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CN101195584A
CN101195584A CNA2006101191073A CN200610119107A CN101195584A CN 101195584 A CN101195584 A CN 101195584A CN A2006101191073 A CNA2006101191073 A CN A2006101191073A CN 200610119107 A CN200610119107 A CN 200610119107A CN 101195584 A CN101195584 A CN 101195584A
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王明伟
刘青
李娜
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Shanghai Institute of Materia Medica of CAS
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Abstract

The invention provides a compound which is provided with substituted cyclopropane structure represented in the general formula I as follows and a method for preparing the compound and application as hyperglycemic glycogenolytic peptide-1 receptor adjustor for preventing and/or treating metabolic disorder disease (containing but not limited by diabetes, insulin resistance and obesity), cardiovascular disease and nerve degenerative disease (such as Alzheimer's disease) and the like.

Description

One class has compound, preparation method and the medical usage thereof of substituted cyclopropane alkyl structure
Technical field
The present invention relates to compound that a class has the substituted cyclopropane alkyl structure, preparation method with and as pancreas hyperglycemia sample peptide-1 receptor (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 etc.), cardiovascular disorder, nerve degenerative diseases (as Alzheimer ' s disease) etc.
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-1 receptor, 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 ExpTher, 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 PhysiolEndocrinol Metab, 2004,287:E1209-E1215; 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 Novo Nordisk 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
The object of the present invention is to provide compound that a class represented by following general formula I and acceptable salt pharmaceutically thereof;
Another object of the present invention is to provide the method for the compound that a kind of preparation represented by following general formula I;
Another purpose of the present invention is to provide a kind of pharmaceutical composition that contains the compound of being represented by following general formula I;
A further object of the present invention be to provide the compound represented by following general formula I 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 the compound represented by following general formula I, or acceptable salt and all solid and optical isomers thereof on its pharmacology, 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, oxygen, sulphur or nitrogen.
R wherein 1Be following any one substituting group: hydrogen; Halogen; Alkane; Naphthenic hydrocarbon; 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; Replace or unsubstituted pyrryl;
R 2, R 3Be following any one substituting group independently of one another: hydrogen; Alkane; Naphthenic hydrocarbon; 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 of above-mentioned formula I is a ring, it is characterized in that: work as X, Y is respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen, R 1For:
Figure A20061011910700381
R wherein 4Be 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 is when S or NH;
R 2, R 3Be respectively:
Figure A20061011910700391
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 2Be (CH 2) n, n is 0-2, O, S or NH;
Perhaps R 2, R 3Be respectively:
Figure A20061011910700401
R wherein 6, R 7Independent 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 2, R 3Be respectively:
R wherein 8Be 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;
Perhaps R 2, R 3Be respectively:
Figure A20061011910700431
R wherein 9, R 10Independent 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.
Work as X, Y is respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen, R 1For:
R wherein 11, R 12Independent 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 is when S or NH;
R 2, R 3Be respectively:
Figure A20061011910700461
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 2Be (CH 2) n, n is 0-2, O, S or NH;
Perhaps R 2, R 3Be respectively:
Figure A20061011910700481
R wherein 6, R 7Independent 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 2Be (CH 2) n, n is 0-2, O, S or NH;
Perhaps R 2, R 3Be respectively:
Figure A20061011910700491
R wherein 8Be 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;
Perhaps R 2, R 3Be respectively:
R wherein 9, R 10Independent 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.
Work as X, Y is respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen, R 1For:
R wherein 13Be 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 is when S or NH;
R 2, R 3Be respectively:
Figure A20061011910700531
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 2Be (CH 2) n, n is 0-2, O, S or NH;
Perhaps R 2, R 3Be respectively:
Figure A20061011910700551
R wherein 6, R 7Independent 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 2Be (CH 2) n, n is 0-2, O, S or NH;
Perhaps R 2, R 3Be respectively:
Figure A20061011910700561
R wherein 8Be 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;
Perhaps R 2, R 3Be respectively:
Figure A20061011910700571
R wherein 9, R 10Independent 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.
Work as X, Y is respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen, R 1For:
Figure A20061011910700591
R wherein 14, R 15Independent 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, and when S or NH,
R 2, R 3Be 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 2Be (CH 2) n, n is 0-2, O, S or NH;
Perhaps R 2, R 3Be respectively:
Figure A20061011910700621
R wherein 6, R 7Independent 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 2, R 3Be respectively:
Figure A20061011910700631
R wherein 8Be 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 2The alkynes acyl group of-C6; 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;
Perhaps R 2, R 3Be respectively:
Figure A20061011910700641
R wherein 9, R 10Independent 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.
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 of representing by following general formula I or its pharmacology on acceptable salt, and all solids and optical isomer, perhaps prevent or treat with its prodrug, its ester, its solvate or its metal complexes with identical pharmacological action:
Figure A20061011910700671
Wherein X and Y are respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen.
R wherein 1Be following any one substituting group: hydrogen; Halogen; Alkane; Naphthenic hydrocarbon; 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; Replace or unsubstituted pyrryl;
R 2, R 3Be following any one substituting group independently of one another: hydrogen; Alkane; Naphthenic hydrocarbon; 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.
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:
Figure A20061011910700672
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, oxygen, sulphur or nitrogen.
R wherein 1Be following any one substituting group: hydrogen; Halogen; Alkane; Naphthenic hydrocarbon; 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; Replace or unsubstituted pyrryl;
R 2, R 3Be following any one substituting group independently of one another: hydrogen; Alkane; Naphthenic hydrocarbon; 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.
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 Biochemical Approach, 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 the compound represented by following general formula I, or acceptable salt and all solid and optical isomers thereof on its pharmacology, perhaps have prodrug, its ester, its solvate or its metal complexes of identical pharmacological action with it.
Figure A20061011910700721
Wherein X and Y are respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen.
R wherein 1Be following any one substituting group: hydrogen; Halogen; Alkane; Naphthenic hydrocarbon; 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; Replace or unsubstituted pyrryl;
R 2, R 3Be following any one substituting group independently of one another: hydrogen; Alkane; Naphthenic hydrocarbon; 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.
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 metabolism disorder disease by giving significant quantity the compound of representing by following general formula I or its pharmacology on acceptable salt, and all solids and optical isomer, perhaps treat or prevent with its prodrug, its ester, its solvate or its metal complexes with identical pharmacological action:
Figure A20061011910700741
Wherein X and Y are respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen.
R wherein 1Be following any one substituting group: hydrogen; Halogen; Alkane; Naphthenic hydrocarbon; 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; Replace or unsubstituted pyrryl;
R 2, R 3Be following any one substituting group independently of one another: hydrogen; Alkane; Naphthenic hydrocarbon; 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.
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 WO01/44815 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 Remedies for diabetes comprise euglycemic agent on its pharmacology.
Preferably, this drug combination comprises acceptable salt on The compounds of this invention or its pharmacology, and all solids and optical isomer, perhaps comprise euglycemic agent with its prodrug, its ester, its solvate or its metal complexes and one or more Remedies for diabetes with identical pharmacological action, this compound is represented by following general formula I:
Figure A20061011910700761
Wherein X and Y are respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen.
R wherein 1Be following any one substituting group: hydrogen; Halogen; Alkane; Naphthenic hydrocarbon; 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; Replace or unsubstituted pyrryl;
R 2, R 3Be following any one substituting group independently of one another: hydrogen; Alkane; Naphthenic hydrocarbon; 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.
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 method of a kind of control metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc. is provided, 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 the acceptable salt operation instruction of preventing and treating metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc.
In a further embodiment, a medicine box is provided, has comprised above-mentioned combined preparation and use described combined preparation to prevent and treat the operation instruction of metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc.
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) 5,736,154,6,197,801 B1,5,741,511,5,886,039,5,941,868,6,258,374B1 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-hydroxypropyl-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 present invention implements as follows:
Figure A20061011910700791
Compound I I (1eq) is dissolved in the methyl alcohol, drips the several vitriol oils, and reflux 8 hours obtains compound III.
Compound III (2eq) is heated to 180 ℃ under protection of nitrogen gas, slowly drips compound IV (1eq), the speed of dropping is as the criterion for 180 ℃-190 ℃ to keep temperature of reaction.Cooling obtains the orange resistates.Add an amount of 10% ether/Skellysolve A, filter, obtain compound V.
Compound V is dissolved in methyl alcohol, adds sodium hydroxide solution, and heating hydrolysis obtains product I.
Description of drawings
Fig. 1. reporter gene method detection compound is to the agonism of GLP-1R.The GLP-1 concentration gradient is 10,1,0.1,0.01,0.001, and 0.0001nM is 100% with 10nM institute inductive luciferase activity, records the EC of GLP-1 50Value is 0.07nM.
Fig. 2. the reporter gene method detects exendin 9-39Antagonistic action to GLP-1.The concentration of choosing GLP-1 is 0.05nM, exendin 9-39Concentration gradient be 10000,1000,100,10,1,0.1,0nM is not to add exendin 9-39Activity be made as 100%, test shows exendin 9-39Can suppress by GLP-1 inductive reporter gene expression, its IC on dose-dependently ground 50Value shows that for 68.22nM its biological activity mediates by GLP-1R.
Fig. 3. cAMP concentration detects the effect of GLP-1 to the conduction of GLP-1R signal in the cell.The GLP-1 concentration gradient is 10,1,0.1,0.01,0.001,0.0001, and 0nM is 100% with the inductive cAMP of 10nM institute activity, records the EC of GLP-1 50Value points out it as the GLP-1R agonist for 0.079nM, but the generation of cAMP in the dose-dependently ground inducing cell.
Fig. 4. receptor competition detects the avidity of GLP-1 to acceptor in conjunction with test method.The GLP-1 concentration gradient is 1000,200,40,8,1.6,0.32,0.064,0nM.GLP-1 can be specifically with 125I marks GLP-1 competitiveness in conjunction with GLP-1R, its IC 50Value is 0.66nM.
Embodiment
Laboratory apparatus and reagent
HP1100 HPLC 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, 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 VarianMercury-300 and Varian Mercury 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
NMR calibration: δ H/C 7.26/77.0ppm (CDCl3); δ H/C 2.50/39.51ppm (DMSO-d6).
Figure A20061011910700811
Compound 2,3-diamino Succinic Acid is dissolved in an amount of 5% sodium hydroxide solution, is cooled to 0 ℃, drips BocNH Benzoyl chloride (2.5eq), room temperature is placed and is spent the night, with hcl acidifying to pH=2, ether extraction, dense doing.Obtain acid amides with the ethanol/water recrystallization.
(1eq) is dissolved in the methyl alcohol with above-mentioned acid amides, drips the several vitriol oils, and reflux 8 hours obtains ester.
Above-mentioned ester and sulfur oxychloride reacting by heating were obtained ring and thing in 2 hours.
Above-mentioned ring and thing (2eq) are heated to 180 ℃ under protection of nitrogen gas, slowly drip phenyldiazomethane (1eq), the speed of dropping is as the criterion for 180 ℃-190 ℃ to keep temperature of reaction.Cooling obtains the orange resistates.Add an amount of 10% ether/Skellysolve A, filter, obtain triatomic ring and thing.
Above-mentioned triatomic ring and thing are dissolved in ethanol, add an amount of potassium hydroxide water and separate and obtain product.
Obtain following product with quadrat method:
Figure A20061011910700821
Embodiment 2
Figure A20061011910700841
Get raw material acid (1eq) and be dissolved in the methyl alcohol, drip the several vitriol oils, reflux 8 hours obtains ester.
Above-mentioned ester (2eq) is heated to 180 ℃ under protection of nitrogen gas, slowly drips compound phenyldiazomethane (1eq), the speed of dropping is as the criterion for 180 ℃-190 ℃ to keep temperature of reaction.Cooling obtains the orange resistates.Add an amount of 10% ether/Skellysolve A, filter, obtain having the compound of substituted cyclopropane alkyl structure.
Above-mentioned compound with substituted cyclopropane alkyl structure is dissolved in methyl alcohol, adds sodium hydroxide solution, heating hydrolysis obtains product.
Obtain following product with quadrat method:
Figure A20061011910700842
Figure A20061011910700851
Embodiment 3
Figure A20061011910700852
Get raw material acid (1eq) and be dissolved in the methyl alcohol, drip the several vitriol oils, reflux 8 hours obtains ester.
Above-mentioned ester (2eq) is heated to 1 80 ℃ under protection of nitrogen gas, slowly drips compound phenyldiazomethane (1eq), the speed of dropping is as the criterion for 180 ℃-190 ℃ to keep temperature of reaction.Cooling obtains the orange resistates.Add an amount of 10% ether/Skellysolve A, filter, obtain having the compound of substituted cyclopropane alkyl structure.
Figure A20061011910700861
Figure A20061011910700871
Embodiment 4: 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-Glo TMLuciferase analytical system (Promega company)
GLP-1 standard substance (Sigma company)
G418 (Invitrogen company)
Forma CO2gas incubator (Forma company);
Victor 2Plate reading machine (Wallac company);
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.The GLP-1 standard substance are diluted to the finite concentration gradient, add in the above-mentioned 96 hole microtest plates with 1 μ l/ hole then.At 37 ℃, 5%CO 2Cultivated 6 hours under the condition.Press Steady-Glo TMThe explanation of luciferase analytical system test kit detects uciferase activity, Victor 2Plate reading machine carries out reading.
1.3 test-results
Result of study show (table 1, Fig. 1), the EC of GLP-1 50Value is 0.07nM.
Table 1. reporter gene expression detects the agonist activity (the % reaction is 100% with the reaction of 10nM GLP-1) of GLP-1
Figure A20061011910700881
Figure A20061011910700891
2.Exendin 9-39Antagonistic effect
For the conclusive evidence active compound has receptor-specific to the activation of reporter gene, we adopt the specific antagonists exendin of GLP-1R 9-39(Eur.J.Pharmacol.1994,269:183-191; 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:
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)
Exendin 9-39 (AnaSpec company)
Steady-Glo TMLuciferase analytical system (Promega company)
G418 (Invitrogen company)
Forma CO2gas incubator (Forma company);
Victor 2Plate reading machine (Wallac company);
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.With Exendin 9-39Be diluted to certain concentration gradient, add in the above-mentioned 96 hole microtest plates with 1 μ l/ hole then, at 37 ℃, 5%CO 2Hatched under the condition 10 minutes, and added 0.05nM GLP-1 then, at 37 ℃, 5%CO 2Cultivated 6 hours under the condition.Press Steady-Glo TMThe explanation of luciferase analytical system test kit detects uciferase activity, Victor 2Plate reading machine carries out reading.
2.3 test-results
Exendin 9-39Can dose-dependently ground inhibition by GLP-1 inductive reporter gene expression (table 2, Fig. 2), its IC 50Value shows that for 68.22nM its biological activity mediates by GLP-1R.
Table 2.Exendin 9-39To the antagonistic action of GLP-1 (the % reaction is 100% with the reaction of 0.05nM GLP-1)
Figure A20061011910700901
3. cAMP concentration determination in the cell
Because of the reporter gene detection method is to judge the method for cAMP concentration level in the cell indirectly.For determining that active compound can make cAMP concentration rising in the cell really, directly carries out functional checking with the cAMP detection kit.
3.1 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
CAMP detection kit (Applied Biosystems company)
Forma CO2gas incubator (Forma company)
Victor 2Plate reading machine (Wallac company)
CAMP standard substance (test kit carries, Applied Biosystems company)
3.2 test method
HEK 293 cells insert 96 well culture plates with 20000/100ul/ hole, and 37 ℃ of overnight incubation, and add in the above-mentioned 96 hole microtest plates with the 1ul/ hole the GLP-1 gradient dilution with methyl-sulphoxide.37 ℃, 5%CO 2Cultivate 15min under the condition.Press the explanation of cAMP-Screen DirectTMSysterm test kit and detect cAMP concentration level in the cell.
3.3 test-results
The generation of cAMP in the GLP-1 dose-dependently ground inducing cell (table 3, Fig. 3), its EC 50Value points out it as the GLP-1R agonist for 0.079nM, to the certain effect of signal conduction having play of GLP-1R.
The inducing action of cAMP in the table 3.GLP-1 pair cell (the % reaction is 100% with the reaction of 10nM GLP-1)
4, 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.25:32 1-35; J Biomol Screen.2000 Vol.5:377-84).
4.1 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)
4.2 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.
4.3 test-results
GLP-1 can be specifically with 125The competitive bind receptor of I mark GLP-1 (table 4, Fig. 4), its IC 50Value is 0.66 nM.
Table 4.GLP-1 testing to GLP-1R in conjunction with vigor
Figure A20061011910700931

Claims (11)

1. acceptable salt and all solid and optical isomers thereof on the compound with substituted cyclopropane alkyl structure represented by following general formula I of a class or its pharmacology perhaps have prodrug, its ester, its solvate or its metal complexes of identical pharmacological action with it:
Figure A2006101191070002C1
Wherein X and Y are respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen;
R 1Be following any one substituting group: hydrogen; Halogen; Alkane; Naphthenic hydrocarbon; 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; Replace or unsubstituted pyrryl;
R 2, R 3Be following any one substituting group independently of one another: hydrogen; Alkane; Naphthenic hydrocarbon; 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.
2. the compound with substituted cyclopropane alkyl structure according to claim 1 is characterized in that:
Work as X, Y is respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen, R 1For:
Figure A2006101191070002C2
R wherein 4Be 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 is when S or NH;
R 2, R 3Be respectively:
Figure A2006101191070004C1
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 2Be (CH 2) n, n is 0-2, O, S or NH;
Perhaps R 2, R 3Be respectively:
Figure A2006101191070005C1
R wherein 6, R 7Independent 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 2, R 3Be respectively:
Figure A2006101191070007C1
R wherein 8Be 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;
Perhaps R 2, R 3Be respectively:
R wherein 9, R 10Independent 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;
Work as X, Y is respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen, R 1For:
Figure A2006101191070010C1
R wherein 11, R 12Independent 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 is when S or NH;
R 2, R 3Be respectively:
Figure A2006101191070011C1
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 replace C interior any one, two or three 2-C 6Enoyl-; C 2-C 6The alkynes acyl group; Contain and comprise halogen atom, C 1-C 6Alkoxyl group or hydroxyl replace C interior any one, two or three 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 2, R 3Be respectively:
Figure A2006101191070012C1
R wherein 6, R 7Independent 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 replace C interior any one, two or three 2-C 6Enoyl-; C 2-C 6The alkynes acyl group; Contain and comprise halogen atom, C 1-C 6Alkoxyl group or hydroxyl replace C interior any one, two or three 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 2, R 3Be respectively:
Figure A2006101191070014C1
R wherein 8Be 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 2, R 3Be respectively:
Figure A2006101191070015C1
R wherein 9, R 10Independent 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;
Work as X, Y is respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen, R 1For:
Figure A2006101191070017C1
R wherein 13Be 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, and when S or NH,
R 2, R 3Be 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 2Be (CH 2) n, n is 0-2, O, S or NH;
Perhaps R 2, R 3Be respectively:
Figure A2006101191070019C1
R wherein 6, R 7Independent 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 2, R 3Be respectively:
Figure A2006101191070021C1
R wherein 8Be 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;
Perhaps R 2, R 3Be respectively:
Figure A2006101191070022C1
R wherein 9, R 10Independent 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.
Work as X, Y is respectively (CH 2) n, n is 0-2, oxygen, sulphur or nitrogen, R 1For:
Figure A2006101191070024C1
R wherein 14, R 15Independent 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, and when S or NH,
R 2, R 3Be respectively:
Figure A2006101191070025C1
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 2Be (CH 2) n, n is 0-2, O, S or NH;
Perhaps R 2, R 3Be respectively:
Figure A2006101191070027C1
R wherein 6, R 7Independent 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 2, R 3Be respectively:
Figure A2006101191070028C1
R wherein 8Be 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;
Perhaps R 2, R 3Be respectively:
Figure A2006101191070029C1
R wherein 9, R 10Independent 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
3. according to any described compound of claim 1 to 2, it is characterized in that when having chiral carbon in the molecule described compound is raceme or optically active body with substituted cyclopropane alkyl structure.
4. each described preparation method with compound of substituted cyclopropane alkyl structure of a tree name claim 1 to 3 implements as follows:
Figure A2006101191070031C1
Compound I I (1eq) is dissolved in the methyl alcohol, drips the several vitriol oils, and reflux 8 hours obtains compound III;
Compound III (2eq) is heated to 180 ℃ under protection of nitrogen gas, slowly drips compound IV (1eq), the speed of dropping is as the criterion for 180 ℃-190 ℃ to keep temperature of reaction, cooling obtains the orange resistates, adds an amount of 10% ether/Skellysolve A, filter, obtain compound V;
Compound V is dissolved in methyl alcohol, adds sodium hydroxide solution, and heating hydrolysis obtains product I.
5. 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) etc. according to acceptable salt on any described compound with substituted cyclopropane alkyl structure or its pharmacology in the claim 1 to 3.
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 with substituted cyclopropane alkyl structure and this compounds in the claim 1 to 3 of activeconstituents on pharmacology 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. as pharmaceutical composition as described in the claim 6, it is characterized in that described disease or symptom can be because of producing resistance to the medicine that has gone on the market or toxic side effects causes.
9. combined preparation comprises as acceptable salt and other treatment medicine on any described compound with substituted cyclopropane alkyl structure or its pharmacology in the claim 1 to 3.
10. medicine box, it comprises in the claim 1 to 3 acceptable salt on any described compound with substituted cyclopropane alkyl structure 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) etc.
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) etc.
CNA2006101191073A 2006-12-05 2006-12-05 Compound with substituted cyclopropane structure, production method and medicine use thereof Pending CN101195584A (en)

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CN100453533C (en) * 2003-12-12 2009-01-21 中国科学院上海药物研究所 Acceptor excitant of a class of pancreas hyperglycemia peptide-1, preparation method and usage
CN1884278A (en) * 2005-06-24 2006-12-27 中国科学院上海药物研究所 Glucagon-like peptide-1 receptor regulator, its preparation method and uses

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CN107698417A (en) * 2017-09-21 2018-02-16 宁波九胜创新医药科技有限公司 A kind of preparation method of the compound of ciprofloxacin eye drops containing alkynyl
CN107698417B (en) * 2017-09-21 2020-08-25 宁波九胜创新医药科技有限公司 Preparation method of alkynyl-containing cyclopropyl compound
CN112745319A (en) * 2019-10-30 2021-05-04 中国科学院上海药物研究所 Compound with substituted tricyclic structure, preparation method and application thereof
CN112745319B (en) * 2019-10-30 2022-06-17 中国科学院上海药物研究所 Compound with substituted tricyclic structure, preparation method and application thereof

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