CN101195612A - Compound with substituted cyclobutane structure, production method and medicine use thereof - Google Patents
Compound with substituted cyclobutane structure, production method and medicine use thereof Download PDFInfo
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- CN101195612A CN101195612A CNA2006101191069A CN200610119106A CN101195612A CN 101195612 A CN101195612 A CN 101195612A CN A2006101191069 A CNA2006101191069 A CN A2006101191069A CN 200610119106 A CN200610119106 A CN 200610119106A CN 101195612 A CN101195612 A CN 101195612A
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Abstract
The invention provides a compound with substituted cyclobutane structure represented as formula I or II, a relative preparation method, and an application of being glucagon-like peptide-1 receptor modulator to prevent and/or treat metabolic disorder (as diabetes, insulin resistance and obesity or the like), cardiovascular disease and neurodegenerative disease (as Alzheimer's) or the like.
Description
Technical field
The present invention relates to compound that a class has substituted ring butane 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 or II 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 or II;
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 or II;
A further object of the present invention be to provide the compound represented by following general formula I or II 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 II or acceptable salt on its pharmacology:
Or
And all solids and optical isomer, perhaps have prodrug, its ester, its solvate or its metal complexes of identical pharmacological action with it.
Wherein X and Y are respectively (CH
2)
n, n is 0-2; O; S or NH.
R wherein
1, R
2Be following any one substituting group independently of one another: 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
3, R
4Be 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 and II is characterised in that: X, Y are respectively (CH
2) n, n is 0-2; O; S or NH, R
1, R
2Independently be separately respectively:
R wherein
5For following any one substituting group is 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; The pyrans formyl radical; X
1Be (CH
2)
n, n is 0-2; O; When S or NH;
R
3, R
4Be respectively:
R wherein
6Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
2Be (CH
2)
n, n is 0-2; O; S or NH; Perhaps R
3, R
4Be respectively:
R wherein
7, R
8Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
9Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
10, R
11Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH.
Work as R
1, R
2Independently be separately respectively:
R wherein
12, R
13Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; When S or NH;
R
3, R
4Be respectively:
R wherein
6Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
7, R
8Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
9Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
10, R
11Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n,, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH.
In addition more preferably, work as R
1, R
2Independently be separately respectively:
R wherein
14Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH;
R
3, R
4Be respectively:
R wherein
6Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
7, R
8Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
9Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
10, R
11Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH.
Work as R
1, R
2Independently be separately respectively:
R wherein
15, R
16Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; When S or NH,
R
3, R
4Be respectively:
R wherein
6Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
7, R
8Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
9Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
10, R
11Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH.
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 II or its pharmacology on acceptable salt prevent or treat:
Or
And all solids and optical isomer, perhaps have prodrug, its ester, its solvate or its metal complexes of identical pharmacological action with it.
Wherein X and Y are respectively (CH
2)
n, n is 0-2; O; S or NH.
R wherein
1, R
2Be following any one substituting group independently of one another: 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
3, R
4Be 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 or II:
And all solids and optical isomer, perhaps have prodrug, its ester, its solvate or its metal complexes of identical pharmacological action with it.
Wherein X and Y are respectively (CH
2)
n, n is 0-2; O; S or NH.
R wherein
1, R
2Be following any one substituting group independently of one another: 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
3, R
4Be 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 II or acceptable salt on its pharmacology:
And all solids and optical isomer, perhaps have prodrug, its ester, its solvate or its metal complexes of identical pharmacological action with it.
Wherein X and Y are respectively (CH
2)
n, n is 0-2; O; S or NH.
R wherein
1, R
2Be following any one substituting group independently of one another: 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
3, R
4Be 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 disease by giving significant quantity the compound of representing by following general formula I or II or its pharmacology on acceptable salt treat or prevent:
And all solids and optical isomer, perhaps have prodrug, its ester, its solvate or its metal complexes of identical pharmacological action with it.
Wherein X and Y are respectively (CH
2)
n, n is 0-2; O; S or NH.
R wherein
1, R
2Be following any one substituting group independently of one another: 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
3, R
4Be 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 metabolism disorder disease therapeutic medicines comprise euglycemic agent on its pharmacology.
Preferably, this drug combination comprises that acceptable salt comprises euglycemic agent with one or more metabolism disorder disease therapeutic medicines on The compounds of this invention or its pharmacology, and this compound is represented by following general formula I or II:
Or
And all solids and optical isomer, perhaps have prodrug, its ester, its solvate or its metal complexes of identical pharmacological action with it.
Wherein X and Y are respectively (CH
2)
n, n is 0-2; O; S or NH.
R wherein
1, R
2Be following any one substituting group independently of one another: 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
3, R
4Be 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 disease that provides a kind of treatment or prevention to cause or followed or the method for symptom by insulin secretion and/or dysfunction, this method comprises needs and is ready to receive treatment or the object that prevents gives the above-mentioned combined preparation of significant quantity, or acceptable salt on its pharmacology, thereby treat or prevent above-mentioned disease or symptom.
In another particular, a medicine box is provided, comprising acceptable salt on compound of the present invention or its pharmacology and use above-claimed cpd or its pharmacology on acceptable salt prevent and treat by insulin secretion and/or dysfunction and cause or the disease followed or the operation instruction of symptom.
In a further embodiment, provide a medicine box, comprised above-mentioned combined preparation and use treatment of described combined preparation or prevention to cause or the disease followed or the operation instruction of symptom by insulin secretion and/or dysfunction.
E prescription and dosage
According to the present invention, compound of the present invention, separately or with other medicament, carrier or vehicle associating, for any suitable route of administration is formulated preparation, for example intracavitary administration, subcutaneous injection, intravenous injection, intramuscularly, intradermal are injected, oral or local application.Present method can be used injecting and administering preparations, with the form of single dose at ampoule, or in the multi-dose container with the buffer reagent drug administration by injection that adds.Preparation can be taked following form such as suspension, solution or the emulsion in oiliness or aqueous media.Preparation can contain prescription reagent such as suspensoid, stablizer and/or dispersion agent.In addition, before the use, activeconstituents can powder type and suitable carriers, aseptic no heat source water or other solvents formation formulation.Local application of the present invention can adopt foam, gel, and ointment, ointment changes leather diaphragm, or paste.
Operable medicinal compositions and the method that is used for administration includes, but are not limited among the present invention, United States Patent (USP) 5,736,154,6,197,801 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-hydroxyl-propyl group-beta-cyclodextrin are closely mixed.According to the needs of dispensing, can adopt the special carrier of universal support, part or parenteral route.Prepare non-parenteral dosage forms, for example intravenous injection or the composition inculcated can adopt similar medicine medium, water known in those skilled in the art, ethylene glycol, oil, buffer reagent, sugar, sanitas, liposome etc.The example of this non-enteron aisle composition comprises, but is not restricted to dextrose, physiological saline or other solution of 5%W/V.The total dose of compound of the present invention, separately or and other preparation Combined Preparation, the administration of available bottle intravenous fluid, volume is approximately from 1 milliliter to 2000 milliliters.According to the total dose of administration, the dilution liquid measure also can be different.
The present invention also provides the medicine box of realizing treatment plan.This medicine box is united the The compounds of this invention of effective dose separately or with other reagent with acceptable form on the pharmacology, is included in one or more containers.Preferably medicament forms is and Sterile Saline, dextrose solution, and buffered soln, or other drug is learned upward, and acceptable sterile liquid share.Perhaps, composition can be by freeze-drying or drying; In this case, medicine box is randomly further with acceptable solution on a kind of pharmacology, and preferred aseptic solution is included in the container, is formed for injecting the solution of purpose to reformulate mixture.Acceptable solution is physiological saline and dextrose solution on the typical pharmacology.
In another embodiment, medicine box of the present invention further comprises and is used for the preferred with the pin of sterile form packing or the alcohol pads of syringe and/or packing of injectable composition.Can randomly comprise specification sheets for doctor or patient's use.
The F preparation method
Raw materials used among the present invention (0601-0610) (application number: the synthetic method 200310109331.0) is synthetic with reference to Chinese patent.The present invention implements as follows:
Get in the mixed solvent that compound 1 (leq) and compound 2 (leq) be dissolved in an amount of methylene dichloride, water, ethylene dichloride, DMSO, dioxane or above-mentioned solvent (or add catalytic amount benzophenone), temperature of reaction is controlled between 0 ℃～60 ℃, placed under 150W high voltage mercury lamp or the natural light illumination 1 day to 2 months, during detect with HPLC and to follow the tracks of reaction.Lyophilize removes and desolvates, and residuum obtains product with the reversed-phase silica gel column chromatography separation.
Description of drawings
Fig. 1. reporter gene method detection compound is to the agonism of GLP-1R
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 65: 35, and flow velocity is 0.2ml/min, and the detection wavelength is 254nm.Fusing point adopts IA6304 type fusing point instrument to measure; NMR is recorded by 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: the preparation of compound GLP-A-1
NMR calibration: δ H 2.50ppm (DMSO-d
6).
(1g) is dissolved among an amount of DMSO with compound 0601, places under the 150W high voltage mercury lamp irradiation 3 days, adds 1ml water, continues irradiation 25-30 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, and lyophilize removes and desolvates, and residuum separates with reversed-phase silica gel column chromatography.Obtain light yellow powdery solid chemical compound GLP-A-1.
1HNMR(300MHz，DMSO-d
6)10.118(2H，br.s)，8.615(2H，br.s)，8.095(2H，dd，J
1＝4.8Hz，J
2＝1.2Hz)，8.027(2H，dd，J
1＝3.9Hz，J
2＝1.5Hz)，7.569(4H，d，J＝8.4Hz)，7.365(4H，d，J＝8.7Hz)，7.318(2H，dd，J
1＝3.9Hz，J
2＝5.1Hz)，7.280(2H，m)，7.260(2H，m)，7.203(2H，br.d，J＝8.1Hz)，4.981(2H，s)，3.228(6H，s)，2.015(6H，s)。
Embodiment 2: the preparation of compound GLP-A-2
NMR calibration: δ H 2.50ppm (DMSO-d
6).
(10g) is dissolved among an amount of DMSO with compound 0602, places under the 150W high voltage mercury lamp irradiation 3 days, adds 1ml water, continues irradiation 25-30 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, and lyophilize removes and desolvates, and residuum separates with reversed-phase silica gel column chromatography.Obtain light yellow powdery solid chemical compound GLP-A-2.
1H?NMR(300MHz，DMSO-d
6)δ8.770(2H，br.s)，8.090(2H，d，J＝5.1Hz)，8.026(2H，d，J＝3.9Hz)，7.2-7.5(18H，m)，5.011(2H，s)，3.231(6H，s)。
Embodiment 3: the preparation of compound GLP-B-1
NMR calibration: δ H 2.50ppm (DMSO-d
6).
(1.5g) is dissolved among an amount of DMSO with compound 0603, places under the 150W high voltage mercury lamp irradiation 3 days, adds 1ml water, continues irradiation 25-30 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, and lyophilize removes and desolvates, and residuum separates with reversed-phase silica gel column chromatography.Obtain light yellow powdery solid chemical compound GLP-B-1.
1H?NMR(300MHz，DMSO-d
6)δ9.532(2H，br.s)，8.433(2H，br.s)，7.534(4H，m)，7.428(4H，d，J＝8.7Hz)，7.329(4H，d，J＝8.4Hz)，7.234(6H，m)，4.912(2H，s)，1.453(18H，s)。
Embodiment 4: the preparation of compound GLP-B-2
NMR calibration: δ H 2.50ppm (DMSO-d
6).
(2.7g) is dissolved among an amount of DMSO with compound 0604, places under the 150W high voltage mercury lamp irradiation 3 days, adds 1ml water, continues irradiation 20-25 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, and lyophilize removes and desolvates, and residuum separates with reversed-phase silica gel column chromatography.Obtain light yellow powdery solid chemical compound GLP-B-2.
1H?NMR(300MHz，DMSO-d
6)δ9.585(2H，br.s)，8.451(2H，br.s)，7.456(4H，d，J＝8.7Hz)，7.2-7.4(12H，m)，7.1-7.2(8H，m)，6.854(2H，d，J＝7.8Hz)，4.926(2H，s)，4.384(4H，s)，1.463(18H，s)。
Embodiment 5: the preparation of compound GLP-B-3
NMR calibration: δ H 2.51ppm (DMSO-d
6).
(1.4g) is dissolved among an amount of DMSO with compound 0605, places under the 150W high voltage mercury lamp irradiation 3 days, adds 1ml water, continues irradiation 25-30 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, and lyophilize removes and desolvates, and residuum separates with reversed-phase silica gel column chromatography.Obtain light yellow powdery solid chemical compound GLP-B-3.
1H?NMR(300MHz，DMSO-d
6)δ9.554(2H，br.s)，8.527(2H，br.s)，7.420(4H，d，J＝8.4Hz)，7.283(4H，d，J＝8.7Hz)，7.215(2H，br.s)，7.137(2H，d，J＝9.0Hz)，7.092(2H，d，J＝8.1Hz)，4.916(2H，br.s)，3.229(6H，s)，2.257(6H，s)，1.450(18H，s)。
Embodiment 6: the preparation of compound GLP-B-4
NMR calibration: δ H 2.50ppm (DMSO-d
6).
(2.2g) is dissolved among an amount of DMSO with compound 0606, places under the 150W high voltage mercury lamp irradiation 3 days, adds 1ml water, continues irradiation 25-30 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, and lyophilize removes and desolvates, and residuum separates with reversed-phase silica gel column chromatography.Obtain light yellow powdery solid chemical compound GLP-B-4.
1H?NMR(300MHz，DMSO-d
6)δ9.565(2H，br.s)，8.215(2H，br.s)，7.464(8H，s)，7.436(2H，m)，7.122(2H，m)，6.991(2H，dd，J
1＝4.5Hz，J
2＝3.9Hz)，5.055(2H，s)，1.465(18H，s)。
Embodiment 7: the preparation of compound GLP-B-5
NMR calibration: δ H 2.50ppm (DMSO-d
6).
(3.4g) is dissolved among an amount of DMSO with compound 0607, places under the 150W high voltage mercury lamp irradiation 3 days, adds 1ml water, continues irradiation 20-25 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, and lyophilize removes and desolvates, and residuum separates with reversed-phase silica gel column chromatography.Obtain light yellow powdery solid chemical compound GLP-B-5.
1H?NMR(300MHz，DMSO-d
6)δ9.661(2H，br.s)，8.220(2H，m)，7.495(4H，d，J＝8.4Hz)，7.428(4H，d，J＝8.7Hz)，7.4-7.6(4H，m)，7.305(4H，m)，5.875(2H，s)，1.467(18H，s)。
Embodiment 8: the preparation of compound GLP-B-6
NMR calibration: δ H 2.50ppm (DMSO-d
6).
(5g) is dissolved among an amount of DMSO with compound 0608, places under the 150W high voltage mercury lamp irradiation 3 days, adds 1ml water, continues irradiation 25-30 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, and lyophilize removes and desolvates, and residuum separates with reversed-phase silica gel column chromatography.Obtain light yellow powdery solid chemical compound GLP-B-6.
1H?NMR(300MHz，DMSO-d
6)δ9.584(2H，br.s)，8.927(2H，br.s)，8.055(2H，d，J＝5.1Hz)，7.977(2H，d，J＝2.7Hz)，7.631(4H，d，J＝8.4Hz)，7.546(4H，d，J＝9.0Hz)，7.489(4H，d，J＝8.7Hz)，7.275(2H，dd，J
1＝4.5Hz，J
2＝3.9Hz)，7.053(4H，d，J＝8.7Hz)，5.298(2H，s)，1.481(18H，s)。
Embodiment 9: the preparation of compound GLP-B-7
NMR calibration: δ H 2.50ppm (DMSO-d
6).
(2.6g) is dissolved among an amount of DMSO with compound 0609, places under the 150W high voltage mercury lamp irradiation 3 days, adds 1ml water, continues irradiation 25-30 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, and lyophilize removes and desolvates, and residuum separates with reversed-phase silica gel column chromatography.Obtain light yellow powdery solid chemical compound GLP-B-7.
1H?NMR(300MHz，DMSO-d
6)δ9.542(2H，br.s)，8.306(2H，br.s)，7.2-7.5(22H，m)，6.903(4H，d，J＝8.7Hz)，5.066(4H，s)，4.797(2H，s)，1.462(18H，s)。
Embodiment 10: the preparation of compound GLP-C-1
NMR calibration: δ H 2.50ppm (DMSO-d
6).
(4.5g) is dissolved among an amount of DMSO with compound 0610, places under the 150W high voltage mercury lamp irradiation 3 days, adds 1ml water, continues irradiation 25-30 days, during detect with HPLC and to follow the tracks of reaction.Reaction finishes, and lyophilize removes and desolvates, and residuum separates with reversed-phase silica gel column chromatography.Obtain light yellow powdery solid chemical compound GLP-C-1.
1H?NMR(300MHz，DMSO-d
6)δ8.513(2H，br.s)，7347(4H，m)，7.267(4H，d，J＝7.8Hz)，7.190(4H，d，J＝7.8Hz)，7.143(2H，d，J＝7.5Hz)，7.042(2H，d，J＝7.5Hz)，4.880(2H，s)，2.292(6H，s)，2.137(6H，s)。
Embodiment 11: the preparation of compound GLP-D-1
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 12: the preparation of compound GLP-D-2
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 13: the preparation of compound GLP-D-3
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 14: the preparation of compound GLP-D-4
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 15: the preparation of compound GLP-D-5
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 16: the preparation of compound GLP-D-6
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 17: the preparation of compound GLP-D-7
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 18: the preparation of compound GLP-D-8
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 19: the preparation of compound GLP-D-9
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 20: the preparation of compound GLP-D-10
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 21: the preparation of compound GLP-D-11
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 22: the preparation of compound GLP-D-12
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 23: the preparation of compound GLP-D-13
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 24: the preparation of compound GLP-D-14
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 25: the preparation of compound GLP-D-15
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 26: the preparation of compound GLP-D-16
NMR calibration: δ H 2.50ppm (DMSO-d
6).
Embodiment 27: the biological activity test 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);
Testing compound: GLP-A-1, GLP-B-3, GLP-B-6, GLP-B-7
1.2 test method
The HEK293/GLP1R+Luc cell inserts 96 well culture plates with 20,000/100 μ l/ holes, cultivates based on 37 ℃ of overnight incubation with the DMEM that contains 10% foetal calf serum and 500 μ g/ml G418.GLP-1 standard substance and testing compound GLP-A-1, GLP-B-3, GLP-B-6, GLP-B-7 are diluted to the finite concentration gradient respectively, add in the above-mentioned 96 hole microtest plates with 1 μ l/ hole then.At 37 ℃, 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 shows (Fig. 1, table 1 and table 2), and compound GLP-A-1, GLP-B-3, GLP-B-6, GLP-B-7 all show certain agonist activity.GLP-1 institute inductive luciferase activity with 10nM is 100%, and the highest response efficient of above-mentioned each compound is respectively 48.8%, 45.3%, 49.3% and 19.7%, wherein the EC of compound GLP-A-1
50Value is 318.2nM.The EC of GLP-1 in the same pilot system
50Value is 0.11nM.
The agonist activity of table 1. reporter gene detection compound GLP-B-3 and GLP-B-6 (% reaction is 100% with the reaction of 10nM GLP-1)
The agonist activity of table 2. reporter gene detection compound GLP-B-7 and GLP-A-1
(% reaction is 100% with the reaction of 10nM GLP-1)
Claims (17)
1. acceptable salt and all solid and optical isomers thereof on the compound with substituted ring butane structure represented by following general formula I or II of a class or 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; O; S or NH;
R wherein
1, R
2Be following any one substituting group independently of one another: 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
3, R
4Be 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 ring butane structure according to claim 1 is characterized in that:
X, Y are respectively (CH
2)
n, n is 0-2; O; S or NH; R
1, R
2Independently be separately respectively:
R wherein
5Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; The pyrans formyl radical; X
1Be (CH
2)
n, n is 0-2; O; S or NH;
R
3, R
4Be respectively:
R wherein
6Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
7, R
8Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
9Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
10, R
11Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Work as R
1, R
2Independently be separately respectively:
R wherein
12, R
13Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; When S or NH,
R
3, R
4Be respectively:
R wherein
6Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
2-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
7, R
8Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
9Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
10, R
11Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
In addition preferably, work as R
1, R
2Independently be separately respectively:
R wherein
14Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; When S or NH,
R
3, R
4Be respectively:
R wherein
6Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
7, R
8Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
9Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
10, R
11Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Work as R
1, R
2Independently be separately respectively:
R wherein
15, R
16Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; When S or NH,
R
3, R
4Be respectively:
R wherein
6Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
7, R
8Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
9Be following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH;
Perhaps R
3, R
4Be respectively:
R wherein
10, R
11Independent separately is following any one substituting group: H; C
1-C
6Alkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyl; C
2-C
6Thiazolinyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Thiazolinyl; C
2-C
6Alkynyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Alkynyl; C
3-C
6Cycloalkyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6Cycloalkyl; Aryl; Benzyl; Furyl; Pyranyl; Thienyl; Pyrryl; Pyridyl; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyridyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise halogen atom, C
1-C
4Alkyl, nitro, carboxyl, aldehyde radical, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements; C
1-C
6Alkyloyl; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
1-C
6Alkyloyl; C
2-C
6Enoyl-; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6Enoyl-; C
2-C
6The alkynes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
2-C
6The alkynes acyl group; C
3-C
6The cycloalkanes acyl group; Contain and comprise halogen atom, C
1-C
6Alkoxyl group or hydroxyl at interior any one, the C of two or three replacements
3-C
6The cycloalkanes acyl group; Diamantane formyl radical, replacement diamantane formyl radical; Aroyl; The benzyl acyl group; Furancarbonyl; The pyrans formyl radical; Thenoyl; Pyrroyl group; X
1Be (CH
2)
n, n is 0-2; O; S or NH; X
2Be (CH
2)
n, n is 0-2; O; S or NH.
3. according to any described compound of claim 1 to 2, it is characterized in that when having geometrical isomer in the molecule described compound is various independent geometrical isomers or its mixture with substituted ring butane structure.
4. according to any described compound of claim 1 to 3, it is characterized in that when having chiral carbon in the molecule described compound is raceme or optically active body.
5. one kind prepares in the claim 1 to 4 each and describedly has the series of compounds of substituted ring butane structure and a method of salt thereof, be characterised in that with reactant add utilize in the solvent ordinary light according to or under lamp and high pressure mercury, carry out.
6. the described preparation method with compound of substituted ring butane structure of root a tree name claim 5 is characterized in that the illumination reaction solvent is the mixed solvent of methylene dichloride, water, ethylene dichloride, DMSO, dioxane or above-mentioned solvent.
7. the preparation method with compound of substituted ring butane structure according to claim 5 is characterized in that temperature of reaction is 0 ℃ to 60 ℃.
8. the preparation method with compound of substituted ring butane structure according to claim 5, the water that adds appropriate amount when it is characterized in that reacting makes and reacts completely.
9. the preparation method with compound of substituted ring butane structure according to claim 5, used light can be natural light, more preferably high voltage mercury lamp when it is characterized in that reacting.
10. the described preparation method with compound of substituted ring butane structure of root a tree name claim 5, the benzophenone that adds catalytic amount when it is characterized in that reacting promotes reaction to carry out.
11. 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 any described compound or pharmaceutically acceptable salt thereof in the claim 1 to 4.
12. a pharmaceutical composition that is used to prevent and/or treat metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc., said composition contain as each described compound and this compounds in the claim 1 to 4 of activeconstituents in treatment acceptable salt and with the concatenator of other molecule or carrier.
13. pharmaceutical composition according to claim 12 is characterized in that further containing acceptable carrier and vehicle on the pharmacology.
14., 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 as pharmaceutical composition as described in the claim 12.
15. a combined preparation comprises as acceptable salt and other treatment medicine on compound as described in the claim 1 to 4 any or its pharmacology.
16. medicine box, it comprises in the claim 1 to 4 acceptable salt on any described compound or its pharmacology, and uses acceptable salt on described compound or its pharmacology to prevent and/or treat the explanation of metabolism disorder disease (including, but not limited to diabetes, insulin resistant and obesity), cardiovascular disorder and nerve degenerative diseases (as Alzheimer ' s disease) etc.
17. medicine box, it comprises the described combined preparation of claim 15 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.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006101191069A CN101195612B (en) | 2006-12-05 | 2006-12-05 | Compound with substituted cyclobutane structure, production method and medicine use thereof |
| PCT/CN2007/002768 WO2008067709A1 (en) | 2006-12-05 | 2007-09-19 | Substituted cyclobutane compounds, preparation methods and pharmaceutical uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006101191069A CN101195612B (en) | 2006-12-05 | 2006-12-05 | Compound with substituted cyclobutane structure, production method and medicine use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101195612A true CN101195612A (en) | 2008-06-11 |
| CN101195612B CN101195612B (en) | 2012-08-08 |
Family
ID=39491648
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006101191069A Expired - Fee Related CN101195612B (en) | 2006-12-05 | 2006-12-05 | Compound with substituted cyclobutane structure, production method and medicine use thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101195612B (en) |
| WO (1) | WO2008067709A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101195613B (en) * | 2006-12-05 | 2012-08-08 | 中国科学院上海药物研究所 | Compound with substituted tetratomic ring structure and medicine use thereof |
| US11123405B2 (en) | 2015-12-23 | 2021-09-21 | The Johns Hopkins University | Long-acting GLP-1R agonist as a therapy of neurological and neurodegenerative conditions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101195613B (en) * | 2006-12-05 | 2012-08-08 | 中国科学院上海药物研究所 | Compound with substituted tetratomic ring structure and medicine use thereof |
-
2006
- 2006-12-05 CN CN2006101191069A patent/CN101195612B/en not_active Expired - Fee Related
-
2007
- 2007-09-19 WO PCT/CN2007/002768 patent/WO2008067709A1/en active Application Filing
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101195613B (en) * | 2006-12-05 | 2012-08-08 | 中国科学院上海药物研究所 | Compound with substituted tetratomic ring structure and medicine use thereof |
| US11123405B2 (en) | 2015-12-23 | 2021-09-21 | The Johns Hopkins University | Long-acting GLP-1R agonist as a therapy of neurological and neurodegenerative conditions |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101195612B (en) | 2012-08-08 |
| WO2008067709A1 (en) | 2008-06-12 |
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