CN101007798B - Benzodioxole derivatives and their preparation method and medicinal uses - Google Patents
Benzodioxole derivatives and their preparation method and medicinal uses Download PDFInfo
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- CN101007798B CN101007798B CN2006100020814A CN200610002081A CN101007798B CN 101007798 B CN101007798 B CN 101007798B CN 2006100020814 A CN2006100020814 A CN 2006100020814A CN 200610002081 A CN200610002081 A CN 200610002081A CN 101007798 B CN101007798 B CN 101007798B
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- 0 *C1(C*C(O*)=O)Oc2cc(*)ccc2O1 Chemical compound *C1(C*C(O*)=O)Oc2cc(*)ccc2O1 0.000 description 1
- JQDWFSVGFSHDSB-UHFFFAOYSA-N CCOC1Oc(cc(cc2)N=C=S)c2O1 Chemical compound CCOC1Oc(cc(cc2)N=C=S)c2O1 JQDWFSVGFSHDSB-UHFFFAOYSA-N 0.000 description 1
- QISOLHGEFLVDHF-UHFFFAOYSA-N Cc1c(CSc(cc2)cc(O)c2O)[s]c(-c(cc2)ccc2OC)n1 Chemical compound Cc1c(CSc(cc2)cc(O)c2O)[s]c(-c(cc2)ccc2OC)n1 QISOLHGEFLVDHF-UHFFFAOYSA-N 0.000 description 1
- HIZVUGNTJSGSDJ-UHFFFAOYSA-N Cc1c(CSc(cc2O)ccc2O)[s]c(-c(cc2)ccc2F)n1 Chemical compound Cc1c(CSc(cc2O)ccc2O)[s]c(-c(cc2)ccc2F)n1 HIZVUGNTJSGSDJ-UHFFFAOYSA-N 0.000 description 1
- PGJQTTXKGWRHFJ-UHFFFAOYSA-N Oc(c(O)c1)ccc1N=C=S Chemical compound Oc(c(O)c1)ccc1N=C=S PGJQTTXKGWRHFJ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention relates to compound in general formula I, comprising its racemic or optical isomer, or salt accepted by pharmacy or solvate. The definition of each substituent group is expressed in claims. The invention also relates to the method for preparing said compoundin in general formula I and the its application in preparing medicine for treating and/ or preventing diseases relevant to human hyperoxide enzyme propagation factor activation reacptor (hPPAR).
Description
Technical field
The present invention relates to the benzo benzodioxole derivatives of the novel peroxisome proliferator-activated acceptor of energy activation of human (being called for short hPPAR), the preparation method of these compounds, the pharmaceutical composition that comprises above-claimed cpd, and described compound is used to prepare the purposes of the medicine of the disease that treats and/or prevents hPPAR mediation or illness.
Background technology
Peroxisome proliferator-activated acceptor (abbreviating PPAR as) is the ligand-dependent type transcription factor that belongs to nuclear receptor superfamily with glucocorticoid receptor, retinoid receptor and pth receptor etc.Up to now, found that PPARs exists three kinds of hypotype: α, γ and δ (also claiming β), they are by different genes encodings.And PPAR γ is divided into two kinds of isoform: γ owing to promotor is different with connecting method
1, γ
2, both are N terminal sequence difference (Vidal-Puig, J.Clin.Invest., 97:2553-2561,1996) only.After being activated by specific small molecules, PPARs can interact with the PPARs response element (PPRE) in target gene promoters zone, thereby regulates this expression of gene.PPARs is the important transcription regulaton factor of glucose in the body, lipid, cholesterol metabolic.
PPAR α mainly expresses in the tissue that lipid is had high catabolic activity such as brown adipose tissue and liver, secondly is in kidney, heart, skeletal muscle (Endocnnology, 1995,137,354).Carry relevant gene (for example acyl-CoA synthetic enzyme, fatty acid binding protein matter and lipoprotein lipase) and the lipophorin (AI relevant in its energy positive regulation or negative control and fatty acid metabolism and the born of the same parents with the metabolism of cholesterol and neutral lipid; AII, CIII) expression of gene.PPAR γ mainly is present in the fatty tissue, also is present on a small quantity in skeletal muscle, liver, colon, retina, the immunity system.Result of study is also pointed out recently, and it highly is expressed in scavenger cell, comprises in the atherosclerotic foam cell.Wherein, PPAR γ
2Main specificity expression in fatty tissue, and PPAR γ
1Discovery is then all arranged in various tissues, express the highest at kidney, intestines and heart.PPAR γ mainly regulates and relates to adipocyte differentiation and insulin sensitivity expression of gene (J.Lipid.Res., 1996,37,907).PPAR δ is widely distributed, and expression is all arranged in many tissues, expresses the highest in its midgut, kidney, the heart.Verified, the activation of PPAR δ can cause the reduction of increase, LDL and the VLDL level of HDL level.
Thiazolidinediones medicine such as troglitazone, rosiglitazone show the insulin action that can strengthen the type ii diabetes patient clinically, reduce serum glucose.Reported that thiazolidinedione is effectively and the optionally activator of PPAR γ, and directly be attached to PPAR γ acceptor (J.M.Lehmann etc., J.Biol.Chem.12953-12956,270 (1995)).
Special class (fibrates) medicine one of shellfish can reduce serum triglyceride (20-50%), LDLc (10-15%) to the curative that is widely used as hyperlipidaemia, and increases HDLc (10-15%).Experiment shows, fibrates is activation mediation by PPAR α to the effect of serum lipid, referring to for example B.staels etc., and Curr.Pharm.Des., 1-14,3 (1), (1997).The activation of PPAR α causes increases transcribing of lipid acid katabolism and the enzyme that reduces lipid acid synthetic once more (causing the synthetic and VLDL generation/secretion minimizing of triglyceride level) in the liver.In addition, PPAR α activates the generation that reduces apoC-III.The minimizing that apoC-III (the active inhibitor of LPL) produces has increased the removing (J.Auwerx etc., Atherosclerosis, J59-S37,124 (Suppl), (1996)) of VLDL.
PPAR relates to many bioprocesss and morbid state, comprise hypercholesterolemia, hyperlipemia and diabetes etc., and present medicine is owing to reasons such as toxic side effect, effect is not very desirable, therefore need the exciting medicine of a kind of PPAR safely and effectively, it optionally activates a hypotype, or activates a plurality of hypotypes simultaneously.
Summary of the invention
The objective of the invention is to seek and develop micromolecular compound with PPAR agonist activity, be used for treating disease, risk factor or the illness of hPPAR mediation, as hyperlipemia, hyperlipidaemia, hypercholesterolemia, atherosclerosis, hyperglycemia, type i diabetes, type ii diabetes, insulin resistance, diabetic complication, anti-sugared functional defect, X syndrome, heart failure, cardiovascular disease, suffer from adjusting as the appetite and the food absorption of obesity, apositia, exessive appetite and patients with anorexia nervosa.
The present invention has been found that the compound of general formula I can be used for the treatment of or prevent multiple disease, risk factor or the illness of hPPAR mediation.
Therefore, on the one hand, the invention provides compound of Formula I, its raceme or optically active isomer or its pharmacy acceptable salt and solvate:
Wherein:
R
1Be selected from H, C
1-C
6The straight or branched alkyl, choose wantonly on phenyl ring by one or polysubstituted benzyl, described substituting group is selected from C
1-C
6Straight or branched alkoxyl group, C
1-C
6Straight or branched alkyl, C
2-C
6The thiazolinyl of straight or branched, C
3-C
6Cycloalkyl, halogen, itrile group, trifluoromethyl, trifluoromethoxy;
R
2Be selected from H, halogen, C
1-C
6The straight or branched alkyl, C
2-C
6The straight or branched thiazolinyl, C
3-C
6Cycloalkyl, the aromatic carbocyclic of 5-6 unit or aromatic heterocycle, described aromatic heterocycle comprise 1-3 and are selected from O, S, the heteroatoms of N, and described aromatic carbocyclic or aromatic heterocycle can be chosen wantonly and be selected from following substituting group by 1-5 and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C
1-C
6The straight or branched alkyl, C
2-C
6The straight or branched thiazolinyl, C
1-C
4Alkoxyl group, C
2-C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino;
M and n are selected from 0,1,2,3 independently of one another, and 4,5 and 6;
X
1, X
2And X
3Do not exist independently of one another or be O, S, NR
3, NR
4C (=O), SO, S (O)
2, CO, C (=N-OR
5), CH (OR
6), (CH
2)
Y, C=C, C ≡ C, wherein, R
3, R
4, R
5And R
6Be selected from hydrogen atom or C independently of one another
1-C
6The straight or branched alkyl, Y is selected from 1,2 and 3;
Ar
1Be aromatic carbocyclic or aromatic heterocycle, ring wherein can be monocycle, dicyclo or three rings; Each ring is made up of 5-6 atom, comprises in the described aromatic heterocycle that 1-4 is selected from the heteroatoms of O, N, S, and described aromatic carbocyclic or aromatic heterocycle can be chosen wantonly and be selected from following substituting group by 1-5 and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C
1-C
6The straight or branched alkyl, C
2-C
6The straight or branched thiazolinyl, C
1-C
4Alkoxyl group, C
2-C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino;
Ar
2Be selected from H atom, aromatic carbocyclic or aromatic heterocycle, ring wherein can be monocycle, dicyclo or three rings; Each ring is made up of 5-6 atom, comprises in the described aromatic heterocycle that 1-4 is selected from the heteroatoms of O, N, S, and described aromatic carbocyclic or aromatic heterocycle can be chosen wantonly and be selected from following substituting group by 1-5 and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C
1-C
6The straight or branched alkyl, C
2-C
6The straight or branched thiazolinyl, C
1-C
4Alkoxyl group, C
2-C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino.
On the other hand, the invention provides the medicinal compositions that comprises general formula of the present invention (I) compound, it contains at least a compound of Formula I, its raceme or optically active isomer or its pharmacologically acceptable salt, solvate, and one or more pharmaceutical carriers or vehicle.
On the other hand, the invention still further relates to the method for preparing compound of Formula I or its pharmacologically acceptable salt or solvate.
Aspect another, the present invention relates to the purposes that compound of Formula I is used to prepare the medicine of the disease that treats and/or prevents hPPAR mediation or illness.
Aspect another, the invention provides the method for the disease, risk factor or the illness that treat and/or prevent the hPPAR mediation, comprise that the object that these needs are arranged treats and/or prevents the The compounds of this invention of significant quantity.
Disease, risk factor or the illness of the hPPAR mediation described in the present invention comprise hyperlipemia, hyperlipidaemia, hypercholesterolemia, atherosclerosis, hyperglycemia, type i diabetes, type ii diabetes, insulin resistance, diabetic complication, anti-sugared functional defect, X syndrome, heart failure, cardiovascular disease, suffer from the adjusting as the appetite and the food absorption of obesity, apositia, exessive appetite and patients with anorexia nervosa.
In an embodiment of the invention, the invention provides compound of Formula I, its raceme or optically active isomer, its pharmacologically acceptable salt or solvate:
Wherein:
R
1Be selected from H, C
1-C
6The straight or branched alkyl, choose wantonly on phenyl ring by one or polysubstituted benzyl, described substituting group is selected from C
1-C
6Straight or branched alkoxyl group, C
1-C
6Straight or branched alkyl, C
2-C
6The thiazolinyl of straight or branched, C
3-C
6Cycloalkyl, halogen, itrile group, trifluoromethyl, trifluoromethoxy;
R
2Be selected from H, halogen, C
1-C
6The straight or branched alkyl, C
2-C
6The straight or branched thiazolinyl, C
3-C
6Cycloalkyl, the aromatic carbocyclic of 5-6 unit or aromatic heterocycle, described aromatic heterocycle comprise 1-3 and are selected from O, S, the heteroatoms of N, and described aromatic carbocyclic or aromatic heterocycle can be chosen wantonly and be selected from following substituting group by 1-5 and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C
1-C
6The straight or branched alkyl, C
2-C
6The straight or branched thiazolinyl, C
1-C
4Alkoxyl group, C
2-C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino;
M and n are selected from 0,1,2,3 independently of one another, and 4,5 and 6;
X
1, X
2And X
3Do not exist independently of one another or be O, S, NR
3, NR
4C (=O), SO, S (O)
2, CO, C (=N-OR
5), CH (OR
6), (CH
2)
Y, C=C, C ≡ C, wherein, R
3, R
4, R
5And R
6Be selected from hydrogen atom or C independently of one another
1-C
6The straight or branched alkyl, Y is selected from 1,2 and 3;
Ar
1Be aromatic carbocyclic or aromatic heterocycle, ring wherein can be monocycle, dicyclo or three rings; Each ring is made up of 5-6 atom, comprises in the described aromatic heterocycle that 1-4 is selected from the heteroatoms of O, N, S, and described aromatic carbocyclic or aromatic heterocycle can be chosen wantonly and be selected from following substituting group by 1-5 and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C
1-C
6The straight or branched alkyl, C
2-C
6The straight or branched thiazolinyl, C
1-C
4Alkoxyl group, C
2-C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino;
Ar
2Be selected from H atom, aromatic carbocyclic or aromatic heterocycle, ring wherein can be monocycle, dicyclo or three rings; Each ring is made up of 5-6 atom, comprises in the described aromatic heterocycle that 1-4 is selected from the heteroatoms of O, N, S, and described aromatic carbocyclic or aromatic heterocycle can be chosen wantonly and be selected from following substituting group by 1-5 and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C
1-C
6The straight or branched alkyl, C
2-C
6The straight or branched thiazolinyl, C
1-C
4Alkoxyl group, C
2-C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino.
According to the present invention, the example of term " aromatic carbocyclic " includes but not limited to benzene, naphthalene, anthracene, phenanthrene, 1,3-benzo dioxole, indenes, fluorenes, acenaphthene.
According to the present invention, the example of term " aromatic heterocycle " includes but not limited to pyridine, pyrroles, furans, thiophene, gives a tongue-lashing azoles, imidazoles, thiazole, oxazole, isoxazole, indoles, cumarone, benzoglyoxaline, carbazole, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline 99.9, purine, thiodiphenylamine, phenoxazine.
In a preferred embodiment of the present invention, the invention provides the compound of general formula I I representative, comprise its raceme or optically active isomer or its pharmacologically acceptable salt or solvate:
Wherein:
M, n independently are selected from 0,1,2,3, and 4,5 and 6;
X
1, X
2And X
3Do not exist independently of one another or be O, S, NR
3, NR
4C (=O), SO, S (O)
2, CO, C (=N-OR
5), CH (OR
6), (CH
2)
Y, C=C, C ≡ C, wherein, R
3, R
4, R
5And R
6Be selected from hydrogen atom or C independently of one another
1-C
6The straight or branched alkyl, Y is selected from 1,2 and 3;
Ar
1Be aromatic carbocyclic or aromatic heterocycle, ring wherein can be monocycle, dicyclo or three rings; Each ring is made up of 5-6 atom, comprises in the described aromatic heterocycle that 1-4 is selected from the heteroatoms of O, N, S, and described aromatic carbocyclic or aromatic heterocycle can be chosen wantonly and be selected from following substituting group by 1-5 and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C
1-C
6The straight or branched alkyl, C
2-C
6The straight or branched thiazolinyl, C
1-C
4Alkoxyl group, C
2-C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino;
Ar
2Be selected from H atom, aromatic carbocyclic or aromatic heterocycle, ring wherein can be monocycle, dicyclo or three rings; Each ring is made up of 5-6 atom, comprises in the described aromatic heterocycle that 1-4 is selected from the heteroatoms of O, N, S, and described aromatic carbocyclic or aromatic heterocycle can be chosen wantonly and be selected from following substituting group by 1-5 and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C
1-C
6The straight or branched alkyl, C
2-C
6The straight or branched thiazolinyl, C
1-C
4Alkoxyl group, C
2-C
4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl or amino.
The preferred compound of the present invention comprises:
2-{5-[(4-methyl-2-phenyl-1,3-thiazoles-5-yl)-and methylthio group]-1,3-benzo dioxole }-acetate;
2-(5-{[4-methyl-2-(4-trifluoromethyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(4-bromophenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(4-fluorophenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(4-p-methoxy-phenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(3, the 5-Dimethoxyphenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(2,4 dichloro benzene base)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(4-tert-butyl-phenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(thiophene-2-yl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(thiene-3-yl-)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(naphthalene-2-yl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(1,3-benzo dioxole-5-yl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-[5-(2-{4-[(4-ethyl) phenyl] phenoxy group } ethylmercapto group)-1,3-benzo dioxole]-acetate;
2-{5-[2-(carbazole-9-yl) ethylmercapto group]-1,3-benzo dioxole }-acetate;
2-{5-[2-(thiodiphenylamine-10-yl) ethylmercapto group]-1,3-benzo dioxole }-acetate;
Or its pharmacologically acceptable salt or solvate.
According to the present invention, above-mentioned general formula I and/or general formula I I compound or pharmaceutically acceptable salt thereof or solvate can prepare with following method, and it may further comprise the steps:
1) in the presence of bromine and Sodium Bromide, pyrocatechol and Sodium Thiocyanate 99 are reacted the compound that obtains formula III, with the compound and the triethyl orthoformate reaction of formula III, obtain the compound of formula IV;
2) compound of formula IV is used earlier sodium borohydride reduction, then the intermediate with formula V reacts in the presence of alkali, for example sodium hydroxide, cesium carbonate, salt of wormwood,
Wherein, Ar
1, Ar
2, X
2, X
3, the definition of n is described with general formula I, and X is a halogen, obtains the compound of formula VI,
Wherein, Ar
1, Ar
2, X
2, X
3, the definition of n is described with general formula I;
3) make compound deprotection in the presence of tosic acid of formula VI, obtain X
1It is the formula VII compound of S.
4) compound of formula VII and the compound of formula VIII are reacted:
Wherein, R
1And R
2Define as general formula I, but R
1Be not H, obtain wherein m=1, R
1Be not H, X
1Compound for the general formula I of S:
Wherein, Ar
1, Ar
2, X
2, X
3, the same general formula I of the definition of n.
The synthetic of the formula VIII compound of using in the above-mentioned reaction scheme can reference: Tetrahedron Letters 1989,30 (34), described in the 4525-4526.
The formula V intermediate of using in the reaction scheme can prepare by following method:
A) work as X
2Be O, S, NR
3, (O=) CNR
4-time, preparation formula V intermediate as follows
Wherein, Ar
1, Ar
2, X
3, the same general formula I of the definition of n, X are halogen.With alkylene dihalide a2 to X among the raw material a1
2Heteroatoms carries out hydrocarbon and promptly gets formula V intermediate for reaction.
B) work as X
2Be SO, SO
2The time, the sulfide oxidation that utilizes method to obtain in a) promptly gets formula V intermediate
Wherein, Ar
1, Ar
2, X
3, the same general formula I of the definition of n, X are halogen.
C) work as X
2Be CO, C (=N-OR
5), CH (OR
6) or-R
4NC (=O) time, can prepare as follows
Utilize carboxylic acid halides to aromatic nucleus Ar
1Carry out acylation reaction, then to the ketone carbonyl carry out the conversion of corresponding functional group get final product X
2Be CO, C (=N-OR
5), CH (OR
6) formula V intermediate; Perhaps
Utilize carboxylic acid halides to aromatic nucleus Ar
1On amido carry out acidylate get final product X
2For-R
4NC (=O) formula V intermediate.
Wherein, Ar
1, Ar
2, X
3, n, R
4, R
5, R
6The same general formula I of definition, X is a halogen.D) work as X
2Do not exist or for (CH
2)
Y, when C=C, C ≡ C, then can select the earlier synthetic d1 compound of suitable feedstock for use according to practical situation, again to the hydroxy halogeno in the d1 compound get final product formula V intermediate.
Wherein, Ar
1, Ar
2, X
3, the same general formula I of the definition of n, X are halogen.
Further, can with the compound of the above-mentioned general formula I that obtains and alkali metal hydroxide reaction or with acid-responss such as dilute hydrochloric acid, trifluoracetic acid, obtain m=1, X through hydrolysis
1Be S, R
1Compound for the general formula I of H:
Wherein, Ar
1, Ar
2, X
2, X
3, n and R
2Definition described with general formula I.
In the said hydrolyzed product, work as R
2During for H, promptly be m=1, X
1Compound for the general formula I I of S
Wherein, Ar
1, Ar
2, X
2, X
3, the definition of n is described with general formula I I.
More than be X
1Be the preparation method of general formula I and the II compound of S, work as X
1Be O, NR
3, NR
4C (=O) (R
3And R
4The same general formula I of definition) time still can prepare general formula I and II compound as stated above, only need change the starting raw material III in the step 1 into corresponding 4-substituent pyrocatechol; Can prepare X as stated above again after sulfide oxidation among the intermediate VI become sulfone or sulfoxide
1Be S (=O), S (=O)
2General formula I and II compound; For X
1Be C (=O), C (=N-OR
5), CH (OR
6), (CH
2)
Y, C=C, C ≡ C general formula I and II compound (R
5, R
6With the same general formula I of the definition of Y) preparation then only need first preparation formula VII compound, after this synthetic route is the same.
Particularly, the building-up reactions scheme of compound of Formula I sees following reaction scheme for details: reactions steps one:
With Br
2The methanol solution of/NaBr slowly is added drop-wise in 0 ℃ the methyl alcohol reaction solution of pyrocatechol and Sodium Thiocyanate 99, and 0 ℃ is reacted after 3-4 hour water termination reaction, saturated NaHCO
3Water transfers to nearly neutrality, ethyl acetate extraction, drying.Filter, concentrate rear pillar and separate (eluent: n-hexane/ethyl acetate/acetate system), get the formula III compound of white solid.With formula III compound, triethyl orthoformate, acidic ion exchange resin, 4
Molecular sieve in dry-out benzene backflow 72-96 hour filters, and concentrates, and post separates that (silica gel is conventional column chromatography silica gel, granularity 10-40 μ m; Eluent:, obtain the formula IV compound of light yellow oily the n-hexane/ethyl acetate system).
Reactions steps two:
Wherein, Ar
1, Ar
2, X
2, X
3, the same general formula I of the definition of n, X are halogen, preferred Br, Cl.
With the compound of formula IV and sodium borohydride in ethanol after backflow 10-15 minute, cooling, the compound that adds alkali (cesium carbonate, salt of wormwood or sodium hydroxide) back dropping formula V, room temperature reaction spends the night or returns and slipped 3-8 hour, filter, concentrate, post separates (eluent:, obtain the formula VI compound of yellow oily the n-hexane/ethyl acetate system).
Reactions steps three:
The compound of formula VI in the methanol reaction system, is used the tosic acid deprotection, after room temperature reaction 12-24 hour, concentrate, post separates (eluent:, obtain white to xanchromatic formula VII compound the chloroform/methanol system).
Reactions steps four:
With 4-(N, N-dimethyl amido) pyridine (DMAP) is catalyzer, make formula VII compound and formula VIII compound in anhydrous acetonitrile or acetone room temperature reaction 2-5 hour, concentrate rear pillar and separate (eluent: the n-hexane/ethyl acetate system), obtain light yellow compound to xanchromatic oily general formula I, wherein, m=1, R
1Be not H, X
1Be S atom, Ar
1, Ar
2, X
2, X
3, R
2With the same general formula I of the definition of n.
Further, can be with above-mentioned m=1, R
1Be not H, X
1For the compound of the general formula I of S atom and alkali metal hydroxide reaction or with acid-respons 2-6 such as dilute hydrochloric acid, trifluoracetic acid hours, obtain m=1, X through hydrolysis
1Be S, R
1Compound for the general formula I of H atom.
Wherein, Ar
1, Ar
2, X
2, X
3, n and R
3The same general formula I of definition.
In the said hydrolyzed product, work as R
2During for H, be m=1, X
1General formula I I compound for S
Wherein, Ar
1, Ar
2, X
2, X
3, the definition of n is with general formula I I.
Those skilled in the art will recognize that there are three-dimensional center in formula I or formula II compound.When needs formula I or formula II compound are single enantiomorph, can use the reactant that in all possible step, all is in single enantiomeric forms to prepare, perhaps in the presence of the reagent of single enantiomeric forms or catalyzer, react and prepare, perhaps split stereoisomer mixture and prepare by ordinary method.Some preferable methods comprise uses microorganism to split, the salt of the diastereomer that any spendable acid such as fractionation and chiral acid such as amygdalic acid, camphorsulfonic acid, tartrate, lactic acid forms, the perhaps salt of the diastereomer of formation such as fractionation and chiral base such as brucine (bracine), Peruvian bark alkaloid and derivative thereof.Method commonly used is seen " Enantiomers, Racemates andResolution " (Wiley Interscienee, 1981) that people such as Jaques edits.
It will be appreciated by those skilled in the art that The compounds of this invention also can use with its pharmacologically acceptable salt or solvate forms.The pharmacologically acceptable salt of formula I compound comprises the salt of the routine that forms with pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases and the acid salt of quaternary ammonium.The concrete example of suitable hydrochlorate comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetate, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, pounces on the salt of acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, tannic acid etc.Other acid as oxalic acid, though itself be not pharmaceutically acceptable, can be used to prepare the salt as intermediate, to obtain The compounds of this invention or its pharmacologically acceptable salt.The concrete example of suitable alkali salt comprises sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethanolamine, quadrol, N-methylglucosamine and procaine salt.When after this relating to compound of the present invention, comprise formula I compound and pharmacologically acceptable salt thereof and solvate.
The present invention also comprises the prodrug of The compounds of this invention, and this prodrug promptly carries out chemical conversion by metabolic process once administration, becomes afterwards to have active medicine.Usually, this class prodrug is the functional derivatives of The compounds of this invention, and it changes into the compound of required formula (I) in vivo easily.For example, at " Design Of Prodrugs ", H Bund Saard, Elsevier edits, and has described in 1985 and has selected and the ordinary method of the suitable prodrug derivant of preparation.
The present invention also comprises the active metabolite of The compounds of this invention.
The compounds of this invention can activate the hPPAR acceptor, preferably, and The compounds of this invention selectively activate hPPAR δ acceptor.Compound of the present invention can adopt following method to measure to the agonism of PPAR.
Functional effect to compound transient transfection in the 293-T cell screens, and activates the ability of PPAR hypotype to measure them.Adopt and set up of the influence of Chimerical receptor systematic comparison receptor subtype in advance, reduce the endogenous influence as interior mark with Rluc to identical target gene transcriptional activity.People PPAR α, PPAR γ and PPAR 2-delta ligand are combined the territory with yeast transcription factor GAL4DNA separately in conjunction with the territory to be merged.Be connected on the mammiferous expression vector pM, make up pM-hPPAR α/GAL4, pM-PPAR γ/GAL4 and three kinds of plasmids of pM-PPAR δ/GAL4.The GAL4DNA land is connected with pB4-tk-luc, constitutes pB4-RES-tk-luc (reporter gene that contains the Photinus pyralis LUC of GAL4DNA binding site).Influence as positive transfection efficiency of interior calibration and endogenous with pRL-CMV-Rluc.
Particularly, the 293-T cell inoculation is gone into 48 orifice plates, cell density is 2-4 * 10
4Individual/hole, nutrient solution is 1640 substratum of the no phenol red antibiotic-free of 10% degreasing foetal calf serum (FCS).After 48 hours, nutrient solution is replaced by 1640 substratum of the no phenol red antibiotic-free of 5% degreasing FCS, then respectively the pM-hPPAR/GAL4 of three kinds of hypotypes, pB4-RES-tk-luc and three kinds of plasmid cotransfections of pRL-CMV-Rluc in the 293-T cell, administration after 24 hours.Then, after administration, detected the intensity of luciferase in 24 hours.The result shows that The compounds of this invention all has very strong agonism to each hypotype of PPAR, and is particularly strong to the agonism of PPAR δ.
Pharmaceutical composition of the present invention comprises formula I compound or pharmaceutically acceptable salt thereof of the present invention or hydrate and one or more suitable pharmaceutically acceptable carrier of effective dose.It can be used for interior therapeutic and has biocompatibility.Described pharmaceutical composition can be prepared into various formulations according to the needs of different way of administration.
Described pharmaceutical carrier includes but not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum albumin, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, lanolin.
The pharmaceutical composition of The compounds of this invention can be used with following any-mode: oral, spraying sucks, rectal application, nasal cavity applied medicine, the cheek medication, local application, non-enterally administer, as in subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenous administration mode.
When medicine for oral use, The compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet uses generally comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.If desired, also can add some sweeting agents, perfume compound or tinting material in the above oral preparations form.
When local medication, particularly treat local external application easy to reach and suffer from face or organ, during as eyes, skin or lower intestinal tract nervous system disease, can The compounds of this invention be made different local application's dosage forms, specify as follows according to different trouble faces or organ:
When the eye topical application, The compounds of this invention can be mixed with the dosage form of a kind of micronization suspension or solution, and the carrier that uses is the Sterile Saline of isoosmotic certain pH, wherein can add also not adding preservative agent such as zephiran chloride alkoxide.For eye usefulness, also compound can be made paste form such as vaseline paste.
When topical application, The compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of The compounds of this invention comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilization also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
It may be noted that in addition, the using dosage of The compounds of this invention and using method depend on all multifactor, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between 0.01～100mg/kg body weight/day, and wherein optimal dosage is in the 5mg/kg-10mg/kg body weight/day.
Embodiment
Following embodiment will further specify the present invention, but these embodiment do not constitute any limitation of the invention.
Melting point compound is measured by YRT-3 type fusing point instrument, and temperature is not calibrated.
1H-NMR spectrum is measured by Bruker ARX 400 type nuclear magnetic resonance spectrometers.The FAB mass spectrum is measured by Zabspect high resolution magnetic mass spectrometer.
The preparation of intermediate
The general operation A for preparing 2-aromatic base-4-methyl-5-hydroxymethylthiazole by fragrant methane amide
(a) in the dried toluene of 100ml, add 2mmol P
4S
10, 20mmol NaHCO
3,, reflux 30 minutes adds the 10mmol acid amides, and the 1-2h afterreaction is complete, filters, and evaporating column separates (eluent system: n-hexane/ethyl acetate) get solid sulfo-fragrance methane amide.
(b) in 100ml ethanol, add sulfo-fragrance methane amide, the 11mmol2-chloro-3-oxo-ethyl butyrate (available from ACROS) that 10mmol replaces, reflux 12-24 hour, concentrate, post separates (eluent system: n-hexane/ethyl acetate) get (2-substituted aromatic base-4-methylthiazol-5-yl) ethyl formate.
(c) the 100ml dry tetrahydrofuran drips of solution of 10mmol (2-substituted aromatic base-4-methylthiazol-5-yl) ethyl formate is added in 0 ℃ the 30ml dry tetrahydrofuran reaction solution of 11mmol Lithium Aluminium Hydride, dropwise, after room temperature reaction 2-4 hour, drip little water, 15% aqueous sodium hydroxide solution, water termination reaction, anhydrous magnesium sulfate drying, filter, evaporate to dryness promptly gets product 2-aromatic base-4-methyl-5-hydroxymethylthiazole.
Intermediate 1
Title compound is raw material with the benzamide as preparation as described in the general operation A, white solid.
MS[M]+＝205.2m/e；
1H-NMR(400MHz，DMSO)δ7.89-7.87(m，2H)，7.50-7.44(m，3H)，5.55(t，1H)，4.64(d，2H)，2.35(s，3H)。
Intermediate 2
Title compound to be being raw material to trifluoromethyl benzamide as preparation as described in the general operation A, white solid.mp：120.5-122℃
MS[M]+＝273.1m/e；
1H-NMR(400MHz，DMSO)δ8.10(d，2H)，7.83(d，2H)，5.66(t，1H)，4.67(d，2H)，2.37(s，3H)。
Intermediate 3
Title compound to be being raw material to brombenzamide as preparation as described in the general operation A, light yellow solid.
MS[M]+＝284.1m/e；
1H-NMR(400MHz，DMSO)δ7.82(d，2H)，7.67(d，2H)，5.58(t，1H)，4.63(d，2H)，2.34(s，3H)。
Intermediate 4
Title compound to be being raw material to fluorobenzamide as preparation as described in the general operation A, white solid.MS[M]+＝223.3m/e
Intermediate 5
Title compound to be being raw material to methoxy benzamide as preparation as described in the general operation A, light yellow solid.MS[M]+＝235.3m/e
Intermediate 6
Title compound is with 2, and 4-dimethoxy benzamide is a raw material as preparation as described in the general operation A, light yellow solid.MS[M]+＝265.3m/e
Intermediate 7
Title compound is a raw material as preparation as described in the general operation A with the 2,4 dichloro benzene methane amide, yellow solid.MS[M]+＝274.2m/e
Intermediate 8
Title compound to be being raw material to the tert.-butylbenzene methane amide as preparation as described in the general operation A, light yellow solid.MS[M]+＝261.4m/e
Intermediate 9
Title compound is a raw material as preparation as described in the general operation A with the 2-thenoyl amine, light yellow solid.MS[M]+＝211.3m/e
Intermediate 10
Title compound is a raw material as preparation as described in the general operation A with the 3-thenoyl amine, light yellow solid.MS[M]+＝211.3m/e
Intermediate 11
Title compound is a raw material as preparation as described in the general operation A with the 2-naphthoamide, light yellow solid.MS[M]+＝255.3m/e
Intermediate 12
Title compound is a raw material as preparation as described in the general operation A with the piperonyl acid amides, light yellow solid.MS[M]+＝249.2m/e
Intermediate 13
After 2.42g (10mmol) 4-adds the KOH of 15mmol in to the 50ml dry acetone solution of ethylphenyl phenol, slowly drip 1.88g (10mmol) 1, the 2-ethylene dibromide, 50 ℃ of reactions are 8 little, the time after-filtration, concentrate, post separates (eluent system: n-hexane/ethyl acetate), get the above-mentioned intermediate 13 of oily, yield 45%.MS[M]+＝305.2m/e
Intermediate 14
1.99g thiodiphenylamine (10mmol) is dissolved in the anhydrous butanone of 50ml, add 0.94g (16.7mmol) potassium hydroxide powder, cooling, keep about 0 ℃ to add the anhydrous butanone of 15ml be dissolved with 0.79g (18mmol) oxyethane in 2 hours, 0 ℃ of reaction is warming up to 50-60 ℃ of reaction 2 hours after 2 hours, cold after, filter, concentrate, post separates (eluent system: n-hexane/ethyl acetate) get 1.85g product, yield 76%.MS[M]+＝243.3m/e
Intermediate 15
After 8.8g (80mmol) the 100ml methanol solution of pyrocatechol and 20.8g (256mmol) Sodium Thiocyanate 99 is reduced to 0 ℃, slowly drip the 100ml methanol solution of 4.4ml bromine (80mmol) and 8.24g (480mmol) Sodium Bromide, keep 0 ℃ of reaction after 3 hours, add 300ml water termination reaction, saturated NaHCO
3The aqueous solution transfers to nearly neutrality, ethyl acetate extraction, and drying concentrates, and post separates (eluent system: n-hexane/ethyl acetate/acetate), get white solid product 12.73g, yield 95.3%, mp:133.0-134.5 ℃.MS[M]+＝167.1m/e；
1H-NMR(400MHz，DMSO)δ9.66(d，2H)，7.00(s，1H)，6.93(dd，1H)，6.84(d，1H)。
Intermediate 16
In the 150ml round-bottomed bottle, add 4-sulphur itrile group pyrocatechol (intermediate 15) 7.5g (44.9mmol), triethyl orthoformate 9.98g (67.4mmol), acidic ion exchange resin 0.5g, 4
Molecular sieve 0.8g, the 100ml dry-out benzene, backflow 72-96 hour, filter, concentrate, post separates (eluent system: n-hexane/ethyl acetate=25: 1), get the pale yellow oily product of 7.24g, yield 72.3%.MS[M]+＝223.2m/e；
1H-NMR(400MHz，CDCl
3)δ7.12(d，1H)，7.11(s，1H)，6.93(s，1H)，6.90(dd，1H)，3.73(q，2H)，1.28(t，3H)。
Prepare 4-[(2-aromatic base-4-methyl thiazolium by 2-aromatic base-4-methyl-5-hydroxymethylthiazole
Azoles-5-yl) methylthio group]-1, the general operation B of 2-pyrocatechol
(I) 2-aromatic base-4-methyl-5-hydroxymethylthiazole (5mmol) is dissolved in the dry chloroform of 20ml Dropwise 5 ml SOCl
2, distill behind time slide 3-5h, evaporated under reduced pressure, product is stand-by.(II) in the 100ml round-bottomed bottle, add the 6mmol 4-thiocyano pyrocatechol (intermediate 16) that triethyl orthoformate is protected, 35ml absolute ethanol, N
2Protection slowly adds NaBH
4(6.6mmol), reduce to room temperature after backflow 10-15 minute, behind the adding cesium carbonate, drip the reaction product of (I), room temperature, N
2Reaction is spent the night, and filters, and the ethyl acetate washing concentrates, and post separates (eluent system: n-hexane/ethyl acetate), get yellow oil product.
(III) reaction product with (II) is dissolved in 40ml 90% methanol aqueous solution, added behind the 500mg tosic acid room temperature reaction 12-24 hour, concentrate, post separates (eluent system: chloroform/methanol), get pale yellow to xanchromatic 4-[(2-aromatic base-4-methylthiazol-5-yl) methylthio group]-1, the 2-pyrocatechol.
Intermediate 17
Title compound is a raw material as preparation as described in the general operation B with intermediate 1, light yellow solid.MS[M]+＝329.4m/e；
1H-NMR(400MHz，DMSO)δ9.10(d，2H)，δ7.84(m，2H)，7.46(m，3H)，6.77(s，1H)，6.67(s，2H)，4.20(s，2H)，2.12(s，3H)。
Intermediate 18
Title compound is a raw material as preparation as described in the general operation B with intermediate 2, faint yellow solid.MS[M]+＝397.3m/e；
1H-NMR(400MHz，DMSO)δ9.11(d，2H)，δ8.05(d，2H)，7.82(d，2H)，6.76(s，1H)，6.66(s，2H)，4.21(s，2H)，2.12(s，3H)。
Intermediate 19
Title compound is a raw material as preparation as described in the general operation B with intermediate 3, faint yellow solid.MS[M]+＝408.3m/e；
1H-NMR(400MHz，DMSO)δ9.11(d，2H)，δ7.77(d，2H)，7.66(d，2H)，6.77(s，1H)，6.67(s，2H)，4.21(s，2H)，2.14(s，3H)。
Intermediate 20
Title compound is a raw material as preparation as described in the general operation B with intermediate 4, faint yellow solid.MS[M]+＝347.4m/e；
1H-NMR(400MHz，DMSO)δ9.11(d，2H)，δ7.88(m，2H)，7.31(m，2H)，6.77(s，1H)，6.67(s，2H)，4.20(s，2H)，2.12(s，3H)。
Intermediate 21
Title compound is a raw material as preparation as described in the general operation B with intermediate 5, faint yellow solid.MS[M]+＝359.5m/e
Intermediate 22
Title compound is a raw material as preparation as described in the general operation B with intermediate 6, faint yellow solid.MS[M]+＝389.3m/e
Intermediate 23
Title compound is a raw material as preparation as described in the general operation B with intermediate 7, faint yellow solid.MS[M]+＝398.3m/e
Intermediate 24
Title compound is a raw material as preparation as described in the general operation B with intermediate 8, white solid.MS[M]+＝385.5m/e
Intermediate 25
Title compound is a raw material as preparation as described in the general operation B with intermediate 9, white solid.MS[M]+＝335.4m/e
Intermediate 26
Title compound is a raw material as preparation as described in the general operation B with intermediate 10, faint yellow solid.MS[M]+＝335.4m/e
Intermediate 27
Title compound is a raw material as preparation as described in the general operation B with intermediate 11, faint yellow solid.MS[M]+＝379.5m/e
Intermediate 28
Title compound is a raw material as preparation as described in the general operation B with intermediate 12, faint yellow solid.MS[M]+＝373.4m/e
Intermediate 29
1.34g (6mmol) the 4-thiocyano pyrocatechol (intermediate 16) that in the 100ml round-bottomed bottle, adds the triethyl orthoformate protection, 35ml absolute ethanol, N
2Protection slowly adds NaBH
4(0.24g 6.6mmol), refluxes and reduces to room temperature after 10 minutes, behind adding 0.55g (9.9mmol) KOH, drips the chloroformic solution of 1.52g (5mmol) intermediate 13, N
2Protection refluxes after 8 reactions hour, filters, and the ethyl acetate washing concentrates, post separate (eluent system: n-hexane/ethyl acetate), yellow oil product (be triethyl orthoformate protect intermediate 29).This oily matter is dissolved in 90% methanol aqueous solution of 40ml, adds the 500mg tosic acid, room temperature concentrated after 24 hours, post separate (eluent system: chloroform/methanol), faint yellow solid 0.712g.MS[M]+＝366.3m/e
Intermediate 30
(1.06g 5mmol) is dissolved in the dry chloroform of 20ml Dropwise 5 ml SOCl with 2-(carbazole-9-yl) ethanol (available from ACROS)
2, distill behind the backflow 4h, evaporated under reduced pressure, product is stand-by.
1.34g (6mmol) the 4-thiocyano pyrocatechol (intermediate 16) that in the 100ml round-bottomed bottle, adds the triethyl orthoformate protection, 35ml absolute ethanol, N
2Protection slowly adds NaBH
4(0.24g 6.6mmol), refluxes and reduces to room temperature after 10 minutes, behind adding 0.55g (9.9mmol) KOH and the 50mgKI, drips the above-mentioned chloro-product that obtains, N
2Protection backflow 6 hours is filtered, and the ethyl acetate washing concentrates, and post separates (eluent system: n-hexane/ethyl acetate), get yellow oil product (being the intermediate 30 of triethyl orthoformate protection).
The above-mentioned yellow product that obtains is dissolved in 40ml 90% methanol aqueous solution, room temperature reaction is 24 hours behind the adding 500mg tosic acid, concentrates, and post separates (eluent system: chloroform/methanol), get xanchromatic 4-[2-(carbazole-9-yl) ethylmercapto group]-1,2-pyrocatechol 0.605g.MS[M]+＝335.4m/e
Intermediate 31
With intermediate 14 is preparation method's operation that raw material is pressed intermediate 30, gets yellow solid 4-[2-(thiodiphenylamine-10-yl) ethylmercapto group]-1, the 2-pyrocatechol.MS[M]+＝367.5m/e
Intermediate 32
2.8g (40mmol) propynoic acid and 6.9g (50mmol) p-methoxybenzyl alcohol is dissolved in the 40ml dry methylene chloride, after being cooled to-20 ℃, slowly drip the 100ml dry methylene chloride solution of 9.28g (45mmol) DCC and 0.37g (3mmol) DMAP (4-N, N-dimethyl amine yl pyridines), after 30 minutes, rose to room temperature reaction 12 hours, filter, concentrate, post separates (eluent system: n-hexane/ethyl acetate), get light yellow oil 4.95g, yield 65.1%.
1H-NMR(400MHz，CDCl
3)δ7.32(d，2H)，6.90(d，2H)，5.16(s，2H)，3.82(s，3H)，2.87(s，1H)。
Embodiment
Embodiment 1:2-{5-[(4-methyl-2-phenyl-1,3-thiazoles-5-yl)-and methylthio group]-1,3-benzo dioxole }-acetate
With 0.4g (1.22mmol) intermediate 17 and 0.223g (1.83mmol) DMAP (4-N, N-dimethyl amine yl pyridines) is dissolved in the dry acetonitrile of 20ml, slowly drip the 5ml dry acetonitrile solution of 0.254g (1.34mmol) propynoic acid to methoxy benzyl ester (intermediate 32), behind the room temperature reaction 2h, concentrate, post separates (eluent system: n-hexane/ethyl acetate), get 0.573g buttery 2-{5-[(4-methyl-2-phenyl-1,3-thiazole-5-yl)-and methylthio group]-1,3-benzo dioxole }-acetate is to methoxy benzyl ester, yield 90.2%.
With 0.573g (1.1mmol) 2-{5-[(4-methyl-2-phenyl-1,3-thiazole-5-yl)-and methylthio group]-1,3-benzo dioxole }-acetate is dissolved in the 16ml methylene dichloride methoxy benzyl ester, after adding 0.82ml (11mmol) trifluoracetic acid, room temperature reaction 4.5h, concentrate, post separates (eluent system: methylene chloride), get the 2-{5-[(4-methyl-2-phenyl-1 of light yellow amorphous solid, 3-thiazole-5-yl)-and methylthio group]-1,3-benzo dioxole }-acetate 0.325g, yield 74.0%.
MS[M]+＝400.0m/e；
1H-NMR(400MHz，DMSO-d
6)δ12.79(brs，1H，)，7.85-7.82(m，2H)，7.48-7.45(m，3H)，7.04(d，1H)，6.85(d，2H)，6.52(t，1H)，4.35(s，2H)，2.96(d，2H)，2.20(s，3H)
Embodiment 2:2-(5-{[4-methyl-2-(4-trifluoromethyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 18, light yellow amorphous solid 2-(5-{[4-methyl-2-(4-trifluoromethyl)-1,3-thiazoles-5-yl]-methylthio group-1,3-benzo dioxole)-acetate.
MS[M]+＝468.0m/e；
1H-NMR(400MHz，DMSO-d
6)δ12.77(brs，1H，)，8.05(d，2H)，7.82(d，2H)，7.04(d，1H)，6.85(m，2H)，6.52(t，1H)，4.38(s，2H)，2.96(d，2H)，2.23(s，3H)
Embodiment 3:2-(5-{[4-methyl-2-(4-bromophenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 19, light yellow amorphous solid 2-(5-{[4-methyl-2-(4-bromophenyl)-1,3-thiazoles-5-yl]-methylthio group-1,3-benzo dioxole)-acetate.
MS[M]+＝478.0m/e；
1H-NMR(400MHz，DMSO-d
6)7.78(d，2H)，7.65(d，2H)，6.96(d，1H)，6.82-6.76(m，2H)，6.46(s，1H)，4.32(s，2H)，2.64(s，2H)，2.18(s，3H)
Embodiment 4:2-(5-{[4-methyl-2-(4-fluorophenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 20, light yellow amorphous solid 2-(5-{[4-methyl-2-(4-fluorophenyl)-1,3-thiazoles-5-yl]-methylthio group-1,3-benzo dioxole)-acetate.
MS[M]+＝418.0m/e；
1H-NMR(400MHz，DMSO-d
6)12.67(brs，1H)，7.88(m，2H)，7.29(m，2H)，7.03(d，1H)，6.84(d，2H)，6.52(t，1H)，4.34(s，2H)，2.96(d，2H)，2.19(s，3H)
Embodiment 5:2-(5-{[4-methyl-2-(4-p-methoxy-phenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 21, light yellow amorphous solid 2-(5-{[4-methyl-2-(4-p-methoxy-phenyl)-1,3-thiazoles-5-yl]-methylthio group-1,3-benzo dioxole)-acetate.
MS[M]+＝430.0m/e；
1H-NMR(400MHz，DMSO-d
6)7.77(d，2H)，7.01(m，3H)，6.83(m，2H)，6.50(s，1H)，4.31(s，2H)，3.80(s，3H)，2.87(s，2H)，2.16(s，3H)
Embodiment 6:2-(5-{[4-methyl-2-(3, the 5-Dimethoxyphenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change intermediate 17 wherein into intermediate 22, get the 2-(5-{[4-methyl-2-(3, the 5-Dimethoxyphenyl)-1 of light yellow amorphous solid, 3-thiazole-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate.
MS[M]+＝460.1m/e；
1H-NMR(400MHz，DMSO-d
6)7.01(s，1H)，6.94(d，2H)，6.82(s，2H)，6.58(t，1H)，6.50(s，1H)，4.33(s，2H)，3.80(s，6H)，2.86(s，2H)，2.19(s，3H)
Embodiment 7:2-(5-{[4-methyl-2-(2,4 dichloro benzene base)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 23, light yellow amorphous solid 2-(5-{[4-methyl-2-(2,4 dichloro benzene base)-1,3-thiazoles-5-yl]-methylthio group-1,3-benzo dioxole)-acetate.
MS[M]+＝468.0m/e；
1H-NMR(400MHz，DMSO-d
6)8.17(d，1H)，7.79(d，1H)，7.54(dd，1H)，6.96(d，1H)，6.81(dd，1H)，6.77(d，1H)，6.46(s，1H)，4.36(s，2H)，2.67(s，2H)，2.23(s，3H)
Embodiment 8:2-(5-{[4-methyl-2-(4-tert-butyl-phenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 24, light yellow amorphous solid 2-(5-{[4-methyl-2-(4-tert-butyl-phenyl)-1,3-thiazoles-5-yl]-methylthio group-1,3-benzo dioxole)-acetate.
MS[M]+＝456.0m/e；
1H-NMR(400MHz，DMSO-d
6)7.75(d，2H)，7.47(d，2H)，6.97(s，1H)，6.83-6.77(m，2H)，6.47(s，1H)，4.31(s，2H)，2.71(s，2H)，2.18(s，3H)，1.29(s，9H)
Embodiment 9:2-(5-{[4-methyl-2-(thiophene-2-yl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 25, light yellow amorphous solid 2-(5-{[4-methyl-2-(thiophene-2-yl)-1,3-thiazoles-5-yl]-methylthio group-1,3-benzo dioxole)-acetate.
MS[M]+＝406.0m/e；
1H-NMR(400MHz，DMSO-d
6)7.66(d，1H)，7.55(d，1H)，7.12(t，1H)，6.98(s，1H)，6.83-6.78(m，2H)，6.47(s，1H)，4.30(s，2H)，2.73(s，2H)，2.13(s，3H)
Embodiment 10:2-(5-{[4-methyl-2-(thiene-3-yl-)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 26, light yellow amorphous solid 2-(5-{[4-methyl-2-(thiene-3-yl-)-1,3-thiazoles-5-yl]-methylthio group-1,3-benzo dioxole)-acetate.
MS[M]+＝406.0m/e；
1H-NMR(400MHz，DMSO-d
6)8.03(s，1H)，7.65(m，1H)，7.48(d，1H)，6.97(s，1H)，6.83-6.77(m，2H)，6.47(s，1H)，4.30(s，2H)，2.74(s，2H)，2.15(s，3H)
Embodiment 11:2-(5-{[4-methyl-2-(naphthalene-2-yl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 27, light yellow amorphous solid 2-(5-{[4-methyl-2-(naphthalene-2-yl)-1,3-thiazoles-5-yl]-methylthio group-1,3-benzo dioxole)-acetate.
MS[M]+＝450.0m/e；
1H-NMR(400MHz，DMSO-d
6)8.43(s，1H)，8.08-7.94(m，4H)，7.57(m，2H)，7.06(s，1H)，6.89-6.84(m，2H)，6.52(t，1H)，4.38(s，2H)，2.97(d，2H)，2.24(s，3H)
Embodiment 12:2-(5-{[4-methyl-2-(1,3-benzo dioxole-5-yl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate
Adopt the preparation method of embodiment 1, change intermediate 17 wherein into intermediate 28, get the 2-(5-{[4-methyl-2-(1,3-benzo dioxole-5-yl)-1 of light yellow amorphous solid, 3-thiazole-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate.
MS[M]+＝444.0m/e；
1H-NMR(400MHz，DMSO-d
6)12.77(brs，1H)，7.35-7.33(m，2H)，7.02-6.97(m，2H)，6.84(s，2H)，6.52(t，1H)，6.09(s，2H)，4.31(s，2H)，2.96(d，2H)，2.16(s，3H)
Embodiment 13:2-[5-(2-{4-[(4-ethyl) phenyl] phenoxy group } ethylmercapto group)-1,3-benzo dioxole]-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 29,2-[5-(2-{4-[(4-ethyl) phenyl of light yellow amorphous solid] phenoxy group ethylmercapto group)-1,3-benzo dioxole]-acetate.
MS[M]+＝437.0m/e；
1H-NMR(400MHz，DMSO-d
6)7.44-7.36(m，4H)，7.15(d，2H)，6.98(s，1H)，6.85-6.79(m，4H)，6.47(s，1H)，4.26(t，2H)，3.15(t，2H)，2.74(s，2H)，2.55(q，2H)，1.18(t，3H)
Embodiment 14:2-{5-[2-(carbazole-9-yl) ethylmercapto group]-1,3-benzo dioxole }-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 30,2-{5-[2-(carbazole-9-yl) ethylmercapto group of light yellow amorphous solid]-1,3-benzo dioxole }-acetate.
MS[M]+＝406.0m/e；
1H-NMR(400MHz，CDCl
3)8.07(m，2H)，7.47(m，4H)，7.25(m，2H)，6.96(s，1H)，6.80(m，2H)，6.44(s，1H)，4.21(t，2H)，3.28(t，2H)，2.70(s，2H)
Embodiment 15:2-{5-[2-(thiodiphenylamine-10-yl) ethylmercapto group]-1,3-benzo dioxole }-acetate
Adopt the preparation method of embodiment 1, change wherein intermediate 17 into intermediate 31,2-{5-[2-(thiodiphenylamine-10-yl) ethylmercapto group of light yellow amorphous solid] 1,3-benzo dioxole }-acetate.
MS[M]+＝438.0m/e；
1H-NMR(400MHz，CDCl
3)7.38-7.03(m，8H)，6.97(s，1H)，6.82(m，2H)，6.46(s，1H)，4.18(t，2H)，3.24(t，2H)，2.72(s，2H)。
Embodiment 16: the part The compounds of this invention is to the agonism of PPAR
The 293-T cell inoculation is gone into 48 orifice plates, and cell density is 2-4 * 10
4Individual/hole, nutrient solution is 1640 substratum of the no phenol red antibiotic-free of 10% degreasing foetal calf serum (FCS).After 48 hours, nutrient solution is replaced by 1640 substratum of the no phenol red antibiotic-free of 5% degreasing FCS, then respectively the pM-hPPAR/GAL4 of three kinds of hypotypes, pB4-RES-tk-luc and three kinds of plasmid cotransfections of pRL-CMV-Rluc in the 293-T cell, administration after 24 hours, with the positive control drug of dual agonists GW409544, with the positive control drug of GW501516 as the δ hypotype as α and γ hypotype.Detected the intensity of luciferase after the administration in 24 hours, the result is with PPAR activation energy (with respect to the value of control drug (100%)) and to the EC of PPAR δ
50Value representation sees Table 1 and table 2 respectively.
Table 1. part The compounds of this invention is to the agonism of PPAR
Table 2. part The compounds of this invention is to the EC of PPAR δ
50Value
| Compound | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 |
| EC50(uM) | 0.396 | 0.084 | 0.092 | 0.416 | 0.149 |
| Compound | Embodiment 7 | Embodiment 9 | Embodiment 10 | Embodiment 11 | Embodiment 12 |
| EC50(uM) | 0.147 | 1.042 | 0.684 | 0.117 | 0.454 |
Claims (13)
1. compound of Formula I, or its pharmacologically acceptable salt,
Wherein:
R
1Be H or C
1-C
6The straight or branched alkyl;
R
2Be H;
M is 1;
N is 1;
X
1Be S;
X
2For not existing;
X
3For not existing;
Ar
1Be aromatic heterocycle, it is a thiazole ring, and it can choose individual following substituting group replacement: the C that is selected from by 1-5 wantonly
1-C
6The straight or branched alkyl;
Ar
2Be selected from aromatic carbocyclic or aromatic heterocycle, ring wherein is monocycle or dicyclo; Each ring is made up of 5-6 atom, comprises in the described aromatic heterocycle that 1-4 is selected from the heteroatoms of O, S, and described aromatic carbocyclic or aromatic heterocycle can be chosen wantonly and be selected from following substituting group by 1-5 and replace: halogen, trifluoromethyl, C
1-C
6The straight or branched alkyl, C
1-C
4Alkoxyl group.
2. the compound of claim 1, it is selected from:
2-{5-[(4-methyl-2-phenyl-1,3-thiazoles-5-yl)-and methylthio group]-1,3-benzo dioxole }-acetate;
2-(5-{[4-methyl-2-(4-trifluoromethyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(4-bromophenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(4-fluorophenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(4-p-methoxy-phenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(3, the 5-Dimethoxyphenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(2,4 dichloro benzene base)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(4-tert-butyl-phenyl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(thiophene-2-yl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(thiene-3-yl-)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
2-(5-{[4-methyl-2-(naphthalene-2-yl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate; With
2-(5-{[4-methyl-2-(1,3-benzo dioxole-5-yl)-1,3-thiazoles-5-yl]-methylthio group }-1,3-benzo dioxole)-acetate;
Or its pharmacologically acceptable salt.
3. prepare the method for the described compound of claim 1, it may further comprise the steps:
1) in the presence of bromine and Sodium Bromide, pyrocatechol and Sodium Thiocyanate 99 are reacted the compound that obtains formula III, with the compound and the triethyl orthoformate reaction of formula III, obtain the compound of formula IV;
2) compound of formula IV is used earlier sodium borohydride reduction, then the intermediate with formula V reacts in the presence of alkali,
Wherein, Ar
1, Ar
2, X
2, X
3, the definition of n is with claim 1, and X is a halogen, obtains the compound of formula VI,
Wherein, Ar
1, Ar
2, X
2, X
3, the definition of n is with claim 1;
3) make compound deprotection in the presence of tosic acid of formula VI, obtain X
1Be the formula VII compound of S,
4) compound of formula VII and the compound of formula VIII are reacted:
Wherein, R
1Be C
1-C
6The straight or branched alkyl, R
2Define with claim 1, obtain wherein m=1, X
1Compound for the general formula I of S:
I
Wherein, Ar
1, Ar
2, X
2, X
3, n and R
2Definition with claim 1, R
1Be C
1-C
6The straight or branched alkyl;
Randomly, with the above-mentioned R that obtains
1Be C
1-C
6The compound of general formula I of straight or branched alkyl and the alkali metal hydroxide reaction or be selected from dilute hydrochloric acid, trifluoroacetic acid-respons, obtain m=1, X through hydrolysis
1Be S, R
1Compound for the following general formula I of H:
Wherein, Ar
1, Ar
2, X
2, X
3, n, R
2Definition with claim 1.
4. the method for claim 3, wherein step 2) described in alkali be selected from sodium hydroxide, cesium carbonate, salt of wormwood.
5. the raceme of the compound of claim 1.
6. medicinal compositions, it contains among the claim 1-2 each compound, or its pharmacologically acceptable salt, or the raceme of claim 5, and at least a pharmaceutically acceptable carrier or vehicle.
7. the composition of claim 6, wherein said vehicle is a thinner.
8. each compound is used to prepare the purposes of the medicine of the disease, risk factor or the illness that treat and/or prevent hPPAR mediation among the claim 1-2.
9. the purposes of claim 8, wherein said disease, risk factor or illness are hyperlipemia, hyperglycemia, type i diabetes, type ii diabetes, insulin resistance, diabetic complication, anti-sugared functional defect, cardiovascular disease, obesity, apocleisis, exessive appetite.
10. the purposes of claim 9, wherein said cardiovascular disease is an atherosclerosis.
11. the purposes of claim 8, wherein said disease, risk factor or illness are hyperlipidaemia, X syndrome, heart failure, bulimia nervosa.
12. the purposes of claim 8, wherein said disease, risk factor or illness are hypercholesterolemia.
13. each compound is used to prepare the purposes of the medicine that activates hPPAR among the claim 1-2.
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| PCT/CN2006/000373 WO2007085136A1 (en) | 2006-01-24 | 2006-03-13 | 1,3-benzodioxolecyclopentene derivates, preparation process and medical uses thereof |
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| EP2025674A1 (en) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs |
| WO2011107494A1 (en) | 2010-03-03 | 2011-09-09 | Sanofi | Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof |
| EP2582709B1 (en) | 2010-06-18 | 2018-01-24 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
| US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
| TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
| TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
| TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
| WO2012120054A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
| US8901114B2 (en) | 2011-03-08 | 2014-12-02 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
| US8871758B2 (en) | 2011-03-08 | 2014-10-28 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
| EP2683704B1 (en) | 2011-03-08 | 2014-12-17 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
| EP2683699B1 (en) | 2011-03-08 | 2015-06-24 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
| WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| JOP20190024A1 (en) | 2016-08-26 | 2019-02-19 | Gilead Sciences Inc | Substituted pyrrolizine compounds and uses thereof |
| EP3759109B1 (en) | 2018-02-26 | 2023-08-30 | Gilead Sciences, Inc. | Substituted pyrrolizine compounds as hbv replication inhibitors |
| CA3098428A1 (en) | 2018-04-18 | 2019-10-24 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| CA3100977A1 (en) | 2018-05-21 | 2019-11-28 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
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| James A. Turner, et al,.Origin of enantiomeric selectivity inthearyloxyphenoxypropionic acid class of herbicidalacetylcoenzyme A carboxylase (ACCase) inhibitors.J. Agric. Food. Chem.50 16.2002,50(16),第4562页Scheme 1,化合物7,7a. * |
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Assignee: Hunan Coloured Hiboi Biological Pharmaceutical Co., Ltd. Assignor: Institute of Poisonous Substance and Medicine of Military of Military academy of medical sciences of Contract record no.: 2011430000205 Denomination of invention: Benzodioxole derivatives and their preparation method and medicinal uses Granted publication date: 20110126 License type: Exclusive License Open date: 20070801 Record date: 20111008 |
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