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CN1571766A - Novel compounds, their preparation and use - Google Patents

Novel compounds, their preparation and use Download PDF

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Publication number
CN1571766A
CN1571766A CNA028205472A CN02820547A CN1571766A CN 1571766 A CN1571766 A CN 1571766A CN A028205472 A CNA028205472 A CN A028205472A CN 02820547 A CN02820547 A CN 02820547A CN 1571766 A CN1571766 A CN 1571766A
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group
methyl
phenyl
penta
alkene
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P·绍尔博格
P·S·布里
L·杰普森
J·P·莫根森
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Novo Nordisk AS
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Abstract

本发明公开了新的一类二羧酸衍生物、这些化合物作为药物组合物的应用、包含所述化合物的药物组合物及应用这些化合物和组合物的治疗方法。本发明化合物可用于治疗和/或预防过氧化物酶体增生物活化的受体(PPAR)介导的状况。The invention discloses a new class of dicarboxylic acid derivatives, the application of these compounds as pharmaceutical compositions, the pharmaceutical composition containing the compounds and the treatment method using these compounds and compositions. The compounds of the invention are useful in the treatment and/or prevention of peroxisome proliferator-activated receptor (PPAR) mediated conditions.

Description

Dicarboxylic acid derivatives, its preparation and treatment are used
Technical field
The present invention relates to new dicarboxylic acid derivatives, these compounds as the application of pharmaceutical composition, comprise the pharmaceutical composition of described compound and use the methods of treatment of these compounds and composition.Body more, The compounds of this invention can be used for treating and/or preventing the situation of peroxisome Proliferators activated receptors (PPAR) mediation.
Background technology
Coronary artery disease (CAD) is the dead main inducing of 2-type diabetes and patients with metabolic syndrome (drop on promptly that impaired glucose is stood, the patient of insulin resistance, hypertriglyceridemia and/or fat " fatal quartet " scope).
The fibrate and the antidiabetic thiazolidinedione that reduce piarhemia have shown that respectively appropriateness effectively reduces the tri-glyceride activity, although they were both also effective inadequately effectively inadequately, can't select as the treatment of frequent observed dyslipidaemia in 2-type diabetes or patients with metabolic syndrome separately.Thiazolidinedione also reduces 2-type diabetes animal model and people's circulating-glucose levels effectively.But the fibrate compounds does not have useful effect to glucemia.To studies show that of the molecularity of these compounds, thiazolidinedione and fibrate cause the expression with reducing of the increase of certain enzyme and lipophorin (the two is all playing an important role aspect the adjusting plasma triglyceride content) to play a role respectively by the different transcription factor of activation peroxisome Proliferators activated receptors (PPAR) family.On the one hand, fibrate is a PPAR α activator, mainly plays a role at liver.On the other hand, thiazolidinedione is the high-affinity part of PPAR γ, mainly fatty tissue is had effect.
Fatty tissue is in vertebrate lipid running balance and keep and play central role aspect the energy balance.Adipocyte is in overnutrition form storage power with tri-glyceride in the stage, and the form with free fatty acids releases energy when under-nutrition.The development of white adipose tissue is the result who runs through the continuous discrimination process in all one's life.A lot of signs have shown that PPAR γ activation is starting and regulating the center role of this cell in distinguishing.Distinguish at adipocyte to induce several highly single-minded protein in the process, the major part in them involves the storage and the metabolism of lipid.The accurate contact that PPAR γ activation and glucose metabolism change between (the most significant is the reduction of insulin resistance in muscle) is not clear.A kind of possible contact is by free fatty acids, makes the activation of PPAR γ at fatty tissue but not induce lipoprotein lipase (LPL) in the muscle tissue, fatty acid transport protein (FATP) and acyl group-CoA synthetic enzyme (ACS).This significantly reduces the concentration of free fatty acids in blood plasma again, and because the substrate competition on the cell levels, skeletal muscle and other tissue with hypermetabolism speed finally turn to glucose oxidase by Fatty Acid Oxidation, and the result has reduced insulin resistance.
In the lipid acid β-Yang Hua that stimulates, relate to PPAR α.In rodent, the change of related expression of gene is based upon peroxysome hyperplasia (a kind of polydirectional cellular response in the alpha mediated fatty acid metabolism of PPAR, mainly be confined in liver and the kidney, and can in rodent, cause liver cancer to take place) on the basis of phenomenon.Described peroxysome hyperplasia phenomenon is not found in human body.Except the effect in rodent peroxysome hyperplasia, PPAR α also participates in the control of HDL cholesterol levels in rodent and human body.This effect is based on the alpha mediated main HDL lipophorin of PPAR, the i.e. transcriptional regulatory of apoA-l and apoA-II at least in part.The reduction blood triglyceride effect of Fibrate and lipid acid also relates to PPAR α, and can be summarized as follows: (I) because steatolysis and removing to the increase of remainder particulate that the variation of lipoprotein lipase and apoC-III causes; (II) by induced lipolysis acid bonding albumen and acyl group-CoA synthetic enzyme, the lipid acid of irritation cell absorbs and subsequent transformation is acyl group-CoA derivative; (III) induced lipolysis acid β-Yang Hua path; (IV) reducing lipid acid and tri-glyceride synthesizes; Reducing VLDL with last (V) produces.Therefore, the mechanism of fibrate reduction piarhemia effect comprises the katabolism of rich tri-glyceride particulate raising and the VLDL particulate secretion of reduction.
Report at first, the adjusting of glucose and triglyceride level do not relate to PPAR δ activation (Berger et al., J.Biol.Chem., 1999, Vol 274, pp.6718-6725).Show afterwards, and the HDL cholesterol levels that the activation of PPAR δ causes increasing in the dbldb mouse (Leibowitz et al.FEBS letters 2000,473,333-336).And, under the situation of fasting tri-glyceride and fasting Regular Insulin, when the rhesus monkey of the obesity in the middle age that is administered into synalbumin, the PPAR delta agonists causes that the serum hdl cholesterol of tangible dependent dose raises, and level (the Oliver et al.PNAS 2001 of reduction low density LDL, 98,5306-5311).Same piece of writing article shows that also the activation of PPAR δ has increased reverse cholesterol transport albumin A TP binding substances A1 and induced aPoA 1 specific cholesterol effluent.Integrate, these results hint PPAR δ activation in treatment and preventing cardiovascular disease and situation, comprise in atherosclerosis, hypertriglyceridemia and the blended dyslipidaemia it being useful people such as (PCT application WO01/00603 () Chao).
Chemical compound lot has been in the news and has can be used for treating hyperglycemia, hyperlipidaemia and hypercholesterolemia (U.S.P.5,306,726, PCT applies for WO 91/19702, WO95/03038, and WO 96/04260, WO 94/13650, WO 94/01420, WO97/36579, and WO 97/25042, WO 95/17394, WO 99/08501, and WO 99/19313, WO 99/16758 and WO 01/00603).WO 99/63983 discloses the many binding compounds (multibindingcompound) that are attached on the PPAR γ acceptor.
As single method, glucose reduces can not overcome the big vascular complication relevant with metabolism syndrome with 2-type diabetes.Therefore, the new methods of treatment of 2-type diabetes and metabolism syndrome must can either reduce the tangible hypertriglyceridemia relevant with these syndromes, can relax hyperglycemia again.
This shows, PPAR α to showed different, the research of the compound of PPAR γ and PPAR δ activation should cause finding effectively to reduce the medicine of tri-glyceride and/or cholesterol and/or glucose, this medicine can be used for the treatment of disease probably, 2-type diabetes for example, dyslipidaemia, syndrome X (comprise metabolism syndrome, promptly impaired glucose is stood, insulin resistance, hypertriglyceridemia and/or obesity), cardiovascular disorder (comprising atherosclerosis) and hypercholesterolemia.
Definition
In the structural formula and whole specification sheets that this paper provides, following term has described implication:
When using herein, wherein n ' can be the term " C of 2-6 1-n '-alkyl " expression has the straight chain of described carbonatoms or a saturated hydrocarbon chain of branching.Such examples of groups includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, isohexyl etc.
When being used alone or in combination herein, wherein n ' can be the term " C of 4-6 3-n '-cycloalkyl " expression has the saturated monocycle alkyl of described carbonatoms.Such examples of groups includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
When using herein, wherein n ' can be the term " C of 2-6 1-n '-alkylidene group " expression has the saturated hydrocarbon chain of described carbonatoms, divalence, straight chain or branching.Such examples of groups includes but not limited to methylene radical, ethylidene, trimethylene, tetramethylene, propylene, 1,2-butylidene, methyl isophthalic acid, 2-propylidene, ethyl-propylene etc.
When using herein, wherein n ' can be the term " C of 5-6 4-n '-cycloalkylidene " expression has a divalence saturated mono cyclic hydrocarbon radical of described carbonatoms.Such examples of groups includes but not limited to cyclopentylidene, cyclohexylidene etc.
When using herein, wherein n ' can be the term " C of 3-6 2-n '-alkenyl " expression have 2 to the carbon atom of specified number and have at least one two key, the undersaturated branching of olefinic or straight-chain alkyl.Such examples of groups includes but not limited to vinyl, 1-propenyl, 2-propenyl, allyl group, different-propenyl, 1,3-butadiene base, 1-butylene base, hexenyl, pentenyl etc.
When using herein, wherein n ' can be the term " C of 3-6 2-n '-alkylene group " expression has 2 to the carbon atom of specified number and have at least one two key, divalence, undersaturated branching of olefinic or straight-chain alkyl.Such examples of groups include but not limited to vinylidene (CH=CH-), each propenylidene isomer (for example-CH 2CH=CH-and-C (CH 3)=CH-), each crotonylidene isomer (for example-CH 2CH=C (CH 3)-and-CH 2CH 2CH=CH-) etc.
When using herein, term " C 4-n '-Ene alkynyl base " expression has 4 to the carbon atom of specified number and have at least one two key and at least one triple-linked, undersaturated branching or straight-chain alkyl.Such examples of groups includes but not limited to 1-amylene-4-alkynes, pirylene, 1,3-hexadiene-5-alkynes etc., preferred especially 1-amylene-4-alkynes.
When using herein, wherein n ' can be the term " C of 5-6 4-n '-Ya cycloalkenyl group " expression has 4 to the carbon atoms of specified number and at least one two key, divalence, unsaturated monocyclic hydrocarbon base.Such examples of groups includes but not limited to phenylidene etc.
When using herein, wherein n ' can be the term " C of 4-6 3-n '-alkynyl " expression has 2 to the carbon atom of specified number and have at least one triple-linked, undersaturated, branching or straight-chain alkyl.Such examples of groups includes but not limited to 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base etc.
When using herein, wherein n ' can be the term " C of 3-6 2-n '-alkynylene " expression have 2 to the carbon atom of specified number and have at least one triple-linked, divalence, undersaturated, branching or straight-chain alkyl.Such examples of groups includes but not limited to inferior proyl (CH 2C ≡ C-), each butynelene isomer (for example-CH 2CH 2C ≡ C-and-CH 2C ≡ CCH 2-) etc.
When using herein, wherein n ' can be the term " C of 5-9 4-n '-Ya Ene alkynyl base " expression has 4 carbon atoms to specified number, and have at least one two key and at least one triple-linked, divalence, undersaturated, branching or straight-chain alkyl.Such examples of groups includes but not limited to inferior 1-amylene-4-alkynyl, inferior pirylene base, Asia 1,3-hexadiene-5-alkynyl etc.
When using herein, wherein n ' can be the term " C of 4-9 3-n '-divalence unsaturated carbon chains " expression has 3 carbon atoms to specified number, and have at least one two key (alkenylene) or at least one triple bond (alkynylene) or its combination is (inferior Ene alkynyl base), divalence, undersaturated, branching or straight-chain alkyl.Such examples of groups include but not limited to vinylidene (CH=CH-), each propenylidene isomer (for example-CH 2CH=CH-and-C (CH 3)=CH-), each crotonylidene isomer (for example-CH 2CH=C (CH 3)-and-CH 2CH 2CH=CH-), inferior proyl (CH 2C ≡ C-), each butynelene isomer (for example-CH 2CH 2C ≡ C-,-CH 2C ≡ CCH 2-), inferior 1-amylene-4-alkynyl, inferior pirylene base, inferior 1,3-hexadiene-5-alkynyl etc.
When being used alone or in combination herein, wherein n ' can be the term " C of 2-6 1-n '-alkoxyl group " be meant that free valence bond is from straight chain or branched structure ether oxygen, that pass through the connection of ether oxygen.The example of such straight chain alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy etc.The example of such branched alkoxy includes but not limited to isopropoxy, sec-butoxy, tert.-butoxy, isopentyloxy, different hexyloxy etc.
When being used alone or in combination herein, wherein n ' can be the term " C of 4-6 3-n '-cycloalkyloxy " be meant that free valence bond is from ether oxygen, that connect by ether oxygen, monocycle alkyl that have described carbonatoms, saturated.The example of such cycloalkyloxy includes but not limited to encircle propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
When being used alone or in combination herein, wherein n ' can be the term " C of 2-6 1-n '-alkylthio " be meant connect by bivalent sulfur atom, free valence bond from sulphur atom and have 1-6 carbon atom, comprise C 1-6The straight chain of alkyl or branching unit price substituting group.Such examples of groups includes but not limited to methylthio group, ethylmercapto group, rosickyite base, butylthio, penta sulfenyl etc.
When being used alone or in combination herein, wherein n ' can be the term " C of 4-6 3-n '-cycloalkylthio " be meant connect by bivalent sulfur atom, free valence bond is from sulphur atom, have described carbonatoms, saturated mono cyclic hydrocarbon radical.The example of such cycloalkyloxy includes but not limited to encircle rosickyite base, ring butylthio, ring penta sulfenyl, hexamethylene sulfenyl etc.
Term used herein " aryl " is meant aromatic series monocycle or aromatic series condensed-bicyclic or tricyclic hydrocarbon base.Such examples of groups includes but not limited to phenyl, naphthyl, anthryl, phenanthryl, Azulene base etc.
Term used herein " arylidene " is meant the aromatic series monocycle of divalence or the aromatic series condensed-bicyclic or the tricyclic hydrocarbon base (derived from aryl) of divalence.Such examples of groups includes but not limited to phenylene, naphthylidene etc.
When being used alone or in combination herein, term " heteroaryl " is meant divalent substituent, it comprises and contains one or more nitrogen that are selected from, the bicyclic condensed aroma system of heteroatomic 5-7 unit's monocycle aroma system or 8-10 unit of oxygen and sulphur, or contain one or more nitrogen that are selected from, the heteroatomic 10-16 of oxygen and sulphur first tricyclic condensed aroma system, for example furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, pyrazinyl, pyrimidyl, pyridazinyl, isothiazolyl isoxazolyl oxazolyl oxadiazole base, thiadiazolyl group, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, indyl, benzimidazolyl-, benzofuryl, pteridine radicals, purine radicals, carbazyl, the β-Ka Lin base, acridyl, the phenanthroline base, phenazinyl phenoxazinyl, phenothiazinyl etc.
When being used alone or in combination herein, term " inferior heteroaryl " is meant divalent substituent (derived from heteroaryl), it comprises and contains one or more nitrogen that are selected from, heteroatomic 5-7 unit's monocycle aroma system of oxygen and sulphur or 8-10 unit Bicyclic system, or contain one or more nitrogen that are selected from, the heteroatomic 10-16 of oxygen and sulphur first tricyclic condensed aroma system, for example furylidene, inferior thienyl, inferior pyrryl, inferior imidazolyl, inferior pyrazolyl, inferior triazolyl, inferior pyrazinyl, inferior pyrimidyl, inferior pyridazinyl, inferior isothiazolyl Ya isoxazolyl Ya oxazolyl Ya oxadiazole base, inferior thiadiazolyl group, quinolinediyl, inferior isoquinolyl, inferior quinazolyl, inferior quinoxalinyl, inferior indyl, inferior benzimidazolyl-, inferior benzofuryl, inferior pteridine radicals, inferior purine radicals, inferior carbazyl, inferior β-Ka Lin base, inferior acridyl, inferior phenanthroline base, inferior phenazinyl Ya phenoxazinyl, inferior phenothiazinyl etc.
When using herein, term " divalence is encircled ring system more " is meant the divalent group that is formed by the many rings ring system that contains by a singly linked 2-4 independent of each other aryl or heteroaryl ring system.Have 2 to 4 identical aryl ring systems this inferior two-, three-and tetra-arylated example include but not limited to biphenylene, inferior binaphthylyl, inferior terphenyl, inferior three binaphthylyl, inferior tetrad phenyl, inferior tetrad naphthyl etc.Have 2 to 4 identical heteroaryl ring systems this inferior two-, three-and the example of four heteroaryls include but not limited to inferior bipyridyl, inferior biindolyl base, inferior terpyridyl base, inferior three biindolyl bases, inferior tetrad pyridyl, inferior tetrad indyl etc.Example with this many ring ring systems of ring system inequality includes but not limited to biphenyl-pyridine etc.
When using herein, term " aralkoxy " is meant the C that is replaced by aromatic hydrocarbon 1-6Alkoxyl group, for example benzyloxy, benzene oxyethyl group, 3-phenyl propoxy-, 1-naphthyl methoxyl group, 2-(1-naphthyl) oxyethyl group etc.
When using herein, term " aralkyl " is meant the straight or branched saturated carbon chains that is replaced by aromatic hydrocarbon, contain 1-6 carbon atom, for example benzyl, styroyl, 3-phenyl propyl, 1-naphthyl methyl, 2-(1-naphthyl) ethyl etc.
Term " halogen " is meant fluorine, chlorine, bromine or iodine.
Term used herein " treatment " comprises treatment, prevention and handles the situation that is mediated by peroxisome Proliferators activated receptors (PPAR).
More than some term defined above may occur once in structural formula, and in this case, each term should be defined independently of one another.
Term used herein " optional replacement " is meant that the group of being discussed is not substituted, and perhaps appointed one or more substituting groups replace.When the group of being discussed was replaced by an above substituting group, described substituting group can be identical or different.
Summary of the invention
The present invention relates to the compound of general formula (I), or its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing, or any tautomer, steric isomer, the mixture of steric isomer (comprising racemic mixture), or polymorph:
Figure A0282054700331
Wherein
A is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio or aralkoxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen or C 1-3-alkyl, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or arylidene, it is chosen wantonly and is replaced by one or more halogens;
Zero R 4The optional aryl that is replaced by one or more halogens of expression; Or
A is-O-A ' or-S-A ', wherein-O-or-S-is connected on the X in the formula (I), and wherein A ' is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio or aralkoxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen or C 1-3-alkyl, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or arylidene, it is chosen wantonly and is replaced by one or more halogens;
Zero R 4The optional aryl that is replaced by one or more halogens of expression; And
B is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio or aralkoxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen or C 1-3-alkyl, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or arylidene, it is chosen wantonly and is replaced by one or more halogens;
Zero R 4The optional aryl that is replaced by one or more halogens of expression; Or
B is-O-B ' or-S-B ', wherein-O-or-S-is connected on the Y in the formula (I), and wherein B ' is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio or aralkoxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen or C 1-3-alkyl, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or arylidene, it is chosen wantonly and is replaced by one or more halogens;
Zero R 4The optional aryl that is replaced by one or more halogens of expression; And
D is H, C 1-6-alkyl or C 3-6-cycloalkyl; And
E is H, C 1-6-alkyl or C 3-6-cycloalkyl; And
L and M be independently-O-or-S-; And
T is C 3-9The divalence unsaturated carbon chains optional be selected from following substituting group and replace by one or more:
● halogen or hydroxyl; Or
● aryl, aralkoxy or C 1-3-alkoxyl group, it is chosen wantonly and is replaced by halogen; And
U is C 3-9The divalence unsaturated carbon chains optional be selected from following substituting group and replace by one or more:
● halogen or hydroxyl; Or
● aryl, aralkoxy or C 1-3-alkoxyl group, it is chosen wantonly and is replaced by halogen; And
X is arylidene or inferior heteroaryl, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen or hydroxyl; Or
● C 1-6-alkyl, C 3-6-cycloalkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio, aforementioned each group is optional to be replaced by one or more halogens; Or
Y is arylidene or inferior heteroaryl, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen or hydroxyl; Or
● C 1-6-alkyl, C 3-6-cycloalkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio, aforementioned each group is optional to be replaced by one or more halogens; Or
Z is that arylidene, inferior heteroaryl or divalence are encircled ring system more, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen, oxo or hydroxyl; Or
● C 1-6-alkyl, C 3-6-cycloalkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio, aforementioned each group is optional to be replaced by one or more halogens.
In one embodiment, the present invention relates to formula (I) compound, wherein A is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● methyl, C 1-3-alkoxyl group, C 3-6-cycloalkyloxy, or benzyloxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or the optional phenylene that is replaced by one or more halogens;
Zero R 4The optional phenyl that is replaced by one or more halogens of expression.
In another embodiment, the present invention relates to formula (I) compound, wherein A is methylene radical or ethylidene, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● methoxy or ethoxy; Or
● NR 1R 2, R wherein 1Expression hydrogen, R 2Expression-R 3-(C=O)-R 4, R wherein 3And R 4The expression phenyl.
In another embodiment, the present invention relates to formula (I) compound, wherein A is an ethylidene, and it is chosen wantonly and is replaced by oxyethyl group.
In another embodiment, the present invention relates to formula (I) compound, wherein A be-O-A ' or-S-A ', wherein-O-or-S-is connected on the X in the formula (I), and wherein A ' is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy or aralkoxy, aforementioned each group is optional to be replaced by halogen.
In another embodiment, the present invention relates to formula (I) compound, wherein A be-O-A ' or-S-A ', wherein-O-or-S-is connected on the X in the formula (I), and wherein A ' is methylene radical or ethylidene, aforementioned each group is optional by one or more methyl that are selected from, and the substituting group of methoxy or ethoxy replaces.
In another embodiment, the present invention relates to formula (I) compound, wherein B is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● methyl, C 1-3-alkoxyl group, C 3-6-cycloalkyloxy, or benzyloxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or the optional phenylene that is replaced by one or more halogens;
Zero R 4The optional phenyl that is replaced by one or more halogens of expression.
In another embodiment, the present invention relates to formula (I) compound, wherein B is methylene radical or ethylidene, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● methoxy or ethoxy; Or
● NR 1R 2, R wherein 1Expression hydrogen, R 2Expression-R 3-(C=O)-R 4, R wherein 3And R 4The expression phenyl.
In another embodiment, the present invention relates to formula (I) compound, wherein B is an ethylidene, and it is chosen wantonly and is replaced by oxyethyl group.
In another embodiment, the present invention relates to formula (I) compound, wherein B be-O-B ' or-S-B ', wherein-O-or-S-is connected on the Y in the formula (I), and wherein B ' is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy or aralkoxy, aforementioned each group is optional to be replaced by halogen.
In another embodiment, the present invention relates to formula (I) compound, wherein B be-O-B ' or-S-B ', wherein-O-or-S-is connected on the Y in the formula (I), and wherein B ' is methylene radical or ethylidene, aforementioned each group is optional by one or more methyl that are selected from, and the substituting group of methoxy or ethoxy replaces.
In another embodiment, the present invention relates to formula (I) compound, wherein D is H.
In another embodiment, the present invention relates to formula (I) compound, wherein D is methyl or ethyl.
In another embodiment, the present invention relates to formula (I) compound, wherein E is H.
In another embodiment, the present invention relates to formula (I) compound, wherein E is methyl or ethyl.
In another embodiment, the present invention relates to formula (I) compound, wherein L is-O-.
In another embodiment, the present invention relates to formula (I) compound, wherein L is-S-.
In another embodiment, the present invention relates to formula (I) compound, wherein M is-O-.
In another embodiment, the present invention relates to formula (I) compound, wherein M is-S-.
In another embodiment, the present invention relates to formula (I) compound, wherein T is C 3-9The divalence unsaturated carbon chains optional be selected from following substituting group and replace by one or more: phenyl, benzyloxy or C 1-3-alkoxyl group, it is chosen wantonly and is replaced by halogen.
In another embodiment, the present invention relates to formula (I) compound, wherein T is unsubstituted C 3-9The divalence unsaturated carbon chains.
In another embodiment, the present invention relates to formula (I) compound, wherein T is C 3-9Alkenylene.
In another embodiment, the present invention relates to formula (I) compound, wherein T is C 3-9Alkynylene.
In another embodiment, the present invention relates to formula (I) compound, wherein T is C 5-9Inferior Ene alkynyl base.
In another embodiment, the present invention relates to formula (I) compound, wherein U is C 3-9The divalence unsaturated carbon chains optional be selected from following substituting group and replace by one or more: phenyl, benzyloxy or C 1-3-alkoxyl group, it is chosen wantonly and is replaced by halogen.
In another embodiment, the present invention relates to formula (I) compound, wherein U is unsubstituted C 3-9The divalence unsaturated carbon chains.
In another embodiment, the present invention relates to formula (I) compound, wherein U is C 3-9Alkenylene.
In another embodiment, the present invention relates to formula (I) compound, wherein U is C 3-9Alkynylene.
In another embodiment, the present invention relates to formula (I) compound, wherein U is C 5-9Inferior Ene alkynyl base.
In another embodiment, the present invention relates to formula (I) compound, wherein X is arylidene or inferior heteroaryl, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● the optional C that is replaced by one or more halogens 1-6-alkyl.
In another embodiment, the present invention relates to formula (I) compound, wherein X is an arylidene, optional be selected from following substituting group and replace by one or more:
● halogen, or
● the optional C that is replaced by one or more halogens 1-6-alkyl.
In another embodiment, the present invention relates to formula (I) compound, wherein X is optional by one or more phenylenes that are selected from following substituting group replacement:
● halogen, or
● the optional C that is replaced by one or more halogens 1-3-alkyl.
In another embodiment, the present invention relates to formula (I) compound, wherein X is a phenylene, chooses wantonly to be replaced by one or more halogens.
In another embodiment, the present invention relates to formula (I) compound, wherein Y is arylidene or inferior heteroaryl, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● the optional C that is replaced by one or more halogens 1-6-alkyl.
In another embodiment, the present invention relates to formula (I) compound, wherein Y is an arylidene, optional be selected from following substituting group and replace by one or more:
● halogen, or
● the optional C that is replaced by one or more halogens 1-6-alkyl.
In another embodiment, the present invention relates to formula (I) compound, wherein Y is a phenylene, optional be selected from following substituting group and replace by one or more:
● halogen, or
● the optional C that is replaced by one or more halogens 1-3-alkyl.
In another embodiment, the present invention relates to formula (I) compound, wherein Y is the optional phenylene that is replaced by one or more halogens.
In another embodiment, the present invention relates to formula (I) compound, wherein Z is that arylidene, inferior heteroaryl or divalence are encircled ring system more, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen, oxo, or
● C 1-6-alkyl, C 1-6-alkoxyl group, aforementioned each group is optional to be replaced by one or more halogens.
In another embodiment, the present invention relates to formula (I) compound, wherein Z is selected from following groups;
Figure A0282054700401
It is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-6-alkyl or C 1-6-alkoxyl group, aforementioned each group is optional to be replaced by one or more halogens.
In another embodiment, the present invention relates to formula (I) compound, wherein Z is selected from following groups:
In another embodiment, the present invention relates to formula (I) compound, wherein Z is selected from following groups:
Figure A0282054700412
In another embodiment, the present invention relates to compound as the described general formula of general formula (II) (I), or its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing, or any tautomer, steric isomer comprises the mixture of the steric isomer of racemic mixture or polymorph:
D wherein, A, X, L, Z, U, M, Y, B and E such as formula (I) or in any above-mentioned preferred embodiment definition; And
G 1Be H, C 1-3-alkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen; With
G 2Be H, C 1-3-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6-Ene alkynyl base, aryl, aralkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen.
In another embodiment, the present invention relates to formula (II) compound, D wherein, A, X, L, Z, U, M, Y, B and E such as in formula (I) or any above-mentioned embodiment preferred definition; And
G 1Be H, C 1-3-alkyl or C 1-3-alkoxyl group, aforementioned each group is optional to be replaced by halogen; With
G 2Be H, C 1-3-alkyl or aryl, aforementioned each group is optional to be replaced by halogen.
In another embodiment, the present invention relates to formula (II) compound, D wherein, A, X, L, Z, U, M, Y, B and E such as formula (I) or in any above-mentioned embodiment preferred definition; And
G 1Be H; With
G 2Be H or methyl.
In another embodiment, the present invention relates to compound as the described general formula of general formula (III) (I), or its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing, or any tautomer, steric isomer comprises the mixture of the steric isomer of racemic mixture or polymorph:
Figure A0282054700421
D wherein, A, X, L, Z, M, Y, B and E such as general formula (I) or in any above-mentioned preferred embodiment definition; And
G 1And G 4Be H independently of one another, C 1-3-alkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen; With
G 2And G 3Be H independently of one another, C 1-3-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6-Ene alkynyl base, aryl, aralkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen.
In another embodiment, the present invention relates to formula (III) compound, D wherein, A, X, L, Z, M, Y, B and E such as formula (I) or in any above-mentioned preferred embodiment definition; And
G 1And G 4Be H independently of one another, C 1-3-alkyl or C 1-3-alkoxyl group, aforementioned each group is optional to be replaced by halogen; With
G 2And G 3Be H independently of one another, C 1-3-alkyl or aryl, aforementioned each group is optional to be replaced by halogen.
In another embodiment, the present invention relates to formula (III) compound, D wherein, A, X, L, Z, M, Y, B and E such as formula (I) or in any above-mentioned preferred embodiment definition; And
G 1And G 4Be H; With
G 2And G 3Be H or methyl independently of one another.
In another embodiment, the present invention relates to compound as the described general formula of general formula (IV) (I), or its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing, or any tautomer, steric isomer comprises the mixture of the steric isomer of racemic mixture or polymorph:
Figure A0282054700431
D wherein, A, X, L, Z, U, M, Y, B and E such as formula (I) or in any above-mentioned preferred embodiment definition; And
G 1Be H, C 1-3-alkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen; With
G 2Be H, C 1-3-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6-Ene alkynyl base, aryl, aralkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen.
In another embodiment, the present invention relates to formula (IV) compound, D wherein, A, X, L, Z, U, M, Y, B and E define suc as formula (I) or any above-mentioned embodiment preferred; And
G 1Be H, C 1-3-alkyl or C 1-3-alkoxyl group, aforementioned each group is optional to be replaced by halogen; With
G 2Be H, C 1-3-alkyl or aryl, aforementioned each group is optional to be replaced by halogen.
In another embodiment, the present invention relates to formula (IV) compound, D wherein, A, X, L, Z, U, M, Y, B and E define suc as formula (I) or any above-mentioned embodiment preferred; And
G 1Be H; With
G 2Be H or methyl.
In another embodiment, the present invention relates to compound as the logical described general formula of formula V (I), or its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing, or any tautomer, steric isomer comprises the mixture of the steric isomer of racemic mixture or polymorph:
D wherein, A, X, L, Z, M, Y, B and E are suc as formula (I) or any above-mentioned preferred
Embodiment defines; And
G 1And G 4Be H independently of one another, C 1-3-alkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen; With
G 2And G 3Be H independently of one another, C 1-3-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6-Ene alkynyl base, aryl, aralkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen.
In another embodiment, the present invention relates to the formula V compound, D wherein, A, X, L, Z, M, Y, B and E such as formula (I) or in any above-mentioned preferred embodiment definition; And
G 1And G 4Be H independently of one another, C 1-3-alkyl or C 1-3-alkoxyl group, aforementioned each group is optional to be replaced by halogen; With
G 2And G 3Be H independently of one another, C 1-3-alkyl or aryl, aforementioned each group is optional to be replaced by halogen.
In another embodiment, the present invention relates to the formula V compound, D wherein, A, X, L, Z, M, Y, B and E such as formula (I) or in any above-mentioned preferred embodiment definition; And
G 1And G 4Be H; With
G 2And G 3Be H or methyl independently of one another.
In another embodiment, if possible, the The compounds of this invention that the present invention relates to has transconfiguration.
In another embodiment, if possible, the The compounds of this invention that the present invention relates to has (S)-configuration.
In another embodiment, if possible, the The compounds of this invention that the present invention relates to has cis-configuration.
In another embodiment, the The compounds of this invention that the present invention relates to has blended PPAR α/PPAR γ mode of action.
In another embodiment, the The compounds of this invention that the present invention relates to has blended PPAR α/PPAR δ mode of action.
In another embodiment, the The compounds of this invention that the present invention relates to has blended PPAR γ/PPAR δ mode of action.
In another embodiment, the The compounds of this invention that the present invention relates to has blended PPAR α/PPAR γ/PPAR δ mode of action.
In another embodiment, the present invention relates to have the optionally The compounds of this invention of the PPAR α mode of action.
In another embodiment, the present invention relates to have the optionally The compounds of this invention of the PPAR γ mode of action.
In another embodiment, the present invention relates to have the optionally The compounds of this invention of the PPAR δ mode of action.
The example of particular compound of the present invention is:
2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
3-{4-[5-(4-{5-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-2-oxyethyl group-propionic acid;
3-chloro-4-(5-{4-[5-(3-chloro-4-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate;
[4-(5-{4-[5-(4-carboxyl methyl-3-chloro phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl]-acetate;
2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
3-[4-[5-(3-{5-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-2-oxyethyl group-propionic acid;
[3-chloro-4-(5-{3-[5-(2-chloro-4-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate;
[4-(5-{3-[5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl]-acetate;
2-(2-benzoyl-phenyl amino)-3-(4-{5-[4-(5-{4-[2-(2-benzoyl-phenyl amino)-2-methoxycarbonyl ethyl]-phenoxy group }-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-4-alkynyloxy base }-phenyl)-methyl propionate;
2-(2-benzoyl-phenyl amino)-3-(4-{5-[4-(5-{4-[2-(2-benzoyl-phenyl amino)-2-carboxyl-ethyl]-phenoxy group }-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-4-alkynyloxy base }-phenyl)-propionic acid;
2-oxyethyl group-3-{4-[3-(4 '-3-[4-(2-oxyethyl group-2-ethoxy carbonyl-ethyl)-phenoxy group]-1-methyl-propenyl }-biphenyl-4-yl)-but-2-ene base oxygen base]-phenyl }-ethyl propionate;
3-{4-[3-(4 '-3-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-1-methyl-propenyl }-biphenyl-4-yl)-but-2-ene base oxygen base]-phenyl }-2-oxyethyl group-propionic acid;
2-oxyethyl group-3-{4-[5-(7-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
3-{4-[5-(7-{5-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-2-oxyethyl group-propionic acid;
[4-(3-{3-[3-(4-methoxycarbonyl methyl-phenoxy group)-third-1-alkynyl]-phenyl }-Propargyl oxygen base)-phenyl]-methyl acetate;
[4-(3-{3-[3-(4-methoxycarbonyl methyl-phenoxy group)-third-1-alkynyl]-phenyl }-Propargyl oxygen base)-phenyl]-acetate;
[4-(5-4-[5-(4-methoxycarbonyl methoxyl group-3-methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-2-methyl-phenoxy group]-methyl acetate;
[4-(5-(4-[5-(4-methoxycarbonyl methoxyl group-3-methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-2-methyl-phenoxy group]-acetate;
3-{3-bromo-4-[5-(4-{5-[2-bromo-4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-2-oxyethyl group-ethyl propionate;
3-{3-bromo-4-[5-(4-{5-[2-bromo-4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-2-oxyethyl group-propionic acid;
[3-(5-{4-[5-(3-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate;
[3-(5-{4-[5-(3-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-acetate;
2-oxyethyl group-3-{4-[5-(4 '-5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
2-oxyethyl group-3-{4-[5-(4 '-5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-propionic acid;
2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-propionic acid;
2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-propionic acid;
[4-(3-{7-[3-(4-methoxycarbonyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl]-9H-fluorenes-2-yl }-the allyl group sulfenyl)-2-methyl-phenoxy group]-methyl acetate; Or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of any optical isomer or optical isomer, comprise racemic mixture, or any tautomer.
Other example of particular compound of the present invention is:
(4-(3-(4 '-(3-(4-carboxyl methoxyl group-3-aminomethyl phenyl sulfenyl)-propenyl)-biphenyl-4-yl) the allyl group sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(3-(4 '-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-propenyl)-biphenyl-4-yl)-the allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-(2-carboxyl-2-ethoxyethyl group)-phenoxy group)-propenyl)-biphenyl-4-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-biphenyl-4-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-biphenyl-4-yl) the allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(3-(4 '-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-biphenyl-4-yl)-the allyl group sulfenyl)-2-methyl-phenoxy group)-acetate;
(4-(3-(4 '-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-biphenyl-4-yl)-allyloxy)-the 3-chlorophenyl)-acetate;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-biphenyl-4-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-biphenyl-4-yl)-the allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(3-(7-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-9H-fluorenes-2-yl)-allyl group sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(3-(7-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-9H-fluorenes-2-yl)-allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(7-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-9H-fluorenes-2-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
(4-(3-(7-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-9H-fluorenes-2-yl)-allyloxy)-3-chlorophenyl)-acetate;
3-(4-(3-(7-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-9H-fluorenes-2-yl)-allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(7-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-9H-fluorenes-2-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(7-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-propenyl)-9H-fluorenes-2-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(7-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-propenyl)-9H-fluorenes-2-yl)-allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(3-(7-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-9H-fluorenes-2-yl)-allyloxy)-3-chlorophenyl)-acetate;
3-(4-(3-(4 '-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base oxygen base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-1-methyl-propenyl)-xenyl-4-yl)-but-2-ene base sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(3-(4 '-(3-(4-carboxyl methyl-2-chloro phenoxy group)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base oxygen base)-the 3-chlorophenyl)-acetate;
(4-(3-(4 '-(3-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base oxygen base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base oxygen base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
4-(5-(4-(5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-3-chlorophenyl)-acetate;
4-(5-(4-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyloxy group)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
4-(5-(4 '-(5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl)-acetate;
4-(5-(4 '-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4 '-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(4 '-(5-(4-carboxyl methyl-2-chloro phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl)-acetate;
(4-(5-(4 '-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-xenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4 '-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-xenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
(4-(5-(4 "-(5-(4-carboxyl methyl-2-chloro phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl)-acetate;
(4-(5-(4 "-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4 "-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl oxygen base)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
4-(5-(4 "-(5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl)-acetate;
4-(5-(4 "-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4 "-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(4-(5-(4-carboxyl methyl-2-chloro phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-3-chlorophenyl)-acetate;
(4-(5-(4-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
4-(5-(3-(5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-3-chlorophenyl)-acetate;
4-(5-(3-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(3-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(3-(5-(4-carboxyl methyl-2-chloro phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-3-chlorophenyl)-acetate;
(4-(5-(3-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(3-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy group)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-9H-carbazole-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9H-carbazole-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9H-carbazole-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl-penta-3-alkene-1-alkynyl)-9H-carbazole-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-9H-carbazole-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate, or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of any optical isomer or optical isomer, comprise racemic mixture, or any tautomer.
The present invention also comprises the pharmacologically acceptable salts of The compounds of this invention.Such salt comprises the acceptable acid salt of pharmacy, the acceptable base addition salt of pharmacy, the acceptable metal-salt of pharmacy, ammonium salt and alkylammonium salt.Acid salt comprises mineral acid and organic acid salt.The representational example of suitable mineral acid comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid, nitric acid etc.The representational example of appropriate organic comprises formic acid, acetate, trichoroacetic acid(TCA), trifluoroacetic acid, propionic acid, phenylformic acid, styracin, citric acid, fumaric acid, oxyacetic acid, lactic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, oxalic acid, picric acid, pyruvic acid, Whitfield's ointment, succsinic acid, methylsulfonic acid, ethyl sulfonic acid, tartrate, xitix, pamoic, the dimethylene Whitfield's ointment, ethane disulfonic acid, glyconic acid, citraconic acid, aspartic acid, stearic acid, palmitinic acid, EDTA, oxyacetic acid, Para-Aminobenzoic, L-glutamic acid, Phenylsulfonic acid, right-toluenesulphonic acids, sulfuric ester (salt), nitric ether (salt), phosphoric acid ester (salt), perchloric acid ester's (salt), boric acid ester (salt), acetic ester (salt), benzoic ether (salt), hydroxynaphthoic acid ester (salt), glycerophosphate, ketoglutarate etc.Acceptable other example inorganic or organic acid addition salt of pharmacy is included in J.Pharm.Sci.1977, listed pharmacologically acceptable salts in 66,2, and the document is combined in herein by reference.The example of metal-salt comprises lithium, sodium, potassium, magnesium, zinc, calcium salt etc.The example of ammonia and organic amine comprises ammonium, methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, propylamine, butylamine, tetramethylene amine, thanomin, diethanolamine, trolamine, meglumine, quadrol, choline, N, N '-dibenzyl-ethylenediamin, N-benzyl-1-phenylethylamine, N-methyl D-glycosamine, guanidine etc.The example of cationic amino acid comprises Methionin, arginine, Histidine etc.
The acceptable salt of described pharmacology can be by making the normal alkali of The compounds of this invention and 1-4, for example sodium hydroxide, sodium methylate, sodium hydride, potassium tert.-butoxide, calcium hydroxide, magnesium hydroxide etc. react in solvent such as ether, THF, methyl alcohol, trimethyl carbinol, diox, Virahol, ethanol etc. and prepare.Can use solvent mixture.Also can use organic bases, for example Methionin, arginine, diethanolamine, choline, guanidine and derivative thereof etc.Perhaps, in suitable, by using acid, for example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, tosic acid, methylsulfonic acid, acetate, citric acid, toxilic acid, Whitfield's ointment, hydroxynaphthoic acid, xitix, palmitinic acid, succsinic acid, phenylformic acid, Phenylsulfonic acid, tartrate etc. are handled in the solvent such as ethyl acetate, ether, alcohols, acetone, THF, diox etc. and are prepared acid salt.Also can use solvent mixture.
The steric isomer that constitutes the described compound of a part of the present invention can prepare by the following method: when possibility, in described method, use the reagent of single enantiomeric forms, perhaps in the presence of the reagent of single enantiomeric forms or catalyzer, react, perhaps split the mixture of steric isomer by ordinary method.Some preferable methods comprises the non-mapping salt that uses that microorganism splits, enzyme splits, splits when appropriate the non-mapping salt that forms with chiral acid such as amygdalic acid, camphorsulfonic acid, tartrate, lactic acid etc. or form with chiral base such as brucine, (R)-or (S)-phenylethylamine, cinchona alkaloid and derivative thereof etc.Jaques etc., " Enantiomers, Racemates andResolution " (Wiley Interscience, 1981) collected method of frequent use.More specifically, by using Chiral Amine, amino acid, handling derived from amino acid whose amino alcohol, The compounds of this invention can be converted into 1: 1 mixture of non-mapping acid amides.Can adopt conventional reaction conditions that acid is converted into acid amides.Described diastereomer can separate by fractional crystallization or chromatography, and can prepare the steric isomer of The compounds of this invention by the described pure non-mapping acid amides of hydrolysis.
Constitute the various polymorphs of the The compounds of this invention of a part of the present invention, can prepare by crystallization The compounds of this invention under different condition.For example, use normally used different solvents or their mixture to carry out crystallization; Crystallization under differing temps; From crystallisation process, being cooled to the various types of cooling of refrigerative very slowly very fast.Polymorphic form can also or melt described compound by heating, little by little or apace cools off then to prepare.The existence of polymorphic form can be determined by solid probe nmr spectrum, ir spectrum, dsc, powder X-ray-optical diffraction or other this class technology.
The present invention also comprises the prodrug of The compounds of this invention, and it carries out chemical transformation and become active pharmacological agents through metabolic process after administration.Usually, this class prodrug is the functional derivative of The compounds of this invention, and it changes into desired The compounds of this invention easily in vivo.The ordinary method of selecting and preparing suitable prodrug for example is disclosed in " Design of Prodrugs ", ed.H.Bundgaard, Elsevier, 1985.
The present invention also comprises the active metabolite of The compounds of this invention.
The invention still further relates to pharmaceutical composition, it comprises as at least a The compounds of this invention of activeconstituents or its any optics or geometrical isomer or tautomer (mixture that comprises these) or the acceptable salt of its pharmacology, and one or more pharmacology acceptable carrier or thinners.
And, the present invention relates to The compounds of this invention, or its tautomer, its steric isomer, its polymorph, its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing is used for the treatment of and/or prevents by nuclear receptor in preparation, the situation of peroxisome Proliferators activated receptors (PPAR) mediation particularly, for example application in the pharmaceutical composition of above-mentioned condition.
On the other hand, the present invention relates to treat and/or prevent the method for I type or type ii diabetes.
On the other hand, the present invention relates to one or more The compounds of this invention or its pharmacologically acceptable salts is used for the treatment of and/or prevents purposes in the pharmaceutical composition of I type or type ii diabetes in preparation.
On the other hand, The compounds of this invention can be used for treating and/or preventing IGT.
On the other hand, The compounds of this invention can be used for treating and/or preventing type ii diabetes.
On the other hand, The compounds of this invention can be used for postponing or prevents the development of IGT to type ii diabetes.
On the other hand, The compounds of this invention can be used for postponing or do not need to prevent the development of the type ii diabetes of Regular Insulin to the type ii diabetes that needs Regular Insulin.
On the other hand, the level of The compounds of this invention lowering blood glucose and tri-glyceride, and therefore can be used for treating and/or preventing disease and dysfunction, for example diabetes and/or obesity.
On the other hand, The compounds of this invention can be used for treating and/or preventing that insulin resistance (diabetes B), impaired glucose are stood, hyperlipemia, the disease (as hypertension, obesity, insulin resistance, hyperglycemia, arteriosclerosis, hyperlipidemia, coronary artery disease, myocardial ischemia and other cardiovascular disorder) relevant with syndrome X.
On the other hand, The compounds of this invention can effectively reduce the apoptosis of the beta cell of mammalian cell such as pancreas islet.
On the other hand, The compounds of this invention can be used for treating some ephrosis, comprises glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis.
On the other hand, The compounds of this invention also can be used for improving dull-witted patient's cognitive function, treatment diabetic complication, psoriasis, polycystic ovary syndrome (PCOS), and prevention and the forfeiture of treatment bone, for example osteoporosis.
The compounds of this invention can also with one or more other pharmacological active substance Combined Preparation, described other pharmacological active substance for example is selected from antiobesity agent, antidiabetic medicine, antihypertensive drug, be used for the treatment of and/or prevent diabetes causes or with the medicine of diabetes complications associated with arterial system and be used for the treatment of and/or prevention of obesity causes or with fat complications associated with arterial system and handicapped medicine.
Therefore, in another aspect of this invention, The compounds of this invention can with one or more antiobesity agents or appetite stimulator Combined Preparation.
These medicines can be selected from: CART (transcript that the Cocaine amphetamine is regulated) agonist, NPY (neuropeptide tyrosine) antagonist, MC4 (melanocortin (melano-cortin) 4) agonist, the orexin antagonist, TNF (tumour necrosis factor) agonist, CRF (corticotropin releasing factor(CRF)) agonist, CRF BP (corticotropin releasing factor(CRF) is conjugated protein) antagonist, Urocortin (urocortin) agonist, β 3 agonists, MSH (melanotropin) agonist, MCH (melanophore concentrates (melanocyte-concentrating) hormone) antagonist, CCK (cholecystokinin) agonist, the serotonin reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, blended serotonin and norepinephrine energy compound, 5HT (serotonin) agonist, the bombasin agonist, the galanin antagonist, tethelin, growth hormone releasing compounds, TRH (thyrotropic hormone release compound) agonist, UCP2 or 3 (the connection albumen 2 or 3 of uncoupling) conditioning agent, the leptin agonist, and the DA agonist (bromocriptine, doprexin), lipase/amylase inhibitor, RXR (retinoids X acceptor) conditioning agent or TR beta-agonists.
In one embodiment of the invention, described antiobesity agent is leptine (leptin).
In another embodiment, described antiobesity agent is dextroamphetamine or amphetamine.
In another embodiment, described antiobesity agent is S-768 or Isomeride.
In another embodiment, described antiobesity agent is sibutramin (sibutramine).
In another embodiment, described antiobesity agent is orlistat.
In another embodiment, described antiobesity agent is SaH-42548 or phentermine.
Suitable antidiabetic medicine comprises Regular Insulin, GLP-1 (the class pancreas rises sugared plain peptide-1) derivative (for example those disclosed (this patent is by reference in conjunction with in this application) among the WO 98/08871 of Novo Nordisk A/S), and oral active hypoglycemia agent.
Described oral active hypoglycemia agent preferably comprises sulfonylurea, biguanides, meglitinides, alpha-glucosidase inhibitors, pancreas rises sugared plain antagonist (as at Novo NordiskA/S and Agouron Pharmaceuticals, Inc. those disclosed among the WO 99/01423), the GLP-1 agonist, potassium channel openers (as those disclosed in the WO 97/26265 of Novo Nordisk A/S and WO 99/03861, described patent is by reference in conjunction with in this application), DPP-IV (dipeptidyl peptidase-IV) inhibitor, the inhibitor of the liver enzyme that in stimulating gluconeogenesis and/or glycogenolysis, relates to, the glucose uptake conditioning agent, the compound of adjusting lipid metabolism is lipidemia agent and hyperlipemia agent such as HMGCoA inhibitor (statin) for example, reduce the compound of food intake, the medicine of the rxr agonist and the potassium channel of the β cell that acts on the ATP-dependence.
In one embodiment of the invention, The compounds of this invention and insulin combination administration.
In another embodiment, The compounds of this invention and sulfonylurea such as tolbutamide, Glyburide, Glipizide or gliclazide Combined Preparation.
In another embodiment, The compounds of this invention and biguanides such as N1,N1-Dimethylbiguanide Combined Preparation.
In another embodiment, The compounds of this invention and meglitinide such as repaglinide or senaglinide Combined Preparation.
In another embodiment, The compounds of this invention and alpha-glucosidase inhibitor such as miglitol or acarbose Combined Preparation.
In another embodiment, medicine such as tolbutamide, Glyburide, Glipizide, gliclazide or the repaglinide Combined Preparation of The compounds of this invention and the potassium channel that acts on the β cell that ATP-relies on.
In addition, The compounds of this invention can with the nateglinide Combined Preparation.
In another embodiment, The compounds of this invention and lipidemia agent or hyperlipemia agent such as QUESTRAN, cholestipol, chlorine Bei Te, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine Combined Preparation.
In another embodiment, The compounds of this invention and more than one above-claimed cpd Combined Preparation, for example with sulfonylurea and N1,N1-Dimethylbiguanide, with sulfonylurea and acarbose, with repaglinide and N1,N1-Dimethylbiguanide, with Regular Insulin and sulfonylurea, with Regular Insulin and N1,N1-Dimethylbiguanide, with Combined Preparation such as Regular Insulin and lovastatins.
In addition, The compounds of this invention can with one or more antihypertensive drug Combined Preparation.The example of antihypertensive drug is: beta-blocker, as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol; ACE (hypertensin conversion enzyme) inhibitor is as benazepril, captopril, enalapril, Fosinopril, lisinopril, quinapril and Ramipril; Calcium channel blocker, for example nifedipine, Felodipine, nicardipine, Isrodipine, nimodipine, diltiazem and verapamil; And alpha-blocking agent, for example Doxazosin, piperidines first urine pyridine, Prazosin and terazosin.Can also be with reference to Remington:The Science and Practice ofPharmacy, 19 ThEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
Be noted that The compounds of this invention and one or more above-claimed cpds and any appropriate combination of one or more other pharmacological active substances randomly, all be considered at this
In the invention scope.
The invention still further relates to the method for preparation new compound recited above, its derivative, its analogue, its tautomer, its steric isomer, its polymorph, its pharmacologically acceptable salts or its pharmacy acceptable solvent thing.
Pharmaceutical composition
The compounds of this invention can be by independent administration, or with pharmaceutically acceptable carrier or excipient composition administration, with single agent or with the form of multi-agent.Can be according to the technology of routine, with pharmaceutically acceptable carrier or thinner and any other known auxiliary agent and the composite pharmaceutical composition of the present invention of vehicle, the technology of described routine for example is to be disclosed in Remington:The Science and Practice of Pharmacy, 19 ThEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, those in 1995.Described composition can be conventional form, for example capsule, tablet, aerosol, solution, suspensoid or topical application formulation.
Typical composition comprises that (described vehicle can be carrier or thinner with the acceptable vehicle of pharmacy, or suppressed by vector dilutes) bonded, or wrap in compound of the present invention or the acceptable acid salt of its pharmacy in the carrier (it can be the form of capsule, pouch, paper or other container).When the described composition of preparation, can use the routine techniques of pharmaceutical compositions.For example, described active compound mixes with carrier usually, or dilutes with carrier, or wraps in the carrier of the form that is ampoule, capsule, pouch, paper or other container.When described carrier was used as thinner, it can be solid, semisolid or fluent material, and it can play the effect of carrier, vehicle or the medium of active compound.Described active compound for example can be attracted on the particulate solid container in pouch.Some examples of suitable carriers are water, salts solution, alcohol, polyethylene glycols, the Viscotrol C of poly-hydroxy ethoxylation, peanut oil, sweet oil, gelatin, lactose, terra alba, sucrose, cyclodextrin, amylose starch, Magnesium Stearate, talcum, gelatin, agar, pectin, kordofan gum, stearic acid or cellulosic lower alkyl ether, silicic acid, lipid acid, fatty acid amine, monoglyceride and difatty acid glyceryl ester, pentaerythritol fatty ester, polyoxyethylene, Walocel MT 20.000PV and Polyvinylpyrolidone (PVP).Similarly, described carrier or thinner can comprise any slow-release material known in the art, and for example glyceryl monostearate or distearin use separately or mix use with wax.Described preparation can also comprise wetting agent, emulsification and suspension agent, sanitas, sweeting agent or sweetener.Preparation of the present invention can be re-dubbed snap-out release, the slowly-releasing that activeconstituents can be provided or postpone to discharge after being administered into patient by methods known in the art form.
Described pharmaceutical composition can be sterilized, and if desired, can with or not do not mix auxiliary, the emulsifying agent of described active compound generation adverse reaction, the salt that influences osmotic pressure, buffer reagent and/or coloring material etc.
The administration route can be any approach that can effectively active compound be transported to the site of action of suitable or needs, for example oral, intranasal, through lung, in skin or parenteral such as rectum, storage vault (depot), subcutaneous, intravenously, urethra, in the intramuscular, nose, intraocular solution or ointment, oral route is preferred.
If a kind of solid carrier is used for oral administration, described preparation can be made into tablet, be placed in the hard capsule with powder type or particle form, and perhaps can be lozenge or lozenge.If use liquid vehicle, described preparation can be the form of syrup, emulsion, soft capsule or aseptic injection liquid such as water-based or non-aqueous liquid suspensoid or solution.
For nose administration, described preparation can contain and is dissolved or suspended in liquid vehicle, and particularly the The compounds of this invention in the aqueous carrier is used for aerosol and uses.Described carrier can contain additive, and for example solubilizing agent such as propylene glycol, absorb rising agent such as Yelkin TTS (phosphatidylcholine) or cyclodextrin at tensio-active agent, or sanitas such as parabens.
For parenteral applications, specially suitable is injection solution or suspensoid, and preferred active substance is dissolved in the aqueous solution in the polyhydroxylated Viscotrol C.
Tablet, sugar-coat agent or capsule with talcum and/or carbohydrate carrier or tackiness agent etc. are particularly suitable for oral application.The preferred carrier that is used for tablet, sugar-coat agent or capsule comprises lactose, W-Gum and/or potato starch.Syrup or elixir can be used for wherein can adopting the situation that adds sugar carrier.
A kind of typical tablet that can prepare by the tabletting technology of routine can contain:
Core:
Active compound (free cpds or its salt) 5mg
Colloid silica (Aerosil) 1.5mg
Microcrystalline Cellulose (Avicel) 70mg
Modified cellulose gum (Ac-Di-Sol) 7.5mg
Magnesium Stearate Ad.
Coating:
The about 9mg of HPMC
*The about 0.9mg of Mywacett 9-40T
*Acidylate monoglyceride as the softening agent of filming
If desired, pharmaceutical composition of the present invention can comprise and other pharmacological active substances those The compounds of this invention that combine as the aforementioned.
The compounds of this invention can be administered into the Mammals, particularly people of the treatment, prevention, elimination, mitigation or the improvement that need this and blood glucose regulation diseases associated.
Such Mammals also comprises animal, has wherein both comprised domestic animal such as household pet also comprising non-domestic animal, for example wildlife.
The compounds of this invention all is effective in very wide dosage range.Typical oral dosage is about 0.001 to about 100mg/kg body weight/day, and preferably about 0.01 to about 50mg/kg body weight/day, and more preferably from about 0.05 to about 10mg/kg body weight/day, with potion or multi-agent such as 1-3 agent administration.Accurate dose will depend on administration frequency and mode, sex, age, body weight and by the general situation of treatment object, by sanatory character and severity, any disease of following of being treated and other factors, this is conspicuous to those skilled in the art.
Described preparation can be made the form of unitary dose easily by method known to those skilled in the art.Be used for once a day or repeatedly the typical unit doses form of (as 1-3 time) oral administration can contain the about 1000mg of 0.05-, the about 500mg of preferably about 0.1-, the more preferably from about about 200mg of 0.5mg-.
It is basic for purposes of the invention that any new feature described herein or characteristics combination should be considered to.
In following representative embodiment, further illustrate the present invention, but the scope that these embodiment do not limit the present invention in any way.
Embodiment
As the compound or the compound known of raw material, or the compound that can easily prepare according to method known per se.The structure of compound by ultimate analysis (MA), nucleus magnetic resonance (NMR, 300MHz), mass spectrum (MS) or rotational analysis confirm.The chemical shift of NMR (δ) is counted (ppm) very much with hundred and is provided, and only provides selected peak.Mp is a fusing point, and ℃ to provide.Column chromatography adopts W.C.Still etal, J.Org.Chem.1978, and 43, the method that 2923-2925 describes is carried out on Merck silica gel 60 (Art9385).
The abbreviation of Shi Yonging has following implication in an embodiment:
THF: tetrahydrofuran (THF)
DMSO: methyl-sulphoxide
CDCl 3: deuterochloroform
DMF:N, dinethylformamide
Min: minute
H: hour
Universal method (A)
Steps A:
By cross-coupling reaction, adopt Pd catalyzer such as Pd (PPh 3) 2Or PdCl 2(PPh 3) 2For example cupric iodide (I) and for example organic amine alkali and solubility promoter if desired with catalytic amount make formula (a) compound
Hlg-Z-Hlg (a)
Wherein Z defines as above, and wherein Hlg is chlorine, bromine or iodine, with the wherein suitable combination thing reaction of T definition formula T-OH as above, to provide formula (b) compound
HO-T-Z-Hlg (b)
Wherein Z and T define as above, and wherein Hlg is chlorine, bromine or iodine.
Step B:
By cross-coupling reaction, adopt Pd catalyzer such as Pd (PPh 3) 2Or PdCl 2(PPh 3) 2For example cupric iodide (I) and for example organic amine alkali with catalytic amount, solubility promoter if desired, make wherein Z and T definition as above, and wherein Hlg is formula (b) compound of chlorine, bromine or iodine and the wherein suitable combination thing reaction of U definition formula U-OH as above, to provide the compound of formula (c)
HO-T-Z-U-OH (c)
Wherein Z, T and U definition as above.
Step C:
Under the Mitsunobu condition, use reagent such as triphenylphosphine/diethylazodicarboxylate etc., make wherein Z, T and U definition formula (c) compound as above, with A wherein, X and D definition as above, just D is not formula (d) compound of hydrogen
Reaction obtains the compound of formula (I), A wherein, B, D, E, L, M, T, U, X, Y and Z definition as above, just D and E are not hydrogen, and wherein A is identical with B, X is identical with Y, and L and M are oxygen.
Universal method (B)
Steps A:
Under the Mitsunobu condition, use reagent such as triphenylphosphine/diethylazodicarboxylate etc., make wherein T and Z definition as above, and wherein Hlg is formula (b) compound of chlorine, bromine or iodine, with A wherein, X and D definition as above, just D is not formula (d) the compound reaction of hydrogen, obtain the compound of formula (e)
A wherein, D, T, X and Z definition as above, just D is not a hydrogen, and wherein Hlg is chlorine, bromine and iodine, L is an oxygen.
Step B:
By cross-coupling reaction, adopt Pd catalyzer such as Pd (PPh 3) 2Or PdCl 2(PPh 3) 2For example cupric iodide (I) and for example organic amine alkali with catalytic amount, solubility promoter if desired, make wherein A, D, T, X and Z definition are as above, and wherein Hlg is chlorine, bromine or iodine, and L is formula (e) compound of oxygen, with the compound reaction of suitable wherein U definition formula U-OH as above, provide the compound of formula (f)
A wherein, D, T, U, X and Z definition as above, and wherein L is an oxygen.
Step C:
Under the Mitsunobu condition, use reagent such as triphenylphosphine/diethylazodicarboxylate etc., make wherein A, D, T, U, X and Z define as above, but D is not a hydrogen, and wherein L is the compound of the formula (f) of oxygen, with B wherein, E and Y definition as above, but E is not the compound of the formula (g) of hydrogen
Figure A0282054700691
Reaction obtains the compound of formula (I), A wherein, B, D, E, L, M, T, U, X, Y and Z definition as above, just D and E are not hydrogen, and wherein L and M are oxygen.
Universal method (C)
Steps A:
To wherein T, in Z and U definition formula (c) compound as above-OH functional group is converted into suitable leavings group (Q), for example p-toluenesulfonic esters, methanesulfonates, halogen are (for example by disclosed method: Houben-Weyl in the following document, Methoden derorganischen Chemie, Alkohole III, 6/1b, Thieme-Verlag 1984,4thEd., pp.927-939; Comprehensive Organic Transformations.Aguide to functional group preparations, VCH Publishers 1989,1 StEd., PP.353-363 and J.Org.Chem., Vol.36 (20), 3044-3045,1971), triflate etc., to provide the compound of formula (h)
Q-T-Z-U-Q (h)
Q wherein, T, U and Z definition are as above.
Step B:
Make wherein that Q is a leavings group, for example p-toluenesulfonic esters, methanesulfonates, halogen, triflate etc., and T wherein, U and Z definition formula (h) compound as above, with A wherein, X and D definition are not as above reacted but D be formula (d) compound of hydrogen, obtain the compound of formula (I), A wherein, B, D, E, L, M, T, U, X, Y and Z definition are as above, just D and E are not hydrogen, and wherein A is identical with B, and X is identical with Y.
Universal method (D)
Steps A:
Wherein T and Z definition as above, and wherein Hlg be in formula (b) compound of chlorine, bromine and iodine-OH functional group is converted into suitable leavings group (Q), for example p-toluenesulfonic esters, methanesulfonates, halogen are (for example by disclosed method: Houben-Weyl in the following document, Methoden der organischen Chemie, Alkohole III, 6/1b, Thieme-Verlag 1984,4th Ed., pp.927-939; ComprehensiveOrganic Transformations.A guide to functional grouppreparations, VCH Publishers 1989,1st Ed., pp.353-363 and J.Org.Chem., Vol.36 (20), 3044-3045,1971), triflate etc., to provide the compound of formula (i)
Q-T-Z-Hlg (i)
Q wherein, T and Z definition as above, and wherein Hlg is chlorine, bromine or iodine.
Step B:
Make wherein that Q is a leavings group, for example p-toluenesulfonic esters, methanesulfonates, halogen, triflate etc., and T and Z definition formula (i) compound as above, with A wherein, X, D and L definition as above but D is not formula (j) compound of hydrogen
Reaction obtains wherein A, D, and L, T, X and Z define as above, and just D is not a hydrogen, and wherein Hlg is the compound of the formula (e) of chlorine, bromine and iodine.
Step C:
By cross-coupling reaction, adopt Pd catalyzer such as Pd (PPh 3) 2Or PdCl 2(PPh 3) 2For example cupric iodide (I) and for example organic amine alkali and solubility promoter if desired with catalytic amount make wherein A, D, L, T, X and Z define as above, and wherein Hlg is the compound of the formula (e) of chlorine, bromine or iodine, with the wherein suitable combination thing reaction of U definition formula U-OH as above, form wherein A, D, L, T, U, the compound of X and Z definition formula (f) as above.
Step D:
To wherein A, D, L, T, U, in X and Z definition formula (f) compound as above-OH functional group is converted into suitable leavings group (Q), and for example p-toluenesulfonic esters, methanesulfonates, halogen are (for example by disclosed method: Houben-Weyl in the following document, Methodender organischen Chemie, Alkohole III, 6/1b, Thieme-Verlag 1984,4th Ed., pp.927-939; Comprehensive Organic Transformations.Aguide to functional group preparations, VCH Publishers 1989,1stEd., pp.353-363 and J.Org.Chem., Vol.36 (20), 3044-3045,1971), triflate etc., to provide the compound of formula (k)
Figure A0282054700711
A wherein, D, L, T, U, Q, X and Z definition are as above.
Step e:
Making wherein Q is leavings group such as tosylate, methanesulfonates, halogen, triflate etc., and A wherein, D, L, T, U, X and Z definition formula (k) compound as above, with B wherein, E, M and Y definition as above, but E is not formula (l) compound of hydrogen
Reaction provides wherein A, B, and D, E, L, M, T, U, X, Y and Z define as above, but D and E are not formula (I) compounds of hydrogen.
Universal method (E)
Steps A:
By chemistry or enzyme process saponification A wherein, B, D, E, L, M, T, U, X, Y and Z definition as above, but D and E are not formula (I) compounds of hydrogen, provide wherein A, B, L, M, T, U, X, Y and Z definition as above, and D and E are formula (I) compounds of hydrogen.
Universal method (F)
Steps A:
By the method for similar Wei Tixi, in the presence of alkali such as sodium hydride, EtONa etc., make wherein Z 1And Z 2Form together as above and encircle ring system more, and wherein Hlg is chlorine, bromine or iodine, wherein G in the face of the divalence of Z definition 3The compound of definition formula (m) as above,
With for example (EtO) 2PO (CHG 4) COOR 6(R wherein 6Be C 1-3-alkyl, and G 4Definition is as above) react, provide the compound of formula (n),
Figure A0282054700722
R wherein 6Definition as above, and Z wherein 1And Z 2Form together as above and encircle ring system more, and wherein Hlg is chlorine, bromine or iodine, wherein G in the face of the divalence of Z definition 3And G 4Definition as above.
Step B:
Reduce wherein R with suitable reagent such as diisobutylaluminium hydride 6Define as above Z 1And Z 2Form together as above and encircle ring system in the face of the divalence of Z definition more, Hlg is chlorine, bromine or iodine, G 3And G 4Define formula (n) compound as above, provide the compound of formula (o),
Z wherein 1And Z 2Form together as above and encircle ring system in the face of the divalence of Z definition more, Hlg is chlorine, bromine or iodine, and G 3And G 4Definition as above.
Step C:
Make wherein G 3And G 4Define as above Z 1And Z 2Form together as above and encircle ring system more, and Hlg is formula (o) compound of chlorine, bromine or iodine, with Z wherein in the face of the divalence of Z definition 2And Z 1Form together as above and encircle ring system more in the face of the divalence of Z definition, and G 2The suitable acid reaction of definition formula (p) as above,
Provide the compound of formula (q),
Z wherein, G 2, G 3And G 4Definition as above.
Step D:
With suitable blocking group, for example t-butyldimethylsilyl is protected wherein Z, G 2, G 3And G 4Define the hydroxy functional group in formula (q) compound as above, provide the compound of formula (r)
Figure A0282054700733
Z wherein, G 2, G 3And G 4Define as above, and P is suitable blocking group, for example t-butyldimethylsilyl.
Step e:
By the method for similar Wei Tixi, in the presence of alkali such as sodium hydride, EtONa etc., make wherein Z, G 2, G 3And G 4Definition as above, and P is suitable blocking group such as the formula of t-butyldimethylsilyl (r) compound, with for example (EtO) 2PO (CHG 1) COOR 6(R wherein 6Be C 1-3-alkyl, and G 1Definition is as above) react, provide the compound of formula (s),
Z wherein, G 1, G 2, G 3And G 4Define as above, P is suitable blocking group such as t-butyldimethylsilyl, and R 6Be C 1-3-alkyl.
Step F:
Reduce wherein Z with suitable reagent such as diisobutylaluminium hydride, G 1, G 2, G 3And G 4Define as above, P is suitable blocking group such as t-butyldimethylsilyl, and R 6Be C 1-3The compound of the formula of-alkyl (s) provides the compound of formula (t),
Figure A0282054700742
Z wherein, G 1, G 2, G 3And G 4Define as above, and P is suitable blocking group such as t-butyldimethylsilyl.
Step G:
Under the Mitsunobu condition, use reagent such as triphenylphosphine/diethylazodicarboxylate etc., make wherein Z, G 1, G 2, G 3And G 4Definition as above, and P is suitable blocking group such as the formula of t-butyldimethylsilyl (t) compound, with D wherein, A and X definition formula (d) compound reaction as above,
Provide the compound of formula (u)
Figure A0282054700751
A wherein, D, X, Z, G 1, G 2, G 3And G 4Define as above, and P is suitable blocking group such as t-butyldimethylsilyl.
Step H:
To wherein A, D, X, Z, G 1, G 2, G 3And G 4Definition as above, and P is the compound deprotection of suitable blocking group such as the formula of t-butyldimethylsilyl (u), provides formula (compound v)
Figure A0282054700752
A wherein, D, X, Z, G 1, G 2, G 3And G 4Definition as above.
Step I:
Under the Mitsunobu condition, use reagent such as triphenylphosphine/diethylazodicarboxylate etc., make wherein A, D, X, Z, G 1, G 2, G 3And G 4As above formula of definition (v) compound, with Y wherein, B and E definition formula (x) compound reaction as above,
Provide the compound of formula (I), A wherein, B, D, E, X, Y and Z definition as above, but D and E are not hydrogen, and wherein L and M are oxygen, T is-CH 2(CG 1)=(CG 2)-and U be-CH 2(CG 3)=(CG 4)-.
Universal method (G)
Steps A:
By cross-coupling reaction, adopt Pd catalyzer such as Pd (PPh 3) 2Or PdCl 2(PPh 3) 2With for example cupric iodide (I) and for example organic amine alkali and the solubility promoter if desired of catalytic amount, make wherein the Z definition as above, and Hlg is formula (a) compound of chlorine, bromine or iodine, with T definition wherein as above, and R 5Be C 1-6The formula T-COOR of-alkyl 5Suitable combination thing reaction, provide the compound of formula (y)
R 5OOC-T-Z-Hlg (y)
Wherein Z and T define as above, and Hlg is chlorine, bromine or iodine, and R 5Be C 1-6-alkyl.
Step B:
By cross-coupling reaction, adopt Pd catalyzer such as Pd (PPh 3) 2Or PdCl 2(PPh 3) 2With for example cupric iodide (I) and for example organic amine alkali and the solubility promoter if desired of catalytic amount, make wherein Z and T definition as above, Hlg is chlorine, bromine or iodine, and R 5Be C 1-6The formula of-alkyl (y) compound, with the definition of U wherein as above, and R 5Be C 1-6The formula U-COOR of-alkyl 5Suitable combination thing reaction, provide the compound of formula (z)
R 5OOC-T-Z-U-COOR 5 (z)
Wherein Z, T, U and R 5Definition as above.
Step C:
With suitable reagent, wherein Z, T, U and R of diisobutylaluminium hydride or aluminum chloride/lithium aluminium hydride reduction for example 5Define formula (z) compound as above, provide the compound of formula (c).
Use the combination or the similar approach of aforesaid method, can prepare all cpds in the scope of the invention.
Embodiment 1 (universal method A)
(E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl-ethyl propionate
Figure A0282054700771
Steps A-B:
Under nitrogen atmosphere, to 1, the 4-diiodo-benzene (1.32g, 4.0mmol) in the solution in diisopropylamine (12mL), add cupric iodide (I) (60mg, 0.3mmol) and four (triphenylphosphines) close palladium (80mg, 0.07mmol).After stirring this mixture 1h, add 2-amylene-4-alkynes-1-alcohol (1.0g, 12.0mmol) solution in diisopropylamine (7mL).Under nitrogen atmosphere in 60 ℃ stir 8h after, filter reaction mixture, and filtrate is evaporated to dried.Product uses toluene/ethyl acetate (2: 1) to transit to ethyl acetate gradually as eluent by purification by flash chromatography, provides (E) (E) 5-[4-(5-hydroxyl-penta-3-alkene-1-alkynyl)-phenyl of 520mg (55%)]-penta-2-alkene-4-alkynes-1-alcohol.
1H?NMR(CDCl 3)：δ1.47(2H，bs)，4.28(2H，bs)，5.97(2H，dt)，6.38(2H，dt)，7.38(4H，s).
Step C:
Under nitrogen atmosphere, at 0-5 ℃, with azo-2-carboxylic acid's two piperidines acid amides (azodicarboxylic dipiperidide) (504mg, 2.0mmol) join tributylphosphine (404mg, 2.0mmol), (S)-2-oxyethyl group-3-(4-hydroxy phenyl) ethyl propionate (Tetrahedron Letters, Vol.35, No 19,3139-3142,1994) (357mg, 1.5mmol) and (E) (E) 5-[4-(5-hydroxyl-penta-3-alkene-1-alkynyl)-phenyl]-(120mg is 0.5mmol) in the solution that is stirring in dry THF (25mL) for penta-2-alkene-4-alkynes-1-alcohol.Behind the 24h, filter reaction mixture, and filtrate decompression is concentrated.Described crude product uses toluene/ethyl acetate (19: 1) to transit to toluene/ethyl acetate (4: 1) gradually as eluent by purification by flash chromatography, provides 90mg (27%) title compound.
1H?NMR(CDCl 3)：δ1.18(6H，t)，1.23(6H，t)，2.95(4H，d)，3.30-3.43(2H，m)，3.55-3.67(2H，m)，3.98(2H，t)，4.18(4H，q)，4.63(4H，dd)，6.07(2H，dt)，6.39(2H，dt)，6.85(4H，d)，7.17(4H，d)，7.27(4H，s)，7.37(4H，s).
Embodiment 2 (universal method E)
(E) (E) (S) (S) 3-{4-[5-(4-{5-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl-2-oxyethyl group-propionic acid
Steps A:
To (E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl-solution of ethyl propionate (embodiment 1) (88mg 0.13mmol) in THF (3mL) and ethanol (3mL) in, add 1N sodium hydroxide (2mL).After at room temperature stirring 1h, with the reaction mixture concentrating under reduced pressure, adding entry and 1N hydrochloric acid to pH value is 1.Dichloromethane extraction three times of described product, the organic phase of merging sal epsom (MgSO 4) drying, filter and concentrating under reduced pressure, provide title compound, be crystalline product.Described product provides the 35mg title compound with ethyl acetate and sherwood oil recrystallization.
1H NMR (acetone-d 6): δ 1.18 (6H, t), 2.95 (2H, dd), 3.10 (2H, dd), 3.42-3.53 (2H, m), 3.55-3.68 (2H, m), 4.07 (2H, dd), 4.63 (3H, dd), 6.07 (2H, dt), 6.39 (2H, dt), 6.85 (4H, d), 7.15 (4H, d), 7.38 (4H, s).
Embodiment 3 (universal method A)
(E) (E) 3-chloro 4-(5-4-[5-(3-chloro-4-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate
Step C:
Under nitrogen atmosphere, at 0-5 ℃, with azo-2-carboxylic acid two piperidines acid amides (504mg, 2.0mmol) join tributylphosphine (404mg, 2.0mmol), (3-chloro-4-hydroxy phenyl) ethyl propionate (322mg, 1.5mmol) and (E) (E) 5-[4-(5-hydroxyl-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-(embodiment 1 for 4-alkynes-1-alcohol, steps A-B) (120mg is 0.5mmol) in the solution that is stirring in dry THF (25mL).Behind the 1h, filter reaction mixture, and filtrate decompression is concentrated.Described crude product uses toluene to transit to toluene/ethyl acetate (1: 1) gradually as eluent by purification by flash chromatography.The product re-crystallizing in ethyl acetate provides 150mg (48%) title compound.
1H?NMR(CDCl 3)：δ1.24(6H，t)，3.53(4H，s)，4.15(4H，q)，4.71(2H，d)，6.15(2H，dt)，6.40(2H，dt)，6.88(2H，d)，7.14(2H，dd)，7.33(2H，d)，7.38(4H，s).
Embodiment 4 (universal method E)
(E) (E) [4-(5-4-[5-(4-carboxyl methyl-3-chloro phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl]-acetate
Steps A:
To (E) (E) 3-chloro-4-(5-{4-[5-(3-chloro-4-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl-penta-2-alkene-4-alkynyloxy base)-phenyl]-solution of ethyl acetate (embodiment 3) (150mg 0.24mmol) in THF (8mL) and ethanol (4mL) in, add 1N sodium hydroxide (4mL).After at room temperature stirring 1h, with the reaction mixture concentrating under reduced pressure, adding entry and 1N hydrochloric acid to pH value is 1.Dichloromethane extraction three times of described product, the organic phase of merging sal epsom (MgSO 4) drying, filter and concentrating under reduced pressure, provide title compound, be crystalline product.Described product provides 90mg (66%) title compound with ethyl acetate/THF and sherwood oil recrystallization.
1H NMR (acetone-d 6): δ 3.59 (4H, s), 4.82 (4H, d), 6.23 (2H, dt), 6.49 (2H, dt), 7.10 (2H, d), 7.23 (2H, dd), 7.40 (2H, d), 7.47 (4H, s).
Embodiment 5 (universal method A)
(E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl-ethyl propionate
Figure A0282054700801
Steps A-B:
Under nitrogen atmosphere, to 1, the 3-diiodo-benzene (2.64g, 8.0mmol) in the solution in diisopropylamine (25mL), add cupric iodide (I) (75mg, 0.4mmol) and four (triphenylphosphines) close palladium (80mg, 0.07mmol).After stirring this mixture 1h, add 2-amylene-4-alkynes-1-alcohol (2.0g, 24.0mmol) solution in diisopropylamine (10mL).Behind 60 ℃ of stirring 16h, filter reaction mixture also is evaporated to filtrate dried.Product uses toluene/ethyl acetate (9: 1) to transit to ethyl acetate gradually as eluent by purification by flash chromatography, provides (E) (E) 5-[3-(5-hydroxyl-penta-3-alkene-1-alkynyl)-phenyl of 1.35g (71%)]-penta-2-alkene-4-alkynes-1-alcohol.
1H?NMR(CDCl 3)：δ4.26(4H，d)，5.95(2H，dt)，6.35(2H，dt)，7.23-7.30(m，1H)，7.38(2H，dd)，7.52(1H，s).
Step C:
Under nitrogen atmosphere, at 0-5 ℃, with azo-2-carboxylic acid two piperidines acid amides (423mg, 1.68mmol) join tributylphosphine (340mg, 1.68mmol), (S)-2-oxyethyl group-3-(4-hydroxy phenyl)-ethyl propionate (Tetrahedron Letters, Vol.35, No 19,3139-3142,1994) (400mg, 1.68mmol) and (E) (E) 5-[3-(5-hydroxyl-penta-3-alkene-1-alkynyl)-phenyl]-(200mg is 0.84mmol) in the solution that is stirring in dry THF (20mL) for penta-2-alkene-4-alkynes-1-alcohol.Behind the 1h, filter reaction mixture, and filtrate decompression is concentrated.Described crude product uses toluene/ethyl acetate (9: 1) as eluent by purification by flash chromatography, provides 130mg (23%) title compound.
1H?NMR(CDCl 3)；δ1.17(6H，t)，1.22(6H，t)，2.95(4H，d)，3.30-3.42(2H，m)，3.55-3.65(2H，m)，3.98(2H，t)，4.18(4H，q)，4.62(4H，dd)，6.05(2H，dt)，6.39(2H，dt)，6.85(4H，d)，7.17(4H，d)，7.23-7.30(m，1H)，7.37(2H，dd)，7.50(1H，s).
Embodiment 6 (universal method E)
(E) (E) (S) (S) 3-{4-[5-(3-{5-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl-2-oxyethyl group-propionic acid
Steps A:
To (E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl-solution of ethyl propionate (embodiment 5) (130mg 0.2mmol) in THF (3mL) and ethanol (3mL) in, add 1N sodium hydroxide (1.5mL).After at room temperature stirring 2h, with the reaction mixture concentrating under reduced pressure, adding entry and 1N hydrochloric acid to pH value is 1.Dichloromethane extraction three times of described product, the organic phase of merging sal epsom (MgSO 4) drying, filter and concentrating under reduced pressure, provide title compound, be crystalline product.Described product provides 72mg (58%) title compound with tetrachloromethane and sherwood oil recrystallization.
1H NMR (acetone-d 6): δ 1.12 (6H, t), 2.88 (2H, dd), 3.02 (2H, dd), and 3.32-3.43 (2H, m), 3.57-3.68 (2H, m), 4.04 (2H, dd), 4.70 (4H, dd), 6.15 (2H, dt), 6.47 (2H, dt), 6.90 (4H, d), 7.23 (4H, d), 7.38-7.49 (m, 1H), 7.37 (2H, dd), 7.52 (1H, s).
Embodiment 7 (universal method A)
(E) (E) [3-chloro-4-(5-{3-[5-(2-chloro-4-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate
Step C:
Under nitrogen atmosphere, at 0-5 ℃, with azo-2-carboxylic acid two piperidines acid amides (423mg, 1.68mmol) join tributylphosphine (340mg, 1.68mmol), (3-chloro-4-hydroxy phenyl) ethyl propionate (361mg, 1.68mmol) and (E) (E) 5-[3-(5-hydroxyl-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-(embodiment 5 for 4-alkynes-1-alcohol, steps A-B) (200mg is 0.84mmol) in the solution that is stirring in dry THF (20mL).Behind the 1h, filter reaction mixture, and filtrate decompression is concentrated.Described crude product uses toluene/ethyl acetate (19: 1) as eluent by purification by flash chromatography, provides 180mg (34%) title compound.
1H?NMR(CDCl 3)：δ1.26(6H，t)，3.53(4H，s)，4.15(4H，q)，4.69(2H，d)，6.13(2H，dt)，6.39(2H，dt)，6.87(2H，d)，7.12(2H，dd)，7.20-7.38(5H，m)，7.50(1H，s).
Embodiment 8 (universal method E)
(E) (E) [4-(5-{3-[5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl]-acetate
Steps A:
To (E) (E) [3-chloro-4-(5-{3-[5-(2-chloro-4-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate (embodiment 7) (180mg, 0.28mmol) in the solution in THF (3mL) and ethanol (3mL), add 1N sodium hydroxide (1.5mL).After at room temperature stirring 4h, with the reaction mixture concentrating under reduced pressure, adding entry and 1N hydrochloric acid to pH value is 1.Described product extracts three times with methylene dichloride/Virahol, the organic phase of merging sal epsom (MgSO 4) drying, filter and concentrating under reduced pressure, provide the 125mg title compound, be crystalline product.
1H NMR (acetone-d 6): δ 3.60 (4H, s), 4.82 (4H, d), 6.23 (2H, dt), 6.50 (2H, dt), 7.10 (2H, d), 7.23 (2H, dd), 7.39-7.50 (5H, m), 7.53 (1H, s).
Embodiment 9 (universal method A)
(E) (E) (S) (S) 2-(2-benzoyl-phenyl amino)-3-(4-{5-[4-(5-{4-[2-(2-benzoyl-phenyl amino)-2-methoxycarbonyl ethyl]-phenoxy group-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-4-alkynyloxy base-phenyl)-methyl propionate
Step C:
Under nitrogen atmosphere, at 0-5 ℃, with azo-2-carboxylic acid two piperidines acid amides (1.0g, 4.0mmol) join tributylphosphine (808mg, 4.0mmol), (S)-2-(2-benzoyloxy-phenyl amino)-3-(4-hydroxy phenyl)-methyl propionate (820mg, 2.18mmol) and (E) (E) 5-[4-(5-hydroxyl-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-(embodiment 1 for 4-alkynes-1-alcohol, steps A-B) (260mg is 1.1mmol) in the solution that is stirring in dry THF (20mL).Behind the 2h, filter reaction mixture, and filtrate decompression is concentrated.Crude product uses toluene/ethyl acetate (19: 1) as eluent by purification by flash chromatography, provides 370mg (36%) title compound, is oily matter.
1H?NMR(CDCl 3)：δ3.12(2H，dd)，3.23(2H，dd)，3.70(6H，s)，4.39(2H，q)，4.60(4H，d)，6.04(2H，dt)，6.37(2H，dt)，6.53-6.67(4H，m)，6.85(4H，d)，7.14-7.63(22H，m)，8.87(2H，d).
Embodiment 10 (universal method E)
(E) (E) (S) (S) 2-(2-benzoyl-phenyl amino)-3-(4-{5-[4-(5-{4-[2-(2-benzoyl-phenyl amino)-2-carboxyl-ethyl]-phenoxy group-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-4-alkynyloxy base-phenyl)-propionic acid
Steps A:
To (E) (E) (S) (S) 2-(2-benzoyl-phenyl amino)-3-(4-{5-[4-(5-{4-[2-(2-benzoyl-phenyl amino)-2-methoxycarbonyl ethyl]-phenoxy group-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-4-alkynyloxy base-phenyl)-solution of methyl propionate (embodiment 9) (370mg 0.39mmol) in THF (3mL) and ethanol (3mL) in, add 1N sodium hydroxide (2mL).After at room temperature stirring 1h, with the reaction mixture concentrating under reduced pressure, adding entry and 1N hydrochloric acid to pH value is 1.Product dichloromethane extraction three times, the organic phase of merging sal epsom (MgSO 4) drying, filter and concentrating under reduced pressure, provide title compound, be crystalline product.Described product provides the 200mg title compound with ethyl acetate and sherwood oil recrystallization.
1H?NMR(CDCl 3)：δ3.15(2H，dd)，3.29(2H，dd)，4.40(2H，bs)，4.55(4H，d)，6.03(2H，d)，6.35(2H，dt)，6.57-6.74(4H，m)，6.82(4H，d)，7.22(4H，d)，7.30-7.63(18H，m)，8.85(2H，bs).
Embodiment 11 (universal method F)
(E) (E) (S) (S) 2-oxyethyl group-3-{4-[3-(4 '-{ 3-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-1-methyl-propenyl }-biphenyl-4-yl)-but-2-ene base oxygen base]-phenyl }-ethyl propionate
Figure A0282054700851
Steps A:
(5.52g 0.24mol) is dissolved in the ethanol (200mL) with sodium.Slowly add phosphine acyl acetic acid three ethyl (62.7g, 0.28mol) solution in ethanol (100mL).This mixture was stirred 20 minutes, and add 4-phenyl-iodide ethyl ketone (49.21g, 0.20mol) solution in hot ethanol (200mL).This mixture is stirred 66h at 80 ℃.With this mixture cooling, and evaporate ethanol.In resistates, add 1N HCl (400mL) and ethyl acetate (400mL).Water layer is further used ethyl acetate (2 * 200mL) extractions.The organic phase salt water washing that merges, and dry (MgSO 4), filter and evaporation.Product uses heptane/ethyl acetate (39: 1) as eluent by the column chromatography purifying, provides (E) 3-(4-iodine substituted phenyl) fourth-2-keto acid ethyl ester of 30.0g (46%).
1H?NMR(CDCl 3)：δ1.31(3H，t)，2.53(3H，s)，4.21(2H，q)，6.11(1H，s)，7.19(2H，d)，7.69(2H，d).
Step B:
Under nitrogen atmosphere, (10.1g 32.0mmol) is dissolved among the exsiccant THF (300mL) with (E) 3-(4-iodine substituted phenyl) fourth-2-keto acid ethyl ester.This solution is cooled to-15 ℃, and slowly add 1M the DIBAL-H toluene solution (96.0ml, 96.0mmol).This mixture slowly is warmed to room temperature and stirs 1h.Add methyl alcohol (50ml) carefully, add 1N HCl (500ml) then, and (3 * 500ml) extract the mixture that obtains with ethyl acetate.With the organic extract that the salt water washing merges, dry (MgSO 4), and evaporation, provide 8.8g (E) 3-(4-iodine substituted phenyl) but-2-ene-1-alcohol.
1H?NMR(CDCl 3)：δ1.42(1H，ds)，2.04(3H，s)，4.35(2H，d)，5.97(1H，t)，7.13(2H，d)，7.63(2H，d).
Step C:
Under nitrogen atmosphere, four (triphenylphosphines) are closed palladium (O), and (0.46g, 0.4mmol 4mol%) join (E) 3-(4-iodine substituted phenyl) but-2-ene-1-alcohol (2.74g, 10.0mmol) in the solution that is stirring in DME (100mL), and this solution at room temperature stirred 10 minutes.(30.0ml 60.0mmol), stirred this mixture 10 minutes, and (3.28g 20.0mmol), is heated to 65 ℃ with reaction mixture and keeps 18h, is refluxing and is at room temperature keeping 3 days again to add 4-ethanoyl boric acid then to add the aqueous sodium carbonate of 2M then.Reaction mixture is with 1N HCl (200ml) dilution, and with ethyl acetate (2 * 200ml) extraction products.With the organic extract that the salt water washing merges, dry (MgSO 4), and evaporation, provide crude product.This crude product purification by silica gel column chromatography, use heptane/ethyl acetate (3: 2) as eluent, transit to heptane/ethyl acetate (2: 3) gradually as eluent, provide (E) 1-[4 '-(3-hydroxyl-1-methyl-propenyl)-biphenyl-4-yl of 2.0g (75%)]-ethyl ketone.
1H?NMR(CDCl 3)：δ2.12(3H，s)，2.64(3H，s)，4.41(2H，q)，6.07(1H，t)，7.51(2H，d)，7.61(2H，d)，7.71(2H，d)，8.03(2H，d).
Step D:
Under nitrogen atmosphere, to (E) 1-[4 '-(3-hydroxyl-1-methyl-propenyl)-biphenyl-4-yl]-(1.1g 4.13mmol) in the suspension in methylene dichloride (40mL), adds imidazoles (0.42g to ethyl ketone, 6.20mmol) and a chlorine tertiary butyl dimethylsilane (0.78g, 5.15mmol).This mixture is at room temperature stirred 18h.Add methylene dichloride (15mL), and water, sodium hydrogen carbonate solution and this reaction mixture of salt water washing.Organic phase (the MgSO that is dried 4), filter and concentrating under reduced pressure.Resistates is carried out silica gel column chromatography separate, use heptane/ethyl acetate (4: 1) as eluent, provide (E) 1-{4 '-[3-(tertiary butyl dimethylsilyl oxygen base)-1-methylpropenyl]-biphenyl-4-yl of 1.36g (87%) ethyl ketone.M.p.100-106℃.
1H?NMR(CDCl 3)：δ0.13(6H，s)，0.97(9H，s)，2.10(3H，s)，2.65(3H，s)，4.13(2H，d)，5.98(1H，dt)，7.51(2H，d)，7.60(2H，d)7.69(2H，d)，8.02(2H，d).
Step e:
At 20 ℃, (0.42g 18.0mmol) joins in the ethanol (50mL), and stirs the mixture up to described metal complete reaction with sodium.Add phosphine acyl acetic acid three ethyl (2.4mL; 12.0mmol); and stirred the mixture 5 minutes, under agitation in this solution, add (E) 1-{4 '-[3-(tertiary butyl dimethylsilyl oxygen base)-1-methylpropenyl]-biphenyl-4-yl then } and ethyl ketone (1.14g, 3.0mmol).This mixture is at room temperature stirred 24h.In reaction mixture, add entry, and with twice of ethyl acetate extraction product.The organic phase salt water washing that merges, dry (MgSO 4), filter and concentrating under reduced pressure.Resistates is carried out silica gel column chromatography to be separated, use heptane/ethyl acetate (4: 1) as eluent, provide (E) (E) 3-(4 '-{ 3-[(tertiary butyl dimethylsilyl)-methoxyl group of 1.13g (81%)]-the 1-methylpropenyl }-biphenyl-4-yl)-the but-2-ene acetoacetic ester.
1H?NMR(CDCl 3)：δ0.12(6H，s)，0.92(9H，s)，1.32(3H，t)，2.08(3H，s)，2.62(3H，s)，4.22(2H，q)，4.42(2H，d)，5.97(1H，dt)，6.20(1H，d)，7.43-7.63(8H，m).
Step F:
Under nitrogen atmosphere, at-70 ℃, with 20 minutes, DIBAL-H toluene solution (7.3mL with 1M, 7.3mmol) be added drop-wise to (E) (E) 3-(4 '-{ 3-[(tertiary butyl dimethylsilyl)-methoxyl group]-the 1-methylpropenyl }-biphenyl-4-yl)-(1.13g is 2.43mmol) in the solution that is stirring in dry THF (25mL) for the but-2-ene acetoacetic ester.Stir this mixture 30 minutes, and at room temperature stirred 2h then.Add ethanol (1mL) carefully, then add 1N HCl (50mL), and (2 * 50mL) extract the mixture that obtains with ethyl acetate.The organic extract salt water washing that merges, dry (MgSO 4), and evaporation, provide (E) (E) 3-(4 '-{ 3-[(tertiary butyl dimethylsilyl)-methoxyl group of 1.02g (99%)]-the 1-methylpropenyl }-biphenyl-4-yl)-but-2-ene-1-alcohol.
1H?NMR(CDCl 3)：δ0.13(6H，s)，0.96(9H，s)，1.57(1H，s)，2.07(3H，s)，2.13(3H，s)，4.37-4.46(4H，m)，5.85(1H，t)，5.93(1H，t)，7.46-7.52(4H，m)，7.53-7.61(4H，m).
Step G:
Under nitrogen atmosphere, at 0-5 ℃, with azo-2-carboxylic acid two piperidines acid amides (0.91g, 3.62mmol) join tributylphosphine (0.89mL, 3.62mmoL), (S)-2-oxyethyl group-3-(4-hydroxy phenyl)-ethyl propionate (0.60g, 2.53mmol) and (E) (E) 3-(4 '-{ 3-[(tertiary butyl dimethylsilyl)-methoxyl group]-the 1-methylpropenyl)-biphenyl-4-yl)-(1.02g is 2.41mmol) in the solution that is stirring in dry THF (15ml) for but-2-ene-1-alcohol.This compound is warming to room temperature, and stirs 18h.The mixture that water and ethyl acetate dilution obtain is collected water layer and is further used ethyl acetate extraction.Merge organic layer, use the salt water washing, dry (MgSO 4), and evaporation.Crude product passes through silica gel chromatography then, use heptane/ethyl acetate (4: 1) as eluent, provide (E) (E) (S) 3-{4-[3-(4 '-{ 3-[(tertiary butyl dimethylsilyl)-methoxyl group of 1.18g (76%)]-the 1-methylpropenyl }-biphenyl-4-yl)-but-2-ene base oxygen base]-phenyl }-2-oxyethyl group-ethyl propionate.
1H?NMR(CDCl 3)：δ0.13(6H，s)，0.93(9H，s)，1.18(3H，t)，1.23(3H，t)，2.07(3H，s)，2.18(3H，s)，2.95(2H，d)，3.31-3.42(1H，m)，3.55-3.67(1H，m)，3.98(1H，t)，4.17(2H，q)，4.42(2H，d)，4.73(2H，d)，5.95(1H，t)，6.12(1H，t)，6.88(2H，d)，7.18(2H，d)，7.45-7.60(8H，m).
Step H:
With (E) (E) (S) 3-{4-[3-(4 '-{ 3-[(tertiary butyl dimethylsilyl)-methoxyl group]-the 1-methylpropenyl }-biphenyl-4-yl)-but-2-ene base oxygen base]-phenyl }-2-oxyethyl group-ethyl propionate (1.18g, 1.84mmol) solution in dry THF is in cooled on ice, and slowly add 1.1M the tetrabutylammonium tetrahydrofuran solution (1.93mL, 1.93mmol).This reaction mixture is at room temperature stirred 3h.The mixture that water and ethyl acetate dilution obtain is collected water layer and is further used ethyl acetate extraction.Merge organic layer, use the salt water washing, dry (MgSO 4), and evaporation, provide (E) (S) 2-oxyethyl group-3-(4-{3-[4 '-{ 3-hydroxyl-1-methylpropenyl)-biphenyl-4-yl of 0.94g (E)]-but-2-ene base oxygen base }-phenyl)-ethyl propionate.
1H?NMR(CDCl 3)：δ1.18(3H，t)，1.22(3H，t)，2.12(3H，s)，2.18(3H，s)，2.96(2H，d)，3.30-3.42(1H，m)，3.53-3.67(1H，m)，3.98(1H，t)，4.17(2H，q)，4.40(2H，d)，4.74(2H，d)，6.04(1H，t)，6.12(1H，t)，6.88(2H，d)，7.18(2H，d)，7.45-7.62(8H，m).
Step I:
Under nitrogen atmosphere, at 0-5 ℃, with azo-2-carboxylic acid two piperidines acid amides (0.50g, 1.89mmol) join tributylphosphine (0.37mL, 1.89mmoL), (S) 2-oxyethyl group-3-(4-hydroxy phenyl)-ethyl propionate (0.32g, 1.32mmol) and (E) (E) (S) 2-oxyethyl group-3-(4-{3-[4 '-{ 3-hydroxyl-1-methyl-propenyl)-biphenyl-4-yl]-but-2-ene base oxygen base-phenyl)-(0.65g is 1.26mmol) in the solution that is stirring in dry THF (15ml) for ethyl propionate.This compound is warming to room temperature, and stirs 18h.The mixture that water and ethyl acetate dilution obtain is collected water layer and is further used ethyl acetate extraction.Merge organic layer, use the salt water washing, dry (MgSO 4), and evaporation, provide 580mg (63%) title compound.
1H?NMR(CDCl 3)：δ1.17(6H，t)，1.22(6H，t)，2.16(6H，s)，2.97(4H，d)，3.27-3.43(2H，m)，3.52-3.69(2H，m)，3.98(2H，t)，4.17(4H，q)，4.73(4H，d)，6.12(2H，t)，6.88(4H，d)，7.18(4H，d)，7.43-7.63(8H，m).
Embodiment 12 (universal method E)
(E) (E) (S) (S) 3-{4-[3-(4 '-{ 3-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-1-methyl-propenyl }-biphenyl-4-yl)-but-2-ene base oxygen base]-phenyl }-2-oxyethyl group-propionic acid
Steps A:
To (E) (E) (S) (S) 2-oxyethyl group-3-(4-[3-(4 '-{ 3-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-1-methyl-propenyl }-biphenyl-4-yl)-but-2-ene base oxygen base]-phenyl-solution of ethyl propionate (embodiment 11) (367mg 0.5mmol) in ethanol (10mL) in, add 1N sodium hydroxide (2mL).This reaction mixture is at room temperature stirred 18h, and stir 1h at 60 ℃.The mixture that water and ethyl acetate dilution obtain is collected water layer and is further used ethyl acetate extraction three times.Merge organic layer, use the salt water washing, dry (MgSO 4), and evaporation, provide 180mg (53%) title compound.
1H NMR (CDCl 3+ 1 DMSO): δ 1.15 (6H, t), 2.93 (2H, dd), 3.04 (2H, dd), 3.30-3.42 (2H, m), 3.60-3.71 (2H, m), 3.95 (2H, dd), 4.73 (4H, d), 6.11 (2H, t), 6.88 (4H, d), 7.21 (4H, d), 7.51 (4H, d), 7.57 (4H, d).
Embodiment 13 (universal method A)
(E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(7-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl-ethyl propionate
Figure A0282054700902
Steps A-B:
Under nitrogen atmosphere, to 2,7-two bromos-9-Fluorenone (338mg, 1.0mmol) in the solution in dry THF (17mL), add cupric iodide (I) (30mg, 0.16mmol) and dichloride two (triphenylphosphine) close palladium (II) (70mg, 0.10mmol), it is trans-the 3-methyl-the 2-amylene-4-alkynes-1-alcohol that (481mg is 5.0mmol) with exsiccant isopropylamine (17mL).After at room temperature stirring 6h, filter reaction mixture also is evaporated to filtrate dried.Product uses methylene dichloride/THF (10: 1) as eluent by silica gel chromatography, and (E) that provides 200mg (71%) (E) 2, two (5-hydroxy-3-methyl-penta-3-alkene-1-alkynyl)-fluorenes-9-ketone of 7-.
1H?NMR(DMSO)：δ1.87(6H，s)，4.10(4H，t)，4.83(2H，t)，6.05(2H，dt)，7.57(2H，s)，7.66(2H，d)，7.82(2H，d).
Step C:
Under nitrogen atmosphere, to (E) (E) 2, two (5-hydroxy-3-methyl-penta-3-alkene-1-alkynyl)-fluorenes-9-ketone (179mg of 7-, 0.49mmol) in the solution in dry THF (10mL), add triphenylphosphine (385mg, 1.47mmol) and (S)-(467mg 1.96mmol), and cools off this mixture 2-oxyethyl group-3-(4-hydroxy phenyl)-ethyl propionate on ice bath.After stirring 10 minutes, and the adding diethylazodicarboxylate (227mg, 0.256mmol).After stirring 1h, in reaction mixture, add entry and methylene dichloride.Water layer is further used twice of dichloromethane extraction.Dry organic phase (the MgSO that merges 4), filter and evaporation.This product uses methylene dichloride/THF (10: 1) as eluent by the column chromatography purifying, provides 220mg (55%) title compound.
1H?NMR(CDCl 3)：δ1.17(6H，t)，1.22(6H，t)，1.98(6H，s)，2.95(4H，d)，3.30-3.40(2H，m)，3.54-3.65(2H，m)，3.98(2H，t)，4.18(4H，q)，4.62(4H，d)，6.20(2H，t)，6.85(4H，d)，7.17(4H，d)，7.43(2H，d)，7.52(2H，d)，7.68(2H，s).
Embodiment 14 (universal method E)
(E) (E) (S) (S) 3-{4-[5-(7-{5-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl-2-oxyethyl group-propionic acid
Steps A:
To (E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(7-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl-ethyl propionate (embodiment 13) (185mg, 0.23mmol) in the solution in ethanol (10mL), add 1N sodium hydroxide (2.3mL).After 30 minutes, with the reaction mixture concentrating under reduced pressure, adding entry and 1N hydrochloric acid to pH value is 1 60 ℃ of stirrings.With dichloromethane extraction product three times, and dry (MgSO 4) organic phase that merges, filter and concentrating under reduced pressure, provide the title compound of 160mg, be crystalline product.
1H?NMR(CDCl 3)：δ1.18(6H，t)，1.98(6H，s)，2.97(2H，dd)，3.10(2H，dd)，3.38-3.51(2H，m)，3.57-3.69(2H，m)，4.05(2H，dd)，4.63(4H，d)，6.17(2H，t)，6.85(4H，d)，7.15(4H，d)，7.41(2H，d)，7.52(2H，d)，7.65(2H，s).
Embodiment 15 (universal method A)
[4-(3-{3-[3-(4-methoxycarbonyl methyl-phenoxy group)-third-1-alkynyl]-phenyl }-Propargyl oxygen base)-phenyl]-methyl acetate
Step C:
Under nitrogen atmosphere, at 0-5 ℃, with azo-2-carboxylic acid two piperidines acid amides (406mg, 1.61mmol) join tributylphosphine (325mg, 1.61mmol), 4-hydroxyphenyl acetic acid methyl esters (268mg, 1.61mmol) and 3-[3-(3-hydroxyl-third-1-alkynyl)-phenyl]-third-2-alkynes-1-alcohol (J Pharmacol Exp Ther 298:1260-1268,2001) (150mg is 0.81mmol) in the solution that is stirring in dry THF (20mL).This reaction mixture is stirred 1h at 0-5 ℃, and at room temperature stir 16h.With the reaction mixture concentrating under reduced pressure.Crude product uses heptane/ethyl acetate (1: 1) as eluent by purification by flash chromatography, provides 218mg (56%) title compound.
1H?NMR(DMSO)：δ3.35(6H，s)，3.53(4H，s)，5.03(4H，s)，6.93(2H，d)，7.22(2H，d)，7.40(2H，dd)，7.45-7.50(3H，m).
Embodiment 16 (universal method E)
[4-(3-{3-[3-(4-methoxycarbonyl methyl-phenoxy group)-third-1-alkynyl]-phenyl)-Propargyl oxygen base)-phenyl]-acetate
Figure A0282054700931
Steps A:
To [4-(3-{3-[3-(4-methoxycarbonyl methyl-phenoxy group)-third-1-alkynyl]-phenyl }-Propargyl oxygen base)-phenyl]-methyl acetate (embodiment 15) (200mg, 0.42mmol) in the solution in ethanol (3mL), adding 1N sodium hydroxide (1.6mmol, 1.6mL).Behind stirring at room 16h, adding 1N hydrochloric acid to pH value in reaction mixture is 1.By filtering separation product and dry, provide the title compound of 100mg (53%), be crystalline product.
1H NMR (acetone-d 6): δ 3.55 (4H, s), 5.00 (4H, s), 7.00 (4H, d), 7.27 (4H, d), 7.38 (1H, dd), 7.43 (1H, s), 7.48 (2H, dd).
Embodiment 17 (universal method A)
(E) (E) [4-(5-{4-[5-(4-methoxycarbonyl methoxyl group-3-methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-2-methyl-phenoxy group]-methyl acetate
Figure A0282054700941
Step C:
Under nitrogen atmosphere, in room temperature, with azo-2-carboxylic acid two piperidines acid amides (252mg, 1.0mmol) join tributylphosphine (202mg, 1.0mmol), (4-hydroxy-2-methyl-phenoxy group)-methyl acetate (WO 01/00603 A1) (170mg, 0.86mmol) and (E) (E) 5-[4-(5-hydroxyl-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-(embodiment 1 for 4-alkynes-1-alcohol, steps A-B) (103mg is 0.43mmol) in the solution that is stirring in dry THF (20mL).Behind 2h, in reaction mixture, add entry, and use the ethyl acetate extraction product.The dry organic phase that merges is filtered and concentrating under reduced pressure.Crude product uses heptane as eluent by purification by flash chromatography, carries out the transition to heptane/ethyl acetate (1: 1) eluent gradually, provides the 10mg title compound.
1H?NMR(CDCl 3)：δ2.28(6H，s)，3.78(6H，s)，4.54-4.60(4H，m)，4.60(4H，s)，6.03(2H，dt)，6.38(2H，dt)，6.66(4H，s)，6.78(2H，s)，7.37(4H，s).
Embodiment 18 (universal method E)
(E) (E) [4-(5-{4-[5-(4-methoxycarbonyl methoxyl group-3-methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-2-methyl-phenoxy group]-acetate
Figure A0282054700942
Steps A:
To (E) (E) [4-(5-4-[5-(4-methoxycarbonyl methoxyl group-3-methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-2-methyl-phenoxy group]-methyl acetate (embodiment 17) (15mg, 0.025mmol) in the solution in ethanol (15mL) and THF (5mL), add 1N sodium hydroxide (1.0ml).After 30 minutes, adding entry and 1N hydrochloric acid to pH value in reaction mixture is 1 in stirring at room.With dichloromethane extraction product three times, dry (MgSO 4) organic phase that merges, filter and concentrating under reduced pressure, provide the title compound of 10mg.
Embodiment 19 (universal method A)
(E) (E) (S) (S) 3-{3-bromo-4-[5-(4-{5-[2-bromo-4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl-2-oxyethyl group-ethyl propionate
Step C:
A) to (S)-2-oxyethyl group-3-(4-hydroxy phenyl)-ethyl propionate (TetrahedronLetters, Vol.35, No 19,3139-3142,1994) (9.5g, 40mmol) in the solution that is stirring in dry methylene chloride (100ml), in room temperature, with the bromine of 1h dropping in methylene dichloride (40ml).This reaction mixture was stirred 60 minutes, with saturated sodium sulfite and salt water washing.Dry (MgSO 4) organic phase and evaporation.Resistates is by the column chromatography purifying, and use heptane: ethyl acetate (9: 1) provides (S)-3-(3-bromo-4-hydroxyl-phenyl)-2-oxyethyl group-ethyl propionate of 11.25g (88%) as eluent.
1H?NMR(CDCl 3)：δ1.18(3H，t)，1.23(3H，t)，2.92(2H，d)，3.30-3.43(1H，m)，3.57-3.70(1H，m)，3.96(1H，dd)，4.18(4H，q)，5.72(1H，s)，6.90(1H，d)，7.09(1H，dd)，7.35(1H，d).
B) under nitrogen atmosphere, with azo-2-carboxylic acid two piperidines acid amides (504mg, 2.0mmol) join tributylphosphine (325mg, 1.3mmol), (S)-3-(3-bromo-4-hydroxyl-phenyl)-2-oxyethyl group-ethyl propionate (450mg, 1.89mmol) and (E) (E) 5-[4-(5-hydroxyl-penta-3-alkene-1-alkynyl)-phenyl]-(embodiment 1, and steps A-B) (150mg is 0.63mmol) in the solution that is stirring in dry THF (30mL) for penta-2-alkene-4-alkynes-1-alcohol.Behind 1h, in reaction mixture, add entry, and with ethyl acetate extraction product three times.The dry organic phase that merges is filtered and concentrating under reduced pressure.Crude product uses heptane/ethyl acetate (4: 1) as eluent by purification by flash chromatography, provides the 250mg title compound.
1H?NMR(CDCl 3)：δ1.18(6H，t)，1.23(6H，t)，2.95(4H，m)，3.30-3.43(2H，m)，3.55-3.67(2H，m)，3.98(2H，t)，4.18(4H，q)，4.63(4H，dd)，6.07(2H，dt)，6.39(2H，dt)，6.80(2H，d)，7.13(2H，dd)，7.38(4H，s)，7.45(2H，dd).
Embodiment 20 (universal method E)
(E) (E) (S) (S) 3-{3-bromo-4-[5-(4-{5-[2-bromo-4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl-2-oxyethyl group-propionic acid
Figure A0282054700961
Steps A:
To (E) (E) (S) (S) 3-{3-bromo-4-[5-(4-{5-[2-bromo-4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl-solution of 2-oxyethyl group-ethyl propionate (embodiment 19) (250mg 0.30mmol) in THF (2mL) and ethanol (3mL) in, add 1N sodium hydroxide (3ml).Behind stirring at room 1h, the concentrating under reduced pressure reaction mixture, adding entry and 1N hydrochloric acid to pH value is 1.With ethyl acetate extraction product three times, wash the organic phase of merging with water, dry (MgSO 4), filter and concentrating under reduced pressure, provide the title compound of 230mg.
1H?NMR(CDCl 3)：δ1.18(6H，t)，2.93(2H，dd)，3.04(2H，dd)，3.35-3.48(2H，m)，3.58-3.72(2H，m)，4.03(2H，dd)，4.68(4H，dd)，6.18(2H，dt)，6.39(2H，dt)，6.80(2H，d)，7.15(2H，dd)，7.39(4H，s)，7.49(2H，d)，10.24(2H，bs).
Embodiment 21 (universal method A)
(E) (E) [3-(5-{4-[5-(3-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate
Figure A0282054700971
Step C:
Under nitrogen atmosphere, with azo-2-carboxylic acid two piperidines acid amides (325mg, 1.3mmol) join (3-hydroxy phenyl)-ethyl acetate (340mg, 1.89mmol), (E) (E) 5-[4-(5-hydroxyl-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-(embodiment 1 for 4-alkynes-1-alcohol, steps A-B) (150mg, 0.63mmol) and tributylphosphine (365mg is 1.3mmol) in the solution that is stirring in dry THF (30mL).Behind 1h, in reaction mixture, add entry, and with ethyl acetate extraction product three times.Wash the organic phase of merging with water, dry (MgSO 4), filter and concentrating under reduced pressure.Crude product uses heptane/ethyl acetate (4: 1) as eluent by purification by flash chromatography, provides the 200mg title compound.
1H?NMR(CDCl 3)：δ1.23(6H，t)，3.55(4H，s)，4.15(4H，q)，4.62(4H，dd)，6.05(2H，dt)，6.38(2H，dt)，6.78-6.92(6H，m)，7.20-7.25(2H，m)，7.37(4H，s).
Embodiment 22 (universal method E)
(E) (E) [3-(5-{4-[5-(3-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-acetate
Steps A:
To (E) (E) [3-(5-{4-[5-(3-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate (embodiment 21) (200mg, 0.35mmol) in the solution in THF (2mL) and ethanol (6mL), add 1N sodium hydroxide (1ml).Behind stirring at room 3h, in reaction mixture, add 1N hydrochloric acid and ethyl acetate.Isolate title compound by filtering mixt, yield is 50mg.
1H?NMR(DMSO-d 6)：δ3.53(4H，s)，4.69(4H，d)，6.16(2H，d)，6.44(2H，dt)，6.80-6.92(6H，m)，7.23(2H，t)，7.45(4H，s).
Embodiment 23 (universal method A)
(E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(4 '-{ 5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate
Steps A-B:
Under nitrogen atmosphere, to 4,4 '-diiodo biphenyl (1.22g, 3.0mmol) in the solution in diisopropylamine (12mL), add cupric iodide (I) (30mg, 0.15mmol) and four (triphenylphosphines) close palladium (30mg, 0.03mmol).After stirring 1h, add trans-3-methyl-2-amylene-4-alkynes-1-alcohol (1.15g, 12.0mmol) solution in diisopropylamine (6mL).Behind 60 ℃ of stirring 8h, filter reaction mixture, and filtrate is evaporated to dried.Product uses methylene dichloride/THF (20: 1) as eluent by purification by flash chromatography, and (E) that provides 603mg (59%) be 5-[4 '-(5-hydroxy-3-methyl-penta-3-alkene-1-alkynyl)-biphenyl-4-yl (E)]-3-methyl-penta-2-alkene-4-alkynes-1-alcohol.
1H?NMR(DMSO-d 6)：δ1.87(6H，s)，4.10(4H，t)，4.80(2H，t)，6.01(2H，t)，7.53(4H，d)，7.73(4H，d).
Step C:
Under nitrogen atmosphere, at 0-5 ℃, with diethylazodicarboxylate (261mg, 1.5mmol) join (S)-2-oxyethyl group-3-(4-hydroxy phenyl)-ethyl propionate (TetrahedronLetters, Vol.35, No 19,3139-3142,1994) (476mg, 2.0mmol), (E) (E) 5-[4 '-(5-hydroxy-3-methyl-penta-3-alkene-1-alkynyl)-biphenyl-4-yl]-3-methyl-penta-2-alkene-4-alkynes-1-alcohol (171mg, 0.50mmol) and triphenylphosphine (393mg is 1.5mmol) in the solution that is stirring in dry THF (10mL).0-5 ℃ stir 1h after, in reaction mixture, add entry, and with twice of dichloromethane extraction product.Dry (MgSO 4) organic phase that merges, filter and concentrating under reduced pressure.Crude product uses methylene dichloride/THF (40: 1) as eluent by purification by flash chromatography, provides 213mg (56%) title compound.
1H?NMR(CDCl 3)：δ1.17(6H，t)，1.22(6H，t)，2.00(6H，s)，2.97(4H，d)，3.30-3.41(2H，m)，3.55-3.67(2H，m)，3.97(2H，t)，4.15(4H，q)，4.63(4H，d)，6.18(2H，dt)，6.85(4H，d)，7.17(4H，d)，7.49(4H，d)，7.57(4H，d).
Embodiment 24 (universal method E)
(E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(4 '-{ 5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-propionic acid
Steps A:
To (E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(4 '-{ 5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl-solution of ethyl propionate (embodiment 23) (210mg 0.27mmol) in ethanol (10mL) in, add 1N sodium hydroxide (2.7ml).60 ℃ stir 30 minutes after, concentrating under reduced pressure reaction mixture, and add 1N hydrochloric acid.With dichloromethane extraction product three times, dry (MgSO 4) organic phase that merges, filter and concentrating under reduced pressure, provide the title compound of 170mg (87%).
1H?NMR(CDCl 3)：δ1.19(6H，t)，2.00(6H，s)，2.97(2H，dd)，3.08(2H，dd)，3.39-3.50(2H，m)，3.55-3.68(2H，m)，4.05(2H，dd)，4.63(4H，d)，6.20(2H，dt)，6.85(4H，d)，7.18(4H，d)，7.48(4H，d)，7.53(4H，d).
Embodiment 25 (universal method A)
(E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl-ethyl propionate
Figure A0282054701001
Steps A-B:
Under nitrogen atmosphere, to 1, the 4-diiodo-benzene (0.99g, 3.0mmol) in the solution in diisopropylamine (12mL), add cupric iodide (I) (30mg, 0.15mmol) and four (triphenylphosphines) close palladium (30mg, 0.03mmol).After stirring 1h, add trans-3-methyl-2-amylene-4-alkynes-1-alcohol (1.15g, 12.0mmol) solution in diisopropylamine (6mL).60 ℃ stir 8h hour after, filter reaction mixture, and filtrate is evaporated to dried.Product uses methylene dichloride/THF (20: 1) as eluent by purification by flash chromatography, and (E) that provides 500mg (63%) be 5-[4-(5-hydroxy-3-methyl-penta-3-alkene-1-alkynyl)-phenyl (E)]-3-methyl-penta-2-alkene-4-alkynes-1-alcohol.
1H?NMR(DMSO-d 6)：δ1.83(6H，s)，4.08(4H，t)，4.80(2H，t)，5.98(2H，t)，7.42(4H，s).
Step C:
Under nitrogen atmosphere, at 0-5 ℃, with diethylazodicarboxylate (261mg, 1.5mmol) join (S)-2-oxyethyl group-3-(4-hydroxy phenyl)-ethyl propionate (TetrahedronLetters, Vol.35, No 19,3139-3142,1994) (476mg, 2.0mmol), (E) (E) 5-[4-(5-hydroxy-3-methyl-penta-3-alkene-1-alkynyl)-phenyl]-3-methyl-penta-2-alkene-4-alkynes-1-alcohol (133mg, 0.50mmol) and triphenylphosphine (393mg is 1.5mmol) in the solution that is stirring in dry THF (10mL).0-5 ℃ stir 1h after, in reaction mixture, add entry, and with twice of dichloromethane extraction product.Dry (MgSO 4) organic phase that merges, filter and concentrating under reduced pressure.Crude product uses methylene dichloride/THF (40: 1) as eluent by purification by flash chromatography, provides 290mg (82%) title compound.
1H?NMR(CDCl 3)：δ1.18(6H，t)，1.23(6H，t)，1.97(6H，s)，2.95(4H，d)，3.30-3.41(2H，m)，3.53-3.63(2H，m)，3.98(2H，t)，4.17(4H，q)，4.63(4H，d)，6.18(2H，dt)，6.82(4H，d)，7.15(4H，d)，7.36(4H，s).
Embodiment 26 (universal method E)
(E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl-propionic acid
Figure A0282054701011
Steps A:
To (E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl-solution of ethyl propionate (embodiment 25) (280mg 0.40mmol) in ethanol (10mL) in, add 1N sodium hydroxide (4.0ml).60 ℃ stir 30 minutes after, concentrating under reduced pressure reaction mixture, and add 1N hydrochloric acid.With dichloromethane extraction product three times, dry (MgSO 4) organic phase that merges, filter and concentrating under reduced pressure, provide 241mg (93%) title compound.
1H?NMR(CDCl 3)：δ1.18(6H，t)，1.98(6H，s)，2.95(2H，dd)，3.07(2H，dd)，3.37-3.49(2H，m)，3.57-3.68(2H，m)，4.04(2H，dd)，4.62(4H，d)，6.16(2H，dt)，6.83(4H，d)，7.18(4H，d)，7.36(4H，s).
Embodiment 27 (universal method A)
(E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl-ethyl propionate
Figure A0282054701021
Steps A-B:
Under nitrogen atmosphere, to 1, the 3-diiodo-benzene (0.99g, 3.0mmol) in the solution in diisopropylamine (12mL), add cupric iodide (I) (30mg, 0.15mmol) and four (triphenylphosphines) close palladium (30mg, 0.03mmol).After stirring 1h, add trans-3-methyl-2-amylene-4-alkynes-1-alcohol (1.15g, 12.0mmol) solution in diisopropylamine (6mL).60 ℃ stir 8h hour after, filter reaction mixture, and filtrate is evaporated to dried.Product uses methylene dichloride/THF (20: 1) as eluent by purification by flash chromatography, and (E) that provides 780mg (99%) be 5-[3-(5-hydroxy-3-methyl-penta-3-alkene-1-alkynyl)-phenyl (E)]-3-methyl-penta-2-alkene-4-alkynes-1-alcohol.
1H?NMR(DMSO-d 6)：δ1.84(6H，s)，4.07(4H，t)，4.82(2H，t)，6.01(2H，t)，7.35-7.45(3H，m)，7.48(1H，s).
Step C:
Under nitrogen atmosphere, at 0 ℃, with diethylazodicarboxylate (261mg, 1.5mmol) join (S)-2-oxyethyl group-3-(4-hydroxy phenyl)-ethyl propionate (TetrahedronLetters, Vol.35, No 19,3139-3142,1994) (476mg, 2.0mmol), (E) (E) 5-[3-(5-hydroxy-3-methyl-penta-3-alkene-1-alkynyl)-phenyl]-3-methyl-penta-2-alkene-4-alkynes-1-alcohol (133mg, 0.50mmol) and triphenylphosphine (393mg is 1.5mmol) in the solution that is stirring in dry THF (10mL).0 ℃ stir 1h after, in reaction mixture, add entry, and with twice of dichloromethane extraction product.Dry (MgSO 4) organic phase that merges, filter and concentrating under reduced pressure.Crude product uses methylene dichloride/THF (40: 1) as eluent by purification by flash chromatography, provides the title compound of 250mg (71%).
1H?NMR(CDCl 3)：δ1.18(6H，t)，1.23(6H，t)，1.97(6H，s)，2.95(4H，d)，3.30-3.41(2H，m)，3.53-3.63(2H，m)，3.98(2H，t)，4.17(4H，q)，4.63(4H，d)，6.18(2H，dt)，6.82(4H，d)，7.17(4H，d)，7.20-7.28(1H，dd)，7.35(2H，d)，7.52(1H，s).
Embodiment 28 (universal method E)
(E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl-propionic acid
Figure A0282054701031
Steps A:
To (E) (E) (S) (S) 2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl-solution of ethyl propionate (embodiment 27) (255mg 0.36mmol) in ethanol (10mL) in, add 1N sodium hydroxide (3.6ml).60 ℃ stir 30 minutes after, concentrating under reduced pressure reaction mixture, and add 1N hydrochloric acid.With dichloromethane extraction product three times, dry (MgSO 4) organic phase that merges, filter and concentrating under reduced pressure, provide the title compound of 232mg (99%).
1H?NMR(CDCl 3)：δ1.18(6H，t)，1.98(6H，s)，2.95(2H，dd)，3.07(2H，dd)，3.37-3.49(2H，m)，3.57-3.68(2H，m)，4.04(2H，dd)，4.62(4H，d)，6.16(2H，dt)，6.83(4H，d)，7.18(4H，d)，7.25(1H，dd)，7.35(2H，d)，7.50(1H，s).
Embodiment 29
[4-(3-{7-[3-(4-methoxycarbonyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl]-9H-fluorenes-2-yl }-the allyl group sulfenyl)-2-methyl-phenoxy group]-methyl acetate
(universal method G)
Steps A-B:
With 2,7-dibromo fluorenes (Ber.53,1236 (1920)) (48.6g, 0.15mmol), acid chloride (II) (1.0g, 4.45mmol), triphenylphosphine (3.0g, 11.4mmol), triethylamine (30.3g, 0.3mol), methyl acrylate (38.7g, 0.45mol) and the mixture of dimethyl formamide (150mL) stirs and at 110 ℃ of heating 7h.This mixture is poured in 1 premium on currency, filtered out the solid of generation, and use the chloroform recrystallization, provide the fluorenes-2 of 36.8g (74%), 7-diacrylate dimethyl ester.M.p.206-209℃.
Step C:
With the solution of aluminum chloride (19.6g 0.147mol) in ether (150mL) join lithium aluminum hydride in ether (150mL) (16.6g, 0.44mol) in, described mixture was stirred 30 minutes.At 25-50 ℃, the fluorenes-2 of portion-wise addition in THF (1000mL) in this mixture, (25.5g 76.3mmol), and continues to stir 8h to 7-diacrylate dimethyl ester.Drip 20% NaOH (150mL), this suspension of decantation, and organic phase poured in the water (3000mL).In refrigerator, after 3 days, filter out 3-[7-(3-hydroxyl-propenyl)-9H-fluorenes-2-base-vinylcarbinol, and use the chloroform/methanol recrystallization, obtain 16.5g (78%) yellow solid.
1H?NMR(250MHz，DMSO-d 6)：δ3.88(2H，s)，4.13(4H，t)，4.87(2H，t)，6.40(2H，dt)，6.60(2H，d)，7.40(2H，d)，7.60(2H，s)，7.77(2H，d).
(universal method A)
Step C:
A) with ortho-cresol (100g 0.925mol) is dissolved in the 2-butanone (1200ml), add salt of wormwood (191.7g, 1.5mol) and ethyl bromoacetate (162.2g 0.971mol), and stirs backflow 24h down with this mixture, and placement is spent the night then.Filter out solid, evaporated filtrate, resistates are dissolved in the benzene (400ml).Water (200ml), 5% sodium carbonate solution (100ml) washs this solution and uses MgSO 4Dry.Resistates (about 200g) underpressure distillation provides (2-methyl-phenoxy group)-ethyl acetate of 161.9g (90.1%), b.p.120-130 ℃/2kPa.
B) with chlorsulfonic acid (180.9g, 104ml 1.553mol) is cooled to-2～0 ℃, under agitation drips above-mentioned (2-methyl-phenoxy group)-ethyl acetate (75.35g then, 0.388mol), the control rate of addition makes the temperature of reaction mixture be no more than 0 ℃ (20min).Make reaction mixture be warming up to room temperature (1h) naturally, pour into then in the trash ice (1kg).Filter out crystallized product, water (500ml) washing, and at air drying to constant weight, provide 108.4g (95.5%) (4-chlorosulfonyl-2-methylphenoxy)-ethyl acetate crude product.This product provides the pure product of 73.3g (64.6%) with hexanaphthene (500ml) recrystallization.M.p.86-89℃.
1H?NMR(300MHz，CDCl 3)：δ7.84(2H，m)，6.80(1H，m)，4.76(2H，s)，4.29(2H，q)，2.37(3H，s)，1.31(3H，s).
C) (97.7g, 0.333mol), (189.9g is 1.59mol) and in the mixture of methyl alcohol (170ml), under vigorous stirring, with dripping concentrated hydrochloric acid in 20 minutes for tin to above-mentioned (4-chlorosulfonyl-2-methylphenoxy)-ethyl acetate.Reaction beginning heat release, and begin spontaneous backflow.Reaction mixture was continued reflux 3 hours, cool off then and be poured in the trash ice (1kg).(3 * 200ml) extract this mixture, and (2 * 80ml) washing ethereal solutions are used MgSO to water with ether 4Drying, and reduction vaporization.Resistates (97.7g) is dissolved in the benzene (300ml), and (Fluka 60,800g), and with this post of benzene (2500ml) drip washing by silicagel column.The benzole soln that evaporation is collected, and underpressure distillation resistates provide 41.3g (58.4%) (4-sulfydryl-2-methylphenoxy)-methyl acetate, are oily matter, b.p.136.5-137 ℃/133Pa.
1H?NMR(250MHz，CDCl 3)：δ7.04(m)+7.04(m)，∑2H，6.54(1H，m)，2.20(3H，m)，4.56(2H，s)，3.73(3H，s)，3.34(1H，s).
D). will be at the above-mentioned 3-[7-in the dry THF (10mL) (3-hydroxyl-propenyl)-9H-fluorenes-2-base-vinylcarbinol (85mg, 0.3mmol) and tributylphosphine (242mg, 1.2mmol) in cooled on ice, and under nitrogen atmosphere, add azo-2-carboxylic acid's two piperidines acid amides (302mg, 1.2mmol).0 ℃ stir 10 minutes after, in this reaction mixture, slowly add above-mentioned (4-sulfydryl-2-methylphenoxy)-methyl acetate (255mg, 1.2mmol).Stirred 2 hours and after 16 hours, in reaction mixture, add entry (20mL) at 0 ℃ in stirring at room, and with methylene dichloride (3 * 25mL) extraction products.Dry (MgSO 4) organic phase that merges, filter and concentrating under reduced pressure.Crude product uses heptane/ethyl acetate (5: 2) by purification by flash chromatography, then uses methylene dichloride as eluent, provides the title compound of 34mg (17%).
1H?NMR(CDCl 3)：δ2.25(6H，s)，3.62(2H，d)，3.79(6H，s)，3.85(2H，s)，4.62(4H，s)，6.25(2H，dt)，6.37(2H，d)，6.62(2H，d)，7.21(1H，d)，7.25(2H，s)，7.28(2H，d)，7.48(2H，s)，7.63(2H，d).
Pharmacological method
External PPAR α, PPAR γ and PPAR δ activating activities
The instantaneous Transactivation of described PPAR (transient transactivation) analysis is based on two kinds of plasmid transient transfections of chimeric test albumen of encoding respectively (chimeric test protein) and receptor protein to people HEK293 cell.Described chimeric test albumen is in conjunction with territory (DBD) fusion with the proteic ligand binding domain of people PPAR (LBD) from the DNA of yeast GAL4 transcription factor.Described PPAR-LBD partly except that being positioned at ligand binding pocket, also is positioned at natural activation domain (activation official energy 2=AF2), allows fusion rotein to play the effect of PPAR ligand-dependent transcription factor.Described GAL4 DBD instructs described chimeric protein only to be incorporated into Gal4 intensifying factor (it is not present in the HEK293 cell).Described receptor plasmid contains the Gal4 intensifying factor that promotes the luciferin enzyme protein expression.After transfection, HEK293 cell expressing GAL4-DBD-PPAR-LBD fusion rotein.This fusion rotein then be incorporated into the Gal4 intensifying factor of control luciferase expression and does not play a role when not having part.In case in this cell, add the PPAR part, then will give birth to luciferase protein with volume production corresponding to the proteic activation of PPAR.After adding suitable substrate, measure the amount of luciferase protein by light emission.
Cell cultures and transfection
The HEK293 cell is grown in DMEM+10%FCS.Before transfection one day, with cell inoculation on the 96-orifice plate, to provide the fusion (confluency) of 50-80% when the transfection.Use the FuGene transfection reagent,, will contain 0.64 μ g pM1 α/γ LBD, 0.1 μ g pCMV β Gal, 0.08 μ gpGL2 (Gal4) according to producer's indication (Roche) 5Arrive every hole with the 0.8 μ g DNA transfection altogether of 0.02 μ g pADVANTAGE.Allow cell expressing albumen 48h, then add compound.
Plasmid: by pcr amplification, use, obtain people's PPAR alpha, gamma and δ by the mRNA reverse transcription synthetic cDNA that derives from people's liver, fatty tissue and placenta respectively.The cDNA of amplification is cloned into pCR2.1 and sequencing.The ligand binding domain (LBD) of each PPAR isomer (isoform) produces (PPAR α: aa 167-C-end by PCR; PPAR γ: aa 165-C-end; PPAR δ: aa 128-C-end), and in vehicle pM1, be fused to the DNA of yeast transcription factor GAL4 in conjunction with territory (DBD) (Sadowski et al. (1992), Gene 118,137) by the described fragment of subclone, produce plasmid pM1 α LBD, pM1 γ LBD and pM1 δ.Examine fusion by sequencing.By 5 multiple GAL4 recognition sequences (5xCGGAGTACTGTCCTCCG (AG)) (Webster et al. (1988) that will encode, Nucleic Acids Res.16,8192) oligonucleotide is inserted into vehicle pGL2 promotor (Promega), produce plasmid pGL2 (GAL4) 5, make up described acceptor.PCMV β Gal is available from Clontech, and pADVANTAGE is available from Promega.
External Transactivation analysis
Compound: all compound dissolutions are in DMSO, and by joining in the cell after the dilution in 1: 1000.Compound parallel testing four times, concentration range are 0.001-300 μ M.Cell carries out the luciferase analysis then with described compound treatment 24 hours.Each compound is tested in two independent experiments at least.
Luciferase is analyzed: sucking-off comprises the medium of test compound, and adds the 100 μ lPBS that comprise 1mM Mg++ and Ca++ in every hole.Use the LucLite test kit, carry out the luciferase analysis according to manufacturers's indication (Packard Instruments).Quantize light emission by counting on Packard LumiCounter.For measuring betagalactosidase activity, will transfer in the new micro plate from the 25 μ l upper strata stillnesss of night of each transfection lysate.In this microwell plate, use the test kit that derives from Promega to carry out the beta-galactosidase enzymes analysis and reading on Labsystems Ascent Multiscan reader.Described beta-galactosidase enzymes data are used for the described luciferase data of normalization method (transfection efficiency, cell growth etc.).
Statistical method
The activity of compound is to calculate with the doubling method of induction of untreated samples comparison.For every kind of compound, effect (maximum activity) with Wy14,643 (for PPAR α), the relative reactivity of Rosiglitazone (for PPAR γ) and Carbacyclin (for PPAR δ) provides.Described EC50 is the concentration when providing active 50% value of maximum observation.The EC50 value is by non-linear regression, and (GraphPadSoftware, San Diego Ca) calculates to use GraphPad PRISM 3.02.The result represents with mean value ± SD.

Claims (71)

1. the compound of a general formula (I), or its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing, or any tautomer, steric isomer comprises the mixture of the steric isomer of racemic mixture or polymorph:
Wherein
A is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio or aralkoxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen or C 1-3-alkyl, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or arylidene, it is chosen wantonly and is replaced by one or more halogens;
Zero R 4The optional aryl that is replaced by one or more halogens of expression; Or
A is-O-A ' or-S-A ', wherein-O-or-S-is connected on the X in the formula (I), and wherein A ' is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio or aralkoxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen or C 1-3-alkyl, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or arylidene, it is chosen wantonly and is replaced by one or more halogens;
Zero R 4The optional aryl that is replaced by one or more halogens of expression; And
B is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio or aralkoxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen or C 1-3-alkyl, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or arylidene, it is chosen wantonly and is replaced by one or more halogens;
Zero R 4The optional aryl that is replaced by one or more halogens of expression; Or
B is-O-B ' or-S-B ', wherein-O-or-S-is connected on the Y in the formula (I), and wherein B ' is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio or aralkoxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen or C 1-3-alkyl, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or arylidene, it is chosen wantonly and is replaced by one or more halogens;
Zero R 4The optional aryl that is replaced by one or more halogens of expression; And
D is H, C 1-6-alkyl or C 3-6-cycloalkyl; And
E is H, C 1-6-alkyl or C 3-6-cycloalkyl; And
L and M be independently-O-or-S-; And
T is C 3-9The divalence unsaturated carbon chains, it is optional to be selected from following substituting group and to replace by one or more:
● halogen or hydroxyl; Or
● aryl, aralkoxy or C 1-3-alkoxyl group, it is chosen wantonly and is replaced by halogen; And
U is C 3-9The divalence unsaturated carbon chains, it is optional to be selected from following substituting group and to replace by one or more:
● halogen or hydroxyl; Or
● aryl, aralkoxy or C 1-3-alkoxyl group, it is chosen wantonly and is replaced by halogen; And
X is arylidene or inferior heteroaryl, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen or hydroxyl; Or
● C 1-6-alkyl, C 3-6-cycloalkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio, aforementioned each group is optional to be replaced by one or more halogens; Or
Y is arylidene or inferior heteroaryl, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen or hydroxyl; Or
● C 1-6-alkyl, C 3-6-cycloalkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio, aforementioned each group is optional to be replaced by one or more halogens; Or
Z is that arylidene, inferior heteroaryl or divalence are encircled ring system more, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen, oxo or hydroxyl; Or
● C 1-6-alkyl, C 3-6-cycloalkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy, C 1-6-alkylthio, C 3-6-cycloalkylthio, aforementioned each group is optional to be replaced by one or more halogens.
2. according to the compound of claim 1, wherein A is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● methyl, C 1-3-alkoxyl group, C 3-6-cycloalkyloxy, or benzyloxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or the optional phenylene that is replaced by one or more halogens;
Zero R 4The optional phenyl that is replaced by one or more halogens of expression.
3. according to the compound of claim 2, wherein A is methylene radical or ethylidene, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● methoxy or ethoxy; Or
● NR 1R 2, R wherein 1Expression hydrogen, R 2Expression-R 3-(C=O)-R 4, R wherein 3And R 4The expression phenyl.
4. according to compound any among the claim 2-3, wherein A is an ethylidene, and it is chosen wantonly and is replaced by oxyethyl group.
5. according to the compound of claim 1, wherein A be-O-A ' or-S-A ', wherein-O-or-S-is connected on the X in the formula (I), and wherein A ' is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy or aralkoxy, aforementioned each group is optional to be replaced by halogen.
6. according to the compound of claim 5, wherein A be-O-A ' or-S-A ', wherein-O-or-S-is connected on the X in the formula (I), and wherein A ' is methylene radical or ethylidene, aforementioned each group is optional by one or more methyl that are selected from, and the substituting group of methoxy or ethoxy replaces.
7. according to compound any in the aforementioned claim, wherein B is the C1-3-alkylidene group, and it is optional to be selected from following substituting group and to replace by one or more:
● methyl, C 1-3-alkoxyl group, C 3-6-cycloalkyloxy, or benzyloxy, aforementioned each group is optional to be replaced by halogen; Or
● NR 1R 2, R wherein 1Expression hydrogen, R 2Expression-R 3-(C=O)-R 4, wherein:
Zero R 3Expression C 1-6-alkylidene group, C 2-6-alkenylene, C 4-6-cycloalkylidene, C 4-6-Ya cycloalkenyl group, or the optional phenylene that is replaced by one or more halogens;
Zero R 4The optional phenyl that is replaced by one or more halogens of expression.
8. according to the compound of claim 7, wherein B is methylene radical or ethylidene, and aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● methoxy or ethoxy; Or
● NR 1R 2, R wherein 1Expression hydrogen, R 2Expression-R 3-(C=O)-R 4, R wherein 3And R 4The expression phenyl.
9. according to compound any among the claim 7-8, wherein B is an ethylidene, and it is chosen wantonly and is replaced by oxyethyl group.
10. according to compound any among the claim 1-7, wherein B be-O-B ' or-S-B ', wherein-O-or-S-is connected on the Y in the formula (I), and wherein B ' is C 1-3-alkylidene group, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-3-alkyl, C 1-6-alkoxyl group, C 3-6-cycloalkyloxy or aralkoxy, aforementioned each group is optional to be replaced by halogen.
11. compound according to claim 10, wherein B be-O-B ' or-S-B ', wherein-O-or-S-is connected on the Y in the formula (I), and wherein B ' is methylene radical or ethylidene, aforementioned each group is optional by one or more methyl that are selected from, and the substituting group of methoxy or ethoxy replaces.
12. according to compound any in the aforementioned claim, wherein D is H.
13. according to compound any among the claim 1-11, wherein D is methyl or ethyl.
14. according to compound any in the aforementioned claim, wherein E is H.
15. according to compound any among the claim 1-13, wherein E is methyl or ethyl.
16. according to compound any in the aforementioned claim, wherein L is-O-.
17. according to compound any in the aforementioned claim, wherein L is-S-.
18. according to compound any in the aforementioned claim, wherein M is-O-.
19. according to compound any in the aforementioned claim, wherein M is-S-.
20. according to compound any in the aforementioned claim, wherein T is C 3-9The divalence unsaturated carbon chains, it is optional to be selected from following substituting group and to replace by one or more: phenyl, benzyloxy or C 1-3-alkoxyl group, it is chosen wantonly and is replaced by halogen.
21. according to the compound of claim 20, wherein T is unsubstituted C 3-9The divalence unsaturated carbon chains.
22. according to compound any among the claim 20-21, wherein T is C 3-9Alkenylene.
23. according to compound any among the claim 20-21, wherein T is C 3-9Alkynylene.
24. according to compound any among the claim 20-21, wherein T is C 5-9Inferior Ene alkynyl base.
25. according to compound any in the aforementioned claim, wherein U is C 3-9The divalence unsaturated carbon chains, it is optional to be selected from following substituting group and to replace by one or more: phenyl, benzyloxy or C 1-3-alkoxyl group, it is chosen wantonly and is replaced by halogen.
26. according to the compound of claim 25, wherein U is unsubstituted C 3-9The divalence unsaturated carbon chains.
27. according to compound any among the claim 25-26, wherein U is C 3-9Alkenylene.
28. according to compound any among the claim 25-26, wherein U is C 3-9Alkynylene.
29. according to compound any among the claim 25-26, wherein U is C 5-9Inferior Ene alkynyl base.
30. according to compound any in the aforementioned claim, wherein X is arylidene or inferior heteroaryl, aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● the optional C that is replaced by one or more halogens 1-6-alkyl.
31. according to the compound of claim 30, wherein X is an arylidene, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● the optional C that is replaced by one or more halogens 1-6-alkyl.
32. according to compound any among the claim 30-31, wherein X is optional by one or more phenylenes that are selected from following substituting group replacement:
● halogen, or
● the optional C that is replaced by one or more halogens 1-3-alkyl.
33. according to compound any among the claim 30-32, wherein X is a phenylene, it is chosen wantonly and is replaced by one or more halogens.
34. according to compound any in the aforementioned claim, wherein Y is arylidene or inferior heteroaryl, aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● the optional C that is replaced by one or more halogens 1-6-alkyl.
35. according to the compound of claim 34, wherein Y is an arylidene, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● the optional C that is replaced by one or more halogens 1-6-alkyl.
36. according to compound any among the claim 34-35, wherein Y is a phenylene, it is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● the optional C that is replaced by one or more halogens 1-3-alkyl.
37. according to compound any among the claim 34-36, wherein Y is the optional phenylene that is replaced by one or more halogens.
38. according to compound any in the aforementioned claim, wherein Z is that arylidene, inferior heteroaryl or divalence are encircled ring system more, aforementioned each group is optional to be selected from following substituting group and to replace by one or more:
● halogen, oxo, or
● C 1-6-alkyl, C 1-6-alkoxyl group, aforementioned each group is optional to be replaced by one or more halogens.
39. according to the compound of claim 38, wherein Z is selected from following groups:
Figure A028205470008C1
It is optional to be selected from following substituting group and to replace by one or more:
● halogen, or
● C 1-6-alkyl or C 1-6-alkoxyl group, aforementioned each group is optional to be replaced by one or more halogens.
40. according to compound any among the claim 38-39, wherein Z is selected from following groups:
Figure A028205470009C1
41. according to compound any among the claim 38-40, wherein Z is selected from following groups:
Figure A028205470009C2
42. compound according to claim 1, or its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing, or any tautomer, steric isomer, the mixture that comprises the steric isomer of racemic mixture, or polymorph, its formula of (I) such as general formula (II) description:
D wherein, A, X, L, Z, U, M, Y, B and E such as in any one of claim 1-19 or 25-41 definition; And
G 1Be H, C 1-3-alkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen; With
G 2Be H, C 1-3-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6-Ene alkynyl base, aryl, aralkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen.
43. according to the compound of claim 42, wherein G 1Be H, C 1-3-alkyl or C 1-3-alkoxyl group, aforementioned each group is optional to be replaced by halogen; With
G 2Be H, C 1-3-alkyl or aryl, aforementioned each group is optional to be replaced by halogen.
44. according to compound any among the claim 42-43, wherein G 1Be H, and G 2Be H or methyl.
45. compound according to claim 1, or its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing, or any tautomer, steric isomer, the mixture that comprises the steric isomer of racemic mixture, or polymorph, its formula of (I) such as general formula (III) description:
D wherein, A, X, L, Z, M, Y, B and E in any one of claim 1-19 or the 30-41 definition; And
G 1And G 4Be H independently of one another, C 1-3-alkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen; With
G 2And G 3Be H independently of one another, C 1-3-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6-Ene alkynyl base, aryl, aralkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen.
46. according to the compound of claim 45, wherein G 1And G 4Be H independently of one another, C 1-3-alkyl or C 1-3-alkoxyl group, aforementioned each group is optional to be replaced by halogen; With
G 2And G 3Be H independently of one another, C 1-3-alkyl or aryl, aforementioned each group is optional to be replaced by halogen.
47. according to compound any among the claim 45-46, wherein G 1And G 4Be H; With
G 2And G 3Be H or methyl independently of one another.
48. compound according to claim 1, or its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing, or any tautomer, steric isomer, the mixture that comprises the steric isomer of racemic mixture, or polymorph, its formula of (I) such as general formula (IV) description:
D wherein, A, X, L, Z, U, M, Y, B and E in any one of claim 1-19 or the 25-41 definition; And
G 1Be H, C 1-3-alkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen; With
G 2Be H, C 1-3-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6-Ene alkynyl base, aryl, aralkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen.
49. according to the compound of claim 48, wherein G 1Be H, C 1-3-alkyl or C 1-3-alkoxyl group, aforementioned each group is optional to be replaced by halogen; With
G 2Be H, C 1-3-alkyl or aryl, aforementioned each group is optional to be replaced by halogen.
50. the compound any, wherein G according to claim 48-49 1Be H and G 2Be H or methyl.
51. according to the compound of claim 1, or its pharmacologically acceptable salts, or its pharmacy acceptable solvent thing, or any tautomer, steric isomer comprises the mixture of the steric isomer of racemic mixture, or polymorph, its formula of (I) is described as logical formula V:
Figure A028205470011C2
D wherein, A, X, L, Z, M, Y, B and E such as claim 1-19 or 30-41 any one definition; And
G 1And G 4Be H independently of one another, C 1-3-alkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen; With
G 2And G 3Be H independently of one another, C 1-3-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6-Ene alkynyl base, aryl, aralkyl, C 1-3-alkoxyl group or C 1-3-aralkoxy, aforementioned each group is optional to be replaced by halogen.
52. according to the compound of claim 51, wherein G 1And G 4Be H independently of one another, C 1-3-alkyl or C 1-3-alkoxyl group, aforementioned each group is optional to be replaced by halogen; With
G 2And G 3Be H independently of one another, C 1-3-alkyl or aryl, aforementioned each group is optional to be replaced by halogen.
53. according to compound any among the claim 51-52, wherein G 1And G 4Be H; With
G 2And G 3Be H or methyl independently of one another.
54. according to compound any in the aforementioned claim, it is:
2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
3-{4-[5-(4-{5-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-2-oxyethyl group-propionic acid;
3-chloro-4-(5-{4-[5-(3-chloro-4-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate;
[4-(5-{4-[5-(4-carboxyl methyl-3-chloro phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl]-acetate;
2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
3-[4-[5-(3-{5-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-2-oxyethyl group-propionic acid;
[3-chloro-4-(5-{3-[5-(2-chloro-4-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate;
[4-(5-{3-[5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl]-acetate;
2-(2-benzoyl-phenyl amino)-3-(4-{5-[4-(5-{4-[2-(2-benzoyl-phenyl amino)-2-methoxycarbonyl ethyl]-phenoxy group }-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-4-alkynyloxy base }-phenyl)-methyl propionate;
2-(2-benzoyl-phenyl amino)-3-(4-{5-[4-(5-{4-[2-(2-benzoyl-phenyl amino)-2-carboxyl-ethyl]-phenoxy group }-penta-3-alkene-1-alkynyl)-phenyl]-penta-2-alkene-4-alkynyloxy base }-phenyl)-propionic acid;
2-oxyethyl group-3-{4-[3-(4 '-3-[4-(2-oxyethyl group-2-ethoxy carbonyl-ethyl)-phenoxy group]-1-methyl-propenyl }-biphenyl-4-yl)-but-2-ene base oxygen base]-phenyl }-ethyl propionate;
3-{4-[3-(4 '-3-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-1-methyl-propenyl }-biphenyl-4-yl)-but-2-ene base oxygen base]-phenyl }-2-oxyethyl group-propionic acid;
2-oxyethyl group-3-{4-[5-(7-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
3-{4-[5-(7-{5-[4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-2-oxyethyl group-propionic acid; Or
The salt of itself and acceptable acid of pharmacy or alkali, or the mixture of any optical isomer or optical isomer comprise racemic mixture, or any tautomer.
55. according to compound any among the claim 1-53, it is:
[4-(3-{3-[3-(4-methoxycarbonyl methyl-phenoxy group)-third-1-alkynyl]-phenyl }-Propargyl oxygen base)-phenyl]-methyl acetate;
[4-(3-{3-[3-(4-methoxycarbonyl methyl-phenoxy group)-third-1-alkynyl]-phenyl }-Propargyl oxygen base)-phenyl]-acetate;
[4-(5-4-[5-(4-methoxycarbonyl methoxyl group-3-methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-2-methyl-phenoxy group]-methyl acetate;
[4-(5-(4-[5-(4-methoxycarbonyl methoxyl group-3-methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-2-methyl-phenoxy group]-acetate;
3-{3-bromo-4-[5-(4-{5-[2-bromo-4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-2-oxyethyl group-ethyl propionate;
3-{3-bromo-4-[5-(4-{5-[2-bromo-4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-penta-3-alkene-1-alkynyl }-phenyl)-penta-2-alkene-4-alkynyloxy base]-phenyl }-2-oxyethyl group-propionic acid;
[3-(5-{4-[5-(3-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-ethyl acetate;
[3-(5-{4-[5-(3-ethoxy carbonyl methyl-phenoxy group)-penta-3-alkene-1-alkynyl]-phenyl }-penta-2-alkene-4-alkynyloxy base)-phenyl]-acetate;
2-oxyethyl group-3-{4-[5-(4 '-5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
2-oxyethyl group-3-{4-[5-(4 '-5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-propionic acid;
2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
2-oxyethyl group-3-{4-[5-(4-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-propionic acid;
2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-ethyl propionate;
2-oxyethyl group-3-{4-[5-(3-{5-[4-(2-oxyethyl group-2-ethoxy carbonyl ethyl)-phenoxy group]-3-methyl-penta-3-alkene-1-alkynyl }-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base]-phenyl }-propionic acid;
[4-(3-{7-[3-(4-methoxycarbonyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl]-9H-fluorenes-2-yl }-the allyl group sulfenyl)-2-methyl-phenoxy group]-methyl acetate; Or
The salt of itself and acceptable acid of pharmacy or alkali, or the mixture of any optical isomer or optical isomer comprise racemic mixture, or any tautomer.
56. according to compound any among the claim 1-53, it is:
(4-(3-(4 '-(3-(4-carboxyl methoxyl group-3-aminomethyl phenyl sulfenyl)-propenyl)-biphenyl-4-yl) the allyl group sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(3-(4 '-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-propenyl)-biphenyl-4-yl)-the allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-(2-carboxyl-2-ethoxyethyl group)-phenoxy group)-propenyl)-biphenyl-4-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-biphenyl-4-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-biphenyl-4-yl) the allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(3-(4 '-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-biphenyl-4-yl)-the allyl group sulfenyl)-2-methyl-phenoxy group)-acetate;
(4-(3-(4 '-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-biphenyl-4-yl)-allyloxy)-the 3-chlorophenyl)-acetate;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-biphenyl-4-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-biphenyl-4-yl)-the allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(3-(7-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-9H-fluorenes-2-yl)-allyl group sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(3-(7-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-9H-fluorenes-2-yl)-allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(7-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-9H-fluorenes-2-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
(4-(3-(7-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-propenyl)-9H-fluorenes-2-yl)-allyloxy)-3-chlorophenyl)-acetate;
3-(4-(3-(7-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-9H-fluorenes-2-yl)-allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(7-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-9H-fluorenes-2-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(7-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-propenyl)-9H-fluorenes-2-yl)-allyloxy)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(7-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-propenyl)-9H-fluorenes-2-yl)-allyl group sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(3-(7-(3-(4-carboxyl methoxyl group-2-chloro phenoxy group)-propenyl)-9H-fluorenes-2-yl)-allyloxy)-3-chlorophenyl)-acetate;
3-(4-(3-(4 '-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base oxygen base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-1-methyl-propenyl)-xenyl-4-yl)-but-2-ene base sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(3-(4 '-(3-(4-carboxyl methyl-2-chloro phenoxy group)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base oxygen base)-the 3-chlorophenyl)-acetate;
(4-(3-(4 '-(3-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base oxygen base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(3-(4 '-(3-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-1-methyl-propenyl)-biphenyl-4-yl)-but-2-ene base oxygen base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
4-(5-(4-(5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-3-chlorophenyl)-acetate;
4-(5-(4-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyloxy group)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
4-(5-(4 '-(5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl)-acetate;
4-(5-(4 '-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4 '-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(4 '-(5-(4-carboxyl methyl-2-chloro phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl)-acetate;
(4-(5-(4 '-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-xenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4 '-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-xenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 '-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) biphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
(4-(5-(4 "-(5-(4-carboxyl methyl-2-chloro phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl)-acetate;
(4-(5-(4 "-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4 "-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl oxygen base)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
4-(5-(4 "-(5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyloxy base)-the 3-chlorophenyl)-acetate;
4-(5-(4 "-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4 "-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(4 "-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-[1,1 '; 4 ' 1 "] terphenyl-4-yl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(4-(5-(4-carboxyl methyl-2-chloro phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-3-chlorophenyl)-acetate;
(4-(5-(4-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(4-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(4-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
4-(5-(3-(5-(4-carboxyl methyl-2-chloro phenoxy group)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-3-chlorophenyl)-acetate;
4-(5-(3-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(3-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-phenyl)-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(3-(5-(4-carboxyl methyl-2-chloro phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-3-chlorophenyl)-acetate;
(4-(5-(3-(5-(4-carboxyl methyl-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(3-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-phenyl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(3-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl) phenyl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy group)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-9-oxo-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group)-3-methyl-penta-3-alkene-1-alkynyl)-9H-carbazole-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9H-carbazole-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-3-methyl-penta-3-alkene-1-alkynyl)-9H-carbazole-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenoxy group-penta-3-alkene-1-alkynyl)-9H-fluorenes-2-yl)-3-methyl-penta-2-alkene-4-alkynyloxy base)-phenyl)-2-oxyethyl group-propionic acid;
3-(4-(5-(7-(5-(4-(2-carboxyl-2-oxyethyl group-ethyl)-phenyl sulfenyl-penta-3-alkene-1-alkynyl)-9H-carbazole-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-phenyl)-2-oxyethyl group-propionic acid;
(4-(5-(7-(5-(4-carboxyl methoxyl group-3-methyl-phenyl sulfenyl)-penta-3-alkene-1-alkynyl)-9H-carbazole-2-yl)-3-methyl-penta-2-alkene-4-alkynyl sulfenyl)-2-methyl-phenoxy group)-acetate, or
The salt of itself and acceptable acid of pharmacy or alkali, or the mixture of any optical isomer or optical isomer comprise racemic mixture, or any tautomer.
57. any described compound is as the application of pharmaceutical composition in the aforementioned claim.
58. a pharmaceutical composition comprises any described compound as at least a claim 1-56 of activeconstituents, and one or more pharmaceutically acceptable carriers or vehicle.
59. the pharmaceutical composition according to claim 58 is unit dosage, comprises the about 1000mg/ of about 0.05-days, preferably about 0.1-about 500mg/ days, any described compound among about 200mg/ days the claim 1-56 of especially preferably about 0.5-.
60. be used for the treatment of by nuclear receptor, the pharmaceutical composition of the situation of peroxisome Proliferators activated receptors (PPAR) mediation particularly, described composition comprises any described compound of claim 1-56, and one or more pharmaceutically acceptable carriers or vehicle.
(comprise metabolism syndrome 61. be used for the treatment of type i diabetes, type ii diabetes, hyperlipemia, syndrome X, be that impaired glucose is stood, insulin resistance, hypertriglyceridemia and/or obesity), the pharmaceutical composition of cardiovascular disorder (comprising arteriosclerosis) or hypercholesterolemia, it comprises any described compound of claim 1-56, and one or more pharmaceutically acceptable carriers or vehicle.
62. according to pharmaceutical composition any among the claim 58-61, be used for oral, intranasal, through skin, through lung or administered parenterally.
63. any described compound is used for the treatment of by nuclear receptor in preparation among the claim 1-56, particularly the application in the pharmaceutical composition of the situation of peroxisome Proliferators activated receptors (PPAR) mediation.
64. any described compound is used for the treatment of application in the pharmaceutical composition of type i diabetes or type ii diabetes in preparation among the claim 1-56.
65. any described compound is used for the treatment of application in the pharmaceutical composition of hyperlipemia in preparation among the claim 1-56.
66. any described compound is used for the treatment of syndrome X in preparation among the claim 1-56, comprises metabolism syndrome, promptly impaired glucose is stood, the application in insulin resistance, hypertriglyceridemia and/or the fat pharmaceutical composition.
67. any described compound is used for the treatment of cardiovascular disorder in preparation among the claim 1-56, comprises the application in the arteriosclerotic pharmaceutical composition.
68. any described compound is used for the treatment of application in the pharmaceutical composition of hypercholesterolemia in preparation among the claim 1-56.
69. treatment is by nuclear receptor, the method of the situation of peroxisome Proliferators activated receptors (PPAR) mediation particularly, this method comprise to the object of needs treatment takes any described compound among the claim 1-56 of significant quantity or comprises the pharmaceutical composition of described compound.
70. treatment type i diabetes, type ii diabetes, hyperlipemia, syndrome X (comprise metabolism syndrome, be that impaired glucose is stood, insulin resistance, hypertriglyceridemia and/or obesity), the method for cardiovascular disorder (comprising arteriosclerosis) or hypercholesterolemia, this method comprises to the object of needs treatment takes any described compound among the claim 1-56 of significant quantity or comprises the pharmaceutical composition of described compound.
71. according to the method for claim 69 or 70, the significant quantity of any described compound is the about 1000mg/ of about 0.05-days among the wherein said claim 1-56, preferably about 0.1-about 500mg/ days, especially preferably about 0.5-about 200mg/ days.
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