CN1175211A - 4, 4 -(disubstituted) cyclohexan-one monomers and related compounds - Google Patents

4, 4 -(disubstituted) cyclohexan-one monomers and related compounds Download PDF

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CN1175211A
CN1175211A CN95197681A CN95197681A CN1175211A CN 1175211 A CN1175211 A CN 1175211A CN 95197681 A CN95197681 A CN 95197681A CN 95197681 A CN95197681 A CN 95197681A CN 1175211 A CN1175211 A CN 1175211A
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Prior art keywords
methoxyphenyl
hexamethylene
ketone
oxygen
cyclopenta
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S·B·克里斯藤森四世
J·M·卡尔平斯基
M·D·赖安
P·E·奔德尔
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Abstract

The present invention relates to derivatives of 4,4-(disubstituted)cyclohexan-1-ones and related compounds which are useful for treating allergic and inflammatory diseases.

Description

4,4-(two replace) hexamethylene-1-one monomers and related compound
Invention field
The present invention relates to novel 4,4-(two replace) hexamethylene-1-one monomers and associated chemical compound; The pharmaceutical composition that contains these chemical compounds; They are in the application of the aspects such as generation of treatment anaphylactic disease and inflammation and inhibition tumor necrosis factor (TNF).
Background of invention
Bronchial asthma is a multifactorial complex disease, and feature is that the trachea reversibility narrows down, the undue reaction that respiratory system stimulates to external world.
The difficulty of screening treatment asthma new drug is that multiple medium is depended in this advancing of disease.Like this, be used for by what eliminate single medium that fundamentally to influence three factors of chronic asthma seemingly impossible.Can replace " medium approach ", be regulate the relevant cell activity of sick therewith pathophysiology.
One of this method is to improve cAMP level (cyclic adenosine monophosphate).Ring AMP has been considered to the second message,second messenger, bio signal is passed to hormone, neurotransmitter and the medicine of broad range; [Krebs Endocrinology Proceedings of the 4th International CongressExcerpta Medica, 17-29,1973.The 4th International Society of Endocrinology's words collected works, Excerpta Medica, 17-29,1973].When appropriate agonist was attached to the specificity cell surface receptor, adenyl cyclase was activated, and had quickened Mg + 2-ATP is to the conversion of cAMP.
CAMP regulation and control great majority (even not being whole) are to the effective cell activity of exogenous (allergy) asthma Pathophysiology.The raising of cAMP level will produce following useful effect like this: 1) tracheal smooth muscle is lax; 2) release of inhibition labrocyte medium; 3) threshing of inhibition neutrophilic leukocyte; 4) threshing of inhibition basophilic leukocyte; 5) activation of inhibition mononuclear cell and macrophage.Therefore, can activate the unsuitable activation that chemical compound that adenyl cyclase maybe can suppress phosphodiesterase should be able to suppress tracheal smooth muscle and various inflammatory cells effectively.The main cell mechanism of the mechanism of passivation cAMP is to come hydrolysis 3 '-phosphodiester bond by the isozyme that a class or a few class are called cyclic nucleotide phosphodiesterase (PDEs).
Studies show that, a kind of special cyclic nucleotide phosphodiesterase (PDE) isozyme, PDEIV is to cause the destructive principal element of cAMP in tracheal smooth muscle and the inflammatory cell.[Torphy, " Phosphodiesterase Isozymes:Potential Targets for Novel Anti-asthmaticAgents " (" phosphodiesterase isoenzyme: the potential target of novel anti asthma agent ") in New Drugsfor Asthma, Barnes, ed.IBC Technical Services Ltd., 1989].Studies show that the inhibitory action of this enzyme not only produces the smooth muscle loosening of trachea, and suppresses mastocyte, basophil and neutrophil's threshing, also suppresses mononuclear cell and neutrophil's activation simultaneously.And, when the adenylate cyclase activity of target cell by suitable hormone or after the body working substance improved, the beneficial effect of PDE IV inhibitor had been reinforced significantly, situation also should be like this in the body.Like this, work as prostaglandin E 2And after the raising of prostacyclin (activator of adenyl cyclase) content, PDE IV should be an effective inhibitors to the asthma lung.Such compounds will be opened up the approach of a uniqueness for the Drug therapy of bronchial asthma, and than current commercially available medicine, its obvious superiority be arranged.
For tumor necrosis factor (TNF), a kind of seroglycoid, chemical compound of the present invention also suppresses its generation.Excessive or the immoderate generation of tumor necrosis factor is often with the generation of some disease with worsen relevant.For example, rheumatic arthritis, rheumatic spondylitis, osteoarthritis, gouty arthritis and other arthritis; Sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pneumonia, anthraco-silicosis, pneumonia sarcoma ice, bone resorption, reperfusion injury, transplant back host's reaction, the rejection effect after the heteroplastic transplantation is owing to infect fever and the myalgia that causes, influenza for example, infect or malignant tumor cachexia after being ill the complication of people's acquired immune deficiency syndrome (AIDS) (AIDS), AIDS, ARC (syndrome relevant) with AIDS, the generation of keloid, scar tissue forms, Crohn disease, ulcerative colitis, or Pyresis, in addition, to a series of autoimmune diseasees, as multiple cirrhosis, autoimmune diabetes and system lupus erythematosus etc. all has the excessive or uncontrolled generation of tumor necrosis factor.
Acquired immune deficiency syndrome (AIDS) (AIDS) is because the T lymphocyte has infected due to the human immunodeficiency virus (HIV).At least identified three types HIV, i.e. HIV-1, HIV-2 and HIV-3.Result of infection, the cell-mediated immunologic function of T-reduces, and the infected demonstrates serious opportunistic infection, and/or produces abnormal newborn tumor.Behind the T lymphocyte activation, HIV just can enter the T lymphocyte.Virus as HIV-1 or HIV-2 infect T cell and the proteic expression thereof that has activated and/or duplicate, and only could transmit behind the T cell activation and lasting.In case the activated T lymphocyte is infected by HIV, the T lymphocyte must continue to remain on the state of activation, the HIV gene is expressed and/or HIV duplicates.
Cytokine, especially TNF work in keeping the lymphocytic state of activation of T, make it to be associated with the proteic expression of HIV and/or the duplicating of virus of activating T cell mediation.Therefore, adopt the generation that suppresses cytokine in HIV the infected's body, especially TNF, come the interference cell factor active, help to make T cell activation state not keep, so just reduced HIV to the not invasion and attack of interference cell, reached and reduce or eliminated the further deterioration that HIV infects the immunodeficiency disease that caused.Mononuclear cell, macrophage and some associated cells also infect relevant with lasting HIV as Kupffer and neurogliocyte etc.These cells as T cell etc., be the target of virus replication, and the level of virus replication depend on the state of activation of these cells.[please refer to Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol.57,1989].Monokine (monokines) shows as TNF, duplicating of HIV of activation [consulted Polietal. in mononuclear cell and/or macrophage, Proc.Natl.Acad.Sci., 87:782-784,1990], therefore, suppress monokaryon because of the generation of putting down (monokine) or suppress its activity, to help to limit the expansion that HIV infects, this is as above-mentioned T cell.
TNF also plays various effect for the infection of other virus, and for example for cytomegalovirus (CMV), influenza virus, adenovirus and herpesvirus etc., the mechanism of action is with top described.
TNF also is related with yeast and fungal infection.Especially candida albicans has shown the generation of inducing TNF in external person monocytic cell and natural killer cell.[consult Riipi et al., Infection and Immunity, 58 (9): 2750-54,1990; Jafari et al., Journal of Infectious Diseases164:389-95,1991.Also see also Wasanet al., Antimicrobial Agents and Chemotherapy, 35, (10): 2046-48,1991; Luke et al., Journal of Infectious Diseases, 162:211-214,1990].
Suppress TNF to there being the mammal that needs to use The compounds of this invention, can further strengthen the ability of its control TNF ill effect.Chemical compound of the present invention also can be used for treating the TNF disease states mediated, and these morbid states are to cause or aggravate owing to the excessive and/or uncontrolled generation of TNF.
Summary of the invention
At first, the present invention relates to the compound or pharmaceutically acceptable salt thereof class of general formula (I):
Figure A9519768100141
R wherein 1Be-(CR 4R 5) nC (O) O (CR 4R 5) mR 6, (CR 4R 5) nC (O) NR 4(CR 4R 5) mR 6,-(CR 4R 5) nO (CR 4R 5) mR 6, or-(CR 4R 5) rR 6Wherein alkyl group can be replaced by one or several fluorine atom, or is not substituted;
M is 0 to 2
N is 0 to 4
R is 0 to 6
R 4And R 5It is hydrogen atom or contain the alkyl of 1-2 carbon atom independently;
R 6Be hydrogen, methyl, hydroxyl, aromatic radical, halogenated aryl, aryloxy group C 1-3Alkyl, halo aryloxy group C 1-3Alkyl, 2, the 3-dihydro is for indenyl, indenyl, C 7-11Poly-cycloalkyl, tetrahydrofuran base, furyl, THP trtrahydropyranyl, pyranose, tetrahydro-thienyl, thienyl, tetrahydro thiapyran base, thiapyran base, C 3-6Cycloalkyl, or the C of 1 or 2 unsaturated bond is wherein arranged 4-6Cyclic hydrocarbon radical, its cycloalkyl moiety or heterocyclic moiety can not be substituted, also can be by 1-3 methyl, 1 ethyl or hydroxyl replace; Condition is:
A) work as R 6When being hydroxyl, m is 2; Or
B) work as R 6When being hydroxyl, r is 2 to 6; Or
C) work as R 6Be the 2-THP trtrahydropyranyl, the 2-tetrahydro thiapyran base, when 2-tetrahydrofuran base or 2-tetrahydro-thienyl, m is 1 or 2; Or
D) work as R 6Be the 2-THP trtrahydropyranyl, the 2-tetrahydro thiapyran base, when 2-tetrahydrofuran base or 2-tetrahydro-thienyl, r is 1 to 6;
E) when n be 1, m is 0 o'clock ,-(CR 4R 5) nO (CR 4R 5) mR 6In R 6Not H;
X is YR 2, F, NR 4R 5Or Methanamide;
Y is O or S (O) m;
M ' is 0,1 or 2;
X 2Be O or NR 8
X 3Be hydrogen or X;
R 2Be independently to be selected from-CH 3Or-CH 2CH 3, they are not substituted or are replaced by the fluorine more than 1 or 1;
S is 0 to 4;
R 3Be COOR 14, C (O) NR 4R 14Or R 7
W is the alkyl of 2-6 carbon atom, the alkynyl of the alkenyl of a 2-6 carbon atom or 2-6 carbon atom;
Z is O, NR 7, NCR 4R 5C 2-6Alkenyl, NOR 14, NOR 15, NOCR 4R 5C 2-6Olefine, NNR 4R 14, NNR 4R 15, NCN, NNR 8C (O) NR 8R 14, NNR 8C (S) NR 8R 14, or=Z is 2-(1, the 3-dithiane), 2-(1, the 3-dithiolane), dimethyl ketone mercaptol, metacetone mercaptol, 2-(1, the 3-dioxolanes), 2-(1, the 3-diox), 2-(1,3-Evil Thiophane), dimethyl ketal or diethyl ketal;
R 7Be-(CR 4R 5) qR 12Or C 1-6Alkyl, wherein R 12Or C 1-6Alkyl or be not substituted, or replaced one or many by methyl or ethyl, methyl here or ethyl or unsubstituted are perhaps replaced by 1-3 fluorine atom, or by following radicals replacement one or many:
-F ,-Br ,-Cl ,-NO 2,-NR 10R 11,-C (O) R 8,-CO 2R 8,-O (CH 2) 2-4OR 8,-O (CH 2) qR 8,-CN ,-C (O) NR 10R 11,-O (CH 2) qC (O) NR 10R 11,-O (CH 2) qC (O) R 9,-NR 10C (O) NR 10R 11,-NR 10C (O) R 11,-NR 10C (O) OR 9,-NR 10C (O) R 13,-C (NR 10) NR 10R 11,-C (NCN) NR 10R 11,-C (NCN) SR 9,-NR 10C (NCN) SR 9,-NR 10C (NCN) NR 10R 11,-NR 10S (O) 2R 9,-S (O) m' R 9,-NR 10C (O) C (O) NR 10R 11,-NR 10C (O) C (O) R 10, or R 13
Q is 0,1 or 2;
R 12Be R 13, C 3-7Cycloalkyl, (2-, 3-or 4-pyridine radicals), pyrimidine radicals, pyrazolyl, (1-or 2-imidazole radicals), pyrrole radicals, piperazinyl, piperidyl, morpholinyl, furyl, (2-or 3-thienyl), quinolyl, naphthyl or phenyl;
R 8Be hydrogen or R 9
R 9Be C 1-4Alkyl, this alkyl or be not substituted, or replaced by 1 to 3 fluorine;
R 10Be OR 8Or R 11
R 11Be H or C 1-4Alkyl, this alkyl is not substituted, or is replaced by 1-3 F; Or work as R 10And R 11Form NR 10R 11The time, they can form 5-7 person ring with N, carbon atoms or also randomly comprise the hetero atom that at least one is selected from O, N and S except that carbon atom more only in its medium ring.
R 13Be following heterocyclic aryl group: oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazole radical, imidazole radicals, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazole base and thiadiazolyl group, the wherein R that is not substituted or replaces 13At R 12Or R 13Last replacement, these rings are connected per second R by a C atom 13Ring may be unsubstituted, or by 1 or two C 1-2Alkyl replaces, this C 1-2Alkyl or unsubstituted, or replaced by 1 to 3 fluorine atom on the methyl.
R 14Be H or R 7Work as R 8And R 14Form NR 8R 14The time, they can form 5-7 person ring jointly with N, in the ring only carbon atoms or except that carbon atoms also optional one or several hetero atom O, N or the S of also comprising;
Condition is:
(f) R 7Not the C that is not substituted or is replaced by 1-3 F 1-4Alkyl.
Another group chemical compound of the present invention, (II) is expressed as general formula, or its officinal salt,
Figure A9519768100161
In the formula:
R 1Be-(CR 4R 5) nC (O) O (CR 4R 5) mR 6,-(CR 4R 5) nC (O) NR 4(CR 4R 5) mR 6,-(CR 4R 5) nO (CR 4R 5) mR 6, or-(CR 4R 5) rR 6, wherein moieties may not be substituted or replaced by one or several F;
M is 0 to 2
N is 0 to 4
R is 0 to 6
R 4And R 5Be H or C independently 1-2Alkyl;
R 6Be H, methyl, hydroxyl, aryl, halogenated aryl, aryloxy group C 1-3Alkyl, halo aryloxy group C 1-3Alkyl, 2, the 3-dihydro is for indenyl, indenyl, C 7-11Poly-cycloalkyl, tetrahydrofuran base, furyl, THP trtrahydropyranyl, pyranose, tetrahydro-thienyl, thienyl, tetrahydro thiapyran base, thiapyran base, C 3-6Cycloalkyl or contain the C of 1 or 2 unsaturated bond 4-6Cyclic hydrocarbon radical, wherein cycloalkyl or heterocyclic moiety are unsubstituted, or replaced by 1-3 methyl, ethyl or hydroxyl;
Condition is:
A) work as R 6When being hydroxyl, m is 2; Or
B) work as R 6When being hydroxyl, r is 2 to 6; Or
C) work as R 6When being 2-THP trtrahydropyranyl, 2-tetrahydro thiapyran base, 2-tetrahydrofuran base or 2-tetrahydro-thienyl, m is 1 or 2; Or
D) work as R 6When being 2-THP trtrahydropyranyl, 2-tetrahydro thiapyran base, 2-tetrahydrofuran base or 2-tetrahydro-thienyl, r is 1 to 6;
E) when n be 1, m is 0 o'clock ,-(CR 4R 5) nO (CR 4R 5) mR 6Middle R 6Not H;
X is YR 2, F, NR 4R 5Or Methanamide;
Y is O or S (O) m';
M ' is 0,1 or 2;
X 2Be O or NR 8
X 3Be H or X;
R 2Be independently to be selected from-CH 3Or-CH 2CH 3, they are not substituted, or are replaced by one or several F;
S is 0 to 4;
R 3Be COOR 14, C (O) NR 4R 14Or R 7
W is the alkyl of 2 to 6 C atoms, the thiazolinyl of 2 to 6 C atoms or the alkynyl of 2-6 C atom;
Z ' is C (Y ') R 14, C (O) OR 14, C (Y ') NR 10R 14, C (NR 10) NR 10R 14, CN,
C(NOR 8)R 14，C(O)NR 8NR 8C(O)R 8，C(O)NR 8NR 10R 14，C(NOR 14)R 8，
C (NR 8) NR 10R 14, C (NR 14) NR 8R 8C (NCN) NR 10R 14, C (NCN) SR 9, (2-, 4-, or 5-imidazole radicals), (3-, 4-or 5-pyrazolyl), (4-or 5-triazolyl [1,2,3]), (3-or 5-triazolyl [1,2,4]), (5-tetrazole radical), (2-, 4-or 5-oxazolyl), (3-, 4-or 5-isoxazolyl), (3-or 5-oxadiazole base [1,2,4]), (2-oxadiazole base [1,3,4]), (2-thiadiazolyl group [1,3,4]), (2-, 4-or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-or 5-thiazolidinyl) or (2-, 4-or 5-imidazolidinyl); Wherein have a position or several position on all heterocycles by R 14Replace;
Y ' is O or S;
R 7Be-(CR 4R 5) qR 12Or C 1-6Alkyl, wherein R 12Perhaps C 1-6Alkyl is not to be substituted, or is replaced one or many by methyl or ethyl, and this methyl or ethyl are not replace or replaced by 1 to 3 fluorine, or are replaced one or many by following radicals:
-F，-Br，-Cl，-NO 2，-NR 10R 11，-C(O)R 8，-CO 2R 8，
-O(CH 2) 2-4OR 8，-O(CH 2) qR 8，-CN，-C(O)NR 10R 11，-O(CH 2) qC(O)NR 10R 11，
-O(CH 2) qC(O)R 9，-NR 10C(O)NR 10R 11，-NR 10C(O)R 11，-NR 10C(O)OR 9，
-NR 10C(O)R 13，-C(NR 10)NR 10R 11，-C(NCN)NR 10R 11，-C(NCN)SR 9，
-NR 10C(NCN)SR 9，-NR 10C(NCN)NR 10R 11，-NR 10S(O) 2R 9，-S(O) m′R 9，
-NR 10C (O) C (O) NR 10R 11,-NR 10C (O) C (O) R 10, or R 13
Q is 0,1 or 2;
R 12Be R 13, C 3-7Cycloalkyl or not replacement or substituted aryl or heteroaryl, be selected from (2-, 3-or 4-pyridine radicals), pyrimidine radicals, pyrazolyl, (1-or 2-imidazole radicals), pyrrole radicals, piperazinyl, piperidyl, morpholinyl, furyl, (2-or 3-thienyl), quinolyl, naphthyl and phenyl;
R 8Be from H or R 9Middle independent selection;
R 9Be C 1-4Alkyl, it is not substituted or is replaced by 1 to 3 F;
R 10Be OR 8Or R 11
R 11Be H or C 1-4Alkyl, this alkyl are not substituted or are replaced by 1-3 F; Perhaps work as R 10With R 11Form NR 10R 11, they can form 5-7 person ring with N, and this only encircles carbon atoms or carbon atoms and contains at least one hetero atom O, N or S again;
R 13Be one of following heterocyclic aryl, they are substituted or are not substituted: oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazole radical, imidazole radicals, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazole base and thiadiazolyl group; If R 13Replace and occur in R 12Or R 13On, these rings are connected by the C atom, per second R 13Ring can be unsubstituted, or by 1 or 2 C 1-2Alkyl replaces, this C 1-2Alkyl is unsubstituted or is replaced by 1 to 3 fluorine on methyl.
R 14Be H or R 7Perhaps work as R 8With R 14Form NR 8R 14The time, they can encircle with 5-7 person of the common formation of N, and this encircles only carbon atoms or carbon atoms and at least one hetero atom O, N or S; Condition is:
(f) R 7Not the C that is not substituted or is replaced by 1-3 F 1-4Alkyl.
The scope of the invention also comprises the pharmaceutical composition that contains general formula (I) and chemical compound (II) and pharmaceutical carrier or diluent.
The invention still further relates to the method that in mammal (comprising the mankind) body, mediates or suppress PDE IV enzymatic activity (or catalytic activity), to general formula (I) and (II) the chemical compound of the mammal that needs treatment, specific as follows with effective dose.
The present invention further provides the method for the irritated and inflammation of treatment, comprised the mammal (comprising the mankind) treated to needs general formula (I) and chemical compound (II) with effective dose.
The present invention also provides the method for treatment asthma, comprises to the mammal (comprising the mankind) of needs treatment general formula (I) and the chemical compound (II) with effective dose.
The present invention also relates in mammalian body, (to comprise the mankind) and suppress the method that TNF produces, give the mammal (comprising the mankind) that needs treatment to suppress the general formula (I) and the chemical compound (II) of TNF effective dose.This method may be used for prophylactic treatment, stops some symptom of some TNF mediation.
The present invention also relates to treat the method for human infection's HIV (human immunodeficiency virus) (HIV), comprise that the people to the needs treatment throws general formula (I) and the chemical compound (II) that suppresses the TNF effective dose.
General formula (I) and chemical compound (II) also are used for treating the disease of other viral infection, and it is responsive that these viruses raise for TNF, perhaps induce TNF to produce in vivo.
In addition, general formula (I) and (II) chemical compound also be used for the treatment of yeast and fungal infection, yeast herein and fungus are raised responsive to TNF or induce TNF to produce in vivo.The detailed description of invention
The method that the present invention relates to need the interior mediation of mammalian body of treatment or suppress PDE IV enzymatic activity (or catalytic activity), also relate to the interior TNF generation of mammalian body that inhibition need be treated, comprise the general formula (I) and the chemical compound (II) that give above-mentioned mammal effective dose.
Phosphodiesterase IV inhibitors is used for the treatment of following various anaphylactic disease or inflammation: reperfusion injury, chronic glomerulonephritis, endotoxin shock and the adult respiratory distress syndrome of asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, anaphylaxis conjunctivitis, youth conjunctivitis, eosinophilic granuloma, psoriasis, rheumatic arthritis, septic shock, ulcerative colitis, Crohn disease, cardiac muscle and brain.In addition, PDE IV inhibitor can be used for treating diabetes insipidus and central nervous system disorder such as depression and multi-infarct dementia.
The virus that expection will be treated is that those make the sufferer produce TNF, or those are responsive for suppressing, and reduces it directly or indirectly as the tnf inhibitor of making by general formula (I) and chemical compound (II) and duplicates.This viroid comprises influenza virus (but being not limited to) down: HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza virus, adenovirus, herpesvirus group are as viruses such as herpes zoster and herpes simplexs.
The invention particularly relates to the bitter mammal Therapeutic Method that suffers HIV (human immunodeficiency virus) (HIV) infection, comprise that the mammal that needs treatment suppresses the general formula (I) and the chemical compound (II) of TNF effective dose.
Chemical compound of the present invention also may be related with the veterinary except outside the Pass having with the treatment human diseases, in order to the generation of TNF in the beasts body that suppresses to need to treat.At the animal apoplexy due to endogenous wind, treatment comprises above-mentioned various diseases, most importantly viral infection by the disease (comprising treatment or prevention) of TNF mediation.For example, these viruses (but being not limited to): cat species immunity defective virus (FIV) or other retroviral infection, as the anemia virus that equine infects, caprine arthritis virus, visna virus, maedi virus and other Lenfiviruses.
Chemical compound of the present invention also is used for the treatment of the infection of yeast or fungus, is responsive as long as these yeast and fungus are raised TNF, and perhaps they bring out TNF and produce in vivo.Better a kind of disease of curative effect is the fungus leptomenigitis.In addition, general formula (I) and chemical compound (II) also can cooperate with the medicine that other suitable selection is used for whole body yeast and fungal infection.Be the treatment fungal infection, select for use the medicine (being not limited thereto) of cooperation to have: polymyxins, as polymycin B; Glyoxaline compound is as clotrimazole, econazole, miconazole, ketoconazole; Triazole class compounds, as Fluconazole and itranazole, and amphotericin compounds, particularly amphotericin B and liposome amphotericin b.
To general formula (I) and (II) the chemical compound of the mammal that needs treatment, also can suppress and/or reduce the toxic and side effects of antifungal, antibacterial agent and antiviral agent with effective dose.The toxicity of these chemical compounds inhibition or minimizing amphotericin is more effective, especially to amphotericin B.
" the C here 1-3Alkyl ", " C 1-4Alkyl ", " C 1-6Alkyl " or groups such as " alkyl ", comprise the straight or branched group of 1-10 carbon, including, but is not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group unless chain length has been limited, and analog.
" alkenyl " comprises the straight or branched of 1-6 C, unless chain length is limited, includes, but is not limited to vinyl, 1-acrylic, 2-acrylic or 3-methyl-2-acrylic.
Term " cycloalkyl " or " cycloalkyl-alkyl " are meant 3-7 C atomic radical, as cyclopropyl, cyclopropyl methyl, cyclopenta or cyclohexyl.
" aryl " or " aralkyl " except that specifying, is meant the aromatic rings or the ring system that contain 6-10 C, as phenyl, benzyl, phenethyl or naphthyl.Monocyclic aryl is better, and promptly phenyl is better.Alkyl chain refers to the straight or branched of 1-4 C." heteroaryl " is to contain one or several heteroatomic aromatic rings.
" halogen " is meant that all halogens are fluorine, chlorine, bromine or iodine.
The meaning of " generation of inhibition IL-1 " or " suppressing TNF produces " is:
A) in human body, all cells comprises that the effect of mononuclear cell or macrophage (but being not limited thereto two kinds of cells) release IL-1 is suppressed, and makes interior excessive IL-1 or the TNF of body be reduced to normal level respectively or be lower than normal level;
B) in human body, on the level of translating or transcribing, excessive IL-1 or TNF are lowered to normal level respectively or are lower than normal level; Or
C) by suppressing the level of directly synthesizing or suppress TNF of IL-1, the downward modulation of translation back.
" TNF mediation disease or morbid state " is meant all diseases that TNF works, or because TNF generation itself is caused a disease, or TNF causes other release of cytokines, causes a disease as the release of IL-1 or IL-6 (but being not limited thereto).For example in a certain morbid state, IL-1 is a main component, and its generation or effect are reinforced corresponding to TNF or secrete, and so this morbid state promptly is considered to the morbid state of TNF mediation.Because it is very similar to TNF-α (also being called α-Zhong Liuhuaisiyinzi) structure that TNF-is β (also being called lymphocytotoxin), and with identical cell receptor combination, produce similar biological effect, TNF-α and TNF-β also can both be suppressed by chemical compound of the present invention, therefore, except that specifying, they are referred to as " TNF ".It is better to suppress TNF-α.
" cytokine " is meant any one excretory polypeptide, and it influences cell function; Be a kind of molecule of in immunity, inflammation or hemopoietic are replied, regulating cell-cell interaction simultaneously.Cytokine includes, but not limited to monokine and lymphokine, produces no matter what cell they are.Be used for the treatment of be subjected to cytokine the mankind that HIV infects, that suppress by The compounds of this invention must be following (a) and/or (b) in the cytokine of indication, the HIV gene expression of (a) initiation of T-cell activation effect and/or keep and/or activated T-cell-mediated and/or duplicate, (b) with the problem of any cytokine mediated disease association, as cachexia (cachexia) or muscle deterioration.Preferably its cytokine is TNF-α.
In mammal (the comprising the people) body of needs treatment, all general formulas (I) and chemical compound (II) are useful in the method that suppresses the TNF generation, preferably suppress the TNF in the macrophage, the TNF in the mononuclear cell, or the TNF in macrophage and the mononuclear cell.All general formulas (I) or chemical compound (II) suppress or the method for the enzymatic activity of mediation PDE IV or catalytic activity in be useful, when its transmission of treatment ill, be useful.
Chemical compound is as follows preferably:
In general formula (I) and chemical compound (II), R 1By the alkyl that one or several halogen replaces, wherein halogen is preferably F and Cl, and R 1Preferably by 1 or the C that replaces of several F 1-4Alkyl.The chain length of haloalkyl is to contain 1-2 C atom preferably, and preferably :-CF 3,-CH 2F ,-CHF 2,-CF 2CHF 2, CH 2CF 3And CH 2CHF 2In general formula (I) and chemical compound (II), preferred R 1Substituent group is CH 2-cyclopropyl, CH 2C 5-6Replace or the unsubstituted C of cycloalkyl, OH 4-6Cycloalkyl, C 7-11Poly-cycloalkyl, (3-or 4-cyclopentenyl), phenyl, oxolane-3-base, do not replace or by 1 or several F benzyl or the C that replace 1-2Alkyl ,-(CH 2) 1-3C (O) O (CH 2) 0-2CH 3,-(CH 2) 1-3O (CH 2) 0-2CH 3With-(CH 2) 2-4OH.
Work as R 1Be (CR 4R 5) time, R 4And R 5Independently be H or alkyl.This side chain of considering one MU (methylene unit) is as (CR 4R 5) nOr (CR 4R 5) mEach multiple MU (methylene unit) is independent of each other, for example, when n=2, (CR then 4R 5) nMay be-CH 2CH (CH 3)-.The single H atom of multiple MU (methylene unit) or branched-chain hydrocarbons can be unsubstituted, or is replaced by F independent of each other, so that obtain R preferably as mentioned above 1Substituent group.
Work as R 1Be C 7-11Multi-ring alkyl, for example dicyclo [2.2.1]-heptyl, dicyclo [2.2.2] octyl group, dicyclo [3.2.1] octyl group, three ring [5.2.1.0 2,6] decyl, or the like.Other example sees also: Saccamano etc., WO is open on November 5th, 87/06576,1987.Its content is collected in this as a reference.
Z is preferably: O, NCN, NR 7, NOR 14, NOR 15, NNR 4R 14, NNR 4R 15, 2-(1, the 3-dithiane), dimethyl ketone mercaptol, 2-(1, the 3-dioxolanes) or dimethyl ketal.Z is O, NR preferably 7, NOR 14, NOR 15And 2-(1, the 3-dioxolanes).
General formula (I) and (II) in preferred X group be YR 2, Y is an oxygen.General formula (I) and (II) in X preferably 2Group is O; General formula (I) and (II) in X preferably 3Group is H; Where applicable, R preferably 2Group is the C that is not substituted or is replaced by 1 or several halogen 1-2Alkyl.Halogen atom is preferably F and Cl, preferably F.R preferably 2Group is a methyl, or fluoro-alkyl, particularly fluoro C 1-2Alkyl, as-CF 3,-CHF 2, or-CH 2CHF 2And best R 2Group is-CHF 2With-CH 3
R 7Comprise preferably: R 13, unsubstituted or substituted-(CH 2) 0-2(2-, 3-or 4-pyridine radicals), (CH 2) 1-2(2-imidazole radicals), (CH 2) 2(4-morpholinyl), (CH 2) 2(4-piperazinyl), (CH 2) 1-2(2-thienyl), (CH 2) 1-2(4-thiazolyl), substituted or unsubstituted pyrimidine radicals and substituted or unsubstituted (CH 2) 0-2Phenyl.
Work as R 10And R 11Composition-NR 10R 11, R 10And R 11The N that is connected with them forms 5-7 person's ring, and only when carbon atoms or carbon atom and at least one other hetero atoms O, N or S, this ring includes, but is not limited to preferably: 1-imidazole radicals, 2-(R on the ring 8)-1-imidazole radicals, 1-pyrazolyl, 3-(R 8)-1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R 8)-1-triazolyl, 5-(R 8)-2-triazolyl, 5-(R 8)-1-tetrazole radical, 5-(R 8)-2-tetrazole radical, 1-tetrazole radical, 2-tetrazole radical, morpholinyl, piperazinyl, 4-(R 8)-1-piperazinyl or pyrroles's basic ring.
Work as R 8With R 14Formation-NR aR 14, R 8With R 14The N that is connected with them forms 5-7 person's ring, only carbon atoms or carbon atom and other hetero atoms O at least on the ring, when N or S, this ring includes, but is not limited to preferably: 1-imidazole radicals, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazole radical, 2-tetrazole radical, morpholinyl, piperazinyl and pyrrole radicals.Each ring can be substituted again in the time of suitably, and promptly possible N or C atom are by R 7Replace R 7Definition referring to general formula (I) and (II).Replacement on the C atom includes, but is not limited to: 2-(R 7)-1-imidazole radicals, 4-(R 7)-1-imidazole radicals, 5-(R 7)-1-imidazole radicals, 3-(R 7)-1-pyrazolyl, 4-(R 7)-1-pyrazolyl, 5-(R 7)-1-pyrazolyl, 4-(R 7)-2-triazolyl, 5-(R 7)-2-triazolyl, 4-(R 7)-1-triazolyl, 5-(R 7)-1-triazolyl, 5-(R 7)-1-tetrazole radical and 5-(R 7)-2-tetrazole radical.R on the N atom 7Replacement includes, but is not limited to: 1-(R 7)-2-tetrazole radical, 2-(R 7)-1-tetrazole radical, 4-(R 7)-1-piperazinyl.Some ring may be by R 7Replace once or several times.
Contain heterocyclic NR 8R 14Group preferably be: 5-(R 14)-1-tetrazole radical, 2-(R 14)-1-imidazole radicals, 5-(R 14)-2-tetrazole radical, 4-(R 14)-1-piperazinyl or 4-(R 15)-1-piperazinyl.
R preferably 13Ring comprises: (2-, 4-or 5-imidazole radicals), (3-, 4-or 5-pyrazolyl), (4-or 5-triazolyl [1,2,3]), (3-or 5-triazolyl [1,2,4]), (5-tetrazole radical), (2-, 4-or 5-oxazolyl), (3-, 4-or 5-isoxazolyl), (3-or 5-oxadiazole base [1,2,4]), (2-oxadiazole base [1,3,4]), (2-thiadiazolyl group [1,3,4]), (2-, 4-or 5-thiazolyl), (2-, 4-, 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl) or (2-, 4-or 5-imidazolidinyl).
Work as R 7Group is unsubstituted, or by following heterocyclic substituted: when imidazole radicals, pyrazolyl, pyrimidine radicals, triazolyl, tetrazole radical or thiazolyl, heterocycle itself can be unsubstituted, also can be by R on N on the ring or C atom 8Replace, as: 1-(R 8)-2-imidazole radicals, 1-(R 8)-4-imidazole radicals, 1-(R 8)-5-imidazole radicals, 1-(R 8)-3-pyrazolyl, 1-(R 8)-4-pyrazolyl, 1-(R 8)-5-pyrazolyl, 1-(R 8)-4-triazolyl or 1-(R 8)-5-triazolyl.In the time of suitably, ring may be by R 8Replace-inferior or several times.
W group preferably is alkyl, alkenyl or the alkynyl of 3-5C atom.In alkenyl or alkynyl, exist 1 or 2 two key or three key.The best group of W is acetenyl or 1,3-diacetylene base.
General formula (I) and chemical compound (II) are preferably: R 1Be-CH 2-cyclopropyl ,-CH 2-C 5-6Cycloalkyl, unsubstituted or by OH replace-C 4-6Cycloalkyl, oxolane-3-base, (3-or 4-cyclopentenyl), benzyl unsubstituted or that replaced by one or several F or-C 1-2Alkyl and-(CH 2) 2-4OH; R 2Be methyl or fluoro-alkyl; R 3Be R 7, R wherein 7Be aryl or hetero-aromatic ring base unsubstituted or that replace; X is YR 2Z is O, NR 7
Z ' is preferably COOR 14
Best chemical compound is: R wherein 1For-CH 2-cyclopropyl, cyclopenta ,-3-hydroxycyclopent base, methyl or-CF 2H; X is YR 2Y is O; X 2Be O; X 3Be H; R 2Be CF 2H or methyl; W is acetenyl or 1,3-diacetylene base; R 3Be that replace or unsubstituted pyrimidine-ring; Z is O, NR 7
Medicinal salts by the The compounds of this invention preparation is also included within the scope of the invention.These salt can be used as medicinal.Be the biological activity that these salt are keeping original chemical compound, and untoward reaction or toxic and side effects when using and treat, do not occur.
The medicinal salts of chemical compound prepares by standard method.Parent compound is dissolved in the appropriate solvent, handles with excessive organic acid or mineral acid, it is alkaline for example working as parent compound, adds the processed with acid salify, perhaps when parent molecule comprises COOH, adds excessive organic or inorganic alkali and then makes its medicinal salts.
Pharmaceutical composition of the present invention includes pharmaceutical carrier or diluent and a certain amount of general formula (I) and chemical compound (II).The content of chemical compound can be the dosage that reaches effective physiologic response, also can be less content, and at this moment user will be used several unit dose more, to reach therapeutic effect.These compositionss can be solid, liquid or gas form.These three kinds of forms can be changed mutually during use.For example solid-state medicine can be made into aerosol form and uses, liquid medicine, also sprayable use or make aerosol and use.
Depend primarily on the approach of administration by the characteristic of the pharmaceutical composition of invention compound and pharmaceutical carrier or diluent, for example parenteral administration, local application, oral or inhalation administration or the like.
Pharmaceutical composition for local application should be Emulsion, ointment, liniment, lotion and paste, aerosol and drop, so that treatment skin, eyes, ear or nose.
For adapting to non-enterally administer, pharmaceutical composition should be made aseptic injection, as ampoule, and perhaps water or nonaqueous phase liquid suspension.
Pharmaceutical composition for oral administration should be tablet, capsule, powder, pill, atroche, lozenge, syrup, oral liquid or Emulsion.
When preparation of pharmaceutical compositions became solution or suspension, suitable pharmaceutical carrier or diluent had: Aquo System, as water; Non-aqueous system has ethanol, glycerol, propylene glycol, Semen Maydis oil, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum sesami, liquid paraffin, and the mixture of they and water; To solid system, with lactose, kaolin and mannitol; For the aerosol system, with dichlorodifluoromethane, trifluoro-chloroethane and compression arbon dioxide etc.Except that pharmaceutical carrier or diluent, may also comprise other composition in the compositions, as stabilizing agent, antioxidant, antiseptic, lubricant, suspending agent, viscosity modifier or the like, as long as these compositions do not produce ill effect when treatment.
Aforementioned pharmaceutical compositions is according to common preparation process, obtains the final products that need.
The amount of carrier or diluent is not fixed in these pharmaceutical compositions, and general reasonable way is to make these carriers or diluent account for main ratio in the medicament suspension of active component or solution.When diluent was solid, its content can be less than, be equal to or greater than solid active component.
Usually, the dosage of the chemical compound of general formula (I) is to grasp enough suppressing disease, and is unlikely the generation toxic and side effects, and the factor of this disease comprises leukotriene.In the prescription of topical, active component accounts for 0.01-5.0%, decides on the prevention of infected area or the needs of treatment.When adopting oral or when other gi system administration or drug administration by injection, when the dosage of compositions was selected at each medication, active constituent content was at 50mg-1, between the 000mg.For convenience, every day, medication was 1-5 time, and each dosage is identical, made the every day dosage about 50-5, between the 000mg.
Will be appreciated that some general formula (I) and chemical compound (II) exist the form or the optical activity form of racemization; Some also exists visibly different diastereomeric form, thereby has visibly different physics and biological property.It is within the scope of the present invention that all these chemical compounds are considered.
The chemical compound of general formula (I) (wherein Z is O) or the chemical compound of general formula (II) may exist tautomeric form, as enol form.This situation can find out from following situation, with respect to cyclohexane ring, "=O " be exocyclic (or ); This and interior to ring or-C (OH)=C (R)-part is inequality, latter's cyclohexane ring is undersaturated in the 1-2 position, i.e. hexamethylene-1-alkene, or
Figure A9519768100262
, in general formula (II), R is Z.It should also be appreciated that the 2-position of outer synform ring, can replace (R), as at general formula (I) or (II).
Following example is in order to further specify the invention of description.These examples only are in order to explain invention, never give invention with restriction any that inventor's claim is stated from claims in form.
According to medication of the present invention, unacceptable toxic and side effects can not appear.Preparation method
Synthetic reaction formula, and the explanation of annex word
The chemical compound of general formula (I); can prepare by following technology; for example comprise; in appropriate solvent (as amine); under the triphenyl phasphine existence condition; adopt suitable catalyst such as copper halide (1 valency copper) and palladium compound (palladium is divalent or 0 valency); make Compound I alkynes end group and halogenated aryl hydrocarbon (for example iodobenzene) reaction in the reaction equation 1; according to Brandsma et al (Syn.Comm.1990; 20,1889) program is carried out, then under standard conditions; the ketal protected group of hydrolysis obtains the chemical compound of the general formula 2 of reaction equation I.The chemical compound of the general formula 1 of reaction equation I, can be by the U.S. Patent application of common pending trial, 07/862,083,07/968,753 and PCT/US93/01990 (specifying the U.S. to submit WIPO publication number WO93/19748 on March 5th, 1993) or PCT application PCT/US93/02325 publication number be that the similar method of introducing among the WO93/19750 prepares.
Reaction equation 1
Figure A9519768100271
A) Pd (PPh 3) 4, PPh 3, Cul, C 6H 5L, piperidines; B) pyridine p-toluenesulfonic esters (H 3C) 2CO/H 2O
The chemical compound of general formula (I) also can prepare like this.For example in appropriate solvent (for example amine) under as the triphenyl phasphine existence condition, adopts suitable catalyst, as copper halide (1 valency) and bivalence or non-valent palladium compound, makes chemical compound 1 Terminal Acetylenes and suitable halides in the reaction equation 2, R 3X (R here 3Be the R of definition in the general formula (I) 3, perhaps can change R into 3Group) reaction, carry out according to the program of Brandsma et al (Syn.Comm.1990,20,1889), obtain the chemical compound of the general formula 2 of reaction equation 2.To R 3Part, by the canonical transformation of functional group, these chemical compounds of general formula (I) are convertible into other chemical compound of general formula (I).Employing is similar to the US application 07/862 of common pending trial, 083,07/968,753 and PCT/US93/01990 (specify the U.S., on March 5th, 1993 submitted to, WIPO publication number WO93/19748) or PCT application PCT/US93/62325, publication number is the method among the WO93/19750, but the chemical compound of preparation feedback formula 2 general formulas 1.
Reaction equation 2
Figure A9519768100272
A) Pd (PPh 3) 4, PPh 3, Cul, R 3X, piperidines
Other method is Terminal Acetylenes hydrocarbon (for example chemical compound 1 of reaction equation a 3) oxidative carbonylation.For example utilize the palladium salt of proper metal salt (as mantoquita) and catalytic amount, exist down, in suitable alcohol (as methanol), according to Tsujiet al (Tet.Letter., 1990,21,849) method at suitable alkali (for example sodium acetate, as acid absorbent); Follow hydrolysis methyl ester under standard conditions, obtain the chemical compound (chemical compound 2 of reaction equation 3) of general formula (I); By the canonical transformation of carboxyl ester part, these chemical compounds of general formula (I) can be transformed into other chemical compound of general formula (I).
Reaction equation 3 A) PdCl 2, CuCl 2, NaO 2CCH 3, CO, CH 3OH
The preparation of the chemical compound of general formula (II) is shown in reaction equation 4, and preparation method is similar to above-mentioned reaction equation 1,2 and 3.Depend on the definite character of Z1 group in the chemical compound of general formula (II), need the protection of two O base at coupling step, for example, the chemical compound of general formula (II) wherein "=O " is dimethyl ketal or 2-(1, the 3-dioxolanes), then deprotection.Then according to the U.S. Patent application 07/862 of common pending trial, 083,07/968,753 and PCT/US93/01990 (specify the U.S., submit on March 5th, 1993, WIPO publication number WO93/19748) or PCT/US93/02325 (method of introducing among the publication number WO93/19750 is carried out synthetic reaction, obtains the chemical compound of general formula (II); Equally, Z 1Group may need protection at coupling step, and then deprotection obtains the chemical compound of general formula (II), and the person skilled in the art understands for these blocking groups very much.(consulting Greene, T.and Wuts, P.G.M., the blocking group in the organic synthesis, second edition, John Wiley and Sons, New York, 1991.) reaction equation 4
Figure A9519768100291
A) Pd (PPh 3) 4, PPh 3.Cul, R 3X, piperidines
The preparation of general formula (I) and other chemical compound (II) can be adopted the similar above-mentioned method among the embodiment that reaches.
Will be appreciated that general formula (I) and chemical compound (II) may exist different diastereomeric form, they have visibly different physics and biological property; These isomers can separate by the chromatographic process of standard.
Provide embodiment below and further explain the present invention.These embodiment only for explaining the present invention, never should think by mistake and limit the present invention by any way.Inventor's claim is stated from the claim.Synthetic embodiment
Embodiment 14-(3-cyclopenta oxygen-4-methoxyphenyl)-1, the preparation 1a of 1-(ethylidene dioxy)-4-(2-pyridine acetenyl) cyclohexane extraction) 4-cyano group-4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy) cyclohexane extraction
4-cyano group-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone (1.0g; 3.19mmol; press the method preparation of PCT application PCT/US93/01990 (WIPO publication number WO93/19748) as describing among the PCT application PCT/US93/02325 (WIPO publication number WO93/19750)) with the solution of benzene (25ml) with p-methyl benzenesulfonic acid (5mg) and ethylene glycol (0.18ml; 3.19 mmol) handle and under argon shield reflux, remove from mixture through the Dean-Stark trap and to anhydrate.1.5 after hour, add diethyl ether (200ml), solution is washed with 5% sodium bicarbonate aqueous solution, with the saturated common salt washing, uses the Anhydrous potassium carbonate drying, and evaporation obtains limpid colorless oil.
1H?NMR(250MHz，
CDCl 3)δ7.0(m，2H)，6.85(d，J＝7?Hz，1H)，4.8(m，1H)，4.0(m，4H)，3.85(s，3H)，
1.58-2.20(m，16H)。1b) 4-(3-cyclopenta oxygen-4-anisyl)-1,1-(ethylidene dioxy)-4-formoxyl cyclohexane extraction
Diisobutylaluminium hydride (the toluene solution of 1.0M; 8.13ml; 8.13mmol) under argon shield, be added drop-wise to 4-cyano group-4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy) cyclohexane extraction (1.16g, 3.19mmol) with the solution of toluene (20ml) in.Behind the room temperature reaction 18 hours, add saturated sodium sulfite solution (100ml), mixture dichloromethane extraction 3 times.Merge organic extract liquid, with saturated common salt washing, Anhydrous potassium carbonate drying, evaporation.Use the flash chromatography purification,, obtain limpid colorless oil with 4: 1 hexane/ethyl acetate eluting.
1H?NMR(400MHz，CDCl 3)δ
9.35(s，1H)，6.88(brs，2H)，6.80(s，1H)，4.73(m，1H)，3.95(m，4H)，3.85(s，3H)，
2.33(m，2H)，2.10(m，2H)，1.57-1.99(m，12H)。1c) 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-acetenyl cyclohexane extraction
(0.516g, 3.44mmol press Seyferth to (dizaomethyl) dimethyl phosphate, D.; Marmor, R.S.; Hilbert; P.J.Org.Chem, 1971,36 (10); 1379-1386 preparation) with the solution of anhydrous tetrahydro furan (10ml) under-78 ℃ and argon shield through conduit be added drop-wise to potassium tert-butoxide (0.386g, 3.4mmol) with the solution of anhydrous tetrahydro furan (10ml) in.Add 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1 in this solution rapidly, (0.62g is 1.72mmol) with the solution of anhydrous tetrahydro furan (10ml) for 1-(ethylidene dioxy)-4-formoxyl cyclohexane extraction.Afterreaction solution rose to room temperature in 2 hours, added water, mixture ethyl acetate extraction 3 times.Merge organic extract liquid, with saturated and Sal washing, anhydrous sodium sulfate drying, evaporation.Use the flash chromatography purification,, get white solid with 3: 1 hexane/ethyl acetate eluting.mp53.5-55℃。1d) 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-(2-pyridine acetenyl) cyclohexane extraction
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1 under argon shield; 1-(ethylidene dioxy)-4-acetenyl cyclohexane extraction (0.15g; 0.42mmol); 2-bromopyridine (0.040ml; 0.42mmol) with the solution of piperidines (2ml) in add four (triphenylphosphine)-palladiums (0) (0.02g, 4%), Hydro-Giene (Water Science). (I) (0.005g; 6%) and the little crystallization of triphenylphosphine, mixture was in 80 ℃ of heating 0.5 hour.Add water, mixture dichloromethane extraction 3 times, extract anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 35: 65 ethyl acetate/hexane eluting, get 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-(2-pyridine acetenyl) cyclohexane extraction is white bubble gum shape thing.
mp41-42℃. 1H-NMR(400MHz，
CDCl 3)δ8.58(d，J＝4.6Hz，1H)，7.65(t，J＝7.7Hz，1H)，7.43(d，J＝8.0Hz，1H)，7.21
(m，2H)，7.17(d，J＝8.5Hz，1H)，6.84(d，J＝8.5Hz，1H)，4.81(m，1H)，3.99(s，4H)，
3.84(s，3H)，2.25(m，2H)，2.15(m，4H)，1.8-2.0(m，8H)，1.59(m，2H)。
Embodiment 24-(3-cyclopenta oxygen-4-methoxyphenyl)-1, the preparation of 1-(ethylidene dioxy)-4-(phenylacetylene base) hexamethylene-1-ketone
1, (0.15g 0.42mmol) handles with micro-triphenylphosphine, tetrakis triphenylphosphine palladium (O) and Hydro-Giene (Water Science). (I) sample of 1-(ethylidene dioxy)-4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl cyclohexane extraction.(0.47ml, 4.2mmol) and piperidines (2ml), mixture heats under argon shield to add iodobenzene then.After 3 hours, mixture is washed 1 time with dilute hydrochloric acid solution with ethyl acetate (50ml) dilution, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification,, obtain limpid colorless oil with 4: 1 hexane-eluent ethyl acetates.
1H?NMR(400MHz，CDCl 3)δ
7.44(m，2H)，7.3(m，3H)，7.23(d，J＝2Hz，1H)，7.12(dd，J＝2?and?8Hz，1H)，6.81
(d，J＝8Hz，1H)，4.8(m，1H)，4.0(s，4H)，3.85(s，3H)，2.25(m，2H)，2.10(m，2H)，
1.78-2.03(m，10H)，1.6(m，2H)。
The preparation of embodiment 34-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(phenylacetylene base) hexamethylene-1-ketone
Toward 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-(phenylacetylene base) hexamethylene-1-ketone (0.18g, 0.42mmol) with 4: 1 acetone (5ml) solution in add p-methyl benzenesulfonic acid pyridine (5ml).Mixture is reflux under argon shield.Add water (15ml) after 6 hours, mixture ethyl acetate extraction 3 times.Merge organic extract liquid, anhydrous magnesium sulfate drying, evaporation.Carry out purification with the ether/hexane grinding, get white solid.mp.99-100℃。
The preparation of embodiment 44-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-pyridine radicals acetenyl) hexamethylene-1-ketone
4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-(2-pyridine acetenyl) cyclohexane extraction (0.17g, 0.39mmol), the p-methyl benzenesulfonic acid pyridine (0.10g, 0.39mmol), the mixture of acetone (4ml) and water (1ml) refluxed evaporation 3 days.Add water, mixture dichloromethane extraction 3 times, extract anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 25: 75 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-pyridine acetenyl) hexamethylene-1-ketone, be wax.
1H-NMR(400MHz，CDCl 3)δ8.61(d，J＝4.8Hz，1H)，7.68(dt，J＝7.8，
1.8Hz，1H)，7.47(d，J＝7.8Hz，1H)，7.27(m，1H)，7.20(d，J＝2.3Hz，1H)，7.15(dd，
J＝8.5，2.4Hz，1H)，6.87(d，J＝8.5Hz，1H)，4.81(m，1H)，3.85(s，3H)，3.07(dt，
J＝14.4，5.8Hz，2H)，2.49(d，J＝14.8Hz，2H)，2.41(m，2H)，2.27(dt，J＝13.4，3.9
Hz，2H)，1.8-2.0(m，6H)，1.61(m，2H)。Analyze (C 25H 27NO 30.65H 2O) calcd:C,
74.84; H, 7.11; N, 3.49; Actual measurement: C, 75.00; H, 6.83; N, 3.52.
Embodiment 54-(3-cyclopenta oxygen-4-methoxyphenyl)-1, the preparation of 1-(ethylidene dioxy)-4-(4-nitrobenzene acetylene base) cyclohexane extraction
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1 under argon shield; 1-(ethylidene dioxy)-4-acetylene cyclohexane extraction (0.15g; 0.42mmol), 4-iodonitrobenzene phenol (0.11g; 0.42mmol) with the solution of piperidines (2ml) in add four (triphenylphosphine)-palladium (0) (0.02g; 4%), Hydro-Giene (Water Science). (I) (0.005g, 6%) and the little crystallization of triphenylphosphine.After 0.5 hour, add water and 1N hydrochloric acid in 80 ℃ of heating.Mixture dichloromethane extraction 3 times, extract anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 2: 8 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-(4-nitrobenzene acetylene base) cyclohexane extraction is the salmon pink wax.
mp58-59℃. 1H-NMR(400MHz，CDCl 3)δ8.18(d，J＝8.7Hz，2H)，
7.58(d，J＝8.7Hz，2H)，7.16(d，J＝2.5Hz，1H)，7.12(dd，J＝8.4，2.5Hz，1H)，6.86(d，
J＝8.4Hz，1H)，4.80(m，1H)，4.01(s，4H)，3.85(s，3H)，1.8-2.3(m，14H)，1.6(m，
2H)。
The preparation of embodiment 64-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-aminophenyl acetenyl) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-anisyl)-1 under argon shield; 1-(ethylidene dioxy)-4-(4-nitrobenzophenone acetenyl) cyclohexane extraction (0.19g; 0.40mmol) with the solution of methanol (1ml), acetic acid (1.2ml) and water (1.2ml) in add titanous chloride. (0.3g, 2mmol).After the stirring at room 1.5 hours, add water (1.2ml) and ammonium hydroxide (2.5ml).Behind the restir 1 hour, add methanol (17.5ml), 5% sodium carbonate (17.5ml) and dichloromethane (35ml), continue to stir 3 days.Suspension kieselguhr Filter, fully wash, evaporation with dichloromethane.Add water, mixture dichloromethane extraction 3 times, extract anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 3: 7 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-aminophenyl acetylene) hexamethylene-1-ketone, be colorless oil.
1H-
NMR(400MHz，CDCl 3)δ7.28(d，J＝8.4Hz，2H)，7.24(d，J＝2.1Hz，1H)，7.12(d，
J＝8.5Hz，1H)，6.85(d，J＝8.5Hz，1H)，6.64(d，J＝8.1Hz，2H)，4.80(m，1H)，3.85(s，
3H)，3.05(dt，J＝14.3，4.1Hz，2H)，2.45(brd，J＝14.6Hz，2H)，2.29(m，4H)，1.8-2.0
(m，6H)，1.61(m，2H)。
The preparation of embodiment 74-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-acetamido phenylacetylene base) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-aminobenzene acetenyl) hexamethylene-1-ketone (0.12g under argon shield; 0.29mmol) with the solution of dichloromethane (3ml) in add pyridine (5) and acetic anhydride (0.081ml; 0.86mmol), reactant mixture stirring at room 2 hours.Add 1N hydrochloric acid, mixture dichloromethane extraction 3 times, extract anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 1: 1 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxybenzene)-4-(4-acetamido phenylacetylene base) hexamethylene-1-ketone, be white solid.Mp.79-80 ℃; Elementary analysis (C 28H 31NO 40.5H 2O), value of calculation: C, 73.98; H, 7.10; N, 3.08; Measured value: C74.11; H, 7.24; N, 3.03.
Embodiment 84-(3-cyclopenta oxygen-4-methoxyphenyl)-1, the preparation of 1-(ethylidene dioxy)-4-(3-nitrobenzophenone acetenyl) cyclohexane extraction
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1 under argon shield; 1-(ethylidene dioxy)-4-acetenyl cyclohexane extraction (0.14g; 0.38mmol), 3-iodonitrobenzene phenol (0.10g; 0.38mmol) with the solution of piperidines (2ml) in add four (triphenylphosphine)-palladiums (0) (0.028; 4%) small crystals of Hydro-Giene (Water Science). (I) (0.005g, 6%) and triphenylphosphine.70 ℃ of heating are after 0.33 hour, and mixture dilutes with dichloromethane, with the pickling of 1N salt, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 2: 8 ethyl acetate: the hexane eluting, 1,1-(ethylidene dioxy)-4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-nitrobenzophenone acetenyl) cyclohexane extraction is the salmon pink wax.
1H-NMR
(400MHz，CDCl 3)δ8.29(s，1H)，8.16(d，J＝9.0Hz，1H)，7.75(d，J＝7.9Hz，1H)，
7.50(t，J＝8.0Hz，1H)，7.26(d，J＝2Hz，1H)，7.14(dd，J＝8.3，2Hz，1H)，6.86(d，
J＝8.3Hz，1H)，4.82(m，1H)，4.01(s，4H)，3.85(s，3H)，2.18(m，4H)，2.07(m，2H)
1.93(m，4H)，1.85(m，4H)，1.6(m，2H)。
The preparation of embodiment 94-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-aminophenyl acetenyl) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1 under argon shield; 1-(ethylidene dioxy)-4-(3-nitrobenzophenone acetenyl) cyclohexane extraction (0.17g; 0.35mmol) with the solution of methanol (1ml), acetic acid (1.2ml) and water (1.2ml) in add titanous chloride. (0.3g, 2mmol).After the stirring at room 1.5 hours, (0.3g, 2mmol) and water (1.2ml), mixture is in stirring at room 0.5 hour, stirs 0.5 hour in 45-50 ℃, is chilled to room temperature then to add titanous chloride..Add water (1.2ml) and ammonium hydroxide (2.5ml).Behind the restir 1 hour, add methanol (17.5ml), 5% sodium carbonate (17.5ml) and dichloromethane (35ml) continue to stir 2 hours.Suspension kieselguhr Filter, fully wash, extraction, evaporation with dichloromethane.Residue dilutes with dichloromethane, and organic layer was with 5: 95 ammonium hydroxide: washing, Anhydrous potassium carbonate drying, evaporation.The flash chromatography purification, with 3: 7 ethyl acetate: the hexane eluting, get 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-aminophenyl acetenyl) hexamethylene-1-ketone and 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1, the mixture (0.07g) of 1-(ethylidene dioxy)-4-(3-aminophenyl acetenyl) cyclohexane extraction.This mixture and one is scraped spear p-methyl benzenesulfonic acid pyridine, 4ml acetone and water (1ml) and was refluxed 3 days, then evaporation.Add water, mixture dichloromethane extraction 3 times, extract anhydrous magnesium sulfate drying, evaporation.The flash chromatography purification, with 35: 65 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-aminophenyl acetenyl) hexamethylene-1-ketone, be colorless oil.
1H-
NMR(400MHz，CDCl 3)δ7.22(d，J＝2.2Hz，1H)，7.14(m，2H)，6.87(m，2H)，6.82
(d，J＝2.8Hz，1H)，6.66(dd，J＝9.0，2.4Hz，1H)，4.8(m，1H)，3.85(s，3H)，3.7(br，
2H)，3.04(dt，J＝14.3，6.0Hz，2H)，2.47(brd，J＝14.6Hz，2H)，2.2-2.3(m，4H)，1.8-
2.0(m，6H)，1.61(m，2H)。
The preparation of embodiment 104-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-acetamido phenylacetylene base) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-aminophenyl acetenyl) hexamethylene-1-ketone (0.07g under argon shield; 0.18mmol) with the solution of dichloromethane (2ml) in add pyridine (3) and acetic anhydride (0.05ml; 0.53mmol), reactant mixture was in stirring at room 2 hours.Add 1N hydrochloric acid, mixture dichloromethane extraction 3 times, extract anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 45: 55 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-acetamido phenylacetylene base) Ketohexamethylene, be white solid.Mp.63-64 ℃; Elementary analysis (C 28H 31NO 41.75H 2O), value of calculation: C, 70.49; H, 7.29; N, 2.94; Measured value: C70.09; H, 6.94; N, 2.83.
Embodiment 114-(3-cyclopenta oxygen-4-methoxyphenyl)-1, the preparation of 1-(ethylidene dioxy)-4-(3-methoxycarbonyl group phenylacetylene base) cyclohexane extraction
Under argon shield; 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1; 1-(ethylidene dioxy)-4-acetenyl cyclohexane extraction (0.150g; 0.421mmol) and 3-iodo-benzoic acid methyl ester (0.110g; 0.421mmol) with the mixture of piperidines (2.1ml, anhydrous) with tetrakis triphenylphosphine palladium (0) (0.020g, 0.017mmol), Hydro-Giene (Water Science). (0.010g; 0.053mmol) and triphenylphosphine (crystallization) processing, mixture was in 80 ℃ of heating 40 minutes.Reactant mixture is chilled to 0 ℃, in the impouring frozen water, uses the 3N hcl acidifying, uses dichloromethane extraction 5 times.Organic layer is washed with dilute hydrochloric acid successively, washing, saturated common salt washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure.Residue is adsorbed onto reuse silica gel chromatogram purification on the silica gel earlier, with 15% to 20% ethyl acetate-hexane eluting, obtains glassy yellow grease.
1H-NMR(250
MHz，CDCl 3)δ8.11(t，J＝1.4Hz，1H)，7.97(d-d，J＝1.3Hz；J＝7.9Hz，1H)，7.63(d-d，
J＝7.8Hz；J＝1.3Hz，1H)，7.39(t，J＝7.8Hz，1H)，7.23(d，J＝2.2，1H)，7.15(d-d，J＝8.4
Hz；J＝2.3Hz，1H)，6.89(d，J＝8.4Hz，1H)，4.80(m，1H)，4.00(s，br，4H)，3.92(s，
3H)，3.84(s，3H)，2.4?to?1.75(m，18H).
The preparation of embodiment 124-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-methoxycarbonyl group phenylacetylene base) hexamethylene-1-ketone
4-(3-cyclopenta oxygen-4-methoxyphenyl)-1; (0.060g, 0.12mmol) solution with the oxolane (5ml) that contains 3N hydrochloric acid (0.60ml) heated 2 hours in 55-60 ℃ under argon shield 1-(ethylidene dioxy)-4-(3-methoxycarbonyl group phenylacetylene base) cyclohexane extraction.Cold reactant mixture distributes between ice-cold aqueous sodium carbonate and ethyl acetate.Organic layer washes with water, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue silica gel chromatography purification with 15% ethyl acetate/hexane eluting, gets the resin-like thing.Elementary analysis (C 28H 30O 51/4H 2O), value of calculation: C, 74.56; H, 6.82; Measured value: C74.43; H, 6.80.
1H-NMR(400MHz，CDCl 3)δ8.15(s，1H)，
8.00(d-d，J＝1.5Hz；J＝6.6Hz，1H)，7.65(d-d，J＝1.3Hz，J＝7.7Hz，1H)，7.43(t，J＝7.7
Hz，1H)，7.21(d，J＝2.1，1H)，7.12(d-d，J＝2.0Hz，J＝8.5Hz，1H)，6.87(d，J＝8.5
Hz，1H)，4.81(m，1H)，3.94(s，3H)，3.86(s，3H)，3.04(d-t，J＝6.0Hz，J＝14.2，2H)，
2.50(d，br，J＝14.8，2H)，2.4-2.2(m，4H)，2.0-1.5(m)。
Embodiment 134-(3-cyclopenta oxygen-4-methoxyphenyl)-1, the preparation of 1-(ethylidene dioxy)-4-(3-carboxyl phenyl acetenyl) cyclohexane extraction
4-under argon shield (3-cyclopenta oxygen-4-methoxyphenyl)-1; 1-(ethylidene dioxy)-4-(3-methoxycarbonyl group phenylacetylene base) cyclohexane extraction (0.12g; 0.245mmol) with the solution of methanol (5ml) with 10% sodium hydrate aqueous solution (0.3ml; 0.734mmol) handle, and in 55-60 ℃ of heating 2.5 hours.Cold reaction mixture concentrates in argon gas stream, and residue is distributing between acidifying cold water and the dichloromethane with dilute hydrochloric acid.Water layer extracts 2 times with dichloromethane again, merges organic layer, and anhydrous magnesium sulfate drying, the title compound that obtains are grease.
1H-NMR(400MHz，CDCl 3)δ8.18(s，1H)，8.02(d，J＝7.9Hz，1H)，7.68(d，
J＝7.8Hz，1H)，7.42(t，J＝7.8Hz，1H)，7.23(d，J＝2.2，1H)，7.14(d-d，J＝8.4Hz；J＝2.3
Hz，1H)，6.85(d，J＝8.4Hz，1H)，4.82(p，1H)，4.01(t，4.2H)，3.85(s，3.2H)，2.4?to
1.5(m，17H)。
The preparation of embodiment 144-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-carboxyl phenyl acetenyl) hexamethylene-1-ketone
4-(3-cyclopenta oxygen-4-methoxyphenyl)-1; (0.11g, 0.23mmol) solution with the oxolane (6ml) that contains 3N hydrochloric acid (0.7ml) heated 2 hours at 55-70 ℃ under argon shield 1-(methylene dioxy)-4-(3-carboxyl phenyl acetenyl) cyclohexane extraction.The cold reaction mixture concentrating under reduced pressure, residue distributes between cold water and dichloromethane.Organic layer is washed with saturated common salt, anhydrous magnesium sulfate drying, evaporation.Residue silica gel chromatography purification is with methylene chloride/water (90/5/0.25 to 90/10/0.5) eluting, concentrating under reduced pressure.Residue is dissolved in methanol, and the concentrating under reduced pressure foaming gets the vitreous body of white fragmentation.Elementary analysis (C 27H 28O 51/4H 2O1/4CH 3OH), value of calculation: C, 73.55; H, 6.68; Measured value: C73.51; H, 6.66.
1H-NMR(400MHz，CDCl 3)δ8.22(t，J＝1.5Hz，1H)，8.09(d-d，
J＝1.3Hz；J＝7.9Hz，1H)，7.72(d-d，J＝1.3Hz，J＝7.8Hz，1H)，7.47(t，J＝7.8Hz，1H)，
7.22(d，J＝2.2，1H)，7.13(d-d，J＝2.3Hz，J＝8.4Hz，1H)，6.88(d，J＝8.5Hz，1H)，4.82
(p，1H)，3.86(s，3H)，3.25(d，J＝20Hz，CH 3OH，0.55H)，3.04(d-t，J＝5.8Hz，J＝14.5，
1.7H)，2.50(d，br，J＝14.8，1.8H)，2.4-2.2(m，4H)，2.0-1.5(m)。
Embodiment 154-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-pyridine acetenyl) hexamethylene-1-ketone 15a) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-pyridine acetenyl)-1,1-(ethylidene dioxy) cyclohexane extraction
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl-1 under argon shield; 1-(ethylidene dioxy) cyclohexane extraction (0.10g; 0.28mmol) and 4-bromopyridine (0.54g; 2.8mmol) with the solution of piperidines (1.5ml) in add tetrakis triphenylphosphine palladium (0) (0.013g; 4%) Hydro-Giene (Water Science). (I) (0.004g; 6%) and the little crystallization of triphenylphosphine, mixture was in 80-85 ℃ of heating 0.5 hour.Add water, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 35: 65 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-pyridine radicals acetenyl)-1,1-(ethylidene dioxy) cyclohexane extraction is light yellow oil (0.11g, 93%).
1H-NMR(400MHz，CDCl 3)δ8.56(d，J＝5.3Hz，2H)，7.33(d，J＝5.3Hz，2H)，7.16
(d，J＝2.2Hz，1H)，7.09(dd，J＝8.5，2.2Hz，1H)，6.85(d，J＝8.5Hz，1H)，4.80(m，1H)，
4.00(m，4H)，3.85(s，3H)，2.0-2.2(m，6H)，1.8-2.0(m，8H)，1.59(m，2H)。15b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-pyridine acetenyl) hexamethylene-1-ketone
4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-pyridine acetenyl)-1,1-(ethylidene dioxy) cyclohexane extraction (0.10g, 0.24mmol), the p-methyl benzenesulfonic acid pyridine (0.06g, 0.24mmol), the mixture of acetone (4ml) and water (1ml) refluxed evaporation then 20 hours.Add water, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 35: 65 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-pyridine acetenyl) hexamethylene-1-ketone (0.08g, 91%), be white solid, mp.148-149 ℃.Elementary analysis (C 25H 27NO 30.5H 2O), value of calculation: C, 75.29; H, 7.08; N, 3.51; Measured value: C, 75.51, H, 6.95; N, 3.42.
Embodiment 164-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-pyridine radicals acetenyl) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.22g under argon shield; 0.70mmol) and 3-bromopyridine (0.70ml; 7.0mmol) with the solution of piperidines (2ml) in add four-(triphenylphosphine) palladium (0) (0.034g; 4%) Hydro-Giene (Water Science). (I) (0.009g; 6%) and the small crystals of triphenylphosphine, mixture was 80-85 ℃ of heating 0.5 hour.Add ammonium chloride, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 35: 65 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-piperidine acetylene base) hexamethylene-1-ketone, be beige solid (0.22g, 80%).This product further grinds with ether-hexane, mp.88-89 ℃.Elementary analysis (C 25H 27NO 30.375H 2O), value of calculation: C, 75.78; H, 7.03; N, 3.53; Measured value: C, 75.77, H, 6.89; N, 3.40.
Embodiment 174-(2-methoxycarbonyl group thiophene-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone 17a) .2-bromo-5-carboxymethyl thiophene
2-bromo-5-carboxymethyl thiophene makes by the known standard method of document, is white solid, mp59-60 ℃.17b) .4-(2-methoxycarbonyl group thiophene-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.21g under argon shield; 0.7mmol) and 2-bromo-5-carboxymethyl thiophene (0.18g; 1.2mmol) with the solution of triethylamine (2ml) in add tetrakis triphenylphosphine palladium (0) (0.031g; 4%) Hydro-Giene (Water Science). (I) (0.008g; 6%), mixture was in 80-85 ℃ of heating 4.5 hours.Add ammonium chloride, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.The flash chromatography purification, with 2: 8 ethyl acetate: the hexane eluting, 4-(2-methoxycarbonyl group thiophene-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, be yellow oil (0.25g, 82%).
1H-NMR(400MHz，CDCl 3)δ7.67(d，J＝4.0Hz，1H)，7.16(d，J＝4.0Hz，1H)，7.15
(d，J＝2.2Hz，1H)，7.07(dd，J＝8.4，2.2Hz，1H)，6.87(d，J＝8.4Hz，1H)，4.80(m，1
H)，3.89(s，3H)，3.85(s，3H)，2.95(dt，J＝14.5，5.9Hz，2H)，2.49(brd，J＝14.5Hz，
2H)，2.36(m，2H)，2.26(dt，J＝13.4，4.0Hz，2H)，1.8-2.0(m，6H)，1.6(m，2H)
ppm。Elementary analysis (C 26H 28O 5S0.25H 2O), value of calculation: C, 68.32; H, 6.28; Measured value: C, 68.25; H, 6.12.
Embodiment 184-(2-carboxy thiophene-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone.Sodium salt,
4-(2-methoxycarbonyl group thiophene-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone (0.13g; 0.30mmol) and the potassium hydroxide (0.025g of rough lapping; 0.45mmol) with the solution of oxolane (5ml), methanol (5ml), water (2ml) under argon shield, stirring at room 24 hours.Reactant mixture 10% hcl acidifying is with 5: 95 methanol: dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Thick product 10% naoh treatment generates salt.The reversed phase chromatography purification, with 1: 1 methanol: water elution, 4-(2-carboxy thiophene-5-ethyl-acetylene base)-4-(3-cyclopentyloxy-4-methoxyphenyl) hexamethylene-1-ketone, sodium salt is white solid (0.070g, 55%), mp194-195 ℃.Elementary analysis (C 25H 25O 5SNa1.25H 2O) value of calculation: C, 62.16; H, 5.74; Measured value: C, 61.90; H, 5.49.
Embodiment 194-(2-cyano thiophene-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone 19a) .2-bromo-5-cyano thiophene
2-bromo-5-cyano thiophene makes by literature method, is colorless oil,
1H-NMR(400MHz，CDCl 3)：δ7.40
(d，J＝4Hz，1H)，7.10(d，J＝4Hz，1H)ppm。19b) .4-(2-cyano thiophene-5-ethyl-acetylene base)-4-(3-cyclopentyloxy-4-methoxyphenyl) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.22g under argon shield; 0.7mmol), 2-bromo-5-cyano thiophene (0.13g; 0.7mmol) with the solution of triethylamine (5ml) in add tetrakis triphenylphosphine palladium (0) (0.034g; 4%) and Hydro-Giene (Water Science). (I) (0.007g; 6%), mixture was 85-90 ℃ of heating 2 hours.Add ammonium chloride, anhydrous magnesium sulfate drying is used in mixture dichloromethane extraction 3 times, evaporation.Use the flash chromatography purification, with 2: 8 ethyl acetate: the hexane eluting, 4-(2-cyano thiophene-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone (0.06g, 18%).This product merges with the product (0.017g) that similar reaction for the second time obtains, and grinds with dichloromethane-hexane, obtains white solid, mp.106-107 ℃.Elementary analysis (C 25H 25NO 3S0.5H 2O), value of calculation: C, 70.07; H, 6.11; N, 3.27, measured value: C, 70.15; H, 5.84; N, 3.32.
Embodiment 204-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(5-(the 5-methyl-[and 1,2,4] oxadiazole-2-yls) thiophene-2-ethyl-acetylene base) hexamethylene-1-ketone 20a) .2-bromo-5-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) thiophene
2-bromo-5-) 5-methyl-(1,2,4 〕 oxadiazole-2-yl) thiophene makes by literature method, is white solid, mp.48-49 ℃.20b) .4-(3-cyclopenta oxygen-4-anisyl)-4-(5-(5-methyl-[1,2,4] oxadiazole-2-yls) thiophene-2-ethyl-acetylene base) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl-hexamethylene-1-ketone under argon shield) 0.17g; 0.88mmol (with 2-bromo-5-(5-methyl-(1; 2; 4 〕 oxadiazole-2-yl) thiophene (0.18g; 1.2mmol) with the solution of triethylamine (5ml) in add tetrakis triphenylphosphine palladium (0) (0.037g; 4%) and Hydro-Giene (Water Science). (I) (0.010g, 6%), mixture was 85-90 ℃ of heating 2 hours.Add ammonium chloride, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 25: 75 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(5-(5-methyl-(1,2,4) thiophene-2-ethyl-acetylene base oxadiazole-2-yl)) hexamethylene-1-ketone is white wax, mp94-95 ℃.Elementary analysis (C 27H 28N 2O 4S), value of calculation: C, 68.04; H, 5.92; N, 5.88, measured value: C, 67.83; H, 5.89; N, 5.92.
Embodiment 214-(2-methoxycarbonyl group thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone 21a) .4-bromo-2-carboxymethyl thiophene
4-bromo-2-carboxymethyl thiophene makes by literature method, is brown oil.
1H-NMR(400MHz，CDCl 3)δ7.69(d，J＝1.5Hz，1H)，7.45(d，J＝1.5Hz，1H)，3.90(s，3H)ppm。21b) .4-(2-methoxycarbonyl group thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-anisyl)-4-acetenyl hexamethylene-1-ketone (0.25g under argon shield; 0.8mmol) and 4-bromo-2-carboxymethyl thiophene (0.27g; 1.2mmol) with the solution of triethylamine (3.5ml) in add tetrakis triphenylphosphine palladium (0) (0.038g; 4%) and Hydro-Giene (Water Science). (I) (0.010g; 6%), mixture was 80-85 ℃ of heating 0.5 hour.Add ammonium chloride, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 2: 8 ethyl acetate: the hexane eluting, 4-(2-methoxycarbonyl group thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, be yellow glass body (0.15g, 42%).
1H-NMR(400MHz，CDCl 3)δ7.81(d，J＝1.3Hz，1H)，7.60(d，J＝1.3Hz，1
H)，7.16(d，J＝2.2Hz，1H)，7.10(dd，J＝8.5，2.2Hz，1H)，6.86(d，J＝8.5Hz，1H)，
4.80(m，1H)，3.90(s，3H)，3.84(s，3H)，2.98(dt，J＝14.8，5.7Hz，2H)，2.48(brd，
J＝14.8Hz，2H)，3.33(m，2H)，2.26(dt，J＝13.6，4Hz，2H)，1.9-2.0(m，6H)，1.6
(m，2H)ppm。Analyze (C 26H 28O 5S) calculate: C, 69.00; H, 6.24; Actual measurement .:C, 68.82; H, 6.04.
Embodiment 224-(2-carboxy thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
4-(2-methoxycarbonyl group thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone (0.19g; 0.43mmol) and the potassium hydroxide of rough lapping (0.036g, 0.64mmol) solution with oxolane (2ml), methanol (2ml) and water (0.4ml) stirred 24 hours under room temperature and argon shield.Reactant mixture 10% hcl acidifying is with 5: 95 methanol: dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.The flash chromatography purification, with 0.1: 3: 97 acetic acid: methanol: the dichloromethane eluting, 4-(2-carboxy thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, be beige solid (0.18g, 95%), mp80-82 ℃.Elementary analysis (C 25H 26O 5S0.25H 2O) value of calculation: C, 67.78; H, 6.03; Measured value: C, 67.72; H, 6.02.
Embodiment 234-(2-cyano thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone 23a) .4-bromo-2-cyano thiophene
4-bromo-2-cyano thiophene makes by the document known method, is pink solid, mp43-44 ℃.23b) .4-(2-cyano thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-anisyl) 4-acetenyl hexamethylene-1-ketone (0.25g under argon shield; 0.8mmol) and 4-bromo-2-cyano thiophene (0.15g; 0.8mmol) with the solution of triethylamine (5ml) in add tetrakis triphenylphosphine palladium (0) (0.038g; 4%) and Hydro-Giene (Water Science). (I) (0.008g; 6%), mixture was 85-90 ℃ of heating 24 hours.Add water, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 2: 8 ethyl acetate: the hexane eluting, get 4-(2-cyano thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, this product advances-goes on foot with dichloromethane-hexane to grind to form white solid (0.08g, 24%), mp112-113 ℃, elementary analysis (C 25H 25NO 3S0.375H 2O) value of calculation: C, 70.44; H, 6.09; N, 3.29; Measured value: C, 70.38; H, 5.94; N, 3.20.
Embodiment 244-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(the 5-methyl-[and 1,2,4] oxadiazole-2-yls) thiophene-4-ethyl-acetylene base) hexamethylene-1-ketone 24a) .4-bromo-2-(the 5-methyl-[and 1,2,4] oxadiazole-2-yls) thiophene
4-bromo-2-(5-methyl-[1,2,4] oxadiazole-2-yls) thiophene is pressed the literature method preparation, is white solid, mp66-67 ℃.24b). cis-(4-(3-cyclopenta oxygen-4-anisyl)-4-(2-(5-methyl-(1,2,4) oxadiazole-2-yl) thiophene-4-ethyl-acetylene base) hexamethylene-1-alcohol
Argon shield is down toward trans-(4-(3-cyclopentyloxy-4-methoxyphenyl)-4-acetenyl hexamethylene-1-alcohol) (0.25g; 0.8mmol; according to pending application P50287; submit on the same day; the middle method of describing prepares) and 4-bromo-2-(5-methyl (1; 2; 4 〕 oxadiazole-2-yl) thiophene (0.20g; 0.8mmol) with the solution of triethylamine (5ml) in add tetrakis triphenylphosphine palladium (0) (0.038g; 4%) Hydro-Giene (Water Science). (I) (0.009g; 6%) and the little crystallization of triphenylphosphine, mixture was in 70-75 ℃ of heating 0.5 hour.Add 5% hydrochloric acid, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, 1: 1 ethyl acetate: hexane eluting, get cis-(4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) (0.20g hexamethylene-1-alcohol thiophene-4-ethyl-acetylene base)), 53%), this product reuse dichloromethane-hexane grinds to form white solid, mp142-143 ℃.Elementary analysis (C 27H 30N 2O 4S), value of calculation: C, 67.76; H, 6.32; N, 5.85; Measured value: C, 67.85; H, 6.42; N, 5.54.24c) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) thiophene-4-ethyl-acetylene) hexamethylene-1-ketone
Past pyridinium chlorochromate (0.04g under argon shield; 0.20mmol) with the suspension of dichloromethane (1ml) under room temperature, add cis-(4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(5-methyl-(1 rapidly; 2; 4 〕 oxadiazole-2-yl) (0.06g hexamethylene-1-alcohol thiophene-4-ethyl-acetylene base)); 0.13mmol) with the solution of dichloromethane (2ml), mixture stirred 1 hour.Add diethyl ether (20ml), continue to stir 0.25 hour.Mixture kieselguhr Filter evaporation.Use the flash chromatography purification, with 25: 75 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) thiophene-4-ethyl-acetylene base) hexamethylene-1-ketone is colorless oil.With dichloromethane-hexane recrystallization, get white solid (0.033g, 53%), mp94-95 ℃.Elementary analysis (C 27H 28N 2O 4S1.0H 2O), value of calculation: C, 66.57; H, 6.11; N, 5.66; Measured value: C, 65.46; H, 5.74; N, 5.60.
Embodiment 254-(4-methoxycarbonyl group thiophene-2-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone 25a) .2-bromo-4-carboxymethyl thiophene
2-bromo-4-carboxymethyl thiophene is pressed the preparation of document known method, is brown oil.
1H-NMR (400MHz, CDCl 3) δ 7.99 (s, 1H), 7.47 (s, 1H), 3.86 (s, 3H) ppm..25b) .4-(4-methoxycarbonyl group thiophene-2-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
Argon shield is down toward 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.35g; 1.12mmol) and 2-bromo-4-carboxymethyl thiophene (0.25g; 1.13mmol) with the solution of triethylamine (5ml) in add tetrakis triphenylphosphine palladium (0) (0.044g; 4%) Hydro-Giene (Water Science). (I) (0.011g; 6%) and the small crystals of triphenylphosphine, mixture was in 80-85 ℃ of heating 0.5 hour.Add water and 10% hydrochloric acid, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 2: 8 ethyl acetate: the hexane eluting, 4-(4-methoxycarbonyl group thiophene-2-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, be yellow jelly (0.29g, 58%).
1H-NMR(400
MHz，CDCl 3)δ8.00(d，J＝1.1Hz，1H)，7.61(d，J＝1.1Hz，1H)，7.16(d，J＝2.2Hz，1
H)，7.07(dd，J＝8.4，2.2Hz，1H)，6.87(d，J＝8.4Hz，1H)，4.81(m，1H)，3.88(s，3
H)，3.86(s，3H)，2.97(dt，J＝14.4，5.7Hz，2H)，2.49(brd，J＝13.5Hz，2H)，2.35(m，
2H), 2.29 (m, 2H), 1.9-2.0 (m, 6H), 1.6 (m, 2H) ppm analysis (C 26H 28O 5S) calculate:
C, 69.00; H, 6.24; Actual measurement: C, 68.76; H, 6.46.
Embodiment 264-(4-carboxy thiophene-2-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
4-(4-methoxycarbonyl group thiophene-2-ethyl-acetylene base)-4-(3-cyclopentyloxy-4-methoxyphenyl) hexamethylene-1-ketone (0.12g; 0.427mmol) and the rough lapping potassium hydroxide (0.045g is 0.81mmol) with the solution of oxolane (2.5ml), methanol (2.5ml) and water (0.5ml) stirring at room 3 days under argon shield.Reactant mixture 10% hcl acidifying, with 5: 95 methanol: dichloromethane extraction 3 times, use anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 0.25: 2.5: 97.5 acetic acid: methanol: the dichloromethane eluting, 4-(4-carboxy thiophene-2-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, be cream-coloured bubble gum shape thing (0.11g, 94%), mp75-76 ℃.Elementary analysis (C 25H 26O 5S0.25H 2O), value of calculation: C, 67.78; H, 6.03; Measured value: C, 67.73; H, 5.80.
Embodiment 274-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) thiophene-2-ethyl-acetylene base) hexamethylene-1-ketone 27a) .2-bromo-4-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) thiophene
(5-methyl-(1,2,4 〕 oxadiazole-2-yl) thiophene makes by literature method 2-bromo-4-, is white solid, mp.72-73 ℃.27b). cis-(4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-(5-methyl-(1,2,4) oxadiazole-2-yl) thiophene-2-yl) hexamethylene-1-alcohol
Under argon shield toward trans-(4-(3-cyclopenta oxygen-4-methoxyphenyl) 4-acetenyl hexamethylene-1-alcohol (0.25g; 0.8mmol; press pending application book P50287; submit on the same day; the middle same procedure of describing prepares) and 2-bromo-4-(5-methyl-(1; 2; 4 〕 oxadiazole-2-yl) thiophene (0.20g; 0.8mmol) with the solution of triethylamine (5ml) in add tetrakis triphenylphosphine palladium (0) (0.038g; 4%) Hydro-Giene (Water Science). (I) (0.009g; 6%) and the small crystals of triphenylphosphine, mixture was in 70-75 ℃ of heating 0.5 hour.Add 5% hydrochloric acid, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 1: 1 ethyl acetate: the hexane eluting, get cis-(4-(3-cyclopenta oxygen-4-anisyl)-4-(4-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) hexamethylene-1-alcohol thiophene-2-ethyl-acetylene base)), reuse dichloromethane-hexane grinds, and gets white solid) 0.20g, 53% (, mp142-143 ℃.Elementary analysis (C 27H 30N 2O 4S0.75H 2O), value of calculation: C, 65.90; H, 6.45; N, 5.69; Measured value: C, 66.06; H, 6.42; N, 5.50.27c) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) thiophene-2-ethyl-acetylene base) hexamethylene-1-ketone
Under argon shield and room temperature; toward pyridinium chlorochromate (0.07g; 0.31mmol) with the solution of dichloromethane (1ml) in add cis-(4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-(5-methyl-(1 rapidly; 2; 4 〕 oxadiazole-2-yl) (0.10g hexamethylene-1-alcohol thiophene-2-ethyl-acetylene base)); 0.21mmol) with the solution of dichloromethane (2ml), stirred 0.5 hour.Add diethyl ether (20ml) restir 0.5 hour.Mixture filters with kieselguhr , evaporation.Use the flash chromatography purification, with 25: 75 ethyl acetate: the hexane purification, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) thiophene-2-ethyl-acetylene base) hexamethylene-1-ketone is white solid, mp90-91 ℃.Elementary analysis (C 27H 28N 2O 4S0.25H 2O), value of calculation: C, 67.41; H, 5.97; N, 5.82; Measured value: C, 67.43; H, 5.87; N, 5.80.
Embodiment 284-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-methanesulfonyl pyrimidine-4-ethyl-acetylene base) hexamethylene-1-ketone 28a) .4-iodo-2-sulfidomethyl pyrimidine
4-iodo-2-sulfidomethyl pyrimidine is pressed the literature method preparation.(AJ.Majeed,  .Antonsen, T.Benneche, K.Undheim.Tetrahedron1989,45,993-1006) .28b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-methylthiopyrimidine-4-ethyl-acetylene base) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.35g under argon shield; 1.12mmol) and 4-iodo-2-sulfidomethyl pyrimidine (0.56g; 2.4mmol; mixture for 4-iodo-2-sulfidomethyl pyrimidine and 4-chloro-2-sulfidomethyl pyrimidine) and in the solution of triethylamine (5ml) add tetrakis triphenylphosphine palladium (0) (0.051g; 4%) and Hydro-Giene (Water Science). (I) (0.014g; 6%), mixture was 85-90 ℃ of heating 0.5 hour.Add ammonium chloride, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 25: 75 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-methylthiopyrimidine-4-ethyl-acetylene base) hexamethylene-1-ketone, be yellow resin-like thing (0.35g, 72%).
1H-NMR(400MHz，CDCl 3)δ8.50(d，J＝5.3Hz，1H)，7.17(d，J＝2.3Hz，1H)，7.08
(dd，J＝8.5，2.3Hz，1H)，7.03(d，J＝5.3Hz，1H)，6.87(d，J＝8.5Hz，1H)，4.81(m，1
H)，3.86(s，3H)，2.99(dt，J＝14.7，8.7Hz，2H)，2.58(s，3H)，2.46(brd，J＝18.7Hz，
2H)，2.40(m，2H)，2.29(m，2H)，1.8-2.0(m，6H)，1.6(m，2H)ppm。28c) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-methanesulfonyl pyrimidine-4-ethyl-acetylene base) hexamethylene-1-ketone
Toward 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-methylthiopyrimidine-4-ethyl-acetylene base) hexamethylene-1-ketone (0.35g; 0.81mmol) with the solution of chloroform (5ml) in; under-10 ℃ and argon shield; drip 3-chlorine and cross chlorobenzoic acid (0.31g; 1.78mmol) chloroformic solution, last 20 minutes.Reactant mixture stirred 1 hour prior to-10 ℃, in stirring at room 1 hour, handled with 5% sodium carbonate then again, and with dichloromethane extraction 3 times, the Anhydrous potassium carbonate drying is evaporated.The flash chromatography purification, 1: 99 methanol: the dichloromethane eluting, get 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-sulfonyloxy methyl yl pyrimidines-4-ethyl-acetylene base) hexamethylene-1-ketone, be white bubble gum shape thing (0.27g, 72%), mp60-64 ℃.Second batch obtains white bubble gum shape thing, m.p71-73 ℃ with the sulfone oxidation.Elementary analysis (C 25H 28N 2O 5S0.25H 2O) value of calculation: C, 63.47; H, 6.07; N, 5.92; Measured value: C, 63.43; H, 6.07; N, 5.58.
Embodiment 294-(2-aminopyrimidine-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
Toward 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-sulfonyloxy methyl yl pyrimidines-4-ethyl-acetylene base) hexamethylene-1-ketone (0.26g; 0.56mmol) with the solution of methanol (4ml) in-78 ℃ of condensation liquefied ammonia (4ml); the sealing compression tube, reactant liquor stirring at room 2.5 hours.Boil off solvent after the cooling.Twice flash chromatography carries out purification, for the first time purification was with 2: 98 methanol: the dichloromethane eluting, for the second time purification was with 4: 6 ethyl acetate: the hexane eluting, get 4-(2-aminopyrimidine-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, be white solid (0.18g, 73%), mp68-70 ℃.Elementary analysis (C 24H 27N 3O 30.2H 2O), value of calculation: C, 70.46; H, 6.75; N, 10.27; Measured value: C, 70.73; H, 6.79; N, 9.87.
Embodiment 304-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(1-Methylimidazole .-2-ethyl-acetylene base) hexamethylene-1-ketone 30a) .1-methyl-2-iodine imidazoles
1-methyl-2-iodine imidazoles is pressed the literature method preparation, is white solid, mp58-59 ℃.30b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(1-Methylimidazole .-2-ethyl-acetylene base) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.50g under argon shield; 1.6mmol) and 1-methyl-2-iodine imidazoles (0.35g; 1.6mmol) with the solution of triethylamine (50ml) in add tetrakis triphenylphosphine palladium (0) (0.074g; 4%) Hydro-Giene (Water Science). (I) (0.018g; 6%) and the little crystallization of triphenylphosphine, mixture was in 80-85 ℃ of heating 1 hour.Add water, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 3: 1 ethyl acetate: the hexane eluting, obtain impure 4-(4-methoxycarbonyl group thiophene-2-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone (0.16g, 26%), with product (the 0.16g second time, 43%) merges, use the flash chromatography purification, with 1: 99 methanol: the dichloromethane eluting, with dichloromethane-hexane recrystallization, obtain pure 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(1-Methylimidazole .-2-ethyl-acetylene base) hexamethylene-1-ketone (0.12g), be beige solid, mp137-138 ℃.Elementary analysis (C 24H 28N 2O 30.2H 2O), value of calculation: C, 72.77; H, 7.23; N, 7.07; Measured value: C, 72.82; H, 7.99; N, 6.97.
Embodiment 314-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(imidazoles-2-ethyl-acetylene base) hexamethylene-1-keto hydrochloride 31a) .1-tert-butyl group carbonyl-2-iodine imidazoles
1-tert-butyl group carbonyl-2-iodine imidazoles is pressed the literature method preparation, is white solid, mp77-78 ℃.31b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(1-tert-butyl group carboxyl imidazoles-2-ethyl-acetylene base) hexamethylene-1-ketone
Past 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.28g under argon shield; 0.9mmol) and 1-tert-butyl group carbonyl-2-iodine imidazoles (0.29g; 0.97mmol) with the solution of triethylamine (5ml) in add tetrakis triphenylphosphine palladium (0) (0.042g; 4%) Hydro-Giene (Water Science). (I) (0.005g; 6%) and the little crystallization of triphenylphosphine, mixture was in 80-85 ℃ of heating 1 hour.Add water, mixture dichloromethane extraction 3 times, anhydrous magnesium sulfate drying, evaporation.Use the flash chromatography purification, with 3: 7 ethyl acetate: the hexane eluting, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(1-tert-butyl group carbonylic imidazole-2-ethyl-acetylene base) hexamethylene-1-ketone (0.18g, 4%), be colorless oil.
1H-NMR(400MHz，CDCl 3)δ7.36(s，1H)，7.20(d，J＝2.1Hz，1H)，7.17(dd，J＝8.5，2.1Hz，1H)，7.01(s，1H)，6.85(d，J＝8.5Hz，1H)，4.85(m，1H)，3.84(s，3H)，3.18(m，2H)，2.44(m，4H)，2.22(m，2H)，1.8-2.0(m，6H)，1.6(m，11H)ppm。31c) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(imidazoles-2-ethyl-acetylene base) hexamethylene-1-keto hydrochloride
4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(1-tert-butyl group carbonylic imidazole-2-ethyl-acetylene base) hexamethylene-1-ketone (0.18g, 0.37mmol) and the solution of the saturated ethyl acetate (40) of hydrogen chloride and ethyl acetate (10ml) stirring at room 24 hours under argon shield.Suspension is chilled to 0 ℃, filters, and gets 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(imidazoles-2-ethyl-acetylene base) hexamethylene-1-keto hydrochloride (0.12g, 76%), is white solid, mp183-184 ℃.Elementary analysis (C 23H 26N 2O 3HCl0.25H 2O), value of calculation: C, 65.70; H, 6.83; N, 6.66; Measured value: C, 65.46; H, 6.65; N, 6.44.
The preparation 32a of embodiment 324-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(4-(2-hydroxyl ethane-1-oxygen) phenyl) acetenyl) hexamethylene-1-ketone). iodate 4-(2-hydroxyl-oxethyl) benzene
Under argon shield, be melted in ethylene carbonate in the vial (6.5g, 74mmol) with the 4-iodophenol (0.400g, 1.82mmol) and potassium carbonate powder (1.26g 9.1mmol) handles, and in 90 ℃ of stirrings 3 hours.Mixture is handled with cold dilute hydrochloric acid, removes excessive potassium carbonate, slowly adds excessive sodium hydrate aqueous solution then, and mixture stirs and spends the night.The suspension dichloromethane extraction washes with water, saturated common salt washing, anhydrous sodium sulfate drying, filtrate concentrate white solid, with sudden strain of a muscle formula silica gel (20ml) chromatogram purification, use the dichloromethane eluting, must (0.128g, 27%) title intermediate is white solid, mp76-77.5 ℃.32b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(4-(2-hydroxyl ethane-1-oxygen) phenyl) acetenyl)-1,1-(ethylidene dioxy) cyclohexane extraction
It is described to press embodiment 11, iodo 4-(2-hydroxyl-oxethyl) benzene (0.059g, 0.22mmol), 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-acetenyl cyclohexane extraction (0.080g, 0.22mmol) with the solution of anhydrous piperidines (1ml) with tetrakis triphenylphosphine palladium (0) (0.013g, 0.011mmol), Hydro-Giene (Water Science). (0.0025g, 0.013mmol) and triphenylphosphine (crystallization) handle.Thick product chromatogram purification (silica gel, 1 to 2% methanol-dichloromethane), concentrating under reduced pressure obtains the title intermediate, is thickness grease.
1H-NMR(400MHz，CDCl 3)δ7.39(d，J＝9.0Hz，2H)，7.24(d，J＝2.1
Hz，1H)，7.13(d-d，J＝8.3Hz，J＝2.1Hz，1H)，6.85(d，J＝8.7，2H)，6.84(d，J＝8.3Hz，
1H)，4.81(p，J＝2.0Hz，1H)，4.09(t，J＝4.4Hz，2H)，4.00(s，4H)，3.97(t，J＝4.4Hz，
2H), 3.84 (s, 3H), 2.3 to 1.5 (m, 21H and H 2O).32c) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(4-(2-hydroxyl ethane-1-oxygen) phenyl) acetenyl) hexamethylene-1-ketone
Press the method for embodiment 12, with 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(4-(2-hydroxyl ethane-1-oxygen) phenyl) acetenyl)-1, (0.090g 0.18mmol) handles with 3N hydrochloric acid (0.9ml) with the solution of oxolane (8ml) 1-(ethylidene dioxy) cyclohexane extraction.With chromatogram purification (silica gel, 40% to 50% ethyl acetate-hexane eluting), be evaporated in 60 ℃ dried, title compound, be vitreous body.Elementary analysis (C 28H 32O 51/4H 2O), value of calculation: C, 74.23; H, 7.23; Measured value: C, 74.31; H, 7.24.
1H-NMR
(400MHz，CDCl 3)δ7.41(d，J＝8.9Hz，2H)，7.23(d，J＝2.3Hz，1H)，7.13(d-d，
J＝8.5Hz，J＝2.3Hz，1H)，6.89(d，J＝8.7，2H)，6.86(d，J＝8.3Hz，1H)，4.80(p，1H)，
4.11(t，J＝4.5Hz，2H)，3.98(t，J＝4.4Hz，2H)，3.85(s，3H)，3.04(d-t，J＝14.1Hz，
J=6.1Hz, 2H), 2.47 (d, br, J=13.0,2H), 2.4 to 1.5 (m, 19H and H 2O).
The preparation 33a of embodiment 334-(4-methoxycarbonyl group phenylacetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone) .4-(4-methoxycarbonyl group phenylacetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy) cyclohexane extraction
Press the method for embodiment 1d, stir down 4-(4-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-acetenyl cyclohexane extraction (0.200g, 0.56mmol) and 4-iodo-benzoic acid methyl ester (0.147g, 0.56mmol) and triethylamine (2.5ml, anhydrous) solution with tetrakis triphenylphosphine palladium (0) (0.032g, 0.028mmol), Hydro-Giene (Water Science). (I) (0.0064g, 0.034mmol) and triphenylphosphine (crystallization) handle.Reactant mixture is pressed method extraction, the chromatogram purification of embodiment 1d, and concentrating under reduced pressure gets glassy yellow grease (0.25g, 91%).
1H-NMR
(400MHz，CDCl 3)δ7.98(d，9.4Hz，2H)，7.50(d，J＝9.4Hz，2H)，7.20(d，J＝1.9Hz，
1H)，7.12(d-d，J＝1.9Hz，J＝8.6Hz，1H)，6.84(d，J＝8.6，1H)，4.80(p，J＝3.8Hz，1H)，
4.00 (s, br, 4H), 3.92 (s, 3H), 3.85 (s, 3H), 2.3 to 1.5 (m, 17H and H 2O).33b) .4-(4-methoxycarbonyl group phenylacetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) cyclohexane extraction
It is described to press embodiment 14, stir down 4-(4-methoxycarbonyl group phenylacetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl)-1, (0.150g 0.12mmol) handles with 3N hydrochloric acid (0.70ml) with the solution of oxolane (7ml) 1-(ethylidene dioxy) cyclohexane extraction.Thick product chromatogram purification (silica gel, 20% ethyl acetate/hexane eluting), removal of solvent under reduced pressure gets title compound, is resin-like thing (0.063g, 46%).Elementary analysis (C 28H 30O 51/10H 2O), value of calculation: C, 75.01; H, 6.79; Measured value: C, 74.97; H, 6.87.
1H-NMR(400MHz，CDCl 3)δ8.01(d，J＝8.5Hz，2H)，
7.53(d，J＝8.5Hz，2H)，7.20(d，J＝2.4Hz，1H)，7.11(d-d，J＝8.5Hz，J＝2.4Hz，1H)，
6.87(d，J＝8.5，1H)，4.80(p，1H)，3.93(s，3H)，3.86(s，3H)，3.04(d-t，J＝6.2Hz，
J＝14.4，2H)，2.50(d，br，J＝14.9，2H)，2.42-2.32(m，2H)，2.26(d-t，J＝2.8Hz，J＝14.4
Hz, 2H), 2.00-1.5 (m, 11H and H 2O).
The preparation of embodiment 344-(4-carboxyl phenyl acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
It is described to press embodiment 13; 4-(4-methoxycarbonyl group phenylacetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) cyclohexane extraction (0.146g under stirring and argon shield; 0.326mmol) with the solution of absolute methanol (5ml) with 10% sodium hydrate aqueous solution (0.46ml, 1.15mmol) processing.Thick acid chromatogram purification (silica gel, 10: 90: 1 eluting of ethyl acetate/dichloromethane/formic acid), the fraction that contains product washes concentrating under reduced pressure with water 3 times, use the ether crystallization, vacuum drying gets title compound, be white solid (0.077g, 55%), mp170-171 ℃.Elementary analysis (C 27H 28O 5), value of calculation: C, 74.98; H, 6.53; Measured value: C, 74.78; H, 6.54.
The preparation 35a of embodiment 354-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(4-(1-piperidino carbonyl methoxyl group) phenyl) acetenyl) hexamethylene-1-ketone) .4-iodobenzene fluoroacetic acid methyl ester
The 4-iodophenol (0.50g, 2.27mmol), the 2-methyl bromoacetate (0.382g, 2.50mmol) and potassium carbonate powder (0.314g, 2.27mmol) with mixture tube sealing under argon shield of anhydrous propanone, 70 ℃ of heating 4 hours.Cold mixt filters, and filtrate decompression concentrates.Residue chromatogram purification (silica gel, 40% to 50% dichloromethane-cyclohexane extraction eluting), removal of solvent under reduced pressure gets the title intermediate, is white solid (0.41g, 62%), mp69-70 ℃.35b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-(2-(4-(1-piperidino carbonyl methoxyl group) phenyl) acetenyl) cyclohexane extraction
Press the method for embodiment 11,4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-acetenyl cyclohexane extraction (0.150g, 0.42mmol) and 4-iodobenzene fluoroacetic acid methyl ester (0.123g, 0.42mmol) with the mixture of anhydrous piperidines (2ml) in stirring and 80 ℃ times and tetrakis triphenylphosphine palladium (0.027g, 0.023mmol), Hydro-Giene (Water Science). (0.0048g, 0.025mmol) and the mixture reaction of triphenylphosphine (crystallization) 1.5 hours.Thick product chromatogram purification (silica gel, 50% to 75% ethyl acetate-petroleum ether eluting), concentrating under reduced pressure gets the title intermediate, is heavy-gravity yellow oil (0.232g, 96%).
1H-NMR (400MHz, CDCl 3) δ 7.38 (d, J=8.7Hz, 2H), 7.24 (d, J=2.3Hz, 1H), 7.13 (d-d, J=8.4Hz, J=2.3Hz, 1H), 6.89 (d, J=8.9,1H), 6.84 (d, J=8.4,1H), 4.81 (p, 1H), 4.69 (s, 2H), 4.00 (s, 4H), 3.84 (s, 3H), 3.56 (t, J=5.5Hz, 2H), 3.49 (t, J=5.5Hz, 2H), 2.3 to 1.5 (m, 32H and H 2O).35c) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(4-(1-piperidino carbonyl methoxyl group) phenyl) acetenyl) hexamethylene-1-ketone
It is described to press embodiment 12,4-(3-cyclopenta oxygen-4-methoxyphenyl)-1, (0.232g 0.40mmol) handles with 3N hydrochloric acid (0.90ml) in stirring down with the solution of oxolane (9ml) 1-(ethylidene dioxy)-4-(2-(4-(1-piperidino carbonyl methoxyl group) phenyl) acetenyl) cyclohexane extraction.Thick product chromatogram purification (silica gel, 50% ethyl acetate/hexane eluting), removal of solvent under reduced pressure gets title compound, is resin-like thing (0.127g, 59%).Elementary analysis (C 28H 30O 51/10H 2O), value of calculation: C, 75.01; H, 6.79; Measured value: C, 74.97; H, 6.87.
1H-NMR (400MHz, CDCl 3) δ 7.41 (d, J=9.1Hz, 2H), 7.22 (d, J=2.3Hz, 1H), 7.11 (d-d, J=8.4Hz, J=2.3Hz, 1H), 6.92 (d, J=8.6,1H), 6.86 (d, J=8.5,1H), 4.80 (p, 1H), 4.70 (s, 2H), 4.00 (s, 4H), 3.85 (s, 3H), 3.56 (t, J=5.5Hz, 2H), 3.48 (t, J=5.5Hz, 2H), 3.03 (d-t, J=6.1Hz, J=14.3,2H), 2.47 (d, br, J=14.9,2H), 2.4-2.2 (m, 4H), 2.0 to 1.5 (m, 25H and H 2O).
The preparation 36a of embodiment 364-(2-(4-carboxyl methoxyphenyl) acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone) .4-(2-(4-carbo methoxy group methoxyphenyl) acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy) cyclohexane extraction
Method according to embodiment 11,4-(3-cyclopenta oxygen-4-methoxyphenyl)-1,1-(ethylidene dioxy)-4-acetenyl cyclohexane extraction (0.075g, 0.21mmol) and 4-iodobenzene fluoroacetic acid methyl ester (0.060g, 0.21mmol, press the method preparation of embodiment 35a) with the mixture of anhydrous triethylamine (2ml) in stir following 80 ℃ with tetrakis triphenylphosphine palladium (0.018g, 0.016mmol), Hydro-Giene (Water Science). (0.004g, 0.021mmol) and the mixture reaction of triphenylphosphine (crystallization) 1.5 hours.Thick product chromatogram purification (silica gel, 40% to 50% ethyl acetate/hexane eluting), concentrating under reduced pressure gets the title intermediate, is kermesinus grease (0.080g, 73%).
1H-NMR (400MHz, CDCl 3) δ 7.98 (d, 9.4Hz, 2H), 7.50 (d, J=9.4Hz, 2H), 7.20 (d, J=1.9Hz, 1H), 7.12 (d-d, J=1.9Hz, J=8.6Hz, 1H), 6.84 (d, J=8.6,1H), 4.80 (p, J=3.8Hz, 1H), 4.00 (s, br, 4H), 3.92 (s, 3H), 3.85 (s, 3H), 2.3 to 1.5 (m, 17H and H 2O).32b) .4-(2-(4-carboxyl methoxyphenyl) acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
It is described to press embodiment 12,4-(2-(4-methoxycarbonyl group methoxyphenyl) acetenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-1, (0.232g 0.40mmol) handles with 3N hydrochloric acid (0.90ml) in stirring down with the solution of oxolane (9ml) 1-(ethylidene dioxy) cyclohexane extraction.Thick product chromatogram purification (silica gel, 50% ethyl acetate/hexane eluting), removal of solvent under reduced pressure gets title compound, is resin-like thing (0.127g, 59%).Elementary analysis (C 28H 30O 51/10H 2O), value of calculation: C, 75.01; H, 6.79; Measured value: C, 74.97; H, 6.87.
1H-NMR (400MHz, CDCl 3) δ 8.01 (d, J=8.5Hz, 2H), 7.53 (d, J=8.5Hz, 2H), 7.20 (d, J=2.4Hz, 1H), 7.11 (d-d, J=8.5Hz, J=2.4Hz, 1H), 6.87 (d, J=8.5,1H), 4.80 (p, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.04 (d-t, J=6.2Hz, J=14.4,2H), 2.50 (d, br, J=14.9,2H), 2.42-2.32 (m, 2H), 2.26 (d-t, J=2.8Hz, J=14.4Hz, 2H), 2.00-1.5 (m, 11H and H 2O).
The preparation of embodiment 374-(2-(4-methoxycarbonyl group methoxyphenyl) acetenyl)-4-(3-cyclopentyloxy-4-anisyl) hexamethylene-1-ketone
4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.075g; 0.24mmol) and 4-iodobenzene fluoroacetic acid methyl ester (0.070g; 0.24mmol; press embodiment 35a preparation) with the mixture and the tetrakis triphenylphosphine palladium (0.012g of anhydrous triethylamine (1.2ml); 0.010mmol), Hydro-Giene (Water Science). (0.0024g; 0.013mmol) and the mixture of triphenylphosphine (little crystallization) under argon shield, 75 ℃ of reactions 1 hour.The reactant mixture concentrating under reduced pressure, residue is handled with cold dilute hydrochloric acid, uses ethyl acetate extraction 2 times, and organic layer washes with water, saturated common salt washing, anhydrous sodium sulfate drying.Thick product chromatogram purification (silica gel is with 25% to 30% ethyl acetate/hexane eluting), concentrating under reduced pressure obtains the title intermediate, is penak shape thing (0.097g, 85%).Elementary analysis (C 29H 32O 6), value of calculation: C, 73.09; H, 6.77; Measured value: C, 72.91; H, 6.78.
1H-NMR (400MHz, CDCl 3) δ 7.41 (d, J=8.9Hz, 2H), 7.21 (d, J=2.2Hz, 1H), 7.11 (d-d, J=1.9Hz, J=8.4Hz, 1H), 6.87 (d, J=8.9,2H), 6.85 (d, J=8.4,1H), 4.80 (p, J=4.4Hz, 1H), 4.65 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.02 (d-t, J=6.2Hz, J=14.2,2H), 2.46 (d, br, J=14.8,2H), 2.4-1.5 (m, 16H and H 2O).
The preparation of embodiment 384-(2-methoxycarbonyl group phenylacetylene base)-4-(3-cyclopentyloxy-4-methoxyphenyl) hexamethylene-1-ketone
4-(4-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.150g; 0.48mmol) and 2-iodo-benzoic acid methyl ester (0.126g; 0.48mmol) and triethylamine (2.4ml; anhydrous) mixture stirring, argon shield and 80 ℃ down and tetrakis triphenylphosphine palladium (0) (0.024g; 0.021mmol), Hydro-Giene (Water Science). (0.0048g, 0.026mmol) and the mixture reaction of triphenylphosphine (crystallization) 7 hours.Reactant mixture concentrating under reduced pressure, residue are pressed embodiment 20 described processing, twice chromatogram purification (silica gel, 20% ethyl acetate/hexane; 2% ethyl acetate/dichloromethane eluting), ethyl acetate: the hexane crystallization, 60 ℃ of vacuum dryings get white powder (0.051g, 24%), mp88.5-90 ℃.Elementary analysis (C 28H 30O 5), value of calculation: C, 75.31; H, 6.77; Measured value: C, 75.11; H, 6.78.
The preparation of embodiment 394-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3,5-dimethoxycarbonyl phenyl) acetenyl) hexamethylene-1-ketone
4-(4-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.075g; 0.24mmol) and the different dimethyl phthalate of 5-iodine (Trans WorldChemicals; 0.107g; 0.33mmol) and triethylamine (1.9ml; anhydrous) mixture and tetrakis triphenylphosphine palladium (0.012g; 0.010mmol), Hydro-Giene (Water Science). (0.0025g, 0.013mmol) and the mixture of triphenylphosphine (little crystallization) in stirring, argon shield and 80 ℃ reaction 1 hour down.The reactant mixture concentrating under reduced pressure, residue chromatogram purification (silica gel, 1% to 2% ethyl acetate/dichloromethane eluting), 50 ℃ of vacuum dryings get chocolate brown powder (0.100g, 83%), mp133.5-135 ℃.Elementary analysis (C 30H 33O 7), value of calculation: C, 71.44; H, 6.93; Measured value: C, 71.19; H, 6.41.
The preparation of embodiment 404-(2-(4-chlorphenyl) acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
4-(4-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.075g; 0.24mmol) and 4-chloro-1-iodobenzene (0.057g; 0.24mmol) and triethylamine (1.7ml; anhydrous) mixture and tetrakis triphenylphosphine palladium (0.012g; 0.010mmol), the mixture of Hydro-Giene (Water Science). (0.0025g, 0.013 mmol) and triphenylphosphine (little crystallization) is in stirring, argon shield and 80 ℃ reaction 2 hours down.The reactant mixture concentrating under reduced pressure, residue is handled with dilute hydrochloric acid, uses ethyl acetate extraction 3 times, organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue gets white powder (0.051g, 50%), mp104-105 ℃ with chromatogram purification (silica gel, 3: 1 eluant solutions of the dichloromethane/hexane of 0.05% to 1% ethyl acetate), title compound in 25 ℃ of vacuum dryings.Elementary analysis (C 26H 27ClO 3), value of calculation: C, 73.83; H, 6.43; Measured value: C, 73.69; H, 6.41.
Embodiment 414-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(the preparation 41a of 2-(3-(5-methyl (1,2,4 〕 oxadiazole-3-yl) phenyl) acetenyl) hexamethylene-1-ketone) .3-(3-iodophenyl)-5-methyl-(1,2,4 〕 oxadiazoles
3-(3-iodophenyl)-5-methyl-(1,2,4 〕 oxadiazoles are pressed the literature method preparation, are white solid, mp90-91.5 ℃.41b) .4-(3-cyclopenta oxygen-4-anisyl)-4-(2-(3-(5-methyl-(1,2,4 〕 oxadiazole-3-yl) phenyl) acetenyl) hexamethylene-1-ketone
4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.200g; 0.64mmol) and 3-(3-iodophenyl)-5-methyl (1; 2; 4 〕 oxadiazole (0.201g; 0.70mmol) with the mixture and the tetrakis triphenylphosphine palladium (0.032g of anhydrous triethylamine (4.6ml); 0.028mmol), Hydro-Giene (Water Science). (0.0067g, 0.035mmol) and the mixture of triphenylphosphine (little crystallization) in stirring, argon shield and 75 ℃ reaction 1 hour 20 minutes down.The reactant mixture concentrating under reduced pressure, residue is handled with dilute hydrochloric acid, uses dichloromethane extraction 2 times, and organic layer washes with water, saturated common salt washing, anhydrous sodium sulfate drying.Thick product merges pure fraction, concentrating under reduced pressure with chromatogram purification (silica gel, 4: 1 solution of the dichloromethane/hexane of 3% to 6% ethyl acetate), the ether crystallization, 60 ℃ of vacuum dryings get title compound, be white solid (0.235g, 78%), mp122.5-123.5 ℃.Elementary analysis (C 29H 30N 2O 4), value of calculation: C, 74.02; H, 6.43; N, 5.95; Measured value: C, 73.94; H, 6.37; N, 5.96.
Embodiment 424-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(the preparation 42a of 2-(3-(3-methyl (1,2,4 〕 oxadiazole-5-yl) phenyl) acetenyl) hexamethylene-1-ketone) .5-(3-iodophenyl)-3-methyl-(1,2,4 〕 oxadiazoles
5-(3-iodophenyl)-3-methyl-(1,2,4 〕 oxadiazoles are pressed the literature method preparation, are white solid, mp102-103 ℃.42b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(3-methyl (1,2,4 〕 oxadiazole-5-yl) phenyl) acetenyl) hexamethylene-1-ketone
4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.200g, 0.64mmol) and 5-(3-iodophenyl)-3-methyl (1,2,4 〕 oxadiazole (0.201g, 0.70mmol) with the mixture and the tetrakis triphenylphosphine palladium (0.032g of anhydrous triethylamine (4.6ml), 0.028mmol), Hydro-Giene (Water Science). (0.0067g, 0.035mmol) and the mixture of triphenylphosphine (little crystallization) under agitation in 70 ℃ the reaction 1 hour, in 25 ℃ the reaction 15 hours.The reactant mixture concentrating under reduced pressure, residue dissolves in dichloromethane, handles anhydrous sodium sulfate drying with cold dilute hydrochloric acid.Thick product chromatogram purification (silica gel, the dichloromethane of 5% to 10% ethyl acetate: hexane: 1: 1 eluant solution), merge pure fraction, concentrating under reduced pressure is used the ether crystallization, in 60 ℃ of vacuum dryings, getting title compound is cream-coloured powder (0.235g, 78%), mp88-91 ℃.Elementary analysis (C 29H 30N 2O 4), value of calculation: C, 74.02; H, 6.43; N, 5.95; Measured value: C, 73.77; H, 6.53; N, 5.78.
The preparation of embodiment 434-(2-(3-cyano-phenyl) acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone
4-(4-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.100g, 0.32mmol) and 3-iodine benzyl cyanogen (0.088g, 0.38mmol) and triethylamine (2.5ml, anhydrous) mixture and four (triphenylphosphine) (0.016g, 0.013mmol), Hydro-Giene (Water Science). (0.033g, 0.017mmol) and the mixture of triphenylphosphine (little crystallization) in stirring down, 75 ℃ of reactions 1 hour 15 minutes, the ambient temperature reaction is 15 hours then.The reactant mixture concentrating under reduced pressure, residue dissolves in dichloromethane, washes washing, saturated common salt washing, anhydrous sodium sulfate drying successively with dilute hydrochloric acid.Thick product gets white solid (0.075g, 47%), mp123.5-125.5 ℃ with chromatogram purification (silica gel, 4: 1 solution of the dichloromethane/hexane of 3% ethyl acetate), title compound in 60 ℃ of vacuum dryings.Elementary analysis (C 27H 27NO 3), value of calculation: C, 78.42; H, 6.58; N, 3.39; Measured value: C, 78.13; H, 6.67; N, 3.40.
The preparation 44a of embodiment 444-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3,5-dicyano phenyl) acetenyl) hexamethylene-1-ketone). iodo 3,5-dicyanobenzenes
Iodo 3,5-dicyanobenzenes are pressed the literature method preparation, are white solid, mp145.5-146.5.44b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3,5-dicyano phenyl) acetenyl) hexamethylene-1-ketone
4-(4-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl cyclohexyl-1-ketone (0.15g; 0.48mmol) and iodo 3; 5-dicyanobenzenes (0.171g; 0.67mmol) and triethylamine (7.5ml; anhydrous) mixture and tetrakis triphenylphosphine palladium (0.024g, 0.021mmol), Hydro-Giene (Water Science). (0.005g, 0.026mmol) and the mixture of triphenylphosphine (little crystallization) stir and argon shield under; in 80 ℃ of reactions 0.5 hour, in 25 ℃ of reactions 15 hours.The reactant mixture concentrating under reduced pressure, residue dissolves in dichloromethane, washes washing, saturated common salt washing, anhydrous sodium sulfate drying successively with dilute hydrochloric acid.Residue chromatogram purification (silica gel, 9: 1 eluant solution of the dichloromethane/hexane of 2% to 3% ethyl acetate), vacuum drying gets white powder (0.177g, 84%), mp147.5-148.5 ℃.Elementary analysis (C 28H 26N 2O 3), value of calculation: C, 76.69; H, 5.98; N, 6.39; Measured value: C, 76.41; H, 5.92; N, 6.39.
The preparation of embodiment 454-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(4-hydroxy phenyl) acetenyl) hexamethylene-1-ketone
4-(4-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.090g; 0.29mmol) and 4-iodophenol (0.076g; 0.35mmol) and triethylamine (3ml; anhydrous) mixture and tetrakis triphenylphosphine palladium (0.013g; 0.012mmol), Hydro-Giene (Water Science). (0.003g, 0.016mmol) and the mixture of triphenylphosphine (little crystallization) stirring, argon shield and 75 ℃ of reactions 40 minutes.The reactant mixture concentrating under reduced pressure, residue is dissolved in dichloromethane, successively with dilute hydrochloric acid wash, the washing of washing, saturated common salt, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue chromatogram purification (silica gel, the dichloromethane/hexane of 4% to 7% ethyl acetate is dissolved in eluting at 4: 1), the title compound recrystallizing methanol gets white powder (0.035g, 30%), mp144-146 ℃.Elementary analysis (C 26H 28O 41/5H 2O), value of calculation: C, 76.52; H, 7.01; Measured value: C, 76.57; H, 6.97.
1H-NMR(400MHz，CDCl 3)δ7.36(d，8.5Hz，2H)，7.23(d，J＝2.2
Hz，1H)，7.12(d-d，J＝2.2Hz，J＝8.5Hz，1H)，6.86(d，J＝8.5，1H)，6.80(d，J＝8.5，2H)，
5.22(s，1H)，4.80(p，J＝3.8Hz，1H)，3.85(s，3H)，3.04(d-t，J＝6.0Hz，J＝14.2，2H)，
2.47 (d, br, J=14.8,2H), 2.4-2.1 (m, 4H), 2.0 to 1.5 (m, 12H and H 2O).
The preparation 46a of embodiment 464-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-methyl (1,3,4) thiadiazoles-2-yl) phenyl) acetenyl) hexamethylene-1-ketone) .2-(3-iodophenyl)-5-methyl (1,3,4) thiadiazoles
2-(3-iodophenyl)-5-methyl (1,3,4) thiadiazoles is pressed the literature method preparation.46b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-methyl-(1,3,4) thiadiazoles-2-yl) phenyl) acetenyl) hexamethylene-1-ketone
4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.100g, 0.32mmol) and 2-(3-iodophenyl)-5-methyl (1,3,4) thiadiazoles (0.097g, 0.32mmol) with the mixture and the tetrakis triphenylphosphine palladium (0.016g of anhydrous triethylamine (2.5ml), 0.013mmol), Hydro-Giene (Water Science). (0.0033g, 0.017mmol) and the mixture of triphenylphosphine (little crystallization) in 70 ℃ the reaction 1 hour, in 25 ℃ the reaction 15 hours.The reactant mixture concentrating under reduced pressure, residue distributes between dichloromethane and dilute hydrochloric acid.Organic layer merges pure fraction with chromatogram purification (silica gel, 10% to 20% ethyl acetate/dichloromethane eluting), concentrating under reduced pressure, and in 50 ℃ of vacuum dryings, frangible resin-like thing is ground into yellow powder sample title compound (0.128g, 79%).Elementary analysis (C 29H 30N 2O 3SH 2O), value of calculation: C, 69.02; H, 6.39; N, 5.55; Measured value: C, 68.91; H, 6.21; N, 5.35.
1H-NMR (400MHz, CDCl 3) δ 8.06 (t, J=1.6Hz, 1H), 7.88 (d-t, J=1.4Hz, J=8.1Hz, 1H), 7.58 (d-d, J=1.2Hz, J=9.0Hz, 1H), 7.45 (t, J=7.8Hz), 7.21 (d, J=2.2,1H), 7.14 (d-d, J=8.4Hz, J=2.1Hz, 1H), 6.88 (d, J=8.5,1H), 4.82 (p, J=4.1Hz, 1H), 3.86 (s, 3H), 3.04 (dt, J=6.1Hz, J=14.2,2H), 2.84 (s, 3H), 2.50 (d, br, J=14.9,2H), 2.42-2.32 (m, 2H), 2.27 (d-t, J=2.8Hz, J=14.2Hz, 2H), 2.00-1.5 (m, 12H and H 2O).
Embodiment 474-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(the preparation 47a of 2-(3-(5-methyl (1,3,4 〕 oxadiazole-2-yl) phenyl) acetenyl) hexamethylene-1-ketone) .2-(3-iodophenyl)-5-methyl (1,3,4 〕 oxadiazoles
(1,3,4 〕 oxadiazoles are pressed the literature method preparation to 2-(3-iodophenyl)-5-methyl, are white solid, mp112.5-113.5 ℃.47b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-methyl (1,3,4 〕 oxadiazole-2-yl) phenyl) acetenyl) hexamethylene-1-ketone
4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-acetenyl hexamethylene-1-ketone (0.100g, 0.32mmol) and 5-(3-iodophenyl)-2-methyl (1,3,4 〕 oxadiazole (0.0915g, 0.32mmol) with the mixture and the tetrakis triphenylphosphine palladium (0.016g of anhydrous triethylamine (3.5ml), 0.013mmol), Hydro-Giene (Water Science). (0.0033g, 0.017mmol) and the mixture of triphenylphosphine (little crystallization) stir down in 75 ℃ of reactions 1 hour.Reactant mixture concentrating under reduced pressure, residue come together in the dichloromethane, and organic layer is washed with cold dilute hydrochloric acid, washing, saturated common salt washing, anhydrous sodium sulfate drying.Chromatogram purification (silica gel, 10% to 20% ethyl acetate/dichloromethane eluting), 50 ℃ of vacuum dryings, getting title compound is white powder (0.068g, 45%).mp139-141℃。Elementary analysis (C 29H 30N 2O 41/3H 2O), value of calculation: C, 73.09; H, 6.49; N, 5.88; Measured value: C, 73.07; H, 6.35; N, 5.79.
1H-NMR (400MHz, CDCl 3) δ 8.15 (t, J=1.6Hz, 1H), 8.01 (d-t, J=1.4Hz, J=7.9Hz, 1H), 7.62 (d-d, J=1.5Hz, J=7.8Hz, 1H), 7.49 (t, J=7.9Hz), 7.21 (d, J=2.3,1H), 7.14 (d-d, J=8.5Hz, J=2.4Hz, 1H), 6.88 (d, J=8.5,1H), 4.82 (p, J=4.2Hz, 1H), 3.86 (s, 3H), 3.04 (d-t, J=6.1Hz, J=14.2,2H), 2.64 (s, 3H), 2.51 (d, br, J=15.0,2H), 2.42-2.32 (m, 2H), 2.27 (d-t, J=2.8Hz, J=14.2Hz, 2H), 2.00-1.5 (m, 9H and H 2O).
The preparation 48a of embodiment 484-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2 (E)-(3-cyano-phenyl) acetenyl) hexamethylene-1-ketone) .3-cyano group benzylphosphonic acid diethylester
Triethyl phosphate (0.500g, 2.95mmol) and the 3-cyano-benzyl bromide (0.609g, mixture 2.95mmol) under argon shield in 140 ℃ of stirring and refluxing 2 hours; the volatile component of generation is removed in decompression under the room temperature; obtain the title intermediate, be colorless oil (0.62g, 84%).
1H-NMR (400MHz, CDCl 3) δ 7.7-7.5 (m, 3H), 7.44 (t, J=7.8Hz, 1H), 4.06 (p, J=7.6Hz, 4H), 3.17 (d J=21.8Hz, 2H), 1.27 (t, J=7.1Hz, 6H), 48b) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2 (E)-(3-cyano-phenyl) acetenyl)-1,1 (ethylidene dioxy) cyclohexane extraction
3-cyano group benzylphosphonic acid diethylester (0.54g, 2.13mmol) with the solution of anhydrous tetrahydro furan (7ml) via conduit be added to potassium tert-butoxide (0.237g, 2.11mmol) with the solution of anhydrous tetrahydro furan (15ml) in, two solution are chilled to 0 ℃ under argon shield.Stir after 45 minutes, drip 4-(3-cyclopenta oxygen-4-methoxyphenyl)-1 inward, (0.38g is 1.06mmol) with the solution of anhydrous tetrahydro furan (5ml) for 1-(ethylidene dioxy)-4-formoxyl cyclohexane extraction.Reactant mixture is warming up to room temperature.The afterreaction mixture quenched with aqueous ammonium chloride solution in 15 hours, concentrating under reduced pressure, between dichloromethane and aqueous ammonium chloride solution, distribute, organic extract liquid washes with water, the saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, the mixture of title product that obtains expecting and excess of phosphines acid esters is fat tree smectic thing.
1H-NMR (400MHz, CDCl 3) δ 7.62-7.4 (and m, 4H), 7.36 (t, J=7.8Hz, 1H), 6.90 (s and
d，2H)，6.83(d，J＝8.7Hz，1H)，6.30(d，J＝16.4Hz，1H)，6.16(d，J＝16.3Hz，1H)，
4.75(p，J＝4.4Hz，1H)，4.06(p，J＝7.6Hz，1H)，3.96(q，J＝3.3Hz，4H)，3.84(s，3H)，
3.17 (d J=21.8Hz, 0.3H), 2.35-1.5 (m, 20H and H 2O), 1.27 (t, J=7.1Hz, 1.3H).48c) .4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2 (E)-(3-cyano-phenyl) acetenyl) hexamethylene-1-ketone
4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2 (E)-(3-cyano-phenyl) acetenyl)-1; (0.58g, 1.06mmol) solution and the 3N hydrochloric acid (2.3ml) with oxolane (20ml) reacted 1 hour in 75-80 ℃ under argon shield 1-(ethylidene dioxy) cyclohexane extraction crude product.Add hydrochloric acid (13ml) again, mixture was in 75 ℃ of reheat 15 minutes.The reactant mixture concentrating under reduced pressure is used dichloromethane extraction, and organic extract liquid washes with water, dilute aqueous solution of sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying.Chromatogram purification (silica gel, 1% to 2% ethyl acetate/dichloromethane eluting) is used the ether crystallization, gets title compound, is white solid (0.329g, 74%).mp116-117℃。Elementary analysis (C 27H 29NO 31/6H 2O), value of calculation: C, 77.48; H, 7.06; N, 3.35; Measured value: C, 77.63; H, 6.94; N, 3.33.
1H-NMR(400MHz，CDCl 3)δ7.60(s，1H)，7.55-7.45(m，2H)，7.39(t，J＝7.7Hz，1H)，6.97(d-d，J＝2.4Hz，J＝8.5Hz，1H)，6.89(d，J＝8.4Hz，1H)，6.37(d，J＝16.1Hz，1H)，6.22(d，J＝16.2Hz，1H)，4.77(p，J＝4.5Hz，1H)，3.86(s，3H)，2.6-1.5(m，18H?with?H 2O)。
Embodiment 494-(2-acetamido pyrimidine-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, the preparation of SB240712
Toward pyridinium chlorochromate (0.288g; 1.34mmol) with the suspension of anhydrous methylene chloride (4ml) in stir and argon shield under; add cis-(4-(2-acetamido pyrimidine-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone) (0.20g through conduit; 0.445mmol; by unsettled U.S. Patent application P50287 (submitting on the same day) preparation, with 5ml dichloromethane wiring solution-forming).After 2 hours, add ethyl acetate (about 10ml) in 25 ℃ of reactions, filter, precipitation reuse 10ml ethyl acetate is washed.Filtrate concentrates, residue sudden strain of a muscle formula silica gel chromatography purification, earlier with 1: 9 ethyl acetate: the dichloromethane eluting, 20: 80 to 30: 70 ethyl acetate of reuse: dichloromethane eluted product, obtain 4-(2-acetamido pyrimidine-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, be white solid (0.033g, 5.5%), mp170-171 ℃.
1H-NMR (400MHz, CDCl 3) δ 8.65 (s, 2H), 8.47 (s, 1H), 7.14 (d, J=2.1Hz, 1H), 7.09 (dd, J=8.4,2.3Hz, 1H), 6.87 (d, J=8.5Hz, 1H), 4.80 (p, J=4.7,1H), 3.86 (s, 3H), 2.94 (dt, J=23,8.8Hz, 2H), 2.50 (s is superimposed upon 2.6-2.2m on the water peak, and 9H), (m is superimposed upon ppm on the water peak to 2.0-1.5.
Embodiment 50
Method according to aforementioned one or more embodiment can prepare following chemical compound: 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-trifluoromethyl (1,2,4 〕 oxadiazole-3-yl) hexamethylene-1-ketone acetenyl phenyl)), 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(3-trifluoromethyl (1,2,4 〕 oxadiazole-5-yl) hexamethylene-1-ketone acetenyl phenyl)), 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-trifluoromethyl (1,3,4 〕 oxadiazole-2-yl) hexamethylene-1-ketone acetenyl phenyl)), 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-trifluoromethyl (1,3,4) hexamethylene-1-ketone acetenyl phenyl thiadiazoles-2-yl))), and 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(2-acetamido pyrimidine-5-yl) acetenyl) hexamethylene-1-ketone.Application Example
Embodiment A general formula (I) and chemical compound (II) are in external inhibitory action to producing by human monocyte TNF
General formula (I) and chemical compound (II) are consulted following document: Badger et al., the application number 0411754A2 that EPO (EUROPEAN PATENT OFFICE) announces, on February 6th, 1991 at external assay method to the inhibition effect that produces by human monocyte TNF; And Hanna, WO90/15534, nineteen ninety December 27 days.
Embodiment B
Two models of endotoxin shock have been used for measuring the activity that general formula (I) and chemical compound (II) suppress TNF in vivo.Assay method sees also: Badger et al., the open 0411754A2 of European patent, on February 6th, 1991; And Hanna, WO90/15534, nineteen ninety December 27 days.
In vivo test shows that embodiment 1 chemical compound has reduced because the injection content of TNF in serum that endotaxin induction produced.
Embodiment C
The separation of PDE isozyme
The PDE isozyme that utilizes one group of 5 character to have nothing in common with each other can be measured the phosphodiesterase depressing activity and the selectivity of general formula (I) and chemical compound (II).As follows as organizing of different isozymes source: 1) PDE Ib is from the aorta of pig; 2) PDE Ic is from guinea pig heart; 3) PEY III is also from guinea pig heart; 4) PDE IV is from people's mononuclear cell; 5) PDE V (also claiming " Ia ") is from the tracheal muscle of dog.PDEs Ia, Ib, Ic and III utilize the reference colour spectrometry to carry out partial purification.[consulting: Torphy and Cieslinski, Mol.Pharmacol., 37:206-214,1990] PDE IV then is purified to dynamic homogeneity with heparin-sephadex chromatography by anion exchange.[consulting: Torphy et al., J.Biol.Chem., 267:1798-1804,1992].
With document (Torphy and Cieslinski, Mol.Pharmacol; 37:206-214,1990) method introduced of lining is checked the activity of 3 phosphodiesterases.Half effective inhibition concentration (IC of general formula of introducing in each example of front (I) and chemical compound (II) 50) be that nanomole (nanomolar) is in micromole (μ M) scope.

Claims (10)

1, the compound or pharmaceutically acceptable salt thereof class of general formula (I):
Figure A9519768100021
Wherein:
R 1Be-(CR 4R 5) nC (O) O (CR 4R 5) mR 6,-(CR 4R 5) nC (O) NR 4(CR 4R 5) mR 6,-(CR 4R 5) nO (CR 4R 5) mR 6, or-(CR 4R 5) rR 6, wherein moieties may be not to be substituted, and also can be replaced to several fluorine by 1;
M is 0 to 2
N is 0 to 4
R is 0 to 6
R 4And R 5Independently be hydrogen or C 1-2Alkyl;
R 6Be hydrogen, methyl, hydroxyl, aryl, halogenated aryl, aryloxy group C 1-3Alkyl, halo aryloxy group C 1-3Alkyl, 2, the 3-dihydro is for indenyl, indenyl, C 7-11Poly-cycloalkyl, tetrahydrofuran base, furyl, THP trtrahydropyranyl, pyranose, tetrahydro-thienyl, thienyl, tetrahydro thiapyran base, thiapyran base, C 3-6Cycloalkyl, or the C of 1 or 2 unsaturated bond is arranged 4-6Cyclic hydrocarbon radical, cycloalkyl wherein or heterocyclic moiety can be unsubstituted, also can be replaced by 1-3 methyl, 1 ethyl or a hydroxyl;
Condition is:
A) work as R 6When being hydroxyl, m is 2; Or
B) work as R 6When being hydroxyl, r is 2 to 6; Or
C) work as R 6When being 2-THP trtrahydropyranyl, 2-tetrahydro thiapyran base, 2-tetrahydrofuran base or 2-tetrahydro-thienyl, m is 1 or 2; Or
D) work as R 6Be the 2-THP trtrahydropyranyl, the 2-tetrahydro thiapyran base, when 2-tetrahydrofuran base or 2-tetrahydro-thienyl, r is 1 to 6;
E) when n be 1, m is 0 o'clock ,-(CR 4R 5) nO (CR 4R 5) mR 6In R 6Not H;
X is YR 2, F, NR 4R 5Or Methanamide;
Y is O or S (O) m';
M ' is 0,1 or 2;
X 2Be O or NR 8
X 3Be hydrogen or X;
R 2Be not to be substituted or to be replaced-CH by 1 or several fluorine 3Or-CH 2CH 3,
S is 0 to 4
R 3Be COOR 14, C (O) NR 4R 14Or R 7
W is the alkyl of 2 to 6 carbon atoms, the alkenyl of 2 to 6 carbon atoms, or the alkynyl of 2 to 6 carbon atoms;
Z is O, NR 7, NCR 4R 5C 2-6Alkenyl, NOR 14, NOR 15, NOCR 4R 5C 2-6Alkenyl, NNR 4R 14, NNR 4R 15, NCN, NNR 8C (O) NR 8R 14, NNR 8C (S) NR 8R 14, or=Z is 2-(1, the 3-dithiane), 2-(1, the 3-dithiolane), dimethyl ketone mercaptol, metacetone mercaptol, 2-(1, the 3-dioxolanes), 2-(1, the 3-diox), 2-(1,3-Evil thiophene penta ring), dimethyl ketal or diethyl ketal;
R 7Be-(CR 4R 5) qR 12Or C 1-6Alkyl, wherein R 12Or C 1-6Alkyl is unsubstituted, is perhaps replaced one or many by methyl or ethyl, and methyl here or ethyl be unsubstituted or replaced by 1-3 fluorine, or by following substituent group replacement one or many:
-F，-Br，-Cl，-NO 2，-NR 10R 11，-C(O)R 8，-CO 2R 8，
-O(CH 2) 2-4OR 8，-O(CH 2) qR 8，-CN，-C(O)NR 10R 11，-O(CH 2) qC(O)NR 10R 11，-
O(CH 2) qC(O)R 9，-NR 10C(O)NR 10R 11，-NR 10C(O)R 11，-NR 10C(O)OR 9，
-NR 10C(O)R 13，-C(NR 10)NR 10R 11，-C(NCN)NR 10R 11，-C(NCN)SR 9，
-NR 10C(NCN)SR 9，-NR 10C(NCN)NR 10R 11，-NR 10S(O) 2R 9，-S(O) m’R 9，
-NR 10C (O) C (O) NR 10R 11,-NR 10C (O) C (O) R 10, or R 13
Q is 0,1 or 2;
R 12Be R 13, (CH 2) q, C 3-7Cycloalkyl, (2-, 3-or 4-pyridine radicals), pyrimidine radicals, pyrazolyl, (1-or 2-imidazole radicals), pyrrole radicals, piperazinyl, piperidyl, morpholinyl, furyl, (2-or 3-thienyl), quinolyl, naphthyl or phenyl;
R 8Be hydrogen or R 9
R 9Be the C that is not substituted or is replaced by 1 to 3 fluorine 1-4Alkyl;
R 10Be OR 8Or R 11
R 11Be hydrogen or the C that is not substituted or replaced by 1 to 3 fluorine 1-4Alkyl; Perhaps work as R 10And R 11Form NR 10R 11, they can form 5-7 person ring jointly with N, only carbon atoms or carbon containing and at least one hetero atom O, N or S in the ring;
R 13Shi oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazole radical, imidazole radicals, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazole base or thiadiazolyl group; These rings connect by the C atom, and each ring can not be substituted or by 1 to 2 C 1-2Alkyl replaces, this C 1-2Alkyl can be unsubstituted, or has 1 to 3 to replace fluorine atom on methyl;
R 14Be hydrogen or R 7Perhaps work as R 8And R 14Form NR 8R 14The time, they can form 5-7 person ring jointly with nitrogen, only carbon atoms or carbon containing and at least 1 other hetero atom O, N or S on the ring;
Condition is:
(f) R 7Not C unsubstituted or that replaced by 1 to 3 F 1-4Alkyl.
2, according to the chemical compound of claim 1, R wherein 1Be-CH 2-cyclopropyl, cyclopenta ,-3-hydroxyl cyclopenta, methyl or-CF 2H; X is YR 2Y is an oxygen; X 2Be oxygen; X 3Be H; R 2Be CF 2H or methyl; W is acetenyl or 1,3-diacetylene base; R 3Be pyrimidine-ring unsubstituted or that replace, X is YR 2, Z is O, NR 7
3, the chemical compound of claim 2; be 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-methanesulfonyl pyrimidine-4-ethyl-acetylene base) hexamethylene-1-ketone 4-(2-aminopyrimidine-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, or 4-(2-acetamido pyrimidine-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone.
4, the chemical compound of claim 1, wherein R 1For-CH 2-cyclopropyl ,-cyclopenta ,-3-hydroxycyclopent base, methyl or CF 2H; X is YR 2Y is an oxygen; X 2Be oxygen; X 3Be hydrogen; R 2Be CF 2H or methyl, W are acetenyl or 1,3-diacetylene base; R 3R 3Be R 7, R wherein 7Be not replacement or substituted aryl or heterocycle, X is YR 2, Z is 0.
5, the chemical compound of claim 5, be 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-aminophenyl acetenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-acetamido phenylacetylene base) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-acetamido phenylacetylene base) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-methoxycarbonyl group phenylacetylene base) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-carboxyl phenyl acetenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-aminophenyl acetenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-pyridine radicals acetenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-{[4-(2-hydroxyl ethane-1-oxygen) phenyl] acetenyl } hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(3-pyridine radicals acetenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(4-(2-hydroxyl ethane-1-oxygen) phenyl) acetenyl) hexamethylene-1-ketone, 4-(4-methoxycarbonyl group phenylacetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(4-carboxyl phenyl acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(4-(1-piperidino carbonyl methoxyl group) phenyl)) acetenyl) hexamethylene-1-ketone, 4-(2-(4-carboxyl methoxyphenyl) acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(2-(4-methoxycarbonyl group methoxyphenyl) acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(2-methoxycarbonyl group phenylacetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, (3-cyclopenta oxygen-4-methoxyphenyl)-(2-(3 for 4-for 4-, 5-dimethoxycarbonyl phenyl) hexamethylene-1-ketone acetenyl), 4-(2-(4-chlorphenyl) acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(2-methoxycarbonyl group thiophene-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(2-(3-cyano-phenyl) acetenyl)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(4-hydroxy phenyl) acetenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2 (E)-(3-cyano-phenyl) acetenyl) hexamethylene-1-ketone, (3-cyclopenta oxygen-4-methoxyphenyl)-(2-(3 for 4-for 4-, 5-dicyano phenyl) hexamethylene-1-ketone acetenyl), 4-(2-carboxy thiophene-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, sodium salt, 4-(2-cyano thiophene-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(5-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) hexamethylene-1-ketone thiophene-2-ethyl-acetylene base), 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-methyl-(1,2,4 〕 oxadiazole-3-yl) hexamethylene-1-ketone acetenyl phenyl)), 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(3-methyl-(1,2,4 〕 oxadiazole-5-yl) hexamethylene-1-ketone acetenyl phenyl)), 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(4-(5-methyl-(1,2,4 〕 oxadiazole-2-yl) hexamethylene-1-ketone thiophene-2-ethyl-acetylene base), 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-methyl-(1,3,4 〕 oxadiazole-2-yl) hexamethylene-1-ketone acetenyl phenyl)), 4-(2-methoxycarbonyl group thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, SB 4-(2-carboxy thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, S; 4-(2-cyano thiophene-4-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(3-methyl (1,2,4 〕 oxadiazole-5-yl) hexamethylene-1-ketone acetenyl phenyl)), SB, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(5-methyl (1,2,4 〕 oxadiazole-2-yl) hexamethylene-1-ketone thiophene-4-ethyl-acetylene base), 4-(4-methoxycarbonyl group thiophene-2-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(4-carboxy thiophene-2-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-methyl (1,3,4) hexamethylene-1-ketone acetenyl phenyl thiadiazoles-2-yl))), 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(1-Methylimidazole .-2-ethyl-acetylene base) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(imidazoles-2-ethyl-acetylene base) hexamethylene-1-ketone, hydrochlorate, 4-(2-acetamido pyrimidine-5-ethyl-acetylene base)-4-(3-cyclopenta oxygen-4-methoxyphenyl) hexamethylene-1-ketone, 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-methyl (1,3,4 〕 oxadiazole-2-yl) hexamethylene-1-ketone acetenyl phenyl)), or 4-(3-cyclopenta oxygen-4-methoxyphenyl)-4-(2-(3-(5-methyl (1,3,4) hexamethylene-1-ketone acetenyl phenyl thiadiazoles-2-yl))).
6, the compound or pharmaceutically acceptable salt thereof class of general formula (II),
Wherein:
R 1Be-(CR 4R 5) nC (O) O (CR 4R 5) mR 6,-(CR 4R 5) nC (O) NR 4(CR 4R 5) mR 6,-(CR 4R 5) nO (CR 4R 5) mR 6, perhaps-(CR 4R 5) rR 6Wherein alkyl can be unsubstituted, or replaced by 1 to 3 fluorine;
M is 0 to 2;
N is 0 to 4;
R is 0 to 6;
R 4And R 5Independently be hydrogen or C 1-2Alkyl;
R 6Be hydrogen, methyl, hydroxyl, aryl, halogenated aryl, aryloxy group C 1-3Alkyl, halo aryloxy group C 1-3Alkyl, 2, the 3-dihydro is for indenyl, indenyl, C 7-11Multi-ring alkyl, tetrahydrofuran base, furyl, THP trtrahydropyranyl, pyranose, tetrahydro-thienyl, thienyl, tetrahydro thiapyran base, thiapyran base, C 3-6Cycloalkyl perhaps contains the C of 1-2 unsaturated bond 4-6Cyclic hydrocarbon radical, wherein cycloalkyl or heterocyclic moiety be unsubstituted or by 1 to 3 methyl ,-individual ethyl or hydroxyl replace;
Condition is:
A) work as R 6When being hydroxyl, m is 2; Or
B) work as R 6When being hydroxyl, r is 2 to 6; Or
C) work as R 6When being 2-THP trtrahydropyranyl, 2-tetrahydro thiapyran base, 2-tetrahydrofuran base or 2-tetrahydro-thienyl, m is 1 or 2; Perhaps
D) work as R 6Be the 2-THP trtrahydropyranyl, the 2-tetrahydro thiapyran base, when 2-tetrahydrofuran base or 2-tetrahydro-thienyl, r is 1 to 6;
E) when n be 1, m is 0 o'clock ,-(CR 4R 5) nO (CR 4R 5) mR 6In R 6Not hydrogen;
X is YR 2, F, NR 4R 5Or Methanamide;
Y is O or S (O) m';
M ' is 0,1 or 2;
X 2Be O or NR 8
X 3Be H or X;
R 2Independently be selected from unsubstituted or by 1 or several F replace-CH 3Or-CH 2CH 3,
S is 0 to 4;
R 3Be COOR 14, C (O) NR 4R 14Or R 7
W is the alkyl of 2 to 6 C atoms, the alkynyl of the alkenyl of 2 to 6 atoms or 2 to 6 C atoms;
Z ' is
C(Y’)R 14，C(O)OR 14，C(Y’)NR 10R 14，C(NR 10)NR 10R 14，CN，
C(NOR 8)R 14，C(O)NR 8NR 8C(O)R 8，C(O)NR 8NR 10R 14，C(NOR 14)R 8，
C (NR 8) NR 10R 14, C (NR 14) NR 8R 8C (NCN) NR 10R 14, C (NCN) SR 9, (2-, 4-or 5-imidazole radicals), (3-, 4-or 5-pyrazolyl), (4-or 5-triazolyl [1,2,3]), (3-or 5-triazolyl [1,2,4]), (5-tetrazole radical), (2-, 4-or 5-oxazolyl), (3-, 4-or 5-isoxazolyl), (3-or 5-oxadiazole base [1,2,4]), (2-oxadiazole base [1,3,4]), (2-thiadiazolyl group [1,3,4]), (2-, 4-or 5-thiazolyl), (2-, 4-or 5-oxazolidinyl), (2-, 4-or 5-thiazolidinyl) or (2-, 4-or 5-imidazolidinyl); Wherein all heterocyclic ring systems can be by R 14Replace 1 position or several position;
Y ' is O or S;
R 7Be-(CR 4R 5) qR 12Or C 1-6Alkyl, wherein R 12Be or C 1-6Alkyl is unsubstituted or replaced one or many by methyl or ethyl, and methyl here or ethyl are unsubstituted or are replaced by 1 to 3 F, or replaced one or many by following radicals:
-F，-Br，-Cl，-NO 2，-NR 10R 11，-C(O)R 8，-CO 2R 8，
-O(CH 2) 2- 4OR 8，-O(CH 2) qR 8，-CN，-C(O)NR 10R 11，-O(CH 2) qC(O)NR 10R 11，
-O(CH 2) qC(O)R 9，-NR 10C(O)NR 10R 11，-NR 10C(O)R 11，-NR 10C(O)OR 9，
-NR 10C(O)R 13，-C(NR 10)NR 10R 11，-C(NCN)NR 10R 11，-C(NCN)SR 9，
-NR 10C(NCN)SR 9，-NR 10C(NCN)NR 10R 11，-NR 10S(O) 2R 9，-S(O) m′R 9，
-NR 10C (O) C (O) NR 10R 11,-NR 10C (O) C (O) R 10, or R 13
Q is 0,1 or 2;
R 12Be R 13, (CH 2) q, C 3-7Cycloalkyl, (2-, 3-or 4-pyridine radicals), pyrimidine radicals, pyrazolyl, (1-or 2-imidazole radicals), pyrrole radicals, piperazinyl, piperidyl, morpholinyl, furyl, (2-or 3-thienyl), quinolyl, naphthyl or phenyl;
R 8Independently be selected from H and R 9
R 9Be the C that does not replace or replaced by 1 to 3 F 1-4Alkyl;
R 10Be OR 8Or R 11
R 11Be H or the C that does not replace or replaced by 1 to 3 F 1-4Alkyl; Perhaps work as R 10And R 11Form NR 10R 11The time, they can form 5-7 person ring with N, only carbon atoms or carbon atoms and at least one other hetero atom O, N or S on the ring;
R 13Be replace or unsubstituted following hetero-aromatic ring group: oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazole radical, imidazole radicals, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazole base and thiadiazolyl group; Work as R 13At R 12Or R 13During last replacement, these rings are connected by the C atom, each second R 13Ring can be unsubstituted or by 1 to 2 C 1-2Alkyl replaces, this C 1-2Alkyl is unsubstituted or is replaced on methyl by 1-3 F atom;
R 14Be H or R 7Perhaps work as R 8With R 14Form NR 8R 14The time, they can form 5-7 person ring with the N atom together, only carbon atoms or carbon atoms and at least one other hetero atom O, N or S on the ring;
Condition is:
(f) R 7Not the C that does not replace or replaced by 1 to 3 F 1-4Alkyl.
7, according to the chemical compound of claim 6, R wherein 1Be-CH 2-cyclopropyl, cyclopenta ,-3-hydroxyl cyclopenta, methyl or CF 2H; X is YR 2Y is an oxygen; X 2Be oxygen; X 3Be hydrogen; R 2Be CF 2H or methyl; W is acetenyl or 1,3-diacetylene base; R 3R 3Be R 7, R wherein 7Be replace or unsubstituted aryl or hetero-aromatic ring base, X are YR 2, Z is that O, Z ' are COOR 14
8, the chemical compound of claim 7, wherein W is 1,3-diacetylene base, R 3For not replacing or substituted pyrimidines-5-base.
9, the Pharmaceutical composition that contains arbitrary chemical compound and pharmaceutical excipient in the claim 1 to 5.
10, antasthmatic method, this method comprise the mammal to needs treatments, comprise the people, take arbitrary chemical compound in the claim 1 to 5 of effective dose.
CN95197681A 1994-12-23 1995-12-21 4, 4 -(disubstituted) cyclohexan-one monomers and related compounds Pending CN1175211A (en)

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US45579695A 1995-05-31 1995-05-31
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CZ2002460A3 (en) * 1999-08-10 2002-06-12 Smithkline Beecham Corporation 1,4-Substituted 4,4-diaryl cyclohexanes
EP3209655B1 (en) * 2014-10-24 2020-07-15 Landos Biopharma, Inc. Lanthionine synthetase c-like 2-based therapeutics

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