CN1882537A - Substituted indole acid derivatives and their use as PAI-1 inhibitors - Google Patents

Substituted indole acid derivatives and their use as PAI-1 inhibitors Download PDF

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CN1882537A
CN1882537A CNA2004800344530A CN200480034453A CN1882537A CN 1882537 A CN1882537 A CN 1882537A CN A2004800344530 A CNA2004800344530 A CN A2004800344530A CN 200480034453 A CN200480034453 A CN 200480034453A CN 1882537 A CN1882537 A CN 1882537A
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aryl
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B·胡
J·W·杰特
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Wyeth LLC
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The present invention relates to substituted indoles of formula I and their use as PAI-1 inhibitors.

Description

The indole acid derivatives that replaces and as the application of PAI-1 inhibitor
The cross reference of related application
The application require the U. S. application number of on September 23rd, 2004 application _ _ right of priority, this application requires the right of priority of the U.S. Provisional Application 60/505,820 of application on September 25th, 2003 again, whole disclosures of above-mentioned application are attached to herein by reference.
Background of invention
Indoles that the present invention relates generally to replace and using method thereof.
Serpin PAI-1 is one of main inhibitor of fibrinolytic system.Fibrinolytic system comprises profibr(in)olysin, and this proenzyme is converted into organized enzyme, i.e. Tryptase by one of two kinds of tissue type plasminogen activator t-PA and u-PA.PAI-1 is the major physiological inhibitor of t-PA and u-PA.One of main effect of Tryptase is at vascular injury site digestion scleroproein in the fibrinolytic system.Yet not only responsible the removing from circulation of fibrinolytic system defibrinated, and participates in multiple other biological procedures, comprises that ovulation, embryo's generation, intimal hyperplasia, vasculogenesis, tumour take place and atherosclerosis.
High density PAI-1 is relevant with multiple disease and illness, comprises disease and the illness relevant with the fibrinolytic system obstacle.For example, the PAI-1 of high density relates to thrombotic diseases, for example is characterized as the blood flow of thrombosis, blocking local blood vessel or comes off into the disease of embolus clog downstream blood flow (thromboembolism).(Krishnamurti，Blood，69，798(1987)；Reilly，Arteriosclerosis and Thrombosis，11，1276(1991)；Carmeliet，Journalof Clinical Investigation，92，2756(1993)，Rocha，Fibrinolysis，8，294，1994；Aznar，Haemostasis 24，243(1994))。The active antibody neutralizing effect of PAI-1 promotes endogenous thrombolysis and pours into (Biemond, Circulation, 91,1175 (1995) again; Levi, Circulation 85,305, (1992)).In following disease for example, also relate to high density PAI-1: polycystic ovarian syndrome (Nordt, Journal of clinicalEndocrinology and Metabolism, 85,4,1563 (2000)), bone loss (the Daci that estrogen deficiency brings out, Journal of Bone and Mineral Research, 15,8,1510 (2000)), cystic fibrosis, diabetes, chronic periodontitis, lymphoma, the extracellular matrix accumulation is diseases related, neovascularization dependency malignant tumour and disease, inflammatory diseases, the blood vessel injury of concomitant infections and the disease (for example mammary cancer and ovarian cancer) of following uPA concentration to increase.
Consider above reason, having needs to identify the PAI-1 activity inhibitor, thereby and needs to utilize the inhibitor of being identified to regulate expression or the diseases related method of active treatment high density PAI-1 of patient PAI-1.
Summary of the invention
The invention provides the indoles and the using method thereof of replacement.In certain embodiments, provide the 1-aralkyl or the 1-aryl-1H-indoles of replacement, comprise following formula: compound:
Figure A20048003445300081
Formula 1
Wherein:
X is chemical bond or C 1-C 6Alkylidene group;
R 1And R 2Be hydrogen, C independently 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl, heterocyclic radical ,-C (=O) C 1-C 6Alkyl ,-C (=O) aryl ,-C (=O) heterocycle ,-C (=O) N (R 6) C 1-C 6Alkyl ,-C (=O) N (R 6) aryl ,-C (=O) N (R 6) heterocycle ,-SO 2-C 1-C 6Alkyl ,-SO 2-aryl or-SO 2-heterocycle; Perhaps
R 1And R 2Constitute heterocycle together;
R 3And R 4Be hydrogen, halogen, C independently 1-C 6Alkyl, C 1-C 3Perfluoroalkyl, C 1-C 6Alkoxyl group, C 3-C 8Cycloalkyl ,-C (=O) C 1-C 3Alkyl ,-OH ,-NH 2Or-NO 2
R 5Be hydrogen, C 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl or heterocyclic radical;
A is hydrogen, C 6-C 10Aryl or heterocyclic radical;
R 6Be hydrogen, C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, C 6-C 10Aryl, heterocyclic radical, hydroxyl, C 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, C 1-C 6Alkylamino, dialkyl amido (each moieties all contains 1-6 carbon atom) ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl or-NHSO 2-heterocycle.
The present invention also provides the especially acceptable salt of medicine or the ester-formin of formula 1.
The present invention also further provides the using method of the indoles of replacement.In one aspect of the invention, give the patient, thereby it is diseases related to treat PAI-1 by the PAI-1 activity that for example suppresses the patient with one or more substituted indoles for the treatment of significant quantity.PAI-1 is active relevant with numerous disease and illness.For example, in one embodiment of the invention, PAI-1 is active relevant with the fibrinolytic system obstacle.In other embodiments, PAI-1 is active relevant with following disease and illness: thrombosis (for example venous thrombosis, artery thrombosis, cerebral thrombosis and venous thrombosis), auricular fibrillation, pulmonary fibrosis, operating thromboembolic states complication, cardiovascular disorder be myocardial ischemia, atherosclerotic plaque formation, chronic obstructive pulmonary disease, renal fibrosis, polycystic ovarian syndrome, alzheimer's disease (Alzheimer ' s disease) or cancer for example.
Detailed Description Of The Invention
A. introduction
The invention provides the method that suppresses the active compound of PAI-1, prepares such compound, the method that comprises the pharmaceutical composition of such compound and in therapeutic treatment, use such compound.The compounds of this invention has the characteristic that can be used for multiple various disease of treatment (comprise prevention and suppress) and illness, and described disease and illness comprise the generation that relates to PAI-1 and/or the disease and the illness of effect.They comprise the disease that the fibrinolytic system obstacle causes, and include but not limited to thrombosis, coronary heart disease, renal fibrosis, atherosclerotic plaque formation, tuberculosis, myocardial ischemia, auricular fibrillation, coagulation syndrome, operating thromboembolic states complication, periphery artery occlusion and pulmonary fibrosis.Other disease includes but not limited to polycystic ovarian syndrome, alzheimer's disease and cancer.
No matter be to use separately or use as the integral part of another group, term used herein " alkyl " and " alkylidene group " all refer to replace or unsubstituted aliphatic hydrocarbon chain, difference is that alkyl is monovalent (being end group) in essence, and alkylidene group is divalence and basic as connecting usually.Unless clear and definite explanation is arranged in addition, is not limited to contain 1 otherwise these two kinds of groups include to about 12 carbon atoms, preferred 1 straight chain and side chain to about 6 carbon atoms.For example, term " alkyl " comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-and the tertiary butyl.The definition clear-cut of " alkyl " comprises those optional aliphatic hydrocarbon chain that replaces.In representative embodiment of the present invention, optional substituting group can comprise C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, optional by R 4The aryl that replaces, optional by R 7The heterocyclic radical, hydroxyl, the C that replace 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, alkylamino, dialkyl amido ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl and-NHSO 2-heterocycle.
R 7Be halogen, C 1-C 6Alkoxyl group, C 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, hydroxyl ,-C (=O) C 1-C 7Alkyl ,-SO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl or alkoxy carbonyl alkyl.In certain embodiments, R 7Comprise C 2-7Acyl group.
Carbon number in this paper definition is meant main chain carbon and branched carbon, but does not comprise the carbon atom of substituting group (for example alkoxy substituent etc.).
No matter be to use separately or use as the integral part of another group, term used herein " thiazolinyl " is meant and replaces or unsubstituted aliphatic hydrocarbon chain, includes but not limited to contain 2 straight chain and side chains to about 10 carbon atoms (unless clear and definite explanation is arranged in addition) and at least one two key.Preferred alkenyl part contains 1-2 two key.Such alkenyl part can be E type or Z type conformation, and The compounds of this invention comprises this two kinds of conformations.The definition clear-cut of " thiazolinyl " comprises those optional aliphatic hydrocarbon chain that replaces.In representative embodiment of the present invention, optional substituting group can comprise C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, optional by R 7The aryl that replaces, optional by R 7The heterocyclic radical, hydroxyl, the C that replace 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, alkylamino, dialkyl amido ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl and-NHSO 2-heterocycle.The heteroatoms (for example O or S) that connects thiazolinyl should not connect with the carbon atom that is connected two keys.
Except as otherwise noted, otherwise the independent use of this paper definition or the term " acyl group " that uses in conjunction with other term are meant covalently bound arylalkyl, the heteroarylalkyl, (C that is oxidized to the carbonyl oxidation state to the carbon atom of specifying chemical structure 2-C 10) straight chain or (C 4-C 11) the side chain univalence hydrocarbyl.Such alkyl can be single unsaturated or polyunsaturated, and can be E or Z configuration.The compounds of this invention comprises all possible E and Z configuration.The example of acyl group includes but not limited to such chemical group: ethanoyl, propionyl, butyryl radicals, 3,3-dimethyl butyrate acyl group, trifluoroacetyl group, valeryl, caproyl, hexenoyl, decanoyl, benzoyl, nicotinoyl, different nicotinoyl and homologue, isomer etc.
No matter be to use separately or use as the integral part of another group, term used herein " alkynyl " is meant and replaces or unsubstituted aliphatic hydrocarbon chain, includes but not limited to contain 2 to about 10 carbon atoms (unless clear and definite explanation is arranged in addition) and at least one triple-linked straight chain and side chain.Preferred alkynyl partly contains has an appointment 2 to about 7 carbon atoms.In certain embodiments, alkynyl can comprise a more than triple bond, and under these circumstances, alkynyl must comprise at least three carbon atoms.In representative embodiment of the present invention, optional substituting group can comprise C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, optional by R 7The aryl that replaces, optional by R 7The heterocyclic radical, hydroxyl, the C that replace 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, alkylamino, dialkyl amido ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl and-NHSO 2-heterocycle.The heteroatoms (for example O or S) that connects alkynyl not should with is connected the connection of triple-linked carbon atom.
No matter be to use separately or use as the integral part of another group, term used herein " cycloalkyl " is meant and contains 3 to about 20 carbon atoms (unless clear and definite explanation is arranged in addition), preferred 3 replacement or unsubstituted alicyclic hydrocarbon radicals to about 8 carbon atoms.The definition clear-cut of " cycloalkyl " comprises those optional alicyclic hydrocarbon radicals that replaces.In representative embodiment of the present invention, optional substituting group can comprise C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, optional by R 7The aryl that replaces, optional by R 7The heterocyclic radical, hydroxyl, the C that replace 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, alkylamino, dialkyl amido ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl and-NHSO 2-heterocycle.
No matter be to use separately or use as the integral part of another group, term used herein " aryl " is defined as and contains 5 to about 50 carbon atoms (unless clear and definite explanation is arranged in addition), preferred about 6 replacement or unsubstituted aromatic hydrocarbons cyclic groups to about 10 carbon atoms." aryl " can have a ring or a plurality of condensed ring.Term " aryl " includes but not limited to phenyl, Alpha-Naphthyl, betanaphthyl, xenyl, anthryl, tetralyl, fluorenyl, indanyl, biphenylene and acenaphthenyl.The definition clear-cut of " aryl " comprises those optional aromatic groups that replaces.For example; in representative embodiment of the present invention, " aryl " is optional to be selected from following substituting group replacement by 1-5: acyloxy; hydroxyl; aryl; acyl group; alkyloyl; the alkyl of 1-6 carbon atom; the alkoxyl group of 1-6 carbon atom; the thiazolinyl of 2-6 carbon atom; the alkynyl of 2-6 carbon atom; substituted alkyl; substituted alkoxy; substituted alkenyl; substituted alkynyl; amino; by 1-2 amino that contains the alkyl replacement of 1-6 carbon atom; aminoacyl; acyl amino; azido-; cyano group; halogen; nitro; the thio alkoxy of 1-6 carbon atom; the thio alkoxy and the trihalomethyl group of 1-6 the carbon atom that replaces.In illustrative embodiments of the invention, described optional substituting group comprises C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, optional by R 7The aryl that replaces, optional by R 7The heterocyclic radical, hydroxyl, the C that replace 1-C 6Alkoxyl group, C 1-C 6Perfluoro alkoxy, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, alkylamino, dialkyl amido ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl and-NHSO 2-heterocycle.
Term used herein " alkoxyl group " is meant R 5-O-, wherein R aBe alkyl defined above.The definition clear-cut of " alkoxyl group " comprises those optional alkoxyl groups that replaces.
Term used herein " aryl-oxygen base " is meant R b-O-, wherein R bBe aryl defined above.
Term used herein " alkyloyl " is meant-C (=O)-and alkyl, wherein the definition of alkyl is the same.Exemplary alkyloyl includes but not limited to ethanoyl, positive propionyl, positive butyryl radicals, 2-methylpropionyl, positive pentanoyl, 2-methylbutyryl base, 3-methylbutyryl base, 2,2-dimethyl propylene acyl group, oenanthyl and decanoyl.The moieties of alkyloyl can be chosen wantonly and be substituted.
Term " arylalkyl " or " aralkyl " are meant-R a-R b, R wherein aBy aryl R defined above bThe alkyl defined above that replaces.Preferred described alkyl has 1-6 carbon atom.The example of arylalkyl includes but not limited to benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenyl propyl, 2-phenyl propyl etc.
Term used herein " alkoxy carbonyl alkyl " is meant R c-O-C (=O) R c-, R wherein cBe alkyl defined above.Preferred alkoxy carbonyl alkyl has 3-13 carbon atom.
Term used herein " alkylamino " is meant R c-NH-, wherein R cBe alkyl defined above, and preferably have 1-6 carbon atom.
Term used herein " dialkyl amido " is meant-N (C 1-C 6Alkyl) 2
Term " SO used herein 2-C 1-C 6Alkyl " be meant-S (O 2)-R a, R wherein aIt is the alkyl of 1-6 carbon atom of above definition.
Term " bicyclic alkyl " be meant have 2 bridge joint rings in the structure and comprise about 7 to about 20 carbon atoms (unless clear and definite explanation is arranged in addition) (and all combinations of each scope and recombinant and concrete carbon atom number wherein), preferred about 7 alkyl of the optional replacement of about 11 carbon atoms extremely.Exemplary bicyclic alkyl ring structure includes but not limited to norcamphyl, bornyl, [2.2.2]-two ring octyl group, suitable pinane base, anti-pinane base, camphyl, isobornyl and fenchyl.Representational substituting group comprises for example C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, optional by R 7The aryl that replaces, optional by R 7The heterocyclic radical, hydroxyl, the C that replace 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, alkylamino, dialkyl amido ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl and-NHSO 2-heterocycle.
No matter be to use separately or use as the integral part of another group, term used herein " heterocycle " is meant that stable carbon atoms and 1-4 the heteroatomic 3 yuan of rings that are selected from nitrogen, oxygen and sulphur are to about 10 yuan of rings.Heterocycle of the present invention can be monocycle or second cycle line system, and can be saturated, unsaturated or fractional saturation.Heterocycle can be chosen wantonly with phenyl ring and condense.Heterocyclic radical includes but not limited to aziridinyl, azetidinyl, 1,4-two  alkyl, the hexahydroazepine base, piperazinyl, piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, the dihydrobenzo imidazolyl, dihydro benzo furyl, the dihydrobenzo thienyl, dihydrobenzo  azoles base, the dihydrofuran base, the glyoxalidine base, indolinyl, the different  azoles of dihydro base, the dihydro isothiazolyl, dihydro  di azoly, dihydro  azoles base, the dihydro pyrazinyl, the pyrazoline base, the dihydropyridine base, the dihydro-pyrimidin base, the pyrrolin base, the dihydroquinoline base, the dihydro tetrazyl, the thiodiazoline base, dihydro-thiazolyl, the dihydro-thiophene base, the dihydro triazolyl, the dihydro azetidinyl, dihydro-1,4-two  alkyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydric quinoline group and tetrahydro isoquinolyl.Preferred heterocyclic moiety comprises: (a) contain 1-2 nitrogen-atoms saturated, part is unsaturated or undersaturated 6 yuan of heterocycles, chooses fused benzene rings wantonly; (b) contain saturated, fractional saturation or undersaturated 5 yuan of heterocycles of 1-3 nitrogen-atoms, Sauerstoffatom or sulphur atom, optional fused benzene rings; (c) contain 1-4 nitrogen-atoms, Sauerstoffatom or sulphur atom saturated, part is unsaturated or undersaturated bicyclic heterocycles; (d) carbazole, diphenylene-oxide and dibenzothiophene.The definition clear-cut of " heterocycle " comprises those optional heterocycles that replaces.Representational substituting group comprises for example C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, optional by R 7The aryl that replaces, optional by R 7The heterocyclic radical, hydroxyl, the C that replace 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, alkylamino, dialkyl amido ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl and-NHSO 2-heterocycle.
Term used herein " heteroaryl " is defined as and replaces or unsubstituted aromatic heterocycle system (monocycle or two rings).Heteroaryl can have for example about 3 to about 50 carbon atoms (unless clear and definite explanation is arranged in addition), preferred about 4 to about 10 carbon atoms.In certain embodiments, heteroaryl is to have about 4 aromatic heterocycles to about 14 annular atomses (comprising carbon atom and 1-4 heteroatoms that is selected from oxygen, nitrogen or sulphur) to be.Representative heteroaryl groups is furans, thiophene, indoles, azaindole,  azoles, thiazole, different  azoles, isothiazole, imidazoles, N-Methylimidazole, pyridine, pyrimidine, pyrazine, pyrroles, N-methylpyrrole, pyrazoles, N-methylpyrazole, 1,3,4- diazole, 1,2,4-triazole, 1-methyl isophthalic acid, 2,4-triazole, 1H-tetrazolium, 1-methyl tetrazolium, benzoxazol, benzothiazole, cumarone, benzisoxa  azoles, benzoglyoxaline, N-tolimidazole, azepine benzoglyoxaline, indazole, quinazoline, quinoline and isoquinoline 99.9.The bicyclic aromatic heteroaryl comprises phenyl, pyridine, pyrimidine or pyridazine (pyridizine) ring that condenses following ring: 6 yuan of aromatics (unsaturated) heterocycle that (a) contains 1 nitrogen-atoms; (b) contain 5-6 unit aromatics (unsaturated) heterocycle of 2 nitrogen-atoms; (c) contain 5 yuan of aromatics (unsaturated) heterocycle of 1 nitrogen-atoms and 1 Sauerstoffatom or 1 sulphur atom; Or (d) contain 1 heteroatomic 5 yuan of aromatics (unsaturated) heterocycle that is selected from O, N or S.The definition clear-cut of " heteroaryl " comprises those optional aromatic groups that replaces.Therefore, heteroaryl described herein (for example pyridyl) is meant the group that does not replace or replace.In representative embodiment of the present invention, " heteroaryl " is optional to be selected from following substituting group replacement by 1-5: acyloxy; hydroxyl; acyl group; the alkyl of 1-6 carbon atom; the alkoxyl group of 1-6 carbon atom; the thiazolinyl of 2-6 carbon atom; the alkynyl of 2-6 carbon atom; substituted alkyl; substituted alkoxy; substituted alkenyl; substituted alkynyl; amino; by 1-2 amino that contains the alkyl replacement of 1-6 carbon atom; aminoacyl; acyl amino; azido-; cyano group; halogen; nitro; the thio alkoxy of 1-6 carbon atom; the thio alkoxy and the trihalomethyl group of 1-6 the carbon atom that replaces.
No matter be to use separately or use as the integral part of another group, term used herein " perfluoroalkyl " is meant the radical of saturated aliphatic alkyl that contains 1-6 carbon atom and the fluorine atom more than 2 or 2, includes but not limited to straight or branched, for example-and CF 3,-CH 2CF 3,-CF 2CF 3With-CH (CF 3) 2
Term " halogen " or " halo " are meant chlorine, bromine, fluorine and iodine.
Term " treatment " is meant any indication of successfully improving damage, pathology or disease, comprises any objective or subjective parameters, and for example the alleviating, alleviate or reduce of symptom perhaps makes the patient more can stand damage, pathology or disease; Sex change or decay rates slow down; Weaken final sex change point; Perhaps improve patient's body or mental health conditions.The treatment of symptom or improvement can be based on objective or subjective parameters; Comprise the result that physical examination, neurologic check and/or psychiatry are estimated." treatment PAI-1 diseases related " comprise prevention patient (it is diseases related easily to suffer from PAI-1, but does not also feel or occur the patient of this disease symptoms) symptom generation (prophylactic treatment), suppress this sick symptom (slow down or stop its development), alleviate this sick symptom or side effect (comprising palliative treatment) and/or eliminate this sick symptom (making resolution of symptoms).Therefore, term " treatment " comprises and gives the patient with prevention or postpones, alleviate, stop or suppress the diseases related symptom of PAI-1 or the development of illness (for example cancer be correlated with tumor growth) with The compounds of this invention or medicine.Skilled medical worker knows how to utilize standard method to determine whether the patient suffers from the concentration of PAI-1 and/or actively improve relevant disease, for example after checking the patient, determine whether the patient suffers from concentration and/or the active diseases associated that improves known and PAI-1, perhaps analyze the PAI-1 concentration of suspecting blood plasma or the tissue of suffering from the diseases related individuality of PAI-1, compare with the blood plasma of healthy individual or the PAI-1 concentration of tissue then.It is ill that PAI-1 concentration increases expression.Therefore, the present invention also provides especially and gives patient's method and the method for measuring patient PAI-1 concentration with The compounds of this invention.Patient's PAI-1 concentration can be measured before giving compound and/or afterwards.
In healthy individual, the concentration of PAI-1 in blood plasma low (about 5-26ng/ml), but the concentration in many PAI-1 are diseases related raises, comprise for example atherosclerosis (Schneiderman J. etc., Proc Natl Acad Sci 89:6998-7002,1992), venous thrombosis (Juhan-Vague I etc., Thromb Haemost 57:67-72,1987) and non-insulin-dependent diabetes mellitus (NIDDM) (Juhan-Vague I etc., Thromb Haemost 78:565-660,1997).PAI-1 makes arterial thrombus and phlebothrombosis stable, impels the venous thrombosis after coronary occlusion (Hamsten A etc., Lancet 2:3-9,1987) after the myocardial infarction and the orthopaedic surgery recovery from illness respectively.(Siemens HJ etc., J Clin Anesthesia11:622-629,1999).For example, postmenopausal women's plasma PAI-1 also can raise, and thinks that therefore this is the reason (Koh K etc., N Engl J Med 336:683-690,1997) that causes the sickness rate raising of this type of crowd's cardiovascular disorder.
Term " PAI-1 is diseases related " is meant expresses with PAI-1 or actively improves or strengthen relevant or with the expression of gene of coding PAI-1 or actively improve or strengthen any disease or the illness of being correlated with.The example of the raising of active or expression like this may comprise one or more following situations: protein-active or protein coding gene are expressed the respective horizontal that surpasses normal curee; In normal curee, can not detect usually and detect protein-active in organ, tissue or the cell that protein-active or protein coding gene express or protein coding gene is expressed (expression that is proteic spatial distribution or protein coding gene changes); When protein-active or protein coding gene are expressed in time that the time ratio that exists in organ, tissue or the cell exists when long in normal curee, protein-active or protein coding gene are expressed and are strengthened (being to increase the time length that protein-active or protein coding gene are expressed).Normal or healthy curee does not suffer from the diseases related curee of PAI-1.
Term " pharmaceutically-acceptable excipients " is meant the vehicle that can be used for pharmaceutical compositions, and is safe usually, nontoxic and meet the requirements, and comprises for animals and the human pharmaceutically-acceptable excipients.Such vehicle can be solid, liquid, semisolid, perhaps can also be gas with regard to aerosol combination.
" acceptable salt of medicine and ester " is meant that medicine is acceptable and has the salt and the ester of required pharmacological property.For example, such salt is included in when having acid proton in the compound and can reacts the salt that forms with mineral alkali or organic bases.Suitable inorganic salt for example comprise the salt that forms with basic metal or alkaline-earth metal (for example sodium and potassium, magnesium, calcium and aluminium).Suitable organic salt for example comprises the salt that forms with organic bases (for example amine alkali, for example thanomin, diethanolamine, trolamine, Trometamol, N-methylglucosamine etc.).The acceptable salt of medicine can also comprise acid salt, acid salt generates by the basic moiety (for example amine) in the parent compound and mineral acid (for example hydrochloric acid and Hydrogen bromide) and organic acid (for example acetate, citric acid, toxilic acid, alkane sulfonic acid and aromatic hydrocarbons sulfonic acid, for example methylsulfonic acid and Phenylsulfonic acid) reaction.The acceptable ester of medicine comprises the ester that is formed by the carboxyl that exists in the The compounds of this invention, sulfonyloxy and phosphonato, for example C 1-6Alkyl ester.When having two acidic-groups, acceptable salt of medicine or ester can be single sour single salt, single acid monoester, disalt or diester; Similarly, when having two above acidic-groups, partly or entirely such group can be by salinization or esterification.The compound of naming among the present invention is salinization or no esterification form or salinization and/or esterified form existence not, and the name of such compound comprises former compound (not salinization no esterification) and acceptable salt of medicine and ester.In addition, may there be more than one stereoisomeric forms in any ratio in some compound of naming among the present invention, and the name of such compound comprises all mixtures (no matter being racemic or other form) of all single stereoisomers and such steric isomer.
Express or active " inhibitor ", " activator " and " conditioning agent " are meant respectively and adopt expression or active external and inhibition, activity or modulability molecule that in vivo test is identified.Inhibitor of the present invention is the composition with following function: suppress PAI-1 expression or inhibition in conjunction with PAI-1, partially or completely block the active hormesis of PAI-1, reduce the PAI-1 activity, stop the PAI-1 activity, postpone the active activation of PAI-1, passivation PAI-1 activity, desensitization PAI-1 activity is perhaps reduced the PAI-1 activity.The sample or the assay that comprise PAI-1 can be handled with the present composition, compare with the control sample that does not have the present composition then.The relative reactivity value that can specify control sample (not handling with the present composition) is 100%.In certain embodiments, when the activity value with respect to contrast is about 80% or 80% when following, choosing wantonly is 50%, 25%, 10%, 5% or 1% o'clock, then realizes the inhibition to PAI-1.
When relating to composition, carrier, thinner and reagent, term " medicine is acceptable ", " can tolerate on the physiology " and their other saying are used interchangeably, and represent that described material can administration of human, may not reach the bad physiological action of forbidding giving the The compounds of this invention degree and can not produce, for example feel sick, dizzy, have a stomach upset etc.
" treatment significant quantity " or " medicinal significant quantity " is meant the dosage that gives to produce behind the patient required effect.By way of example, when giving the patient in order to suppress the PAI-1 activity, " treatment significant quantity " is enough to suppress the PAI-1 activity.When giving the patient in order to treat certain disease, " treatment significant quantity " is enough to effectively treat this kind disease.
Except as otherwise noted, otherwise term " curee " or " patient " be used interchangeably, and be meant Mammals, for example patient and non-human primates and laboratory animal (for example rabbit, rat and mouse) and other animal.Therefore, term used herein " curee " or " patient " are meant any mammalian subject or the curee that can give The compounds of this invention.In illustrative embodiments of the invention, in order to determine the patient with the inventive method treatment, the screening method that employing is generally acknowledged is determined disease or the relevant risk factors of illness with target or suspection, perhaps determines the state of patient's present illness or illness.For example, these screening methods comprise the routine inspection that is used for determining the risk factors relevant with the disease of target or suspection or illness.Above method and other ordinary method allow the patient that the clinicist selects needs to use the inventive method and preparation for treating.
When any variable occurred one time incessantly in any component or structural formula, the definition of this variable when at every turn occurring was independent of its definition when other occurs at every turn.The combination of substituting group and/or variable only just is allowed to when such combination can produce stable compound.
B. the indoles of Qu Daiing
The invention provides the indoles of replacement.Preferably give PAI-1 expression or activity that such compound is used to suppress the patient, that finally treats the patient increases relevant disease or illness with the PAI-1 activity, and for example PAI-1 is diseases related.
The indoles that replaces comprises following formula: compound:
Figure A20048003445300201
Formula 1
Wherein:
X is chemical bond or C 1-C 6Alkylidene group;
R 1And R 2Be hydrogen, C independently 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl, heterocyclic radical ,-C (=O) C 1-C 6Alkyl ,-C (=O) aryl ,-C (=O) heterocycle ,-C (=O) N (R 6) C 1-C 6Alkyl ,-C (=O) N (R 6) aryl ,-C (=O) N (R 6) heterocycle ,-SO 2-C 1-C 6Alkyl ,-SO 2-aryl or-SO 2-heterocycle; Perhaps
R 1And R 2Constitute heterocycle together;
R 3And R 4Be hydrogen, halogen, C independently 1-C 6Alkyl, C 1-C 3Perfluoroalkyl, C 1-C 6Alkoxyl group, C 3-C 8Cycloalkyl ,-C (=O) C 1-C 3Alkyl ,-OH ,-NH 2Or-NO 2
R 5Be hydrogen, C 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl or heterocyclic radical;
A is hydrogen, C 6-C 10Aryl or heterocyclic radical;
R 6Be hydrogen, C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, optional by R 7The C that replaces 6-C 10Aryl, optional by R 7The heterocyclic radical, hydroxyl, the C that replace 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, C 1-C 6Alkylamino, dialkyl amido (each moieties all contains 1-6 carbon atom) ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl or-NHSO 2-heterocycle.
The compounds of this invention also comprises the acceptable salt of prodrug, steric isomer or medicine or the ester-formin of formula 1.
For purposes of the present invention, R 1And R 2Can be hydrogen, C 1-C 6Alkyl, Cx-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl, heterocyclic radical ,-C (=O) C 1-C 6Alkyl ,-C (=O) aryl ,-C (=O) heterocycle ,-C (=O) N (R 6) C 1-C 6Alkyl ,-C (=O) N (R 6) aryl ,-C (=O) N (R 6) heterocycle ,-SO 2-C 1-C 6Alkyl ,-SO 2-aryl or-SO 2-heterocycle.In some exemplary of the present invention, R 1Or R 2Be hydrogen, SO independently 2-alkyl or optional quilt-OCF 3, the SO that replaces of aryl or alkyl 2-aryl.In some preferred embodiment, R 1Be hydrogen, R 2Be SO 2-methyl or optional quilt-OCF 3, the SO that replaces of phenyl or the tertiary butyl 2-phenyl.In such embodiments, R 3, R 4, R 5, R 6, X and A be as definition herein.
In part exemplary of the present invention, R 1And R 2Constitute heterocycle together.For example, in certain embodiments, R 1And R 2Constitute the pyrroles together.In such embodiments, R 3, R 4, R 5, R 6, X and A be as definition herein.
R 3And R 4Can be hydrogen, halogen, C 1-C 6Alkyl, C 1-C 3Perfluoroalkyl, C 1-C 6Alkoxyl group, C 3-C 8Cycloalkyl ,-C (=O) C 1-C 3Alkyl ,-OH ,-NH 2Or-NO 2In part embodiment of the present invention, R 3And R 4Be independently hydrogen or optional by halogen ,-alkyl that CN or alkoxyl group replace.In some preferred embodiment, R 3And R 4Be hydrogen.In such embodiments, R 1, R 2, R 5, R 6, X and A be as definition herein.
R 5Can be hydrogen, C 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl or heterocyclic radical.In some exemplary of the present invention, R 5Be hydrogen.In such embodiments, R 1, R 2, R 3, R 4, R 6, X and A be as definition herein.
R 6Can be C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, optional by R 7The C that replaces 6-C 10Aryl, optional by R 7The heterocyclic radical, hydroxyl, the C that replace 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, C 1-C 6Alkylamino, dialkyl amido (each moieties all contains 1-6 carbon atom) ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl or-NHSO 2-heterocycle.
A can be hydrogen, C 6-C 10Aryl or heterocyclic radical.In some exemplary of the present invention, A is hydrogen, phenyl or thiophene.In such embodiments, R 1, R 2, R 3, R 4, R 5, R 6With X as herein the definition.
Preferred compound of the present invention comprises such compound: wherein
X is chemical bond or unsubstituted C 1-C 6Alkylidene group;
R 1And R 2Be hydrogen, C independently 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl, heterocyclic radical, unsubstituted-C (=O) C 1-C 6Alkyl, unsubstituted-C (=O) aryl, unsubstituted-C (=O) heterocycle, unsubstituted-C (=O) N (R 6) C 1-C 6Alkyl, unsubstituted-C (=O) N (R 6) aryl, unsubstituted-C (=O) N (R 6) heterocycle, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-SO 2-aryl or unsubstituted-SO 2-heterocycle;
Wherein said C 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl, heterocyclic radical are chosen wantonly and are replaced by following group: unsubstituted C 1-C 6Alkyl, halogen, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, unsubstituted C 3-C 8Cycloalkyl, unsubstituted aralkyl, hydroxyl, unsubstituted C 1-C 6Alkoxyl group, unsubstituted aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H, unsubstituted-OCO 2C 1-C 6Alkyl, unsubstituted CO 2C 1-C 6Alkyl, unsubstituted-CO 2-aryl, unsubstituted-CO 2(C 1-C 6Alkyl) aryl, unsubstituted-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, unsubstituted amino, unsubstituted alkyl amino, unsubstituted dialkyl amido, unsubstituted-NHC (=O) NH-C 1-C 6Alkyl, unsubstituted-NHSO 2-C 1-C 6Alkyl, unsubstituted-NHSO 2-aryl, unsubstituted-NHSO 2-heterocycle, aryl (are chosen wantonly and are replaced by following group: halogen, unsubstituted C 1-C 6Alkoxyl group, unsubstituted C 1-C 6Alkyl, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, hydroxyl, unsubstituted-C (=O) C 1-C 7Alkyl, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-CO 2-C 1-C 6Alkyl or unsubstituted alkoxy carbonyl alkyl) or heterocyclic radical (optional replaced: halogen, unsubstituted C by following group 1-C 6Alkoxyl group, unsubstituted C 1-C 6Alkyl, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, hydroxyl, unsubstituted-C (=O) C 1-C 7Alkyl, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-CO 2-C 1-C 6Alkyl or unsubstituted alkoxy carbonyl alkyl); Perhaps
R 1And R 2Constitute the optional heterocycle that is replaced by following group together: unsubstituted C 1-C 6Alkyl, halogen, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, unsubstituted C 3-C 8Cycloalkyl, unsubstituted aralkyl, hydroxyl, unsubstituted C 1-C 6Alkoxyl group, unsubstituted aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H, unsubstituted-OCO 2C 1-C 6Alkyl, unsubstituted CO 2C 1-C 6Alkyl, unsubstituted-CO 2-aryl, unsubstituted-CO 2(C 1-C 6Alkyl) aryl, unsubstituted-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, unsubstituted amino, unsubstituted alkyl amino, unsubstituted dialkyl amido, unsubstituted-NHC (=O) NH-C 1-C 6Alkyl, unsubstituted-NHSO 2-C 1-C 6Alkyl, unsubstituted-NHSO 2-aryl, unsubstituted-NHSO 2-heterocycle, aryl (are chosen wantonly and are replaced by following group: halogen, unsubstituted C 1-C 6Alkoxyl group, unsubstituted C 1-C 6Alkyl, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, hydroxyl, unsubstituted-C (=O) C 1-C 7Alkyl, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-CO 2-C 1-C 6Alkyl or unsubstituted alkoxy carbonyl alkyl) or heterocyclic radical (optional replaced: halogen, unsubstituted C by following group 1-C 6Alkoxyl group, unsubstituted C 1-C 6Alkyl, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, hydroxyl, unsubstituted-C (=O) C 1-C 7Alkyl, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-CO 2-C 1-C 6Alkyl or unsubstituted alkoxy carbonyl alkyl);
R 3And R 4Be hydrogen, halogen, unsubstituted C independently 1-C 3Perfluoroalkyl, unsubstituted C 1-C 6Alkoxyl group, unsubstituted C 3-C 8Cycloalkyl, unsubstituted-C (=O) C 1-C 3Alkyl ,-OH ,-NH 2,-NO 2Or optional by halogen ,-CN or C 1-C 3The C that alkoxyl group replaces 1-C 6Alkyl;
R 5Be hydrogen, C 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl or heterocyclic radical,
Wherein said C 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl or heterocyclic radical are optional to be replaced by following group: unsubstituted C 1-C 6Alkyl, halogen, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, unsubstituted C 3-C 8Cycloalkyl, unsubstituted aralkyl, hydroxyl, unsubstituted C 1-C 6Alkoxyl group, unsubstituted aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H, unsubstituted-OCO 2C 1-C 6Alkyl, unsubstituted CO 2C 1-C 6Alkyl, unsubstituted-CO 2-aryl, unsubstituted-CO 2(C 1-C 6Alkyl) aryl, unsubstituted-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, unsubstituted amino, unsubstituted alkyl amino, unsubstituted dialkyl amido, unsubstituted-NHC (=O) NH-C 1-C 6Alkyl, unsubstituted-NHSO 2-C 1-C 6Alkyl, unsubstituted-NHSO 2-aryl, unsubstituted-NHSO 2-heterocycle, aryl (are chosen wantonly and are replaced by following group: halogen, unsubstituted C 1-C 6Alkoxyl group, unsubstituted C 1-C 6Alkyl, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, hydroxyl, unsubstituted-C (=O) C 1-C 7Alkyl, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-CO 2-C 1-C 6Alkyl or unsubstituted alkoxy carbonyl alkyl) or heterocyclic radical (optional replaced: halogen, unsubstituted C by following group 1-C 6Alkoxyl group, unsubstituted C 1-C 6Alkyl, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, hydroxyl, unsubstituted-C (=O) C 1-C 7Alkyl, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-CO 2-C 1-C 6Alkyl or unsubstituted alkoxy carbonyl alkyl);
A is hydrogen, C 6-C 10Aryl or heterocyclic radical,
Wherein said aryl or heterocyclic radical are optional to be replaced by following group: unsubstituted C 1-C 6Alkyl, halogen, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, unsubstituted C 3-C 8Cycloalkyl, unsubstituted aralkyl, hydroxyl, unsubstituted C 1-C 6Alkoxyl group, unsubstituted aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H, unsubstituted-OCO 2C 1-C 6Alkyl, unsubstituted CO 2C 1-C 6Alkyl, unsubstituted-CO 2-aryl, unsubstituted-CO 2(C 1-C 6Alkyl) aryl, unsubstituted-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, unsubstituted amino, unsubstituted alkyl amino, unsubstituted dialkyl amido, unsubstituted-NHC (=O) NH-C 1-C 6Alkyl, unsubstituted-NHSO 2-C 1-C 6Alkyl, unsubstituted-NHSO 2-aryl, unsubstituted-NHSO 2-heterocycle, aryl (are chosen wantonly and are replaced by following group: halogen, unsubstituted C 1-C 6Alkoxyl group, unsubstituted C 1-C 6Alkyl, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, hydroxyl, unsubstituted-C (=O) C 1-C 7Alkyl, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-CO 2-C 1-C 6Alkyl or unsubstituted alkoxy carbonyl alkyl) or heterocyclic radical (optional replaced: halogen, unsubstituted C by following group 1-C 6Alkoxyl group, unsubstituted C 1-C 6Alkyl, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, hydroxyl, unsubstituted-C (=O) C 1-C 7Alkyl, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-CO 2-C 1-C 6Alkyl or unsubstituted alkoxy carbonyl alkyl);
R 6Be hydrogen, unsubstituted C 1-C 6Alkyl, halogen, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, unsubstituted C 3-C 8Cycloalkyl, unsubstituted aralkyl, hydroxyl, unsubstituted C 1-C 6Alkoxyl group, unsubstituted aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H, unsubstituted-OCO 2C 1-C 6Alkyl, unsubstituted CO 2C 1-C 6Alkyl, unsubstituted-CO 2-aryl, unsubstituted-CO 2(C 1-C 6Alkyl) aryl, unsubstituted-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, unsubstituted amino, unsubstituted alkyl amino, unsubstituted dialkyl amido, unsubstituted-NHC (=O) NH-C 1-C 6Alkyl, unsubstituted-NHSO 2-C 1-C 6Alkyl, unsubstituted-NHSO 2-aryl, unsubstituted-NHSO 2-heterocycle, aryl (are chosen wantonly and are replaced by following group: halogen, unsubstituted C 1-C 6Alkoxyl group, unsubstituted C 1-C 6Alkyl, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, hydroxyl, unsubstituted-C (=O) C 1-C 7Alkyl, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-CO 2-C 1-C 6Alkyl or unsubstituted alkoxy carbonyl alkyl) or heterocyclic radical (optional replaced: halogen, unsubstituted C by following group 1-C 6Alkoxyl group, unsubstituted C 1-C 6Alkyl, unsubstituted C 2-C 7Thiazolinyl, unsubstituted C 2-C 7Alkynyl, hydroxyl, unsubstituted-C (=O) C 1-C 7Alkyl, unsubstituted-SO 2-C 1-C 6Alkyl, unsubstituted-CO 2-C 1-C 6Alkyl or unsubstituted alkoxy carbonyl alkyl).
In certain embodiments of the invention, the indoles of replacement comprises following formula: compound:
Figure A20048003445300251
Formula 2
R wherein 3, R 4, X, A and n definition the same,
Y is-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl ,-NHSO 2-heterocycle, pyrroles ,-the NH-aryl or-the NH-heterocycle.
In representative embodiment of the present invention, described pyrryl is replaced by following group: C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, n are aralkyl, aryl, heterocyclic radical, hydroxyl, the C of 1-6 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, alkylamino, dialkyl amido ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl or-NHSO 2-heterocycle.
The 1-aralkyl of the replacement that the present invention is exemplary or 1-aryl-1H-indoles include but not limited to following compounds:
(1) 1-[4-({ [4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) phenyl]-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(2) 1-[4-(1H-pyrroles-1-yl) phenyl]-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(3) 1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(4) 1-(4-{[(4-tert-butyl-phenyl) alkylsulfonyl] amino } benzyl)-1H-indole-5-carboxylic acid or acceptable salt of its medicine or ester-formin;
(5) 1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indole-5-carboxylic acid or acceptable salt of its medicine or ester-formin;
(6) 1-(4-{[(4-tert-butyl-phenyl) alkylsulfonyl] amino } benzyl)-1H-indole-3-carboxylic acid or acceptable salt of its medicine or ester-formin;
(7) 1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indole-3-carboxylic acid or acceptable salt of its medicine or ester-formin;
(8) 1-(4-{[(4-tert-butyl-phenyl) alkylsulfonyl] amino } benzyl)-1H-indoles-4-formic acid or acceptable salt of its medicine or ester-formin;
(9) 1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indoles-4-formic acid or acceptable salt of its medicine or ester-formin;
(10) 1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indoles-6-formic acid or acceptable salt of its medicine or ester-formin;
(11) amino 3-phenyl-1-{4-[(phenyl sulfonyl)] benzyl }-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(12) amino 1-{4-[(methyl sulphonyl)] benzyl }-3-phenyl-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(13) amino 1-{4-[(phenyl sulfonyl)] benzyl }-3-thiophene-2-base-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(14) amino 1-{4-[(methyl sulphonyl)] benzyl }-3-thiophene-2-base-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(15) 1-[4-(2,5-dimethyl-1H-pyrroles-1-yl) benzyl]-3-phenyl-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(16) 1-(4-anilino benzyl)-3-phenyl-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(17) 1-(4-anilino benzyl)-3-thiophene-2-base-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin.
The present invention also provides composition, and said composition comprises substituted indole (compound or its steric isomer or the acceptable salt of medicine that comprise formula 1 and formula 2) and one or more medicine acceptable carriers, vehicle or thinner.Such composition comprises and being used for the treatment of or the disease that control is relevant with the PAI-1 increased activity or the pharmaceutical composition of illness.In certain embodiments, described composition comprises the mixture of one or more substituted indoles.
The part of compounds of formula 1 and formula 2 comprises chirality (stereogenic) carbon atom or other chiral element, produces steric isomer thus, comprises enantiomer and diastereomer.The present invention includes all steric isomers of formula 1 and formula 2 and the mixture of these steric isomers.In the application's full text, when not pointing out the absolute configuration of asymmetric center, name of product comprises each steric isomer and stereoisomer mixture.
When preferred certain enantiomer, in the part embodiment, can provide the preferred enantiomer that does not have corresponding enantiomer substantially.Therefore, do not have the enantiomer of corresponding enantiomer substantially, be meant the compound that does not have corresponding enantiomer of or preparation isolating through isolation technique." not having substantially " used herein is meant that described compound is made up of a kind of enantiomer that accounts for significant proportion.In preferred embodiments, described compound contains the preferred enantiomer at least about 90% (weight).In other embodiment of the present invention, described compound contains the preferred enantiomer at least about 99% (weight).Preferred enantiomer can be separated from racemic mixture by adopting any method well known by persons skilled in the art, comprise high performance liquid chromatography (HPLC) and form also crystallization chirality salt, perhaps preferred enantiomer can prepare by the method that this paper introduces.The preparation method of preferred enantiomer is for example having description: Jacques etc. in the following document, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H. etc., Tetrahedron 33:2725 (1977); Eliel, E.L.Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, and the 268th page of S.H.Tablesof Resolving Agents and Optical Resolutions (E.L.Eliel edits, Univ.of Notre Dame Press, and Notre Dame, IN 1972).
The exemplary salt form of The compounds of this invention includes but not limited to sodium salt and sylvite.The exemplary salt form of other of these compounds includes but not limited to the salt with the acceptable mineral alkali of medicine known in the art, organic bases, mineral acid or organic acid formation.When The compounds of this invention comprised basic moiety, described acid comprised for example acetate, propionic acid, lactic acid, citric acid, tartrate, succsinic acid, fumaric acid, toxilic acid, propanedioic acid, amygdalic acid, oxysuccinic acid, phthalic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, naphthene sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids, camphorsulfonic acid and known similar acceptable acid.The oxyhydroxide, carbonate or the supercarbonate that comprise last acceptable basic metal of treatment or alkaline-earth metal (for example sodium, potassium, magnesium, calcium etc.) with the salt form of mineral alkali preparation.Acceptable organic bases comprises amine, benzylamine, monoalkylamine, dialkylamine and the trialkylamine (alkyl that preferably has 1-6 carbon atom for example, the more preferably alkyl of 1-3 carbon atom), for example methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, monoethanolamine, diethanolamine and trolamine.Exemplary salt also comprises the Alkylenediamine that contains 6 carbon atoms at most, for example hexamethylene-diamine; Contain the saturated or undersaturated alkali of ring-type of 6 carbon atoms at most, comprise tetramethyleneimine, piperidines, morpholine, piperazine and N-alkyl thereof and N-hydroxyalkyl derivative, for example N-methyl-morpholine and N-(2-hydroxyethyl)-piperidines, or pyridine.Also can form quaternary ammonium salt, tetraalkyl form (for example tetramethyl-form), alkyl-alkanol form (for example methyl-three ethanol or trimethylammonium-monoethanolamine form) and ring-type ammonium salts (for example N-picoline  salt, N-methyl-N-(2-hydroxyethyl)-morpholine  salt, N for example, N-thebaine  salt, N-methyl-N-(2-hydroxyethyl)-morpholine  salt or N, N-dimethyl-piperidines  salt form).These salt forms can prepare with the acidic cpd and the methods known in the art of formula 1 or formula 2.
The branched alkyl ester (comprising methyl ester, ethyl ester, propyl diester, butyl ester, 2-methyl-propyl ester and 1,1-dimethyl ethyl ester) that the exemplary ester-formin of The compounds of this invention includes but not limited to contain the straight chained alkyl ester of 1-6 carbon atom or contain 1-6 carbon atom, cycloalkyl ester, alkyl aryl ester, benzyl ester etc.Other exemplary ester includes but not limited to formula-COOR 12Ester, R wherein 12Be selected from following formula:
R wherein 8, R 9, R 10And R 11Independently be selected from the alkyl of hydrogen, a 1-10 carbon atom, the aryl of a 6-12 carbon atom, the arylalkyl of a 6-12 carbon atom; Heteroaryl or miscellaneous alkyl aryl (wherein heteroaryl ring connects the alkyl chain of 1-6 carbon atom).
Preferred compound of the present invention suppresses the PAI-1 activity.Therefore, it is diseases related that The compounds of this invention can be used for treatment (comprise prevention, suppress and/or improvement) patient's PAI-1, comprises for example non-insulin-dependent diabetes mellitus (NIDDM), cardiovascular disorder and the thrombosis incident relevant with coronary artery and cerebro-vascular diseases.Adopt the inventive method, skilled medical worker knows how substituted indole (compound that comprises formula 1 and formula 2 expressions) is suffered from patient active with PAI-1 or that express the relevant any disease (for example diabetes or cardiovascular disorder) of enhancing, so that effectively treat this kind disease.
In an exemplary, give the patient with substituted indole so that treatment relates to the lysis of state before thrombosis and the thrombosis, include but not limited to the thromboembolic states complication and the periphery artery occlusion of atherosclerotic plaque formation, vein and artery thrombosis, myocardial ischemia, auricular fibrillation, venous thrombosis, coagulation syndrome, lung thrombosis, cerebral thrombosis, surgical operation (for example joint or hip replacement surgery).
Patient's any and PAI-1 activity or expression strengthen relevant disease or illness and can treat with substituted indole of the present invention.Exemplary disease and illness comprise apoplexy, apoplexy for example relevant with auricular fibrillation or that auricular fibrillation causes; The extracellular matrix accumulation is diseases related, includes but not limited to renal fibrosis, chronic obstructive pulmonary disease, polycystic ovarian syndrome, restenosis, renal vascular disease and organ transplant rejection; Generate relevant disease with neovascularity, include but not limited to diabetic retinopathy; Alzheimer's disease for example raises or recovers by the Tryptase concentration level that makes the patient and normally treats; The myelofibrosis of following the marrow alienation to give birth to for example increases by adjusting stroma cell propagation and extracellular matrix protein and treats; Diabetic nephropathy and the kidney dialysis disease of following ephrosis; Malignant tumour or cancer include but not limited to leukemia, mammary cancer and ovarian cancer; Tumour includes but not limited to liposarcoma and epithelioma; Septicemia; Obesity; Insulin resistant; Proliferative disease includes but not limited to psoriasis; Follow the unusual disease of blood coagulation balance; Low grade of malignancy vascular inflammation; Cerebrovascular disease; Hypertension; Dull-witted; Osteoporosis; Sacroiliitis; Respiratory tract disease, for example asthma; In heart failure; Irregular pulse; Angina includes but not limited to stenocardia; Atherosclerosis and sequela thereof; Renal failure; Multiple sclerosis; Osteoporosis; Osteopenia; Dull-witted; Peripheral vascular disease; Peripheral arterial disease; The acute vascular syndromes; The microvascular disease includes but not limited to ephrosis, neuropathy, retinopathy and nephrotic syndrome; Hypertension; I type and type ii diabetes and relative disease; Hyperglycemia; Hyperinsulinemia; Malignant change; Precancerous lesion; Gastrointestinal cancer; Coronary heart disease includes but not limited to one-level and secondary prevention myocardial infarction, stable and unstable angina, crown incident of primary prevention and secondary prevention cardiovascular event; Inflammatory diseases includes but not limited to the blood vessel injury of septic shock and concomitant infections.
The compounds of this invention can also be united second kind of medicine (including but not limited to short thrombolytic (prothrombolytic), fibrinolytic and anticoagulant) and be given the patient, perhaps treat in conjunction with other therapies, the high reactivity antiretroviral therapy (HAART) that for example contains proteinase inhibitor, this therapy are used for the treatment of the disease that the Hypercoagulability by fibrinolysis obstacle and HIV-1 the infected causes.In certain embodiments, The compounds of this invention can be in conjunction with relating to the therapy of keeping vessel open and/or administration after described therapy, and described therapy includes but not limited to vascular surgery, vascular transplantation, insert support (stent patency), organ, tissue and cell implantation and transplantation.The compounds of this invention also can be used for handling the blood that uses in the dialysis and blood products, the liquid blood that stores, and is particularly useful for the platelet aggregation that exsomatizes.The compounds of this invention can also give the patient as the hormone replacement medicine, perhaps is used to reduce inflammation sign or c reactive protein.Can give The compounds of this invention and be used for wound healing (for example preventing the scar scar to form) to improve blood coagulation balance, endothelial function or part.The compounds of this invention can give the patient carries out myocardium revascularization with reduction risk.The compounds of this invention also can add in the human plasma when carrying out blood chemical analysis with mensuration plasma fibrin dissolving power with hospital device.In certain embodiments, The compounds of this invention can be used as contrast medium and is used to confirm metastatic carcinoma.
C. substituted indole is synthetic
The organic synthesis those skilled in the art can be by reagent and the raw material that adopts ordinary method and obtain easily, the preparation The compounds of this invention.Representative compounds of the present invention can be according to following synthesis flow preparation.The technician knows how to change these method stepss, and these variations itself are well known in the art.In following reaction process, R 1, R 2, R 3, R 4, R 5, R 6And the definition of Ar (aryl) is together with the definition among the following formula I.
Flow process 1
1H-indoles 1 can be with the nitrobenzyl halogen that replaces at alkali (K for example 2CO 3, Cs 2CO 3, KOH or NaH) have alkylation down, use inert solvent for example THF, two  alkane, pyridine, DMF, NMP or DMSO, temperature of reaction is-40 ℃ to 100 ℃.Gained nitro intermediate 2 can with Raney  nickel in hydrazine and alcoholic acid mixture after 0-40 ℃ of processing, be reduced to aniline 3.Then at 0-40 ℃, compound 3 usefulness sulfonic acid halides (SULPHURYL CHLORIDE of preferred alkyl, aryl or heterocyclic radical) and alkali (for example N, N-diisopropylethylamine) were handled 0.5-24 hour in anhydrous solvent (for example methylene dichloride), be converted into sulphonamide 4, wherein R 13Be alkyl, aryl or Het.Make aniline 3 with excessive 1,4-dicarbonyl compound (for example acetonyl-acetone) condensation, utilize the Dean this-Rodney Stark couch water trap (Dean-Stark trap) removes azeotropic water, obtains pyrryl indoles 6 (Paal-Knorr synthesis method), wherein R 14And R 15Be hydrogen, alkyl, aryl or heterocyclic radical independently.The pyrroles that can use the synthetic 1-of changing method of Paal-Knorr synthesis method to replace, i.e. aniline 3 and excessive cyclic acetal 2, the reaction of 5-dimethoxy-tetrahydrofuran.At room temperature, the also available boric acid of aniline 3 is at alkali (preferred 2,6-lutidine), additive (for example tetradecanoic acid) and Cu (OAc) 2Exist down and in inert solvent (for example toluene), be converted into diarylamine 8.The corresponding ester 4,6 or 8 of basic hydrolysis obtains final product acid 5,7 or 9.In this reaction, lithium hydroxide, sodium hydroxide, potassium hydroxide etc. can be used as alkali, and the mixture of water or water and methyl alcohol, ethanol, two  alkane etc. can be used as solvent.Final product can pass through recrystallization, grinding, preparative thin-layer chromatography method, silica gel flash column chromatography or high performance liquid chromatography purifying.The purifying of intermediate can be realized by identical method.Optional by adding acid or alkali (for example hydrogen chloride gas or hydrochloric acid) preparation salt.
Flow process II
Method or method known to those skilled in the art that (hetero) aryl indole derivatives 12 also is easy to introduce by document prepare.For example, the method shown in the flow process II, at 0-40 ℃, 1H-indoles 1 can be with the 4-fluoronitrobenzene that replaces at alkali (Cs for example 2CO 3) there is an arylation in inert solvent (for example DMF) down.Gained nitro intermediate 10 can with Raney  nickel in hydrazine and alcoholic acid mixture after 0-40 ℃ of processing, be reduced to required aniline 11.Aniline 11 can be converted into N-(hetero) aryl indole derivatives 12 according to the method that flow process 1 is introduced, for example sulphonamide, pyrroles and diarylamine.
Flow process III
Figure A20048003445300341
C 3The indole derivatives 16 that aryl or heterocyclic radical replace (R wherein 16Be aryl or heterocyclic radical) can be easy to prepare according to method shown in the flow process III.At first, with the known halogenating agent of substituted indole 1 usefulness (for example chlorine, bromine, N-chlorosuccinimide, N-bromo-succinimide etc.) at indoles C 3For example tetracol phenixin, chloroform, dimethyl formamide (DMF) or N-Methyl pyrrolidone (NMP) are used in halogenation on the position, solvent, and temperature of reaction is 0-30 ℃.The halogen of compound 13 is chlorine, bromine or iodine.C 3-R 16Can be at alkali (preferred Na 2CO 3) and Pd (PPh 3) 4Exist down and introduce, use for example toluene of inert solvent, temperature of reaction 80-100 ℃ by the Suzuki coupled reaction.Then 14 alkylations of 1H-indoles intermediate or arylation are obtained required intermediate 15, its method of introducing according to flow process 1 and flow process 2 is converted into final product 16.
D. be used as the substituted indole of pharmaceutical composition
The invention provides substituted indole as medicine.In a preferred embodiment, the indoles of replacement is configured to medicine, thereby treats and the relevant disease of the active increase of PAI-1 by the PAI-1 that for example suppresses the patient is active.
Usually, the indoles that replaces can give with pharmaceutical composition by giving the known any method in medicine field, comprise oral, contain clothes, part, general (for example transdermal, nose is interior or pass through the suppository administration) or parenteral (for example intramuscular, subcutaneous or intravenous injection) administration.Composition can adopt tablet, pill, capsule, semi-solid preparation, powder, sustained release preparation, solution, suspensoid, emulsion, syrup, elixir, aerosol or any other suitable composition forms; And comprise at least a The compounds of this invention and at least a pharmaceutically-acceptable excipients.Suitable vehicle is well known to those of ordinary skill in the art, the suitable vehicle and the method for compositions formulated can be referring to for example following canonical reference documents: Alfonso AR, Remington ' s Pharmaceutical Sciences, the 17th edition, MackPublishing Company, Easton PA, 1985.Suitable liquid vehicle (in particular for the liquid vehicle of injection solution) comprises water, salt brine solution, D/W and ethylene glycol.In part embodiment of the present invention, the substituted indole that is suitable for the present invention's practice will be given or be united other compound of at least a the present invention separately and be given.The substituted indole that is suitable for the present invention practice also can with at least a medication combined medication of other conventional treatment that is used for the disease for the treatment of.
The vehicle that aqueous suspension of the present invention can comprise substituted indole and be fit to the preparation aqueous suspension.Such vehicle can comprise suspension agent, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, polyvinylpyrrolidone, tragakanta and Sudan Gum-arabic; And dispersion agent or wetting agent, for example natural phosphatide (for example Yelkin TTS), the condensation product of epoxy alkane and lipid acid (for example polyoxyethylene stearic acid ester), the condensation product of oxyethane and long chain aliphatic alcohol (for example 17 carbon vinyloxy group hexadecanols (heptadecaethylene oxycetanol)), oxyethane with by the condensation product (for example polyoxyethylene sorbitol monoleate) of lipid acid and hexitol deutero-partial ester, perhaps oxyethane with by the condensation product (for example polyoxyethylene sorbitanic monoleate) of lipid acid and hexitan deutero-partial ester.Aqueous suspension also can comprise one or more sanitass (for example ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl), one or more tinting materials, one or more correctivess and one or more sweeting agents (for example sucrose, aspartame or asccharin).Can regulate the osmolarity of preparation.
Substituted indole is suspended in vegetables oil (for example peanut oil, sweet oil, sesame oil or Oleum Cocois), mineral oil (for example whiteruss) or their mixture, can prepares the oiliness suspensoid.The oiliness suspensoid can comprise thickening material, for example beeswax, solid paraffin or hexadecanol.Can add sweeting agent for example glycerine, Sorbitol Powder or sucrose, so that agreeable to the taste oral preparations to be provided.These preparations can be preserved by adding antioxidant (for example xitix).The example of injection oiliness solvent is referring to Minto, J.Pharmacol.Exp.Ther.281:93-102,1997.Pharmaceutical preparation of the present invention also can be oil-in-water emulsion.Oil phase can be above-mentioned vegetables oil or mineral oil or its mixture.Suitable emulsifying agent comprises natural gum (for example Sudan Gum-arabic and tragakanta), natural phospholipid (for example soybean lecithin), derived from the ester of lipid acid and hexitan or the condensation product (for example polyoxyethylene sorbitanic monoleate) of partial ester (for example sorbitanic monoleate) and these partial esters and oxyethane.Emulsion can also comprise with syrup and elixir in the same sweeting agent and correctives.Such preparation can also comprise negative catalyst, sanitas or tinting material.
Selected compounds can separately or be united other appropriate ingredients and is prepared as aerosol (be them can by " atomizing "), is used for inhalation.Aerosol can be placed into acceptable pressurization propellent, for example Refrigerant 12, propane, nitrogen etc.
Be fit to the preparation of parenteral (for example intraarticular, intravenously, intramuscular, intradermal, intraperitoneal and subcutaneous) administration, comprise water-based and non-aqueous isotonic sterile injection solution (they can comprise antioxidant, buffer reagent, fungistat and make preparation and the isoosmotic solute of intended recipient's blood) and water-based and non-aqueous aseptic suspensoid (they can comprise suspension agent, solubilizing agent, thickening material, stablizer and sanitas).Operable acceptable solvent and solvent have water, ringer's solution and isotonic sodium chloride.In addition, aseptic expressed oil can be used as solvent or suspension medium usually.Any gentle expressed oil be can use for this reason, synthetic monoglyceride or triglyceride comprised.In addition, lipid acid (for example oleic acid) can be used for injection formulations equally.These solution are aseptic, and do not contain unwanted material usually.When compound had enough solvabilities, they can directly be dissolved in physiological saline, can use or not use appropriate organic solvent (for example propylene glycol or polyoxyethylene glycol).The dispersion of miniaturization compound can prepare in the aqueous solution of starch or Xylo-Mucine or suitable oil (for example peanut oil).These preparations can be by conventional known sterilising technology degerming.Described preparation can comprise near the acceptable auxiliary substance of the required medicine of physiological condition, for example pH regulator agent and buffer reagent, toxicity conditioning agent, for example sodium acetate, sodium-chlor, Repone K, calcium chloride, Sodium.alpha.-hydroxypropionate etc.Substituted indole concentration in these preparations can change in relative broad range, and according to selected concrete administering mode and patient's needs, mainly makes one's options based on factors such as liquid volume, viscosity, body weight.For intravenous administration, preparation can be aseptic injection preparation, for example aseptic injection water-based or oiliness suspensoid.This suspensoid can use suitable dispersion agent or wetting agent and suspension agent to prepare according to known technique.Aseptic injection preparation also can be aseptic injectable solution agent or the suspensoid in nontoxic parenteral acceptable diluent or the solvent, for example solution in the 1,3 butylene glycol.The preparation of recommending can be contained in unitary dose or multiple doses sealed vessel for example in ampoule and the bottle.
Injection solution and suspensoid can be used sterile powder injection, granule and the tablet preparation of aforementioned type.
But be applicable to the substituted indole orally give that the present invention puts into practice.According to the other factors that types of compositions, unitary dose size, categories of excipients and those of ordinary skills know, the The compounds of this invention consumption can change in relative broad range in the composition.Usually, final composition can comprise for example substituted indole of 0.000001%-10% weight (%w), preferred 0.00001%w to 1%w, and remaining composition is one or more vehicle.
Oral drug preparation can be with medicine acceptable carrier well known in the art to be fit to oral dosage preparation.Such carrier makes pharmaceutical preparation can be formulated as the unit dosage that is fit to patient's absorption: tablet, pill, powder, dragee, capsule, liquid preparation, lozenge, gelifying agent, syrup, pulpous state agent, suspensoid etc.Being fit to oral preparation can comprise: (a) liquor agent, and for example the packing nucleic acid of significant quantity is suspended in thinner, for example water, salt solution or PEG 400; (b) capsule, sachet or tablet, each self-contained predetermined amount be the activeconstituents of liquid, solid, particle or gelatin; (c) suspensoid in the suitable liquid; (d) suitable emulsion.
Oral drug preparation can followingly obtain: if desired, The compounds of this invention mixed with solid excipient, and the optional gained mixture that grinds, the processing granular mixture takes the circumstances into consideration to obtain tablet or lozenge nuclear behind other suitable compound of adding then.Suitable solid excipient has carbohydrate or protein weighting agent, includes but not limited to sugar, comprises lactose, sucrose, N.F,USP MANNITOL or Sorbitol Powder; The starch of corn, wheat, paddy rice, potato or other plant; Mierocrystalline cellulose, for example methylcellulose gum, Walocel MT 20.000PV, Vltra tears or Xylo-Mucine; And natural gum, comprise Sudan Gum-arabic and tragakanta; And protein, for example gelatin and collagen.If desired, can add disintegrating agent or solubilizing agent, for example cross-linked polyvinylpyrrolidone, agar, Lalgine or their salt, for example sodium alginate.Tablet can comprise one or more lactose, sucrose, N.F,USP MANNITOL, Sorbitol Powder, calcium phosphate, W-Gum, yam starch, Microcrystalline Cellulose, gelatin, colloidal silica, talcum powder, Magnesium Stearate, stearic acid and the compatible carrier of other vehicle, tinting material, weighting agent, tackiness agent, thinner, buffer reagent, wetting agent, sanitas, correctives, dyestuff, disintegrating agent and medicine.Lozenge can comprise activeconstituents in correctives (for example sucrose), also can in inert base (for example milk sap of gelatin and glycerine or sucrose and Sudan Gum-arabic, gel etc.), comprise activeconstituents, except that activeconstituents, also comprise carrier known in the art.
Substituted indole of the present invention can also suppository form be used for rectal administration.These preparations can be mixed with by medicine and suitable non-irritating excipient, and described vehicle is a solid at normal temperature, and are liquid in rectal temperature, therefore will discharge medicine in the rectum fusing.Such material has theobroma oil and polyoxyethylene glycol.
The compounds of this invention can also by in the nose, intraocular, intravaginal and internal rectum administration, comprise suppository, insufflation, powder and aerosol (steroid inhalation for example, referring to Rohatagi, J.Clin.Pharmacol.35:1187-1193,1995; Tjwa, Ann.AllergyAsthma Immunol.75:107-111,1995).
Substituted indole of the present invention can be formulated as medicated sound, solution, suspensoid, emulsion, gelifying agent, ointment, ointment, paste, jelly (jellies), paint, powder and aerosol by local approach transdermal administration.
Coating material also can use with The compounds of this invention, and term " composition " can comprise activeconstituents and coating material as preparation, contains or do not contain other carrier.For example, all right microballoon administration of The compounds of this invention is used for slowly discharging in vivo.In one embodiment, microballoon can give by the microballoon that intradermal injection contains medicine, they subcutaneous slow release medicine (referring to Rao, J.Biomater Sci.Polym.Ed.7:623-645,1995; As biodegradable injected gel agent (referring to for example Gao, Pharm.Res.12:857-863,1995); Perhaps as oral microsphere (referring to for example Eyles, J.Pharm.Pharmacol.49:669-674,1997).Transdermal and intradermal administration all provide the constant release of several weeks or several months.Cachet also can be used for giving The compounds of this invention, for example Antiatherosclerosis medicine.
In another embodiment, The compounds of this invention can utilize the liposome administration, and liposome and cytolemma merge, perhaps by endocytosis, the part that promptly utilize to connect the part of liposome or directly connect oligonucleotide is attached on the surface membrane protein acceptor of cell, thereby causes endocytosis.By utilizing liposome, especially be loaded with the target cell ligands specific or in others preferred direction certain organs at surface of liposome, compound can be concentrated and give intravital target cell.(referring to for example Al-Muhammed, J.Microencapsul.13:293-306,1996; Chonn, Curr.Opin.Biotechnol.6:698-708,1995; Ostro, Am.J.Hosp.Pharm.46:1576-1587,1989).
In other cases, preferred preparation can be lyophilized injectable powder, and it can comprise for example following any or all of composition: the 1mM-50mM Histidine, and 0.1%-2% sucrose, 2%-7% N.F,USP MANNITOL, pH 4.5-5.5, this preparation can mix with damping fluid facing with preceding.
Pharmaceutical composition of the present invention also can be chosen wantonly and comprises that at least a other is used for the treatment of and PAI-1 is active increases relevant disease or treatment of conditions medicine except that comprising substituted indole.
It is aseptic, isoosmotic substantially that pharmaceutical composition is usually formulated as, and meet Good Manufacturing Practice and Quality Control of Drug (Good ManufacturingPractice, all regulations GMP) of FDA Food and Drug Administration fully.
E. determine the dosage of substituted indole
The invention provides the PAI-1 activity that adopts substituted indole to suppress the patient and increase the relevant disease and the method for illness with the PAI-1 activity with treatment.In illustrative embodiments of the invention, the technician will suffer from and PAI-1 concentration and/or the active patient who increases relevant disease with the The compounds of this invention treatment.
For therapeutic purpose, composition disclosed herein or compound can be by the heavy dose of administrations of single, give the patient by long-time continuous administering mode (for example continuously transdermal, mucous membrane or intravenously administrable), perhaps give the patient (for example by per hour, every day, weekly multiple dosing scheme) by the multiple dosing scheme.For example, pharmaceutical preparation of the present invention can give one or many every day, 3 times or 1 time weekly weekly.In illustrative embodiments of the invention, pharmaceutical preparation oral administration every day of the present invention 1 time or 2 times.
About this point, the treatment effective dose of biologically active drug can comprise the multidose in the long-term treatment regimen, and described scheme will obtain significant curative effect clinically, thereby alleviates the illness that one or more symptoms relevant with the active increase of PAI-1 maybe can detect.Thus, determining effective dose usually based on Research of Animal Model for Study, is the human clinical trial then, and determines with the dosage regimen of generation that significantly reduces patient's target symptom or disease or severity by measuring effective dose.In this respect, proper model comprises for example mouse, rat, pig, cat, non-human primate and other acceptable animal model known in the art.Perhaps, effective dose can use external model (for example immune analysis and histopathological analysis) to measure.When using such model, usually only need conventional calculating and adjust required proper concn and the dosage of biologically active drug that just can determine to treat significant quantity (amount that for example nose is interior, transdermal, vein or intramuscular effectively cause required reaction).In alternate embodiment, for treatment or diagnostic purpose, " significant quantity " of biologically active drug or " treatment effective dose " will only suppress or strengthen one or more selected biological activitys relevant with above-mentioned disease or illness.
Certainly, the actual dose of biologically active drug will change according to various factors, for example sphere of action and patient's concrete state (for example patient's age, build, healthy state, symptom degree, susceptibility factor etc.), administration time, route of administration and other medicines that give simultaneously or therapy.Can adjust dosage to obtain best preventative or therapeutic reaction." the treatment effective dose " of this paper is meant the dosage of generation effect after the administration.More particularly, the treatment effective dose of The compounds of this invention is preferably alleviated active symptom, complication or the biochemical indicator that increases relevant disease with PAI-1.Accurately dosage will depend on therapeutic purpose, and by those skilled in the art with known technology determine (referring to for example Lieberman, PharmaceuticalDosage Forms (1-3 volume, 1992); Lloyd, 1999, The Art, Science, andTechnology of Pharmaceutical Compounding; Pickar, 1999, DosageCalculations).The treatment effective dose also is such dosage: with clinical term, the treatment beneficial effect that is exactly active medicine surpasses its any toxicity or harmful side effect.What need further to note is, for each concrete patient, the professional's that concrete dosage should give according to individual need and supervision compound judgement is estimated and made adjustment in time.
In illustrative embodiments of the invention, the unit dosage of preparation compound is used for the standard dosage regimen.Like this, composition is easy to be divided into littler dosage again under the doctor instructs.For example, unitary dose can be packaged powders, bottle or ampoule, is preferably capsule or tablet.Active compound content in these unit dosage of composition can be for example about 1 gram to about 15 grams or more, according to patient's concrete needs once a day or multiple dosing.The treatment plan of beginning can utilize the haemoconcentration of PAI-1 and patient's remission to analyze to determine need still to be greatlyyer littler dosage with the minimum per daily dose of about 1 gram.For example, effective oral dosage of The compounds of this invention can for about 0.1mg/kg/ days to about 1,000mg/kg/ days.Preferably about 10mg/kg/ days to about 600mg/kg/ days, more preferably from about 25mg/kg/ days to about 200mg/kg/ days, even more preferably from about 50mg/kg/ days to about 100mg/kg/ days.
In certain embodiments, the present invention relates to the prodrug of formula 1 and formula 2 compounds.Term used herein " prodrug " is meant the compound that is converted into formula 1 or formula 2 compounds by metabolic way (for example hydrolysis) in vivo.The various forms of prodrug is known in the art, the form that for example following document is set forth: Bundgaard (editor), Design of Prodrugs, Elsevier (1985); Widder etc. (editor), Methods in Enzymology, the 4th volume, AcademicPress (1985); Krogsgaard-Larsen etc. (editor), " Design and Application ofProdrugs; Textbook ofDrug Design and Development, the 5th chapter, 113-191 (1991); Bundgaard etc.; Journal of Drug Delivery Reviews, 8:1-38 (1992), Bundgaard; J.of Pharmaceutical Sciences, 77:285 and following or the like (1988); Higuchi and Stella (editor), Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975).
F. medicine box
After the medicine that comprises substituted indole is formulated in the suitable carrier, the proper container of it can being packed into, and stick the label that is used for the treatment of PAI-1 diseases related (for example leukemia).In addition, comprise also can pack into container and stick the label that is used for the treatment of corresponding indication of at least a another medicine that can be used for treating other diseases related medicine of PAI-1.Perhaps, single medicine comprises substituted indole and at least aly can be used for treating other diseases related medicine of PAI-1, with its proper container and stick the treatment label of packing into.Comprise substituted indole and at least a administration that can be used for treating the combination medicine of other diseases related medicine of PAI-1 for the medicine that comprises substituted indole and in a kind of medicine, such label will comprise the explanation of for example relevant dosage, administration frequency and medication.Similarly, for the administration of the multiple medicine that provides in the container, such label for example will comprise the explanation about dosage, administration frequency and the medication of each medicine.
Embodiment
Embodiment 1-17 describes the synthetic of compound 1-17 respectively.
Embodiment 1:1-[4-({ [4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) phenyl]-1H-indole-2-carboxylic acid synthetic
Step 1: a large amount of excessive Raney  nickel are joined in batches in the 20ml ethanol stirred solution of 1-(4-nitrophenyl)-1H-indole-2-carboxylic acid (1.40g, 5.0mmol), hydrazine (1.0ml, 32mmol).After 2 hours, catalyzer removes by filter by Celite  521 short pads in stirring at room.Concentrated filtrate obtains 1-(4-aminophenyl)-1H-indole-2-carboxylic acid (1.0g, 80%), is light brown solid: MS (ESI) m/z 253 (MH +); MS (ESI) m/z 251 ([M-H] -).
Step 2: to 1-(4-the aminophenyl)-1H-indole-2-carboxylic acid that stirs (0.4g, in 1: 1 methylene dichloride/saturated aqueous solution of sodium bicarbonate of 10ml 1.59mmol), add 4-trifluoromethoxy-benzene sulfonyl chloride (0.40g, 1.53mmol).After 1 hour, collect solid, in stirring at room with half preparation HPLC purifying (chromatographic column: Phenomenex C18Luna 21.6mm * 60mm, 5 μ M; Solvent orange 2 A: water (0.1%TFA damping fluid); Solvent B: acetonitrile (0.1%TFA damping fluid); Solvent gradient: 0 minute: 0%B; 10 minutes: 100%B; Keep 100%B 5min.Flow velocity: 22.5ml/min), obtain 0.105g (15%) title compound, be light yellow solid:
1H NMR(DMSO-d 6)δ6.89(d，J＝8.3Hz，1H)，7.10-7.30(m，6H)，7.39(d，J＝2.1Hz，1H)，7.60(d，J＝7.2Hz，2H)，7.71(d，J＝6.0Hz，1H)，7.90-8.00(m，2H)，10.63(br s，1H)，12.74(br s，1H)；MS(ESI)m/z 477(MH +)；MS(ESI)m/z475([M-H] -)；
C 22H 16F 3N 2O 5S HRMS calculated value: 477.0721; Measured value (ESI +): 477.0719; C 22H 15F 3N 2O 5S0.2H 2O analytical calculation value: C, 55.05; H, 3.23; N, 5.84.Measured value: C, 54.97; H, 3.41; N, 5.82.
Embodiment 2:1-[4-(1H-pyrroles-1-yl) phenyl]-1H-indole-2-carboxylic acid synthetic
(0.4g, 1.59mmol) with 2, (0.50g, 15ml glacial acetic acid solution 3.78mmol) was 90 ℃ of heating 1.5 hours for the 5-dimethoxy-tetrahydrofuran with 1-(4-aminophenyl)-1H-indole-2-carboxylic acid.Remove desolvate after, resistates obtains title compound (0.095mg, 20%, light brown solid) with half preparation HPLC purifying:
1H NMR(DMSO-d 6)δ6.32(s，2H)，7.08(d，J＝8.4Hz，1H)，7.15-7.25(m，1H)，7.25-7.35(m，1H)，7.40-7.55(m，5H)，7.60-7.70(m，3H)，12.82(br s，1H)；MS(ESI)m/z303(MH +)；MS(ESI)m/z 301([M-H] -)；
C 19H 15N 2O 2HRMS calculated value: 303.1122; Measured value (ESI +): 303.1124; C 19H 14N 2O 20.1H 2O analytical calculation value: C, 75.0; H, 4.71; N, 9.21.Measured value: C, 74.90; H, 4.42; N, 9.33.
Embodiment 3:1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indole-2-carboxylic acid synthetic
Step 1: with 4-nitrobenzyl bromine (1.85g, 8.56mmol), the 1H-indole-2-ethyl formate (1.62g, 8.56mmol), salt of wormwood (4.17g, 30mmol) and the mixture of 100ml acetone refluxed 1 day.After being cooled to room temperature,, between water and methylene dichloride, distribute then by adding entry quencher reactant.Organic phase concentrates through dried over mgso, obtains 1-(4-nitrobenzyl)-1H-indole-2-ethyl formate (2.0g, 72%, pale solid):
1H NMR(DMSO-d 6)δ1.27(t，J＝7.1Hz，3H)，4.26(q，J＝7.1Hz，3H)，5.99(s，2H)，7.18(t，J＝7.0Hz，1H)，7.22(d，J＝9.0Hz，2H)，7.34(t，J＝7.0Hz，1H)，7.43(s，1H)，7.58(d，J＝13.8Hz，1H)，7.76(d，J＝13.8Hz，1H)，8.15(d，J＝9.0Hz，2H)；MS(ESI)m/z325(MH +).
Step 2: with a large amount of excessive Raney  nickel join in batches 1-(4-nitrobenzyl)-1H-indole-2-ethyl formate (0.65g, 2mmol), (0.5ml is in 25ml ethanol stirred solution 16mmol) for hydrazine.After 2 hours, catalyzer removes by filter by Celite  521 short pads in stirring at room.Concentrated filtrate obtains gumminess solid 1-(4-aminobenzyl)-1H-indole-2-ethyl formate (MS (ESI) m/z 294.2 (MH +)).Then this gumminess solid is dissolved in the 15ml methylene dichloride.In solution, add diisopropylethylamine (0.5ml, 2.9mmol) and xenyl 4-SULPHURYL CHLORIDE (0.5g, 1.0mmol).Concentration response thing after stirred overnight at room temperature is dissolved in 15ml 2: 1 again with resistates: in the 1THF/MeOH/ water.Add lithium hydroxide monohydrate (0.2g, 4.8mmol), with mixture in stirred overnight at room temperature.Remove most of organic solvent, reaction mixture with Glacial acetic acid acidifying (pH 6), is collected solid, with half preparation HPLC purifying.Absorb the collection product according to UV, concentrate, obtain title compound (0.11g, 22%, brown solid):
1H NMR(DMSO-d 6)δ5.75(s，2H)，6.93(d，J＝8.9Hz，2H)，7.01(d，J＝8.9Hz，2H)，7.09(t，J＝8.0Hz，1H)，7.43(t，J＝8.0Hz，1H)，7.49(s，1H)，7.40-7.55(m，4H)；7.65-7.80(m，3H)，7.75-7.82(m，4H)，10.30(s，1H)，12.93(s，1H)；
C 28H 23N 2O 4S HRMS calculated value: 483.1367; Measured value (ESI +): 483.1374; C 28H 22N 2O 4S0.2H 2O analytical calculation value: C, 69.18; H, 4.64; N, 5.76.Measured value: C, 69.21; H, 4.60; N, 5.78.
Embodiment 4:1-(4-{[(4-tert-butyl-phenyl) alkylsulfonyl] amino } benzyl)-1H-indole-5-carboxylic acid synthetic
Step 1: according to the method for embodiment 3 steps 1, use 1H-indole-5-carboxylic acid methyl esters and 4-nitrobenzyl bromine, preparation 1-(4-nitro-benzyl)-1H-indole-5-carboxylic acid methyl esters obtains yellow powder:
1H NMR(DMSO-d 6)δ3.84(s，3H)，5.67(s，2H)，6.71(dd，J＝3.2，0.8Hz，1H)，7.40(d，J＝8.8Hz，2H)，7.54(d，J＝8.7Hz，1H)，7.67(d，J＝0.8Hz，1H)，7.73(dd，J＝8.8，1.7Hz，1H)，8.19(d，J＝8.8Hz，2H)，8.29(d，J＝1.0Hz，1H)；MS(ESI)m/z 311(MH +)，309([M-H] -)；
C 17H 15N 2O 4HRMS calculated value: 311.1030; Measured value (ESI +): 311.1021.
Step 2: according to the method for embodiment 3 steps 2, use 1-(4-nitro-benzyl)-1H-indole-5-carboxylic acid methyl esters and 4-tert.-butylbenzene SULPHURYL CHLORIDE, the preparation title compound obtains light brown solid:
1H NMR(DMSO-d 6)δ1.24(s，9H)，5.33(s，2H)，6.59(d，J＝3.2Hz，1H)，7.02(d，J＝8.7Hz，2H)，7.07(d，J＝8.7Hz，2H)，7.45(d，J＝8.7Hz，1H)，7.51-7.54(m，3H)，7.65(d，J＝8.5Hz，2H)，7.69(d，J＝1.7Hz，1H)，8.21(d，J＝1.3Hz，1H)，10.23(br s，1H)，12.39(br s，1H)；MS(ESI)m/z463(MH +)，461([M-H] -)；
C 26H 26N 2O 4S HRMS calculated value: 463.1690; Measured value (ESI +): 463.1681.
Embodiment 5:1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indole-5-carboxylic acid synthetic
According to the method for embodiment 3 steps 2, use 1-(4-nitro-benzyl)-1H-indole-5-carboxylic acid methyl esters and xenyl-4-SULPHURYL CHLORIDE, the preparation title compound obtains white solid:
1H NMR(DMSO-d 6)δ5.34(s，3H)，6.59(d，J＝3.1Hz，1H)，7.06(d，J＝11.2Hz，2H)，7.10(d，J＝8.7Hz，2H)，7.40-7.48(m，4H)，7.52(d，J＝3.1Hz，1H)，7.67-7.70(m，3H)，7.75-7.85(m，4H)，8.21(d，J＝1.4Hz，1H)，10.34(br s，1H)，12.37(br s，1H)；MS(ESI)m/z483(MH +)，481([M-H] -)；
C 28H 23N 2O 4S HRMS calculated value: 483.1376; Measured value (ESI +): 483.1368.
Embodiment 6:1-(4-{[(4-tert-butyl-phenyl) alkylsulfonyl] amino } benzyl)-1H-indole-3-carboxylic acid synthetic
Step 1: according to the method for embodiment 3 steps 1, use 1H-indole-3-carboxylic acid methyl esters and 4-nitrobenzyl bromine, preparation 1-(4-nitro-benzyl)-1H-indole-3-carboxylic acid methyl esters (113220-11) obtains yellow powder:
1H NMR(DMSO-d 6)δ3.83(s，3H)，5.70(s，2H)，7.23(ddd，J＝9.9，4.6，0.8Hz，2H)，7.47(d，J＝8.8Hz，2H)，7.50(ddd，J＝9.9，4.6，0.8Hz，1H)，8.05(ddd，J＝9.9，4.6，0.8Hz，1H)，8.19(d，J＝8.8Hz，2H)，8.40(s，1H)；MS(ESI)m/z311(MH +)，309([M-H] -).
Step 2: according to the method for embodiment 3 steps 2, use 1-(4-nitro-benzyl)-1H-indole-3-carboxylic acid methyl esters and 4-tert.-butylbenzene SULPHURYL CHLORIDE, the preparation title compound obtains light brown solid:
1H NMR(DMSO-d 6)δ1.24(s，9H)，5.36(s，2H)，7.04(d，J＝8.5Hz，2H)，7.13-7.18(m，4H)，7.45(dd，J＝6.1，2.6Hz，1H)，7.52(d，J＝8.8Hz，2H)，7.66(d，J＝8.8Hz，2H)，8.00(dd，J＝6.1，2.6Hz，1H)，8.13(s，1H)，10.23(br s，1H)，11.98(br s，1H)；MS(ESI)m/z463(MH +)，461([M-H] -)；
C 26H 27N 2O 4S HRMS calculated value: 463.1690; Measured value (ESI +): 463.1681; Calculated value C 26H 26N 2O 4S0.06TFA:C, 67.51; H, 5.67; N, 6.06.Measured value: C, 67.40; H, 5.65; N, 6.04.
Embodiment 7:1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indole-3-carboxylic acid synthetic
According to the method for embodiment 3 steps 2, use 1-(4-nitro-benzyl)-1H-indole-3-carboxylic acid methyl esters and xenyl-4-SULPHURYL CHLORIDE, the preparation title compound is pale solid:
1H NMR(DMSO-d 6)δ5.37(s，2H)，7.07(d，J＝8.7Hz，2H)，7.13-7.18(m，4H)，7.40-7.51(m，4H)，7.67(d，J＝7.1Hz，2H)，7.75-7.85(m，4H)，8.00(dd，J＝5.8，0.7Hz，1H)，8.14(s，1H)，10.36(br s，1H)，12.01(br s，1H)；MS(ESI)m/z483(MH +)，481([M-H] -)；
C 28H 23N 2O 4S HRMS calculated value, 483.1376; Measured value (ESI +): 483.1367; C 28H 22N 2O 4S0.1TFA analytical calculation value: C, 68.57; H, 4.51; N, 5.67.Measured value: C, 68.67; H, 4.50; N, 5.70.
Embodiment 8:1-(4-{[(4-tert-butyl-phenyl) alkylsulfonyl] amino } benzyl)-1H-indoles-4-formic acid synthetic
Step 1: according to the method for embodiment 3 steps 1, use 1H-indoles-4-methyl-formiate and 4-nitrobenzyl bromine, preparation 1-(4-nitro-benzyl)-1H-indoles-4-methyl-formiate obtains yellow powder:
1H NMR(DMSO-d 6)δ3.90(s，3H)，5.69(s，2H)，7.05(dd，J＝3.1，0.9Hz，1H)，7.22(t，J＝7.6Hz，1H)，7.36(d，J＝8.9Hz，2H)，7.75(td，J＝7.6，3.1Hz，3H)，8.18(d，J＝8.9Hz，2H)；MS(ESI)m/z311(MH +)，309([M-H] -)；
C 17H 14N 2O 4Analytical calculation value: C, 65.80; H, 4.55; N, 9.03.Measured value: C, 65.81; H, 4.50; N, 8.98.
Step 2: according to the method for embodiment 3 steps 2, use 1-(4-nitro-benzyl)-1H-indoles-4-methyl-formiate and 4-tert.-butylbenzene SULPHURYL CHLORIDE, the preparation title compound obtains pale pink look solid:
1H NMR(DMSO-d 6)δ1.24(s，9H)，5.35(s，2H)，6.96(d，J＝3.1Hz，1H)，7.03(d，J＝8.7Hz，2H)，7.07(d，J＝8.0Hz，2H)，7.15(t，J＝7.8Hz，1H)，7.53(d，J＝8.8Hz，2H)，7.57(d，J＝3.2Hz，1H)，7.62-7.68(m，3H)，7.70(dd，J＝7.5，0.9Hz，1H)，10.26(br s，1H)，12.59(br s，1H)；MS(ESI)m/z463(MH +)，461([M-H] -)；
C 26H 27N 2O 4S HRMS calculated value: 463.1690; Measured value (ESI +): 463.1674.
Embodiment 9:1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indoles-4-formic acid synthetic
According to the method for embodiment 3 steps 2, use 1-(4-nitro-benzyl)-1H-indoles-4-methyl-formiate and xenyl-4-SULPHURYL CHLORIDE, the preparation title compound obtains pale solid:
1H NMR(DMSO-d 6)δ5.36(s，2H)，6.96(d，J＝3.1Hz，1H)，7.05(d，J＝8.0Hz，2H)，7.09(d，J＝9.0Hz，2H)，7.15(t，J＝7.8Hz，1H)，7.40-7.47(m，1H)，7.49-7.51(m，2H)，7.57(d，J＝3.1Hz，1H)，7.64-7.71(m，4H)，7.75-7.85(m，4H)，10.33(br s，1H)，12.58(br s，1H)；MS(ESI)m/z 483(MH +)；481([M-H] -)；
C 28H 23N 2O 4S HRMS calculated value: 483.1376; Measured value (ESI +): 483.1367.
Embodiment 10:1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indoles-6-formic acid synthetic
Step 1: according to the method for embodiment 3 steps 1, use 1H-indoles-6-methyl-formiate and 4-nitrobenzyl bromine, preparation 1-(4-nitrobenzyl)-1H-indoles-6-methyl-formiate obtains yellow powder:
1H NMR(DMSO-d 6)δ3.85(s，3H)，5.75(s，2H)，6.66(dd，J＝3.1，0.6Hz，1H)，7.34(d，J＝8.7Hz，2H)，7.60(t，J＝2.8Hz，1H)，7.79(d，J＝3.1Hz，1H)，8.07(s，1H)，8.15(s，1H)，8.19(d，J＝8.8Hz，1H)，8.28(d，J＝8.7Hz，2H)；MS(ESI)m/z 311(MH +)；309([M-H] -).
Step 2: according to the method for embodiment 3 steps 2, use 1-(4-nitro-benzyl)-1H-indoles-6-methyl-formiate and xenyl-4-SULPHURYL CHLORIDE, the preparation title compound obtains light yellow solid:
1H NMR(DMSO-d 6)δ5.40(s，2H)，6.55(d，J＝3.9Hz，1H)，7.06(s，4H)，7.40-7.43(m，1H)，7.47-7.51(m，2H)，7.60(d，J＝1.2Hz，1H)，7.63(d，J＝3.1Hz，1H)，7.67(dt，J＝7.0，1.2Hz，2H)，7.75-7.85(m，4H)，7.99(d，J＝0.9Hz，1H)，10.32(br s，1H)，12.55(br s，1H)；MS(ESI)m/z 483(MH +)；481([M-H] -)；
C 28H 23N 2O 4S HRMS calculated value: 483.1376; Measured value (ESI +): 483.1368; C 28H 22N 2O 4S0.02TFA analytical calculation value: C, 69.21; H, 4.60; N, 5.76.Measured value: C, 69.01; H, 4.48; N, 5.78.
Embodiment 11:3-phenyl-1-{4-[(phenyl sulfonyl) amino] benzyl }-1H-indole-2-carboxylic acid synthetic
Step 1: at 0～5 ℃, (4.94g, DMF 27.7mmol) (20ml) drips of solution is added to the 1H-indole-2-ethyl formate, and (5.0g is in DMF 26.4mmol) (15ml) stirred solution with the N-bromo-succinimide.After adding finishes, reactant is heated to room temperature, continuously stirring is 1.5 hours again.Reaction mixture is poured on the frozen water, collects the gained precipitation, drying obtains 3-bromo-1H-indolecarboxylic acid ethyl ester (6.68g, 81%), is white solid:
1H NMR(DMSO-d 6)δ1.37(t，J＝7.2Hz，3H)，4.38(q，J＝7.2Hz，2H)，7.18-7.22(m，1H)，7.34-7.38(m，1H)，7.50(dd，J＝8.3，0.8Hz，1H)，7.55(dd，J＝8.3，0.8Hz，1H)，12.22(br s，1H)；MS(ESI)m/z 268(MH +)；266([M-H] -).
Step 2: with 3-bromo-1H-indolecarboxylic acid ethyl ester (0.50g, 1.87mmol), phenyl-boron dihydroxide (0.27g, 2.25mmol), 2M aqueous sodium carbonate (8ml), four (triphenylphosphines) close palladium (O) (0.20g, 0.17mmol), the mixture of ethanol (16ml) and toluene (30ml) is in 65 ℃ of heating 16 hours, cooling then.Reaction mixture is used ethyl acetate extraction then with the dilution of 1N hydrochloric acid.Organic extract liquid washes with water, through dried over mgso, concentrates.With fast silica gel chromatogram method purifying (using ethyl acetate/hexane) as eluent, obtain 0.34g (68%) 3-phenyl-1H-indolecarboxylic acid ethyl ester, be pink solid:
1H NMR(DMSO-d 6)δ1.18(t，J＝7.2Hz，3H)，4.22(q，J＝7.2Hz，2H)，7.07-7.11(m，1H)，7.29-7.33(m，1H)7.45(dd，J＝8.3，0.8Hz，1H)，7.48-7.50(m，5H)，7.50(dd，J＝8.3，0.8Hz，1H)，11.90(br s，1H)；MS(ESI)m/z 266(MH +)；264([M-H] -).
Step 3: according to the method for embodiment 3 steps 1, use 3-phenyl-1H-indolecarboxylic acid ethyl ester and 4-nitrobenzyl bromine, preparation 1-(4-nitro-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester obtains yellow powder:
1H NMR(DMSO-d 6)δ 1HNMR(DMSO-d 6)δ0.91(t，J＝7.2Hz，3H)，4.05(q，J＝7.2Hz，2H)，5.97(s，2H)，7.17-7.23(m，1H)，7.32(d，J＝8.8Hz，2H)，7.36-7.42(m，1H)，7.38-7.42(m，1H)，7.45-7.48(m，4H)，7.52(d，J＝8.2Hz，1H)，7.62(d，J＝8.2Hz，1H)，8.19(d，J＝8.8Hz，2H)；MS(ESI)m/z 401(MH +)；399([M-H] -)；
C 24H 21N 2O 4HRMS calculated value: 401.1490; Measured value (ESI +): 401.1494; C 24H 20N 2O 40.05TFA analytical calculation value: C, 71.99; H, 5.03; N, 7.00.Measured value: C, 71.27; H, 4.98; N, 6.90.
Step 4: according to the method for embodiment 1 step 1, use 1-(4-nitro-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester, preparation 1-(4-amino-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester obtains yellow soup compound:
1H NMR(DMSO-d 6)δ0.98(t，J＝7.2Hz，3H)，4.11(q，J＝7.2Hz，2H)，4.99(br s，2H)，5.59(s，2H)，6.44(d，J＝8.41Hz，2H)，6.85(d，J＝8.4Hz，2H)，7.13(td，J＝7.1，0.8Hz，1H)，7.34(td，J＝7.1，0.8Hz，1H)，7.38-7.41(m，3H)，7.44-7.49(m，3H)，7.69(d，J＝8.4Hz，1H)；MS(ESI)m/z 371(MH +)；369([M-H] -)；
C 24H 22N 2O 20.04TFA analytical calculation value: C, 71.12; H, 5.92; N, 7.47.Measured value: C, 71.03; H, 5.87; N, 7.36.
Step 5: according to the method for embodiment 3 steps 2, use 1-(4-amino-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester and benzene sulfonyl chloride, the preparation title compound obtains pale solid:
1H NMR(DMSO-d 6)δ5.72(s，2H)，6.95-7.00(m，4H)，7.09-7.13(m，1H)，7.27-7.31(m，1H)，7.33-7.37(m，1H)，7.42-7.45(m，5H)，7.49-7.55(m，3H)，7.57-7.61(m，1H)，7.72(dd，J＝7.1，1.4Hz，2H)，10.26(br s，1H)，12.83(br s，1H)；MS(ESI)m/z 481([M-H] -)；
C 28H 21N 2O 4S HRMS calculated value: 481.1224; Measured value (ESI -): 481.1228.
Embodiment 12:1-{4-[(methyl sulphonyl) amino] benzyl }-3-phenyl-1H-indole-2-carboxylic acid synthetic
According to the method for embodiment 3 steps 2, use 1-(4-nitro-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester and methylsulfonyl chloride, the preparation title compound obtains pale solid:
1H NMR(DMSO-d 6)δ2.94(s，3H)，5.80(s，2H)，7.05-7.15(m，5H)，7.31-7.38(m，2H)，7.43-7.47(m，5H)，7.62(d，J＝8.4Hz，1H)，9.68(br s，1H)，12.87(br s，1H)；MS(ESI)m/z 419([M-H] -)；
C 23H 19N 2O 4S HRMS calculated value: 419.1068; Measured value (ESI -): 419.1074.
Embodiment 13:1-{4-[(phenyl sulfonyl) amino] benzyl }-3-thiophene-2-base-1H-indole-2-carboxylic acid synthetic
Step 1: according to the method for embodiment 11 steps 2, use 3-bromo-1H-indolecarboxylic acid ethyl ester and 2-thienyl boric acid, preparation 3-thiophene-2-base-1H-indole-2-ethyl formate obtains buff powder:
1H NMR(DMSO-d 6)δ1.27(t，J＝7.2Hz，3H)，4.30(q，J＝7.2Hz，2H)，7.12-7.16(m，1H)，7.17-7.20(m，1H)，7.31-7.34(m，1H)，7.36(dd，J＝5.1，1.5Hz，1H)，7.51(d，J＝8.3Hz，1H)，7.63(d，J＝6.3Hz，1H)，7.71(d，J＝8.2Hz，1H)，12.02(br s，1H)；MS(ESI)m/z 272(MH +)；270([M-H] -).
Step 2: according to the method for embodiment 3 steps 1, use 3-thiophene-2-base-1H-indole-2-ethyl formate and 4-nitrobenzyl bromine, preparation 1-(4-nitro-benzyl)-3-thiophene-2-base-1H-indole-2-ethyl formate obtains yellow powder:
1H NMR(DMSO-d 6)δ1.02(t，J＝7.2Hz，3H)，4.15(q，J＝7.2Hz，2H)，7.20(dd，J＝6.9，3.4Hz，1H)，7.24(dd，J＝6.2，0.8Hz，1H)，7.25-7.27(m，1H)，7.31(d，J＝8.8Hz，2H)，7.37-7.43(m，1H)，7.62(d，J＝8.4Hz，1H)，7.68(dd，J＝5.2，1.2Hz，1H)，7.71(d，J＝4.1Hz，1H)，8.19(d，J＝8.8Hz，2H)；MS(ESI)m/z 407(MH +)；405([M-H] -)；
C 22H 18N 2O 4S analytical calculation value: C, 65.01; H, 4.46; N, 6.89.Measured value: C, 65.04; H, 6.62; N, 6.82.
Step 3: according to the method for embodiment 1 step 1, use 1-(4-nitro-benzyl)-3-thiophene-2-base-1H-indole-2-ethyl formate, preparation 1-(4-amino-benzyl)-3-thiophene-2-base-1H-indole-2-ethyl formate:
1H NMR(DMSO-d 6)δ1.10(t，J＝7.2Hz，3H)，4.20(q，J＝7.2Hz，2H)，5.01(brs，2H)，5.55(s，2H)，6.45(d，J＝8.5Hz，2H)，6.84(d，J＝8.5Hz，2H)，7.16-7.20(m，3H)，7.35(td，J＝7.3，1.0Hz，1H)，7.62(dd，J＝5.2，1.2Hz，1H)，7.65(d，J＝4.1Hz，1H)，7.71(d，J＝8.8Hz，1H)；MS(ESI)m/z 377(MH +)；375([M-H] -)；
C 22H 20N 2O 2S0.05TFA analytical calculation value: C, 69.46; H, 5.29; N, 7.33.Measured value: C, 69.66; H, 5.04; N, 7.72.
Step 4: according to the method for embodiment 3 steps 2, use 1-(4-amino-benzyl)-3-thiophene-2-base-1H-indole-2-ethyl formate and benzene sulfonyl chloride, the preparation title compound obtains light brown solid:
1H NMR(DMSO-d 6)δ5.67(s，2H)，6.95-7.05(m，4H)，7.14-7.23(m，3H)，7.30-735(m，1H)，7.49-7.75(m，8H)，10.26(br s，1H)，13.24(br s，1H)；MS(ESI)m/z 489(MH +)；
C 26H 21N 2O 4S 2HRMS calculated value: 489.0940; Measured value (ESI +): 489.0935.
Embodiment 14:1-{4-[(methyl sulphonyl) amino] benzyl }-3-thiophene-2-base-1H-indole-2-carboxylic acid synthetic
According to the method for embodiment 3 steps 2, use 1-(4-nitro-benzyl)-3-thiophene-2-base-1H-indole-2-ethyl formate and methylsulfonyl chloride, the preparation title compound obtains light yellow solid:
1H NMR(DMSO-d 6)δ2.94(s，3H)，5.76(s，2H)，7.08-7.24(m，7H)，7.34(td，J＝8.4，1.2Hz，1H)，7.60-7.70(m，3H)，9.69(br s，1H)，13.25(brs，1H)；MS(ESI)m/z 427(MH +)；MS(ESI)m/z 425([M-H] -)；
C 21H 19N 2O 4S 2HRMS calculated value: 427.0784; Measured value (ESI +): 427.0779.
Embodiment 15:1-[4-(2,5-dimethyl-1H-pyrroles-1-yl) benzyl]-3-phenyl-1H-indole-2-carboxylic acid synthetic
Under nitrogen atmosphere, with 1-(4-amino-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester (0.20g, 0.54mmol), acetonyl-acetone (0.16ml, 1.35mmol) and the mixture reflux of toluene (15ml) 6 hours, use the Dean this-Rodney Stark couch water trap (Dean-Starktrap).Reactant cooling back concentrates.Resistates is dissolved in 10ml 2: 1 again: in the 1THF/MeOH/ water.Add lithium hydroxide monohydrate (0.09g, 2.1mmol), with mixture in stirred overnight at room temperature.Remove most of organic solvent, reaction mixture with Glacial acetic acid acidifying (pH 6), collected solid, use the HPLC purifying, obtain title compound (0.027g, 6%, brown solid):
1H NMR(DMSO-d 6)δ1.91(s，6H)，5.75(s，2H)，7.01-7.30(m，6H)，7.32-7.38(m，2H)，7.40-7.50(m，6H)，7.68(d，J＝8.54Hz，1H)，12.80(br s，1H)；MS(ESI)m/z 421(MH +)；MS(ESI)m/z 419([M-H] -)；
C 28H 26N 2O 2HRMS calculated value: 421.1905; Measured value (ESI +): 421.1915.
Synthesizing of embodiment 16:1-(4-anilino benzyl)-3-phenyl-1H-indole-2-carboxylic acid
With phenyl-boron dihydroxide (0.16g, 0.81mmol), Cu (OAc) 2(0.049g, 0.27mmol) and tetradecanoic acid (0.037g 0.16mmol) mixes in being equipped with the 100ml round-bottomed flask of big stirring rod.Load onto rubber septum, add dry toluene (2ml), 2 successively, the 6-lutidine (0.066ml, 0.57mmol) and 1-(4-amino-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester (0.20g, 0.54mmol).With gained mixture high-speed stirring 24 hours, with ethyl acetate (10ml) dilution, filter by silicagel pad, use column chromatography purifying (5-25%EtOAc/ hexane) then, obtain the gumminess solid.To the gumminess solid 15ml that stirs 2: 1: add in the 1THF/MeOH/ aqueous solution lithium hydroxide monohydrate (0.1g, 2.4mmol).40 ℃ of reaction stirred 5 hours.Remove most of organic solvent, reaction mixture with Glacial acetic acid acidifying (pH 6), collected solid, use the HPLC purifying, obtain white powder (0.023g, 10%):
1H NMR(DMSO-d 6)δ5.64(s，2H)，6.77(t，J＝7.4Hz，1H)，6.96(d，J＝8.5Hz，2H)，7.00(dd，J＝7.6，0.9Hz，2H)，7.04(t，J＝7.1Hz，1H)，7.15-7.19(m，4H)，7.25(t，J＝7.11Hz，1H)，7.39(t，J＝7.4Hz，2H)，7.46-7.53(m，1H)，7.53(t，J＝7.4Hz，2H)，7.54-7.56(m，2H)，8.08(br s，1H)，13.01(br s，1H)；MS(ESI)m/z 419(MH +)；MS(ESI)m/z 417([M-H] -)；
C 28H 23N 2O 2HRMS calculated value: 419.1757; Measured value (ESI +): 419.1755.
Synthesizing of embodiment 17:1-(4-anilino benzyl)-3-thiophene-2-base-1H-indole-2-carboxylic acid
According to the method for embodiment 16, use 1-(4-amino-benzyl)-3-thiophene-2-base-1H-indole-2-ethyl formate and phenyl-boron dihydroxide, the preparation title compound obtains the light green solid:
1H NMR(DMSO-d 6)δ5.70(s，2H)，6.78(td，J＝7.4，1.0Hz，1H)，6.98(d，J＝8.7Hz，2H)，7.01(dd，J＝8.5，1.0Hz，2H)，7.04(d，J＝8.7Hz，2H)，7.16(t，J＝3.5Hz，1H)，7.17(dd，J＝5.2，1.6Hz，2H)，7.21(dd，J＝6.9，2.1Hz，2H)，7.33-7.37(m，1H)，7.61(dd，J＝5.1，1.3Hz，1H)，7.66(t，J＝8.7Hz，2H)，8.12(br s，1H)，13.34(br s，1H)；MS(ESI)m/z 425(MH +)；MS(ESI)m/z 423([M-H] -)；
C 26H 21N 2O 2S HRMS calculated value: 425.1321; Measured value (ESI +): 425.1319.
The preliminary screening that embodiment 18:PAI-1 suppresses
Test compound is dissolved in DMSO, and final concentration is 10mM, then with 100 times of physiological buffer dilutions.Inhibition test at first joins test compound (final concentration 1-100 μ M, 0.2% maximum DMSO concentration) and contains 140nM recombinant human plasminogen activator inhibitor-1 (PAI-1; Molecular Innovations, Royal Oak is in damping fluid MI) (pH 6.6).At room temperature incubation is after 1 hour, adds the 70nM recombinant human and organizes profibr(in)olysin activator (tPA), with the mixture of test compound, PAI-1 and tPA incubation 30 minutes again.Behind the incubation, (American Diagnostica, Greenwich CT), read absorbancy at the 0th minute and the 60th minute in 405nm to the chromogenic substrate Spectrozyme-tPA of adding tPA for the second time.The PAI-1 inhibition equals the residual tPA activity in the presence of test compound and PAI-1 relatively.Control treatment is included in without any test compound and acts under the situation of tPA, and TPA is suppressed fully by PAI-1 (mol ratio 2: 1).
Embodiment 19: the IC that determines to suppress PAI-1 50Test
This test is based on the interaction of can dissociating of the non-SDS between tPA and the active PAI-1.At first, test board is wrapped quilt with buman tPA (10 μ g/ml).Test compound of the present invention is dissolved in DMSO, and concentration is 10mM, and using physiological buffer (pH 7.5) to be diluted to final concentration then is 1-50 μ M.With test compound with people PAI-1 (50ng/ml) incubation 15 minutes at room temperature.The tPA bag is sealed this plate then by the solution washing of plate with 0.05% tween (Tween)-20 and 0.1%BSA with 3%BSA solution.Add the aliquots containig of substituted indole/PAI-1 solution in tPA wraps by plate, incubation is 1 hour under the room temperature, then washing.The active PAI-1 of following evaluation board: add the aliquots containig of the 33B8 monoclonal antibody of 1: 1000 dilution anti-people PAI-1, with this plate at room temperature incubation 1 hour (Molecular Innovations, RoyalOak, MI).Wash plate adds with lowlenthal serum and pressed 1: 50, the goat anti-mouse IgG-alkaline phosphatase conjugate solution of 000 dilution once more.With this plate incubation 30 minutes at room temperature, washing adds alkaline phosphatase substrate solution then.With this plate incubation 45 minutes at room temperature, at OD 405nmMeasure colour developing.Quantitative assay is in conjunction with the active PAI-1 of tPA, to measure IC under the different tests compound concentration 50Utilization logarithm best fit equation is analyzed the result.According to the typical curve test of 0-100ng/ml, drawing sensitivity is 5ng/ml people PAI-1.
The compounds of this invention suppresses profibr(in)olysin activator inhibitor-1, the results are shown in Table 1.
Table 1
Compound number IC 50 μM Inhibition percentage ratio at 10 μ M Inhibition percentage ratio at 25 μ M
1 39 40
2 15 35
3 66
4 27
5 22
6 19 28
7 25 27
8 27 47
9 26 35
10 26 30
11 51 71
12 42 49
Compound number IC 50 μM Inhibition percentage ratio at 10 μ M Inhibition percentage ratio at 25 μ M
13 50 79
14 45 53
15 2.51 53 69
16 26 32
17 25 35
Although for the purpose of clear understanding, above describe the present invention in detail by embodiment, for the technician, it is evident that, comprise some changes and improvements in the disclosed content, these changes and improvements need not too much experiment and just can put into practice, thereby fall in the scope of appended claims, embodiment is an illustrative and nonrestrictive.
All publications cited above and patent documentation all are attached to by reference and are used for all purposes herein, and its degree indicates separately as each publication or patent documentation and is attached to herein.

Claims (23)

1. compound or an acceptable salt of its medicine or ester-formin with following formula structure:
Figure A2004800344530002C1
Wherein:
X is chemical bond or C 1-C 6Alkylidene group;
R 1And R 2Be hydrogen, C independently 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl, heterocyclic radical ,-C (=O) C 1-C 6Alkyl ,-C (=O) aryl ,-C (=O) heterocycle ,-C (=O) N (R 6) C 1-C 6Alkyl ,-C (=O) N (R 6) aryl ,-C (=O) N (R 6) heterocycle ,-SO 2-C 1-C 6Alkyl ,-SO 2-aryl or-SO 2-heterocycle; Perhaps
R 1And R 2Constitute heterocycle together;
R 3And R 4Be hydrogen, halogen, C independently 1-C 6Alkyl, C 1-C 3Perfluoroalkyl, C 1-C 6Alkoxyl group, C 3-C 8Cycloalkyl ,-C (=O) C 1-C 3Alkyl ,-OH ,-NH 2Or-NO 2
R 5Be hydrogen, C 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl or heterocyclic radical;
When A exists hydrogen, C 6-C 10Aryl or heterocyclic radical;
R 6Be hydrogen, C 1-C 6Alkyl, halogen, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, aralkyl, C 6-C 10Aryl, heterocyclic radical, hydroxyl, C 1-C 6Alkoxyl group, aryl-oxygen base, oxo (=O) ,-CN ,-C (=O) H ,-CO 2H ,-OCO 2C 1-C 6Alkyl ,-CO 2C 1-C 6Alkyl ,-CO 2-aryl ,-CO 2(C 1-C 6Alkyl) aryl ,-OCO 2-aryl ,-C (=O) NH 2,-C (=O) NHOH, amino, C 1-C 6Alkylamino, each moieties all contain 1-6 carbon atom dialkyl amido ,-NHC (=O) NH-C 1-C 6Alkyl ,-NHSO 2-C 1-C 6Alkyl ,-NHSO 2-aryl or-NHSO 2-heterocycle;
Wherein said alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, aryl and heterocyclic radical are optional separately by 1,2,3 or the replacement of more a plurality of substituting group.
2. the compound of claim 1 or acceptable salt of its medicine or ester-formin, described compound has the following formula structure:
Wherein Y is NHSO 2-C 1-C 6Alkyl, NHSO 2-aryl, NHSO 2-heterocycle, pyrroles, NH-aryl or NH-heterocycle.
3. the compound of claim 1, wherein R 1And R 2Be hydrogen, unsubstituted C independently 1-C 6Alkyl, C 2-C 7Thiazolinyl, C 2-C 7Alkynyl, C 3-C 8Cycloalkyl, C 7-C 11Bicyclic alkyl, C 6-C 10Aryl, heterocyclic radical ,-C (=O) C 1-C 6Alkyl ,-C (=O) aryl ,-C (=O) heterocycle ,-C (=O) N (R 6) C 1-C 6Alkyl ,-C (=O) N (R 6) aryl ,-C (=O) N (R 6) heterocycle ,-SO 2-C 1-C 6Alkyl ,-SO 2-aryl or-SO 2-heterocycle.
4. the compound of claim 1, wherein R 1And R 2Be hydrogen, unsubstituted SO independently 2-alkyl, unsubstituted SO 2-aryl or optional quilt-OCF 3, the SO that replaces of aryl or alkyl 2-aryl.
5. the compound of claim 1, wherein R 1And R 2Constitute heterocycle with nitrogen.
6. the compound of claim 5, wherein R 1And R 2Constitute optional by 1-2 C with nitrogen 1-C 6The pyrroles that alkyl replaces.
7. each compound, wherein R among the claim 1-6 3And R 4Be hydrogen, halogen, C independently 1-C 3Perfluoroalkyl, C 1-C 6Alkoxyl group, C 3-C 8Cycloalkyl ,-C (=O) C 1-C 3Alkyl ,-OH ,-NH 2,-NO 2, unsubstituted C 1-C 6Alkyl or by halogen ,-C that CN or alkoxyl group replace 1-C 6Alkyl.
8. each compound, wherein R among the claim 1-7 5Be hydrogen.
9. each compound among the claim 1-8 is hydrogen, phenyl or thiophene when wherein A exists.
10. the compound of claim 1, described compound is one of following compounds:
(1) 1-[4-({ [4-(trifluoromethoxy) phenyl] alkylsulfonyl } amino) phenyl]-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(2) 1-[4-(1H-pyrroles-1-yl) phenyl]-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(3) 1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(4) 1-(4-{[(4-tert-butyl-phenyl) alkylsulfonyl] amino } benzyl)-1H-indole-5-carboxylic acid or acceptable salt of its medicine or ester-formin; Or
(5) 1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indole-5-carboxylic acid or acceptable salt of its medicine or ester-formin.
11. the compound of claim 1, described compound is one of following compounds:
(1) 1-(4-{[(4-tert-butyl-phenyl) alkylsulfonyl] amino } benzyl)-1H-indole-3-carboxylic acid or acceptable salt of its medicine or ester-formin;
(2) 1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indole-3-carboxylic acid or acceptable salt of its medicine or ester-formin;
(3) 1-(4-{[(4-tert-butyl-phenyl) alkylsulfonyl] amino } benzyl)-1H-indoles-4-formic acid or acceptable salt of its medicine or ester-formin;
(4) 1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indoles-4-formic acid or acceptable salt of its medicine or ester-formin; Or
(5) 1-{4-[(1,1 '-biphenyl-4-base alkylsulfonyl) amino] benzyl }-1H-indoles-6-formic acid or acceptable salt of its medicine or ester-formin.
12. the compound of claim 1, described compound is one of following compounds:
(1) amino 3-phenyl-1-{4-[(phenyl sulfonyl)] benzyl }-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(2) amino 1-{4-[(methyl sulphonyl)] benzyl }-3-phenyl-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(3) amino 1-{4-[(phenyl sulfonyl)] benzyl }-3-thiophene-2-base-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin;
(4) amino 1-{4-[(methyl sulphonyl)] benzyl }-3-thiophene-2-base-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin; Or
(5) 1-[4-(2,5-dimethyl-1H-pyrroles-1-yl) benzyl]-3-phenyl-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formin.
13. the compound of claim 1, described compound are 1-(4-anilino benzyl)-3-phenyl-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formins.
14. the compound of claim 1, described compound are 1-(4-anilino benzyl)-3-thiophene-2-base-1H-indole-2-carboxylic acid or acceptable salt of its medicine or ester-formins.
15. one kind is suppressed the active method of PAI-1, this method comprises among the claim 1-15 that needs the patient treatment of this inhibition significant quantity each compound.
16. treat the diseases related method of PAI-1 for one kind, this method comprises among the claim 1-15 that needs the patient treatment of this treatment significant quantity each compound.
17. the method for claim 16, wherein said PAI-1 is diseases related to be the fibrinolytic system obstacle.
18. the method for claim 16, wherein said PAI-1 is diseases related to be thrombosis, auricular fibrillation, pulmonary fibrosis, myocardial ischemia, apoplexy, operating thromboembolic states complication, cardiovascular disorder, atherosclerotic plaque formation, chronic obstructive pulmonary disease, renal fibrosis, polycystic ovarian syndrome, diabetes, alzheimer's disease or cancer.
19. the method for claim 19, wherein said thrombosis is selected from venous thrombosis, artery thrombosis, cerebral thrombosis and venous thrombosis.
20. the method for claim 18, wherein said PAI-1 is diseases related to be the cardiovascular disorder that the non-insulin-dependent diabetes mellitus (NIDDM) by the patient causes.
21. each method among the claim 16-21, wherein said treatment significant quantity are 25mg/kg/ days to 200mg/kg/ days.
22. a pharmaceutical composition, said composition comprise among the claim 1-15 each compound or the acceptable salt of its medicine or ester-formin and pharmaceutically-acceptable excipients or carrier.
23. a method for the treatment of thrombosis, auricular fibrillation, pulmonary fibrosis, operating thromboembolic states complication, apoplexy, myocardial ischemia, atherosclerotic plaque formation, chronic obstructive pulmonary disease or renal fibrosis, this method comprise among the claim 1-15 that needs the patient treatment of this treatment significant quantity each compound.
CNA2004800344530A 2003-09-25 2004-09-24 Substituted indole acid derivatives and their use as PAI-1 inhibitors Pending CN1882537A (en)

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Publication number Priority date Publication date Assignee Title
WO2018059427A1 (en) * 2016-09-27 2018-04-05 深圳微芯生物科技有限责任公司 Method for preparing phenylalanine compound

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018059427A1 (en) * 2016-09-27 2018-04-05 深圳微芯生物科技有限责任公司 Method for preparing phenylalanine compound
KR20190049883A (en) * 2016-09-27 2019-05-09 쉔젠 칩스크린 바이오사이언스 씨오., 엘티디. Method for producing phenylalanine compound
US10640465B2 (en) 2016-09-27 2020-05-05 Shenzhen Chipscreen Biosciences Co., Ltd. Method for preparing phenylalanine compound
KR102264868B1 (en) 2016-09-27 2021-06-14 쉔젠 칩스크린 바이오사이언스 씨오., 엘티디. Method for producing phenylalanine compound

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