MX2007002176A - Thiazolo-naphthyl acids as inhibitors of plasminogen activator inhibitor-1 - Google Patents

Abstract

The present invention relates to thiazolo-naphthyl acids of the formula (I) and methods of using them to modulate PAI-1 expression and to treat PAI-1 related disorders.

Description

ACIDOS DE TIAZOLO-NAFTILO FIELD OF THE INVENTION The present invention relates, in general, to thiazolo-naphthyl acids and methods for using them. BACKGROUND OF THE INVENTION The p-rotease serine inhibitor PAI-1 is one of the primary inhibitors of the fibrinolytic system. The fibrinolytic system comprises the plasminogen of proenzymes, which is converted to the active enzyme, plasmin, by one of two tissue-type plasminogen activators, t-PA or u-PA. PAI-1 is the main physiological inhibitor of t-PA or u-PA. One of the main functions of plasmin in the fibibolytic system is to digest fibrin at the site of the vascular lesion. However, the fibrinolytic system is not only responsible for the elimination of fibrin from the circulation but is also involved in several other biological processes including ovulation, embryogenesis, intimal proliferation, angiogenesis, tumorigenesis and atherosclerosis. Elevated levels of PAI-1 have been associated with a variety of diseases and conditions including those associated with insufficiency of the fibrinolytic system. For example, elevated levels of PAI-1 have been implicated in thrombotic diseases, for example, diseases in which the thrombus obstructs local blood circulation or deviates and embolizes to occlude. l blood flow down (Krishnamurti, Blood 69, 798 (1987), Reilly, Arteriesclerosis and thrombosis, 11, 1276 (1991), Carmeliet, Journal of Clinical use them in order to modulate the activity or expression of PAI-1, for example, in the treatment of disorders associated with high levels of PAI-1. BRIEF DESCRIPTION OF THE INVENTION In iere aia acids F o or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof, wherein: Ar is aryl or heteroajryl; Ri is hydrogen, Ci-Ci2 alkyl, C6-14 aryl, C6-i4 ar (Ci-6) 1 alkyl, - (CH2) p-heteroaryl, -CH2) p-CO-aryl, - (CH2) P - CO-1 heteroaryl, - (CH2) P -CO- (Ci-C6) alkyl, C2 C7 alkenyl, C2 C7 alkynyl, C3-C3 cycloalkyl, halogen Ci-C3 perfluoroalkyl or Ci-C3j perfluoroalkoxy; I R2 and R3 are independently hydrogen, Ci-Ci2 alkyl, C6-14 aryl, C6-i4 ar (Ci_6) alkyl, - (CH2) p-heteroaryl, halogen, Ci-C3 j perfluoroalkyl, Ci-C3 perfluoroalkoxy, Ci- C3 lalkoxy, alkoxyaryl, nitro, carboxy (Ci-Ce) alkyl, carbamide, carbamate or C3-C8 cycloalkyl; R4 is -CH (R6) (CH2) nR1, -C (CH3) 2R6, -CH (R5) (CH2) nR6, -CH (R5) C6H4R6, -CH (R5) C6H3 (C02k) 2, CH ( R5) C6H2 (C02H) 3 or a mimic acid; R5 is hydrogen, Ci-C6 alkyl, C6-i2 aryl, aralkyl, C3 - C8 cycloalkyl or - (CH2) n (R7) i a is from 0 to 6. The present invention furthermore discloses, inter alia, methods for using thiazolo-naphthyl acids to, for example, modulate the activity and / or expression of PAI-1. In some I procedures, a therapeutically effective amount of one or more compounds of the present invention is administered to a subject to treat a disorder related to PAI-1. Exemplary procedures are those that involve inhibition of PAI-1 activity in the subject, such as those associated with insufficiency of the fibrinolytic system. In some embodiments, one or more compounds of the present invention are administered to a subject to treat thrombosis, for example, venous thrombosis, arterial thrombosis, cerebral thrombosis and deep vein thrombosis, atrial fibrillation, pulmonary fibrosis, thromboembolic complications of the surgery, cardiovascular disease, for example, myocardial ischemia, formation of atherosclerotic plaques, chronic obstructive pulmonary disease, renal fibrosis, polycystic ovary syndrome, and Alzheimer's disease or cancer. DETAILED DESCRIPTION OF THE INVENTION t I A. GENERAL VISION | The present invention provides compounds that inhibit the activity of PAI-lj, processes for preparing said compounds, pharmaceutical compositions containing said compounds and methods for using said compounds, for example, in medical therapies. Preferred compounds have properties which are useful for the prevention and / or inhibition of a wide range of diseases and disorders involving the production and / or action of PAI-1. Compounds of the present invention can be used to treat insufficiency of the fibrinolytic system, including, without limitation, thrombosis, coronary heart disease, renal fibrosis, formation of atherosclerotic plaques, pulmonary disease, myocardial ischemia, atrial fibrillation, pulmonary fibrosis, thromboembolic complications of surgery, peripheral arterial occlusion and pulmonary fibrosis. Other disorders treatable by the compounds of the present invention include, if limitation, polycystic ovary syndrome, Alzheimer's disease and cancer. The terms "alkyl" and "alkylene" as used herein, used alone or as part of another group, refer to substituted or unsubstituted aliphatic hydrocarbon chains, the difference being that the alkyl groups are monovalent (ie say, terminals) by their very nature while the alkylene groups are divalent and often serve as liaison elements. Both include, without limitation, straight and branched chains containing from 1 to 12 carbon atoms, (preferably 1 to 6 carbon atoms, unless otherwise explicitly specified.) For example, methyl, ethyl, propyl, isopropyl, encompassed by the term within the definition of "alkyl" are the aliphatic hydrocarbon chains which are optionally substituted.As a consequence, the alkyl groups, described herein, refer to both substituted and unsubstituted groups. Representative I include, without limitation, halogens, -CN, hydroxy, oxo (= 0), acyloxy, alkoxy, amino, amino substituted by one or two alkyl groups of 1 to 6 carbon atoms, aminoacyl, acylamino, thioalkoxy, 1 to 6 carbon atoms, substituted thioalkoxy of 1 to 6 carbon atoms and trihalomethyl Preferred substituents include halogens, -CN, -OH, oxo (= 0) and amino groups The number of carbon atoms , as used in the definitions given herein, refers to carbon skeletons and carbon branching, but does not include the carbon atoms of | substituents, such as alkoxy substitutions and the like. The term "alkenyl" as used herein, used alone or as part of another group, refers to a chain of substituted or unsubstituted aliphatic hydrocarbons and includes, without limitation, straight and branched chains having 2 to 10 atoms of carbon (unless explicitly specified otherwise) and containing at least one double bond Preferably, the alkenyl molecule part has 1 or 2 double bonds Preferably, the part of the alkenyl molecule has approximately 2 to 7 carbon atoms, said molecular alkenyl moieties may exist in the E or Z conformations and the compounds i of this invention j include both conformations.

Specifically included j within the definition of i "alekinyl" are the chains of aliphatic hydrocarbons that I. They are optionally replaced. Accordingly, the alkenyl groups described herein refer to substituted or unsubstituted groups, j Representative optional substituents include, without limitation, halogens, -CN, hydroxy, acyloxy, alkoxy, amino, amino substituted by one or two alkyl groups of lj to 6 carbon atoms, aminoacyl, acylamino, thioalkoxy of 6 to 6 carbon atoms, substituted thioalkoxy of 1 to 6 carbon atoms and trialomethyl. The heteroatoms, such as! 0 or S bound to an alkenyl, not I must be attached to a carbon atom that is linked to a double bond. Preferred substituents include halogens, -CN, -OH and amino groups. ! The term "alkynyl", as used herein, used alone or as part of another group, refers to a chain of substituted or unsubstituted aliphatic hydrocarbons and includes, without limitation,! straight and branched chains that I have 2 to 10 carbon atoms (unless explicitly specified otherwise) and that contain at least one triple bond. Preferentially, the alkynyl molecule part has from 2 to 7 carbon atoms. In some embodiments, the akinyl may contain more than one triple bond and, in such cases, the alkynyl group must contain at least 4 carbon atoms. Specifically included within the definition of "alkynyl" are the aliphatic hydrocarbon chains which are optionally substituted. Accordingly, the alkynyl groups described herein refer to substituted or unsubstituted groups. Substituents i! representative optionals include, without limitation, halogens, -CN, hydroxy, acyloxy, alkoxy, amino, amino substituted by one or two alkyl groups of 1 to 6 carbon atoms, aminoacyl, acyamino, thioalkoxy of 1 to 6 carbon atoms, thioalkoxy substituted from 1 to 6 carbon atoms and trihalomethyl. Preferred substituents include halogens, -i CN, -OH and amino groups. Heteroatoms, such as 0 or S attached to an alkynyl, should not be attached to a carbon that is bound to a triple bond. The term "cycloalkyl" as used herein, only I or as part of another group, refers to a group of substituted or unsubstituted alicyclic hydrocarbons having 3 to 20 carbon atoms (unless otherwise specified). i explicitly otherwise), preferably 3 to 8 carbon atoms and more preferably, 3 to 6 carbon atoms. Specifically included within the definition of "cycloalkyl" are the groups of alicyclic hydrocarbons which are optionally substituted. Accordingly, the cycloalkyl groups herein described refer to substituted or unsubstituted groups. Representative optional substituents include, without limitation, halogens, -CN, hydroxy, oxo (= 0), acyloxy, alkoxy, amino, amino substituted by one or two alkyl groups of 1 to 6 carbon atoms, aminoacyl, acyamino , thioalkoxy of 1 to 6 carbon atoms, I thioalkoxy substituted of | 1 to 6 carbon atoms and i trihalomethyl. The term "aryl", as used herein, used only I or as part of another group, is defined as a group of i rings of substituted or unsubstituted aromatic hydrocarbons having from 5 to 50 carbon atoms (a not to be explicitly specified otherwise) with the preferred embodiment of 6 to 14 carbon atoms and more preferably, of 6 to 12 carbon atoms. The group "Aryl" can have a single ring I or multiple fused rings. The term "aryl" includes, without limitation, I phenyl, α-naphthyl,: β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthenyl. Specifically included within the definition of "aryl" are the aromatic gjupos that are optional substituted. Accordingly, the aryl groups (e.g., phenyl, naphthyl and fluoroaryl), described herein, refer to substituted or unsubstituted groups. In representative embodiments of the present invention, the "aryl" groups are optionally substituted with from 1 to 5 substituents I selected from the group | consisting of acyloxy, hydroxy, acyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 and carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, C3-C6 cycloalkyl , - (CH2) p-C3 - C6 cycloalkyl, halogen, Ci-C3 perfluoroalkyl, Ci-C3 perfluoroalkoxy, | - (CH2) p-phenyl, -O (CH2) p-phenyl, amino, amino substituted by one or two alkyl groups of 1 to 6 carbon atoms, aminoacyl, acylamino, azido, cyano, halo, nitro, trioalkoxy 1 to 6 carbon atoms, substituted thioalkoxy of 1 to 6 carbon atoms and trihalomethyl. For example, the "aryl" groups can optionally be substituted with one of three groups selected from Ci-Ce alkyl, Ci-C6 alkoxy, hydroxy, C3-C6 cycloalkyl, - (CH2) P- C3-C6 cycloalkyl, halogen, Ci-C3 perfluoroalkyl, Ci-C3 perfluoroalkoxy, i (CH2) p-phenyl and -0 (CH2) p-phenyl. The phenyl group of - (CH 2) pj phenyl and -O (CH 2) p-phenyl may be optionally substituted with, for example, from 1 to 3 groups j selected from Ci-C6 alkyl, Ci-C6 alkoxy, - (CH2 P-phenyl, halogen, trifluoromethyl or trifluoromethoxy. P is a halo, cyano, nitro, trihalomethyl and Ci-C6 thioalkoxy. As used herein, the term "heteroaryl", used alone or as part of another group, is defined as a system of substituted or non-substituted heterocyclic and aromatic rings. The groups! heteroaryl can have, for example, from 3 to 50 carbon atoms (unless otherwise explicitly specified), with from 4 to 10 carbon atoms as a preferred embodiment. In some embodiments, the heteroaryl groups are methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2 systems. 4-triazole, 1-methyl-1,1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzthiazole, benzothiazole, benzofuran, benzothiophene, benzothiazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline and isoquinoline I Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridicine rings that are (a) fused with a 6-membered heterocyclic and aromatic ring | (unsaturated) that have a single nitrogen atom; (b) fused to an aromatic heterocyclic ring of 5 or 6 elements (unsaturated) having two I atoms of nitrogen; (c) | fused to an aromatic (unsaturated) heterocyclic ring of 5 elements having a single nitrogen atom together with an oxygen atom or a sulfur atom or (d) fused to an aromatic (unsaturated) heterocyclic ring of 5 elements which has a heteroatom selected from 0, N or js. Specifically included within the definition of "heteroaryl" are the aromatic groups that are optionally substituted. Accordingly, the alkoxy, phenyl, halogen, trifluoromethyl or trifluoromethoxy.

P is an integer number from 0 to 3. Preferred heteroaryls i of the present invention include furanyl,? thienyl, benzofuranyl, benzothienyl, thiophenyl, indolyl, pyrazolyl and thiazolyl substituted and unsubstituted. The term "alkoxy" as used herein refers to the group Ra-0- wherein Ra is an alkyl group as defined above. The term "thioalkoxy", as used herein, refers to the group -0-Ra-S where Ra is an alkyl group as defined above. Specifically I. . . , included within the definition of "alkoxy" and "thioalkoxy" are the groups that j are optionally substituted. Preferred substituents! in the alkoxy and thioalkoxy groups include halogens, -CN, j-OH and amino groups. The term "alkoxyaryl", as used herein, refers to the group Ra-O-aryl wherein Ra is an alkyl group as defined above and aryl is as previously defined. The term "arylalkyloyl" or "aralkyl" refers to the group Ra-Rb where Ra is, an alkylene group as defined! previously, replaced; by Rb an aryl group. Preferred alalkyl groups include the groups of Ce ar (Ci alkyl) The aralkyl groups of the present invention are optionally substituted For example, in preferred embodiments, the benzyl groups of the present invention are optionally substituted with from 1 to 3 groups selected from Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, C3-Ce cycloalkyl, - (CH2) P | L C3 - Ce cycloalkyl, halogen, Ci-C3 perfluoroalkyl, Ci - | c3 perfluoroalkoxy, - (CH2) P - phenyl and -0 (CH2) p-phenyl Axles of parts of the arylalkyl molecule include, without limitation, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. "perfluoroalkyl", as used herein, used alone or as part of another group, refers to a saturated aliphatic hydrocarbon having 1 to 6 carbon atoms and two or more fluorine atoms and includes, without limitation, Straight or branched chains, such as -CF3- I CH2CF3, -CF2CF3 and -CH (CF3) 2l I The term "halogen" I or "halo" refers to chlorine, bromine, fluorine and iodine. The term "carbamide", as used here, refers to the group -C (0) R'R "wherein R 'and R" are independently hydrogen, alkyl, aryl or cycloalkyl as defined herein. The term "carbamate", as used herein, refers to the group -OC (O) NR 'R "wherein R' and R" are independently hydrogen, alkyl, aryl or cycloalkyl as defined herein . The term "acyl" refers to a radical of the formula RC (O) -, where R is hydrogen, alkyl, aryl or cycloalkyl as defined herein. Suitable acyl radicals include formyl, acetyl, propioryl and the like. The term "acyloxy" refers to radicals of the formula RC (0) 0- where R is hydrogen, alkyl, aryl or cycloalkyl as defined herein. Suitable acyloxy racials include CH3COO-, CH3CH2COO-, benzoyloxy and the like. The term "acylamino" refers to radicals of the formula RC (0) NH- where R is hydrogen, alkyl, aryl or? cycloalkyl as defined herein. The term "amino acid" refers to radicals of the formula I (R) 0-3C (O) H 2 where R is alkylene as described above. The term "treat" or "treatment" refers to any indication of success in the improvement of an injury, pathology or condition, including any objective or subjective parameter such as relief, remission, diminution of symptoms or the lesion, pathology or condition more tolerable for the patient, decelerating the rate of degeneration or decline, making the end point of degeneration less debilitating or improving the physical or mental well-being of a subject. it can be based on objective or subjective parameters, including the results of a physical examination, neurological examination and / or psychiatric evaluation, etc. The term "treat" or "treatment of a disorder related to PAI-1" includes prevention ij of the initiation of symptoms in a subject who may be predisposed to a condition related to PAI-1, but who still does not experience or show symptoms of the disorder (prophylactic treatment), inhibit the symptoms of the disorder (slowing or stopping its development), provide relief of the symptoms or side effects of the disorder (including palliative treatment) and / or relieve the symptoms of disorder (causing regression). Accordingly, the term j "treat" includes the administration of the compounds or agerites of the present invention to a subject to prevent or delay, to alleviate or to stop or inhibit the development of symptoms or conditions associated with disorders related to PAI- 1, for example, tumor growth! associated with cancer. An experienced medical professional will know how to use standard procedures to determine if a patient is suffering from a disease associated with increases in PAI-1 levels and / or activity, for example, by examining the patient and determining if the patient is suffering from a disease known as j associated with high levels of I PAI-1 or its activity or testing the levels of PAI-1 in blood plasma or tissue of the person suspected of suffering from PAI-1-related disease and comparing levels of PAI-1 in the blood plasma or tissue the person suspected of suffering a disease related to II PAI-1 with levels of PAI-jl in the blood plasma or tissue of a healthy person. Methods known in the art for the detection of nucleic acids and proteins can be used to determine! PAI-1 levels in a subject, eg, PCR, so-called Northern blots and Southern blots, spot jblots (macular transfers), matrix configurations of nucleic acids, Western blots, immunoassays such as immunoprecipitation, ELISA (bound immunosolvent assay to enzymes), proteomic assays and the like. The increased i levels of PAI-1 are indicative of disease. In healthy subjects, the! PAI-1 is found at low levels in the plasma (for example, approximately 5-10 ng / mL), Plasma is also elevated, for example, in post-menopausal women and has been proposed to contribute to the increased incidence of cardiovascular disease in this population (Koh K et al, Ñ Engl J Med 336: 683-690, 1997 ). The term "disease or disorder related to PAI-1" refers to any disease or condition that is associated with the increase or amplification of the expression or activity of PAI-1 or increase or extension of the expression or activity of a PAI. -1 gene encoder. Examples of said increase in expression activity include the following: j protein activity or expression of the gene encoding the protein is increased by a fraction of the level of normal subjects; the activity of the protein or expression of the gene encoding the protein is in an organ, tissue or cell where its presence is not normally detected in normal subjects (eg, spatial distribution of the protein or expression of the gene encoding the protein is modified); i Protein activity or expression of the gene encoding the protein is increased when the activity of the protein or expression is increased when the activity of the protein or I expression of the gene encoding the protein is present in an organ, tissue or cell for a longer period than in a normal subject (p. ^., the duration of activity of the protein b expression of the gene encoding the protein is increased). A normal subject is a person who does not suffer from a disorder related to PAI-1, which is not associated with hyperglycemia is a disorder, for example, that is not caused by elevated blood glucose levels. The term "pharmaceutically acceptable excipient" I means an excipient which is useful for preparing a pharmaceutical composition which is generally safe, non-toxic and desirable and includes excipients that are acceptable for further veterinary use for human pharmaceutical use. Said excipients may be solid, liquid, semisolid or, in the case of an aerosol composition, gaseous. The term "pharmaceutically acceptable salts and esters" refers to salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties.

Said salts include, for example, salts that can be formed where the protons and acids present in the compounds i are capable of reacting | with organic or inorganic bases. Suitable inorganic salts include, for example, those formed with the alkali metals or alkaline and toric metals, for example, sodium and potassium, magnesium, calcium and aluminum. Suitable organic salts include, for example, those formed with orthogonal bases such as the amine bases such as the amino bases, for example, ethanolamine, I-diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. The pharmaceutically acceptable salts may also include acid addition salts formed from the reaction of molecular fractions of amines in the matrix compound with inorganic acids (eg, hydrochloric and hydrobromic acids) and organic acids (eg, acetic acid, citric acid). , maleic acid and the alkane and sulfonic acid acids, such [as methane sulphonic acid and benzenesulfonic acid]. The pharmaceutically acceptable esters include the esters formed from carboxy, sulfonyloxy and phosphonoxy groups present in the compounds, e.g. esters of Ci-? alkyl! When there are two acid groups present, a pharmaceutically acceptable salt or ester can be an ester or monosal j of monoacid or an ester or disal and said compounds are (intended to include all unique stereisomers and all mixtures (racemic or other) of said stereoisomers.j The terms "inhibitors", "activators" "Modulators", as used in relation to expression or activity, refer to inhibitory, activating or modulating molecules, respectively. The inhibitors of the present invention are compositions that inhibit PAI-1 expressions or bind to block, partially or totally, the stimulation, decrease, prevention, delayed activation, inactivation, desensitization or regulation of PAI-1 activity. The samples or assays comprising PAI-1 can be treated with a composition according to the present invention and compared with the control samples without a composition of the present invention. Control samples (not treated with compositions according to the present invention) can be assigned a relative activity value of 100%. In some embodiments, inhibition of PAI-1 is achieved when the value j of the activity relative to the control is about 80% or less, optionally 50% or 25%, 10%, 5% or 1%. i The terms J "pharmaceutically acceptable", "Physiologically tolerable" and its grammatical variations, when referring to compounds, carriers, diluents and reagents, are used! interchangeably and indicate that the materials are capable of administration to a human patient without the production of undesirable physiological effects, such as nausea, drowsiness, gastric disorders and the like, which could be of a degree that would prohibit the administration of the compound. A "therapeutically effective amount" or a "pharmaceutically effective amount" means an amount that, when administered to a subject to treat a disease, is sufficient to effect treatment for said disease. I Excepted when so indicated, the terms "subject" or "patient" are used interchangeably and refer to mammals, such as human patients and non-human primates as well as experimental animals such as rabbits, rats and mice and other animals. Accordingly, the term "subject" or "patient" as used herein means any patient or mammal subject to which the compounds according to the invention can be administered. In an exemplary embodiment! of the present invention, to identify patients! subjects for treatment according to! In accordance with methods of the invention, accepted screening procedures are used to determine the risk factors associated with a suspected or suspected condition or disease or to determine the status of the condition or disease existing in a subject. These selection procedures include, for example, conventional work to determine the risk factors that may be associated with the disease or imminent or suspected condition. These and other routine procedures allow the clinical technician to select patients in need of therapy using the methods and formulations according to the present invention. In some embodiments of the present invention, the subject to be treated with the methods of the invention does not have hyperglycemia and / or a disease that has been caused by hyperglycemia. Procedures for determining whether a subject has hyperglycemia are known in the prior art and include, for example, performing a glucose test that measures the blood glucose level. Two exemplary tests that can be used to measure the presence of excess blood glucose levels include a test that measures the amount of blood glucose after an overnight fast and a test that measures the body's ability to process an excess of sugar presented after . I drink a high glucose test. Under normal conditions, a subject who has a fasting sugar level (sugar level after a nighttime ayujno) of approximately 64 to 110 mg / day does not have hyperglycemia, while a person who has a higher fasting blue level than 110 mg / di presents elevated blood sugar levels. A value of i above 140 mg / di on at least two occasions usually means that the patient has diabetes.

When any variable occurs more than once in any constituent or in any formula, its definition in each occurrence is (independent of its definition in any other occurrence.) Combinations of substituents and / or variables are admissible only if such combinations result in stable compounds B. TIAZOLO ACIDS 4- NAFTILO I As indicated above, the compounds of the present invention include those of the following formula: acceptable or an Ar is aryl or heteroaryl; Ri is hydrogen, Ci-pi2 alkyl, C6-14 aryl, Ce-1 ar (Ci_6) 1 alkyl, - (CH2) p-heteroaryl, -CH2) p-CO-aryl, - (CH2) P -CO-1 heteroaryl, - (CH2) P -CO- (Gi-C6) alkyl, C2 C7 alkenyl, C2-C7 alkynyl, C3-Cs and cycloalkyl, halogen or Ci-C3 perfluoroalkoxy; R2 and R3 are independently hydrogen, Ci-Ci2 alkyl, C6-i4 aryl, C6-i4 ar (Ci-6) alkyl, (CH2) p-heteroaryl, halogen, Ci-C3 alkoxy, kalkoxyaryl, nitro, carboxy (Ci C6 alkyl), carbamide, carbamate or C3-Ce cycloalkyl; R4 is -CH (R6) (CH2) nR5 -C (CH3) 2R6, -CH (R5) (CH2) nR6, -CH (R5) C6H4R6, -CH (R5) C6H3 (C02H) 2, CH (R5) C6H2 (C02H) 3 or a mimic acid; R5 is hydrogen, Ci-C6 alkyl, C6-i2 aryl, C6-i ar (Ci-6 > alkyl, C3-Cs cycloalkyl or - (CH2) n (R7) R6 is C02H, tetrazole or P03H; R7 is n is from 0 to 6; j p is from 0 to 3; B is from 0 to 6 and | A is from 0 to 6 j In some forms of realization, when b is from 1 to 6, Ar is phenyl, furanyl, thienyl, pyrazolyl, thiazolyl or fluorenyl. In some forms of realization, in the definition of Ri i, R2 or R3 said Ci-C12 alkyl is Ci-C3 perfluoroalkyl and i said Ci-C6 alkoxy is Ci C3 perfluoroalkoxy. The thiazolo-naphthyl acids include the following compounds:! ?? Formula 5 Formula 6 i II or solvates, hydrates or their forms of esters or pharmaceutically acceptable salts, wherein: Ar, Rx, R2, R3, R4, b, in and p are as defined above and R8 and R9 R10, 1 Rn and R12 are, independently, hydrogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, p3-C6 cycloalkyl, - (CH2) P-C3-C6 I cycloalkyl, halogen, -j (CH2) p-phenyl or -O ( CH2) P-phenyl. In some embodiments, Ci-C6 alkyl is Ci-C3 perfluoroalkyl or said Ci-C6 alkoxy is Ci-C3 perfluoroalkoxy. In some compound examples, R8, Rg, Rio Ruy R12 are independently hydrogen or halogen. Compounds examples of formulas 1 to 3 include compounds in which arylo is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazolyl or fluorenyl. Exemplary compounds of formulas 1 to 6 include those in which: j Ri is hydrogen, jCi-C6 alkyl, Ci-C3 perfluoroalkyl, halogen or - (CH2) P-phenyl. R2 and R3 are independently hydrogen, Ci-C6 alkyl, phenyl- (CH2) P-, halogen Ci-C3 perfluoroalkyl; R4 is -CHR5 C02H, -CH2-tetrazole or a mimic acid; R5 is hydrogen, or optionally substituted benzyl; I Ar is phenyl, naphyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazolyl or fluorenyl or I alternatively, Ar j is phenyl, furanyl, thienyl, i-purolyl, thiazolyl or fluorenyl or solvates, hydrates or their I forms of pharmaceutically acceptable esters or salts. Exemplary compounds of formulas 1 to 6 include those in which the definitions have one or more, for example all, the following values: Ri is hydrogen or halogen, R2 and R3 are independently hydrogen or halogen;! R4 is -CHR5 C02H, -CH2 -tetrazole or a mimic acid; R5 is optionally substituted hydrogen or benzyl; and Ar is unsubstituted phenyl or substituted phenyl with from 1 to 3 selected groups of Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, C3- G6 cycloalkyl, - (CH2) P-C3-Ce cycloalkyl, halogen, Cij-C3 perfluoroalkyl, Ci-C3 perfluoroalkoxy, - (CH2) p-fjenyl and -O (CH2) phenyl.In some embodiments, when b is from 1 to i1 6, Ar is phenyl, furanyl, thienyl, pyrazolyl, thiazole or fluorenyl and when b is 0, Ar is furanyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazole or fluorenyl. The compounds of the present invention also include prodrugs and stereoisomers of formulas 1 to 6. In some compounds Ri is hydrogen, halogen, Ci-C12 alkyl, Ci-C3 perfluoroalkyl or - (CH2) P-phenyl, wherein i the ring of phenyl is optionally substituted with Ci-C6 alkyl, Ci-C6 alkoxy, halogen, trifluoromethyl or 1 I trifluoromethoxy. In some embodiments of the present invention, Ri is hydrogen or halogen. For example, in some embodiments, Ri is hydrogen or bromine. ! In some compounds according to the present invention, R 2 and R 3 1 are independently hydrogen, Ci-Ci 2 alkyl, halogen, Ci-C 3 perfluoroalkyl or - (CH 2) P-phenyl where the phenyl ring is optionally substituted with Ci. C6-alkyl, Ci-C6 alkoxy, halogen, trifluoromethyl or trifluoromethoxy. In some embodiments of the present invention, R 2 is hydrogen and R 3 is hydrogen or j halogen. For example, R3 is hydrogen or bromine. In some compounds,! R4 is-CHR5C02H, CH2-tetrazole, CH (R5) C6H4C02H, -CH (R5) C6H4 (p02H or a mimic acid In some embodiments, R4 jes CH2COOH, unsubstituted, substituted CH2COOH-CH2-tetrazole or CH ( R5) C6H4C02H In some embodiments, for example, R4 is unsubstituted CH2COOH; I substituted, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazole or fluorenyl. In some embodiments, Ar is substituted or non-substituted phenyl. In some compounds of the present invention, OR4 i substituent is in position j relative to the thiazolo ring (the numbering system used is represented in formula 3). Examples of the thiazolo-naphthyl acids of the present invention include, without limitation, 3-phenyl-2-II ( { [6 - (2-phenyl-1,3; thiazol-4-yl) - 2-naphthylloxy.) Propanic or one of its ester forms or pharmaceutically acceptable salt; 5 - [(. {6- [2- (2-phenyl-1,3-y thiazol-4-yl) -2- Naphthyl.} oxy) methyl] -1H tetraazole or one of its pharmaceutically acceptable salt or ester forms, 2- {[[[bromo-6-i (2-phenyl-1,3-thiazol-4-yl} ) - its forms of { [1-bromo-6 acetic or one acceptable, - 5- ( { [1-bromo-6 - (2 -! phenyl-1,3-thiazol-4-yl) - 2-naphthyl] oxy} methyl) -l H-tetraazole or one of its ester forms or pharmaceutically acceptable salt; (6- {2 - (2,6 I-dichorobenzyl) -1,3 acid tiaz'pl-4-yl] -2- naphthyl-oxy) -acetic I or one of its pharmaceutically acceptable salt or ester forms, 2 - { [1 -i-bromo-6- (5-bromo-2- phenyl I-1,3-thiazole - 4 | - il) - 2 -naphthyl] oxy} - 3-phenylpropanoic acid or one of its salt or ester forms and 4 - (. { [1-bromo-6 - - 4 - yl) - 2 -naphthyl] oxy} methyl) its pharmaceutically acceptable salt or ester forms. The present invention also discloses compositions comprising the thiazolo-naphthyl acids of the present invention, including the compounds of formulas 1 to 6 or a stereoisomer or one of its pharmaceutically acceptable solvate, hydrate, salt or ester forms. acceptable and one or more carriers, excipients or pharmaceutically acceptable diluents. Said compositions include pharmaceutical compositions for treating or controlling disease states or conditions associated with increases of | the activity of PAI-1. In some I embodiments, the compositions comprise mixtures of one or more thiazolo-naphthyl acids. j Some of the compounds of formulas 1 to 6 contain stereogenic carbon atoms or other chiral elements and thus, give rise! to the formation of stereoisomers, including enantiomers! and diastereomers. The present invention includes all stereoisomers of formulas 1 to 7 and I as well as mixtures of stereoisomeric mixtures. Through all! this application, the name of the product, where the absolute configuration of an asymmetric center is not indicated, is intended to encompass the individual stereoisomers as well as mixtures of stereoisomers. Where an enantiomer is preferred, it may, in some embodiments, be provided substantially free of the corresponding enantiomer. Thus, a substantially free enantiomer of the corresponding enantiomer refers to a compound that is isolated or separated by techniques of separation or free preparation of the corresponding enantiomer. The term "substantially free", as used herein, means that the compound is replaced by a significantly greater proportion of an enantiomer. In preferred embodiments, the compound is composed of at least 90% by weight of a preferred antimer. In another embodiment of the invention, the compound consists of at least 99%, for example, in Jacques, | et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al, Tetrahedron 33: 2725 (1977); Eliel, E.L. Sterochemistry of Carbon iCompounds (cGraw-Hill, NY 1962) and i Wilen S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed. J Univ., Of Notre Dame Loans, Notre Dame, IN 1972). Exemplary salt forms of these compounds include, without limitation, sodium salts and potassium salts. Other salt forms of examples of; These compounds include, without limitation, those formed! with pharmaceutically acceptable organic or inorganic acids and bases known in the prior art. Acids include, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, maleic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenosul phonic, fieldsurfonic and similarly known acceptable aids when a compound of this invention contains a basic molecular moiety. Forms of salts prepared using inorganic bases include hydroxides, carbonates or bicarbonates of alkaline metals or alkaline earth metals which are therapeutically acceptable, such as sodium, potassium, magnesium, calcium and the like. Acceptable organic bases include amines, such as benzylamine, mono-, di- and tnalkyl amines, preferably those having alkyl groups of 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, mono-, di- and triethanolamine. Examples of salts include also alkylene diamines containing up to 6 carbon atoms, such as hexamethylenediamine; cyclic bases saturated or unsaturated j containing up to 6j carbon atoms including pyrrolidine, peperidine,! morpholine, piperazine and its N-alkyl and N-hydroxy alkyl derivatives, such as N-methyl-morpholine and N- (2-hydroxyethyl) -piperidine or pyridine. Quaternary salts may also be formed, such as tetralkyl1 forms, such as tetramethyl forms, alkyl-alkanoyl forms, such as methyl triethanol or trimethyl monoethanol and cyclic ammonium salt forms, such as N-methylpyridinium. , N-, methyl-N- (2-hydroxyethyl) -morpholinium, N, N-di-methylmorpholinium, N-methyl-N- (2-hydroxyethyl) -morpholinium or N, N-dimethyl-piperidine salt forms. These salt forms can be prepared using the acidic compounds of formulas 1 to 6 and methods known in the art. Exemplary ester forms of the compounds of this invention include, without limitation, straight chain alkyl esters having from 1 to 6 carbon atoms or branched chain alkyl groups containing 1 to 6 carbon atoms. alkyl of 1 to 6 carbon atoms. The mimic acids and acids, according to the invention, are defined as proton or hydrogen donor groups. I Mimic acids or mimetic examples of the present invention and they R. rug cos gone wherein R18 is Ci alkyl, C2-C6 alkenyl, - C6 cycloalkyl, -CH2-r (C3 cycloalkyl), C3 cycloalkenyl, -CH2- (C3-C6 cloalkenyl), aryl or heteroaryl groups optionally substituted or -aryl groups (Ci-Cs) alkyl-heteroaryl (Ci-C6) ) alkyl, optionally substituted] with the aryl and heteroaryl groups I as defined herein. The preferred compounds of the present invention inhibit the activity of PAI-1. Accordingly, compounds can be used for the treatment, including prevention, inhibition / or improvement of disorders related to PAI-1 in a subject including, for example, in the treatment of non-insulin-dependent diabetes mellitus, in the treatment of disease cardiovascular and in t treatment episodes, thrombotic associated with cerebrovascular disease and coronary artery disease. Using the methods of the present invention, an experienced medical technician will know how to administer the compounds of the present invention, including the! represented by formulas 1 to 6, to a subject suffering from any of the diseases associated with the increaseof the activity or expression of PAI-1, for example, cardiovascular disease or diabetes, in order to carry out the treatment for said disease. In an exemplary embodiment, the compounds of the present invention are administered to a subject to be able to treat disease processes involving thrombotic or pro-thrombotic states including, without limitation, the formation of arteriosclerotic plaques, thrombosis venous and arterial, myocardial ischemia, atrial fibrillation, deep vein thrombosis, coagulation syndromes, pulmonary thrombosis, cerebral thrombosis, thromboembolic complications of surgery (such as hip or joint replacement) and peripheral arterial occlusion. Any disease or condition that is associated with an increase in the activity or expression of PAI-1 in a subject can be treated using the compounds of the present invention, diseases and conditions. Example conditions include stroke, for example, stroke associated with or resulting from atrial fibrillation; diseases associated with extracellular matrix accumulation including, but not limited to, renal fibrosis, chronic obstructive pulmonary disease, polycystic ovarian syndrome, restenosis, renovascular disease, and organ transplant rejection; diseases associated with neoangiogenesis including, without limitation, diabetic retinopathy; Alzheimer's disease, for example, by increasing or normalizing levels | of plasmin concentration in a subject; myelofibrosis with mileoid metaplasia, for example, regulating the hyperplasia Ide extromares cells and increases in extracellular matrix proteins.

The compounds of the present invention can be used to treat, for example, diabetic nephropathy and renal dialysis associated with nephropathy; tumors or cancers including, without limitation, leukemia, breast cancer and ovarian cancer; tumors, including, without limitation, liposarcomas and epithelial tumors; septicemia; obesity; insulin resistance; proliferative diseases including, without limitation, psoriasis, and conditions associated with abnormal clotting homeostasis; low grade vascular inflammation; Cerebrovascular diseases; hypertension; dementia; opsteoporosis; arthritis, asthma; heart failure, arrhythmia; angina including, without limitation, angina pectoris; atherosclerosis and sequelae; kidney failure; multiple sclerosis; j steoporosis; osteopenia; dementia; peripheral vascular disease; Peripheral arterial disease; acute vascular syndromes; microvascular diseases including, without limitation, nephropathy, neuropathy, retinopathy and nephrotic syndrome; hipértensión, type I and II diabetes and I related diseases; hyperglycemia, hyperinsulinemia; malignant lesions; Premalignant lesions; gastrointestinal tumors; coronary heart disease including, without limitation, primary and secondary prevention of myocardial infarction; Stable and unstable angina, primary prevention! of coronary episodes and secondary prevention of cardiovascular events and inflammatory diseases including, without limitation, septic shock and the vascular damage associated with i • nf * ections. The compounds of the present invention can also be administered to a subject in combination with a second therapeutic agent, including, without limitation, I prothrombolytic agents, fibrinobes and anticoagulants or in conjunction with other therapies, for example, protease inhibitor. containing very active antiretroviral therapy (HAART) for the treatment of diseases that have their origin in fibrinolytic insufficiency and the hypercoagulability of patients infected with HIV -1. In some embodiments,! The compounds of the present invention can be administered in conjunction with, and / or following processes and procedures involving maintaining patency or patency including, without limitation, vascular surgery, vascular graft and stent patency. (endoprosthesis), implantation of organs, tissues and cells and transplant. The compounds of the present invention can also be used for the treatment of blood and blood products used in dialysis, storage I of the blood in the filtrate phase, especially aggregation of platelets ex vivo. The compounds of the present invention can also be administered to a subject as a hormone replacement agent or to reduce inflammatory or C-reactive protein markers. The compounds can be administered to improve coagulation homeostasis, to improve endothelial function or as a topical application for wound healing, for example, the prevention of scar formation. The compounds of the present invention can be administered to a subject to reduce the risk of undergoing a myocardial revascularization procedure. The present compounds are! They can also be added to human plasma during blood chemistry analysis in hospital facilities to determine their fibrinolytic capacity. In some embodiments, the compounds of the present invention can be used as imaging agents for the identification of metastatic cancers. C. GENERAL VIEW OF THE SYNTHESIS The compounds of the present invention can be prepared by those skilled in the art of organic synthesis using conventional methods using reagents and readily available starting materials.

Representative compounds; of the present invention can be prepared using the following synthetic reaction scheme. Professionals experienced in this technique will know how to make use of variants of these stages of the process that by themselves are well known in this technique. In the following reaction reaction schemes, the substituents are selected from the previously defined groups I 43. Reaction scheme 1 D. PHARMACEUTICAL COMPOSITIONS The present invention provides thiazolo-naphthyl acids as pharmaceutical products. In a preferred embodiment, the compounds of the present invention are formulated as pharmaceuticals to treat diseases, for example, those associated with the increased activity of PAI-1, eg, by inhibiting the activity of PAI-1 in a subject. In general, the compounds of the present invention can be administered as pharmaceutical compositions by any method known in the art for administering therapeutic drugs including oral, buccal, topical, systemic (p.Je., transdermal, intranasal or suppository) or parenteral ( eg, intramuscular, subcutaneous or intravenous injection)! The compositions can take the form of pills, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, emulsions, syrups, elixirs, aerosols or in this technique and said excipients, and methods for formulating the compositions, can be found in standard references such as Alfonso AR: Remington's I Pharmaceutical Sciences, jl7th ed. , Mack Publishing Company, i I Easton PA, 1985. Suitable liquid carriers, especially for injectable solutions, include water, aqueous saline solution, aqueous desorption solution and glycols. In some embodiments of the present invention, suitable thiazolo-naphthyl acids! for use in the practice of this invention they will be administered individually or in combination with at least one other compound of this invention.

Thiazolo-naphthyl acids can also be administered with at least one other conventional therapeutic agent for the disease to be treated. The aqueous suspensions of the invention may contain thiazolo-naphthyl acids in mixture with excipients I suitable for obtaining aqueous suspensions. Said excipients may include, for example, a suspending agent, such as | sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum and dispersing agents o. humectants, such as naturally occurring phosphatide (eg, lecithin), a condensation product of an alkylene oxide with a long-chain aliphatic alcohol (eg, heptadecaethylene oxypetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (eg, polyoxyethylene sorbitol mono-oleate) or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (eg, polyoxyethylene mono-oleate sorbitan) . The aqueous suspension i may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more sweetening agents and one or more flavoring agents, such as sucrose, aspartame or saccharin. The formulations can be adjusted for osmolarity. I Oily suspensions may be formed by suspending a thiazolo-naphthyl acid in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil, such as liquid paraffin or a mixture The suspensions in oil may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol, Sweetening agents may be added to provide an oral preparation with a pleasant taste, such as glycerol, sorbitol or sucrose. These I formulations can be preserved by the addition of an antioxidant such as ascorbic acid.As an example of an injectable oil vehicle, see Minto, J. Pharmacol, Exp. Ther. 281: 93 L 102, 1997. The pharmaceutical formulations of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, previously described or a mixture of them. Suitable emulsifying agents include natural occurring gums, such as acacia gum and tragacanth gum, naturally occuring phosphatic compounds, such | such as soy lecithin, esters or partial esters derived from 1-hexitol anhydrides and fatty acids, such as sorbitan mono-oleate and condensation products of these partial esters with ethylene oxide, such as pplioxyethylene mono-oleate sorbitan. The emulsion may also contain j sweetening agents and flavoring agents I, as in the formulation of syrups and elixirs. Said formulations may also contain a demulcent, a condom or a coloring agent. The compound of choice, alone or in combination with other suitable components, can be obtained in aerosol formulations (ie, they can be "nebulized") to be administered by inhalation. The aerosol formulations can be placed in acceptable pressurized propellants, such as dichlorodifluoromethane, protopane, nitrogen and the like. Formulations suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous routes include isotonic, aqueous and non-aqueous sterile injection solutions which may contain antioxidants, solutions and I buffers, bacteriostats and solutes that make the formulation isotonic with the blood of the intended recipient and sterile aqueous and non-aqueous suspensions, which may include suspending agents, solubilizers, thickening agents, stabilizers and preservatives. Among vehicles and acceptable solvents, which | can be used, are water and Ringer's solution, uni sodium chloride isotonic. In addition, sterile fixed oils can be conventionally employed as a suspending medium or solvent. For this purpose, any insipid, fixed oil can be used i including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used analogously in the preparation of injectables. These solutions are sterile J and generally free of undesirable matter. When the! The compounds are sufficiently soluble, they can be dissolved directly in normal brine with or without the use of suitable organic solvents, such as propylene glycol or polyethylene glycol. Dispersions of the finely divided compounds can be obtained in the solution of sodium carboxymethyl cellulose or starch in the aqueous state or in suitable oil, such as arachis oil. These formulations can be sterilized by conventional well-known sterilization techniques. The formulations may contain substantial pharmaceutically acceptable adjuvants when required to approximate the conditions; physiological agents such as pH adjusting and buffered agents; toxicity adjusting agents, I for example, isodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of thiazolo-naphthyl acids j in these formulations can vary greatly and will be primarily selected on the basis of volumes of fluids, viscosities, body pejso and the like, in accordance with the particular mode of administration selected and the needs of the patient. patient. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using said suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, non-toxic solvent or solvent, such as a solution of 1,3-butanediol. The recommended formulations can be presented in single-dose or multi-dose sealed containers, such as ampoules and vials. j Can be prepared! suspensions and injection solutions, for example,] from sterile powders, granules and pellets of the kind described above. Suitable compounds! for use in the practice of this invention can be administered orally. The amount of a compound of the present invention in the composition can vary widely depending on type of composition, size of a unit dose, class of excipients and other factors well known to those of ordinary skill in the prior art. In general, the final composition may comprise, for example, 0.0001% by weight (% w) to 10% by weight of the compound, preferably 0.00001% by weight to 1% by weight, with the remainder being jel excipient or excipients. Pharmaceutical formulations for oral administration can be formulated using pharmaceutically acceptable carriers well known in this technique in doses suitable for oral administration. Said carriers enable the pharmaceutical formulations to be formulated in dosage unit forms such as pills, pills, powders, dragees, capsules, syrups, pasty solutions, suspensions, ejtc. suitable for ingestion by the patient. Formulations suitable for oral administration may consist of (a) liquid solutions, such as an effective amount of the packaged nucleic acid suspended in diluents, such as water, brine or PEG 400; (b) capsules, sachets or pills, each containing a predetermined amount ij of the active ingredient, such as liquids, solids, granules or gelatin; (c) suspensions in a suitable liquid and (d) suitable jemulsions. Pharmaceutical preparations for oral use can be obtained by combining the compounds of the present invention with solid excipient, optionally by grinding a resulting mixture and processing the mixture of granules, after adding additional suitable compounds, if desired, to obtain pills or dragee cores. Solid excipients! Suitable include fillers! proteins or carbohydrates and include, without limitation, sugars including lactose, sucrose, mannitol or sorbitol; corn starch, wheat, rice, potato and other plants; cellulose such as mefeilcelulose, hydroxymethylcellulose, hydroxypropylmethylcellulosk or sodium carboxymethylcellulose and gums including arabica and tragacanth as well as proteins such as gelatin and collagen. If so desired, disintegrating or solubilizing agents can be added, such as • crosslinked polyvinyl pyrrolidone, agar, alginic acid or one of its salts, such as sodium alginate. The tablet forms may include, for example, one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid. and other pharmaceutically compatible excipients, colorants, buffering agents, flavoring agents, ntegrants and carriers. The tablet forms may comprise the active ingredient in a flavor, for example, sucrose, as well as tablets comprising the active ingredient in an inert base, such as gelatin and glycerin or acacia and sucrose emulsions, gels and similar elements containing, in addition to the active ingredient, carriers known in this art.1 II The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These formulations can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures, but liquid at rectal temperatures and will therefore melt in the rectum to release the drug. These materials are coconut butter and polyethylene glycols. ! The compounds of the present invention can be administered intranasally, intraocularly, intravaginally and intrarectally including suppositories, insufflation, powders and aerosol formulations (eg, of steroid inhalants), see Rohat gi, J. Clin. Pharmacol. 35: 1187- i 1193, 1995; Tjwa, Ann. Altiergy Asthma Immunol. 75: 107-111, 1995). The compounds of the present invention can be administered in controlled or sustained release dosage forms (eg, employing a biodegradable slow release delivsystem), including reservoir injections, osmotic pumps (such as the implant). of Alzet manufactured by Alza), transdermal transdermal and transdermal pills (including electrotransport) and the like for prolonged administration at a predetermined rate, preferably in the form of unit doses suitable for the single administration of precise doses. The compositions will normally include a conventional pharmaceutical carrier, the invention, in addition, these other active agents,. The compounds of the present invention can be delivered transdermally, via a topical route, formulated as rod applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols. Encapsulating materials can also be used with the compounds of the present invention and the term "composition" is intended to include the active ingredient in combination with an encapsulating material as a formulation with or without other carriers. For example, the compounds of the present invention can also be delivered as microspheres for slow release into the body. of injectable and injectable drugs (see Gao, Pharm, Res 12: 857-63, 1995); or as microspheres for oral administration (see e.g., Eyles J. Pharm, Pharmacol 49: 6 69-674, 1997). Both transdermal and intradermal routes can provide a constant delivfor weeks or months. Wafers can also be used in the delivof the compounds of the present invention, for example, anti-atherosclerotic drugs. In another embodiment, the compounds of the present invention can be delivered through the use of liposomes that are fused with the cell membrane or are endocytosed, for example, by using ligands attached to the liposora or incorporated directly into the oligonucleotide, which binds with the receptors of superficial membrane proteins of the cell giving rise to endocytosis.

By using liposomes in particular where the surface of the liposome supports ligands specific for target cells or are otherwise preferentially directed to a specific organ, the compound delivery can be concentrated in the target cells in vivo (see eg, 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, the preferred preparation may be a lyophilized powder in, for example, 1 M-50 mM histidine, 0.1% sucrose-2%, 2% -7% mannitol in a pH range of 4, 5 to 5.5, which is combined with buffer solution before use. ·; A pharmaceutical composition of the invention may optionally contain, in addition to oxaxol naphthyl acids, at least one other therapeutic agent useful in the treatment of a disease or condition associated with the increase of PAI-1 activity. | The pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) standards of the U.S. Food and Drug Administration (North American Agency of the Medicine). E. DETERMINATION OF DOSAGE REGIMES For treatment purposes, the compositions or compounds given here | knowing can be administered to the subject in a single bolus delivery, by continuous delivery (eg, continuous delivery, transdermal, mucosal or intravenous) for a prolonged period of time or in a repeated protocol of administration (eg, by means of an hourly, daily or weekly and repeated administration protocol). The pharmaceutical formulations of the present invention can be administered, for example, once or more times a day, 3 times a week or weekly. In a preferred embodiment of the present invention, the pharmaceutical formulations of the present invention are I administer orally once or twice a day. Within this context, a therapeutically effective dose of the biologically active agents may include repeated doses within! of a prolonged treatment regimen that will provide clinically significant results to alleviate p plus symptoms or detectable conditions associated with the increased activity of PAI-1. The determination of effective doses in this context is usually based on studies of animal models followed by human clinical tests! and is guided by determining effective doses and administration protocols that significantly reduce the occu- pation or severity of symptoms of objective exposure or conditions in the subject. Suitable models for this respect include, for example, murine, rat, porcine, feline, non-human primate and other subjects of accepted animal models known in this art. Alternatively, effective doses can be determined using in vitro models (e.g., immunological and histopathological assays). Using such models, only ordinary calculations and adjustments may be needed to determine an adequate concentration and the appropriate dose to administer a therapeutically effective amount of the biologically active agents (ie, amounts that are intranasally effective, transdermally effective, and intravenously effective). or intramuscularly effective to elicit a desired response). In alternative embodiments, an "effective amount" or "therapeutically effective dose of biologically active agents will simplify, inhibit or enhance one or more biological activities selected in correlation with a disease or condition, as set forth above, for therapeutic or therapeutic purposes. The actual dosage of biologically active agents will vary, of course, according to factors such as magnitude of exposure and particular state of the subject (eg, the age of the subject, size, physical state, extent of symptoms, susceptibility, etc.), time and route of administration as well as other drugs or treatments that are administered simultaneously Dosage regimens can be adjusted to provide an optimal prophylactic or therapeutic response The term "therapeutically effective dose" means here a dose that produces the effects 1992); Lloyd, 1999, The Art, Science and Technology of Pharmacéutical Compounding and · Pickar, 1999, Dosage Calculations). A therapeutically effective dose is also a dose at which any toxic or detrimental side-effect of the active agent is compensated in clinical terms for therapeutically beneficial effects. In addition, it should be noted that for each particular subject, specific regimens should be evaluated and adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compounds.

In an exemplary embodiment of the present invention, unit dosage forms of the compounds are prepared for standard administration regimens. In this way, the composition can easily be subdivided into smaller doses according to the doctor's guidelines. For example, unit doses can be set in packaged powders, flasks, ampoules and preferably in the form of a capsule or tablet. The active compound present in these 1 unit dosage forms of the composition may be present in one! amount of, for example, from about one gram! to about fifteen grams or more, for administration; daily simple or multiple, according to the I particular need of: patient. Starting the treatment regimen with a minimum daily dose of approximately one gram, blood levels of PAI-1 and the analysis of symptomatic relief of? The agent can be used to determine if a higher or lower dose is indicated. The effective administration of the compounds of this invention can be provided in the oral dose of, for example, I about 0.1 mg / kg / day to about 1,000 mg / kg / day. Preferably, the administration will be from about 10 mg / kg / day to 600 mg / kg / day, more preferably from 25 to 200 mg / kg / day and even more preferably from 50 mg / kg / day to 100 mg / kg / day . In some embodiments, a daily dose of about 1 mg / kg to 250 mg / kg is provided. The present invention compounds can also be solvated, especially hydrated. Hydration can occur during the manufacture of the compounds or compositions comprising the compounds or hydration can occur over time due to the hygroscopic nature of the compounds. In some embodiments, the present invention relates to prodrugs of the compounds of formulas 1 to 6. The term "prodrug", as used herein, means, a compound that is convertible in vivo by Presss (1985); Krogsgaard-Larsen, et al. (Ed.) "Design and I Application of Prodrugs, Textbook of Drug Design and Development, chapter 5, 113-191 (1991), Bundgaard, et al, i Journal of Drug Delivery Reviews, 8: 1-38 (1992), i Bundgaard, J of Pharmaceutical Sciences, 77 .: 285 et seq. I (1988) and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).

The compound of the present invention can be placed in a suitable container and labeled for treatment of a related disorder with PAI-1, for example, leukemia. In addition, another pharmaceutical product comprising at least one other therapeutic agent useful in the treatment of the PAI-1 related disorder can be placed in the container as well as labeled for treatment of the indicated disease. I For the administration! of pharmaceutical products that Step 1: 2-bromo-J 1 - (6-methoxy-2-naphthyl) ethanone. Phenyltrimethylammonium tribromide (9.45 g, 25.1 mmol) was added under nitrogen in portions for about 2 hours, to a solution of 1- (6-methoxy-naphthalene-2-yl) -ethanone (5.05 g). , 25.2 mmol) in 50 mL of anhydrous THF (tetrahydrofuran) at room temperature. After the addition] the reaction was stirred at room temperature for 0.5 hour and then, 250 mL of cold water was added. The solid present was collected by filtration, rinsed with | 50 mL of water and drying under reduced pressure to obtain ß |, 66 g of a solid tanning agent. Recrystallization of the solid by isopropyl alcohol i provided 2-bromo-1; - (6-methoxy-2-naphthyl) ethanone (4.07 g, 58%) as a! Brown solid, mp 109-116a C. Elemental analysis for j Ci3H Br02 calculated: C, 55.94, H, C. After the addition] the reaction was refluxed for 2 hours. The solid was collected by filtration, rinsed with absolute ethanol and dried, under reduced pressure, to obtain phosphorous oxychloride was extracted under reduced pressure to obtain 4 - (- (6-methoxy-2-naphthyl) -2-phenyl 1,3-thiazole (909 mg, 88%), as a white solid, mp 191-193a C. Elemental analysis for calculated C20H15NOS: C, 5j, 68; H, 4.76; N, 4.41; Found: C, 75.37; H, 4.65; N, 4.3-J, I Step 3: 6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthol. suspension of 4 - (6-methoxy-2-naph il) -2-phenyl-1,3-thiazole (804 mg, 2.53 mmol), prepared in the previous step, in 50 mL | of HOAc glacial acid plus 25 mL of 48% I HBr was stirred under nitrogen at 120 ° C. for 3 hours.The solvent was removed under reduced pressure and the residue was parked between 10% methanol chloride and 5% aHC03. (Note: The solid that did not dissolve in one or another layer was collected by filtration and stored as HGL salt of the desired product). The aqueous layer was separated and extracted 3 times with methanol-methylene chloride. The combined extracts were dried (MgSO.sub.4), filtered and the solvent extracted under reduced pressure to obtain 6 - | (2-phenyl-1,3-thiazol-4-yl) -2-naphthol (650 mg, 85%) as a light brown solid, mp 194 - 1972 C.! Elemental analysis for calculated C19H13NOS: C, 75.22; H, 41, 32; N, 4.62, Found: C, 74.22; H H, 4.12; N, 4.43. 1 Step 4: methyl ester of 2-hydroxy-3-phenyl-propinoic acid. Hydrogen chloride was bubbled for 15 minutes in a solution of 2-hydroxy-3-phenyl-propionic acid (10.0 g, 60 mmol) in 100 mL of methanol at room temperature. The vessel was sealed and then stirred overnight at room temperature. The reaction was made basic by the addition of 5% NaHCO 3 and then concentrated under reduced pressure to extract the methanol. The residue was diluted with water and extracted with ethyl acetate. The organic layer was extracted with saturated NaCl, dried (MgSO 4), filtered and the solvent extracted under reduced pressure to obtain methyl ester of 2-hydroxy-3-phenyl-propinoic acid (9.7 g, 90 %) as 1 yellow oil, S m / z 180 [M] +. Elemental analysis for calculated C10H12O3: C; 66, 65; H, 6.71; N, 0.00; Found: C, j 66.52; H, 6.86; N, 0.29. '1 j Step 5: methyl ester of 3-phenyl-2-1 trifluoromethanesulfonyloxy-propionic acid. Triethylamine (93 iL, 6.68 mmol) was added under nitrogen to a solution of methyl ester of 2-hydroxy-3-phenyl-propynoic acid (1.00 g, 5.57 mmol), prepared in step above, in 20 mL of chloroform (99.9%, free of ethanol) at the temperature of acetone! - dry ice. Then, anhydride was added dropwise for 15 minutes. I trifluoromethanesulfonic acid 1 (1.03 mL, 6.13 mmol). The I cooling bath was removed! and the reaction was stirred overnight at room temperature. The reaction was extracted with 1 N HCl, 5% NaHCO 3, dried (MgSO 4), filtered and the solvent removed under reduced pressure to obtain 1.53 g of a brown oil. Purification of the oil in 100 g of silica gel (230-400 mesh) using 3: 1 methylene-hexane chloride as the eluent, I thiazol-4-yl) -2-naphthyl.oxi} propanoate. A mix of 6 -. 6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthol (247 mg, I 0.814 mmol), prepared in step 3, methyl ester of 2-hydroxy-3-y acid phenyl-prophiic (387 mg, 1.24 mmol), prepared in the previous step and cesium carbonate (532 mg, 1.63 mmol) in 1 mL of acetone was stirred under nitrogen at room temperature for 17 hours. The reaction was concentrated under reduced pressure to remove acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted 3 times with Imethylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 449 mg of a brown oil. Purification of the oil in 300 g of silica gel (230-400 mesh) using 1: 1 to 3: 2 methylene chloride: hexane as the eluent provided methyl 3-phenyl i -2-. { [6 - (2-phenyl I-1,3-thiazol-4-yl) -2-naphthyl] oxy} propanoate (3 ^ 3 mg, 88%) as a white foam, MS (ESI) m / z 466 [M + h] +. Elemental analysis for calculated C29H23F3 03S: C; 74.82; H, 4.98; N, 3.01; Found: C, 74.46; H, 4.96; N, 2.81. Step 7: acid 3 - 2 ¡-. { [6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] -oxijpropanoic acid. A mixture of methyl 3-phenyl-2 -. { [6 - (2-f nyl-1,3-thiazol-4-yl) -2-naphthyl-oxy} Propanoate (260 mg, 0.559 mmol), prepared in the previous step, and, and 1 N NaOH (839 mL, 0.839 mmol) in 40 mL of THF, 10 mL of water was refluxed under nitrogen for 3.5 hours and then heated overnight. , maintained overnight at room temperature. Through TLC, material from the game remained. 559 yL (0.559 mmol) of 1 N NaH and the refluxing mixture) was added over 3 hours. The reaction was acidified by the addition of 2 mL of 1N HCl and then concentrated, under pressure; reduced, to eliminate the THF. The gum present was dissolved in methylene chloride and the mixture concentrated under pressure! reduced. The solid present was I collected by filtration, r rinsed with water and dried under reduced pressure to obtain the title compound (234 mg, 92%) as a yellow solid, mp 154-160s. - thiazol-4-yl) - | 2-naphthol (300 mg, 0.990 mmol), prepared in step 3 of example 1, bromoacetonitrile (83 μl, 1.19 mmol) and carbonatp potassium (684 mg, 4, 95 mmol) in 15 mL of DMF was stirred under nitrogen at room temperature for 21 hours. Through TLC, some starting material remained. 34 pL (0.488 mmol) of additional bromoacetonitrile was added and the reaction stirred at room temperature for 3 days. The reaction was partitioned between ethyl acetate and water. The formed emulsion was separated by the addition of saturated sodium chloride. The organic layer was separated, extracted several times with water, dried (MgSO), filtered and the solvent removed under reduced pressure to obtain 311 mg of a brown solid. [Purification of the solid in 250 g of silica gel (230-400 mesh) using 1: 1 to 3: 2 methylene chloride: hexane as the eluent provided. { [6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} acetonitrile (256 mg, 76%), as a white solid, mp 113-117s C. Elemental analysis! for calculated C2iHi4N2OS: C; 73.66; H, 4.12; N, 8.18; Found: C, 72.83; H, 4.18; N, 8.03. Step 2: 5 - ( { [6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} methyl-1H-tetraazole A mixture of { 6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl-oxy} -acetonitrile (204 mg, 0.596 mmol), prepared in step j above sodium azide (119 mg, 1 , 82 mmol) and ammonium chloride (98 mg, 1.82 mmol) in 10 ml of DMF was stirred under nitrogen at 100 ° C. for 5 hours.j The reaction was partitioned between 10% methylene-methylene chloride and 1%. N HC1 The organic layer was separated, extracted three times with water, dried (MgSO), filtered and the solvent extracted under reduced pressure to obtain the title compound (87 mg, 37%) as a white solid, p'm 226-2288 C. Elemental analysis I for C2iHi5N5OS calculated1: C; 64.74; H, 4, 00; N, 17, 98; I Found: C, 63, 46; H, 4, 08; N, 16, 95. Example 3: Synthesis of 2 - acid. { [1-Bromo-6 - (2-phenyl, -1,3-thiazol-4-yl) -2-naphthyl > oxy } - 3-phenylpropanoic. | I Step 1: 1-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthol. Bromine (547 yL, 10, 7 mmol) in 250 mL of glacial HOAc was added, under nitrogen drip, for about 7 hours at! a solution of 1-bromo-6 - (2 phenyl-1,3-thiazol-yl) -2-naphthol (3.24 g, 10.7 mmol), prepared in the country 3 of Example 1, in 600 mL of Glacial HOAc at room temperature. After the addition, the reaction was stirred at room temperature and overnight. The solid was collected by filtration, I rinsed with glacial HOAc and dried under reduced pressure to obtain 4.74 g of yellow solid jun. The solid was dissolved in 500 mL of 20% methanol-methylene chloride and -1 neutralized with 5% NaH03. The aqueous layer was separated and extracted 3 times with 20% methanol-methylene chloride. The combined extracts were dried (MgSO 4), filtered and the solvent removed under reduced pressure to obtain 3.99 g of a light brown solid. Purification of the solid in 1 kg of silica gel (230-400 mesh) using 3: 1 hexane: methylene chloride to 3: 1 methylene chloride: hexane, as the eluents, provided 1-bromo-6 - (2 - phenyl-1,3-thiazol-4-yl) -2-naphthol (1.74 g, 43%) as a brown solid, p17 176-1832 C. Elemental analysis for calculated Ci9H12BrNOS: C; 59.70; H, 3.16; N, 3.66; Found: C, 59.16; H, 3.12; N, 3.48. Step 2: Methyl 2. { [II-Bromo-6 (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} - 3 - phenylpropanoate. A mixture of 1-bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthol (303 mg, 0.792 mmol), prepared in the previous step, methyl ester of 3-acid phenyl-2-trifluoromethanesulfonyloxy-propinoic acid (378 mg, 1.21 mmol), i prepared in step 5 of example 1 and cesium carbonate i (517 mg1.59 mmol) in 25 mL of acetone was stirred under nitrogen at room temperature for 18 hours. The reaction was concentrated under reduced pressure to remove acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted 3 times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 514 mg of a light yellow oil. Purification of the oil in 300 g of silica gel (230-400 mesh) using 3: 2 to 1: 1 hexane: methylene chloride as the eluents afforded Methyl 2. { [1 I-Bromo-6 (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} - 3 - phenylpropanoate (372 mg, 86%) as a matt solid I, p.m. 96 -! 101a C. Elemental analysis for C29H22BrN03S calculated: C; 63.97; H, 4.07; N, 2.57; Found: I C, 63.87; H, 4.01; N, 2.44. Step 3: acid 2 -. { [! - Bromo-6 - (2-phenyl-1,3-I thiazol-4-yl) -2-naphthyl-oxy} - 3 - phenylpropanoic. A mixture of Methyl 2. { [1-bromo-6 (2-phenyl-1,3-thiazol-4-yl) -2- 197 mg, 0.363 mmol), pre OH (544 L, 0.544 mmol) plus 10 mL of water was 3 hard. The reaction was filtered, acidified by the addition of 2 mL of 1 N HC1 and then concentrated under reduced pressure. The solid was collected by filtration, rinsed with water and dried under reduced pressure to obtain the title compound (178 pg, 92%) as a white solid, mp 220-2242 C. Elemental analysis for calculated C28H20BrNO3S: C; 63.02; H, 3.85; N, 2.62; Found: C, 63.13; H, 3.70; N, 2, 54.

Example 4: Synthesis of acid. { [1-Bromo-6 - (2-phenyl-1, -1,3-thiazol-4-yl) j-2-naphthyl] oxy} acetic. Step 1: Methyl. { [1-j bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} acetate. A mixture of 1-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthol I (356 mg, 0.931 mmol), prepared in step 1 of Example 3, methyl bromoacetate (106 [mu] g, 1.12 mmol) and cesium carbonate (457 mg, 1.40 mmol) in 25 mL of acetone was stirred under nitrogen at room temperature for 19 hours. The reaction was concentrated under reduced pressure to remove acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted several times with methylene chloride. The combined organic extracts were dried (MgSO.sub.4), filtered and the solvent removed under reduced pressure to obtain Methyl. . { [1-Bromo-6 - (2-phehyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} acetate (401 mg, 5%) as a white matte solid, mp 156-159 a C. Elemental analysis for calculated C22Hi6BrN03S: C; 58.16; H, 3.55; N, 3.08; Found: C, 57.87; I H, 3.43; N, 2.94. 'Step 2: acid. { [1 - bromo-6 - (2-phenyl-1,3-thiazole - 4 - yl) -2-naphthyl] oxdi} acetic. A mixture of Methyl. { [1-Bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl-oxy} acetate (217 jmg, 0.477 mmol), prepared in the previous step and 1N NaOH (716 pL, 0.716 mmol) in 20 mL of THF plus 20 mL of methanol plus 10 mL of water was refluxed under nitrogen for 2j25 hours. The reaction was filtered, acidified by the addition of 3 mL of 1 N HC1 and then concentrated under reduced pressure. The solid formed was collected by filtration, rinsed with water and dried under reduced pressure to obtain the title compound (195 mg, 92%) as a white solid, mp 222-2309 C. Elemental analysis for calculated jC2iHi BrN03S: C; 56.94; H, 3.25; N, 3.16; Found-C, 57.19; H, 3.18; N, 3.04. Example 5. Synthesis of 5 - ( { [1-bromo-6 - (2-phenyl) - 1,3-thiazol-4-yl) -2-naphthyl] oxy} methyl) - 1 H -tetraazole. ! Step 1: . { [1-bromo-6 - (2-phenyl-1,3-thiazole-4 - il) - 2 - naphthyl] oxy} methyl) acetonitrile. A mixture of 1-bromo-6 - (2-phenyl-1, 3-thiazol-4-yl) -2-naphthol (351 mg, 0.918 mmol), prepared in step 1 of Example 3, i bromoacetonitrile (77 pL, 1.11 mmol) and cesium carbonate i (1.505 g, 4.62 mmol) in 125 mL of acetone was stirred under I nitrogen at room temperature for 19 hours (from one day to another). The reaction was concentrated under reduced pressure to remove acetone. The residue partitioned between methylene chloride and water. The aqueous layer was separated and extracted three times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the extracted solvent reduced in reduced pressure to obtain. { [1-bromo-6- (2-phenyl-1,3-thiazole naphthyl] oxy) methyl) acetonitrile (382 mg, 99%) as a light brown solid, mp 157-1609 C. Elemental analysis for C2iHi3BrN02S calculated: C; 59.87; H, 3.11; N, 6.65; Found: C, 59.56; H, 3.28; N, 6.56. Step 2: 5 - ( { [1-brjomo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} methyl) -1H-tetraazole. A mix of . { [1-Bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} mptil) acetonitrile (277 mg, 0.658 mmol), prepared in the previous step, sodium azide (128 mg, dried under reduced pressure to obtain the title compound (276 mg, 82%) as a white matt solid, 227-231 aC. Elemental analysis for C2iHi BrN5OS + 0.48 C3H7NO + 0.47 H20 t i calculated: C; 53.07; H, 3? 63; N, 15.11; Found: C, 53.08; H, 3.61; N, 14.91. ! Example 6: Synthesis | (. {6 - [2 - (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphthyl} oxy) acetic acid. Step 1: 2- (2,6-Dichlorobenzyl) -4- (6-methoxy-2-naphthyl) -1,3-thiazole. A suspension of (2-bromo-1- (6-methoxy-2-naphthyl) ethanone (500 mg, 1.79 mmol), prepared in step 1 of Example 1, in 25 mL of absolute ethanol was heated under nitrogen At this point, all the solid had been dissolved, and at the reflux temperature 2 - (2, - dichlorophenyl) ethanethioamide (395 mg, 1.79 mmol) was added and the reaction was added. reflux for 3 hours.After cooling to room temperature, the solid was collected by filtration, rinsed with absolute ethanol and dried under reduced pressure to obtain 575 mg of a dull white solid.The solid was dissolved in 20% methanol. j- methylene chloride An excess of 5% NaHC03 was added to convert the amine salt to the free base.The aqueous layer was separated and extracted 3 times with 20% methanol-methylene chloride.The combined organic extracts were dried (MgSO4), filtered and the solvent extracted under reduced pressure to obtain 2- (2,6-dichlorobenzyl) -! - (6-methoxy-2-naphthyl) -1,3-do pale, calculated mp: H, 3.67; N, - thiazole - 4 chlorobenzyl) 90 mg, 0.975 mL of glacial HOAc plus 25 mL of HBr al 48% was stirred under nitrogen at 120a C for 3.5 hours and then maintained, overnight, at ambient temperature. The reaction was concentrated under reduced pressure. The residue was dissolved in 20% methanol-methylene chloride and neutralized with the addition of an excess of 5% NaHCO3. The aqueous layer was separated and extracted 3 times with 20% methanol-methylene chloride.

The combined extracts were dried (MgSO4), filtered and i the solvent extracted under reduced pressure to obtain 6 I - [2- (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphthol as a brown solid, pm 191 - 1932 C.

Elemental analysis for! C2oHi3Cl2NOS calculated: C; 62.19; H, 3.39; N, 3.63; Found 'C, 61.31; H, 3.30; N, 3.42. I Step 3: methyl (. {6-j [2 - (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphyl} oxy) acetate. A mixture of 6 - [2 - (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphthol (269 mg, 0.696 mmol), prepared in the previous step, methyl bromoacetate (79 0.835 mmol) and cesium carbonate (341 mg, 1.05 mmol) in 25 mL of acetone was stirred under nitrogen at room temperature for 4 hours. The reaction was concentrated 1 under reduced pressure to extract the acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted 3 times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 298 mg of a brown solid. The solid was triturated several times with hexane and then dried under reduced pressure to obtain methyl (. {6 - [2 - i (2,6-dichlorobenzyl) -j 1,3-thiazol-4-yl] -2 -nafil Oxy) acetate (298 μg, 93%) as a brown solid, mp 174-177 ° C. (Elemental analysis for C23H17CI2 O3S calculated: C, 60.27; H, 3.74; N, 3 , 06; Found: C, 59.03; H, 3.70; N, 2.88. ! Step 4: Acid (. {6 - [2 - (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-jnaphthyl} oxy) acetic acid. A mixture of methyl (. {6 - [2 - (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphyl} oxy) acetate (205 mg, 0.447 mmol), prepared in the previous step, and 1 N NaOH (671 μ? _, 0.671 mmol), in 20 mL of THF plus 20 mL of methanol plus 10 mL of water was refluxed under nitrogen! for 2.5 hours. The reaction was filtered, acidified by the addition of 3 mL of 1 N HC1 and then concentrated under reduced pressure to extract the THF and the methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to obtain the title compound (150 mg, 74%) as a matt white solid, mp 205 - j 207s C. Elemental analysis for C22H15CI2NO3S + 0, 30 H20! calculated: C; 58.75; H, 3.50; N, 3.11; Found: C, 59.09; H, 3.58; N, 2.92.

I I Example 7: Synthesis of 2 - acid. { [1-Bromo-6 - (5-bromo-2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} > - 3 - phenylpropanoic. | Step 1: 1-bromo-6 - (5-bromo-2-phenyl-1,3-thiazol-4-yl) -2-naphthol. Bromine (547 pL, 10.7 mmol) in I 250 mL of glacial HOAc was added under nitrogen by dripping for about 7 hours to a solution of 6 - (2-phenyl-1,3-thiazole - | 4-yl) Naphthol 83.24 g, 10.7 mmol), prepared in step 3 of Example 1 in 600 mL of glacial HOAc at room temperature. After the addition, the reaction was stirred at room temperature overnight. The solid was collected by filtration, rinsed with Glacial HOAc and drying under reduced pressure to obtain 4.74 i! g of a yellow solid. The solid was dissolved in 500 mL of 20% methanol-methylene chloride and neutralized with 5% j NaHCO 3. The aqueous layer was separated and extracted 3 times with % methanol - methylene chloride. The combined extracts were dried (MgSO.sub.4), filtered and the solvent extracted i under reduced pressure to obtain 3.99 g of a light brown solid I. Purification of solid dejl in 1 kg of silica gel (230-400 mesh) using 3: 1 hexane: methylene chloride ia 3: 1 methylene chloride: hexane as the eluents, i provided 1-bromo-6j- (5-bromo-2-phenyl-1,3-thiazole - 4 - yl) -2-naphthol (178 mg, 4%) as a matt white solid, mp 198-1200s C. Elemental analysis for calculated Ci9HiiBr2NOS: C; J. 49, 48; H, 2.40; N, 3, 04; Found: C, 49, 83; H, 2.36; N, 2, 81. Step 2: Methyl 2 -. { (1-Bromo-6 - (5-bromo-2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} - 3-phenylpropanoate A mixture of 1-bromo-6 - (5 - Bromo-2-phenyl-1,3-thiazol-4-yl) -2-naphthol (132 mg, I 0, 286 mmol), prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyloxy-methyl ester The propynoate (136 mg, 0.43 mmol), prepared in step 5 of Example 1 and jasium carbonate (188 mg, 0.577 mmol) in 15 mL of acetone was stirred under nitrogen at room temperature for 20 h. After 5 minutes, the starting material was left in. An additional quantity of 43.8 mg (0. 140 mmol) of 3-phenyl-2-trifluoromethanesulfonyloxy! -propionic acid methyl ester was added and the reaction was continued. The reaction was concentrated under reduced pressure to extract the acetone, the residue partitioned between methylene chloride and water. and separated and extracted 3 times with methylene ilide. The combined extracts were dried! (MgSO 4), filtered and the solvent removed under reduced pressure to obtain 235 mg of a yellow oil. Purification of the oil on silica gel i (230-400 mesh) using 3: 2 hexane-methylene chloride as the eluent provided methyl 2 -. { (1-Bromo-6 - (5-bromo-2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} -. 3-phenijlpropanoate (125 mg, 70%) as a foam yellow, MS (ESI) m / z 622/624/626 [M + H] + Elemental analysis for calculated C29H2iBr2N03S: C: 55.88; H, 3.40; N, 2.25; Found ^ C, 56 , 33; H, 3, 33; N, 2, 14. Step 3: 2 - { [1 - bromo - 6 - (5-bromo-2-phenyl-1,3-thiazol-4-yl) acid) - 2 - naphthyl] oxy} - 3 - I phenylpropanoic A mixture of Methyl 2 -. {(1 - bromo - 6 - (5 i - bromo - 2 - phenyl - i 1, 3 - thiazole - 4 - il) -2-j naphthyl] oxy.} - 3-pheylpropropanoate (134 mg, 0.21 mmol), prepared in the previous step and 1 N NaOH (323 L, 0.323 mmol) in 10 mL of THF plus 10 mL of methanol plus 5 mL of water was refluxed under nitrogen for 2 hours.The reaction was filtered, acidified with 1 N HCl and then concentrated under reduced pressure to remove THF and methanol.The solid present was collected by filtration , rinsed c on water and drying under reduced pressure to obtain the title compound (68 mg, 52%) as a yellow solid, mp 221-223a C. Elemental analysis for C28Hi9Br2 N05S calculated: C; 55.19; H, i 3.14; N, 2.30; Found: C, 56.17; H, 3.45; N, 2.05. Example 8: Synthesis of 4 - ( { [1-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} benzoic acid Step 1: methyl 4 - ( { [i-Bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl-oxy} -methyl) -benzoate A mixture of 1-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthol (0.43 mg, 1.12 mmol), prepared in step 1 of Example 3, methyl 4 - (bromomethyl) benzoate (259) , 7 mg, 1.13 mmol) and cesium carbonate (551.9 mg, 1.69 mmol) in 25 mL of acetone was stirred under (nitrogen at room temperature I for 18 hours.) The reaction was concentrated under reduced pressure. to remove the acetone The reaction was partitioned between methylene chloride and water.The aqueous layer was separated and extracted 3 times with methylene chloride.

The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 514.0 mg of a yellow solid. The purification of the solid in! 300 g of silica gel (230-400 mesh) using hexane: methylene chloride to 3: 2 methylene chloride: hexane as 63.40; H, 3.80; N, 2.64; Found: C, 62.99; H, 4.15; N, I 2.50. ! Step 2: 4 - ( { [1-Bromo-6- (2-phenyl-1,3-l thiazol-4-yl) -2-naphthyl] oxy} methyl) benzoic acid. A mixture of methyl 4 - ( { [Lj-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthoxy] methyl] benzoate (214.8 mg, 0.405 mmol), prepared in the previous step and 1 N NaOH (608 μ?, 0.608 mmol) in 40 mL of THF plus 40 mL of methanol plus 10 mL of water was stirred for 24 hours. An additional amount of 608 yL (0.608 mmol) of 1 N NaOH was added and the mixture subjected to reflux for 24 hours. After cooling to room temperature, the reaction was filtered through TLC. acidified by the addition of 5 mL of 1 N HCl and then concentrated under reduced pressure to remove THF and methanol.The solid present was collected by filtration, washed with water and I dried under reduced pressure to obtain the compound of title (152.9 mg, 73%) such as a white solid, mp 268-2702 C. Elemental analysis for C27Hi8Br 03S calculated: C; 62.36; H, 3.57; N, 2.69; Found: C , 62.38; H, 3.54; N, 2, 62. Example 9: Primary selection for inhibition of PAI-1 The test compounds are dissolved in DMSO I (dimethylsulfoxide) at a final concentration of 10 M and t then, diluted 100X in physiological buffer solution, the inhibitor assay is initiated by the addition of the assay (final concentration 1 - 100 μ ?, maximum concentration i DMSO 0.2%) in a pH 6.6 buffer containing 140 nM of recombinant human plasminogen activator inhibitor - 1 (PAI-lj Molecular Innovations, Royal Oak, MI). After a 1-hour incubation at room temperature, 70 nM of recombinant human plasminogen tissue activator (tPA) is added and the combination in the molar ratio used (2: 1) and the absence of any effect of the test compound About tPA alone. I Example 10: Assay to determine the IC50 value of inhibition of PAI-1 This assay is based on the non-SDS dissociable interaction between tPA and active PAI-1. The test plates are initially coated with human tPA (10 pg / ml). The test compounds of the present invention are dissolved in 10 mM DMSO and then, diluted with physiological buffer solution (pH 7.5) to a final concentration of 1-50 μ. i Test compounds1 are incubated with human PAI-1 (50 i ng / ml) for 15 minutes at room temperature. The plate coated with tPA s washed with a solution of 0.05% I I Tween 20 and 0.1% BSA and then, the plate is blocked by a solution of 3% BSA. An aliquot of the thiazole-naphthylcocid / PAI-1 acid solution is added to the plate at room temperature for 1 hour (Molecular Innovations, Royal Oak, MI). The plate is again washed and dried. add a goat rat-alkaline phosphatase IgG-alkaline phosphatase solution at a dilution of 1; 50,000 in goat serum. The plate is incubated 30 minutes at room temperature, washed and a phosphatase and alkaline substrate solution is added. The plate is incubated for 45 minutes at room temperature and color development is determined at OD4o5nm- The quantification of active PAI-1 bound to tPA at varying concentrations of the test compound is used to determine the IC50 value. The results are analyzed using a logarithmic optimal fit equation. The sensitivity of the assay is 5 ng / ml of human PAI-1 as determined from a standard curve ranging from 0 to 100 ng / ml. The compounds of Ta present invention inhibited the plasminogen-1 activator inhibitor as summarized in Table 1.! · Table 1 to. The value of IC50 | was determined by the antibody assay as described above. Although the above invention has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to the person skilled in the art that some changes and modifications can be made and can be implemented without undue experimentation within the scope of the invention. of the appended claims, which are presented by way of illustrative and not limitedjr. All publications and patent documents cited above are hereby incorporated by reference in their entirety for all purposes to the same extent as if they were I indicated individually. It is noted that with respect to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (21)

1. precedes, rec the following re 1
2. Formula 1 or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof, characterized in that: Ar is aryl or heteroaryl; Ri is hydrogen, Ci - C12 alkyl, C6-i4 aryl, Ce-n ar (Ci-6 < alkyl, - (CH2) p-heteroaryl, -CH2) p-CO-aryl, - (CH2) P -CO-t heteroaryl, - (CH2) P -CO- (Ci-C6) alkyl, C2 C7 alkenyl, C2 I C7 alkynyl, C3-Ca cycloalkyl, halogen or Ci-C3 1 perfluoroalkoxy; J i R2 and R3 are independently hydrogen, Ci-Ci2 alkyl, 1-14 aryl, C6-1 ar (Ci-6 > alkyl, - (CH2) p-heteroaryl, halogen, Ci-C3 alkoxy, jalkoxyaryl, nitro, carboxy (Ci-C6) alkyl, carbamide, carbjamate or C-Cs cycloalkyl; R4 is -CH (R6) (CH2) nR5-C (CH3) 2R6, -CH (R5) (CH2) nR6, -CH (R5) C6H4R6, -CH (R5) C6H3 (C02H) 2, CH (R5) C6H2 (C02H) 3 or a mimic acid; I R5 is hydrogen, Ci4 C6 alkyl, C6-12 aryl, Ce-14 ar (Ci-6) " alkyl, C3-C8 cycloalkyl or - (CH2) n (R7) i R6 is C02H, tetrazole or P03H;
3. that when b: from 1 to 6, Ar is phenyl, furanyl, thienyl, pyrazolyl-1-thiazolyl or fluorenyl. j 1 2. Compound in accordance with claim 1
4. Ci-C6 alkyl, phenyl- (CH2) P-halogeno perfluoroalkyl unsubstituted. 5. Compound in accordance with any of the
5. unsubstituted benzyl or benzyl substituted with from 1 to 3 groups selected from Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, C3-Ce cycloalkyl, - (CH2) P-C3-C6 cycloalkyl, halogen,
6. Ci-C3 perfluoroalkyl, Ci-C3 perfluoroalkoxy, ~ (CH2) P-phenyl and -O (CH2) P-phenyl doride p is from 1 3. I 7. Compound of conformity with any of claims 1 to 6, characterized because it has the formula
7. or a solvate, hydrate or its pharmaceutically acceptable salt or ester form. 1 8. Compound according to any of claims 1 to 6, characterized in that it has the formula 3:
8. Formula or a solvate, hydrate or its pharmaceutically acceptable salt or ester form. 9. Compound according to any of claims 1 to 8,! characterized in that Ar is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl,
9. i claims 1 a | 6, characterized in that it has the
10. salt or ester i0, Rn and Ri2
11. ilo, Ci-C6 alkoxy, hydroxy, C3-C6 cycloalkyl, - (CH2) P-C3-C6 cycloalkyl, halogen, - | (CH2) P-phenyl or -0 (CH2) P-phenyl. a of the formula
12. or ester R11 and i2 are independently hydrogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, cycloalkyl, - (CH2) P-C3-C6 cycloalkyl, halogen, - CK2) p-phenyl or -0 (CH2) P -phenyl 12. Compound according to claim 10 or 11, characterized in that the C1-6 alkyl is Ci-3 perfluoroalkyl and said Ci_6 alkoxy is Ci-3 perfluoroalkoxy.
13. 13. Compound according to any of claims 1 to 1, characterized in that Ri is hydrogen. !
14. 14. Compound according to any one of claims 1 to 13, characterized in that R4 is -CHR5C02H, CH2-tetrazole or -CH (R5) C6HJCO2H.
15. 15. Compound according to claim 1, characterized in that it is 3-phenyl-2- ( { [6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} acid} propanic; i 2- {[[l-bromo-6- (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl} oxy} phenylpronaic acid; acid { [1-bromo -6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl} oxy) acetic; 5- ( { [1-bromo-6 - (2-phenyl-1,3-thiazol-4-yl] -2-naphthyl] oxy} methyl) -lH-tetraazole or one of its forms ester or pharmaceutically acceptable salt
16. 16. Compound according to claim 1, characterized in that it is 2 - { [1-bromo-6 - (5-bromo-2-phenyl-thiazol-4-yl) -2-acid. -naphthyl] oxy} -3-phenylpropanoic acid (. {6 - [2- (2,6-dichlorobenzyl) -1,3-thiazol-4-yl] -2-naphthyl} oxy) acetic acid 4 - ( { [1-bromo-6 - (2-phenyl-1,3-thiazol-4-yl) -2-naphthyl] oxy} methyl) benzoium or one of its salt forms or Pharmaceutically eptable ester
17. 17. Process characterized in that it comprises administering a compound according to any of claims 1 to 16 to a subject
18. 18. Method according to claim 17, characterized because! comprises, determining a level of PA1 activity in a subject. I •
19. 19. Method of conformance with 18 characterized in that the determination is made before the administration of said compound.
20. 20. Procedure of! according to claim 18, characterized in that | the determination is made after the administration of a compound.
21. 21. Procedure for modulating PAI-1 activity characterized in that it comprises identifying a subject in need of PAI-1 modulation and administering to the subject an effective amount of a compound of formula 1:

    pharmaceutically acceptable salt or an ester form of ellaj, wherein: Ar is aryl or heteroaryl; Ri is hydrogen, Ci-Ci2 alkyl, C6-i4 aryl, Ce-14 ar (Ci-6) alkyl, - (CH2) p-heteroaryl, -CH2) p-CO-aryl, - (CH2) P -CO- heteroaryl, - (CH2) P -CO-. { Ci-C6) alkyl, C2 C7 alkenyl, C2 and C7 alkynyl, C3-c [cycloalkyl, halogen or Ci-C3 perfluoroalkoxy; I R2 and R3 are independently hydrogen, Ci-Ci2 alkyl, C6-i4 aryl, in ar (jCi-6) alkyl, - (CH2) p-heteroaryl, I halogen, Ci-C3 alkoxy, laxaryl, nitro, carboxy (Ci-Ce) -alkyl, carbamide, carbamate or C3-Ca cycloalkyl; R4 is -CH (R6) (CH2) nR5 |, -C (CH3) 2R6, -CH (R5) (CH2) nR6, -CH (R5)

    C6H4R6, -CH (R5) C6H3 (C02H) 2, CH (R5) C6H2 (C02H) 3 or a mimic acid;

    R5 2 aryl, Ce ar (Ci-6) alkyl R6 R7

    n is from 0 to 6; I p is from 0 to 3; 'I b is from 0 to 6 and I a is from 0 to 6 j 22. Process according to claim I 21, characterized in that in the definition of Ri, R2 and R3 said Ci-C12 Ci-C3 alkyl perfluoroalkyl and said Ci-Ce alkoxy is Ci-j c3 perfluoroalkoxy. 2. 3 . Procedure of compliance with the claims

    21 or 22, characterized in that Ar is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazolyl or! fluorenyl. 1 I 24 Process according to any of claims 21 to 23, characterized in that Ar is unsubstituted phenyl or phenyl substituted with from 1 to 3 groups selected from j Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, C3-Ce and cycloalkyl , - (CH2) P C3 C6 cycloalkyl, halogen, | - (CH2) P - phenyl or -0 (CH2) p-phenyl.

    2 5. Process according to claim 24, characterized in that the Ci-Ce alkyl is Ci-C3 perfluoroalkyl or dicijo Ci-C6 alkoxy is Ci-C6 perfluoroalkoxy. 2 6. Procedure in accordance with the claim

    21, characterized in that! Ar is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, thiazolyl or fluorenyl

    Ri is hydrogen, halogen, Ci_ C6 alkyl, or - (CH2) p-phenyl R2 and R3 are independently hydrogen, Ci-C unsubstituted alkyl, phenyl- | (CH2) p-, halogen or Ci-C3 perfluoroalkyl; R4 is -CHR5C02H, -CH2. etrazole or -CH (R5) C6H4C02H or a mimic acid and! R5 is hydrogen or benzyl; or a solvate, hydrate or pharmaceutically acceptable salt I or an ester form thereof. 27 Process characterized in that it is to treat the insufficiency of the fibrinolytic system, thrombosis, atrial fibrillation, lung jfibrosis, thromboembolic complication of surgery, stroke, myocardial ischemia, stroke, thromboembolic complication of surgery, cardiovascular disease, formation of atherosclerotic plaques, obstructive pulmonary disease chronic, renal fibrosis, Alzheimer's disease, (cancer of diabetes or arterial ovarian syndrome, cerebral thrombosis and deep vein thrombosis) 30. Procedure according to claim 27, characterized by that cardiovascular disease is caused by diabetes mellitus not dependent on Insulin 31. Pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 16 Jo 21 to 26, or one of its pharmaceutically acceptable salt or ester forms and a pharmaceutically acceptable excipient or carrier. from a compound as defined in any of Claims 1 to 116 or 21 to 26 in the manufacture of a medicament for treating fibrinolytic system insufficiency, thrombosis, atrial fibrillation, fibrosis? pulmonary, thromboembolic complication I surgery, stroke, myocardial ischemia, atherosclerotic plaque formation, cardiovascular disease, chronic obstructive pulmonary disease, polycystic ovary syndrome, stroke, diabetes, Alzheimer's disease, cancer or renal fibrosis. 33. Use according to claim 32, wherein the thrombosis is selected from the group consisting of venous thrombosis, arterial thrombosis, cerebral thrombosis and deep vein thrombosis. 34. Use according to claim 32, wherein the cardi-vascular disease is caused by non-insulin-dependent diabetes mellitus.

    The thiazolo-naphthyl present of the formula (I) and the procedures for i use them to modulate the expression of PAI-1 and to treat the disorders

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