ES2359508T3 - GLUCOCORTICOID RECEPTOR MODULATORS, AP-1 AND / OR NF-KB ACTIVITY AND ITS USES. - Google Patents

Abstract

A compound having the structure: ** Formula ** or its stereoisomer, or its pharmaceutically acceptable salt, in which: A is a bond or methylene; X is S; R is H, CH3, or C2H5; R1 is selected from alkyl and aryl; and Rb is CN, NO2, Cl, or Br.

Description

Field of the Invention

The present invention relates to a class of non-steroidal compounds that are particularly effective modulators of the glucocorticoid receptor, of AP-1 and / or NF-κB activity and, therefore, are useful for treating diseases such as obesity, diabetes and diseases associated with inflammation and immunity, and a procedure for using said compounds to treat these and other related diseases.

Background of the invention

The transcription factors NF-κB and AP-1 are involved in the regulation of the expression of a series of genes involved in mediating inflammatory and immunological responses. NF-κB regulates gene transcription, including TNF-α, IL-1, IL-2, IL-6, adhesion molecules (such as E-selectin) and chemokines (such as Rantes), among others. AP-1 regulates the production of TNF-α, IL-1, IL-2 cytokines, as well as matrix metalloproteases. Drug therapies targeting TNF-α, a gene whose expression is regulated by NF-κB and AP-1, have proven to be very effective in several human inflammatory diseases, including rheumatoid arthritis and Crohn's disease. Therefore, NF-κB and AP-1 play key roles in the onset and perpetuation of inflammatory and immunological disorders. See, Baldwin, A.S., Journal of Clin. Investigation, 107, 3 (2001); Firestein, G.S., and Manning, A.M., Arthritis and Rheumatism, 42, 609 (1999); and Peltz, G., Curr. Opin. in Biotech., 8, 467 (1997).

There are many signaling molecules (kinases and phosphatases) upstream of AP-1 and NF-κB that are potential targets of therapeutic drugs. JNK kinase plays a fundamental role in regulating phosphorylation and subsequent activation of c-jun, one of the subunits that constitute the AP-1 complex (fos / c-jun). Compounds that inhibit JNK have proven effective in animal models of inflammatory diseases. See, Manning A.M. and Davis R.J., Nature Rev. Drug Disc., v. 2, 554 (2003). A critical kinase for the activation of NF-κB is the IκB kinase (IKK). This kinase plays a key role in phosphorylation of IκB. When IκB phosphorylates, it undergoes degradation that leads to the release of NF-κB that can be translocated to the nucleus and activate transcription of the genes described above. An IKK inhibitor, BMS-345541, has proven effective in animal models of inflammatory disease. See, Burke J.R., Curr. Opin. Drug Discov. Devel., September, 6 (5), 720-728 (2003).

In addition to inhibiting signaling cascades involved in the activation of NF-κB and AP-1, the glucocorticoid receptor has been shown to inhibit the activity of NF-κB and AP-1 through direct physical interactions. The glucocorticoid receptor (GR) is a member of the family of nuclear hormone receptor transcription factors, and a member of the steroid hormone family of transcription factors. Affinity labeling of the glucocorticoid receptor protein allows the production of antibodies against the receptor that facilitate cloning of glucocorticoid receptors. For results in humans, see, Weinberger, et al., Science. 228, 640-742, (1985); Weinberger, et al., Nature, 318, 670-672 (1986); and for results in rats, see, Miesfeld, R., Nature, 312, 779-781 (1985).

Glucocorticoids that interact with GR have been used for more than 50 years to treat inflammatory diseases. It has been clearly shown that glucocorticoids exert their anti-inflammatory activity by GR inhibition of NF-κB and AP-1 transcription factors. This inhibition is called transrepression. It has been found that the main mechanism for inhibition of these transcription factors by GR is performed through a direct physical interaction. This interaction alters the transcription factor complex and inhibits the ability of NF-κB and AP-1 to stimulate transcription. See, Jonat, C., et al., Cell, 62, 1189 (1990); Yang-Yen, H.F., et al., Cell, 62, 1205 (1990); Diamond, M.I. et al., Science, 249, 1266 (1990); and Caldenhoven, E. et al., Mol. Endocrinol., 9, 401 (1995). Other mechanisms have also been proposed, such as kidnapping of coactivators by GR. See, Kamer Y., et al., Cell, 85, 403 (1996); and Chakravarti, D., et al., Nature, 383, 99 (1996).

In addition to causing a transrepression, the interaction of a glucocorticoid with GR can cause GR to induce the transcription of certain genes. This induction of transcription is called transactivation. Transactivation requires GR dimerization and binding to a glucocorticoid response element (GRE).

Recent studies using a mouse deficient in the dimerization of the transgenic GR that cannot bind to DNA have shown that the transactivation activities (DNA binding) of GR can be separated from the transrepressant effect (not binding to DNA) of the GR. These studies also indicate that many of the side effects of glucocorticoid therapy are due to the ability of OR to induce transcription of various genes involved in metabolism, while transrepression, which does not require DNA binding, leads to suppression. of inflammation See, Tuckermann, J. et al., Cell, 93, 531 (1998); and Reichardt, H.M., EMBO J., 20, 7168 (2001).

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PCT application WO 2004/009017, published on January 29, 2004, assigned to the applicant, describes substituted bicyclooctane compounds useful for treating diseases, such as obesity, diabetes and diseases associated with inflammation or immunity.

Compounds that modulate AP-1 and / or NF-κB activity would be useful, since these compounds would be useful for the treatment of inflammatory and immune disorders and diseases, such as osteoarthritis, rheumatoid arthritis, multiple sclerosis, asthma , inflammatory bowel disease, transplant rejection and graft versus host disease.

In addition, with respect to the glucocorticoid receptor pathway, glucocorticoids are known to be potent anti-inflammatory agents, although their systemic use is limited by their side effects. Compounds that maintain the anti-inflammatory efficacy of glucocorticoids while minimizing side effects, such as diabetes, osteoporosis and glaucoma, would be very beneficial for a large number of patients with inflammatory diseases.

In addition, with respect to GR, the technique needs compounds that antagonize transactivation. These compounds may be useful for treating metabolic diseases associated with higher levels of glucocorticoids, such as diabetes, osteoporosis and glaucoma.

In addition, with respect to OR, the technique needs compounds that cause transactivation. These compounds may be useful for treating metabolic diseases associated with a glucocorticoid deficiency. These diseases include Addison's disease.

In addition, new compounds with higher activity are needed, compared to known modulators of GR, AP-1 and NF-κB activity. It is also desirable and preferable to discover compounds with advantageous and improved characteristics in one or more categories, which may be, but are not limited to the following: (a) pharmaceutical properties; (b) dosage requirements; (c) factors that decrease the peak and sinus characteristics of blood concentration; (d) factors that increase the concentration of active drug in the recipient; (e) factors that decrease the propensity for clinical drug-drug interactions; (f) factors that decrease the potential for adverse side effects; (g) factors that improve viability or manufacturing costs; and (h) factors that lead to desirable physical characteristics including, for example, a desirable balance of hydrophilic and lipophilic properties.

Description of the invention

A class of new non-steroidal compounds is provided that is useful for treating diseases associated with the modulation of glucocorticoid receptor, AP-1 and / or NF-κB activity, including obesity, diabetes, inflammatory diseases and immunological, and having a structure according to claim 1. Pharmaceutical compositions are also provided for use in procedures for treating obesity, diabetes, and diseases associated with inflammation and immunity.

According to the present invention, compounds having the following structure are provided:

image 1

or its stereoisomer, or its pharmaceutically acceptable salt, in which: A is a bond or methylene; X is S; R is H, CH3, or C2H5; R1 is selected from alkyl and aryl; Y Rb is CN, NO2, Cl, or Br. Whether or not they are specifically listed, all preferred compounds (including examples of

compounds) described herein include their stereoisomers or pharmaceutically acceptable salts. The

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Four. Five

Preferred compounds include the compounds described in paragraphs numbered 1-2, which appear below.

one.

The compounds as defined above, their stereoisomers or their pharmaceutically acceptable salts, wherein R 1 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, and phenyl.

2.

The compounds as defined above, which have the structure:

image 1

its stereoisomers, or pharmaceutically acceptable salts thereof, wherein R1 is methyl, ethyl, n-propyl, i-propyl, or n-butyl.

Aspects of the preferred embodiments described above, including the individual variables (or groups of variables), may replace related aspects of other embodiments to form other preferred embodiments of the present invention.

In another embodiment of the present invention, pharmaceutical compositions useful for treating endocrine disorders, rheumatic disorders, collagen diseases, dermatological diseases, allergic diseases, ophthalmic diseases, respiratory diseases, hematological diseases, gastrointestinal diseases, inflammatory diseases, autoimmune diseases, diabetes are provided. , obesity, and neoplastic diseases, as well as other uses described herein, which include a therapeutically effective amount (depending on the use) of a compound of the invention and a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides a therapeutically effective amount of a compound of the invention for use in treating endocrine disorders, rheumatic disorders, collagen diseases, dermatological diseases, allergic diseases, ophthalmic diseases, respiratory diseases, hematological diseases, gastrointestinal diseases. , inflammatory diseases, autoimmune diseases, diabetes, obesity and neoplastic diseases, that is, a disease associated with the product of the expression of a gene whose transcription is stimulated or repressed by glucocorticoid receptors,

or a disease associated with transcription induced by AP-1 and / or NF-κB (in particular AP-1), or a disease associated with the expression of genes dependent on AP-1 and / or NF-κB (in particular AP -1), in which the disease is associated with the expression of a gene under the regulatory control of AP-1 and / or NF-κB (in particular AP-1), including inflammatory and immunological disorders and diseases as described in Present it below.

Another embodiment of the present invention provides a therapeutically effective amount of a compound of the invention for use in treating a disease or disorder associated with the product of the expression of a gene whose transcription is stimulated or repressed by glucocorticoid receptors, or a procedure to treat a disease or disorder associated with transcription induced by AP-1 and / or NF-κB (in particular AP-1), or a procedure to treat a disease or disorder associated with the expression of AP-dependent genes -1 and / or NF-κB (in particular AP-1), in which the disease is associated with the expression of a gene under the regulatory control of AP-1 and / or NF-κB (in particular AP-1) , such as inflammatory and immune disorders, cancer and tumor disorders, such as solid tumors, lymphomas and leukemia, and fungal infections, such as fungal fungal infections.

The term "disease associated with GR transactivation", as used herein, refers to a disease associated with the transcription product of a gene whose transcription is transactivated by a GR. These diseases include, but are not limited to osteoporosis, diabetes, glaucoma, muscle loss, facial swelling, personality changes, hypertension, obesity, depression and AIDS, wound healing, primary or secondary adrenocortical insufficiency, and disease. from Addison.

The terms "treat" or "treatment," in all grammatical forms as used herein refer to prevention, reduction or improvement, partial or complete mitigation, or the cure of a disease, disorder or condition. , in which prevention indicates the treatment of a person who is at risk of developing said disease, disorder or condition.

The term "glucocorticoid receptor" and the term "GR", as used herein, refers to a member of the family of nuclear hormone receptor ("NHR") transcription factors that bind glucocorticoids and stimulate or repress transcription, or GR-beta. This term and this term, as used herein, refer to glucocorticoid receptors from any source including, but not limited to human glucocorticoid receptors, as described in Weinberger, et al., Science, 228, pp. . 640-742 (1985); and in Weinberger, et al., Nature, 318, pp. 670-672 (1986); rat glucocorticoid receptors, as described in Miesfeld, R., Nature, 312, pp. 779-781 (1985); mouse glucocortoid receptors, as described in Danielson, M., et al., EMBO J., 5, 2513; sheep glucocorticoid receptors, as described in Yang, K., et al., J. Mol. Endocrinol., 8, pp. 173-180 (1992); marmoset glucocortoid receptors, as described in Brandon, D.D., et al, J. Mol. Endocrinol., 7, pp. 89-96 (1991); and human GR-beta, as described in Hollenberg, S.M., et al., Nature, 318, p. 635, 1985, Bamberger, C.M., et al., J. Clin Invest., 95, p. 2435 (1995).

The term "disease or disorder associated with AP-1 and / or NF-κB", as used herein, refers to a disease associated with the product of the expression of a gene under the regulatory control of AP-1. and / or NF-κB. These diseases include, but are not limited to inflammatory and immunological diseases and disorders, cancer and tumor disorders, such as solid tumors, lymphomas and leukemia, and fungal infections, such as fungal mycoses.

The term "inflammatory or immunological diseases or disorders" is used herein to include any condition, disease or disorder that has an inflammatory or immunological component including, but not limited to each of the following conditions: transplant rejection (eg, kidney, liver, heart, lung, pancreas (for example, islet cells), bone marrow, cornea, small intestine, skin allografts, skin homografts (such as those used in the treatment of burns), heart valve xenografts , serum sickness, and graft versus host disease, autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type I and type II diabetes, juvenile diabetes, obesity, asthma, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), pyoderma gangrenosum, lupus (systemic lupus erythematosus), myasthenia gravis, psoriasis, dermatitis, dermatomyositis, eczema, seborrhea, pulmonary inflammation, uveitis of the eye, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's syndrome (dry mouth / eyes), pernicious or immunohemolytic anemia, atherosclerosis, Addison's disease (autoimmune disease of the adrenal glands), idiopathic adrenal insufficiency, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), glomerulonephritis, scleroderma, morphea, lichen planus, vitiligo (skin depigmentation), alopecia areata, autoimmune alopecia , autoimmune hypopituitarism, Guillen-Barre syndrome, and alveolitis; T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed type hypersensitivity, contact dermatitis (including due to poisoning disease), hives, skin allergies, respiratory allergies (hay fever, allergic rhinitis) and enteropathy of sensitivity to gluten (celiac disease); inflammatory diseases, such as osteoarthritis, acute pancreatitis, chronic pancreatitis, acute respiratory failure syndrome, Sezary syndrome and vascular diseases that have an inflammatory and / or proliferative component, such as restenosis, stenosis and arteriosclerosis. The diseases or disorders associated with inflammation or immunity also include, but are not limited to endocrine disorders, rheumatic disorders, collagen diseases, dermatological disease, allergic disease, ophthalmic disease, respiratory disease, hematological disease, gastrointestinal disease, inflammatory disease, autoimmune disease, congenital adrenal hyperplasia, non-suppurating thyroiditis, hypercalcemia associated with cancer, juvenile rheumatoid arthritis, ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis, post-traumatic osteoarthritis, osteoarthritis synovitis, acute epicondylitis pemphigus, herpetiform bullous dermatitis, severe erythema multiforme, exfoliating dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, conjunct Allergic ivitis, keratitis, ophthalmic herpes zoster, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, chemotherapy of fulminant or disseminated pulmonary tuberculosis, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired hemolytic anemia (autoimmune) adult lymphomas, acute childhood leukemia, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis. Preferred treatments include the treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, psoriasis and chronic lung disease.

In addition, the present invention includes a therapeutically effective amount of a compound of the invention for use in treating a disease associated with transcription induced by AP-1 and / or NF-κB (in particular transcription induced by AP-1) inducing NHR transrepression of transcription induced by AP-1 and / or NFκB (in particular transcription induced by AP-1), thereby treating the disease.

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Other therapeutic agents, such as those described herein below, may be employed with the compounds of the invention. Said other therapeutic agents can be administered before, simultaneously or after administration of the compound or compounds of the present invention.

In a specific embodiment, the compounds of the present invention are useful for the treatment of the above-mentioned examples of disorders, regardless of their etiology, for example, for the treatment of transplant rejection, rheumatoid arthritis, inflammatory bowel disease, and viral infections.

Synthesis procedures

The compounds of the present invention can be synthesized by many procedures available to those skilled in the art of organic chemistry. The general synthetic schemes, according to the present invention, for preparing the compounds of the present invention are described below. These schemes are illustrative and are not intended to limit the possible techniques that those skilled in the art can use to prepare the compounds described herein. Different procedures for preparing the compounds of the present invention will be apparent to those skilled in the art. In addition, the various stages of the syntheses can be performed in alternate sequences to produce the desired compound or compounds. Examples of compounds of the present invention prepared by the procedures described in the general schemes are given in the sections of preparations and examples indicated below.

SCHEME A

image 1

Compounds in which A and B are each condensed phenyl rings, and Ra, c, d are H, are constructed by cycloaddition of a compound 1 with a pure unsaturated compound 2 or in an appropriate solvent, such as xylenes, toluene, nitrobenzene or benzene, at temperatures varying from room temperature to 200 ° C, to form compound 3. It is known that cycloaddition can be facilitated by the use of catalysts, such as diethylaluminium chloride, titanium tetrachloride or etherate. of diethyl boron trifluoride. Cycloaddition can also be performed at higher pressures, such as when reactions are performed in sealed containers. The newly developed microwave technology can be applied to cycloaddition to facilitate the formation of the cycloadduct, in solvents such as nitrobenzene, toluene, dichlorobenzene and DMF at temperatures ranging from 100 ° C to 250 ° C, for 15 minutes to 120 minutes.

SCHEME B

image 1

wherein Z is -A-C (O) -O-R1 described above.

A compound 3 is reacted with an amine 4 by one of the many amidation procedures well known to those skilled in the art (such as treating the compound of formula 3 in a suitable solvent, such as acetonitrile, with 1- hydrochloride [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC), 1-hydroxy-7-azabenzotriazole, triethylamine and amino 4) to provide a compound of the invention.

Definition of terms and expressions

Unless otherwise indicated, the term "lower alkyl" and the terms "alkyl" or "alq", as used herein, alone or as part of another group, include straight and branched chain hydrocarbons, which they contain 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, and may optionally include an oxygen or a nitrogen in the normal chain. Examples of such chains include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, its various branched chain isomers, and the like, as well as groups that include 1 to 4 substituents, such as halogen (including F, Br, Cl or I), CF3, alkoxy, aryl, aryloxy, aryl ( aryl) or diaryl, arylalkyl, arylalkyl, alkenyl, cycloalkyl,

5 cycloalkylalkyl, cycloalkylalkyl, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, HO-N =, cycloheteroalkyl, alkyloxycarbonyl, alkoxyoximyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkyl, aryloxycarkylalkyl, alkyloxylalkyl, aryloxycarkylalkyl, aryloxycarkylalkyl arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and / or alkylthio and / or any of the substituents for aryl.

10 When numbers appear in a subscript after the symbol "C", the subscript defines more specifically the number of carbon atoms that a particular group can contain. The subscript "0" refers to a link. When the term "alkyl" is used together with another group, such as "arylalkyl," the conjunction defines more specifically at least one of the substituents that the alkyl will contain. For example, "arylalkyl" or "(aryl) alkyl" refers to an alkyl group, as defined above, in which at least one of the substituents is an aryl, such

15 as benzyl. In addition, the term aryl (C0-4 alkyl) includes a lower alkyl having at least one aryl substituent and also includes an aryl directly linked to another group, that is, aryl (C0 alkyl).

The term "methylene" refers to {-CH2-} n, where n is 1.

The term "metal ion" refers to alkali metal ions, such as sodium, potassium or lithium, and alkaline earth metal ions, such as magnesium and calcium, as well as zinc and aluminum.

Unless otherwise indicated, the term "aryl", as used herein, alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings). Therefore, the term "aryl" includes, for example:

image 1

and may be optionally substituted through available carbon atoms with 1, 2 or 3 groups selected from hydrogen, halogen, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, , heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylalkyl, arylthio, arylsulfinyl, arylazoyl, heteroarylalkyl, heteroarylalkyl, heteroarylheteroaryl, heteroaryloxy, nitroxy amino, 1-alkyloxy, substituted alkyloxy, alkyloxy, substituted alkyloxy, alkyloxy amino or 2 substituents (which are alkyl, aryl or any of the aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,

arylcarbonyl,

alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy,

arylcarbonyloxy,

alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinyl alkyl, arylsulfonylamino or

arylsulfonamidocarbonyl,

carboxy, cycloalkyl, arylalkoxy, aryloxycarbonyl, cycloalkylaminocarbonyl,

cicloalquilalquilaminocarbonilo, alkoxycarbonylalkyl, alcoxialquilaminocarbonilo, heteroarylaminocarbonyl, heteroarilalquilaminocarbonilo, arylalkylaminocarbonyl, N-hydroxyalkyl (N-alkyl) aminocarbonyl, cicloheteroalquilaminocarbonilo, cicloheteroalquilalquilaminocarbonilo, N-aryl (N- alkyl) aminocarbonyl, N-arylalkyl (Ncianoalquil) aminocarbonyl, dialquilaminoalquilaminocarbonilo, dialkylaminocarbonyl, alkyl- , arylalkyl- and arylcycloheteroalkylaminocarbonyl, N-dialkylaminoalkyl (N-alkyl or N-arylalkyl) aminocarbonyl, N-heteroarylalkyl (Nalkyl) aminocarbonyl, N-arylalkyl (N-arylalkyl) aminocarbonyl, aminoalkyloxycarbonyl, cycloheteroalkyl N = alkylcarbonyl N = alkylcarbonyl aminosulfonyl, heteroarylaminosulfonyl and / or any of the alkyl substituents indicated herein.

The term tautomer refers to compounds of the invention and their salts that may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and, consequently, the chemical bonds between the atoms of the molecules. They redispose. It should be understood that all tautomeric forms, insofar as they exist, are included within the invention.

The terms "pharmaceutically acceptable salt" and "salts" refer to basic salts formed with inorganic and organic bases. Such salts include ammonium salts; alkali metal salts, such as lithium, sodium and potassium salts (which are preferred); alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as amine salts (for example, dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, and hydrabamine salts); and salts with amino acids, such as arginine, lysine and the like; and bipolar ions, the so-called "internal salts". Non-toxic pharmaceutically acceptable salts are preferred, although other salts are also useful, for example to isolate or purify the product.

The terms "pharmaceutically acceptable salt" and "salts" also include acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a halohydric acid, such as HCl or HBr, with strong organic carboxylic acids, such as alkancarboxylic acids of 1 to 4 atoms. of carbon that are not substituted or that are substituted, for example, with halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example, oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acids, such as amino acids (for example, aspartic or glutamic acid, or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as acids ( C1-C4 alkyl or aryl) sulfonic acids which are not substituted or which are substituted, for example with halogen, for example methane acid ultrasonic or p-toluenesulfonic acid.

All stereoisomers of the compounds of the present invention, mixed or in pure form, are contemplated.

or substantially pure. The compounds of the present invention may have asymmetric centers in any of their carbon atoms, including any of the R substituents. Accordingly, the compounds of the invention may exist in enantiomeric or diastereomeric forms or in mixtures thereof. The processes for its preparation can use racemates, enantiomers or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional procedures, for example, chromatographic procedures or fractional crystallization.

The compounds of the invention may be in free form or in the form of solvate (for example, hydrate).

Combinations

When desired, the compounds of the present invention may be used in combination with one or more different types of therapeutic agents, such as immunosuppressants, anticancer agents, antiviral agents, anti-inflammatory agents, antifungal agents, antibiotics, vascular anti-hyperproliferation agents, antidepressant agents. , hypolipidemic agents or lipid lowering agents or lipid modulating agents, antidiabetic agents, anti-obesity agents, antihypertensive agents, inhibitors of platelet aggregation and / or anti-osteoporosis agents, which can be administered orally in the same dosage form, in a separate oral dosage form or by injection.

Immunosuppressants that may optionally be used in combination with the compounds of the invention include cyclosporins, for example cyclosporin A, mycophenolate, interferon-beta, deoxyspergoline, FK-506 or AntIL-2.

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Anticancer agents that may optionally be used in combination with compounds of the invention include azathioprine, 5-fluorouracil, cyclophosphamide, cisplatin, methotrexate, thiotepa, carboplatin and the like.

Antiviral agents that may optionally be used in combination with the compounds of formula I of the invention include abacavir, acyclovir, ganciclovir, zidanocin, vidarabine and the like.

Anti-inflammatory agents that may optionally be used in combination with the compounds of the invention include non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, cox-2 inhibitors, such as celecoxib, rofecoxib, aspirin, naproxen, ketoprofen, diclofenac sodium, indomethacin , pyroxicam, steroids, such as prednisone, dexamethasone, hydrocortisone, triamcinolone diacetate, gold compounds, such as sodium and gold thiomalate, TNF-α inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or its derivatives, infliximab (Remicade® Centocor, Inc.), CTLA4Ig, LEA29Y, antibodies, such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB , anti-CD2, antiCD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, agents that block the interaction between CD40 and CD154 (also known as "gp39"), such as specific antibodies for CD40 and / or CD 15 4, fusion proteins, such as etanercept, fusion proteins constructed from CD40 and / or CD154gp39 (for example, CD40Ig and CD8gp39), inhibitors, such as inhibitors of nuclear translocation, of NFkappa B function, such as deoxyspergualin (DSG)

Antifungal agents that may optionally be used in combination with the compounds of the invention include fluconazole, miconazole, amphotericin B, and the like.

Antibiotics that may optionally be used in combination with the compounds of the invention include penicillin, tetracycline, amoxicillin, ampicillin, erythromycin, doxycycline, vancomycin, minocycline, clindamycin or cephalexin.

Vascular anti-hyperproliferation agents that may optionally be employed with the compounds of the invention include methotrexate, leflunomide, FK506 (tacrolimus, Prograf).

The hypolipidemic agent or lipid lowering agent or lipid modulating agents that may optionally be used in combination with the compounds of the invention may include 1, 2, 3 or more MTP inhibitors, HMG CoA reductase inhibitors, squalene inhibitors synthetase, derivatives of fibric acid, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, inhibitors of Na + ileal / bile acid cotransporter, LDR receptor activity overregulators, bile acid sequestrants and / or nicotinic acid and its derivatives.

The MTP inhibitors employed herein include MTP inhibitors, described in U.S. Patent No. 5,595,872, U.S. Patent No. 5,739,135, U.S. Patent No. 5,712,279, U.S. Patent No. 5,760,246. U.S. Patent No. 5,827,875, U.S. Patent No. 5,885,983, and U.S. Application Serial No. 09 / 175,180, filed October 20, 1998, now U.S. Patent No. 5,962,440. Each of the preferred MTP inhibitors described in each of the foregoing patents and applications are preferred.

The most preferred MTP inhibitors for use according to the present invention include the preferred MTP inhibitors, as indicated in U.S. Patent Nos. 5,739,135 and 5,712,279, and in U.S. Patent No.

5,706,246.

The most preferred MTP inhibitor is 9- [4- [4 - [[2- (2,2,2-trifluoroethoxy) benzoyl] amino] -1-piperidinyl] butyl] -N- (2,2,2trifluoroethyl) -9H-fluoren-9-carboxamide

image 1

The hypolipidemic agent may be an HMG CoA reductase inhibitor that includes, but is not limited to mevastatin and related compounds, as described in US Patent No. 3,983,140, lovastatin (mevinoline) and related compounds, as described in U.S. Patent No. 4,231,938, pravastatin and related compounds, as described in U.S. Patent No. 4,346,227, simvastatin and related compounds, as described in U.S. Patent Nos. 4,448,784 and 4,450 .171. Other HMG CoA reductase inhibitors that may be employed herein include, but are not limited to fluvastatin, described in U.S. Patent No. 5,354,772, cerivastatin, described in U.S. Patent Nos. 5,006,530 and 5,177,080, atorvastatin, described in U.S. Patent Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, Itavastatin (Nissan / Sankyo Nisvastatin (NK-104)), described in U.S. Patent No. 5,011,930, visastatin of ShionogiAstra / Zeneca (ZD-4522), described in U.S. Patent No. 5,260,440, and related statin compounds, described in U.S. Patent No. 5,753,675, pyrazole analogs of mevalonolactone derivatives, as described in US Patent No. 4,613,610, indene analogs of mevalonolactone derivatives, as described in PCT application WO 86/03488, 6- [2- (substituted pyrrol-1-yl) alkyl) pyran-2-ones and their derivatives, as described in US Patent No. 4,647,576, SC-45355 dichloroacetate from Searle (a 3-substituted pentandioic acid derivative), imidazole analogs of mevalonolactone, as described in PCT application WO 86/07054, derivatives of 3-carboxy-2-hydroxypropanphosphonic acid, as described in French Patent No. 2,596,393 , 2,3-disubstituted pyrrole, furan and thiophene derivatives, as described in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone, as described in US Patent No. 4,686,237, octahydronaphthalenes, such as those described in US Patent No. 4,499,289, ketone analogs of mevinoline (lovastatin), as described in European Patent Application No. 0142146 A2, and quinoline and pyridine derivatives, described in US Patents No. 5,506. 219 and 5,691,322.

In addition, GB 2205837 describes phosphonic acid compounds useful for inhibiting HMG CoA reductase suitable for use herein.

Squalene synthetase inhibitors suitable for use herein include, but are not limited to αphosphonosulfonates described in US Patent No. 5,712,396, those described in Biller et al., J. Med. Chem., Vol. 31, nº 10, pp. 1869-1871 (1988), including (phosphinylmethyl) isoprenoid phosphonates, as well as other known squalene synthetase inhibitors, for example, as described in US Patent No. 4,871,721 and 4,924,024, and in Biller, SA , Neuenschwander, K., Ponpipom, MM, and Poulter, CD, Current Pharmaceutical Design, 2, 1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for use herein include terpenoid pyrophosphates described by P. Ortiz de Montellano et al., J. Med. Chem., 1977, 20, 243-249, analogue A of farnesyl disphosphate and pre-squalene pyrophosphate analogues (PSQ-PP), as described in Corey and Volante, J. Am. Chem. Soc., 98, 1291-1293 (1976), the phosphinyl phosphonates indicated in McClard, RW et al., J. Am. Chem. Soc., 1987, 109, 5544 (1987), and the cyclopropanes indicated in Capson, T.L., doctoral thesis, Dept. Med. Quim. U of Utah, Summary, Table of Contents, pp. 16, 17, 40-43, 48-51, Summary (June, 1987).

Other hypolipidemic agents suitable for use herein include, but are not limited to derivatives of fibric acid, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds, as described in the patent. No. 3,674,836, with probucol and gemfibrozil being preferred, bile acid sequestrants, such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®) and cholestagel (Sankyo / Geltex), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (tile derivative), meline (Sumitomo), Sandoz 58-035, American Cyanamid CL-277.082 and CL-283.546 (disubstituted urea derivatives), nicotinic acid (niacin), acipimox, acifrano, neomycin, p-aminosalicylic acid, aspirin, poly (d ialylmethylamine), such as those described in US Patent No. 4,759,923, quaternary poly (diallyldimethylammonium chloride) amine and ionennes, such as those described in US Patent No. 4,027,009, and other cholesterol lowering agents known serum.

The hypolipidemic agent may be an ACAT inhibitor, as described in Drugs of the Future, 24, 9-15 (1999) (avasimibe); "The ACAT inhibitor, C1-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters", Nicolosi et al, Atherosclerosis (Shannon, Irel), 137 (1), 77-85 (1998); "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16 (1), 1630; "RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor", Smith, C., et al., Bioorg. Med. Chem. Lett., 6 (1), 47-50 (1996); "ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals", Krause et al., Editor (s): Ruffolo, Robert R., Jr .; Hollinger, Mannfred A., Inflammation: Mediators Pathways, 173-198 (1995), publisher: CRC, Boca Ratón, Fla .; "ACAT inhibitors: potential antiatherosclerotic agents", Sliskovic et al., Curr. Med. Chem., 1 (3), 204-225 (1994); "Inhibitors of acyl-CoA: cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipidregulating activity. Inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N '- [(1-phenylcyclopentyl) methyl] ureas with enhanced hypocholesterolemic activity ", Stout et al., Chemtracts: Org. Chem., 8 (6), 359-362 (1995); or TS-962 (Taisho Pharmaceutical Co. Ltd).

The hypolipidemic agent may be an overregulator of the activity of the LD2 receptor, such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

The hypolipidemic agent may be a cholesterol absorption inhibitor, preferably Schering-Plow ezetimibe (SCH58235) and SCH48461, as well as those described in Atherosclerosis, 115, 45-63 (1995), and J. Med. Chem., 41, 973 (1998).

The hypolipidemic agent may be an inhibitor of the Na + ileal / bile acid cotransporter, as described in Drugs of the Future, 24, 425-430 (1999).

The lipid modulating agents can be a cholesteryl ester transfer protein (CETP) inhibitor, such as Pfizer CP 529,414 (WO / 0038722 and EP 818448) and Pharmacia SC-744 and SC-795.

The ATP citrate lyase inhibitor that can be used in the combination of the invention may include, for example, those described in US Patent No. 5,447,954.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, itavastatin and visastatin, and ZD-4522.

The quantities and dosages used will be those indicated in the Physician’s Desk Reference and / or in the patents indicated above.

The compounds of the invention will be used in a weight ratio with respect to the hypolipidemic agent (if present) in the range of about 500: 1 to about 1: 500, preferably from about 100: 1 to about 1: 100.

The administered dose should be carefully adjusted according to the age, weight and disorder of the patient, as well as the route of administration, the form and dosage regimen and the desired result.

Dosages and formulations for the hypolipidemic agent will be as described in the various patents and applications discussed above.

Dosages and formulations for the other hypolipidemic agents to be used, when relevant, will be as indicated in the latest edition of the Physician’s Desk Reference.

For oral administration, a satisfactory result can be obtained by using the MTP inhibitor in an amount in the range of about 0.01 mg to about 500 mg, and preferably about 0.1 mg to about 100 mg, one to four times daily.

A preferred oral dosage form, such as tablets or capsules, will contain the MTP inhibitor in an amount of about 1 to about 500 mg, preferably about 2 to about 400 mg, and more preferably about 5 to about 250 mg, of One to four times daily.

For oral administration, a satisfactory result can be obtained using an HMG CoA reductase inhibitor, for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastine, in dosages used as indicated in the Physician's Desk Reference, such as in a amount in the range of about 1 to about 2000 mg, and preferably about 4 to about 200 mg.

The squalene synthetase inhibitor can be used in dosages in an amount in the range of about 10 mg to about 2000 mg, and preferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount of about 0.1 to about 100 mg, preferably about 0.5 to about 80 mg, and more preferably about 1 at about 40 mg.

A preferred oral dosage form, such as tablets or capsules, will contain the squalene synthetase inhibitor in an amount of about 10 to about 500 mg, preferably about 25 to about 200 mg.

The hypolipidemic agent may also be a lipoxygenase inhibitor, including a lipoxygenase (15-LO) inhibitor, such as benzimidazole derivatives, as described in WO 97/12615, 15-LO inhibitors, as described in WO 97/12613, isothiazolones, as described in WO 96/38144, and 15-LO inhibitors, as described in Sendobry et al., "Attenuation of dietinduced atherosclerosis in rabbits with a highly selective 15- lipoxygenase inhibitor lacking significant antioxidant properties ", Brit. J. Pharmacology, 120, 1199-1206 (1997), and Cornicelli et al.," 15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease ", Current Pharmaceutical Design, 5, 11-20 (1999).

The compounds of the invention and the hypolipidemic agent can be used together in the same oral dosage form or in separate oral dosage forms taken at the same time.

The compositions described above can be administered in the dosage forms as described above, in a single dose or in divided doses one to four times daily. It may be advisable for a patient to start with a low dose combination and gradually increase to a high dose combination.

The preferred hypolipidemic agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin, as well as niacin and / or cholestagel.

The other antidiabetic agent that may optionally be used in combination with the compound of the invention may be 1, 2, 3 or more antidiabetic agents or antihyperglycemic agents, including insulin secretagogues or insulin sensitizers, or other antidiabetic agents that preferably have a mechanism of action different from the compounds of formula I of the invention, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPAR-γ agonists, such as thiazolidinediones, aP2 inhibitors, dipeptidyl peptidase IV (DP4) inhibitors SGLT2 and / or meglitinides, as well as insulin and / or glucagon-like peptide-1 (GLP-1).

The other antidiabetic agent may be an oral antihyperglycemic agent, preferably a biguanide, such as metformin or fenformin or its salts, preferably metformin HCl.

When the antidiabetic agent is a biguanide, the compounds of the invention will be employed in a weight ratio with respect to the biguanide in the range of about 0.001: 1 to about 10: 1, preferably from about 0.01: 1 to about 5 :one.

The other antidiabetic agent may also preferably be a sulfonylurea, such as glyburide (also known as glibenclamide), glimepiride (described in US Patent No. 4,379,785), glipizide, glycolide or chlorpropamide, other known sulfonylureas or other antihyperglycemic agents that act on the ATP-dependent channel of β cells, with glyburide and glipizide being preferred, which can be administered in the same oral dosage form or in separate oral dosage forms.

The compounds of the invention will be employed in a weight ratio with respect to sulfonylurea in the range of about 0.01: 1 to about 100: 1, preferably from about 0.02: 1 to about 5: 1.

The oral antidiabetic agent can also be a glucosidase inhibitor, such as acarbose (described in US Patent No. 4,904,769) or Miglitol (described in US Patent No. 4,639,436), which can be administered in the same form of oral dosage or in separate oral dosage forms.

The compounds of the invention will be employed in a weight ratio with respect to the glucosidase inhibitor in the range of from about 0.01: 1 to about 100: 1, preferably from about 0.05: 1 to about 10: 1.

The compounds of the invention can be used in combination with a PPAR-γ agonist, such as a thiazolidinedione oral antidiabetic agent or other insulin sensitizer (having an insulin sensitizing effect in NIDDM patients), such as troglitazone (Rezulin Warner-Lambert ®, described in US Patent No. 4,572,912), Rosiglitazone (SKB), Pioglitazone (Takeda), MCC-555 of Mitsubishi (described in US Patent No. 5,594,016), GL-262570 of Glaxo-Welcome, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer), isaglitazone (MIT / J & J), JTT-501 (JPNT / P & U), L-895645 (Merck), R-1 19702 ( Sankyo / WL), NN-2344 (Dr. Reddy / NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.

The compounds of the invention will be employed in a weight ratio with respect to thiazolidinedione in an amount in the range of about 0.01: 1 to about 100: 1, preferably about 0.05 to about 10: 1.

Sulfonylurea and thiazolidinedione in amounts less than about 150 mg of oral antidiabetic agent can be incorporated into a single tablet with the compounds of the invention.

The compounds of the invention can also be used in combination with an antihyperglycemic agent, such as insulin or with the glucagon-like peptide-1 (GLP-1), such as GLP-1 (1-36) amide, GLP-1 (7 -36) amide, GLP1 (7-37) (as described in US Patent No. 5,614,492 to Habener), as well as AC2993 (Amylin) and LY315902 (Lilly), which can be administered by injection, intranasally, by inhalation or with transdermal or oral devices.

When they are present, metformin, sulfonylureas, such as glyburide, glimepiride, glipiride, glipizide, chlorpropamide and gliclazide, and inhibitors of acarbose glucosidase or miglitol or insulin (injectable, pulmonary, buccal, or oral) can be used in formulations according to described above, and in amounts and dosages indicated in the Physician's Desk Reference (PDR).

When present, metformin or its salt can be used in amounts in the range of about 500 to about 2000 mg daily, which can be administered in single or divided doses one to four times daily.

When present, the thiazolidinedione antidiabetic agent can be used in amounts in the range of about 0.01 to about 2000 mg / day, which can be administered in single or divided doses one to four times daily.

When present, insulin can be used in formulations, quantities and dosage as indicated in the Physician’s Desk Reference.

When GLP-1 peptides are present, they can be administered in oral oral formulations, by nasal or parenteral administration, as described in US Patent Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224.

The other antidiabetic agent can also be a dual agonist of PPAR-α / γ, such as AR-HO39242 (Astra / Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck), as well as those described in Murakami et al., "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation-Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Patty Rats", Diabetes, 47, 1841- 1847 (1998).

The antidiabetic agent may also be an SGLT2 inhibitor, such as those described in US application serial number 09 / 679.027, filed October 4, 2000, using the dosages indicated therein. Compounds denominated as indicated in the previous application are preferred.

The antidiabetic agent may be an aP2 inhibitor, such as those described in US application serial number 09 / 391,053, filed on September 7, 1999, and in US application serial number 09 / 519,079, filed on 6 of March, 2000, using the dosages indicated in them. Compounds denominated as indicated in the previous application are preferred.

The antidiabetic agent may be a DP4 inhibitor, such as those described in US application serial number 09 / 788,173, filed February 16, 2001, WO99 / 38501, WO99 / 46272, WO99 / 67279 (PROBIODRUG) , WO99 / 67278 (PROBIODRUG), WO99 / 61431 (PROBIODRUG), NVP-DPP728A (1 - [[[2 - [(5cianopyridin-2-yl) amino] ethyl] amino] acetyl] -2-cyano- (S) -pyrrolidine) (Novartis) (preferred), as described in Hughes et al., Biochemistry, 38 (36), 11597-11603, (1999), TSL-225 (triptofil-1,2,3,4-tetrahydro acid -isoquinolin-3-carboxylic (described in Yamada et al., Bioorg. & Med. Chem. Lett., 8, 1537-1540 (1998)), 2-cyanopyrrolidides and 4cianopyrrolidides, as described in Ashworth et al., Bioorg . & Med Chem. Lett., Vol. 6, nº 22, pp. 1163-1166 and 2745-2748 (1996), using the dosages indicated in the previous references.

The meglitinide that can optionally be used in combination with the compound of the invention can be repaglinide, nateglinide (Novartis) or KAD1229 (PF / Kissei), with repaglinide being preferred.

The compound of the invention will be used in a weight ratio with respect to meglitinide, the PPAR-γ agonist, the dual PPAR-α / γ agonist, the aP2 inhibitor, the DP4 inhibitor or the SGLT2 inhibitor in a range from about 0.01: 1 to about 100: 1, preferably from about 0.05 to about 10: 1.

The other type of therapeutic agent that can optionally be used with a compound of the invention can be 1, 2, 3 or more of an antiobesity agent, including an adrenergic beta-3 agonist, a lipase inhibitor, a serotonin reuptake inhibitor (and dopamine), an aP2 inhibitor, a thyroid receptor agonist and / or an anorectic agent.

The beta-3 adrenergic agonist that can be optionally employed with a compound of the invention can be AJ9677 (Takeda / Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta-3 agonists, as described in the patents of U.S. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648 being preferred.

The lipase inhibitor that may optionally be used in combination with a compound of the invention may be orlistat or ATL-962 (Alizyme), with orlistat being preferred.

The serotonin (and dopamine) reuptake inhibitor that may optionally be used in combination with a compound of the invention may be sibutramine, topiramate (Johnson & Johnson) or axoquine (Regeneron), with sibutramine and topiramate being preferred.

The thyroid receptor agonist that may optionally be used in combination with a compound of the invention may be a thyroid receptor ligand as described in WO97 / 21993 (U. Cal SF), WO99 / 00353 (KaroBio), WO20000390 (KamBio , in particular in priority document GB98 / 28442), and provisional US application 60 / 183,223, filed on February 17, 2000, the compounds of KaroBio's applications and the previous provisional US application being preferred.

The anorectic agent that can optionally be used in combination with a compound of the invention may be dexamphetamine, phentermine, phenylpropanolamine or mazindole, dexamphetamine being preferred.

The various anti-obesity agents described above can be used in the same dosage form with the compound of the invention or in different dosage forms, in dosages and regimens that are generally known in the art or in PDR.

Antihypertensive agents that can be used in combination with the compound of the invention include ACE inhibitors, angiotensin II receptor antagonists, NEP / ACE inhibitors, as well as calcium channel blockers, β-adrenergic blockers and other types of antihypertensive agents. , including diuretics.

The angiotensin converting enzyme inhibitor that may be employed herein includes those containing a mercapto moiety (-S-), such as substituted proline derivatives, such as any of those described in US Patent No. 4,046,889 of Ondetti et al., Mentioned above, with captopril being preferred, ie 1 - [(2S) -3mercapto-2-methylpropionyl] -L-proline, and mercaptoacyl derivatives of substituted prolines, such as any of those described in the US Patent No. 4,316,906, zofenopril being preferred.

Other examples of ACE inhibitors containing mercapto that may be employed herein include rentiapril (fentiapril, Santen), described in Clin. Exp. Pharmacol. Physiol., 10: 131 (1983), as well as pivopril and YS980.

Other examples of angiotensin converting enzyme inhibitors that may be employed herein include any of those described in US Patent No. 4,374,829 mentioned above, with N- (1-ethoxycarbonyl-3-phenylpropyl) -L- being preferred alanyl-L-proline, ie, enalapril, any of the phosphonate substituted amino or imino acids or salts described in US Patent No. 4,452,790, with (S) -1- [6 amino-2- [ [hydroxy- (4-phenylbutyl) phosphinyl] oxy] -1-oxohexyl] -L-proline (or ceronapzil), the phosphinyl alkanoylprolines described in US Patent No. 4,168,267 mentioned above, with fosinopril being preferred, any of the prolines substituted with phosphinyl alkanoyl described in U.S. Patent No. 4,337,201, and phosphonamidates described in U.S. Patent No. 4,432,971 discussed above.

Other examples of ACE inhibitors that may be employed herein include Beecham BRL 36,378, as described in European Patent Applications No. 80822 and 60668; MC-838 from Chugai, described in C.A. 102: 72588v, and in Jap. J. Pharmacol., 40: 373 (1986); CGS 14824 of Ciba-Geigy (3 - ([1-Ethoxycarbonyl-3-phenyl- (1S) -propyl] amino) -2,3,4,5-tetrahydro-2-oxo-1- (3S) -benzazepin acid HCl -1-acetic acid) described in United Kingdom Patent No. 2103614 and CGS16.617 (3- (S) - [[(1S) -5-amino-1-carboxypentyl] amino] -2,3,4,5 -tetrahydro-2-oxo-1H-1benzazepin-1-ethanoic acid) described in US Patent No. 4,473,575; ketapril (alacepril, Dainippon) described in Eur. Therap. Res., 39: 671 (1986); 40: 543 (1986); ramipril (Hoechsst) described in European Patent No. 79-022, and in Curr. Ther. Res., 40:74 (1986); Ru 44570 (Hoechst) described in Arzneimittelforschung, 34: 1254 (1985); citazapril (Hoffman-LaRoche) described in J. Cardiovasc. Pharmacol., 9:39 (1987); R 31-2201 (Hoffman-LaRoche) described in FEBS Lett., 165: 201 (1984); lisinopril (Merck), indalapril (delapril) described in US Patent No. 4,385,051; indolapril (Schering) described in J. Cardiovasc. Pharmacol., 5: 643, 655 (1983); Spirapril (Schering) described in Acta. Pharmacol. Toxicol., 59 (sup. 5): 173 (1986); perindopril (Servier) described in Eur. J. Clin. Pharmacol., 31: 519 (1987); Quinapril (Warner-Lambert) described in US Patent No. 4,344,949 and CI925 (Warner-Lambert) (Acid HCl [3S- [2 [R (*) R (*)]] - 3R (*)] - 2- [2 - [[1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy3-isoquinolinecarboxylic acid) described in Pharmacologist, 26: 243 , 266 (1984); WY-44221 (Wyeth) described in J. Med. Chem., 26: 394 (1983).

Preferred ACE inhibitors are captopril, fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

NEP / ACE inhibitors may also be used herein, because they possess neutral endopentidase (NEP) inhibitory activity and angiotensin converting enzyme (ACE) inhibitory activity. Examples of NEP / ACE inhibitors suitable for use herein include those described in U.S. Patent Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688, the patent U.S. Patent No. 5,552,397, U.S. Patent No. 5,504,080, U.S. Patent No. 5,612,359, U.S. Patent No. 5,525,723, European Patent Application 0599,444, 0481,522, 0599,444, 0595,610, Application for European patent 0534363A2, the documents

534,396 and 534,492, and European patent application 0629627A2.

NEP / ACE inhibitors and their dosages which are indicated as preferred in the previous patents / applications are preferred; most preferred are omapatrilat, BMS 189.921 ([S- (R *, R *)] - hexahydro-6 - [(2-mercapto1-oxo-3-phenylpropyl) amino] -2,2-dimethyl-7-oxo -1H-azepin-1-acetic (gemopatrilat)) and CGS 30440.

The angiotensin II receptor antagonist (also referred to herein as an angiotensin II antagonist or AII antagonist) suitable for use herein include, but is not limited to irbesartan, losartan, valsartan, candesartan, telmisartan, tasosartan or eprosartan, irbesartano, losartano or valsartano being preferred.

A preferred oral dosage form, such as tablets or capsules, will contain the ACE inhibitor or the AII antagonist in an amount in the range of about 0.1 to about 500 mg, preferably about 5 to about 200 mg, and more preferably from about 10 to about 150 mg.

For parenteral administration, the ACE inhibitor, angiotensin II antagonist or NEP / ACE inhibitor will be used in an amount in the range of about 0.005 mg / kg to about 10 mg / kg, and preferably about 0.01 mg / kg at about 1 mg / kg.

When a drug is to be administered intravenously, it will be formulated in conventional vehicles, such as distilled water, saline solution, Ringer's solution or other conventional vehicles.

It will be appreciated that the preferred dosages of the ACE inhibitor and the AII antagonists, as well as other antihypertensive agents described herein will be as indicated in the latest edition of the Physician’s Desk Reference (PDR).

Other examples of preferred antihypertensive agents suitable for use herein include omapatrilate (Vanlev®), amlodipine besylate (Norvasc®), prazosin HCl (Minipresa®), verapamil, nifedipine, nadolol, diltiazem, folodipine, nipoldipine, isradipine, isradipine, isradipine nicardipine, atenolol, carvedilol, sotalol, terazosin, doxazosin, propranolol, and clonidine HCl (Catapres®).

Diuretics that can be used in combination with the compounds of formula I include hydrochlorothiazide, torasemide, furosemide, spironolactone, and indapamide.

Antiplatelet agents that can be used in combination with the compounds of the invention include aspirin, clopidogrel, ticlopidine, dipyridamole, abciximab, thyrofiban, eptifibatide, anagrelide, and ifetrobano, with clopidogrel and aspirin being preferred.

Antiplatelet drugs can be used in amounts as indicated in PDR. Ifetrobano can be used in amounts as indicated in US Patent No. 5,100,889.

Antiosteoporosis agents suitable for use herein in combination with the compounds of the invention include parathyroid hormone or bisphosphonates, such as MK-217 (alendronate) (Fosamax®).

The dosages used for the above drugs will be as indicated in the Physician’s Desk Reference.

Pharmaceutical formulations

The pharmaceutical composition of the invention includes a pharmaceutically acceptable carrier, adjuvant or vehicle that can be administered to the subject, together with a compound of the present invention, and that does not destroy its pharmacological activity. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to the following: ion exchangers, alumina, aluminum stearate, lectin, self-emulsifying drug delivery systems ("SBDDS" "), Such as d- (tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms, such as Tween or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffering substances, such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium bisphosphate, potassium bisphosphate, sodium chloride, zinc salts, silica colloidal, magnesium trisilicate, polyvinylpyrrolidone, substances based on ce Lulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and anhydrous lanolin. Cyclodextrins, such as α-, β- and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2-and 3-hydroxypropyl-βcyclodextrins, or other solubilized derivatives, can also be used to enhance the administration of modulators of the present invention

The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, using conventional solid or liquid carriers or diluents, as well as pharmaceutical additives of a type appropriate to the desired route of administration (for example , excipients, binders, preservatives, stabilizers, aromas, etc.) according to techniques such as those known in the art of pharmaceutical formulation.

The compounds of the invention can be administered by any suitable means, for example orally, such as in the form of tablets, capsules, granules or powders; sublingually; orally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (for example, as sterile injectable aqueous or non-aqueous suspensions or solutions); nasally, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of suppositories; in unit dosage formulations containing non-toxic pharmaceutically acceptable carriers or diluents. The compounds of the invention can be administered, for example, in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions that include the compounds of the invention or, in particular in the case of extended release, by the use of devices, such as subcutaneous implants or osmotic pumps. The compounds of the invention can also be administered with liposomes.

Examples of compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for imparting charge, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetening or flavoring agents, such as those known. in the art; and immediate release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other binding excipients, extenders, disintegrants, diluents and lubricants, such as those known in the art . The present compounds can also be administered through the oral cavity by sublingual and / or oral administration. Molded tablets, pressed tablets or lyophilized tablets are examples of ways that can be used. Examples of compositions include those formulating the compound or compounds of the invention with fast dissolving diluents, such as mannitol, lactose, sucrose and / or cyclodextrins. Also included in these formulations are high molecular weight excipients, such as cellulose (Avicel) or polyethylene glycols (PEG). These formulations may also include an excipient to aid mucosal adhesion, such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), maleic anhydride copolymer (eg, Gantrez), and agents that control release , such as polyacrylic copolymer (for example, Carbopol 934). Lubricants, glidants, aromas, coloring agents and stabilizers can also be added to facilitate manufacturing and use.

Examples of compositions for administration by inhalation or nasal spray include solutions in saline solution which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability and / or other solubilizing or dispersing agents, such as those known in the art.

Examples of compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, a chloride solution. isotonic sodium, or other suitable suspending and wetting or dispersing agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. The term "parenteral", as used herein, includes infusion or subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection techniques.

Examples of compositions for rectal administration include suppositories that may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at normal temperature but which are liquefied and / or dissolve in the rectal cavity to release the drug.

Examples of compositions for topical administration include a topical vehicle, such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention can be determined by those skilled in the art and includes examples of dosage amounts for an adult human being of approximately 0.1 to 500 mg / kg body weight of active compound daily, or between 5 and 2000 mg daily that can be administered in a single dose or in the form of individual divided doses, such as 1 to 5 times daily. It will be understood that the specific dose level and dosage frequency for any particular subject can be varied and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and the duration of action of said compound, the species, the age, body weight, general health, sex and diet of the subject, the route and time of administration, the rate of excretion, the combination of drugs, and the severity of the particular disorder. Preferred subjects for treatment include animals, more preferably mammalian species, such as humans, and domestic animals, such as dogs, cats and the like.

A typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh screen and packaged in a # 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention in a vial, lyophilizing aseptically and sealing. For use, the contents of the vial are mixed with 2 ml of physiological saline to produce an injectable preparation.

The compounds of the invention are glucocorticoid receptor modulators as demonstrated by their ability to bind glucocorticoid receptors in GR binding assays, or by their ability to inhibit AP-1 activity as indicated in cell transrepression assays, and do not cause or cause minimal transactivation as indicated in cell transcription assays.

The compounds of the invention, including the compounds described in the examples herein, have been tested in at least one of the assays described below and have glucocorticoid receptor (GR) / dexamethasone (Dex) inhibitor activity (> 25 % at 10 µM, preferably> 95% at 10 µM) and / or AP-1 inhibition activity (EC50 less than 15 µM).

Identical and / or similar tests are described in the US patent application being processed together with the present No. 10 / 621,807, filed July 18, 2002.

GR binding assay (Dex)

A commercially available kit (glucocorticoid receptor competitor assay kit, Panvera Col, Madison, WI) was used to measure the binding of compounds to site I on the glucocorticoid receptor. Briefly, a cell lysate containing recombinantly expressed human full-length glucocorticoid receptor was mixed with a fluorescence-labeled glucocorticoid (4 nM FITC-dexamethasone) plus or minus the test molecule. After one hour at room temperature, the fluorescence polarization (FP) of the samples was measured. The FP of a receptor mixture, a fluorescent probe (i.e., FITCdexmethasone) and 1 mM dexamethasone represents the background fluorescence or 100% inhibition, while the FP of the mixture without dexamethasone is considered 100% binding. The percentage of inhibition of the test molecules was then compared with the sample with 1 mM dexamethasone and expressed as the percentage of relative binding activity, the dexamethasone being 100% and the non-inhibition 0%. The test molecules were analyzed in the concentration range of 0.1 nM to 40 µM.

Site I binding assays were performed for any NHR ("Nuclear Hormone Receptor", nuclear hormone receptor) in a similar manner as above. An appropriate purified cell lysate or NHR was used as the source of the NHR. The fluorescent probe and the unlabeled competitor are appropriate for the specific NHR, that is, they are ligands for the specific NHR.

Cellular Transrepression Assay

To measure the ability of the test molecules to inhibit transcriptional activity induced by AP-1, an A549 cell was used that was stably transfected with a plasmid containing 7 x AP-1 DNA binding sites (plasmid pAP- 1-Luc, Stratagene Co., La Jolla, CA), followed by the luciferase gene. The cells were activated with 10 ng / ml of forbolmiristic acid (PMA) plus or minus the test molecules for 7 hours. After 7 hours a luciferase reagent was added to measure the enzymatic activity of luciferase in the cell. After a 10 minute incubation of the luciferase reagent with the cells the luminescence was measured on a TopCount luminescence counter. The repression of AP-1 activity was calculated as the percentage of decrease in signal induced only by PMA. The test molecules were analyzed in the concentration range of 0.1 nM to 40 µM. EC50s were determined using conventional curve fitting procedures, such as Excel adjustment (Microsoft Co.). An EC50 is the concentration of the test molecule at which 50% repression of the maximum transcription inhibition occurs, that is, a 50% reduction in AP-1 activity.

Other indicators and cell lines can also be used in a cell transrepression assay. A similar test is performed in which NF-κB activity is measured. A plasmid containing NF-κB DNA binding sites, such as pNF-kB-Luc (Stratagene, La Jolla, CA) is used and PMA or other stimulus, such as TNF-α or lipopolysaccharides, is used to activate the NF-κB pathway. NF-κB assays similar to those described in Yamamoto K., et al., J. Biol. Chem., December 29; 270 (52): 31315-31320 (1995).

The cell transrepression assays described above can be used to measure transrepression by any NHR. Those skilled in the art will understand that assays may require the addition of components, such as a stimulus (eg, PMA, lipopolysaccharides, TNF-α, etc.) that induce a transcription mediated by AP-1 or NF-κB. In addition, AR-mediated transrepression can be measured by the assay described in Palvimo J.J., et al., J. Biol. Chem., September 27; 271 (39): 24151-24156 (1996), and PR-mediated transrepression can be measured by the assay described in Kalkhoven E., et al., J. Biol. Chem., March 15; 271 (11): 6217-6224 (1996).

Abbreviations

The following abbreviations were used in the following preparations and examples:

Ph = phenyl Bn = benzyl t-Bu = tertiary butyl Me = methyl Et = Etilio TMS = trimethylsilyl TMSN3 = trimethylsilyl azide TBS = tert-butyldimethylsilyl FMOC = fluorenylmethoxycarbonyl Boc = tert-butoxycarbonyl Cbz = carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl THF = tetrahydrofuran Et2O = diethyl ether hex = hexanes EtOAc = ethyl acetate DMF = dimethylformamide MeOH = methanol EtOH = ethanol i-PrOH = isopropanol DMSO = dimethyl sulfoxide DME = 1,2-dimethoxyethane DCE = 1,2-dichloroethane HMPA = triamide hexamethylphosphoric HOAc or AcOH = acetic acid TFA = trifluoroacetic acid TFAA = trifluoroacetic anhydride i-Pr2NEt = diisopropylethylamine Et3N = triethylamine NMM = N-methylmorpholine DMAP = 4-dimethylaminopyridine NaBH4 = sodium borohydride NaBH (OAc) 3 sodium hydroxyl dihydroxyl LAHIBH dihydride = lithium aluminum hydride n-BuLi = n-butyllithium LDA = lithium diisopropylamide Pd / C = palladium on carbon PtO2 = platin oxide or KOH = potassium hydroxide NaOH = sodium hydroxide LiOH = lithium hydroxide K2CO3 = potassium carbonate NaHCO3 = sodium bicarbonate

5

10

fifteen

twenty

25

30

35

40

Four. Five

DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or EDAC = 3-ethyl-3 '- (dimethylamino) propylcarbodiimide hydrochloride (or 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide) HOBT or HOBT.H2O hydrochloride = 1-hydroxybenzotriazole hydrate HOAT = 1-hydroxy-7-azabenzotriazole reagent BOP = benzothriazole-1-dimethyloxy-1-dimethyloxy-hexafluorophosphate NaN (TMS) 2 = sodium hexamethyldisilazide or sodium bis (trimethylsilyl) amide Ph3P = triphenylphosphine Pd (OAc) 2 = palladium acetate (Ph3P) 4Pd = tetrakis (triphenylphosphine) palladium DEAD = diethyl azodicarboxylate DIAD = azodicarbodose diodis -Cl = benzyl chloroformate CAN = citric ammonium nitrate SAX = strong anion exchanger SCX = strong cation exchanger Ar = argon N2 = nitrogen min = minute (s) ho hr = hour (s) l = liter ml = milliliter µl = microliter g = gram (s) mg = milligram (s) mol = moles mmol = millimole (s) meq = milliequivalents TA = room temperature sat. = saturated ac. = aqueous TLC = thin layer chromatography HPLC = high performance liquid chromatography LC / MS = high performance liquid chromatography / MS or Spec mass spectrometry. masses = NMR mass spectrometry = nuclear magnetic resonance NMR spectral data: s = singlet; d = double; m = multiplet; a = width; t = triplet; mp = melting point

Preparations

The preparations indicated below are for the synthesis of reagents that were not obtained from commercial sources and were used for the preparation of the compounds of the invention. All chemical structures in tables and schemes are racemic unless otherwise indicated.

Preparation 1

image2

A sealed 75 ml tube was charged with 9-nitroanthracene (10 g, 0.045 mol, 1.0 eq.), Hydroquinone (0.5 g, 0.0045 mol, 0.1 eq.), Methacrylic acid (39 g , 0.45 mol, 10.0 eq.) And xylene (5 ml). The reaction was heated at 160 ° C for 24 hours. The solution was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and extracted with 1 N NaOH (3 x). The aqueous phase was acidified with 1 N HCl, and the product was extracted with ethyl acetate (3 x). The combined organic phases were concentrated in vacuo to produce the mixture of the crude product. Purification by preparative HPLC (column: YMC, C-18 ballistic, 30 x 100 mm; 10-90% aq. CH3OH / 0.1% TFA, flow rate: 25 ml / min, detection wavelength: 220 nm, same for the other compounds unless indicated

5 otherwise) produced the target isomer 1a as a white solid (8.21 g, 59.3% yield). LC / MS (m / z 308.3 (M-H) +); HPLC (column: Shimadzu VP-ODS, ballistic C-18; 10-90% aq. CH3OH / 0.1% H3PO4, same for the other compounds unless otherwise indicated), Tr: 3.30 min . The ortho 1a ’isomer was also isolated as a white solid (3.69 g, 26.4%). LC / MS (m / z 308.3 (M-H) +); HPLC, Tr: 3.52 min.

In a similar manner, the following compounds were prepared from methacrylic acid and appropriate anthracenes.

Preparation

Structure

1 B

1 C

1d

Preparation 2

image 1

Stage 1

A solution of the commercially available 2-aminothiazol-4-carboxylic acid ethyl ester 2a (3.8 g, 22 mmol) and trityl chloride (6.8 g, 24.3 mmol) in 30 ml of pyridine is stirred at room temperature for 16 hours. The precipitate was removed by filtration and the filtrate was concentrated to reduce the volume to 20 ml. To this 2- (tritylamino) thiazol-4-carboxylic acid ethyl ester in 20 ml of pyridine was added a solution of sodium hydroxide (5.4 g) in 50 ml of 60% ethanol in water. The reaction mixture was stirred at room temperature over

20 over the weekend and then acidified with acetic acid to pH 5. The precipitate was collected and dried to yield 2- (tritylamino) thiazol-4-carboxylic acid as a white solid (6.1 g, yield 72). %). LC / MS (m / z 385.08 (M-M +)); HPLC, Tr: 3.732 min.

Stage 2

To a solution of 2- (tritylamino) thiazol-4-carboxylic acid (400 mg, 1.03 mmol) in DMSO (1 ml) was added KOH (215 mg, 1.55 mmol), followed by the addition of 1 -iodopropane (263 mg, 1.55 mmol). The reaction was heated at 60 ° C for 1 hour. It was taken to water and ethyl acetate. After separation, the organic layer was washed, dried and dried.

5 evaporated. The crude product obtained was purified by a flash column (silica gel, 10% ethyl acetate in hexane) to produce the 2- (tritylamino) thiazole-4-carboxylic acid propyl ester as a white solid (325 mg , 76%). LC / MS (m / z 429.14 (M + H) +); HPLC, Tr: 4.182 min.

Stage 3

To a solution of the 2- (tritylamino) thiazol-4-carboxylic acid propyl ester (300 mg, 0.70 mmol) in chloroform

10 (10 ml) trifluoroacetic acid (5 ml) was added. The reaction was stirred at room temperature for 1.5 hours. After evaporation, the crude product was purified by preparative HPLC to produce the TFA salt of the 2-aminothiazol-4-carboxylic acid 2b propyl ester (202 mg, 96%) as a white solid. LC / MS (m / z 187.14 (M + H) +); HPLC, Tr: 1.305 min.

According to the procedures described in steps 2 and 3, the following esters of 215 aminothiazol-4-carboxylic acid were prepared from 2- (tritylamino) thiazol-4-carboxylic acid and the appropriate iodoalkanes.

Preparation

Structure

2 C

2d

2e

Example

The following examples illustrate embodiments of the compounds of the invention and starting materials, and are not intended to limit the scope of the claims.

Example 1

image 1

To a solution of the acid of preparation 1b (30 mg, 0.104 mmol) in CH3CN (1 ml) was added 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC) (30 mg, 0.156 mmol ) and 1-hydroxy-7-benzotriazole (HOBt) (21 mg, 0.156 mmol). After stirring for 5 minutes, the 2-aminothiazole-4-carboxylic acid 2b propyl ester (40 mg, 0.135 mmol) and diisopropylethylamine (47 mg, 0.063 ml, 0.364 mmol) were added to the solution. The reaction was heated at 90 ° C for 18 hours. The crude product mixture was purified directly through a preparative HPLC to yield the title compound of example 1 (22 mg, 46% yield). LC / MS (m / z 458.1 (M + H) +); HPLC, Tr: 4.102 min.

Examples 2 to 8

Examples 2-8 were prepared in a manner similar to Example 1 by the coupling reactions of the acids (preparations 1a to 1d) and amines (preparations 2a to 2e).

image 1

Example No.

Rb R1 HPLC Tr: minute MS [m / z (M + H)]

2

CN ethyl 3.90 444.26

3

NO2 ethyl 4.01 464.22

4

CN n-butyl 4,153 472.09

5

CN i-propyl 4,142 472.09

6

CN i-propyl 4,073 458.10

7

Cl ethyl 4,258 453.03

8

Br ethyl 4,313 498.95, 496.95

Example 9

image 1

Stage 1

To a solution of the title compound of example 2 (250 mg, 0.563 mmol) in dioxane (30 ml) was added a 10% aqueous solution of KOH (15 ml). The reaction was heated at 50 ° C for 1 hour. The reaction mixture is

10 led to ether and water. After separation, the aqueous layer was acidified to pH 3 with 1 N HCl, and extracted with ethyl acetate (3 times). The combined organic solution was washed, dried (MgSO4) and evaporated to yield thiazol-4-carboxylic acid (233 mg, 99%). LC / MS (m / z 416.28 (M + H) +); HPLC, Tr: 3.62 min.

Stage 2

The thiazol-4-carboxylic acid (30 mg, 0.072 mmol) was dissolved in THF (1 ml), followed by the addition of DMF (0.011 ml,

15 0.144 mmol). The solution was cooled to 0 ° C, and oxylyl chloride (0.36 ml, 0.72 mmol) was added slowly. The reaction was stirred at room temperature for 10 minutes. Methanol (0.009 ml, 0.288 mmol) was added. After 5 minutes, the reaction was heated to room temperature and stirred for 1 hour. After removal of the solvent, the crude product was purified by preparative HPLC to yield the title compound (TFA salt) of Example 9 (20 mg, 65% yield). LC / MS (m / z 430.17 (M + H) +); HPLC, Tr: 3.76 min.

20 Example 10

image 1

In a manner similar to example 1, the acid coupling reaction of preparation 1a (200 mg, 0.647 mmol) and the ethyl ester of (2-aminothiazol-4-yl) acetic acid (193 mg, 0.841 mmol) produced the title compound of example 10 (66.8 mg, 86.2% yield). LC / MS (m / z 478.21 (M + H) +); HPLC, Tr: 3.83 min.

Claims (12)

1.-A compound that has the structure: image 1 or its stereoisomer, or its pharmaceutically acceptable salt, in which: A is a bond or methylene; 5 XesS; R is H, CH3, or C2H5; R1 is selected from alkyl and aryl; Y Rb is CN, NO2, Cl, or Br. 2. A compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein R1 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl and phenyl. 3. A compound according to claim 2, which has the structure: image 1 or its stereoisomer, or its pharmaceutically acceptable salt, wherein R 1 is methyl, ethyl, n-propyl, i-propyl or n-butyl. 4.-A compound that has a structure: image 1 image 1 (ii) its stereoisomer or its pharmaceutically acceptable salt. 5. A compound according to any one of claims 1 to 4, for use in therapy. 6. A compound according to claim 5, for use to treat a disease or disorder that is associated with the product of the expression of a gene whose transcription is stimulated or repressed by receptors of 5 glucocorticoids, or to treat a disease or disorder associated with transcription induced by AP-1 and / or NF-κB, or to treat a disease or disorder associated with gene expression dependent on AP-1 and / or NF -κB, in which the disease or disorder is associated with the expression of a gene under the regulatory control of AP-1 and / or NF-κB. 7. A compound according to claim 6, wherein the disease or disorder is selected from a disorder 10 endocrine, a rheumatic disorder, a collagen disease, a dermatological disease, an allergic disease, an ophthalmic disease, a respiratory disease, a hematological disease, a gastrointestinal disease, an inflammatory disease, an immunological disease, a neoplastic disease or a disease metabolic 8. A compound according to claim 7, wherein the disease or disorder is an inflammatory or autoimmune disease. 9. The compound according to claim 8, wherein the disease or disorder is selected from rejection of transplants of kidney, liver, heart, lung, pancreas, bone marrow, cornea, small intestine, skin allografts, skin grafts , heart valve xenografts, serum sickness, and graft versus host disease, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type I and type II diabetes, juvenile diabetes, obesity, asthma, inflammatory bowel disease, Crohn, ulcerative colitis, pyoderma gangrenosum, systemic lupus erythematosus, myasthenia gravis, psoriasis, dermatitis, dermatomyositis; eczema, seborrhea, pulmonary inflammation, uveitis of the eye, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet or Sjorgen's syndrome, pernicious or immunohemolytic anemia, atherosclerosis, Addison's disease, idiopathic adrenal insufficiency, autoimmune polyglandular disease, glomerulonephritis, scleroderma, morphea, lichen planus, vitiligo, alopecia areata, autoimmune alopecia, autoimmune hypopituitarism, Guillen-Barre syndrome, and alveolitis; contact hypersensitivity, delayed type hypersensitivity, contact dermatitis, urticaria, skin allergies, respiratory allergies, hay fever, allergic rhinitis and gluten-sensitive enteropathy, osteoarthritis, acute pancreatitis, chronic pancreatitis, acute respiratory failure syndrome, Sezary syndrome, restenosis, stenosis and arteriosclerosis, congenital adrenal hyperplasia, non-suppurating thyroiditis, hypercalcemia associated with cancer, juvenile rheumatoid arthritis, ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis, posttraumatic osteoarthritis, posttraumatic osteoarthritis , epicondylitis, acute rheumatic carditis, pemphigus, herpetiform bullous dermatitis, severe multiform erythema, exfoliating dermatitis, psoriasis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjunctivitis, keratitis, ophthalmic herpes zoster, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, chemotherapy of fulminant or disseminated pulmonary tuberculosis, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired hemolytic anemia (autoimmune) Adult lymphomas, acute childhood leukemia, ulcerative colitis, regional enteritis, Crohn's disease, Sjogren's syndrome, autoimmune vasculitis, multiple sclerosis, myasthenia gravis, sepsis or chronic obstructive pulmonary disease. 10. The compound according to claim 9, wherein the disease or disorder is selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type I diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, Psoriasis and chronic lung disease. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, and a pharmaceutically acceptable carrier for it. 12. A pharmaceutical combination comprising a compound according to any one of claims 1 to 4, and an immunosuppressant, an anticancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic, a vascular anti-hyperproliferation agent, an antidepressant agent, a lipid lowering agent, a lipid modulating agent, an antidiabetic agent, an anti-obesity agent, an antihypertensive agent, an inhibitor of platelet aggregation and / or an anti-osteoporosis agent, in which the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonylurea, a glucosidase inhibitor, a PPAR-γ agonist, a dual PPARα / γ agonist, an SGLT2 inhibitor, a DP4 inhibitor, an aP2 inhibitor, a insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and / or a meglitinide, in which the antiobesity agent of an adrenergic beta-3 agonist, a lipase inhibitor, an inhibitor of reuptake of serotonin (and dopamine), a thyroid receptor agonist, and an aP2 inhibitor and / or an anorectic agent, in which the lipid lowering agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a derivative of fibric acid, an overregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor, in which the antihypertensive agent is an ACE inhibitor, a receptor antagonist of angiotensin II, an NEP / ACE inhibitor, a calcium channel blocker and / or a β-adrenergic blocker. 13. The combination according to claim 12, wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipiride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin , G1-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242 GW-409544, KRP297, AC2993, LY31590 and 9839090 / or NVP-DPP728A, in which the antiobesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axoquine, dexamphetamine, phentermine, phenylpropanolamine, and / or mazindole, in which the decrease agent Lipids are pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, itavastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, cholestagel, niacin and / or LY295427 anti-aging agent. ACE inhibitor that is captopril, fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril, ramipril or moexipril; an NEP / ACE inhibitor that is omapatrilate, acid [S [(R *, R *)] - hexahydro-6 - [(2mercapto-1-oxo-3-phenylpropyl) amino] -2,2-dimethyl-7- oxo-1H-azepin-1-acetic acid (gemopatrilate) or CGS 30440; an angiotensin II receptor antagonist that is irbesartan, losartan or valsartan; Amlodipine besylate, prazosin HCl, verapamil, nifedipine, nadolol, propranolol, carvedilol, or clonidine HCl, in which the platelet aggregation inhibitor is aspirin, clopidogrel, ticlopidine, dipyridamole or ifetrobano; the immunosuppressant is a cyclosporine, mycophenolate, interferon-beta, deoxyspergoline, FK-506 or Ant.-IL-2; the anticancer agent is azathioprine, 5-fluorouracil, cyclophosphamide, cisplatin, methotrexate, thiotepa, or carboplatin; the antiviral agent is abacavir, acyclovir, ganciclovir, zidanocin, or vidarabine; and the anti-inflammatory drug is ibuprofen, celecoxib, rofecoxib, aspirin, naproxen, ketoprofen, diclofenac sodium, indomethacin, piroxicam, prednisone, dexamethasone, hydrocortisone, or triamcinolone diacetate.