MXPA00007690A - Novel dihydroxyhexanoic acid derivatives - Google Patents

Abstract

Dihydroxyhexanoic acid derivatives of general formula (I) are useful to treat inflammation and other immune disorders.

Description

NEW DERIVATIVES OF DIHYDROXYHEXANOIC ACID BACKGROUND OF THE INVENTION The present invention relates to new derivatives of dihydroxyhexanoic acid, to methods of use and to pharmaceutical compositions containing them. The compounds of the invention are potent and selective inhibitors of the binding of MIP-1a to its CCR1 receptor, which is found in inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes). The CCR1 receptor is sometimes also called the CCCKR1 receptor. These compounds also inhibit the chemotaxis induced by MIP-1a (and the related chemokine that has been shown to interact with CCR1 (e.g., RANTES and MCP-3)) of THP-1 cells and human leukocytes and are potentially useful for the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (of recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis and vasculitis), acute inflammatory conditions and chronic (such as osteoarthritis, Adult Respiratory Distress Syndrome, Childhood Respiratory Distress Syndrome, reperfusion injury of ischemia and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), rejection of transplanted tissues (chronic and acute), rejection of organs (chronic and acute), atherosclerosis, restenosis, HIV infection (use of co-receptors) and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis). MIP-1a and RANTES are soluble chemotactic peptides (chemokines) that are produced by inflammatory cells, in particular, by CD8 + lymphocytes, polymorphonuclear leukocytes (PMN) and macrophages, Biol. Chem .. 270 (30) 29671-29675 (nineteen ninety five). These chemokines act by inducing the migration and activation of key inflammatory and immunomodulatory cells. High levels of chemokines have been found in the synovial fluid of patients with rheumatoid arthritis, in chronic patients with rejection of tissue transplants and in the nasal secretions of patients with allergic rhinitis after exposure to the allergen (Teran, et al. J. Immunol., 1806-1812 (1996), and Kuna et al. 1, Allergy Clin. Immunol., 321 (1994)). Antibodies that interfere with the chemokine / receptor interaction by neutralizing MIP-1a or gene disruption have provided direct evidence for the role of MIP-1a and RANTES in disease, limiting the recruitment of monocytes and CD8 + lymphocytes ( Smith et al .. J. Immunol., 153. 4704 (1994) and Cook et al .. Science, 269. 1583 (1995)). These data together demonstrate that CCR1 antagonists would be effective in the treatment of various diseases based on the immune system. The disclosed compounds are highly soluble, potent and selective antagonists of CCR1.

U.S. Patent 4,923,864, issued May 8, 1990, refers to certain heterocyclic hexanamides that are useful for the treatment of hypertension. PCT publication WO 89/01488, published on February 23, 1989, refers to renin inhibiting peptides that possess non-peptide bonds. PCT publication WO 93/025057, published on February 4, 1993, refers to dipeptide analogs which, as claimed, inhibit retroviral proteases. PCT publication WO 93/17003, published on September 2, 1993, refers to other dipeptide analogs which, as claimed, inhibit retroviral proteases. PCT publication WO 92/17490, published on October 15, 1992, refers to peptides containing at least one monoester or O-phosphate diester. The compounds are claimed to possess activity to inhibit retroviruses. The publication of European patent 708,085, published on April 24, 1996, refers to antiviral ethers of aspartate protease inhibitors. The provisional patent application of the United States 60/039169, filed on February 26, 1997, refers to other hexanoic acid derivatives that are also antagonists of the MIP-1a / RANTES interaction with CCR1.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of the formula I wherein said compound is: 4 (R) -carbamoyl-1 (S) - (3-chloro-benzyl) -2 (S), 7-dihydroxy-7-methyl-octylj-amide of quinoxaline-2-acid carboxylic; (1S) -benzyl-4 (R) -carbamoyl-2 (S), 7,8-difluoro-quinoline-3-carboxylic acid 7-dihydroxy-7-methyl-octyl) -amide; (1 (S) -benzyl-4 (R) -carbamoyl-2 (S), 7,7-dihydroxy-7-methyl-octyl) -amide of 6,7,8-trifluoro-quinoline-3 -amide carboxylic; [4 (R) -carbamoyl-1 (S) - (3-fluoro-benzyl) - (2S), 7-dihydroxy-7-methyl-octyl] -amide of quinoxaline-2-carboxylic acid; (1 (S) -benzyl-2 (S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl) -amide of quinoxaline-2-carboxylic acid; [4 (R) -carbamoyl-1 (S) - (2-chloro-benzyl) - (2S), 7-dihydroxy-7-methyl-octylj-amide of quinoxaline-2-carboxylic acid; [1 (S) - (2-fluoro-benzyl) -2 (S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl-amide of quinoxaline-2-carboxylic acid; [4 (R) -carbamoyl-1 (S) - (2-fluoro-benzyl) -2 (S), 7-dihydroxy-7-methyl-octylj-amide of quinoxaline-2-carboxylic acid; [1 (S) - (3,4-difluoro-benzyl) -2 (S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl] -amide of quinoxaline-2-carboxylic acid; [4 (R) -carbamoyl-1 (S) - (3,4-difluoro-benzyl) -2 (S), 7-dihydroxy-7-methyl-octylj-amide of quinoxaline-2-carboxylic acid; or [4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-1 (S) -naphthalen-1-ylmethyl-octyl) -amide of the chemoxaline-2-carboxylic acid; and pharmaceutically acceptable salts thereof. The present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of this invention are those form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate salts , bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)]. The invention also relates to the base addition salts of formula I. The chemical bases which can be used as reagents for preparing the pharmaceutically acceptable base salts of the compounds of formula I which are acidic in nature, are those which form salts of non-toxic bases with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations (e.g., sodium and potassium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium addition salts or of water-soluble amines such as N-methylglucamine- (meglumine), the lower alkanolammonium salts and other salts of pharmaceutically acceptable organic amine bases. The present invention also relates to a pharmaceutical composition for the treatment or prevention of a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, sclerosis multiple, polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, Respiratory Distress Syndrome in adults, Respiratory Distress syndrome in infancy, reperfusion injury of ischemia and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Gillian-Barre), rejection of tissue transplantation, atherosclerosis, restenosis, HIV infection (use of co-receptors) and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, preferably a human being, comprising an amount of a compound of the Formula I, or a pharmaceutically acceptable salt thereof, effective in the treatment or prevention of such disorder or condition, and a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition for the treatment or prevention of a disorder or condition that can be treated or prevented by inhibiting the binding of MIP-1a to the CCR1 receptor in a mammal, preferably a human, comprising a The amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in the treatment or prevention of such disorder or condition, and a pharmaceutically acceptable carrier. Examples of such disorders or conditions are those listed in the previous paragraph. The present invention also relates to a method for the treatment or prevention of a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis). , polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, Respiratory Distress Syndrome in adults, Respiratory Distress Syndrome in childhood, reperfusion injury of ischemia and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), rejection of transplanted tissues, atherosclerosis, restenosis, HIV infection (use of co-receptors) and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, pref a human being, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, which is effective in the treatment or prevention of such disorder or condition. The present invention also relates to a method for the treatment or prevention of a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human being, which comprises administering to a mammal in need of such treatment or prevention. an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, which is effective in the treatment or prevention of such disorder or condition. The present invention also relates to a pharmaceutical composition for the treatment or prevention of a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, sclerosis multiple, polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, Respiratory Distress Syndrome in adults, Respiratory Distress syndrome of infancy, reperfusion injury of ischemia and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), rejection of transplanted tissues, atherosclerosis, restenosis, HIV infection (use of co-receptors) and granulomatous diseases ( including sarcoidosis, leprosy and tuberculosis) in a amine, preferably a human, comprising an amount effective to antagonize the CCR1 receptor of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition for the treatment or prevention of a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human, comprising an amount effective to antagonize the CCR1 receptor of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention also relates to a method for the treatment or prevention of a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis). , polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, Respiratory Distress Syndrome in adults, Respiratory Distress syndrome of childhood, reperfusion injury of ischemia and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), rejection of transplanted tissues, atherosclerosis, restenosis, HIV infection (use of co-receptors) and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, pref An amount effective to antagonize the CCR1 receptor of a compound of formula I or of a pharmaceutically acceptable salt thereof is administered to a mammal in need of such treatment or prevention. This invention also includes pharmaceutical compositions containing and methods of treatment or prevention comprising administering prodrugs of compounds of formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted to prodrugs. Prodrugs include compounds in which an amino acid residue or a polypeptide chain of two or more (eg, two, three or four) amino acid residues are covalently linked through peptide bonds with free amino, hydroxy or carboxylic groups of the Formula I. The amino acid residues include the 20 naturally occurring amino acids commonly referred to by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, beta-alanine, gamma acid -aminobutyric acid, citrulline homocysteine, homoserin, ornithine and methionine sulfone. Prodrugs also include compounds in which the above substituents of the formula I are covalently linked to carbonates, carbamates, amides and alkyl esters through the carbonyl carbon of the prodrug side chain. Prodrugs also include compounds of formula I in which an amide nitrogen and a hydroxy group, when taken together, form a cyclic group such as that of the following formula wherein R1 and R2 are as defined in formula I, and U and V are independently carbonyl, methylene, SO2 or SO3, and b is an integer from one to three, wherein each methylene group is optionally substituted with hydroxy.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the formula I can be prepared according to the following reaction and discussion scheme.

SQUEMA 1 Scheme 1 refers to the preparation of compounds of the formula I having the exact stereochemistry. The compounds of the formula I, or any of the intermediates thereof, can be separated by column chromatography according to well-known procedures for humans. of ordinary skill in the art, to produce pure compounds of the formula I. Referring to scheme 1, the compounds of the formula I can be prepared from compounds of formula II by reaction with ammonia or other volatile low molecular weight amine, in a polar solvent, at a temperature of about -10 ° C to about 35 ° C, preferably at about 30 ° C . Suitable solvents include alcohols, such as methanol, ethanol or butanols; or ethers such as glyme or dioxane (an acid catalyst with an ether as the solvent can be used). Preferably, the solvent is methanol. The compounds of formula II are prepared by coupling a compound of formula III with an acid of formula R1CO2H (or an acid chloride thereof in which R1 is quinoxaline-2-carboxylic acid, 7,8-difluoro- quinoline-3-carboxylic or 6,7,8-trifluoroquinoline-3-carboxylic acid). Such a coupling reaction is generally carried out at a temperature from about -30 ° C to about 80 ° C, preferably from about 0 ° C to about 25 ° C. Examples of suitable coupling reagents that activate the carboxylic acid functionality are dicyclohexylcarbodiimide / hydroxybenzo-triazole (DCC / HBT), N-3-dimethylaminopropyl-N'-ethylcarbodiimide (EDC) / HBT, 2-ethoxy-1 ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyl diimidazole (CDI) / dimethylaminopyridine (DMAP) and diethylphosphorylcide. The coupling is carried out in an inert solvent, preferably an aprotic solvent, such as acetonitrile, dichloromethane, chloroform and dimethylformamide. The preferred solvent is dichloromethane. For a discussion of other conditions used for amide coupling, see Houben-Weyl, Vol. XV, part II, E. Wunsch, Ed., George Theime Veriag, 1974, Stuttgart, and those described in M. Bodanszky. Principies of Peptide Synthesis, Springer-Verlag, Berlin (1984) and The Peptides. Analvsis. Synthesis and Bioloqy (Ed. E. Gross and J. Meienhofer), Vois 1-5. (Acac Press, New York) 1979-1983. The compounds of formula III can be prepared by deprotection and hydrolysis of alkenes of compounds of formula IV by reaction with trifluoroacetic acid. Suitable protecting groups of the formula P include t-butoxycarbonyl. The compounds of formula IV can be prepared by the reaction of a compound of formula V with 4-bromo-2-methyl-2-butene, in the presence of a strong base in a polar aprotic solvent. Suitable bases include lithium dialkyl amides, such as lithium N-isopropyl-N-cyclohexylamide LDA or potassium hydride. Suitable solvents include ethers (such as THF, glyme or dioxane), benzene or toluene, preferably THF. The aforesaid reaction is carried out at a temperature from about -78 ° C to about 0 ° C, preferably at about -78 ° C. The compounds of formula V can be prepared by methods well known to those of ordinary skill in the art or commercially available. Specifically, the compounds of the formula V can be prepared by the method of Fray et al .. (J. Ora, Chem .. 51, 4828-4833 (1986)) using an (S) -aldehyde of the formula VII The compounds of the formula VII are prepared by reducing amino acids or amino esters to alcohols (Stanfield et al., J. Org. Chem. 46. 4799-4800 (1981), Soai et al. Bull. Chem. Soc. Jpn. 57, 2327 (1984)), followed by the oxidation of the alcohols to aldehydes of the formula VII (Luly et al., Ora. Chem .. 53 (26), 6109-6112 (1988) and Denis et al. Orq Chem .. 56 (24), 6939-6942 (1991)). The non-natural amino acids can be prepared according to the method of Myers et al .. Tet. Lett. 36 (1995) and Myers et aj. J. Am. Chem. Soc. 117. 8488-8489 (1995). Alternatively, compounds of formula V can also be obtained by the method of DeCamp et al. (Tetrahedron Lett .. 32, 1867 (1991) .Unless otherwise indicated, the pressure of each of the above reactions it is not critical, Generally, the reactions will be carried out at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere) The compounds of the formula I which are basic in nature can form a wide variety of salts With such various inorganic and organic acids, although such salts have to be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter into the free base compound by treatment with an alkaline reagent and, subsequently, converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention are those which form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide salts acid, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, .etanesulfonate and pamoate [ie, 1, 1 '-met.Ien-b¡s- (2-hydroxy-3-naphthoate)]. The compounds of the formula I which are acidic in nature, can form base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the sodium and potassium salts. All these salts are prepared by conventional techniques. The chemical bases that are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those that form non-toxic salts with the acidic compounds described herein. These non-toxic base salts include those derived from pharmacologically cations. acceptable such as sodium, potassium, calcium and magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as indicated above. In any case, stoichiometric amounts of the reagents are preferably employed to ensure that the reaction is completed and maximum yields of the product are obtained. The compounds of the formula I and their pharmaceutically acceptable salts (hereinafter collectively referred to as "the active compounds") are potent antagonists of the CCR1 receptors. The active compounds are useful in the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis), type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, respiratory distress syndrome in adults, Respiratory distress of childhood, reperfusion injury of ischemia and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), rejection of transplanted tissues, atherosclerosis, restenosis, HIV infection (use of co-receptors) and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis). The activity of the compounds of the invention can be evaluated according to methods known to persons of ordinary skill in the art. Examples of recognized methods for determining migration induced by CCR1 can be found in Coligan, J.E., Kruisbeek, A.M., Margulies, D.H. Shevach E.M., Strober, W. editors: Current Protocols In Immunoloav. 6.12.1-6.12.3 (John Wiley & amp;; Sons, NY, 1991). A specific example of how to determine the activity of a compound to inhibit migration is described below.

Chemotaxis Assay: The ability of the compounds to inhibit the chemotaxis of various chemokines can be assessed using conventional 48- or 96-well Boyden Chambers with a 5 micron polycarbonate filter. All reagents and cells can be prepared in conventional RPMI tissue culture medium (BioWhitikker Inc.) supplemented with 1 mg / ml bovine serum albumin. Briefly, MIP-1oc (Peprotech, Inc., P.O. Box 275, Rocky Hill NJ) or other assay agonists were placed in the lower chambers of the Boyden chamber. Then a polycarbonate filter was applied and the upper chamber was fixed. The amount of agonist chosen is that determined to give the maximum amount of chemotaxis in this system (for example, a concentration of 1 nM for MIP-1oc would be adequate). Then THP-1 cells (ATCC TIB-202), primary human monocytes, or primary lymphocytes, isolated by conventional techniques, can be added to the upper chambers in triplicate together with various concentrations of the test compound. Dilutions of the compound can be prepared using conventional serological techniques and mixed with the cells before addition to the chamber. After an adequate incubation period at 37 degrees Celsius (eg, 3.5 hours for THP-1 cells, 90 minutes for primary monocytes), the chamber is removed, the cells in the upper chamber are aspirated, the The top of the filter is cleaned and the number of cells migrating can be determined according to the following procedure. For THP-1 cells, the chamber (a 96-well variety manufactured by Neuroprobe) can be centrifuged to push the cells into the lower chamber and then the number of cells can be quantified against a conventional curve by changing the color of the dye. fluorocein diacetate. For primary human monocytes, or lymphocytes, the filter can be stained with Dif Quik® dye (American Scientific Products) and the number of migrating cells can be determined microscopically. The number of migratory cells in the presence of the compound is divided by the number of migratory cells in the control wells (without the compound). The quotient is the% inhibition for the compound, which can then be represented using conventional graphics techniques versus the concentration of the compound used. The 50% inhibition point is then determined using a linear fit analysis for all concentrations tested. The linear fit for all data points must have a correlation coefficient (R squared) > 90% to be considered a valid test.

All the compounds of the invention that were tested had an Cl50 less than 25 μM, in the chemotaxis assay. The compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention can be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention can also be formulated for sustained release. For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl hypromellose); fillers (for example, lactose, microcrystalline cellulose or calcium phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or may be presented in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, hypromellose or hydrogenated edible fats), emulsifying agents (for example, lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). For buccal administration, the composition may take the form of tablets or dragees formulated in a conventional manner. The active compounds of the invention can be formulated for parenteral administration by injection, including the use of conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in aqueous or oily vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form to be reconstituted with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas containing, for example, conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently administered in the form of a solution or suspension from a spray container with a pump, which is tightened or pumped by the patient, or as a spray presentation. of aerosol from a pressurized container or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to release a dosed amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) can be formulated for use in an inhaler or nsufflator, containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the adult human medium for the treatment of the aforementioned conditions (e.g., rheumatoid arthritis) is 0.1 to 1000 mg of the active ingredient per unit dose. which could be administered, for example, from 1 to 4 times a day. Aerosol formulations for the treatment of the aforementioned conditions (e.g., rheumatoid arthritis) in the average adult human being are preferably arranged so that each measured dose or "puff" (nebulization) of aerosol contains 20 μg a 1000 μg of the compound of the invention. The overall daily dose with an aerosol will be within the range of 0.1 mg to 1000 mg. The administration can be carried out several times a day, for example, 2, 3, 4 or 8 times, administering, for example, 1, 2 or 3 doses each time. The active ingredients can be formulated for sustained release according to procedures well known to those of ordinary skill in the art. Examples of such formulations can be found in U.S. Patents 3,538,214, 4,060,598, 4,173,626, 3,119,742 and 3,492,397. The compounds of the invention can also be used in combination therapy with other therapeutic agents such as with immunosuppressive agents such as cyclosporin A and FK-506, Cellcept®, rapamycin, leuvlonamide or with classical anti-inflammatory agents (eg, inhibitors of cyclooxygenase / lipoxygenase) such as tenidap, aspirin, acetaminophen, naproxen and piroxicam, steroids including prednisone, azathioprine and biological agents such as OKT-3, and anti-IL-2 monoclonal antibodies (such as TAC). The compounds of the present invention possess unexpected solubility that could not be predicted based on US patent application 60/039169, filed on February 26, 1997. Specifically, all compounds of the present invention have a solubility at least 13. times better than would be expected based on the compounds of United States Provisional Application 60/039169. Specifically, both (2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-1 (S) -naphthalen-2-ylmethyl-heptyl) -amide of quinoxaline-2-carboxylic acid (Example 127) ) such as N-1 (S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -5,6-dichloro-nicotinamide (example 247), have solubilities less than 5 μg / ml when tested according to the kinetic solubility test described below. The following examples illustrate the preparation of the compounds of the present invention. The melting points are uncorrected. The NMR data are presented in parts per million (d) and refer to the deuterium stabilization signal of the sample solvent (deuteriochloroform, unless otherwise specified). The commercial reagents were used without further purification. THF refers to tetrahydrofuran. DMF refers to N, N-dimethylformamide. Chromatography refers to column chromatography performed using 32-63 mm of silica gel and was run under nitrogen pressure conditions (ultra-fast chromatography). Low Resolution Mass Spectrums (LRMS) were recorded in a Hewlett Packard 5989®, using chemical ionization (ammonium), or in an Atmospheric Pressure Chemical Ionization Platform (APCI) Fisons (or micro Mass) using a 50 / 50 acetonitrile / water with 0.1% formic acid as an ionizing agent. The ambient temperature refers to 20-25 ° C. All non-aqueous reactions were conducted under a nitrogen atmosphere for convenience and to maximize yields. The concentration under reduced pressure means that a rotary evaporator was used. The names for the compounds of the invention were created by the Autonom 2.0 PC-batch version of Beilstein Informationssysteme GmbH (ISBN 3-89536-976-4). The solubility of the compounds was determined by a kinetic solubility test such as that described in the Advanced Drug Delivery Review. 23. 3-25 (1997). An embodiment of the procedure described in Advanced Drug Deliverv Review is described below. 23, 3-25 (1997). A person of ordinary skill in the art will appreciate that the solubility can be determined by many different methods. The solubility of the compounds is determined at four fixed concentrations and expressed as μg / ml. Solubility or insolubility is measured in phosphate buffer using a turbidometric plate reader by the microautomatic addition of a compound pre-dissolved in DMSO. The solubilities at 50, 100, 200 and 250 or 100, 200, 400 and 500 micrograms / ml can be determined by predisolving 1 mg of compound in sufficient DMSO to reach an initial concentration of 20 to 40 μg / μl. A transparent 96-well Spectramax 250 UV microplate is filled with 200 μl of phosphate buffer stock pH 7. A series of 25 absorption readings is taken in a 5 x 5 matrix at a wavelength of 492 nm for each well , in the microplate containing pH buffer alone. This scan is used as "blank" and the initial optical scattering (OD) values are used as initial values.

The compounds are then added in DMSO solution (column form) under the microplate. Up to 24 samples are tested with each compound placed in four contiguous wells in column form. Each column of the microplate contains four concentrations of compound in ascending concentration and in ascending order of rows (A-D) or rows (E-H). The volume of the DMSO stock solution added to each well varies between 0.25 and 1.25% of the volume of buffer in the well. The plate is then stirred for 20 minutes to facilitate mixing. Conventional Distribution Procedure: After the addition of the compound, a second scan is performed consisting of a series of 25 absorption readings in a 5 x 5 matrix for each well of the microplate, at the same wavelength as the first scan of the blank. The initial OD values of the compound for each reading in the 5 x 5 matrix are subtracted from the corresponding values of the "blank" of the 5 x 5 matrix to provide the initial OD data of solubility.

The data obtained from the Tecan STL Spectra Image Reader is then analyzed using a Visual Basic computer program (or can be calculated manually according to procedures well known to those of ordinary skill in the art), to provide the solubility data for each compound . The compound is considered insoluble when the absorbency value is more than three times higher than the initial value. All the compounds of the invention had solubilities greater than 100 μg / ml.

PREPARATION 1 PROCEDURE A Allylation Alkilación Terc-butil ester of the acid '1 (S) -r4 (R) - (3-methyl-but-2-enyl) -5-oxo-tetrahydrofuran-2 (S) -ip-2- phenyl-ethyl} -carbamic To a round-bottomed flask flame-dried under a nitrogen atmosphere, tetrahydrofuran (40 ml) was added followed by 1,1,1,3,3-hexamethyldisilazane (8 ml, 37.8 mmol). The mixture was cooled to 0 ° C and n-butyl lithium (14.5 ml of a 2.5 M solution in hexanes, 36.0 mmoles) was added. The mixture was stirred for 15 minutes and then cooled to -78 ° C in a dry ice / acetone bath. Tert-butyl ester of the acid was added dropwise via syringe. { 1 (S) - [5-oxo-tetrahydro-furan-2 (S) -yl] -2-phenyl-ethyl} Carbamic (5 g, 16.4 mmol) (prepared by the procedure of Fray, L Orq Chem .. (51) 4828 (1986)) dissolved in tetrahydrofuran (50 ml) and stirring was continued for 30 minutes. A solution of 4-bromo-2-methyl-butene (2.07 ml, 18.0 mmol) in 40 ml of THF was added dropwise via syringe. Stirring was continued for 3 hours, during which time the temperature was raised to -60 ° C. The mixture was quenched by the slow addition of saturated aqueous ammonium chloride (25 ml). After warming to room temperature, the solution was diluted with ether (300 ml) and transferred to a separatory funnel. The organic phase was washed with saturated aqueous citric acid (2 x 100 ml), saturated aqueous sodium bicarbonate (NaHCOa) (2x100 ml) and 100 ml of brine. The organic layer was dried over magnesium sulfate (MgSO4) and the solvent was removed under reduced pressure. Thin layer chromatography in 1: 2 hexane / diethyl ether (Et 2 O) revealed a product with an Rf of 0.8. The resulting crude oil was chromatographed on silica gel (225 g) eluting with 2: 1 hexanes / diethyl ether to provide 4.73 g (77%) of the title compound. TLC: 1: 2 Hexanes / Et20 Rf: 0.8. 1 H NMR (400 MHz, CDCl 3): d 7.27 ppm (5H, m), 5.02 (1H, b), 4.52 (1H, d, J = 9.3 Hz), 4.42 (1 H, t, J = 7.1 Hz), 3.98 (1 H, dt, J = 8.5, 7.8 Hz), 2.93 (2H, m), 2.88 (1 H, b), 2.68 (1 H, m), 2.41 (1 H, m), 2.24 (1 H , m), 1.92 (1 H, m), 1.65 (3 H, s), 1.58 (3 H, s), 1.37 (9 H, s).

PROCEDURE B 1 (S) -Benzyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyloctyl) -amide of q? Inoxaline-2-carboxylic acid To the lactone of procedure A (100 mg, 0.27 mmol) was added pure trifluoroacetic acid (1 ml). The resulting solution was stirred for 1 hour and the trifluoroacetic acid was removed in vacuo. The remaining residue was solvated in methylene chloride (10 ml) and triethylamine (0.15 ml, 1.07 mmol). Quinoxalyl chloride (58 mg, 0.3 mmol) was added in solid form and the mixture was stirred for 18 hours. The mixture was transferred to a separatory funnel and washed with citric acid (2x10 ml), NaHC 3 (10 ml) and brine (10 ml). The organic layer was dried (MgSO4) and the solvents were filtered. The filtrate was concentrated in vacuo and the resulting residue was chromatographed on silica gel (10 g) eluting with 2: 1 hexanes: ethyl acetate to provide 99 mg of quinoxaline amide. This material was solvated in MeOH and ammonia gas was bubbled for 5 minutes. The resulting solution was stirred for 16 hours and the solvent was removed in vacuo. The remaining residue was recrystallized (methylene chloride / methanol / hexanes) to give the title compound (90 mg, 72%). 1 H NMR (400 MHz, CD 3 OD): d 9.38 (1 H, s), 8.21 (1 H, dd, J = 4.4, 2.5 Hz), 8.14 (1 H, dd, J = 4.4, 2.5 Hz), 7.93 ( 2H, m), 7.26 (2H, d, J = 6.9 Hz), 7.17 (2H, t, J = 7.1 Hz), 7.09 (1 H, t, J = 7.3 Hz), 4.30 (1 H, m), 3.75 (1 H, m), 3.03-2.98 (2H, m), 2.47 (1H, m), 1.77 (1H, m), 1.56 (2H, m), 1.4 (2H, m), 1.07 (6H, s ).

EXAMPLE 1 (4 (R) -Carbamoyl-2 (S). 7-dihydroxy-7-methyl-1fS) -thiophen-2-ylmethyl-oct-p-amide of quinoxaline-2-acid carboxylic To a round-bottomed flask flame-dried under a nitrogen atmosphere, tetrahydrofuran (5 ml) was added followed by 1,1,1,3,3-hexamethyldisilazane (0.78 ml, 3.7 mmol). The mixture was cooled to 0 ° C and n-butyl lithium (1.4 ml of a 2.5 M solution in hexanes, 3.38 mmol) was added. The mixture was stirred for 15 minutes and then cooled to -78 ° C in a dry ice / acetone bath. Tert-butyl ester of the acid was added dropwise via syringe. { 1- (S) - [5-oxo-tetrahydro-furan-2 (S) -yl] -2-thienyl-ethyl} carbohydrate (500 mg, 1.61 mmol) (prepared by the procedure of Fray, J. Ora, Chem .. (51) 4828 (1986)) using BOC-L-2-thienylalanine as starting material) dissolved in tetrahydrofuran (6). ml) and the stirring was continued for 30 minutes. A solution of 4-bromo-2-methyl-2-butene (0.21 ml, 1.77 mmol) in 5 ml of THF was added dropwise via syringe. Stirring was continued for 3 hours, during which time the temperature was raised to -60 ° C. The mixture is quenched by the slow addition of saturated aqueous ammonium chloride. After warming to room temperature, the solution was diluted with ether and transferred to a separatory funnel. The organic phase was washed with saturated aqueous citric acid, saturated aqueous sodium bicarbonate (NaHCO3) and brine. The organic layer was dried over magnesium sulfate (MgSO4) and the solvent was removed under reduced pressure. Thin layer chromatography in 1: 2 hexane / diethyl ether (Et20) revealed a product with an Rf of 0.25. The resulting crude oil was chromatographed on silica gel eluting with 2: 1 hexanes / diethyl ether to provide 450 mg (74%) of the lactone. To the above lactone (450 mg, 1.19 mmol) pure trifluoroacetic acid (4.5 ml) was added. The resulting solution was stirred for 1 hour and the trifluoroacetic acid was removed in vacuo. The resulting amine salt (100 mg, 0.34 mmol) was solvated in methylene chloride (15 ml) and triethylamine (0.2 ml, 1.34 mmol). Quinoxalyl chloride (71 mg, 0.37 mmol) was added as a solid and the mixture was stirred for 18 hours. The mixture was transferred to a separatory funnel and washed with citric acid, NaHCO 3 and brine. The organic layer was dried (MgSO4) and the solvents were filtered. The filtrate was concentrated in vacuo and the resulting residue was chromatographed on silica gel eluting with 2: 1 hexanes: ethyl acetate to provide 108 mg (71%) of the quinoxaline amide. This material was solvated in MeOH and ammonia gas was bubbled for 5 minutes. The resulting solution was stirred for 16 hours and the solvent was removed in vacuo. The remaining residue was recrystallized (methylene chloride / methane / hexanes) to give the title compound (60 mg, 53%). Melting point (PF) 158-159. The low resolution mass spectrum (LRMS) 471, 453.436.

Solubility greater than 250 mg / ml. Table 1 refers to the preparation of compounds of formula I by procedures analogous to the procedures of preparation 1 and example 1. TABLE 1

Claims (7)

NOVELTY OF THE INVENTION CLAIMS

1. A compound of the formula wherein said compound is: 4 (S) -carbamoyl-1 (S) - (3-chloro-benzyl) -2 (S), 7-dihydroxy-7-methyl-octyl] -amino of quinoxaline-2-acid carboxylic; (1 (S) -benzyl-4 (R) -carbamoyl-2 (S), 7,8-difluoro-quino-3-carboxylic acid 7-dihydroxy-7-methyl-octyl) -amide; (1- (S) -benzyl-4 (R) -carbamoyl-2 (S), 7,7-dihydroxy-7-methyl-octyl) -amide of 6,7,8-trifluoro-quinoline-3-carboxylic acid; [4 (R) -carbamoyl-1 (S) - (3-fluoro-benzyl) -2 (S), 7-dihydroxy-7-methyl-octyl] -amide of quinoxaline-2-carboxylic acid; (1 (S) -benzyl-2 (S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl) -amide of quinoxaline-2-carboxylic acid; [4- (R) -carbamoyl-1 (S) - (2-chloro-benzyl) -2 (S), 7-dihydroxy-7-methyl-octyl] -amide of quinoxaline-2-carboxylic acid; [1 (S) - (2-fluoro-benzyl) -2 (S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl-amide of quinoxaline-2-carboxylic acid; [4 (R) -carbamoyl-1 (S) - (2-fluoro-benzyl) -2 (S), 7-dihydroxy-7-methyl-octyl] -amide of quinoxaline-2-carboxylic acid; [1 (S) - (3,4-difluoro-benzyl) -2 (S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyro-amide of quinoxaline-2-carboxylic acid; [4 (R) -carbamoyl-1 (S) - (3,4-difluoro-benzyl) -2 (S), 7-dihydroxy-7-methyl-octyl] -amide of quinoxaline-2-carboxylic acid; or (4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-1 (S) -naphthalen-1-ylmethyl-octyl) -amide of quinoxaline-2-carboxylic acid.

2. A pharmaceutical composition for the treatment or prevention of a disorder or condition selected among autoimmune diseases, acute and chronic inflammatory conditions, allergic conditions, infection associated with inflammation, viral diseases, rejection of tissue transplants, atherosclerosis, restenosis, infection for HIV and granulomatous diseases in a mammal, comprising an amount of a compound according to claim 1 that is effective in the treatment or prevention of such disorder or condition, and a pharmaceutically acceptable carrier.

3. A pharmaceutical composition for the treatment or prevention of a disorder or condition that can be treated or prevented by inhibiting the binding of MIP-1a to the CCR1 receptor in a mammal, comprising an amount of a compound according to the claim 1, or a pharmaceutically acceptable salt thereof, effective in the treatment or prevention of such disorder or condition, and a pharmaceutically acceptable carrier.

4. The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disorder or condition selected from autoimmune diseases, inflammatory conditions acute and chronic, allergic conditions, infection associated with inflammation, viral diseases, rejection of tissue transplants, atherosclerosis, restenosis, HIV infection and granulomatous diseases in a mammal.

5. The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disorder or condition that can be treated or prevented by antagonizing the recipient CCR1 in a mammal.

6. A pharmaceutical composition for the treatment or prevention of a disorder or condition selected among autoimmune diseases, acute and chronic inflammatory conditions, allergic conditions, infection associated with inflammation, viral diseases, rejection of tissue transplants, atherosclerosis, restenosis, infection for HIV and granulomatous diseases in a mammal, comprising an amount effective to antagonize the CCR1 receptor of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition for the treatment or prevention of a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, comprising an amount effective to antagonize the CCR1 receptor of a compound according to claim 1, or of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.