MXPA00009904A - (4-arylsulfonylamino)-tetrahydropyran-4-carboxylic acid hydroxamides - Google Patents

Abstract

A compound of formula (I) wherein Q is as defined, is use in the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neurophaty, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis and septic shock. In addition, the compounds of the present invention may be used in combination therapy wtih standard non-steroidal anti-inflammatory drugs (NSAID'S) and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.

Description

HYDROXAMIDES OF THE ACID (4-SULFONYLAMINE-TETRAH »DROPYRAN- 4-CARBOXYLlIC BACKGROUND OF THE INVENTION The present invention relates to hydroxamide derivatives of (4-sulfonylamino) -tetrahydropyran-4-carboxylic acid and to pharmaceutical compositions and methods of treatment. The compounds of the present invention are zinc zinc metalloendopeptidase inhibitors, especially those belonging to the metalloproteinase subfamilies of the matrix (also called MMP or matrixin) and of reprolysin (also known as adamilsin) of the metcinquines (Rawlings, et al., Methods in Enzvmology, 248, 183-228 (1995) and Stocker, et al .. Protein Science, 4, 823-840 (1995)). The subfamily of MMP enzymes, currently has seventeen members (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP- 13, MMP-14, MMP-15, MMP-16, MMP-17, MMP-18, MMP-19 and MMP-20). MMPs are mostly well known for their role in regulating the renewal of extracellular matrix proteins and as such they play important roles in normal physiological processes such as reproduction, development and differentiation. In addition, MMPs are expressed in many pathological situations in which an abnormal renewal of connective tissue occurs. For example, MMP-13, an enzyme with potent activity to degrade type II collagen (the main collagen in cartilage) has been shown to be overexpressed in osteoarthritic cartilage (Mitchell, et al .. J. Clin. Invest. 97, 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also overexpressed in osteoarthritic cartilage and it is expected that the inhibition of some or all of these MMPs will decrease or block the accelerated loss of cartilage typical of diseases of the joints such as osteoarthritis or rheumatoid arthritis. The mammalian reprolysins are known as ADAM [Disintegrid And Metalloproteinase (a disintegrin and metalloproteinase)] (Wolfberg, et al., J. Cell, Biol .. 131, 275-278 (1995)) and contains a disintegrin domain in addition to a domain similar to that of metalloproteinases. To date, twenty-three different ADAMs have been identified. ADAM-17, also known as tumor necrosis factor-alpha converting enzyme (TACE), is the best-known ADAM. ADAM-17 (TACE) is responsible for the separation of tumor necrosis factor alpha linked to cells (TNF-a, also known as cachectin). It is known that TNF-a is involved in many infectious and autoimmune diseases (W. Friers, FEBS Letters, 285, 199 (1991)). In addition, TNF-a has been shown to be the principal mediator of the inflammatory response observed in sepsis and septic shock (Spooner, et al., Clinical Immunology and Immunopathology, 62 S11 (1992)). There are two forms of TNF-α, a type II membrane protein of relative molecular mass 26,000 (26 KD) and a soluble form of 17 KD generated by proteins bound to cells by specific proteolytic cleavage. The soluble 17 KD form of TNF-α is released by the cells and is associated with the deleterious effects of TNF-α. This form of TNF-a can also act at sites far from the site of synthesis. Thus, inhibitors of TACE prevent the formation of soluble TNF-a and prevent the deleterious effects of soluble factor. The selected compounds of the invention are potent aggrecanase inhibitors, an important enzyme in the degradation of cartilage aggrecan. It is also believed that aggrecanase is an ADAM. The loss of aggrecan from the cartilage matrix is an important factor in the progression of joint diseases such as osteoarthritis and rheumatoid arthritis and it is expected that the inhibition of aggrecanase will slow or block the cartilage loss in these diseases. Other ADAMs that have demonstrated their expression in pathological situations include ADAM TS-1 (Kuno et al .. J. Biol. Chem .. 272, 556-562 (1997)) and ADAM 10, 12 and 15 (Wu, et al., Biochem. Biophvs, Res. Comm. 235, 437-442 (1997) As recognition of the expression, it will be appreciated that the association of physiological substrates and diseases of ADAM increases the complete knowledge of the inhibition function of this class of enzymes Diseases in which the inhibition of MMP and / or ADAM will provide a therapeutic benefit include: arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, chronic obstructive pulmonary disease due to asthma, Alzheimer's disease, organ transplant toxicity, cokerxia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa , osteoporisis, lack of firmness in implants of artificial joints, atherosclerosis (including rupture of the atherosclerotic plaque tica), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, cerebrovascular accident, cerebral ischemia, head injury, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune disorders, Huntigton's disease, Parkinson's disease, migraine, depression, neuropathy, peripheral, pain, cerebral amyloid anglopathy, nootropic or cognitive enhancement, amotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal healing of wounds, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal burns, sclerosis, AIDS, septicemia, septic clots and other diseases characterized by expression of metalloproteinases or ADAM. This invention further relates to a method for using the compounds of the invention in the treatment of the above diseases in mammals, especially in humans and to the pharmaceutical compositions useful therefor.

It has been recognized that different combinations of MMP and ADAM are expressed in different pathological situations. As such, for particular diseases inhibitors with specific selectivities for ADAM and / or particular MMPs may be preferred. For example, rheumatoid arthritis is an inflammatory disease of the joints characterized by excessive levels of TNF and loss of the constituents of the joint matrix. In this case, the preferred therapy may be a compound that inhibits TACE and aggrecanase, as well as MMP, such as MMP-13. On the other hand, in a less inflammatory joint disease, such as osteoarthritis, compounds that inhibit MMPs that degrade the matrix such as MMP-13, but not TACE, may be preferred. The authors of the present invention have also discovered that it is possible to design inhibitors with differential metalloproteinase activity. Specifically, for example, the inventors have been able to design molecules that selectively inhibit matrix metalloproteinase-13 (MMP-13), preferably over MMP-1. Inhibitors of matrix metalloproteinases and reprolysin are well known in the literature. Specifically, PCT publication WO 96/33172, published October 24, 1996, refers to cyclic aryisulfonylamino hydroxamic acids which are useful as inhibitors of MMP. U.S. Patent 5,672,615, PCT document publication WO 97/20824, PCT document publication WO / 9808825, PCT document publication WO 98/27069 and PCT document publication WO 98/34918, published on August 13, 1998, entitled "Cyclic arylsulfonyl hydroxamics which are useful as inhibitors of MMPs." PCT publications WO 96/27583 and WO 98/07697, published March 7, 1996 and February 26, 1998, respectively, refer to arylsulfonyl hydroxamic acids The PCT publication WO 98/03516, published on January 29, 1998, relates to phosphinates with activity against MMP The PCT publication WO 98/34915, published August 13, 1998, entitled "N-Hydroxy-b-Sulfonyl Propionamide Derivatives" refers to propionylhydroxamides as useful inhibitors of MMP The publication of PCT document 98/33768, published on August 6, 1998, entitled "Arylsulfonylamino Hydroxamic Acid Deri vatives "refers to N-substituted aryisulfonylamino hydroxamic acids. PCT publication WO 98/30566, published on July 16, 1998, entitled "Cyclic Sulfone Derivatives", refers to cyclic hydroxamic sulfone acids as MMP inhibitors. United States Provisional Patent Application 60/55208, filed August 8, 1997, refers to biaryl hydroxamic acids as inhibitors of MMP. United States Provisional Patent Application Serial No. 60/55207, filed August 8, 1997, entitled "Aryloxyarylsulfonylamino Hydroxamic Acid Derivatives", refers to aryloxyarylsulfonyl hydroxamic acids as inhibitors of MMP. U.S. Provisional Patent Application 60/62766, filed October 24, 1997 entitled "The Use of MMP-13 Selective Inhibitors for the Treatment of Osteoarthritis and Other MMP Mediated Disorders," refers to the use of selective inhibitors of MMP-13 to treat inflammation and other disorders. U.S. Provisional Patent Application Serial No. 60/68261, filed December 19, 1997, relates to the use of MMP inhibitors to treat angiogenesis and other disorders. Each of the aforementioned publications and applications is incorporated herein by reference in its entirety.

BRIEF DESCRIPTION OF THE INVENTION or a pharmaceutically acceptable salt thereof, wherein Q is alkyl dd, C6-C? aryl, C2-C9 heteroaryl, (C6-C? aryloxy) (dd alkyl), (C6-C? 0 aryloxy) ( Ce-Cry aryl), (C6-C6 aryloxy) (C2-C9 heteroaryl), (arylCio) (alkyl dd), (aryl C6-C? 0) (aryl C6-C? 0), (aryl C6-C? 0) (heteroaryl C2-C9), (aryl C6-C0) (aryl -C o) (C -C6 alkyl), (arylCio) (aryl d-Cio) (C6-C? 0 aryl), (C6-C? aryl) (aryl C6-C? 0) ( C2-C9 heteroaryl), (C2-C9 heteroaryl) (C6-C6 alkyl), (C2-C9 heteroaryl) (C6-C6 aryl), (C2-C9 heteroaryl) (C2-C9 heteroaryl), (C6-aryl) -C? 0) (C? -C6 alkoxy) (C? -C6 alkyl), (C6-C? 0 aryl) (C-C6 alkoxy) (C6-C? 0 aryl), (C6-C? Aryl) ) (C6 -C6 alkoxy) (C2-C9 heteroaryl), (C2-C9 heteroaryloxy) (C6-6 alkyl), (C2-C9 heteroaryloxy) (C6-C6 o aryl), (C2-C8 heteroaryloxy) (C2-C9 heteroaryl), (C2-C8 heteroaryl) (alkoxy dd) (C? -C6 alkyl), (C2-C9 heteroaryl) (C? -C6 alkoxy) (C6-C? 0 aryl) or (heteroaryl C2) -C9) (C 1-6 alkoxy) (C 2 -C 9 heteroaryl); wherein each of said aryl radicals -Cio or C2-C9 heteroaryl of said C6-C? ar aryl, C2-C9 heteroaryl, (C6-C? ar aryloxy) (dd alkyl), (C6-C? 0 aryloxy) ( C6-C? 0 aryl), (C6-C? 0 aryloxy) (C2-C9 heteroaryl), (C6-C? 0 aryl) (C? -C6 alkyl), (C6-C? 0 aryl) (C6 aryl) -C? 0), (aryl C6-C? 0) (heteroaryl C2-C9), (aryl C6-C? O) (aryl d-Cio) (C6 alkyl), (aryl C6-C? 0) ( aryl C6-C? 0), (aryl C6-C? 0) (aryl d-Cio) (aryl C6-C? 0) (heteroaryl C2-C9), (heteroaryl C2-C9) (C6-C6 alkyl) , (heteroaryl dd) (arylCio), (C2-C9 heteroaryl) (C2-C9 heteroaryl), (aryl-C10) (alkoxy dd) (C6-C6 alkyl), (C6-C6 aryl) ( alkoxy CrC6) (C6-C? ar aryl), (C6-C? o aryl) (C?-C6-alkoxy) (C2-C9 heteroaryl), (C2-C9-heteroaryloxy) (C C-C6 alkyl), (C2-heteroaryloxy) C9) (C6-C6o aryl), (C2-C9 heteroaryloxy) (C2-C9 heteroaryl), (C2-C9 heteroaryl) (C6-6 alkoxy) (d6C6 alkyl), (C2-C9 heteroaryl) (C 6 -C 6 alkoxy) (C 6 -C 0 aryl) or (C -C 9 heteroaryl) (CrC 6 alkoxy) (C 2 -C 9 heteroaryl) is optionally substituted on Any of the ring carbon atoms capable of forming an additional bond by one or more substituents per ring, independently selected from fluoro, chloro, bromo, dd alkyl, dd alkoxy, perfluoro (C1-C3 alkyl), perfluoro (alkoxy) C1-C3) and aryloxy or one of its pharmaceutically acceptable salts.

The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals with branched or cyclic linear moieties or combinations thereof. The term "alkoxy" as used herein, includes O-alkyl groups in which "alkyl" is defined as above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by the removal of a hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, bromo, perfluoro (C 1 -C 6 alkyl) including trifluoromethyl), C 1 -C 6 alkoxy, C 6 -C 0 aryloxy, perfluoro (alkoxy dd) (including trifluoromethoxy and difluoromethoxy) and alkyl dd. The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of a hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl. , imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl, optionally substituted with 1 to 2 substituents selected from group consisting of fluoro, chloro, trifluoromethyl, alkoxy dd, C6-C? ar aryloxy, trifluoromethoxy, difluoromethoxy and C?-C6 alkyl. Preferred heteroaryls include pyridyl, furyl, thienyl, isothiazolyl, pyrazinyl, pyrimidyl, pyrazolyl, isoxazolyl, thiazolyl or oxazolyl. Most preferred include pyridyl, furyl or thienyl. Preferred compounds of formula I include those in which Q is C6-C6 aryl, (C6-C6 aryl) (C6-C6 aryl), (C6-C6 aryloxy) (C6-C aryl) ? 0), (aryloxy -Cio) (C2-Cg heteroaryl), C2-C9 heteroaryl, (C2-C9 heteroaryl) (C2-C9 heteroaryl), (C6-C6 aryl) (C2-C9 heteroaryl), ( C2-C9 heteroaryl) (C6-C10 aryl), (C2-C9 heteroaryloxy) (C6-C? 0 aryl), (C6-C? o aryl) (C? -C6 alkoxy) (C6-C10 aryl), or (C2-C9 heteroaryl) (alkoxy dd) (C6-C? 0 aryl) optionally substituted. Other preferred compounds of formula I include those in which Q is (aryloxy -Cio) (C6-C? 0 aryl) optionally substituted. Specific compounds of formula I include the following: 4- [4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide; Hydroxyamide of 4- [4- (4-chlorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide; Hydroxyamide of 4- [4- (phenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid; 4- [4- (4-Pyridyloxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide; 4- [4- (4-Fluorophenyl) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide; 4- [4- (4-Fluorophenylmethoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide; 4- [4- (Phenylmethoxy) benzenesulfonylamino-3-tetrahydropyran-4-carboxylic acid hydroxyamide; and Hydroxyamide of 4- [4- (4-fluorophenylethoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid. The present invention also relates to a pharmaceutical composition for the treatment of a disorder selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimer's disease, Organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as cancer with solid tumors including colon cancer, breast cancer, lung cancer and prostate cancer and malignant hematopoietic processes including leukemia and lymphoma) , tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, lack of firmness in artificial joint implants, atherosclerosis (including rupture of atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, cerebrovascular accident, cerebral ischemia, head injury, spinal cord injury, neurodegenerative disorders ( acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, healing abnormality of wounds, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal burns, scleritis, AIDS, sepsis and septic shock and other diseases characterized by metalloproteinase activity and other diseases characterized by reproliferation activity a mammal in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in such treatments and a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition for the inhibition of (a) matrix metalloproteinases and other metalloproteinases involved in the degradation of the matrix, or (b) a mammalian reprolysin (such as aggrecanase or ADAM TS-1, 1). , 0, 12, 15 and 17, most preferably ADAM-17) in a mammal, including a human, comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating a disorder selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimer's disease, toxicity in the organ transplantation, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, lack of firmness in implants of artificial joints, atherosclerosis (including rupture of the atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, cerebrovascular accident, cerebral ischemia, head injury, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune disorders, in Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal healing of wounds, burns, diabetes , tumor invasion, tumor growth, tumor metastasis, corneal burns, scleritis, AIDS, septicemia, septic shock and other diseases characterized by metalloproteinase activity and other diseases characterized by mammalian reprolysin activity in a mammal, including a human being, which it comprises administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat said disorder. The present invention further relates to a method for the inhibition of (a) matrix metalloproteinases or other metalloproteinases involved in the degradation of the matrix, or (b) a mammalian reprofisin (such as aggrecanase or ADAM TS-1, 10, 12, 15 and 17, preferably ADAM-17) in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. This invention also includes pharmaceutical compositions containing prodrugs of the compounds of formula I. This invention also includes methods for treating or preventing disorders that can be treated or prevented by inhibiting matrix metalloproteinases or inhibiting mammalian reprolysin comprising administering prodrugs of compounds of formula I. Compounds of formula I having amino groupsFree amido, hydroxy or carboxyl can be converted into prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more amino acid residues (eg, two, three or four), are covalently linked through peptide bonds to free amino, hydroxy or carboxylic acid groups of the compounds of formula I. The amino acid residues include the 20 natural amino acids commonly designated by three-letter symbols and also include 4-hydroxyproline, hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserin, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters are covalently linked to the above substituents of formula I through the carbonyl carbon of the prodrug side chain. One skilled in the art will appreciate that the compounds of the invention are useful in the treatment of a variety of diseases. One skilled in the art will also appreciate that when the compounds of the invention are used in the treatment of a specific disease, the compounds of the invention can be combined with various existing therapeutic agents used for said disease. For the treatment of rheumatoid arthritis, the compounds of the invention can be combined with agents, such as TNF-a inhibitors such as anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules (such as Enbrel®), low-dose methotrexate , lefunimide, hydroxychloroquine, d-penicillamine, auranofin or gold salts orally or parenterally. The compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents for use in combination include conventional non-steroidal anti-inflammatory agents (hereinafter NSAIDs) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, phenamates such as mefenamic acid, ndometacin, sulindac, apazone, pyrazolones. such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib and rofecoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and sinvisc. The compounds of the present invention can be used in combination with anti-cancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine and antimetabolites such as methotrexate. The compounds of the present invention can also be used in combination with cardiovascular agents such as calcium channel blockers, lipid lowering agents such as statins, fibrates, beta-blockers, ACE inhibitors, receptor antagonists, angiotensin-2 and inhibitors of platelet aggregation. The compounds of the present invention can also be used in combination with agents that act in the CNS as antidepressants (such as sertraline), anti-Parkinson's drugs (such as deprenyl, L-dopa, requip, miratex, MAOB inhibitors such as selegine and rasagiline , comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and neuronal nitric oxide synthetase inhibitors) and Alzheimer's drugs such as Aricept, tacrine, COX-2 inhibitors, propentofylline or metrifonate.

The compounds of the present invention can also be used in combination with osteoporosis agents such as droloxifene or fosomax and immunosuppressive agents such as FK-506 and rapamycin.

DETAILED DESCRIPTION OF THE INVENTION The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless indicated otherwise, Q in the reaction schemes and the following description is as defined above.

SCHEME 1 SCHEME 1 (CONTINUED) Scheme 1 refers to the preparation of compounds of formula I. With reference to scheme 1, the compound of formula I is prepared from the carboxylic acid of formula II by treatment with 1- (3-dimethylaminopropyl) - 3-ethylcarbodimamide and 1-hydroxybenzotriazole in a polar solvent, such as N, N-dimethylformamide, followed by the addition of hydroxylamine to the reaction mixture after a period of time from about 15 minutes to about 1 hour, preferably about 30 minutes. Hydroxylamine is preferably generated in situ from a salt form, such as hydroxylamine hydrochloride in the presence of a base such as triethylamine. Alternatively, the compound of formula I can be prepared from a compound of formula II by reaction with a protected derivative of hydroxylamine or its salt form, where the hydroxyl group is protected as tert-butyl, benzyl, allyl or ether 2- trimethylsilylethyl. The removal of the hydroxyl protecting group is carried out by hydrogenolysis for a benzyl protecting group (the preferred catalyst is 5% palladium on barium sulfate) or treatment with a strong acid such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group can be removed by treatment with tributyltin hydride and acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride. The 2-trimethylsilylethyl ether can be removed by reaction with a strong acid such as trifluoroacetic acid or by reaction with a fluoride source such as boron trifluoride etherate. The reaction of II with hydroxylamine, a hydroxylamine salt, a protected derivative of hydroxylamine or a salt of a protected derivative of hydroxylamine can also be carried out in the presence of (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and a base such as triethylamine in an inert solvent such as methylene chloride. The reaction mixture is stirred at a temperature from about 0 ° C to about 50 ° C, preferably at room temperature, for a period of time from about 1 hour to about 3 days, preferably about 1 day. Another method for converting a compound of formula II to a compound of formula I is to react the compound of formula II with O-benzylhydroxylamine hydrochloride in the presence of (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and triethylamine using methylene chloride as solvent. The subsequent removal of the O-benzyl protecting group to provide a compound of formula I is then carried out by hydrogenolysis under a pressure of 3.04x10 5 Pa at room temperature using 5% palladium on barium sulfate as a catalyst. The preferred solvent is methanol. The reaction time may vary from about 1 hour to about 2 days (8 hours are preferred). The preferred method for converting a compound of formula II into a compound of formula I is to react the compound of formula II with oxalyl chloride in methylene chloride in the presence of a catalytic amount of DMF for 16 hours. The resulting acid chloride is reacted at 0 ° C with N, O-bis trimethylsilyl hydroxylamine formed by reaction of hydroxylamine hydrochloride with chlorotrimethylsilane in pyridine from 0 ° C to room temperature. The product of formula I is obtained after reactions of a few hours from 0 ° C to room temperature, followed by an acidic aqueous treatment that removes all the trimethylsilyl residues. In certain cases, it is preferred to obtain the compound of formula I by reaction of hydroxylamine, a hydroxylamine salt, a protected derivative of hydroxylamine or a salt of a protected derivative of hydroxylamine with an activated ester of formula III. The reaction is carried out in an inert solvent, such as N, N-dimethylformamide at a temperature ranging from about room temperature to about 80 ° C, preferably about 60 ° C, for a period of time from about 1 hour to about 2 days. If a protected derivative of hydroxylamine or a salt of a protected derivative of hydroxylamine is used, removal of the protecting group is carried out as described above. The activated ester derivative of formula III is obtained by treatment of the compound of formula II with (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and a base such as triethylamine in an inert solvent, such as methylene chloride. The reaction mixture is stirred at a temperature from about 0 ° C to about 50 ° C, preferably at room temperature, for a period of time from about 1 hour to about 3 days, preferably about 1 day. The intermediate compound of formula II is prepared by saponification of a compound of formula IV. The reaction is carried out in a solvent such as aqueous ethanol, with an excess of metal hydroxides, such as sodium hydroxide or lithium hydroxide, at a temperature from about 20 ° C to about 100 ° C (i.e., from room temperature to room temperature). reflux temperature of the solvent), preferably about 80 ° C. The reaction mixture is usually stirred at room temperature for a period of time from about 30 minutes to about 1 week, preferably about 16 hours. The compound of formula IV is prepared by reacting a compound of formula V with a reactive functional derivative of a sulfonic acid (QSO2OH), such as sulfonyl chloride (QS02CI), in the presence of a base. Suitable bases include sodium hydroxide, triethylamine or diisopropylethylamine, preferably triethylamine. Suitable solvents include dimethylformamide (DMF), methylene chloride, tetrahydrofuran, dioxane, water or acetonitrile, preferably DMF. The reaction mixture is stirred at a temperature from about 0 ° C to about 50 ° C, preferably from about 20 ° C to about 25 ° C (i.e., room temperature), for a period of time from about 10 minutes to about 2 days, preferably about 1 day. The compound of formula V is prepared by hydrolysis of a compound of formula IV. Especially, the compound of formula VI is treated with aqueous acid, preferably in the presence of an immiscible organic solvent such as ethyl ether, diisopropyl ether or methylene chloride. Suitable acids include hydrochloric and sulfuric acid. The reaction mixture is stirred at a temperature from about 0 ° C to about 50 ° C, preferably from about 20 ° to about 25 ° C (i.e., room temperature), for a period of time from about 10 minutes to about 2 days, preferably approximately 1 day. The compound of formula VI is prepared by reacting the amino acid derivative of formula VII with a compound of formula VIII in the presence of a base and a solvent, wherein X is Cl, Br. I, tosylate or mesylate. Suitable bases include ethylene glycol, sodium hydride, lithium diisopropylamide or sodium hexamethyldisilazide. Suitable solvents include dimethyl ether, dimethylformamide. The reaction mixture is stirred at a temperature from about -20 ° C to about 25 ° C, preferably from about 0 ° C to about 20 ° C (i.e., room temperature), for a time from about 10 minutes to about 2 days, preferably about 1 day. The compounds of formulas VII and VIII can be prepared by methods well known to those skilled in the art. Examples of such compounds include methylglycine benzophenone imine and ethylglycine benzophenone mine. The pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, ie, cationic salts such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as salts of ammonium, trimethylammonium, diethylammonium and tri (hydroxymethyl) methylammonium. Likewise, salts by the addition of acids such as, for example, mineral acids, organic carboxylic acids and organic sulphonic acids are also possible, for example hydrochloric acid, methanesulfonic acid, maleic acid, provided that a basic group with pyridyl forms part of the structure. The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter referred to as compounds of the present invention) to inhibit mammalian matrix or reprolysin metalloproteinases and, therefore, demonstrate their efficacy in treating diseases characterized by inhibition of the matrix metalloproteinases or the production of tumor necrosis factor, is shown by the following in vitro assays.

Biological test Inhibition of human collagenase (MMP-1) Recombinant human collagenase is activated with trypsin. The amount of trypsin is optimized for each batch of collagenase-1, although a typical reaction uses the following ratio: 5 μg of trypsin per 100 μg of collagenase. Trypsin and collagenase are incubated at room temperature for 10 minutes and then a five-fold excess (50 mg / 10 mg trypsin) of soybean trypsin inhibitor is added. 10 mM stock solutions of dimethyl sulfoxide inhibitors are prepared and then diluted using the following scheme: 10 mM 120 μM 12 μM 1.2 0.12 μM. Then, in triplicate, twenty-five microliters of each concentration are added to appropriate wells of a Microfluor plate. 96 wells The final inhibitor concentration will be a 1: 4 dilution after the addition of enzyme and substrate. Positive controls are prepared (with enzyme and without inhibitor) in wells D7-D12 and negative controls (without enzyme and without inhibitor) in wells D1-D6. Collagenase is diluted to 400 ng / ml and 25 ml is then added to appropriate wells of the Microfluor plate. The final concentration of collagenase in the assay is 60 ng / ml. Substrate prepared (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) as a 5 mM stock solution in dimethyl sulfoxide and then diluted to 20 μM in assay buffer. The assay is initiated by the addition of 50 ml of substrate per well of the Microfluor plate to give a final concentration of 10 mM. Fluorescence readings were taken (360 nm of excitation and 460 nm emission) at time 0 and then at 20 minute intervals. The test is carried out at room temperature with a typical test time of 3 hours.

A graph of the fluorescence as a function of time is then constructed, both for the samples containing collagenase and for those of the blank test (in the determinations in triplicate, the average value is determined). To determine the values of the IC50, a time is chosen that provides a good signal (at least five times the target) and that is in the linear part of the curve (normally around 120 minutes). The values corresponding to time zero are used as a target for each compound at each concentration and these values are subtracted from the data corresponding to 120 minutes. The data is plotted as concentration of inhibitor against percent control (fluorescence of the inhibitor divided by fluorescence of collagenase alone and multiplied by 100). The I o are determined from the concentration of inhibitor that gives a signal that is 50% of that of the control. If the I o's are lower than 0.03 mM, then the inhibitors are tested at concentrations of 0.3 mM, 0.03 mM and 0.003 mM.

Inhibition of gelatinase (MMP-2) 72 kD recombinant human gelatinase (MMP-2, gelatinase A) is activated with 1 mM p-aminophenylmercuric acetate for 16-18 hours (from a freshly prepared 100 mM stock solution in 0.2 NaOH) N) at 4 ° C, are gentle oscillations. Serum solutions are diluted in 10 mM dimethyl sulfoxide stock in inhibitors in assay buffer (50 mM TRIS, pH 7.5, 200 mM NaCl, 5 mM CaCl2, 20 μM ZnCl2 and 0.02% BRIJ-35 (vol / vol)) using the following scheme: 10 mM 120 μM 12 μM 1.2 0.12 μM Subsequent dilutions are carried out as necessary following this same scheme. In each test, a minimum of four inhibitory concentrations are made for each compound. 25 μl of each concentration is then added to wells in triplicate of a 96-well black U-bottom Microfluor plate. When the final assay volume is 100 μl, the final inhibitor concentrations are the result of another 1: 4 dilution (ie, 30 μM 3 μM 0.3 μM 0.03 μM, and so on). A blank assay (without enzyme, without inhibitor) and a positive enzyme control (with enzyme, without inhibitor) is also prepared in triplicate. The activated enzyme is diluted to 100 ng / ml in assay buffer, 25 μl per well are added to the appropriate wells of the microtiter plate. The final enzyme concentration in the assay is 25 ng / ml (0.34 nM). A 5 mM dimethyl sulfoxide stock solution (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2) is diluted in the assay buffer to 20 μM. The assay is initiated by the addition of 50 μl of diluted substrate, giving a final assay concentration of 10 μM substrate. At time zero, a fluorescence reading is taken (320 of excitation; 390 of emission) immediately and subsequent readings are taken every fifteen minutes at room temperature with a plate reader PersSeptive Biosystems Cytofluor Multi-Well Píate Reader with gain to 90 units. The average fluorescence value of the enzyme and the blank assay are plotted against time. For the determinations of the I or one of the first times of the linear part of this curve is chosen. The time zero for each compound in each dilution is subtracted from the previous time and the data are then expressed as percent control of the enzyme (fluorescence of the inhibitor divided by fluorescence of the positive enzyme control x 100). The data are represented as concentration of inhibitor versus percent control of the enzyme. IC5o's are defined as the concentration of inhibitor that gives rise to a signal that is 50% of the positive enzyme control.

Inhibition of stromelysin activity (MMP-3) Recombinant human stromelysin (MMP-3, stromelysin-1) is activated for 20-22 hours with 2 nM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock solution in NaOH 0.2N) at 37 ° C. Stock solutions in 10 mM dimethylsulfoxide inhibitors are serially diluted in assay buffer (50 mM TRIS, pH 7.5, 150 mM NaCl, 10 mM CaCl2 and 0.05% BRIJ-35 (vol / vol)) using the following scheme: 10 mM? 120 μM? 12 μM? 1.2 μM? 0.12 μM Subsequent dilutions are carried out as necessary following this same scheme. In each test, a minimum of four inhibitory concentrations are made for each compound. 25 μl of each concentration is then added to wells in triplicate of a 96-well black U-bottom Microfluor plate. Since the final assay volume is 100 μl, the final inhibitor concentrations are the result of another 1: 4 dilution (ie 30 μM - 3 μM - 0.3 μM -> 0.03 μM, and so on). A blank assay (without enzyme, without inhibitor) and a positive enzyme control (with enzyme, without inhibitor) is also prepared in triplicate. The activated enzyme is diluted to 200 ng / ml in assay buffer, 25 μl per well is added to the appropriate wells of the microtiter plate. The final enzyme concentration in the assay is 50 ng / ml (0.875 nM). A 10 mM dimethyl sulfoxide stock solution (Mca-Arg-Pro-Lys-Val-Glu-Nva-Trp-Arg-Lys (Dnp) -NH2) is diluted in the assay buffer to 6 μM. The assay is initiated by the addition of 50 μl of diluted substrate giving a final concentration of 3 μM substrate assay. At time zero, a fluorescence reading is taken (320 of excitation, 390 of emission) immediately and subsequent readings are taken every fifteen minutes at room temperature with a PerSeptive Biosystems CytoFluor Multi-Well Reader Reader plate with gain at 90 units.

The average fluorescence value of the enzyme and the blank assay are plotted against time. For the determinations of the IC 0 one of the first times of the linear part of this curve is chosen. The time zero for each compound in each dilution is subtracted from the previous time and the data are then expressed as percent control of the enzyme (fluorescence of the inhibitor divided by fluorescence of the positive enzyme control x 100). The data are represented as concentration of inhibitor versus percent control of the enzyme. The I o's are defined as the concentration of inhibitor that gives rise to a signal that is 50% of the positive enzyme control.

Inhibition of MMP-13 Recombinant human MMP-13 is activated with 2 mM APMA (p-aminophenylmercuric acetate) for 2.0 hours at 37 ° C and diluted to 240 mg / ml in assay buffer (50 mM Tris, pH 7.5, chloride 200 mM sodium, 5 mM calcium chloride, 20 μM zinc chloride and 0.02% Brij-35). In a 96-well Microfluor plate are added twenty-five microliters of diluted enzyme per well. The enzyme is then diluted at a 1: 4 ratio in the assay by addition of inhibitor and substrate to give a final concentration in the 60 mg / ml assay. Stock solutions (10 mM) of inhibitors in dimethyl sulfoxide are prepared and then diluted in assay buffer according to the dilution scheme of inhibitors of the human collagenase inhibition assay (MMP-1). In the Microfluor plate, twenty-five microliters of each concentration are added in triplicate. The final concentrations in the assay are 30 mM, 3 mM, 0.3 mM and 0.03 mM. Substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) is prepared as in the human collagenase inhibition assay (MMP-1) and 50 μl is added to each well. to give a final concentration in the 10 μM assay. Fluorescence readings are made (360 nm under excitation and 450 nm under emission) at time 0 and at 5 minute intervals for 1 hour. The positive and negative controls are prepared in triplicate as described in the MMP-1 assay. I o are determined as in the human collagenase inhibition assay (MMP-1). If the IC50's are lower than 0.03 mM, then the inhibitors are tested at final concentrations of 0.3 mM, 0.03 mM, 0.003 mM and 0.0003 mM.

Inhibition of TNF production The ability of the compounds or pharmaceutically acceptable salts thereof to inhibit TNF production and, consequently, to demonstrate their efficacy in treating diseases involving the production of TNF is shown by the following assay. in vitro: Mononuclear leukocytes were isolated from anticoagulated human blood, using a one-step Ficoll-hypaque separation technique. (2) The mononuclear leukocytes were washed three times in Hanks Balanced Salt Solution (HBSS) with divalent cations and resuspended at a density of 2 x 106 / ml in HBSS containing 1% BSA. The differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that, in these preparations, the monocytes varied from 17 to 24% of the total cells. Aliquots of 180 μl of the cell suspension were placed in 96-well flat-bottomed plates (Costar). Additions of compounds and LPS (final concentration of 100 ng / ml) gave a final volume of 200 μl. All conditions were performed in triplicate. After incubation for four hours at 37 ° C in a humidified CO2 incubator, the plates were separated and centrifuged (10 minutes at approximately 250xg), the supernatant liquids were separated and TFA-a was assayed in them using the R & amp;; D ELISA.

Inhibition of the production of soluble TNF-α The ability of the compounds or pharmaceutically acceptable salts thereof to inhibit the cellular release of TNF-α and, consequently, to demonstrate its efficacy in treating diseases involving abnormal regulation of TNF -a soluble is shown by the following in vitro assay: Procedure for evaluating the activity of the recombinant TNF-a converting enzyme Expression of recombinant TACE: A DNA fragment encoding the signal sequence, preprodomain, prodomain and catalytic domain of TACE (amino acids 1-473) can be amplified by polymerase chain reaction using a human lung cDNA library as a template. The amplified fragment is then cloned into the pFastBac vector. The DNA sequence of the insert is confirmed for both chains. A bacmid prepared using pFastBac in DHIOBac from E. coli is transfected into SF9 insect cells. The viral particles are then amplified to stages P1, P2, P3. The P3 virus is infected in Sf9 and High Five insect cells and develops for 48 hours at 27 ° C. The medium is collected and used for further tests and purification.

Preparation of the fluorescent inactivated substrate: A substrate is prepared for model peptide TNF-α (LY-LeucinalAlanineGlutamineAlanineValineArginine SerineSerinaLysine (CTMR) -Arginine (LY = Yellow Lucifer; CTMR = Carboxitetramethyl Rodamine)) and the concentration determined by absorbance at 560 nm (E56o , 60,000 M-1 CM-1) according to the procedure of Geoghegan, KF, "Improved Method for converting an unmodified peptide to an energy-transfer substrate for a proteinase". Bioconjuqate Chem. 7, 385-391 (1995). This peptide includes the cleavage site in pro-TNF where it is cleaved in vivo by TACE.

Expression of recombinant TACE A DNA fragment encoding the signal sequence, preprodomain, prodomain and the catalytic domain of TACE (amino acids 1-473) is amplified by polymerase chain reaction using human lung cDNA library as a template. The amplified fragment is then cloned into the pFastBac vector. The DNA sequence of the insect is confirmed for both chains. A bacmid prepared using pFastBac from E. coli is transfected into SF9 insect cells. The viral particles are then amplified to stages P1, P2, P3. The P3 virus is infected in Sf9 and High Five insect cells and develops for 48 hours at 27 ° C. The medium is collected and used for further tests and purification.

Enzymatic reaction The reaction, carried out in a 96-well plate (Dynatech), comprises 70 μl of buffer solution (Hepes 25 mM-HCl, pH 7.5, plus 20 mM ZnCl 2), 10 μl of 100 μM fluorescent inactivated substrate, 10 μl of solution in DMSO (5%) of test compound and an amount of r-TACE enzyme that will produce a 50% cleavage. in 60 minutes - in a total volume of 100 μl. The specificity of the enzymatic cleavage in the amide bond between alanine and valine is verified by HPLC and mass spectrometry. Initial cleavage rates are controlled by measuring the rate of increase in fluorescence at 530 nm (excitation at 409 nm) for 30 minutes. The experiment is controlled as follows: 1) background fluorescence of the substrate; 2) the fluorescence of the fully cleaved substrate; 3) the extinction or increase of fluorescence from the solutions containing test compounds. The data is analyzed as follows. The rates of "control" reactions without test compound are averaged to determine the 100% value. The reaction rate in the presence of test compound was compared to it in the absence of compound and tabulated as "control percentage without test compound". The results are represented as "% control" against the logarithm of the compound concentration and a hemimáximo point or I o value is determined. All compounds of the invention have I or less than 1 μM, preferably less than 50 nM. The most preferred compounds of the invention are at least 100 times less potent against r-MMP-1 than in the previous TACE assay.

Assay of human monocytes Mononuclear leukocytes were isolated from anticoagulated human blood, using a one-step Ficoll-hypaque separation technique. (2) Monocellular leukocytes were washed three times in Hanks Balanced Salt Solution (HBSS) with divalent cations and resuspended at a density of 2 x 106 / ml in HBSS containing 1% BSA. The differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that, in these preparations, the monocytes varied from 17 to 24% of the total cells. Aliquots of 180μl of the cell suspension were placed in 96-well flat bottom plates (Costar). Additions of compounds and LPS (final concentration of 100 ng / ml) gave a final volume of 200 μl. All conditions were performed in triplicate. After incubation for four hours at 37 ° C in a humified CO2 incubator, the plates were separated and centrifuged (10 minutes at approximately 250xg), the supernatants were separated and TFA-a was assayed therein using the R & D ELISA.

Aggrecanase Assay Primary porcine chondrocytes of cartilage of the joint were isolated by sequential digestion in trypsin and collagenase, followed by overnight digestion in collagenase and cultured at a density of 2 x 10 5 cells per well in 48-well plates. 5μCi / ml of 35S (1000 Ci / mmoles) in the plates coated with type I collagen. The marker was allowed to be incorporated into the cells in its proteoglycan matrix (approximately 1 week) at 37 ° C, at a 5% CO 2 atmosphere. %.

The night before the start of the assay, the chondrocyte monolayers were washed twice in DMEM / 1% PSF / G and then allowed to incubate in DMEM / fresh 1% FBS overnight. The next morning, the chondrocytes were washed once in DMEM / 1% PSF / G. The final wash liquid was allowed to stand on the plates in the incubator while the dilutions were made. The media and dilutions can be made as described in the following table.

The plates are marked and only the 24 inner wells of the plate are used. In one of the plates, several columns are designated as IL-1 (without drug) and control (without IL-1, without drug). These columns are counted periodically to control the release of 35S-proteoglycan. The control media of IL-1 are added to the wells (450 μl) followed by the compound (50 μl) in order to start the assay. The plates are incubated at 37 ° C with a 5% CO2 atmosphere. At a release of 40-50% (when the CPM of the IL-1 media are 4-5 times the control means) determined by liquid scintillation counting (LSC) of the samples, the test ends (9-12 hours) . The media is removed from all wells and placed in scintillation tubes. Scintillation fluid is added and radioactive counts (LSC) are taken. To solubilize the layers, 500 μl of papain digestion buffer (0.2 M Tris, pH 7.0, 5 mM EDTA, 5 mM DTT and 1 mg / ml papain) are added to each well. The plates with digestion solution are incubated at 60 ° C overnight. The cell layer is removed from the plates the next day and placed in the scintillation tubes. Scintillation liquid is added and the samples are counted (LSC). The percentage of counts emitted from the totals present is determined in each well. The average of the samples is carried out in triplicate, subtracting the background value of the control from each well. The percent inhibition of compound is based on samples in IL-1 as 0% inhibition (100% of total counts).

For administration to mammals, including humans for the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF), a variety of conventional routes of administration can be used including oral, parenteral and topical routes. In general, the active compound can be administered orally or parenterally in doses ranging from about 0.1 to 25 mg / kg body weight of the subject being treated per day, preferably from about 0.3 to 5 mg / kg. However, some dose variation will necessarily occur depending on the disorder of the subject being treated. The responsible of the administration will determine in any case the appropriate dose for the particular subject. The compounds of the present invention can be administered in a wide range of different dosage forms, in general, the therapeutically effective compounds of this invention are present in said dosage forms at concentration levels ranging from about 5.0% to about 70% in weigh. For oral administration, tablets containing different excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used, together with different disintegrants such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, for the purposes of tablet preparation, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are very often useful. Solid compositions of a similar type can also be employed as fillers in gelatin capsules; also including the preferred materials in this respect lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, also emulsifying and / or suspending agents, together with diluents. as water, ethanol, propylene glycol, glycerol and the different combinations thereof. In the case of animals, these are advantageously contained in the drinking water or animal feed at a concentration of 5-5000 ppm, preferably from 25 to 500 ppm. For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use), a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention may be employed in sesame or peanut oil or in aqueous propylene glycol. The aqueous solutions will be adjusted and buffered in a suitable manner, preferably at pH greater than 8, if necessary and the liquid diluent will first be isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is carried out in a simple manner by conventional pharmaceutical techniques well known to those skilled in the art. In the case of animals, the compounds can be administered intramuscularly or subcutaneously at dose levels of approximately 0.1 to 50 mg / kg / day, advantageously 0.2 to 10 mg / kg / day, administered in a single dose or up to in 3 divided doses. For topical ocular administration, direct application to the affected eye may be employed in the form of a formulation of eye drops, aerosol, gels or ointments, or it may be incorporated into collagen (such as poly-2-hydroxyethyl methacrylate and copolymers thereof). ), or in a hydrophilic coverage. The materials can also be applied as a contact lens or through a local reservoir or as a formulation to be subconjunctively administered. For intraorbital administration, a sterile injectable solution of active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention may be employed in aqueous solution or suspension (particle size less than 100 microns). If necessary, the aqueous solutions will be adjusted and buffered appropriately, preferably at a pH of 5 to 8, and the liquid diluent will first be isotonic. To increase the viscosity or achieve a sustained release, small amounts of polymers (such as cellulose, dextran, polyethylene glycol or alginic acid polymers) can be added. These solutions are suitable for intraorbital injection purposes. The preparation of all these solutions under sterile conditions is easily carried out by conventional pharmaceutical techniques well known to those skilled in the art. In the case of animals, the compounds can be administered intraorbitally at dose levels of approximately 0.1 to 50 mg / kg / day, advantageously 0.2 to 10 mg / kg / day, administered in a single dose or up to 3 doses divided. The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing 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 released in the form of a solution or suspension from a pump spray container that is pressed or pumped by the patient or as an aerosol spray presentation from a pressurized container. or a nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dose can be determined by arranging a valve to release a measured quantity. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules or cartridges (made, for example, of gelatin) can be formulated for use in an inhaler or insufflator, containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

The present invention is illustrated by the following preparations and examples, although it is not limited by the details thereof.

EXAMPLE 1 Hydroxamide of 4-r4- (4-fluorophenoxy) benzenesulfonylamino-1-tetrahydropyran-4-carboxylic acid The ethyl ester of 4-N- (diphenylmethylene) aminoltetrahydropyran-4-carboxylic acid was added. A solution of N- (diphenylmethylene) glycine ethyl ester (20.6 grams, 0.07398 moles) was added. in dimethyl ether of ethylene glycol (50 ml), dropwise via an addition funnel, to a suspension of sodium hydride (6.56 g, 0.164 mol) in ethylene glycol dimethyl ester (150 ml) at 0 ° C. To the solution of ethylene glycol dimethyl ether was added a solution of 2-bromoethyl ether (23.21 g, 0.090 mol) in dimethyl ether of ethylene glycol (50 ml) in 10 ml portions for about 5 minutes. The ice bath was removed and the reaction was stirred at room temperature for 16 hours. The mixture was diluted with diethyl ether and washed with water. The aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated giving a cloudy yellow oil (28692 g). Chromatography on silica gel, eluting first with 4 I of 5% ethyl acetate / hexane, followed by 4 liters of 4% ethyl acetate / hexane gave the ethyl ester of 4- [N- (diphenylmethylene) amino] ] tetrahydropyran-4-carboxylic acid as a light yellow oil (16.114 g, 64%). 1 H NMR (CDCl 3) d 7.58 (d, 2 H), 7.36 (m, 4 H), 7.28 (t, 2 H), 7.08 (m, 2 H), 3.99 (m, 2 H), 3.70 (m, 2 H), 3.66 (q, 2H), 2.10 (m, 2H), 1.99 (m, 2H), 1.08 (t, 3H). Chemical ionization mass spectrum at atmospheric pressure: 338 (M ++ 1).

(B) 4-Aminotetrahydropyran-4-carboxylic acid ethyl ester A 1 M aqueous solution (100 ml) of hydrochloric acid was added to a solution of 4- [N- (diphenylmethylene) amino] tetrahydropyran-4-ethyl ester. carboxylic (16.0 g, 0.047 moles) in diethyl ester (120 ml). The mixture was stirred vigorously at room temperature for 16 hours. The layers were separated and the aqueous layer was washed with diethyl ether. The aqueous layer was brought to pH 10 with dilute aqueous ammonium hydroxide solution and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated to give 4-aminotetrahydropyran-4-carboxylic acid ethyl ester (7.128 g, 71.7%) as an oil. 1 H NMR (CDCl 3) 4.15 (q, 2 H), 3.82 (m, 2 H), 3.62 (m, 2 H), 2.07 (m, 2 H), 1.60 (s, 2 H), 1.44 (m, 2 H), 1.24 ( t, 3H) 13 C NMR (CDCl 3) d 176.48, 63.70, 61.09, 54.78, 35.05, 14.15. Mass spectrum of chemical ionization at atmospheric pressure: 210 (M ++ 1).

(C) 4-β4- (4-Fluorophenoxy) -benzenesulfonylamino-tetrahydropyran-4-carboxylic acid diethyl ester (5.94 ml, 0.043 mol) was added to a solution of 4-aminotetrahydropyran-4-carboxylic acid ethyl ester (7.00) g, 0.0404 moles) in N, N-dimethylformamide (40 ml). Solid 4- (4-fluorophen-xi) benzenesulfonyl chloride (12165 g, 0.0424 mol) was added portionwise. The resulting mixture was stirred at room temperature for 26 hours and then most of the solvent was removed by vacuum evaporation. The residue was partitioned between saturated sodium bicarbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded the crude ethyl 4- [4- (4-fluorophenoxy) benzenesulfonylammonyl] tetrahydro-4-carboxylic acid ester as an amber oil (21.05 g). Flash chromatography on silica gel eluting with 25% ethyl acetate / hexane, followed by 50% ethyl acetate / hexane gave the ethyl ester of 4- [4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran-4-ethyl ester. carboxylic acid as an off-white solid (12.15 g, 71%, mp 116-117 ° C). 1 H NMR (CDCl 3) d 7.79 (d, 2 H), 7.09 (t, 2 H), 7.02 (m, 2 H), 6.97 (d, 2 H), 5.10 (s, 1 H), 4.01 (q, 2 H), 3.60 (m, 4H), 2.08 (m, 2H), 1.84 (broad d, 2H), 1.23 (t, 3H). Mass spectrum of chemical ionization at atmospheric pressure: 424 (M ++ 1).

IOLs 4-í4- (4-fluorophenoxy) bencenosulfonilamino1tetrahidropiran-4-carboxylic acid Procedure To a solution of ethyl 4- [4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid (12.1 g, 0.0286 mol was treated ) in tetrahydrofuran (190 ml) with 3M aqueous sodium hydroxide solution (95 ml, 0.286 moles) and stirred at room temperature for 4 days.

The solvent was evaporated in vacuo and the residue was partitioned between water and ethyl ether. The aqueous layer. The aqueous layer was washed with diethyl ether, acidified to pH 1 with 3M aqueous solution of hydrochloric acid and extracted with dichloromethane. After washing with water, the organic extract was dried over sodium sulfate, and concentrated to give 4- [4- (4-fIuorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid (1211 g, 99%) as a solid yellowish foam.

Procedure B A solution of ethyl 4- [4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran was treated 4-carboxylic acid (34.19 g, 0.807 mol) in ethanol (330 ml) with 3M aqueous sodium hydroxide solution (330 ml, 0.990 moles) and heated to reflux overnight. The solvent was evaporated in vacuo and the residue was partitioned between water and diethyl ether. The aqueous layer was washed with diethyl ether, acidified to pH 1 with 3M aqueous solution of hydrochloric acid and extracted with ethyl acetate. After washing with water, the organic extract was dried over sodium sulfate and concentrated to give 4- [4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid (31.26 g, 98%) as a white crystalline solid. 1 H NMR (CDCl 3) d 7.73 (d, 2 H), 7.03 (t, 2 H), 6.96 (m, 2 H), 6.91 (d, 2 H), 3.56 (m, 2 H), 3.43 (broad m, 3 H), 2.01 (m, 2H), 1.80 (broad d, 2H). Chemical ionization mass spectrum at atmospheric pressure: 394 (M + -1) (¡on -).

(E) benzyloxyamide N- 4- [4- (4-fluorofenoxQbencenosulfonilaminoltetrahidropiran-4-carboxylic acid were added sequentially diisopropylethylamine (3.89 g, 0.030 mol) and hexafluorophosphate (benzotriazol- 1-iIoxi) tris (dimethylamino ) phosphonium hexafluorophosphate (13.27 g, 0.030 mol) to a solution of 4- [4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid (11.22 g, 0.028 mol) in N, N-dimethylformamide (140 ml). The resulting solution was stirred at room temperature for 16 hours, then additional diisopropyl ethylamine (4.0 ml, 0.051 mole) and O-benzyl hydroxylamine hydrochloride (5.46 g, 0.034 mole) were added and the resulting mixture was stirred at 60 ° C. After concentrating in vacuo, the residue was treated with 0.5N aqueous hydrochloric acid solution and extracted with ethyl acetate.The organic extract was washed with saturated aqueous sodium bicarbonate solution, water and brine. dried over corn sulfate gnesium, filtered and concentrated to a quarter of the original volume. The addition of an equal volume of hexane precipitated 4- [4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid N-benzyloxyamide (1595 g, 81.6%) as a white crystalline solid (mp 175-176). ° C). 1 H NMR (CDCl 3) d 7.76 (d, 2 H), 7.35 (m, 5 H), 7.05 (t, 2 H), 6.96 (m, 4 H), 5.38 (broad s, 1 H), 4.86 (s, 2 H) , 3.57 (m, 2H), 3.44 (m, 2H), 2.01 (m, 2H), 1.77 (d, broad, 2H), 1.54 (broad s, 1 H). Chemical ionization mass spectrum at atmospheric pressure: 501 (M ++ 1).

Hydroxamide of 4- [4- (4-fluorophenoxy) benzenesulfonylamino-tetrahydropyran-4-carboxylic acid Procedure A A solution of 4- [4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid N-benzyloxyamide (1.28 g, 0.0225 moles) in ethyl acetate (600 ml) was treated with 5% palladium on barium sulfate (5.0 g) and subjected to hydrogenation on a Parr ™ stirrer at 3.04x105 Pa pressure for 18 hours. After filtration through Nylon (0.45 mm pore size) to separate the catalyst, the filter bed was rinsed with methanol. The combined filtrate and rinse water were evaporated and the residue was suspended in hot methanol. Cooling gave the crude hydroxyamide of crude 4- [4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid (5.941 g, 64%, p.f. 176-177 ° C) as a white crystalline solid. The mother liquor was evaporated and the residue recrystallized from 50% methanol / dichloromethane to give additional 4- [4- (4-fluorophenoxy) -benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxamide (0.660 g, mp 184-185 ° C) like white needles. The mother liquors were again evaporated and the residue was recrystallized from methanol / dichloromethane to give additional product (1861 g, m.p. 176-177 ° C). Recrystallization of the first batch in methanol / dichloromethane afforded analytically pure 4- (4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxamide (3.091 g, mp 184-185 ° C).

Procedure B Oxalyl chloride (11.83 g, 0.0932 moles, 1.1 equivalents) and DMF (0.13 ml) were added to a stirred suspension of carboxylic acid (33.25 g, 0.0841 moles) in dry methylene chloride (300 ml) at room temperature. Some bubbling was observed. The suspension, which slowly turned into a yellowish solution, was stirred overnight at room temperature. Meanwhile, a solution of hydroxylamine hydrochloride (7.65 g, 0.110 mol, 1.3 eq) in dry pyridine (51.4 ml, 0.635 mol, 7.5 eq) was treated at 0 ° C with chlorotrimethylsilane, causing the formation of a white precipitate. This suspension was stirred at room temperature overnight. Both flasks were then cooled to 0 ° C and the acid chloride solution was added to the silylated hydroxylamine suspension. The resulting mixture was stirred at 0 ° C for 1 hour and at room temperature for 2 hours. 1000 ml of 2N aqueous HCl was added and stirred at room temperature for 1 hour. The layers were separated, the aqueous layer was extracted three times with ethyl acetate (500 ml). The combined organic layers were washed with water and brine and dried over magnesium sulfate, filtered and the volume of the filtrate was reduced to 300 ml, at which time a large amount of crystalline white solid had precipitated. This was cooled overnight in a refrigerator. The solid was collected by vacuum filtration, rinsed with cold 1: 1 ethyl acetate / hexane and dried under high vacuum to provide 30.311 g of the desired hydroxamic acid (87.8%) as a white crystalline solid (mp 189-190 ° C). ). 1 H NMR (DMSO-d6) d 10.35 (broad s, 1 H), 8.68 (broad s, 1 H), 7.78 (s, 1 H wide), 7.74 (d, 2H), 7.26 (t, 2H), 7.16 (m, 2H), 7.04 (d, 2H), 3.40 (m, 2H), 3.31 (m, 2H), 1.78 (m, 4H). 13 C NMR (DMSO) d 169.65, 160.66, 137.50, 129.39, 122.34, 122.25, 117.75, 1 17.44, 117.24, 62.94, 58.45, 33.34. Mass spectrum of chemical ionization at atmospheric pressure: 409 (M + -1) (ion -).

PREPARATION A 4- (4-fluorophenoxy) benzenesulfonyl chloride To a 4-fluoro-phenoxybenzene (36.9 g, 0.196 mol) cooled in ice with mechanical stirring, chlorosulfonic acid (26 ml, 0.392 mol) was added dropwise. When the addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4- (4-fluorophenoxy) benzenesulfonyl chloride (18.6 g, 33%) was collected by filtration and air dried.

PREPARATION B 4- (3-Methylbutoxy) sodium benzenesulfonate A solution of 4-hydroxybenzenesulfonic acid- (10.0 g, 43.1 mmol) and sodium hydroxide (3.3 g, 83 mmol) in water (40 ml) was mixed with a solution of 1-iodo-3-methylbutane (1.3 ml 1.3, 86.4). mmoles) in isopropanol (60 ml) and the resulting mixture was heated to reflux for 2 days. The isopropanol was removed by evaporation in vacuo. The title compound, 10.0 grams (87%) was collected by filtration and washed with isopropanol.

PREPARATION C 4- (3-rnet-l-butoxy) -benzenesulfonyl chloride A mixture of sodium 4- (3-methylbutoxy) benzenesulfonate (2.5 g, 9.4 mmol), thionyl chloride (10 ml) and 5 drops of N, N-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was suspended in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated to give the title compound as an oil, 2.34 g (95%).

PREPARATION D 4- (2-Cyclopentylethoxy) sodium benzenesulfonate They were mixed with a solution of 2- (bromoethyl) cyclopentane (15.0 g, 84.7 mmol) in isopropanol (40 ml) a solution of 4-hydroxybenzenesulfonic acid 86.5 g, 28.2 mmol) and sodium hydroxide (2.2 g, 55 mmol) in water (15 ml) and the resulting mixture was heated to reflux for 2 days. The isopropanol was removed by evaporation in vacuo. The title compound, 4.7 g, (57%) was collected by filtration and washed with isopropanol.

PREPARATION E 4- (3-Methylbutoxy) benzenesulfonyl chloride A mixture of sodium 4- (2-cyclopentylethoxy) benzene sulfonate (2.5 g, 8.6 mmol), thionyl chloride (15 ml) and a few drops of N, N-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was suspended in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated giving the title compound as an oil, 2.24 g, (90%).

PREPARATION F 4-Fluorobiphenylsulfonyl chloride 4-Fluorobiphenyl (10.2 g, 59 mmol) was added dropwise, while stirring in an ice bath, chlorosulfonic acid (8.7 g, 0.13 mmol). Stirring was continued with cooling on ice for 0.5 hour and then the reaction mixture was poured onto ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water and brine, dried over magnesium sulfate and concentrated to give a white solid. The desired product, 4-fluorobiphenylsulfonyl chloride (4.3 g, 27%) was separated from 4-fluorobiphenylsulfonic acid (an undesired by-product) by crystallization of the former from ethyl acetate and crystallization of the resulting material from hexane.

PREPARATION G 4- (4-Fl? Orobenzyloxy) sodium benzenesulfonate A solution of 4-fluorobenzyl bromide (3.3 g, 26.5 mmol) in ethanol (20 ml) was added to a solution of 4-hydroxybenzenesulfonic acid (5.13 g, 22.1 mmol) in 1 N aqueous sodium hydroxide solution (23 ml). . The resulting mixture was heated to reflux for 2 days. After cooling at rest, a white solid precipitated. The precipitated product, sodium 4- (4-fluorobenzyloxy) benzenesulfonate, 4.95 g, (74%) was collected by filtration and washed with ethyl acetate and diethyl ether.

PREPARATION H Chloride of 4- (4-fluorobenzyloxy) benzenesulfonyl Phosphorus pentachloride (275 mg, 1.31 mmol) was added to a suspension of sodium 4- (4-fluorobenzyloxy) benzenesulfonate (0.5 g, 1.64 mmol) in methylene chloride (5 ml). The resulting mixture was heated to reflux for 7 hours. After cooling in an ice bath and quenching the reaction with water (15 ml), the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give 4- (4-fluorobenzyloxy) benzenesulfonyl chloride as a white solid (130 mg, 26%).

PREPARATION I Chloride of 4- (4-chlorophenoxy) benzenesulfonyl Chlorosulfonic acid (9.7 ml, 0.147 mol) was added dropwise to 4-chlorophenoxybenzene (12.6 ml, 73.4 mmol) at room temperature and with stirring. When the addition was complete, the mixture was stirred at room temperature for 1 hour and then poured into ice water. The solid was collected by filtration, air dried and recrystallized from petroleum ether and ethyl acetate to provide 4- (4-chlorophenoxy) benzenesulfonyl chloride (7.43 g, 33%). Having described the invention as above, the contents of the following are declared as property:

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula or their pharmaceutically acceptable salts, wherein Q is alkyl dd, arylCio, heteroaryl C2-C9, (aryloxy C6-C? 0) (alkyl dd), (aryloxy C6-C? 0) (aryl d-Cio) , (C6-C6 aryloxy) (C2-C9 heteroaryl), (C6-C6 aryl) (C6-C6 alkyl), (aryl d-Cio) (C6-C6 aryl), (C6 aryl) -C? 0) (C2-C9 heteroaryl), (C6-C? 0 aryl) (C6-C? 0 aryl) (C-C6 alkyl), (C6-C? 0 aryl) (C6-C6 aryl) ) (aryl C6-C? 0), (aryl C6-C? 0) (aryl C6-C? 0) (heteroaryl dd), (heteroaryl C2-C9) (C? -C6 alkyl), (heteroaryl C2-C9) ) (aryl d-Cio), (C2-C9 heteroaryl) (C2-C9 heteroaryl), (C6-C6 aryl) (C6-C6 alkoxy) (C6-alkyl), (C6-C6 aryl) ) (C6-C6 alkoxy) (C6-C6o aryl), (C6-C6 aryl) (Ci-d alkoxy) (C2-C9 heteroaryl), (C2-C9 heteroaryloxy) (C6-C6 alkyl), ( C2-C8 heteroaryloxy) (aryl d-Cio), (C2-C9 heteroaryloxy) (C-C9 heteroaryl), (C2-C9 heteroaryl) (C6-C6 alkoxy) (C6 alkyl), (C2-C9 heteroaryl) (C 1 -C 6 alkoxy) (C 6 -C 0 aryl) or (C 2 -C 9 heteroaryl) (C 6 -C alkoxy) (C 2 -C 9 heteroaryl); wherein each of said aryl C6-C? 0 or C2-C9 heteroaryl of said aryl -Cio, C2-C9 heteroaryl, (aryloxy -Cio) (C?-C6 alkyl), (aryloxy d-Cι) (C6 aryl) -C? 0), (aryloxy -Cio) (C2-C9 heteroaryl), (C6-C? 0 aryl) (C? -C6 alkyl), (C6-C? O aryl) (C6-C? Aryl) , (aryl C6-C? 0) (C2-C9 heteroaryl), (C6-C? 0 aryl) (C6-C? 0 aryl) (C? -C6 alkyl), (C6-C? 0 aryl) (aryl) C6-C? 0) (aryl C6-C? 0), (aryl C6-C? 0) (aryl C6-C? 0) (heteroaryl C2-C9), (heteroaryl C2-C9) (C? -C6 alkyl) ), (C2-C9 heteroaryl) (C6-C6o aryl), (C2-C9 heteroaryl) (C2-C9 heteroaryl), (C6-C6 aryl) (C6-C6 alkoxy) (C6-C6 alkyl) ), (aryl C6-C? 0) (C? -C6 alkoxy) (C6-C? aryl), (C6-C? 0 aryl) (C? -C6 alkoxy) (C2-C9 heteroaryl), (heteroaryloxy) C2-C9) (Ci-) alkyl, (C2-C9 heteroaryloxy) (C6-C? O aryl), (C2-C9 heteroaryloxy) (C2-C9 heteroaryl), (C2-C9 heteroaryl) (C6-C6 alkoxy) (alkyl C? -C6), (C2-C9 heteroaryl) (C? -C6 alkoxy) (C6-C? O aryl) or (C2-Cg heteroaryl) (C6-C6 alkoxy) (C2-C9 heteroaryl) is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or more substituents per ring, independently selected from fluoro, chloro, bromo, C1-d alkyl, C6-C6 alkoxy, perfluoro (C1-6alkyl) C3), perfluoro (C1-C3 alkoxy) and aryloxy d-C10; or one of its pharmaceutically acceptable salts.

2. A compound according to claim 1, wherein Q is aryl C6-C? 0, (aryl C6-C? 0) (aryl C6-C? 0), (aryloxy C6-C? 0) ( C6-C6 aryl), (C2-Cg aryloxy) (C2-Cg heteroaryl), C2-C9 heteroaryl, (C2-C9 heteroaryl) (C2-C9 heteroaryl), (C6-C6 aryl) (C2 heteroaryl -Cg), (C2-Cg heteroaryl) (C6 C10 aryl), (C2-C9 heteroaryloxy) (C6-C? 0 aryl), (C6-C? 0 aryl) (C? -C6 alkoxy) (C6-aryl) C10) or (C2-C8 heteroaryl) (C6-C6 alkoxy) (C6-C6 aryl) optionally substituted.

3. A compound according to claim 1, wherein Q is (C6-C0 aryloxy) (optionally substituted C6-C? 0 aryl).

4. - A compound according to claim 3, wherein the (C6-C6o) aryloxy ring of said group (aryloxy -C o) (C6-C6 o aryl) is optionally mono-substituted at the 4-position From the ring.

5. A compound according to claim 1, said compound being selected from the group consisting of: 4- [4- (4-fluorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide; Hydroxyamide of 4- [4- (4-chlorophenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide; Hydroxyamide of 4- [4- (phenoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid; Hydroxyamide of 4- [4- (4-pyridyloxy) benzenesulfonyl-lane] tetrahydropyran-4-carboxylic acid hydroxyamide; 4- [4- (4-Fluorophenyl) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide; 4- [4- (4-Fluorophenylmethoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide; Hydroxyamide of (phenylmethoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid; and 4- [4- (4-Fluorophenylethoxy) benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide.

6. A pharmaceutical composition for the treatment of a disorder selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis emapollosa, osteoporosis, lack of firmness in implants of artificial joints, atherosclerosis (including rupture of atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and cerebaortic aneurysm), congestive heart failure, myocardial infarction, cerebrovascular accident, cerebischemia , cranial trauma, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheneuropathy, pain, cerebamyloid angiopathy, nootropic or cognitive enhancement, escle amyotrophic laterosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal healing of wounds, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal burns, scleritis, AIDS, septicemia and septic shock in a mammal, including a human, comprising an amount of a compound of claim 1, effective in said treatment and a pharmaceutically acceptable carrier.

7. The use of a compound as claimed in claim 1, for the manufacture of a medicament for treating a disorder selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease , emphysema, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, lack of firmness in artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and cerebaortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebischaemia, head injury, spinal cord injury , neurodegenerative disorders ivos (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheneuropathy, pain, cerebamyloid angiopathy, nootropic or cognitive enhancement, amyotrophic latesclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, degeneration macular, abnormal healing of wounds, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal burns, scleritis, AIDS, septicemia, septic shock in a mammal, including a human being.

8. A pharmaceutical composition for the treatment of a disorder that can be treated by inhibiting matrix metalloproteinases in a mammal, including a human, comprising an amount of a compound of claim 1, effective in said treatment and a pharmaceutically acceptable vehicle.

9. A pharmaceutical composition for the treatment of a disorder that can be treated by the inhibition of a mammalian reprolysin in a mammal, including a human being, comprising an amount of a compound of claim 1, effective in said treatment and a pharmaceutically acceptable vehicle.

10. The use of a compound as claimed in claim 1, for the manufacture of a medicament for the inhibition of matrix metalloproteinases in a mammal, including a human. 1. The use of a compound as claimed in claim 1, for the manufacture of a medicament for the inhibition of a mammalian reprolysin in a mammal, including a human being. SUMMARY OF THE INVENTION A compound of formula wherein Q is as defined, which is useful in the treatment of a disorder selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, disease Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis emapollosa, osteoporosis, lack of firmness in artificial joint implants, atherosclerosis (including rupture) of atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, cerebrovascular accident, cerebral ischemia, head injury, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune disorders, sick Huntington's age, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal healing of wounds, burns, diabetes , tumor invasion, tumor growth, tumor metastasis, corneal burns, scleritis, AIDS, septicemia and septic shock; in addition, the compounds of the present invention can be used in combination therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and conventional analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids as vincristine, in the treatment of cancer. URQUHART / ET / mvh * ald * yac * pbg * jtc * igp * rcp * osu * cgm * mmr * asg * P00 / 1275F