MXPA00009901A - Bicyclic hydroxamic acid derivatives - Google Patents

Abstract

A compound of formula (I), wherein Z and Q are as defined in the specification, to pharmaceutical compositions containing them and to their medicinal use.

Description

BICCLIC DERIVATIVES OF HYDROXAMIC ACID BACKGROUND OF THE INVENTION The present invention relates to bicyclic hydroxamic acid derivatives and to pharmaceutical compositions and methods of treatment. The compounds of the present invention are inhibitors of zinc metalloendopeptidases, especially those belonging to the subfamilies of the matrix metalloproteinases (also called MMPs or matrixmas) and reprolysin (also known as adamlisine) of the metcincins (Rawlings, et al., Methods in Enzvmoloqv, 248, 183-228 (1995) and Stocker, et al .. Protein Science, 4, 823-840 (1995)). The MMP subfamily of enzymes, currently contains 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). Most MMPs are well known for their function of regulating the renewal of extracellular matrix proteins and, as such, 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 is occurring. For example, it has been shown that MMP-13, an enzyme with potent activity in the degradation of type II collagen (the main cartilage collagen), is overexpressed in cartilage with osteoarthritis (Mitchell, et al., J. Clin. Invest., 97, 764 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12) are also overexpressed in the cartilage with osteoarthritis and it is expected that the inhibition of some or all of these MMPs will slow down or block the loss Accelerated cartilage typical of joint diseases such as osteoarthritis and rheumatoid arthritis. Mammalian reprolysins are known as ADAM (A Dissintegrin And Metalloproteinase (a disintegrin and metalloproteinase) (Wolfberg, et al., J. Cell Biol., 131, 175-278 (1995)) and contain a disintegrin domain in addition to a domain similar to a metalloproteinase: Twenty-three different ADAMs have been identified to date, ADAM-17, also known as tumor necrosis factor-alpha (TACE), is ADAM-17 (TACE). responsible for the cleavage of tumor necrosis factor alpha (TNF-a, also known as cachectin) bound to cells.TNF-a is recognized to be involved in many infectious and autoimmune diseases (W. Friers, FEBS Letters, 285, 199 (1991)) In addition, it has been shown that TNF-a is the principal mediator of the inflammatory response seen in sepsis and septic shock (Spooner, et al., Clinical Immunology and Immunopatholoqy, 62 S1 1 (1992 ).) There are two forms of TNF-a, a prot Type II membrane eine with a relative molecular mass of 26,000 (26kD) and a soluble form of 17kD generated from the cell-bound protein by a specific proteolytic cleavage. The soluble 17 kD form of TNF-α is released by the cell and is associated with the deleterious effects of TNF-α. This form of TNF-a is also capable of acting in places far from the synthesis site. Thus, TACE inhibitors prevent the formation of soluble TNF-a and prevent the deleterious effects of soluble factor. The selected compounds of the invention are potent inhibitors of aggrecanase, an important enzyme in the degradation of cartilage aggrecan. Aggrecanase is also considered 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 slows down or blocks the cartilage loss in these diseases . . Other ADAMs that have shown 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 Biophis, Res. Comm., 235, 437-442, (1997)). As knowledge of the expression, physiological substrates and disease association of ADAMs increases, the full significance of the inhibitory function of this class of enzymes will be appreciated. Diseases in which the inhibition of MMP and / or ADAM will provide a beneficial therapeutic effect include: arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, 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 joint implants infections, atherosclerosis (including rupture of atherosclerotic plaques), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischaemia, head trauma, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune diseases, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognitive augmentation, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration , abnormal healing of wounds, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, scarring of the cornea, scleritis, AIDS, sepsis, septic shock and other diseases characterized by expression of metalloproteinases or ADAM. This invention also 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 pharmaceutical compositions useful therefor.

It is recognized that in different pathological situations different combinations of MMP and ADAM are expressed. In the case of individual diseases, such inhibitors may be preferred with specific selectivities by individual ADAM and / or MMPs. For example, rheumatoid arthritis is an inflammatory disease of the joints characterized by excessive levels of TNF and loss of constituents of the joint matrix. In this case, a compound that inhibits TACE and the loss of constituents of the joint matrix. In this case, a compound that inhibits TACE and aggrecanase, as well as MMPs such as MMP-13, may be the preferred therapy. In contrast, 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 present inventors 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 with respect to MMP-1. Inhibitors of matrix metalloproteinases are known in the literature. Specifically, PCT publication WO 96/33172, published on October 24, 1996, refers to cyclic arylsulfonylamino hydroxamic acids which are useful as MMP inhibitors. U.S. Patent 5,672,615, PCT publication WO 97/20824, PCT publication WO 98/08825, PCT publication WO 98/27069 and PCT publication WO 98/34918, published August 13, 1998 and entitled "Arylsulfonyl Hydroxamic Acid Derivatives" refers to cyclic hydroxamic acids that are useful as MMP inhibitors. PCT publications WO 96/27583 and WO 98/07697, published March 7, 1996 and February 26, 1998, respectively, refer to arylsulfonyl hydroxamic acids. PCT publication WO 98/03516, published January 29, 1998, refers to phosphinates with MMP activity. PCT Publication 98/34915, published on August 13, 1998, entitled "N-Hydroy-b-Sulfonyl Propionamide Derivatives" (N-Hydroxy-b-Sulfonyl Propionamide Derivatives), refers to propionyl hydroxamides useful as MMP inhibitors. PCT publication WO 98/33768, published on August 6, 1998, entitled "Arylsulfonylamino Hydroxamic Acid Derivatives", refers to N-unsubstituted 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. U.S. 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" ("The Use of Selective MMP Inhibitors" -13 for the Treatment of Osteoarthritis and Other MMP-Mediated Disorders "), refers to the use of selective inhibitors of MMP-13 for the treatment of inflammation and other disorders. U.S. Provisional Patent Application Serial No. 60/68261, filed December 19, 1997, refers to the use of MMP inhibitors to treat angiogenesis and other disorders. Each of the publications and applications mentioned above are incorporated herein by reference in their entirety.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound of the formula where Z is > CH2 or > NR1; R1 is hydrogen, alkyl (C? -C6), aryl (C6-C? O) alkyl (C? -C6), heteroaryl (C2-C9) -alkyl (C? -C6) or a group of the formula n is an integer from one to six; R2 is hydrogen or alkyl (CrC6); Q is aryl (C6-C? O), heteroaryl (C2-C9), aryloxy (C6-aryloxy (C6-C? 0) aryl (C6-C? O), aryloxy (C6-C? O) heteroaryl (C2) -C9), aryl (Cß-C ?o) alkyl (C?-Cß), aryl (Cß-C ?o) aryl (Cß-C ?O), aryl (C 6 -C 10) heteroaryl (C 2 -C 9), aryl (C6-C? o) aryl (C6-C? o) alkyl (C C6), ariI (C6-C? o) aryl (C6-C? o) aryl (C6-C? 0), aryl (C6) -C?) Aryl (C6-C? O) heteroaryl (C2-C9), heteroaryl (C2-C9) alkyl (C? -C6), heteroaryl (C2-C9) aryl (C6-C? O), heteroaryl (C2-C9) (C2-C9) heteroaryl, (C6-C6) aryl (C6-6) alkoxy (Cr6), aryl (C6- C10) alkoxy (C6-6) aryl (C6-C) ? o), aryl (C6-C? o) alkoxy (C? -C6) heteroaryl (C2-C9), heteroaryloxy (C2-C9) alkyl (C? -C6), heteroaryloxy d-CgJariloíCe-do), heteroariIoxi (C2-C9) heteroaryl (C2-C9), heteroaryl (C2-C9) alkoxy (C6-6) alkyl (C6-6), heteroaryl (C2-C9) alkoxy (C6-6) aryl (C6-) C? O), heteroaryl (C2-C9) alkoxy (C? -C6) heteroaryl (C2-C9), aryloxy Ce-CK ^ ali CrCe ^ riloiCe-C-io), aryloxy (C6-C? O) alkyl ( C6C) heteroaryl (C2-C9), heteroaryloxy (C2-C9) alkyl (C6-6) aryl (C6-C-io) or heteroaryloxy (C2-C9) alkyl (C6-6) heteroaryl (C2) -C9 ); Where each aryl radical (C6-C? 0) or heteroaryl (C2-C9) of said aryl (C6-C-? O), heteroaryl (C2-Cg), aryloxy (C6-C? O) alkyl (CrC6) ), aryl (C6-C? o) aryl (C6-C? 0), aryloxy (C6-C? o) heteroaryl (C2-C9), aryl (C6-C? 0) alkyl (C? -C6), aryl (C6-C10) heteroaryl (C2-C9), ariI (C6-C10) aryl (C6-C? o) alkyl (C? -C?), aryl (C6-C? 0) aryl (C6-C? ) aryl (C6-C? o), aryl (C6-C10) aryl (C6-C10) heteroary (C2-C9), heteroaryl (C2-Cg) alkyl (C? -C6), heteroaryl (C2-Cg) aryl (C6-C10), heteroaryl (C2-Cg) heteroaryl (C2-Cg), aryl (C6-C? O) alkoxy (C? -C6) alkyl (C? -C6), ari Ce-CioJalcoxiíd-CeíariloíCe-Cio ), aryl (C6-C? o) (C-C6) alkoxy (C2-C9) heteroaryl, (C2-Cg) heteroaryloxy (C? -C6) alkyl, (C2-C9) heteroaryloxy (C6-C? ), (C2-C9) heteroaryloxy (C2-C9) heteroaryl (C2-C9) alkoxy (C-C6) alkyl (C6-6), heteroaryl (C2-Cg) alkoxy (C6-6) aryl (C6-C-? o), heteroaryl (C2-Cg) alkoxy (C? -C6) heteroaryl (C2-Cg), aryloxy (C6-C? o) alkyl (C? -6) aryl (C6-) C? O), aryloxy (C6-C? O) alkyl (C? -C6) heteroaryl (C2-C9), heteroaryloxy (C2-C9) alkyl (Cr6) aryl (C6-C? O) or heteroaryloxy (C2-C9) alkyl (C -? - C6) heteroaryl (C2-C9) 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, alkyl (C? -C6), alkoxy (C? -C6), perfluoro-alkyl (C? -C3), perfluoro-alkoxy (C? -C3) and aryloxy (C6-C? o); or 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 above-mentioned 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, 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 [i.e. 1,1 '-methylene-bis- (2-hydroxy-3-naphthoate)]. The invention also relates to the base addition salts of formula I. The chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of the compounds of formula I which are acidic in nature, are those which form base salts. non-toxic with such compounds. Such non-toxic base salts include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and cations and alkaline earth metals (eg, calcium and magnesium), water-soluble ammonium or amine addition salts, such as N-methylglucamine- (meglumine), trimethylammonium or diethylammonium, and the salts lower alkanolammon, such as tris- (hydroxymethyl) -methyl ammonium and other pharmaceutically acceptable organic amine base salts. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term "alkoxy," as used herein, includes O-alkyl groups, wherein "alkyl is as defined 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. The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from a aromatic heterocyclic compound by the removal of a hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl, benzoimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, osobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benothiazolyl or benzoxazolyl Preferred heteroaryls include pyridyl, furyl, thienyl, isothiazolyl, pyrazinyl, pyrimidyl, pyrazole ilo, isoxazolyl, thiazolyl or oxazolyl. More preferred heteroaryls include pyridyl, furyl or thienyl.

The term "acyl", as used herein, unless otherwise indicated, includes a radical of the formula generates R- (C = O) -, where R is alkyl, alkoxy, aryl, arylalkyl or arylalkoxy and the terms "alkyl" or "aryl" are as defined above. The term "acyloxy," as used herein, includes O-acyl groups wherein "acyl" is as defined above. The compound of formula I can have chiral centers and, therefore, exist in different diastereomeric or enantiomeric forms. This invention relates to all optical isomers, tautomers and stereoisomers of the compounds of formula I and mixtures thereof. Preferably, the compounds of formula I exist as the exo isomer of the formula Other preferred compounds of formula I are those in which Q is aryl (C6-C? o), heteroaryloxy (C2-Cg) aryl (C6-C? 0) or aryloxy (C6-C? 0) aryl (C6-) C? O), wherein each aryl or heteroaryl radical of said aryl (Cedo), heteroaryloxy (C2-C9) aryl (C6-C? 0) or aryloxy (Ce-Cio) aryl (C6-do) groups may be optionally substituted by one or more substituents independently selected from fluoro, chloro, bromo, alkyl (d-C6), alkoxy (C? -C6) or perfluoro-alkyl (C? -C3). More preferred compounds of formula I include those in which Q is phenyl, pyridyloxyphenyl (more preferably 4-pyridyl) or phenoxyphenyl, optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, alkyl (CrC6), alkoxy (C? -C6) or perfluoroalkyl (CrC3), more preferably the substituents are selected from fluoro, chloro, alkoxy (C? -C6) or alkyl (d-C6) and more preferably, the substituent is in the position 4. Preferred specific compounds of formula I include the following: 3-Exo [4- (4-fluorophenoxy) benzenesulfonylamino] -8-oxabicyclo [3.2.1] -octane-3-carboxylic acid hydroxyamide; Hydroxyamide of 3-e o- [4- (4-fluorophenoxy) benzenesulfonylmethyl] -8-oxabicyclo [3.2.1] -octane-3-carboxylic acid; 3- (4-Phenoxybenzenesulfonylmethyl) -8-oxabicyclo [3.2.1] -octane-3-carboxylic acid hydroxyamide; 3-Exo- (4-fluorobiphenyl-4-benzenesulfonylmethyl) -8-oxabicyclo- [3.2.1] -octane-3-carboxylic acid hydroxyamide; and 3-Exo- [4- (4-chlorophenoxy) benzenesulfonylmethyl] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide. Other compounds of the invention of formula I include the following: 3-Exo- (4-phenoxybenzenesulfonylamino) -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, 3-exo- [4- (pyridin-4-yloxy) benzenesulfonylamino-8-oxabicyclohydroxyamide [ 3.2.1] octane-3-carboxylic acid, 3-exo- [4- (4-chlorophenoxy) benzenesulfonylamino] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, 3 - [[4- ( 4-chlorophenoxy) benzenesulfonyl] - (3-enoO-hydroxycarbamoyl-8-oxabicyclo [3.2.1] oct-3-yl) amino] propionic acid, 3 - [[4- (4-chlorophenoxy) benzenesulfonyl] - ethyl ester - (3-enoO-hydroxycarbamoyl-8-oxabicyclo [3.2.1] oct-3-yl) amino] propionic acid, 3 - [[4- (4-fluorophenoxy) benzenesulfonyl] (3-endo-hydroxycarbamoyl-8-oxabicyclo) [3.2.1] oct-3-yl) amino] -propionic acid ethyl ester 3 - [[4- (4-fluorophenoxy) benzenesulfonyl] (3-e /. O-hydroxycarbamoyl-8-oxaciclo [3.2.1 ] oct-3-yl) amino] -propionic acid, hydroxyamide of 3-exo- acid. { [4- (4-fluorophenoxy) benzenesulfonyl] methylamino} -8-oxabicyclo [3.2.1] octane-3-carboxylic acid, 3-endo- [4- (4-fIuorophenoxy) benzenesulfonylamino] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, Hydroxyamide of the acid 3-exo-. { [4- (4-fluorophenoxy) benzenesulfonyl] pyridin-3-ylmethylamino} -8-oxabicyclo [3.2.1] octane-3-carboxylic acid, 3-exo- [4- (4-fluorobenzyloxy) benzenesulfonylamino] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, 3-Exo- (4-benzyloxybenzenesulfonylamino) -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, 3-exo- (4-benzyloxybenzenesulfonylmethyl) -8-oxabicyclo [3.2.1] octane- hydroxyamide 3-carboxylic acid, 3-exo- (Methyl- [4- (pyridin-4-yloxy) benzenesulfonyl] amino] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, 3-Exo- (4-methoxybenzenesulfonylamino) -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, 3-exo- (4-methoxybenzenesulfonylmethyl) -8-oxabicyclo [3.2.1] octane hydroxyamide -3-carboxylic acid, 3-exo-5-pyridin-2-ylthiophene-2-sulfonylamino) -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, 3-exo- (4-phenoxybenzenesulfonylamino) hydroxyamide ) -8-oxabicyclo [3.2.1] octane-3-carboxylic acid, 3-exo- [4- (pyridin-4-yloxy) benzenesulfonylmethyl] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, Hydroxyamide 3-exo- [4- (pyridin-4-yloxy) benzenesulfonylamino] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid, 3-exo- [4- (4-chlorophenoxy) benzenesulfonylmethyl hydroxyamide] ] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid, 3-exo- [4- (4-chlorophenoxy) benzenesulfonylamino] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, Acid3- [[4- (4-fluorophenoxy) benzenesulfonyl] - (3-eneO-hydroxycarbamoyl-8-oxabicyclo [3.2.1] oct-3-yl) amino] propionic, 3 - [(3-en-o-hydroxycarbamoyl-8-oxabicyclo [3.2.1] oct-3-yl) - (4-phenoxybenzenesulfonyl) -amino] propionic acid, 3-exo- hydroxyamide. { [4- (4-fluorophenoxy) benzenesulfonyl] pyridin-3-ylmethylamino} -8-oxabicyclo- [3.2.1] octane-3-carboxylic acid, 3-Exo - [(4-phenoxybenzenesulfonyl) pyridin-3-ylmethylamino] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide, 3-exo- Hydroxyamide. { methyl [4-8-pyridin-4-yloxy) benzenesulfonyl] amino} -8-oxabicyclo [3.2.1] octane-3-carboxylic acid, 3-exo- (5-isoxazol-3-yl-thiophene-2-sulfonylamino) -8-oxa bicyclo [3.2.1] octane hydroxyamide -3-carboxylic acid, 3-exo- (5-phenylthiophene-2-sulfonylamino) -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide. The present invention also relates to a pharmaceutical composition for 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, disease of Alzheimer's, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as cancer of solid tumors including colon cancer, breast cancer, lung cancer and prostate cancer, and malignant hematopoietic agents including leukemias and lymphomas), tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, lack of firmness in artificial joint implants, atherosclerosis (including rupture of atherosclerotic plaques), aortic aneurysm (including abdominal aortic aneurysm and aortic aneurysm cerebral), congestive heart failure, myocardial infarction, apolegia, cerebral ischemia, cephalic trauma, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune diseases, Huntington's disease, Parkinson's disease, migraine, depression, neuroperipheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognitive increase, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, scarring of the cornea, scleritis, AIDS, sepsis, septic shock and other diseases characterized by the activity of metalloproteinases and other diseases characterized by the activity of reprolysin in a mammal, including a human being, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt of the same or effective in such treatments, and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition for the inhibition of (a) matrix metalproteinases or other metalloproteinases involved in the degradation of the matrix, or (b) a mammalian reprolysin (such as aggrecanase or ADAM TS-1) , 10, 12, 15, and 17, more 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 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, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis blisters, osteoporosis, lack of firmness in implants of artificial joints, atherosclerosis (including rupture of the atherosclerotic plaques), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischaemia, cephalic trauma, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune diseases , Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, notrópico or cognition increase, aminotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, diabetes burns, tumor invasion, tumor growth, tumor killing, corneal scarring, scleritis, AIDS, sepsis, septic shock and other diseases characterized by metalproteinase activity and other diseases characterized by the activity of reprolysin in a mammal, including a human being, which comprises administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in the treatment of such a condition. The present invention also relates to a method for the inhibition of (a) matrix metalproteinases or other metalloproteins involved in the degradation of the matrix, or (b) a mammalian reprolysin (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 compounds of formula I. This invention also includes methods of treating or preventing disorders that can be treated or prevented by inhibiting matrix metalproteinases or inhibiting mammalian peprolysin, which they comprise 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 those compounds in which an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues is covalently linked through peptide bonds to free amino, hydroxy or carboxylic groups of the compounds of formula I. The amino acid residues include the 20 natural amino acids, commonly referred to as 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. Pro-drug compounds also include compounds in which carbonates are covalently bound, carbamates, amides and alkyl esters to the above substituents of formula I through the carbonyl carbon of the side chain of the prodrug. One of ordinary skill in the art will appreciate that the compounds of the invention are useful in the treatment of a wide range of diseases. One of ordinary skill 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 such a disease. For the treatment of rheumatoid arthritis, the compounds of the invention can be combined with agents such as TNF-α inhibitors, such as anti-TNF monoclonal antibodies and immunoglobulin molecules for the TNF receptor (such as Enbrel®), one dose low of methotrexate, lefunimide, hydroxychloroquine, d-penicillamine, auronofin 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 to be used 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, indomethacin, sulindac, apazona, pyrazolines such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as colexicob and refecoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and sinvisc. The compounds of the present invention can also be used in combination with anti-cancer agents, such as endostatin and angiostatin, or with cytotoxic drugs such as adriamycin, daunomycin, chrysatin, 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 reducing agents such as statins, fibrates, beta-blockers, ACE inhibitors, angiotensin 2 receptor antagonists and beta-blockers. the aggregation of platelets.

The compounds of the present invention can also be used in combination with CNS agents such 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, nicotinic agonists, Dopamine agonists and neuronal nitric oxide synthase inhibitors), and Alzheimer's drugs such as Aricept, tacrine, inhibitors of COX-2, propentofylline or metrifonate. The compounds of the present invention can also be used in combination with agents for osteoporosis such as droloxifene or phosoma 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 otherwise indicated, R1, R2, Q and Z in the reaction schemes and in the discussion that follows them are defined as indicated above.

SCHEME 1 VIII VI Vil V IV SCHEME 1 CONTINUATION 15 SCHEME 2 IX XIV XIII XII SCHEME 2 CONTINUED XI X 15 SCHEME 3 20 SCHEME 4 II 20 Scheme 1 refers to the preparation of compounds of formula I, wherein Z is CH2. Referring to scheme I, a compound of formula I is prepared from a compound of formula II by hydrogenolysis under an atmosphere of hydrogen, in the presence of a catalyst in a solvent inert in the presence of a catalyst in an inert solvent the reaction. Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol. The above reaction can be carried out at a pressure of about 1 to about 5,065 x 10 5 Pa, preferably at about 3,03 x 10 5 Pa. Suitable temperatures for the above reaction range from about 20 ° C (room temperature) to about 60 ° C, preferably the temperature can vary from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is completed in a period of from about 0.5 hours to about 5 hours, preferably in about 3 hours. The compounds of formula II can be prepared from compounds of formula III by reaction with an oxidant in a reaction-inert solvent. Suitable oxidants include metachloroperbenzoic acid, hydrogen peroxide or sodium perborate, preferably meta-chloroperbenzoic acid. Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. Suitable temperatures for the above reaction range from about 0 ° C to about 60 ° C, preferably the temperature can vary from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is completed in a period of from about 0.5 hours to about 24 hours, preferably in about 16 hours. The compound of formula III is prepared from a compound of formula IV by reaction with O-benzylhydroxyamine hydrochloride, an activating agent and a base, in a solvent inert to the reaction. Suitable activating agents include (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, preferably (benzotriazol-1-yloxy) tris- (dimethylamino) hexafluorophosphate. ) phosphonium. Suitable bases include tertiary amines such as triethylamine, diisopropylethylamine or 4-N, N-dimethylaminopyridine, preferably diisopropylethylamine. The temperature of the above reaction may vary from about 0 ° C to about 60 ° C, preferably at about 50 ° C. Suitable solvents include N, N-dimellformamide, halogenated solvents such as methylene chloride or chloroform, or ethers such as THF or diethyl ether, preferably the solvent is N, N-dimethylformamide. The reaction is completed in about 4 hours to about 48 hours, preferably in about 16 hours.

The compounds of the formula IV can be prepared from compounds of the formula V, by reaction with a compound of the formula QSH, where Q is as defined above, in the presence of a strong base in a polar aprotic solvent. Suitable bases include sodium hydride, lithium diisopropylamide, potassium t-butoxide, sodium amide or potassium hydride, preferably sodium hydride. Suitable solvents include ethers (such as THF, diethyl ether or 1,2-dimethoxyethane), or N, N-dimethylformamide, preferably the solvent is THF. The above reaction is carried out at a temperature from about -78 ° C to about 0 ° C, preferably at about 22 ° C (i.e., at room temperature), for a period of 30 minutes to about 24 hours, preferably about 2 hours. hours. The compounds of the formula V are prepared from compounds of the formula VI by dehydration in the presence of a tertiary amine base, preferably triethylamine, optionally in the presence of 4-dimethylaminopyridine, and a dehydrating agent in an inert solvent. Suitable dehydrating agents include trifluoromethanesulfonic anhydride, methanesulfonic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride or benzenesulfonyl chloride, preferably benzenesulfonyl chloride. Suitable solvents include diethyl ether or dichloromethane. The reaction is carried out at a temperature from about -80 ° C to about 0 ° C, preferably at about 0 ° C. The reaction is carried out for about 10 minutes to about 4 hours, preferably for about 1 hour. The compounds of formula VI are prepared from a compound of formula VII, where PG 1 is methyl or ethyl, by saponification with a base, such as lithium hydroxide, in a mixture of solvents. Suitable solvent mixtures include water and methanol or water, methanol and THF. The reaction is carried out at a temperature of about 60 ° C to about 120 ° C, preferably at about the reflux temperature of the solvent mixture used. The reaction is carried out for about 30 minutes to 24 hours, preferably for about 16 hours. The exo-hydroxymethyl isomer of the compound of formula VII is prepared from a compound of formula VIII. In general, a solution of a compound of formula VIII is dissolved in an inert aromatic solvent, preferably benzene or toluene, and is cooled to a temperature of from about -40 ° C to -20 ° C, preferably to about -40 ° C. To the cold solution is added a suitable hindered reducing agent, preferably diisobutylaluminum hydride, in an inert aromatic solvent, keeping the temperature below -25 ° C. After the addition is complete, the reaction is maintained below 0 ° C for about 3 hours. A protic solvent, preferably ethanol, is added at about -15 ° C. After stirring at about -15 ° C for about 1 hour, sodium borohydride is added and the reaction is allowed to warm to about room temperature while stirring for a period of 2 to 24 hours, preferably for about 16 hours. The endo-hydroxymethyl isomer of the compound of formula VII can be prepared from the exohydroxymethyl compound of formula VI by a series of steps which can reverse the stereochemistry around the carbon atom carrying the hydroxymethyl and carboxylic acid groups. Specifically, the exo-hydroxymethyl isomer of formula VI is first converted to the corresponding benzyl ester. The subsequent Jones oxidation of the alcohol to the carboxylic acid and the formation of the alkyl ester (methyl or ethyl) provides a mixed intermediate alkyl benzyl ester (ie the exo ester is methyl or ethyl and the endo ester is benzyl). The benzyl ester is then removed by hydrogenolysis and the resulting carboxylic acid is reduced to alcohol by reduction with diborane, providing the endohydroxymethyl isomer of the compound of formula VII. The compounds of formula VIII, wherein PG1 is ethyl or methyl, are prepared from compounds of formula IX, wherein L is methanesulfonyl, benzenesulfonyl or tosyl, by reaction with dimethyl malonate or diethyl in the presence of a strong base, such as sodium hydride, in a polar solvent, such as N, N-dimethylformamide, for a period of time ranging from about 4 hours to about 24 hours, preferably about 16 hours. The temperature of the above reaction ranges from about 70 ° C to about 150 ° C, preferably about 140 ° C. The compounds of formula IX are known or can be obtained by methods well known to those of ordinary skill in the art. The compounds of the formula QSH can be prepared by the reaction of an alkyl or aryl halide with sodium sulfhydride as described in Jerry March, Advenced Orqanic Chemistrv. 360 and 589 (3rd ed., 1985). Alternatively, the compounds of the formula QSH can also be prepared by reaction of an aryl diazonyl salt with sodium sulfhydride as described in March 1994. Alternatively, the compounds of the formula QSH can also be prepared by reaction of a reagent Grignard with sulfur as described in March jd., At 550. Alternatively, compounds of the formula QSH can also be prepared by reduction of a sulfonyl chloride, sulphonic acid or disulphide as described in March 11 in 1 107 and 11. Scheme 2 refers to the preparation of compounds of formula I, wherein Z is >; NR1 and R1 is hydrogen. Referring to scheme 2, the compounds of formula I can be prepared from compounds of formula X by hydrogenolysis, under an atmosphere of hydrogen, in the presence of a catalyst in a reaction-inert solvent. Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include an alcohol, such as ethanol, methanol or isopropanol, preferably methanol. The above reaction can be carried out at a pressure of about 1013 x 10 5 Pa to about 5,065 x 10 5 Pa, preferably at about 3,033 x 10 5 Pa. Suitable temperatures for the above reaction range from about 20 ° C (room temperature) to about 60 ° C. ° C, preferably the temperature may vary from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is completed in a period of from about 0.5 hours to about 5 hours, preferably in about 3 hours. The compound of formula X is prepared from a compound of formula XI by reaction with O-benzylhydroxylamine hydrochloride in the presence of a catalyst and a base, in a solvent inert to the reaction. Suitable catalysts include (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium hexafluorophosphate or 1- (3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, preferably (benzotriazol-1-yloxy) tris- (dimethylamino) hexafluorophosphate) Phosphonium Suitable bases include tertiary amines such as triethylamine, diisopripylethylamine or 4-N, N-dimethylaminopyridine, preferably diisopropylethylamine The temperature of the above reaction is from about 0 ° C to about 60 ° C, preferably about 50 ° C. Suitable solvents include N, N-dimethylformamide or halogenated solvents such as methylene chloride or chloroform, preferably the solvent is N, N-dimethylformamide The reaction is carried out for a period of from about 4 hours to about 48 hours, preferably for about 16 hours The compounds of the formula XI are prepared from compounds of the formula XII, where PG2 is methyl oe lime, by saponification with a base, such as sodium hydroxide, in a mixture of solvents such as water and ethanol. The reaction is carried out at a temperature of about 60 ° C to about 100 ° C, preferably at about the reflux temperature of the solvent mixture used. The reaction is carried out for about 1 day to about 10 days, preferably for about 6 days. The compounds of formula XII, wherein PG2 is methyl or ethyl, are prepared from compounds of formula XIII, wherein PG2 is methyl or ethyl, by reaction with a compound of the formula QSOaCI in the presence of a base, such as triethylamine and a polar solvent. Suitable solvents include N, N-dimethylformamide, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, water or acetonitrile, preferably N, N-dimethylformamide. The reaction mixture is stirred at room temperature for a period of time ranging from about 1 hour to about 245 hours, preferably about 16 hours. Compounds of formula XIII, wherein PG2 is methyl or ethyl, are prepared from compounds of formula XIV, where PG2 is methyl or ethyl, by hydrolysis in the presence of an aqueous mineral acid and a solvent such as diethyl ether. Suitable mineral acids include hydrochloric and sulfuric acid, preferably hydrochloric acid. The reaction is carried out at a temperature ranging from about 0 ° C to 50 ° C; preferably the temperature may vary from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is carried out for a period of from about 2 hours to about 48 hours, preferably for about 16 hours. Compounds of the formula XIV, where PG2 is methyl, ethyl or benzyl, are prepared from a compound of the formula IX, where L is methanesulfonyl, benzenesulfonyl or tosyl, by reaction with N-diphenylmethylene glycine, methyl, ethyl or benzyl, in the presence of a strong base, such as sodium hydride, in a polar solvent, such as N, N-dimethylformamide, for a period of time from about 4 hours to about 24 hours, preferably about 16 hours. The temperature of the above reaction ranges from about 70 ° C to about 140 ° C, preferably about 100 ° C. The compounds of the formula XIV, where PG2 is methyl, ethyl or benzyl, are obtained in the form of mixtures of diastereoisomers which can be separated by chromatographic techniques. The compounds of the formula QSO2CI and of the formula IX are known, commercially available or can be manufactured by methods well known to those skilled in the art.

Scheme 3 refers to the preparation of compounds of the formula I, wherein Z is NR1 and R1 is alkyl (C? -C6), aryl (C6-C? 0) alkyl (C? -C6), heteroaryl (C2-) C9) alkyl (d-C6) or a group of the formula - (CH2) nCO2R2, where n is 1, 3, 4, 5 or 6 and R2 is alkyl (C6C6). Referring to scheme 3, the compounds of formula I wherein Z is NR1 and R1 is alkyl (C? -C6), aryl (C6-d0) alkyl (C? -C6), heteroaryl (C2-C9) alkyl (d-? Cß) or a group of the formula - (CH 2) nCO 2 R 2, where n is 1, 3, 4, 5 or 6 and R 2 is alkyl (C 1 -C 6), were prepared from compounds of the formula XV by low hydrogenolysis an atmosphere of hydrogen in the presence of a catalyst in a solvent inert to the reaction. Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol. The above reaction can be carried out at a pressure of about 1 to about 5,065 x 10 5 Pa, preferably 3,033 x 10 5 Pa. Suitable temperatures for the above reaction range from about 20 ° C (room temperature) to about 60 ° C, preferably the Temperature can vary from about 20 ° C to about 25 ° C (ie, room temperature). The reaction is completed in a period of from about 0.5 hours to about 5 hours, preferably in about 3 hours.

The compound of formula XV is prepared from a compound of formula XVI by reaction with O-benzylhydroxylamine hydrochloride in the presence of a catalyst and a base in a reaction-inert solvent. Suitable catalysts include (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate or 1- (3-dimethylaminopropyl) -3-ethylcrbodiimide hydrochloride, preferably (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate. Suitable bases include tertiary amines such as triethylamine, diisopropylethylamine or 4-N, N-dimethylaminopyridine, preferably diisopropylethylamipa. The temperature of the above reaction ranges from about 0 ° C to about 60 ° C, preferably about 50 ° C. Suitable solvents include N, N-dimethylformamide or halogenated solvents such as methylene chloride or chloroform, preferably the solvent is N, N-dimethylformamide. The reaction is carried out for a period of about 4 hours to about 48 hours, preferably about 16 hours. The compound of formula XVI is prepared from a compound of formula XVII by removal of the benzyl protecting group. Specifically, the benzyl protecting group is removed by hydrogenolysis using palladium or palladium on carbon in a solvent such as methanol or ethanol, for a period of about 30 minutes to about 48 hours, preferably about 16 hours, at a temperature of about 20 °. C at approximately 25 ° C (i.e., room temperature). The compound of formula XVII is prepared from a compound of formula XII, wherein PG2 is benzyl, by reaction with a reactive derivative of an alcohol of formula R1OH, such as a methanesulfonate, tosylate, chlorine, bromine or iodine derivative , preferably the iodo derivative, in the presence of a base such as potassium carbonate or sodium hydride, preferably sodium hydride, and a polar solvent, such as N, N-dimethylformamide. The reaction mixture is stirred at room temperature for a period of time ranging from about 60 minutes to about 48 hours, preferably about 16 hours. The compounds of formula XII, wherein PG2 is benzyl, are prepared according to the procedures of scheme 2. Scheme 4 refers to the preparation of compounds of formula I, wherein Z is > NR1, R1 is a group of the formula - (CH2) 2CO2R2 (ie, n is 2) and R2 is alkyl (Ci-Cß). Referring to scheme 4, the compounds of said formula I are prepared from compound of formula XVIII, where R 2 is alkyl (Ci-Cß), by reaction with oxalyl chloride or thionyl chloride, preferably oxalyl chloride, and a catalyst, preferably about 2% N, N-dimethylformamide, in an inert solvent, such as methylene chloride, to form an acid chloride in situ which is subsequently reacted with O-trimethylsilylhydroxylamine in the presence of a base, such as pyridine, 4-N, N-dimethylaminopyridine or triethylamine, preferably pyridine. The reaction is carried out at a temperature of about 22 ° C (i.e. at room temperature) for about 1 to about 12 hours, preferably for about 1 hour. The compounds of the formula XVIII, where R2 is alkyl (C? -C6), can be prepared from compounds of the formula XIX, where R2 that alkyl (C-C6), by reduction in a polar solvent. Suitable reducing agents include palladium hydrogen and palladium-on-carbon hydrogen, preferably palladium-on-carbon hydrogen. Suitable solvents include methanol, ethanol and isopropanol, preferably ethanol. The above reaction is carried out at a temperature of about 22 ° C (i.e. at room temperature) for a period of 1 to 7 days, preferably about 2 days. The days of formula XIX, where R2 is alkyl (C? -C6), can be prepared from compounds of formula XII, where PG2 is benzyl, by Michael addition of an propiolate ester and a base in a polar solvent. Suitable propiolates have the formula H-C = C-CO2R2, where R2 is alkyl (d-Cß). Suitable bases include tetrabutylammonium fluoride, potassium carbonate and cesium carbonate, preferably tetrabutylammonium fluoride. Suitable solvents include tetrahydrofuran, acetonitrile, tert-butanol and N, N-dimethylformamide, preferably tetrahydrofuran. The above reaction is carried out at a temperature from about -10 ° C to about 60 ° C, preferably varying from 0 ° C to about 22 ° C (that is, at room temperature). The compounds of formula XIX are obtained in the form of mixtures of geometric isomers around the olefinic double bond; the separation of the isomers is not necessary. The compounds of formula XII, wherein PG2 is benzyl, can be prepared according to the procedures of scheme 2. The compounds of said formula I, wherein Z is > NR1, R1 is a group of the formula - (CH2) nCO2R2, n is from 1 to 6 and R2 is hydrogen, they are prepared from compounds of formula I, where Z is > NR1, R1 is a group of the formula - (CH2) nCO2R2, n is from 1 to 6 and R2 is alkyl (d-Cß), by saponification, using a base such as sodium hydroxyl, in a protic solvent such as ethanol, methanol or water, or a mixture such as water and ethanol, water and toluene, or water and THF. The preferred solvent system is water and ethanol. The reaction is carried out for a period of 30 minutes to 24 hours, preferably for about 2 hours. The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must 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 pharmaceutically acceptable salt. 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 treatment of 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 salts, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or phosphate acid, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [ie, 1, 1 '-methyl-bis- (2-hydroxy-3-naphthoate)]. The compounds of formula I which are acidic in nature, are capable of forming 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 which are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I described herein. These non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, 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 alkane solutions of the acidic compounds and the desired alkali metal alkoxide with each other 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 that maximum yields of the products are obtained. The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter also referred to as the compounds of the present invention) to inhibit metalloproteinases or mammalian reprolysin and, therefore, demonstrate their efficacy for the treatment of diseases characterized by metalloproteinases or by the production of tumor necrosis factor, is shown by the following in vitro tests.

BIOLOGICAL ASSAY 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, but a typical reaction uses the following ratio: 5 μg of trypsin per 100 μg of collagenase. The trypsin and the 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. Stock solutions (10 mM) of inhibitors were prepared in dimethylsulfoxide and then diluted using the following scheme: 10 mM? 120 μM? 12 μM? 1.2 μM? 0.12 μM Twenty-five microliters of each concentration are then added, in triplicate, to the appropriate wells of a 96-well Microfluor plate. The final inhibitor concentration will be a 1: 4 dilution after the addition of enzyme and substrate. Positive controls (with enzyme, without inhibitor) are placed in wells D7-D12 and negative controls (without enzyme and without inhibitor) are arranged in wells D1-D6. Collagenase-1 is diluted to 240 ng / ml and then 25 ml is added to the appropriate wells of the Microfluor plate. The final concentration of the collagenase in the assay is 60 ng / ml. The substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys- (NMA) -NH2) is obtained 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. The fluorescence readings (excitation 360 nm, emission 460 nm) are taken 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. The fluorescence is then plotted against time for both the blank and for the samples containing collagenase (the average of the data from the triplicate determinations is calculated). A time point is chosen that provides a good signal (at least five times greater than the target) and that is in a linear part of the curve (usually around 120 minutes) to determine the IC 50 values. Zero time is used as a target for each compound at each concentration and these values are subtracted from the 120 minute data. The data are plotted as concentration of inhibitor against% control (fluorescence of the inhibitor divided by fluorescence of collagenase alone x 100). Cl50 values are determined from the concentration of inhibitor that provides a signal that is 50% of the control. If Cl50's are less than 0.03M, then the inhibitors are tested at 0.3 mM, 0.03 mM and 0.003 mM.

Inhibition of qelatinase (MMP-2) Recombinant human 72 kD gelatinase (MMP-2, gelatinase A) is activated for 16-18 hours with 1 mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock solution in NaOH 0.2 N), at 4 ° C, with gentle agitation. Stock solutions of inhibitors are diluted in series in 10 mM dimethylsulfoxide, in assay buffer (50 mM TRIS, pH 7.5, 200 mM NaCl, 5 mM CaCl 2, 20 μM ZnCl 2 and 0.02% BRIJ-35 (vol./vol.) ) using the following scheme: 10 mM? 120 μM? 12 μM? 1.2 μM? 0.12 μM When necessary, additional dilutions are made following this same scheme. In each test a minimum of four concentrations of inhibitor per compound is performed. Then 25 μl of each concentration is added, in triplicate, to the wells of a black 96-well Microfluor plate with U-bottom. As the final assay volume is 100 μl, the final and inhibitor concentrations are the result of a dilution Additional 1: 4 (ie, 30 μM, 3 μM, 0.3 μM, 0.03 μM, and so on). A blank is also prepared (without enzyme and without inhibitor) and a positive enzyme control (with enzyme and without inhibitor), in triplicate. The activated enzyme is diluted to 100 ng / ml in assay buffer, 25 μl per well is added to the appropriate wells of the microplate. The final enzyme concentration in the assay is 25 ng / ml (0.34 nM).

A stock solution is diluted in 5 mM dimethylsulfoxide substrate (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2) in 20 μM assay. The assay is initiated by the addition of 50 μl of diluted substrate yielding a final assay concentration of 10 μM substrate. At time zero, the fluorescence reading is immediately taken (excitation 320, emission 390) and subsequently readings are taken every fifteen minutes at room temperature with a Multi-Well Plate Reader Reader PerSeptive Biosystems CytoFluor, with the gain of 90 units. The average fluorescence value of the enzyme and the blank are plotted against time. One of the first time points is chosen on the linear part of this curve for the IC50 determinations. The zero time point for each compound at each dilution is subtracted from the last time point and then the data are expressed as percentage of enzyme control (fluorescence of the inhibitor divided by fluorescence of the positive control of enzyme x 100). The data are represented as concentration and inhibitor against the percentage of enzyme control. IC50's are defined as the concentration of inhibitor that provides a signal that is 50% positive enzyme control.

Inhibition of stromelysin activity (MMP-3) Recombinant human stromelysin (MMP-3, stromelysin 1) is activated for 20-22 hours with 2 mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock solution in NaOH) 0.2 N), at 37 ° C. They are diluted in series of stock solutions of inhibitors in 10 mM dimethylsulfoxide, in test tamm (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 When necessary, additional dilutions are made following this same scheme. In each test a minimum of four concentrations of inhibitor per compound is performed. Then they are added μl of each concentration, in triplicate, to the wells of a black plate 96-well Microfluor with U-bottom. As the final assay volume is 100 μl, the final inhibitor concentrations are the result of an additional 1: 4 dilution (ie, 30 μM, 3 μM, 0.3 μM, 0.03 μM , and so on). A blank is also prepared (without enzyme and without inhibitor) and a positive enzyme control (with enzyme and without inhibitor), 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 microplate. The final enzyme concentration in the assay is 50 ng / ml (0.875 nM). A stock solution in 10 mM dimethylsulfoxide substrate (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys (Dnp) -NH2) is diluted in assay buffer at 6 μM. The assay is initiated by the addition of 50 μl of diluted substrate yielding a final concentration of 3 μM substrate assay. At time zero, the fluorescence reading is immediately taken (excitation 320, emission 390) and subsequently readings are taken every fifteen minutes at room temperature with a Multi-Well Reader Plate Reader PerSeptive Biosystems CytoFluor with the gain at 90 units. The average fluorescence value of the enzyme and the blank are plotted against time. One of the first time points is chosen on the linear part of this curve for the IC50 determinations. The zero time point for each compound at each dilution is subtracted from the last time point and after the data are expressed as percentage of enzyme control (fluorescence of the inhibitor divided by fluorescence of the positive control of enzyme x 100). The data are represented as concentrations of inhibitor against the percentage of enzyme control. The IC5o's are defined as the concentration of the inhibitor that provides a signal that is 50% of the enzyme positive control. Alternatively, the inhibition of stromelysin can be assayed using Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys (Dnp) -NH2 (3 μM) under conditions similar to those of inhibition of human collagenase (MMP-1). Human stromelysin is activated for 20-24 hours at 37 ° C with 2 mM APMA (p-aminophenyl mercuric acetate) and diluted to a final concentration in the 50 ng / ml assay. The inhibitors are diluted as in the case of the inhibition of human collagenase (MMP-1) to give final concentrations in the 30 μm assay, 3 μM, 0.3 μM and 0.03 μM. Each concentration is done in triplicate. The fluorescence readings (320 nm excitation, 390 nm emission) are taken at zero time and then at 15 minute intervals for 3 hours. The Cl50 are determined as in the case of the inhibition of human collagenase (MMP-1). If the Cl50's are less than 0.03 μM, then the inhibitors are tested at the final concentrations of 0.03 μM, 0.003 μM, 0.0003 μM and 0.00003 μM. The IC50 values were determined in the same manner as in the case of collagenase.

Inhibition of MMP-13 Recombinant human MMP-13 is activated with 2 mM APMA (p-aminophenyl mercuric acetate) for 2.0 hours, at 37 ° C and diluted to 240 ng / ml in assay buffer (50 mM Tris, pH 7.5 , 200 mM sodium chloride, 5 mM calcium chloride, 20 μM zinc chloride and 0.02% brij 35). Twenty-five microliters of diluted enzyme is added per well of a 96-well Microfluor plate. The enzyme is then diluted in a 1: 4 ratio by addition and inhibitor and substrate to give a final concentration in the assay of 60 ng / ml. Stem solutions (10 mM) of inhibitors are made in dimethylsulfoxide and then diluted in assay buffer as in the dilution scheme of the inhibitor for the inhibition of human collagenase-1 (MMP-1): twenty-five microliters of each concentration are added in triplicate to the Microfluor plate. The final concentrations in the assay are 30 mM, 3 mM, 0.3 mM and 0.03 mM. The substrate (Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) is prepared as in the case of the inhibition of human collagenase (MMP-1) and 50 μl is added to each well to give a final assay concentration of 10 μM. The fluorescence readings (360 nm excitation, 450 nm emission) are taken at time 0 to every 5 minutes for 1 hour. Positive controls and negative controls are performed in triplicate as indicated in the MMP-1 assay. The IC50's are determined as in the inhibition of human collagenase (MMP-1). If the IC50's are less 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 their pharmaceutically acceptable salts to inhibit TNF production and, therefore, demonstrate their efficacy for the treatment of diseases involving the production of TNF is shown by the following in vitro assay. : Human mononuclear cells were isolated from anticoagulated human blood using a one-step Ficoll-hypaque separation technique. (2) The mononuclear cells 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 monocytes varied from 17 to 24% of the total cells in these preparations. Aliquots of 180 μl of the cell suspension were placed in 96-well flat bottom plates (Costar). Additions of LPS compounds (final concentration 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 removed and centrifuged (10 minutes at approximately 250 x g) and the supernatants were removed and assayed for TNFa. using the R & D ELISA kit.

Inhibition of the production of soluble TNF-a The ability of the compounds or their pharmaceutically acceptable salts to inhibit the cellular release of TNF-a and, consequently, to demonstrate their efficacy for the treatment of diseases involving abnormal regulation of TNF -a soluble, is shown by the following in vitro assay: Procedure for the evaluation of the activity of the recombinant TNF-α converting enzyme expression of recombinant TACE A DNA fragment encoding the signal sequence, the pre-domain, the predominance and the catalytic domain of TACE (amino acids 1-473) can be amplified by a 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 the two chains. A bacmid prepared using pFastBac in E. coli DHI OBac is transfected into SF9 insect cells. The viral particles are then amplified to phases P1, P2 and P3. The P3 virus infects both Sf9 and High Five insect cells and develops at 27 ° C for 48 hours. The medium is collected and used for testing and for further purification.

Preparation of fluorescent inactivated substrate A substrate peptide model of TNF-α (LY-LeucineAlanineGlutamineAlanineValineArginine SerineSerinaLisine (CTMR) -Arginine (LY = Amariyl Lucifer, CTMR = Carboxitetramethyl-Rhodamine)) is prepared and the concentration is estimated 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". Bioconjugate Chem. 7, 385-391 (1995). This peptide includes the cleavage site in pro-TNF that is cleaved in vivo by TACE.

Expression of recombinant TACE A DNA fragment encoding the signal sequence, pre-domain, predominance and TACE catalytic domain (amino acids 1-473) is amplified by polymerase chain reaction using a human lung cDNA library as mold. The amplified fragment is then cloned into the pFastBac vector. The DNA sequence of the insert is conformed for the two chains. A bacmid prepared using pFastBac in E. coli DHI OBac is transfected into SF9 insect cells. The viral particles will then be amplified to the P1, P2, and P3 phases. The P3 virus infects both Sf9 and High Five insect cells and develops at 27 ° C for 48 hours. The measurement is collected and used for testing and for further purification.

Enzyme reaction The reaction, performed in a 96-well plate (Dynatech), is composed of 70 μl of buffer solution (25 mM Hepes-HCl, pH 7.5, plus 20 μM ZnCl 2), 10 μl of inactivated 100 μM fluorescent substrate, μl of a solution of test compound in DMSO (5%) and an amount of r-TACE enzyme that will cause a 50% collision 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. The initial rates of excision are controlled by measuring the rate of fluorescence increase at 530 nm (excitation at 409 nm) for 30 minutes.

The experiment is controlled as follows: 1) for background fluorescence of the substrate; 2) for the fluorescence of the fully cleaved substrate; and 3) for the inactivation or increase of fluorescence of solutions containing the test compound. The data is analyzed as indicated below. The average velocities of the "control" reactions that did not contain test compound were calculated to establish the 100% value. The reaction rate in the presence of the test compound was compared with the rate in the absence of compound and was indicated in the table as "percentage of control that does not contain test compound". The results are represented as "% control" against the log. of compound concentration and the semi-maximum point or IC 50 value is determined. All compounds of the invention have IC 50 values 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.

Human Monocyte Assay Human mononuclear cells are isolated from anticoagulated human blood using a one-step Ficoll-hypaque separation technique. (2) Mononuclear cells are 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 monocytes varied from 17 to 24% of the total cells in these preparations. 180 μm aliquots of the cell suspension were placed in 96-well flat bottom plates (Costar). Additions of the compounds and LPS (100 ng / ml final concentration) gave a final volume of 200 μl. All conditions were performed in triplicate. After a four hour incubation at 37 ° C in a humidified CO2 incubator, the plates were removed and centrifuged (10 minutes at approximately 250 x g) and the supernatants were removed and the TNF-a assayed using the R &; D ELISA. Aggrecanase Assay Primary porcine chondrocytes from articular cartilage are isolated by sequential digestion with trypsin and collagenase followed by digestion with collagenase overnight and cultured at a density of 2 x 10 5 cells per well in 48-well plates with 5 μCi / ml 35S sulfur (1000 Ci / mmol) in plates coated with type I collagen. The cells are allowed to incorporate the marker in their proteoglycan matrix (approximately 1 week) at 37 ° C, under a 5% CO2 atmosphere. The night before starting the assay, chondrocyte monolayers are washed twice in DMEM / 1% PSF / G and then allowed to incubate in DMEM / 1% clean FBS overnight.

The next morning, the chondrocytes are washed once in DMEM / 1% PSF / G. The final wash liquid is left on the plates of the incubator while the dilutions are made. The media and dilutions can be performed as described in the following table. DMEM control medium alone (control medium) IL-1 medium DMEM + IL-1 (5 ng / ml) Dilutions of performing all stock solutions of compound at a drug 10 mM concentration in DMSO. Make a 100 μM stock solution of each compound in DMEM in 96-well plates. Store the freezer overnight. The next day, dilute seriously in DMEM with IL-1 at 5 μM, 500 nM and 50 nM. Aspirate the final washings of the wells and add 50 μl of compound from the previous dilutions to 450 μl of IL-1 medium in appropriate wells of the 48-well plates. Final compound concentrations equal to 500 nM, 50 nM and 5 nM. All samples were completed in triplicate with control and IL-1 samples alone in each plate.

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 and without drug). These control columns are counted periodically to control the release of 35S-proteoglycan. Control medium and IL-1 medium are added to the wells (450 μl) followed by the compound (50 μl) to start the assay. The plates are incubated at 37 ° C with a 5% CO2 atmosphere. When a release of 40-50% is reached (when the CPM value of the IL-1 medium is 4-5 times greater than that of the control medium) as assessed by liquid scintillation counting (LSC) of medium samples, the trial is finished (9-12 hours). The medium is removed from all wells and placed in scintillation tubes. The scintillation fluid is added and the radioactive counts (LSC) are acquired. To solubilize the cell 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) is 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 scintillation tubes. Then the scintillation liquid is added and the samples (LSC) are counted. The percentage of counts released from the total present in each well is determined. Averages of the triplicates are obtained by subtracting the background effect of the control of each well. The percent inhibition of the compound is based on IL-1 samples as 0% inhibition (100% 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 including oral, parenteral (e.g., intravenous) can be used. , intramuscular or subcutaneous), sublingual, anal and topical. In general, the active compounds will be administered in doses ranging from about 0.1 to 25 mg / kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg / kg. Preferably, the active compound will be administered orally or parenterally. However, there will necessarily be some variation in the dosage depending on the condition of the subject to be treated. The person responsible for the administration, in any case, will determine the appropriate dose for the individual subject. The compounds of the present invention can be administered in a wide variety of different dosage forms, in general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70%. % in weigh. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate may be employed., sodium carbonate, dicalcium phosphate and glycine, together with various 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, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for forming tablets. Solid compositions of a similar type can also be employed as fillers in gelatin capsules; Preferred materials in this regard also include 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, as well as, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. In the case of animals, they are advantageously included in the animal feed or in the drinking water 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 in aqueous propylene glycol. The aqueous solutions should be adjusted and buffered conveniently, preferably at a pH greater than 8, if necessary, and the liquid diluent first made 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 easily accomplished 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 dosage 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 such as eye drops, aerosol, gels or ointments, or it may be incorporated into collagen (such as poly-2-hydroxyethylmethacrylate and copolymers thereof), or a hydrophilic polymeric support. The materials can also be applied as a contact lens or by a local deposit or as a formulation for the subconjunctival. For intraorbital administration, a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention may be employed in an aqueous solution or suspension (particle size less than 10 microns). The aqueous solutions can be adjusted and buffered conveniently, preferably at a pH of 5 to 8, if necessary, and the liquid diluent must first be made isotonic. Small amounts of polymers may be added to increase the viscosity or for sustained release (such as cellulose polymers, Dextran, polyethylene glycol or alginic acid). These solutions are suitable for intra-orbital injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by conventional pharmaceutical techniques well known to those skilled in the art. In the case of animals, the compounds can be administered intraorbitally at dosage levels of approximately 0.1 to 50 mg / kg / day, advantageously 0.2 to 10 mg / kg / day administered in a single dose or in 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 delivered in the form of a solution or suspension from a spray container with a boba that is compressed or pumped by the patient, or in the form of a presentation of Spray spray from a pressurized container or nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide and other suitable gases. 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 and 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 starch or lactose. The following preparations and examples illustrate the preparation of the compounds of the present invention. The melting points are uncorrected. The NMR data are expressed in parts per million (d) and refer to the deuterium stabilization signal of the sample solvent (deuteriochloroform unless otherwise specified). 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 silica gel and is carried out under nitrogen pressure conditions (flash chromatography). Ambient temperature refers to 20-25 ° C. All non-aqueous reactions were conducted under a nitrogen atmosphere for reasons of convenience and to maximize yields. The concentration under reduced pressure means that a rotary evaporator was used.

PREPARATION 1: 4- (4-Fluorophenoxy) thiophenol Lithium aluminum hydride (9.95 grams, 0.26 moles) was added in portions to a stirred solution of 4- (4-fluorophenoxy) benzenesulfonyl chloride (30 grams, 0.105 moles) in tetrahydrofuran (700 ml). The resulting mixture was refluxed for 1.5 hours, cooled in an ice bath and quenched by the addition of a 10% aqueous solution of sulfuric acid (100 ml). After stirring for 30 minutes, the mixture was filtered through Celite ™ and the tetrahydrofuran was removed in vacuo. The residue was diluted with water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to provide the title compound as a white solid (23 grams, 100%).

PREPARATION 2 4'-Fluorobiphenyl-4-thiol Lithium aluminum hydride (0.95 grams, 25 mmol) was added in portions to a stirred solution of 4'-fluorobiphenyl-4-sulfonyl chloride (2.7 grams, 10 mmol) in tetrahydrofuran (75 mL). The resulting mixture was refluxed for 4 hours, cooled in an ice bath and quenched by the addition of a 10% aqueous solution of sulfuric acid (100 ml). After stirring for 30 minutes, the mixture was filtered through Celite ™ and the tetrahydrofuran was removed in vacuo. The residue was diluted with water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo until a solid was obtained. Trituration of the solid with diethyl ether, removal of the insoluble material by filtration and concentration of the filtrate afforded the title compound as a yellow solid (1.4 grams, 69%).

PREPARATION 3 4- (4-Chlorophenoxy) thiophenol Lithium aluminum hydride (6.5 grams, 0.17 moles) was added portionwise, maintaining a gentle reflux, to a stirred solution of 4- (4-chlorophenoxy) benzenesulfonyl chloride (20.5 grams) , 68 mmol) in tetrahydrofuran (400 ml). The resulting mixture was stirred at room temperature for 2 hours, cooled in an ice bath and quenched by the addition of a 10% aqueous solution of sulfuric acid (100 ml). After stirring for 30 minutes, the mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (15.9 grams, 99%).

EXAMPLE 1 Hydroxyamide of 3-exo-r4-.4-fluorophenoxy) benzenesulfonylamino-8-oxa-bicyclic-3-octane-3-carboxylic acid A) 3- (Benzhydrylideneamino) -8-oxabicyclic3.2.noctane-3-carboxylic acid ethyl ester To a suspension of sodium hydride (0.41 grams, 17.1 mmol) in N, N-dimethylformamide (50 ml) at 0 ° C , a solution of the ethyl ester of N-diphenylmethylene glycine (2.07 grams, 7.8 mmol) in N, N-dimethylformamide (50 ml) was added dropwise. After stirring for 30 minutes at room temperature, a solution of cis-2,5-bis (hydroxymethyl) -tetrahydrofuran ditosylate (4.1 grams, 9.3 mmol) in N, N-dimethylformamide (50 ml) was added dropwise. The reaction mixture was gradually heated to 100 ° C in an oil bath and stirred at this temperature overnight. The solvent was evaporated in vacuo and the residue was taken up in water and extracted twice with diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated until a brown oil was obtained, from which the title compound was asylated (1.42 grams, 51%, a 3: 1 mixture of diastereomers). exo / endo) by chromatography on silica gel (20% ethyl acetate in hexane as eluent: B) 3-amino-8-oxabicyclo [3.2.1l octane-3-carboxylic acid ethyl ester hydrochloride A two-phase mixture of 3- (benzhydrylideneamino) -8-oxabicyclo [3.2.1] octane- ethyl ester 3-carboxylic acid (1.4 grams, 3.9 mmol) in 1N hydrochloric acid aqueous solution (100 ml) and diethyl ether (100 ml) was stirred at room temperature overnight. The aqueous layer was concentrated to give the title compound (0.70 grams, 79%, in a 3: 1 mixture of diastereoisomers exo / endo) as a light yellow solid.

QL 3-Exo- [4- (4-fluorophenoxy) benzenesulfonylamino-8-oxabicyclo3-octane-3-carboxylic acid ethyl ester A solution of 3-amino-8-oxabicyclo [3.2.1] ethyl ester hydrochloride ] octane-3-carboxylic acid (690 mg, 2.9 mmol), 4- (4-fluorophenoxy) benzenesulfonyl chloride (923 mg, 3.2 mmol) and triethylamine (0.9 ml, 6.5 mmol) in N, N-dimethylformamide (45 ml) it was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was taken up in saturated aqueous sodium bicarbonate solution. After extracting twice with methylene chloride, the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated until a pale oil was obtained. The title compound (492 mg, 38%) was isolated by chromatography on silica gel using 1% methanol in methylene chloride as eluent.

D) 3-Exo-4 (4-fluorophenoxy) -benzenesulfonylamino * -8-oxabicyclo | 3.2.p octane-3-carboxylic acid Sodium hydroxide (1.5 grams, 38 mmol) was added to a solution of ethyl acid ester 3-exo- [4- (4-fluorophenoxy) benzenesulfinylamino] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid (492 mg, 1.09 mmol) in a mixture of ethanol (10 ml) and water (10 ml) The mixture was refluxed for 6 days, cooled and acidified with a 1N aqueous solution of hydrochloric acid.The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and dried. was concentrated to give the title compound (41.1 mg, 89%) as a tan foam. _____ 3-exo.4-.4-fluorophenoxy) benzenesulfonylamino-8-oxabicyclo [3.2.11-octane-3-carboxylic acid benzyloxy acid to a solution of 3-exo- [4- (4-fluorophenoxy) -benzenesulfonylamino] ] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid (41 mg, 0.98 mmol, and triethylamine (0.19 ml, 1.36 mmol) in N, N-dimethylformamide (30 ml) was added (benzotriazole-1-hexafluoroborate). -iloxy) ris- (dimethylamino) phosphonium (474 mg, 1.07 mmol) After stirring at room temperature for 1 hour, added more triethylamine (0.22 ml, 1.28 mmol) and O-benzylhydroxylamine hydrochloride (187 mg, 1.17). mmoles) The reaction mixture was stirred for 1 day at room temperature and then for 1 day at 50 ° C. After concentration in vacuo, the residue was dissolved in ethyl acetate and washed sequentially with a 1 N aqueous solution. of hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and brine, dried the solution over magnesium sulfate and Concentrated until an oil was obtained which was isolated, as a white solid, the title compound (237 mg, 46%), by chromatography (50% ethyl acetate in hexane as eluent). a 3-Exo-.4- (4-Fluoro-phenox-benzenesulfonyl-amino-8-oxa-bicyclo [3.2.11-octane-3-carboxylic acid hydroxyamide A solution of 3-exo- [4- (4-fluorophenoxy) benzenesulfonylamino] benzyloxyamide ] -8-oxabicyclo [3.2.1] -octane-3-carboxylic acid (237 mg, 0.45 mmol) in methanol (25 ml) was treated with 5% palladium on barium sulfate (150 mg) and hydrogenated to a pressure of 3.033 x 105 Pa for 4 hours on a Parr ™ agitator The catalyst was removed by passing through a 0.45 μm nylon filter and the filtrate was concentrated until a white foam was obtained.Crystallization from methylene chloride produced The title compound was in the form of a white solid (62 mg, 32%), a second crop (62 mg, 32%) was obtained by crystallization from ethyl acetate / hexane, MP 138-141 ° C. 1 H NMR (d6). -DMSO: d 10.50 (s broad, 1 H), 8.56 (sa, 1 H), 7.67 (d, J = 8.7 Hz, 2H), 7.66 (sa, 1 H, overlapped), 7.26-7.22 (m, 2H ), 7.16-7.12 (m, 2H), 7.01 (d, J = 8.5 Hz, 2H), 4.09 (s a, 2H), 2.32 (d, J = 14.1 Hz, 2H), 1.68-1.63 (m, 4H), 1.51-1.48 (m, 2H). MS: 435 m / e (M-H). Additional confirmation of the structure and stereochemistry was performed by X-ray crystallography of individual crystals.

EXAMPLE 2 3-Exo-R4- (4-flurofenoxi) benzenesulfinylmethyl-8-oxabicyclo-F3.2.n-octane-3-carboxylic acid hydroxylamide A) 8-Oxo-bicyclo [3.2.11-ocatane-3,3-dicarboxylic acid diethyl ester) Sodium hydride (2.28 grams, 95 mmol) was added in portions to a stirred solution of diethyl malonate (15 ml, 99 mmol) in N, N-dimethylformamide (400 ml). The mixture was stirred for 45 minutes, after which the evolution of hydrogen had ended. Then, a solution of cis-2,5-bis (hydroxymethyl) tetrahydrofuran ditosylate (19.0 grams, 43 mmol) in N, N-dimethylformamide (400 ml) was added dropwise. The mixture was heated in an oil bath at 140 ° C overnight. After cooling to room temperature, the mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and the vacuum concentrated. The residual oil was taken up in water and extracted with diethyl ether. The organic extract was washed with water and brine, dried over magnesium sulfate and concentrated until an oil was obtained. Vacuum distillation afforded the title compound (7.8 grams, 71%) as a clear oil.

B) Ethyl ester of 3-exo-hydroxymethyl-8-oxabicyclo [3.2.11 octane-3-carboxylic acid A 1.2 M solution of diisobutylaluminum hydride in toluene (62.5 ml, 75 mmol) was added dropwise to a solution of 8-oxabicyclo [3.2.1] -octane-3,3-dicarboxylic acid diethyl ester (7.8 grams, 30 mmol) in toluene (80 ml) at -40 ° C. The mixture was allowed to warm to 0 ° C while stirring for a period of 3 hours. It was then cooled to -15 ° C and ethanol (8 ml) was slowly added while maintaining this temperature. After stirring at -15 ° C for 1 hour, sodium borohydride (1.1 grams, 30 mmol) was added. The mixture was stirred at room temperature overnight and quenched by the dropwise addition of a saturated aqueous solution of sodium sulfate. Ethyl acetate was added and, after stirring for 20 minutes, the insoluble material was removed by filtration through Celite ™. The filtrate was washed with brine, dried over magnesium sulfate and concentrated to yield the title compound (5.1 grams, 80%) as a clear oil.

C) 3-Exo-hydroxymethyl-8-oxabicyclo [3.2.1"l-octane-3-carboxylic acid hydrated lithium hydroxide (2.5 grams, 59.5 mmol) to a solution of 3-exo-h-ethyl ester Hydroxy-8-oxabicyclo [3.2.1] octane-3-carboxylic acid (5.1 grams, 23.8 mmol) in a mixture of methanol (25 ml), tetrahydrofuran (25 ml) and water (2.5 ml). reflux overnight, cooled and quenched by the addition of Amberlite IR-120 ™ ion exchange resin After stirring for 20 minutes, the resin was separated by filtration, washed with tetrahydrofuran, evaporation of solvents and grinding of the residue with diethyl ether afforded the title compound (2.35 grams, 53%) as a white solid.

D) 3'-8-Dioxaspiro, bicyclo [3.2.11 octane-3.1'-cyclobutane1-2'-one. Benzenesulfonyl chloride (1.7 ml, 13.5 mmol) was added dropwise to a solution of 3-exo-hydroxymethyl acid. -8-oxabicyclo [3.2.1] octane-3-carboxylic acid (2.3 grams, 12.3 mmol), triethylamine (3.4 ml, 24.7 mmol) and 4-dimethylaminopyridine (300 mg, 2.5 mmol) in methylene chloride (50 ml) a 0 ° C. The mixture was stirred at 0 ° C for 1 hour, diluted with methylene chloride and washed with 1N hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate, the solvent was evaporated yielding the title compound as a white solid (1.8 grams, 90%).

E) 3-exo- [4- (4-fluorophenoxy) phenylsulfanyl-methyp-8-oxabicyclo [3.2.11 octane-3-carboxylic acid] A solution of 4- (4-flurofenoxy) thiophenol (2.2 grams) , 10 mmol) in tetrahydrofuran (10 ml) was added dropwise to a suspension of sodium hydride (270 mg, 1.3 mmol) in tetrahydrofuran (20 ml) at -10 ° C. The mixture was allowed to warm to room temperature while stirring for 30 minutes. After cooling back to -10 ° Ca solution of 3 ', 8-dioxaspiro [bicyclo [3.2.1] octane-3,1' -cyclobutane] -2'-one (1.8 grams, 10 mmol) in tetrahydrofuran (20 ml) was added dropwise. . The cooling bath was removed and stirring was continued at room temperature for 2 hours, after which the mixture was quenched with an aqueous 1 N hydrochloric acid solution and extracted twice with methylene chloride. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and concentrated until a solid was obtained. Recrystallization from diethyl ether / hexane afforded the title compound (1.8 grams, (47%)) as a white solid. The concentration of the mother liquors, followed by chromatography on silica gel (2% methanol in chloroform as eluent) yielded more title compound (500 mg, 13%).

Benzyloxyamide of 3-exo-f4- (4-fluorophenoxy) phenylsulfanylmethyl-8-oxabicyclo [3.2.11 octane-3-carboxylic acid To a solution of 3-exo- [4- (4- fluorophenoxy) benzenesulfanylmethyl] -8-oxabicyclo [3.2.1] octane-3-caboxylic acid (1.0 grams, 2.6 mmol) and diisopropylethylamine (0.5 ml, 2.9 mmol) in N, N-dimethylformamide (20 ml), hexafluoroborate was added. (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium (1.2 grams, 2.7 mmol). After stirring at room temperature for 2.5 hours, more diisopropylethylamine (0.86 ml, 4.9 mmol) and O-benzylhydroxylamine hydrochloride (525 mg, 3.3 mmol) were added. The reaction mixture was stirred for 16 hours at 50 ° C. After concentration in vacuo, the residue was dissolved in ethyl acetate and washed sequentially with 1N hydrochloric acid aqueous solution, saturated aqueous sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated to give an oil from which the title compound (405 mg, 32%) was isolated as a white foam, by chromatography (30% ethyl acetate in hexane as eluent ).

Gl 3-Exo-R4- (4-fluorophenoxy) phenylsulfonylmethyl] -8-oxabicyclo3.3.11 octane-3-carboxylic acid benzyloxy acid 57-85% solid meta-chloroperbenzoic acid (283 mg) was added to a solution of 3-exo- [4- (4-fluorophenoxy) phenylsulfanylmethyl] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid benzyloxylamide in methylene chloride (15 ml). The resulting mixture was stirred at room temperature overnight and then quenched by the addition of saturated aqueous sodium bisulfite solution. After dilution with methylene chloride, the organic layer was separated and washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate and concentrated to give the title compound as a white foam (390 mg, 90%). _____ Hydroxyamide of 3-exo acid, 4- (4-fluorophenoxy) benzenesulfonylmethyl-8-oxabicyclo-r3.2.1] -octane-3-carboxylic acid A solution of benzyloxylamine of 3-exo- [4- (4-fluorophenoxy ) benzenesulfonylmethyl] -8-oxabicyclo [3.2.1] -octane-3-carboxylic acid (390 mg, 0.74 mmol) in methanol (20 ml) was treated with 5% palladium on barium sulfate (195 mg) and hydrogenated a pressure of 3.033 x 105 Pa for 3.5 hours in a Parr ™ agitator. The catalyst was removed by passing through a 0.45 μm nylon filter and the filtrate was concentrated until a white foam was obtained. Crystallization from a mixture of ethyl acetate and hexane afforded the title compound as a white solid (230 mg, 71%). P.f. 134-139 ° C. 1 H NMR (de-DMSO): d 8.55 (br s, 1 H), 7.76 (d, J = 7.5 Hz, 2H), 7.30-7.26 (m, 2H), 7.20-7.16 (m, 2H), 7.09 (d , J = 7.5 Hz, 2H), 4.13 (sa, 2H), 3.40 (s, 2H), 2.24 (d, J = 14.3 Hz, 2H), 1.78-1.73 (m, 4H), 1.57-1.55 (m, 2H), MS m / e 434 (MH). Additional confirmation of the structure and stereochemistry was performed by X-ray crystallography of individual crystals. EXAMPLE 3 3- (4-Phenoxybenzenesulfonylmethyl) -8-oxabicyclo3.2.11 octane-3-carboxylic acid hydroxyamide Prepared according to the same procedure as in example 2, using 4-phenoxyphenylthiophenol in step E. 1 H NMR (de-DMSO): d 8.54 (sa, 1 H), 7.75 (d, J = 8.9 Hz, 2H) , 7.44-7.40 (m, 2H), 7.23-7.21 (m, 1 H), 7.11-7.07 (m, 4H), 4.11 (s, 2H), 3.38 (s, 2H), 2.22 (s, J = 14.3 Hz, 2H), 1.80-1.70 (m, 4H), 1.60-1.50 (m, 2H), MS m / e 416 (MH).

EXAMPLE 4 3-Exo- (4'-Fluorobiphenyl-4-sulfonylmethyl) -8-oxabicyclo-r3.2.poctane-3-carboxylic acid hydroxyamide Prepared according to the same procedure as in example 2, using 4'-fluorobiphenyl-4-thiol in step E. 1 H NMR (de-DMSO): d 10.60 (br s, 1 H), 8.58 (br s, 1 H ), 7.88-7.85 (m, 4H), 7.81-7.78 (m, 2H), 7.36-7.31 (m, 2H), 4.13 (sa, 2H), 3.47 (s, 2H), 2.25 (d, J = 14.5 Hz, 2H), 1.80-1.76 (m, 4H), 1.60-1.55 (m, 2H), MS m / e 418 (MH).

EXAMPLE 5 Hydroxyamide of 3-exo-r4- (4-chlorophenoxy) benzenesulfonylmethin-8-oxa-bicyclo [3.2.noctane-3-carboxylic acid TO 3-Exo- [4-, 4-chlorophenoxy) phenylsulfanylmethyl-p-8-oxabicyclof3.2.1l-octane-3-carboxylic acid. 4- (4-chlorophenoxy) thiophenol (2.07 grams, 6.8 mmol) was added to a suspension. of sodium hydride (180 mg, 7.5 mmol) in tetrahydrofuran (50 ml) at room temperature. The mixture was allowed to stir at room temperature for 45 minutes. 3 ', 8-dioxaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutanol] -2One (1.04 grams, 6.2 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was quenched with aqueous 1 N hydrochloric acid solution and extracted twice with methylene chloride. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated until a solid was obtained. Trituration with diethyl ether produced, after filtration, the title compound as a white solid (1.47 grams, 59%).

BL 3-Exo-.4-, 4-chlorophenoxy) phenylsulfanylmethyl-8-oxabicyclo [3.2.11-octane-3-carboxylic acid hydroxyamide To a suspension of 3-exo- [4- (4-chlorophenoxy) phenylsulfanylmethyl acid) -8-oxabicyclo [3.2.1] octane-3-carboxylic acid (1.47 grams, 3.63 mmol) in methylene chloride (20 ml) at room temperature, oxalyl chloride (0.8 ml, 9.2 mmol) and N were added dropwise. , N-dimethylformamide (1 drop). The mixture was stirred at room temperature overnight. After evaporation of the volatiles in vacuo, the residue was dissolved in methylene chloride (20 ml), cooled to 0 ° C and treated dropwise with O-trimethylsilylhydroxylamine (1.35 ml, 1.0 mmoles) the resulting mixture it was stirred at room temperature for 3.5 hours, cooled in an ice bath and quenched by the addition of a 1 N hydrochloric acid aqueous solution, stirring at 0 ° C for an additional 30 minutes. After dilution with ethyl acetate, the organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated to yield the title compound as a white foam (1.52 grams, 100%).

CL 3-Exo-.4-.4-chlorophenoxybenzenesulfonylmetip-8-oxaabicyclo f3.2.n-octane-3-carboxylic acid hydroxide Oxone ™ (4.2 grams, 8.63 mmol) was added to a solution of 3-hydroxyamide. exo- [4- (4-chlorophenoxy) phenyl-sulfanylmethyl] -8-oxabicyclo [3.2.1.] octane-3-carboxylic acid (1.52 grams, 3.63 mmol) in a mixture of water (30 ml), methanol ( 40 ml) and tetrahydrofuran (12 ml). The resulting mixture was stirred at room temperature overnight, diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated until a foam was obtained from which the title compound was isolated (846 mg, 52%) by chromatography on silica gel (methanol 4). % in chloroform as eluent). 1 H NMR (de-DMSO): d 10.58 (br s, 1 H), 8.53 (br s, 1 H), 7.76 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.15 -7.1 1 (m, 4H), 4.1 1 (sa, 2H), 3.40 (s, 2H), 2.22 (d, J = 14.3 Hz, 2H), 1.76-1.71 (m, 4H), 1.57-1.55 (m , 2H), MS m / e 450 (MH). Having described the invention as above, the contents of the following are declared as property

Claims (27)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula where Z is > CH2 or > NR1; R1 is hydrogen, (C? -C6) alkyl, aryl (C6-C? O) alkyl (C? -C6), heteroaryl (C2-C9) -alkyl (C? -Ce) or a group of the formula n is an integer from one to six; R2 is hydrogen or alkyl (C? -C6); Q is alkyl (C? -C6), aryl (C6-C? O), heteroaryl (C2-C9), aryloxy (C6-C? O) alkyl (C-Ce), aryloxy (C6-C? O) aryl (C6-C? O), aryloxy (C6-C? 0) heteroaryl (C2-C9), aryl (C6-C? O) alkyl (C? -Ce), aryl (C6-C? O) aryl (C6) -C?), Aryl (C6-C? O) heteroaryl (C2-C9), aryl (C6-C? O) aryl (C6-C? O) alkyl (C? -C6), aryl (C6-C) ? o) aryl (C6-C? o) aryl (C6-C? 0), aryl (C6-C? o) aryl (C6-C? o) heteroaryl (C2-C9), heteroaryl (C2-Cg) alk (C? -Ce), heteroaryl (C2-C9) aryl (C6-C? 0), heteroaryl (C2-Cg) heteroaryl (C2-Cg), aryl (C6-doylalkoxy-Cealkyloid-Ce), aryl ( C6-C? O) alkoxy (C? -C6) aryl (C6-C? 0), aryl (C6-C? O) alkoxy (C? -C6) heteroaryl (C2-C9), heteroaryloxy ( C2-Cg) alkyl (C? -Ce), heteroaryloxy (C2-C9) aryl (C6-C? O), heteroaryloxy (C2-C9) heteroaryl (C2-Cg), heteroaryl (C2-C9) alkoxy (C? -C6) alkyl (C? -C6), heteroaryl (C2-Cg) alkoxy (C? -C6) aryl (C6-C? O), heteroaryl (C2-C9) alkoxy (C? -C6) heteroaryl (C2) -C9), aryloxy (C6-C? O) alkyl (C? -C6) aryl (C6-C? O), aryloxy (C6-C? O) alkyl (C? -C6) heteroaryl (C2-Cg) ), heteroaryloxy (C2-C9) alkyl (C? -Ce) aryl (C6-C? o) or hetero (C2-C9) aryloxy (C6-6) alkylheteroaryl (C2-C9) alkyl; wherein each aryl radical (C6-C? 0) or heteroaryl (C2-C9) of said aryl (C6-C? o), heteroaryl (C2-C9), aryloxy (C6-C? o) alkyl (C? -C6) ), aryl (C6-C? o) aryl (C6-C? 0), aryloxy (C6-C? o) heteroaryl (C2-C9), aryl (C6-C? o) alkyl (C? -C6), aryl (C6-C? O) aryl (C6-C? O), aryl (C6-C? 0) heteroaryl (C2-C9), aryl (C6-C? O) ar1l (Ce- C? O) alkyl (C? -C6), aryl (C6-C? O) aryl (C6-C? O) aryl (C6-C? O), aryl (C6-C? O) aryl (C6-C) ?) heteroaryl (C2-C9), heteroaryl (C2-C9) alkyl (C? -C6), heteroaryl (C2-Cg) aryl (C6-C? o), heteroaryl (C2-C9) heteroaryl (C2-C9) ), aryl (C6-C? o) alkoxy (d-C6) alkyl (C? -C6), aryl (C6-C? o) alkoxy (CrC6) aryl (C6-C? o), aryl (C6-C) o) C 1 -C 6 alkoxy heteroaryl (C 2 -C 9), heteroaryloxy (C 2 -C 9) alkyl (C 6 -C 6), heteroaryloxy (C 2 -Cg) aryl (C 6 -C 7), heteroaryloxy (C 2 -C 6) Cg) heteroaryl (C2-Cg), heteroaryl (C2-Cg) alkoxy (C6-6) alkyl (C6-6), heteroaryl (C2-Cg) alkoxy (C6-6) aryl (C6-C6) ), heteroaryl (C2-C9) alkoxy (C? -C6) heteroaryl (C2-C9), aryloxy (C6-C? o) alkyl (Cr) C6) aryl (C6-C? O), aryloxy (C6-C? O) alkyl (C? -Ce) heteroaryl (C2-Cg), heteroaryloxy (C2-C9) alkyl (C? -6) aryl (C6-C10) or (C2-C9) heteroaryloxy (C6-6) alkyl (C2-Cg) heteroaryl optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or more substituents per ring selected independently between fluoro, chloro, bromo, alkyl (C? -C6), alkoxy (C? -C6), perfluoro-alkyl (C? -C3), perfluoro-alkoxy (C? -3) and aryloxy (C6-C? or); or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, with the stereochemistry represented by the formula

3. - A compound according to claim 1, wherein Z is CH2.

4. A compound according to claim 2, wherein Z is CH2.

5. A compound according to claim 1, wherein Z is > NR1 and R1 is a group of the formula and where n is 2.

6. A compound according to claim 2, wherein Z is > NR1 and R1 is a group of the formula and where n is 2.

7. A compound according to claim 1, wherein Z is > NR1 and R1 is hydrogen.

8. A compound according to claim 2, wherein Z is > NR1 and R1 is hydrogen.

9. A compound according to claim 1, wherein Q is aryl (C6-C? O), heteroaryloxy (C2-C9) aryl (Ce-Cio) or aryloxy (C6-C? O) aryl (C6) -C? O), wherein each aryl or heteroaryl radical of said aryl groups (C6-C? O), heteroaryloxy (C2-C9) aryl (C6-C? O) or aryloxy (C6-C? 0) aryl (C6) -C?) May be optionally substituted by one or more substituents independently selected from fluoro, chloro, bromo, alkyl (Ci-Cß), alkoxy (d-Cß) or perfluoro-alkyl (C? -C3).

10. A compound according to claim 2, wherein Q is aryl (C6-C? O), heteroaryloxy (C2-C9) aryl (C6-C? O) or aryloxy (C6-C? O) aryl (C6-C? O), wherein each aryl or heteroaryl radical of said aryl groups (C6-C? 0), heteroaryloxy (C2-Cg) aryl (C6-C? O) or aryloxy (C6-C? O) aryl (C6-do) may be optionally substituted by one or more substituents independently selected from fluoro, chloro, bromo, alkyl (C? -C6), alkoxy (Ci-C?) Or perfluoro-alkyl (C? -C3).

1. A compound according to claim 3, wherein Q is aryl (C6-C? O), heteroaryloxy (C2-C9) aryl (Ce-C o) or aryloxy (C6-C? O) aryl (C6-C? O), wherein each aryl or heteroaryl radical of said aryl groups (C6-C? O), heteroaryloxy (C2-C9) aryl (C6-C? O) or aryloxy (C6-C? O) ar (C6-C? O) may be optionally substituted by one or more substituents independently selected from fluoro, chloro, bromo, alkyl (d-C6), alkoxy (d-C6) or perfluoro-alkyl (C? -C3) .

12. A compound according to claim 5, wherein Q is aryl (Ce-Cio), heteroaryloxy (C2-Cg) aryl (C6-C? O) or aryloxy (Ce-Cio) aryl (C6-C) ? 0), wherein each aryl or heteroaryl radical of said aryl groups (C6-C? O), heteroaryloxy (C2-Cg) aryl (C6-C? 0) or aryloxy (C6-C? O) aryl (Ordo) can optionally being substituted by one or more substituents independently selected from fluoro, chloro, bromo, alkyl (C? -C6), alkoxy (dO.) or perfluoro-alkyl (C? -C3).

13. A compound according to claim 7, wherein Q is aryl (C6-C? 0), heteroaryloxy (C2-C9) aryl (C6-C? 0) or aryloxy (C6-C? O) aryl (Ce-Cio), wherein each aryl or heteroaryl radical of said aryl groups (C6-C? O), heteroaryloxy (C2-C9) aryl (Ce-Cio) or aryloxy (C6-C? 0) aryl (C6-C10) ) may optionally be substituted by one or more substituents independently selected from fluoro, chloro, bromo, (C? -C6) alkyl, (C? -C6) alkoxy or perfluoro-alkyl (CrC3).

14. A compound according to claim 8, wherein Q is aryl (C6-C? 0), heteroaryloxy (C2-C9) aryl (Ce-Cio) or aryloxy (C6-C? O) aryl (Ce -Cio), wherein each aryl or heteroaryl radical of said aryl groups (C6-C? O), heteroaryloxy (C2-Cg) aryl (C6-C? 0) or aryloxy (C6-C? 0) aryl (C6-C) ? 0) may be optionally substituted by one or more substituents independently selected from fluoro, chloro, bromo, alkyl (C? -C6), alkoxy (CrC6) or perfluoro-alkyl (CrC3).

15. A compound according to claim 1, wherein Q is phenyl, pyridyloxyphenyl or phenoxyphenyl, optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, alkyl (d-Cß), alkoxy (C? -C6) or perfluoro-alkyl (C? -C3).

16. A compound according to claim 2, wherein Q is phenyl, pyridyloxyphenyl or phenoxyphenyl, optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, alkyl (C? -C6), alkoxy (d) -C6) or perfluoro-alkyl (C? -C3).

17. A compound according to claim 3, wherein Q is phenyl, pyridyloxyphenyl or phenoxyphenyl, optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, alkyl (C? -C6), alkoxy (d) -Cß) or perfluoro-alkyl (C? -C3).

18. A compound according to claim 5, wherein Q is phenyl, pyridyloxyphenyl or phenoxyphenyl, optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, alkyl (d-Cß), alkoxy (C? -C6) or perfluoro-(C1-C3) alkyl.

19. A compound according to claim 7, wherein Q is phenyl, pyridyloxyphenyl or phenoxyphenyl, optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, alkyl (d-Cß), alkoxy (d-) C6) or perfluoro-alkyl (C? -C3).

20. A compound according to claim 8, wherein Q is phenyl, pyridyloxyphenyl or phenoxyphenyl, optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, alkyl (d-Cß), alkoxy (d-) Cß) or perfluoro-alkyl (C-C3).

21. A compound according to claim 1, wherein said compound is selected from the group consisting of: 3-exo- [4- (4-fluorophenoxy) benzenesulfonylamino] -8-oxabicyclohydroxyamide [3.2.1] ] -octane-3-carboxylic acid; 3-exo- [4- (4-fluorophenoxy) benzenesulfonylmethyl] -8-oxabicyclo [3.2.1] -octane-3-carboxylic acid hydroxyamide; 3- (4-phenoxybenzenesulfonylmethyl) -8-oxabicyclo [3.2.1] -octane-3-carboxylic acid hydroxyamide; 3-exo- (4-fluorobiphenyl-4-sulfonylmethyl) -8-oxabicyclo- [3.2.1] -octane-3-carboxylic acid hydroxyamide; and 3-exo- [4- (4-chlorophenoxy) benzenesulfonylmethyl] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide.

22. A pharmaceutical composition for 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, toxicity of 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 atherosclerotic plaques) , aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, cephalic trauma, 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 augmentation, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, cicatrization of the cornea, scleritis, AIDS, sepsis and septic shock in a mammal, including a human being, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically vehicle acceptable.

23. The use of a compound as claimed in claim 1, for the manufacture of a medicament for the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory disease of the bowel, 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 implants of artificial joints, atherosclerosis (including rupture of atherosclerotic plaques), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, cephalic trauma, the spinal cord, disorders, sick Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognitive augmentation, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, scarring of the cornea, scleritis, AIDS, sepsis and septic shock in a mammal, including a human being.

24. A pharmaceutical composition for the treatment of a condition that can be treated by the inhibition of flask metalloproteinases in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically vehicle acceptable.

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

26. 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.

27. 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.