MXPA99010152A - Hydroxyamide derivatives of 5-oxo-pirrolidine-2-carboxyl acid - Google Patents

Abstract

The present invention relates to a compound of formula, wherein R1, R2 and R3 are as defined above, to pharmaceutical compositions and methods of treatment

Description

DERIVATIVES OF HYDROXY AMID OF THE ACID 5-OXO-PIRROLIDINE-2- CARBOXYLIC BACKGROUND OF THE INVENTION The present invention relates to hydroxyamide derivatives of 5-oxo-pyrrolidine-2-carboxylic acid, and to pharmaceutical compositions and methods of treatment. The compounds of the present invention are zinc-metalloendopeptidase inhibitors, especially those belonging to the subfamilies of the metalloproteinase-type methzincines (also called MMP or matrixin) and the reprolysin-type (also known as adamilsin) (Rawling et al., Methods in Enzimologv, 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, MMP-20). MMPs are for the most part well known for their role in regulating the metabolism of extracellular matrix proteins and as such they can 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 connective tissue metabolism is occurring. For example, it has been shown that MMP-13, an enzyme with potent activity degrading type II collagen (the main collagen in cartilage), is excessively expressed in osteoarthritic cartilage (Mitchell et al., J. Cin. Invest. , 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also excessively expressed in osteoarthritic cartilage and it is expected that the inhibition of some of these MMPs will slow or block the accelerated loss of typical cartilage of joint diseases such as osteoarthritis or rheumatoid arthritis. Mammalian reprolysins are known as ADAM (A Disintegrin And Metalloproteinase) (Wolfberg et al., J. Cell Biol. 131, 275-278 (1995)) and contain a disintegrin domain in addition to a domain such as metalloproteinase. . To date, twenty-three different ADAMs have been identified. ADAM-17, also known as the enzyme that converts tumor necrosis factor-alpha (TACE), is the ADAM that is best known. ADAM-17 (TACE) is responsible for the excision of tumor necrosis factor-alpha (TNF-a, also known as cachectin) bound to the cell. It is recognized that TNF-a is involved in many infectious and autoimmune diseases (W. Friers, FEBS Letters, 285, 199 (1991)). Furthermore, it has been indicated that TNF-a is the principal mediator of the inflammatory response observed in sepsis and septic shock (Spooner et al., Clinical Immunoloqy and Immunopathology, 62 S11 (1992)). There are two forms of TNF-α, a type II membrane protein of relative molecular mass 26,000 (26 kD) and a soluble form of 17 kD, generated from the cell-bound protein by 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 at sites distant from the synthesis site. Thus, TACE inhibitors prevent the formation of soluble TNF-a and prevent the deleterious effects of soluble factor. Some selected compounds of the invention are potent inhibitors of aggrecanase, an important enzyme in the degradation of aggrecan from cartilage. It is also thought that aggrecanase is an ADAM. The loss of aggrecan from the cartilage matrix is an important factor in the progression of joint diseases such as osteoarthritis and rheumatoid arthritis, and it is expected that the inhibition of aggrecanase will slow or block the cartilage loss in these diseases. Other ADAMs that have 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. Biophvs, Res. Comm., 235, 437-442, (1997)). By knowledge of the expression, of the physiological substrates and of the association of the ADAM increases with the disease, the full significance of the role of the inhibition of this class of enzymes will be appreciated. Diseases in which an inhibition of MMP and / or ADAM will provide therapeutic benefits include: arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, obstructive pneumopathy chronic, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, bullous epidermolysis, osteoporosis, artificial joint implants detachment, atherosclerosis (including rupture) of atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neurodegenerative disorders (acute and chronic), disorders au toinmunes, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition improvement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing , burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis, septic shock and other diseases characterized by the expression of metalloproteinases or ADAM. This invention also relates to a method of using the compounds of the invention in the treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefor.

It is recognized that different combinations of MMP and ADAM are expressed in different pathological situations. Therefore, inhibitors with specific selectivities for ADAM and / or individual MMPs for individual diseases may be preferred. For example, rheumatoid arthritis is an inflammatory disease of the joints, characterized by excessive levels of TNF and by the loss of the 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 to a less inflammatory joint disease such as osteoarthritis, compounds that inhibit MMPs that degrade the matrix, such as MMP-13 but not TACE, may be preferred. The authors of the present invention have also discovered that it is possible to devise inhibitors with differential metalloprotease activity. Specifically, for example, the authors of this invention have been able to devise molecules that selectively inhibit metalloprotease-13 (MMP-13) in preference to MMP-1.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula: wherein R 1 is alkyl (Ci-Cß), aryl. { CQ-CW), heteroaryl (C2-C9), aryl (CT-CIO) alkyl (C-C6), aryl (C6-C? 0) aryl (C6-C? 0), aryl (C6-C? 0) heteroaryl (C2-C9), heteroaryl (C2-C9) alkyl (C? -C6), heteroaryl (C2-C9) aryl (Ce-Cio), heteroaryl (C2-C9), aryloxy (C6-C? 0) alkyl (C? -C6), aryloxy (C6-C? 0) aryl (C6-C? 0), aryloxy (C6-C? O) heteroaryl (C2-C9), heteroaryloxy (C2-C9) alkyl (C? C6), heteroaryloxy (C2-C9) aryl (C6-C? O), heteroaryloxy (C2-C9) heteroaryl (C2-C9), aryl (C6-C? 0) alkyl (C? -6) aryl (C6-) C? 0), aryl (C6-C? 0) alkyl (C? -C6) heteroaryl (C2-C9), aryl (C6-C? O) alkoxy (C? -C6) aryl (C6-C? 0) , aryl (C6-C? 0) alkoxy (CrC6) heteroaryl (C-C9), aryloxy (C6-C? 0) alkyl (C? -6) aryl (C6-C? o), aryloxy (C6-C10) alkyl (CrC6) heteroaryl (C2-C9), heteroaryl (C2-C9) alkyl (C? -C6) aryl (C6-C? o), heteroaryl (C2-C9) alkyl (C? -6) heteroaryl (C2-) C9), heteroaryl (C2-C9) alkoxy (C-C6) aryl (C6-C? 0), heteroaryl (C2-C9) alkoxy (Cr6) heteroaryl (C2-C9), heteroaryloxy (C-Cg) alkyl (C ? -C6) aryl (C6-C? O), hetero rhyloxy (C2-Cg) alkyl- (C Ce) heteroaryl (C2-C9), aryl (C6-C? o) aryl (C6-C10) -alkyl (C? -6) or aryl (C6-C? 0) (C C6) alkoxy (Ci-Cß) alkyl, wherein each of said aryl moieties (Ce-C o) or (C2-C9) heteroaryl is optionally substituted, with one or more substituents per ring, in any of the carbon of the ring that are capable of forming an additional bond, said substituents being independently selected from fluoro, chloro, bromo, alkyl (C? -C6), alkoxy (C? -C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1- C3) and aryloxy (C6-C0); and R2 and R3 are independently selected from H, alkyl (C? -C6) and CH -aryl (C6-C? o); and their pharmaceutically acceptable salts. Preferred compounds of the present invention are compounds wherein R 1 is aryl (C 6 -C 0), aryloxy (C 6 -C 0) aryl (C 6 -C 6), aryl (C 6 -C 10) aryl (C 6) C? O), aryloxy (C6-C? 0) heteroaryl (C-C9), heteroaryl (C2-C9), heteroaryl (C2-C9) heteroaryl (C2-C9), aryl (C6-C? 0) alkoxy ( CrC6) aryl (C6-C10), heteroaryloxy (C2-C9) aryl (C6-C10), aryl (Cd-Cio) alkoxy (C1-C6) heteroaryl (C2-C9), heteroaryloxy (C2-C9) heteroaryl (C2 -C9), aryl (Ce-Cio) heteroaryl (C2-C9), heteroaryl (C2-C9) aryl (C6-C? 0), heteroaryl (C2-C9) alkoxy (C? -C6) aryl (C6-C) 0 0), or heteroaryl (C2-Cg) alkoxy (Ci-Cß) heteroaryl (C2-Cg), wherein each of said aryl (Ce-Cyano) or heteroaryl (C2-C9) moieties of said aryl (Ce-Cio) ), aryloxy (Ce-Cι) aryl (CT-C O), aryl (Ce-Cι) aryl (Cβ-C10), aryloxy (C6-C ?o) heteroaryl (C2-C9), heteroaryl (C2-Cg) , aryl (C6-C? 0) (C? -C6) alkoxy, aryl (Ce-Cio), heteroaryloxy (C2-C9) aryl (C6-C? 0), aryl (C6-C? 0) alkoxy (C Ce) ) heteroaryl (C2-C9), heteroaryloxy (C2-Cg) heteroar ilo (C2-Cg), aryl. { C &-C10) heteroaryl (C2-Cg), heteroaryl (C2-Cg) aryl (C6-C? O), heteroaryl (C2-Cg) alkoxy (CrC6) aryl (C6-C? O), or heteroaryl (C2) -Cg) alkoxy (Ci-Cβ) heteroaryl (C2-Cg), is optionally substituted, with one or more substituents per ring (preferably one to three substituents, most preferably 0-2 substituents), on any of the ring carbon atoms that are capable of forming an additional bond, said substituents being independently selected from fluoro, chloro, bromo, alkyl (Ci-Cβ) ), alkoxy (Ci-Cß), perfluoroalkyl (C 1 -C 3), perfluoroalkoxy (C 1 -C 3) and aryloxy (Ce-Cι); and their pharmaceutically acceptable salts. In another embodiment, R2 and R3 are hydrogen. In a further embodiment, one or both of R2 and R3 are independently selected from alkyl ^ -Ce) and CH2-aryl (C6-C? 0). The term "alkyl", as used herein and 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 and unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl or naphthyl, optionally substituted with 1 to 3 substituents selected from the group consisting of fluoro , chlorine, bromine, perfluoroalkyl (C? -C6) (including trifluoromethyl), alkoxy (C? -C6), aryloxy (C6-C? o), perfluoroalkoxy (C1-C3) (including trifluoromethoxy and difluoromethoxy) and alkyl (Ci) -Cß).

The term "heteroaryl", as used herein and unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of a hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl, optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro, chloro , trifluoromethyl, (C? -C6) alkoxy, (C6-C? 0) aryloxy, trifluoromethoxy, difluoromethoxy and alkyl (CI-CT). Preferred heteroaryls include pyridyl, furyl, thienyl, isothiazolyl, pyrazinyl, pyrimidyl, pyrazolyl, isoxazolyl, thiazolyl or oxazolyl. More preferred heteroaryls include pyridyl, furyl or thienyl. The compound of formula I can have chiral centers and, therefore, exist in different enantiomeric forms. This invention relates to all optical isomers, tautomers and stereoisomers of the compounds of formula I and mixtures thereof. More preferred compounds of the present invention are compounds of formula I with the stereochemistry More preferred compounds of the present invention are compounds of formula I, wherein R1 is aryl (C6-C? O), aryloxy (C6-C? O) aryl (C6-C? O), heteroaryloxy (C2-Cg) aryl (C6-C? 0), aryl (C6-C? 0) alkoxy (CrC6) aryl (Ce-Cι) optionally substituted, preferably substituted with one to three substituents (most preferably zero or a substituent) independently selected from hydrogen, fluoro, chloro, alkyl (C? -C6) or alkoxy (dC?). When the compound of formula I possesses a substituent, that substituent is most preferably in the para or ortho position of the terminal ring. Specific preferred compounds of formula I are selected from the group consisting of: (2R, 4S) -4- (4-methoxyphenyl) -5-oxopyrrolidine-2-carboxylic acid hydroxyamide, and (2R, 4S) -4- hydroxyamide [4- (4-fluorophenoxy) -phenyl-5-oxopyrrolidine-2-carboxylic acid. Other compounds of formula I are selected from the group consisting of: (2R, 4S) -5-oxo-4- (4-phenoxy-phenyl) pyrrolidine-2-carboxylic acid hydroxyamide, (2R, 4S) hydroxyamide. -4- [4- (4-chlorophenoxy) -phenyl] -5-oxopyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -4- [3- (4-chlorophenoxy) phenyl-5-oxopyrrolidine-2- carboxylic acid hydroxyamide (2R, 4S) -4- [3- (4-fluorophenoxy) -phenyl-5-oxopyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -5-oxo-4- [4- (pyridin-4-yloxy) -phenyl] pyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -4-biphenyl-4-yl-5-oxo- pyrrolidine-2-carboxylic acid, (2R, 4S) -4- (4'-fluorobiphenyl-4-yl) -5-oxopyrrolidine-2-carboxylic acid hydroxyamide, (2R, 4S) -4- (4-) hydroxyamide benzyloxyphenyl) -5-oxopyrrolidine-2-carboxylic acid, (2R, 4S) -5-oxo-4- (4-phenethylphenyl) -pyrrolidine-2-carboxylic acid hydroxyamide, (2R, 4S) -4- [ 4- (4-Fluorobenzyloxy) -phenyl] -5-oxopyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -4- [4- (3,5-difluorobenzyl-oxy) phenyl] -5-oxopyrrolidine-2 -carboxylic acid (2R, 4S) -4- (4-methoxybenzyl) -5-oxopyrrolidine-2-carboxylic acid hydroxyamide, (2R, 4S) -4- (4'-fluorobiphenl-4-ylmethyl) hydroxyamide ) -5-oxopyrrolidine-2-carboxylic acid, (2R, 4S) -4-naphthalen-2-yl-5-oxo-pyrrolidine-2-carboxylic acid hydroxyamide, (2R, 4S) -4- hydroxyamide [4- (4-fluorophenoxy) -phenyl] -2,4-dimethyl-5-oxo-pyrrolidine-2-carboxylic acid, hydroxyl (2R, 4S) -4- [4- (4-fluorophenoxy) -phenyl] -4-methyl-5-oxo-pyrrolidine-2-carboxylic acid amide, (2R, 4R) -4- hydroxyamide benzyl-5-oxo-4- (4-phenoxyphenyl) -pyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -4- [4- (4-chlorophenoxy) -phenyl] -4-methyl-5-oxo -pyrrolidine-2-carboxylic acid and (2R, 4S) -4- [4- (4-chlorophenoxy) -phenyl] -2,4-dimethyl-5-oxo-pyrrolidine-2-carboxylic acid hydroxyamide. The present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids are used to prepare the pharmaceutically acceptable acid addition salts of the compounds, in the form of bases, of this invention mentioned above are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ie, salts of 1,1'-methylene-bis- (2-hydroxy) 3-naphthoate)].

The invention also relates to addition salts of bases of formula I. The chemical bases that can be used as reagents for preparing salts with pharmaceutically acceptable bases of the compounds of formula I having acid nature are those that form non-toxic base salts with such compounds. Such salts of non-toxic bases include, but are not limited to, those which are derived from pharmacologically acceptable cations such as alkali metal cations. (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), ammonium addition salts or water soluble amines such as N-methylglucamine- (meglumine) and the salts of (lower alkanol) ammonium and other pharmaceutically acceptable organic amine bases. 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, Alzheimer's disease, toxicity by organ transplantation, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, artificial joint implants dislocation, atherosclerosis (including rupture of the atherosclerotic plaque), aneurysm of the aorta (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune disorders, sick Huntington's age, Parkinson's disease, migraine, depression, peripheral neurotapia, pain, cerebral amyloid angiopathy, nootropic or cognition improvement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns , diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis, septic shock and other diseases characterized by metalloproteinase activity and other diseases characterized by mammalian reprolysin activity in a mammal, including a human being, that it comprises an amount of a compound of formula I or a pharmaceutically effective salt thereof in such treatments and a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition for the inhibition of a) matrix metalloproteinases 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, most preferably ADAM-17) in a mammal, including a human, comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating a 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, toxin by transplantation of organs, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, dislocation of artificial joint implants, atherosclerosis (including rupture of atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head injury, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition improvement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis, septic shock and other diseases characterized by metalloproteinase activity and other diseases characterized by mammalian reprolysin activity in a mammal, including a human being, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat said condition. The present invention also relates to a method for the inhibition of a) matrix metalloproteinases or other metalloproteinases involved in the degradation of the matrix, or b) a mammalian 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 one of its pharmaceutically acceptable salts. The invention also encompasses pharmaceutical compositions containing prodrugs of the compounds of formula I. This invention also encompasses methods of treating or preventing diseases that can be treated or prevented by inhibition of matrix metalloproteinases or inhibition of mammalian reprolysin, which comprises administering prodrugs of compounds of formula I. Compounds of formula I having free amino, amido, hydroxy or carboxy groups can be converted into prodrugs. Prodrugs include compounds that contain an amino acid residue or a polypeptide chain of two or more (eg, two, three or four) amino acid residues that are covalently linked through peptide bonds to free amino, hydroxy or carboxy groups of the compounds of formula I. The amino acid residues include the 20 natural amino acids, commonly designated by three-letter symbols and also include 4-hydroxyproline, hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline , homocysteine, homoserin, ornithine and methionine-sulfone. Prodrugs also include compounds containing carbonates, carbamates, amides, and alkyl esters that are covalently bound to the above substituents of formula I through the side chain of the prodrug containing a carbonyl carbon. One skilled in the art will appreciate that the compounds of the invention are useful in the treatment of a wide range of diseases. One skilled in the art will also appreciate that when the compounds of the invention are used in the treatment of a specific disease the compounds of the invention can be combined with various existing therapeutic agents used for that 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 TNF receptor immunoglobulin molecules (such as Enbrel®), low dose methotrexate , lefunimide, hydroxychloroquine, d-penicillamine, auranofin or gold orally or parenterally. The compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents for use in combination include the non-steroidal anti-inflammatory agents (hereinafter referred to as NSAIDs) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and buprofen, phenamates such as mefenamic acid, indomethacin, sulindac , apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib and rofecoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and sinvisc. The compounds of the present invention can also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine and antimetabolites such as methotrexate. The compounds of the present invention can also be used in combination with cardiovascular agents such as calcium channel blockers, lipid lowering agents such as statins, fibrates, beta-blockers, ACE inhibitors, antagonists of recpertor 2. angiotensin and inhibitors of platelet aggregation. The compounds of the present invention can also be used in combination with agents with action on the CNS such antidepressants (as sertraline), anti-parkinsonian drugs (such as deprenyl, L-dopa, requip, miratex, MAOB inhibitors such as selegina and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and neuronal nitric oxide-synthase inhibitors) and anti-Alzheimer's drugs such as Aricept, tacrine, inhibitors 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 fosomax and immunosuppressive agents such as FK-506 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, R3 in the reaction schemes and in the following discussion are defined as above. Reaction scheme 1 shows the synthesis of compounds in which R2 is hydrogen, (C? -C6) alkyl or Ch2-aryl (C6-C? 0) and R3 is hydrogen.

SCHEME 1 With reference to scheme 1, the compounds of formula I are prepared from hydroxamic acid derivatives of formula II, by elimination of the protective group p3 of hydroxyamide. When p3 is benzyl, removal of the hydroxyamide protecting group is carried out by hydroxygenolysis using catalytic palladium on barium sulfate in a polar solvent at a temperature of from about 20 ° C to about 25 ° C, i.e. room temperature, during a period of about 1 hour to about 5 hours, preferably about 3 hours. When p3 is other than benzyl, elimination is facilitated as described in Greene and Wuts, "Protective Groups in Orqanic Synthesis" (Wiley Interscience, 2nd ed.) (1991), see chapter 2. The compound of formula II is prepared from a compound of formula III by removal of the protective group p, where p1 is as defined below. When p1 is a t-butoxycarbonyl protecting group, the removal is carried out using an acid in an inert solvent. When p1 is other than t-butoxycarbonyl, the elimination is carried out as described in Greene and Wuts, id-Pgs. 397-405 (Wiley Interscience, 2nd ed.) (1991). Suitable acids include hydrochloric and trifluoroacetic acid, preferably hydrochloric acid. Suitable solvents include methylene chloride, diethyl ether or chloroform, preferably methylene chloride. The reaction is carried out at a temperature in the range of about -25 ° C to 50 ° C, preferably the temperature can range from about 20 ° C to about 25 ° C (i.e. at room temperature). The reaction is carried out over a period of about 15 minutes to about 2 hours, preferably about 30 minutes. The hydroxamic acid derivative of formula III is prepared from a carboxylic acid of formula IV by reaction with a suitably protected hydroxylamine derivative of formula p3-ONH2, wherein p3 is as defined by Greene and Wuts, id., and (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate in the presence of a base at room temperature, in a polar solvent. Suitable bases include triethylamine, N-methylmorpholine or diisopropylethylamine, preferably diisopropylethylamine. Suitable solvents include THF, methylene chloride, N, N-dimethylformamide or N-methylpyrrolidin-2-one, preferably methylene chloride. Specific p3 protecting groups include benzyl, t-butyldimethylsilyl, trimethylsilyl, 2- (trimethylsilyl) ethyl or allyl. The aforesaid reaction is carried out for a period of from about 2 hours to about 24 hours, preferably about 16 hours. The temperature of the aforesaid reaction ranges from about 0 ° C to about 60 ° C, preferably from about 20 ° C to about 25 ° C (room temperature). The carboxylic acid of formula IV is prepared by oxidation of an alcohol of formula V in the presence of periodic acid and catalytic chromium trioxide, in a polar solvent. Suitable solvents include acetonitrile or water, preferably wet acetonitrile (with 0.75 percent water). Suitable temperatures for the aforesaid reaction range from about -10 ° C to about 25 ° C, preferably the temperature is about 0 ° C. The reaction is complete in the course of about 10 minutes to about 24 hours, preferably about 0.5 hours. Alternative oxidation conditions are described in Zhao et al. Tet Let. 39, 5323-5326 (1998). The alcohol of formula V is prepared from a compound of formula VI by removal of the protecting groups on p2, where p2 is as defined below. When p2 is tert-butyldimethylsilyl, the reaction is carried out by mild hydrolysis in the presence of dilute aqueous mineral acid and a solvent such as diethyl ether. Suitable aqueous mineral acids include hydrochloric acid or dilute sulfuric acid, preferably 0.5 molar hydrochloric acid. The reaction is carried out at a temperature in the range of about 0 ° C to 50 ° C; preferably the temperature may vary from about 20 ° C to about 25 ° C (that is, at room temperature). The reaction is carried out over a period of from about 2 hours to about 48 hours, preferably about 16 hours. The compound of formula VI, wherein R2 is alkyl (C? -C6) or CH2-aryl (C6-C? O), is prepared from a compound of formula VII by reacting Vil with an alkylating agent of formula R2 -Z, wherein Z is bromine or iodine, and a strong base such as lithium diisopropylamide or (bis) trimethylsilylamide of lithium (preferably diisopropylamide of lithium) in an inert solvent such as diethyl ether or tetrahydrofuran (preferably tetrahydrofuran). The reaction is carried out at a temperature of -78 ° C, a 0 ° C, preferably -78 ° C for a period of 1 to 24 hours, preferably around 16 hours. The compound of formula VII is prepared from a compound of formula VIII by hydrogenation under a hydrogen atmosphere in the presence of a catalyst in a reaction-inert solvent.

Suitable catalysts include palladium on barium sulfate, palladium on carbon, palladium hydroxide on carbon or carbon black. The preferred catalyst is palladium hydroxide on carbon. Suitable solvents include an alcohol such as ethanol, methanol, or isopropanol, preferably methanol. The aforesaid reaction can be carried out at a pressure of about 1 to about 5 atmospheres, preferably about 3 atmospheres. Suitable temperatures for the aforesaid reaction range from about 20 ° C (room temperature) to about 60 ° C, preferably the temperature can range from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is complete in the course of about 0.5 hours to about 5 hours, preferably about 3 hours. Alternatively, the reduction can be done using conditions to dissolve metals or using L-SELEC-TRIDE.

The compound of formula VIII can be prepared from a compound of formula IX by Suzuki coupling, preferably by reaction with a boronic acid of the formula: HCL .OH E > I in the presence of a catalyst and a base in a suitable solvent. Suitable catalysts include palladium (II) acetate, tetrakis (triphenylphosphene) palladium and tetrakis- [tris- (2-methoxyphenyl) -phosphine] palladium, preferably tetrakis (triphenylphosphene) palladium. Suitable bases include aqueous sodium carbonate, aqueous potassium carbonate or aqueous cesium carbonate, preferably aqueous sodium carbonate. Suitable solvents include ethers, toluene and hexane, preferably toluene. Suitable temperatures for the aforesaid reaction range from about 20 ° C (room temperature) to about 110 ° C, preferably the temperature can range from about 75 ° C to about 110 ° C. The reaction is complete in the course of about 0.5 hours to about 24 hours, preferably about 16 hours. Suzuki couplings are well known to those skilled in the art, as described in Suzuki, Pure Appl. Chem., 63, 419-422 (1991), Tetrahedron, 263 (1997) and Chem. Rev. 95, 2457-2483 (1995). Boronic acids can also be prepared by methods well known to those skilled in the art, such as those described in Caron et al., JOC. 63, 2054-2055 (1998). The compounds of formula VIII can also be prepared from compounds of formula IX by reaction with organometallic reagents of formula R1-M, where M is magnesium, lithium, tin, zinc, copper or boron, in the presence of a transition metal catalyst suitable such as a catalyst based on palladium or nickel. The compound of formula IX, wherein L is bromine or iodine, can be prepared from a compound of formula X by reaction with a base, phenyl-selenyl bromide and a halogenating agent, followed by oxidation in the presence of hydrogen peroxide. Suitable bases include bis- (trimethylsilyl) lithium amide or lithium diisopropylamide, preferably lithium (trimethylsilyl) amide. Suitable halogenating agents include 1,2-di-bromotetrachloroethane or N-yodosuccinamide, preferably 1,2-dibromotetrachloroethane. Suitable temperatures for the aforesaid reaction range from about -78 ° C to about -30 ° C, preferably the temperature is about -78 ° C. The reaction is complete in the course of about 0.5 hours to about 5 hours, preferably about 3 hours. The oxidation step is carried out at a temperature from about 0 ° C to about 50 ° C, preferably around room temperature. The oxidation step mentioned above is complete in the course of about 2 hours to about 24 hours, preferably about 16 hours. Suitable solvents for the oxidation step include methylene chloride. Other conditions for the reaction mentioned above are described in Fray et al., JOC, 61, 3362-3374 (1996). Compounds of formula X, where p1 and p2 are protecting groups as described by Greene and Wuts, supra, are known or can be prepared by methods well known to those skilled in the art.

An example of a method of preparing a compound of formula X, wherein p1 is terbutoxycarbonyl and p2 is t-butyldimethylsilyl, is described in Yoda et al., Tetrahedron, 7 (7), 2113-2116 (1996). Suitable p1 protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, 2- (trimethylsilyl) ethyloxycarbonyl, trifluoroacetyl or 2,2,2-trichloroethoxycarbonyl. Suitable p2 protecting groups include t-butyldiphenylsilyl, benzyl, methoxymethyl (MOM) or tetrahydropyranyl. Scheme 2 shows the synthesis of compounds in which R2 is hydrogen and R3 is alkyl (C? -C6) or CH2-aryl (C6-C? 0).

SCHEME 2 With reference to scheme 2, the compounds of formula I were prepared from hydroxamic acid derivatives of formula XI by elimination of the hydroxyamide protecting group p3. When p3 is benzyl, removal of the hydroxyamide protecting group is carried out by hydrogenolysis using catalytic palladium on barium sulfate in a polar solvent at a temperature from about 20 ° C to about 25 ° C, ie, room temperature, during a period of about 1 hour to about 5 hours, preferably about 3 hours. When p3 is other than benzyl, elimination is facilitated as described in Greene and Wuts, supra. The compound of formula XI is prepared from a compound of formula XII by treatment with an acid in an inert solvent. Suitable acids include hydrochloric acid and trifluoroacetic acid, preferably hydrochloric acid. Suitable solvents include methylene chloride, diethyl ether or chloroform, preferably methylene chloride. The reaction is carried out at a temperature in the range of about -25 ° C to 50 ° C; preferably the temperature can vary from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is carried out over a period of about 15 minutes to about 2 hours, preferably about 30 minutes. The hydroxamic acid derivative of formula XII is prepared from a carboxylic acid compound of formula XIII by reaction with a suitably protected hydroxylamine derivative of the formula p3-ONH2, where p3 is as defined in Greene and Wuts, id. , and (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate in the presence of a base, at room temperature, in a polar solvent. Suitable bases include triethylamine, N-methylmorpholine or diisopropylethylamine, preferably diisopropylethylamine. Suitable solvents include THF, methylene chloride, N, N-dimethylformamide or N-methylpyrrolidin-2-one, preferably methylene chloride. Specific p3 protecting groups include benzyl, t-butyldimethylsilyl, trimethylsilyl, 2- (trimethylsilyl) ethyl or allyl. The aforesaid reaction is carried out for a period of from about 2 hours to about 24 hours, preferably about 16 hours. The temperature of the aforesaid reaction ranges from about 0 ° C to about 60 ° C, preferably from about 20 ° C to about 25 ° C (room temperature). The compound of formula XIII is prepared from compounds of formula XIV by hydrogenation under an atmosphere of hydrogen in the presence of a catalyst in a reaction-inert solvent. Suitable catalysts include palladium on barium sulfate, palladium on carbon, palladium hydroxide on carbon or carbon black. The preferred catalyst is palladium hydroxide on carbon. Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol. The aforesaid reaction can be carried out at a pressure of about 1 to about 5 atmospheres, preferably around 3 atmospheres. Suitable temperatures for the aforesaid reaction range from about 20 ° C (room temperature) to about 60 ° C, preferably the temperature can range from about 20 ° C to about 25 ° C (i.e., room temperature). The reaction is complete in the course of about 0.5 hours to about 5 hours, preferably about 3 hours. Alternatively, the reduction can be carried out using conditions for dissolving metals. The compound of formula XIV can be prepared from a compound of formula XV by Suzuki coupling, preferably by reaction with a boronic acid of the formula: HCL .OH I R 1 in the presence of a catalyst and a base in a suitable solvent. Suitable catalysts include palladium (II) acetate, tetrakis (triphenylphosphene) palladium and tetrakis- [tris (2-methoxyphenyl) -phosphine] palladium, preferably tetrakis (triphenylphosphene) palladium. Suitable bases include aqueous sodium carbonate, aqueous potassium carbonate or aqueous cesium carbonate, preferably aqueous sodium carbonate. Suitable solvents include ethers, toluene and hexane, preferably toluene. Suitable temperatures for the aforesaid reaction range from about 20 ° C (room temperature) to about 110 ° C, preferably the temperature can range from about 75 ° C to about 110 ° C. The reaction is complete in the course of about 0.5 hours to about 24 hours, preferably about 16 hours. Compounds of formula XIV can also be prepared from compounds of formula XV by reaction with organometallic reagents of formula R1-M, where M is magnesium, lithium, tin, zinc, copper or boron, in the presence of a transition metal catalyst suitable such as a catalyst based on palladium or nickel. Compounds of formula XV, where L is bromine or iodine, can be prepared from compounds of formula XVI by reaction with a base, phenyl selenyl bromide and a halogenating agent, followed by oxidation in the presence of hydrogen peroxide. Suitable bases include bis- (trimethylsilyl) lithium amide or lithium diisopropylamide, preferably, lithium bis (trimethylsilyl) amide. Suitable halogenating agents include 1,2-dibromotetrachloroethane or N-yodosuccinamide, preferably 1,2-dibromotetrachloroethane. Suitable temperatures for the aforesaid reaction range from about -78 ° C to about -30 ° C, preferably the temperature is about -78 ° C. The reaction is complete in the course of about 0.5 hours to about 5 hours, preferably about 3 hours. The oxidation step is carried out at a temperature from about 0 ° C to about 50 ° C, preferably around room temperature. The oxidation step mentioned above is complete in the course of about 2 hours to about 24 hours, preferably about 16 hours. Suitable solvents for the oxidation step include methylene chloride. Other conditions for the reaction mentioned above are described in Fray et al., Supra. Compounds of formula XVI are prepared from compounds of formula XVII by reaction of compounds of formula XVII with di-tert-butyl dicarbonate in the presence of a base such as triethylamine or diisopropylethylamine, preferably triethylamine, and a catalytic amount of 4-dimethylaminopyridine in an inert solvent such as methylene chloride, chloroform or tetrahydrofuran, preferably tetrahydrofuran. The reaction is carried out at a temperature of 0 ° C to 50 ° C, preferably around 25 ° C, for 1 to 48 hours, preferably around 16 hours. The compounds of formula XVII are prepared from compounds of formula XVIII by heating the compounds of formula XVIII in water or in a mixture of tetrahydrofuran, methanol and water, constituted so that XVIII is soluble. This reaction is carried out at a temperature of 50 ° C to 180 ° C for a period of 1 to 48 hours, preferably 16 hours. The compounds of formula VXIII are prepared from the compounds of formula XIX by reacting the amino acid derivative of formula XIX with methyl acrylate and a base such as potassium carbonate, cesium carbonate or cesium hydroxide hydrate, preferably potassium carbonate , in the presence of benzyltriethylammonium chloride, in a solvent such as acetonitrile or methylene chloride, preferably acetonitrile. The reaction is carried out at a temperature of 0 ° C to 50 ° C, preferably around 25 ° C for 1 to 24 hours, preferably about 2 hours. The compounds of formula XIX are known or can be prepared by methods well known to those skilled in the art. Scheme 3 shows the synthesis of compounds of the invention in which R2 and R3 are independently alkyl (C? -C6) or CH2-aryl (C? -C10).

SCHEME 3 XXIII XXII With reference to scheme 3, the compounds of formula I are prepared from hydroxamic acid derivatives of formula XX by elimination of the hydroxyamide protecting group p3. When p3 is benzyl, removal of the hydroxyamide protecting group is carried out by hydrogenolysis using catalytic palladium on barium sulfate in a polar solvent at a temperature from about 20 ° C to about 25 ° C, ie, room temperature, during a period of about 1 hour to about 5 hours, preferably 3 hours. When p3 is other than benzyl, elimination is facilitated as described in Greene and Wuts, supra. The hydroxamic acid derivatives of formula XX are prepared from carboxylic acid compounds of formula XXI by reaction with a suitably protected hydroxylamine derivative of the formula p3-ONH2, where p3 is as defined in Greene and Wuts, id., and (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate in the presence of a base, at room temperature, in a polar solvent. Suitable bases include triethylamine, N-methylmorpholine or diisopropylethylamine, preferably diisopropylethylamine. Suitable solvents include THF, methylene chloride, N, N-dimethylformamide or N-methylpyrrolidin-2-one, preferably methylene chloride. Specific p3 protective products include benzyl, t-butyldimethylsilyl, trimethylsilyl, 2- (trimethylsilyl) ethyl or allyl. The aforesaid reaction is carried out for a period over a period of from about 2 hours to about 24 hours, preferably about 16 hours. The temperature of the aforesaid reaction ranges from about 0 ° C to about 60 ° C, preferably from about 20 ° C to about 25 ° C (room temperature). Compounds of formula XXI are prepared from compounds of formula XXII by reacting compounds of formula XXII with a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide, in a mixture of water, ethanol and tetrahydrofuran (constituted so that XXII is soluble). The reaction is carried out at a reaction temperature of 20 ° C to 60 ° C, preferably around 25 ° C for 1 to 48 hours, preferably about 2 hours. The compounds of formula XXII are prepared from compounds of formula XXXIII by treatment in an acid in an inert solvent. Suitable acids include hydrochloric and trifluoroacetic acid, preferably hydrochloric acid. Suitable solvents include methylene chloride, diethyl ether or chloroform, preferably methylene chloride. The reaction is carried out at a temperature in the range of about -25 ° 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 over a period of about 15 minutes to about 2 hours, preferably about 30 minutes.

The compounds of formula XXIII are prepared from compounds of formula XXIV by reacting XXIV with an alkylating agent of formula R2-Z, wherein Z is bromine or iodine, and strong base such as lithium diisopropylamide or (bis) trimethylsilylamide lithium ( preferably lithium diisopropylamide) in an inert solvent such as diethyl ether or tetrahydrofuran (preferably tetrahydrofuran). The reaction is carried out at a temperature of -78 ° C to 0 ° C, preferably -78 ° C for a period of 1 to 24 hours, preferably around 16 hours. The compounds of formula XXIV are prepared from compounds of formula XIII by reacting compounds of formula XIII with methyl iodide and a base such as potassium carbonate or cesium carbonate, preferably cesium carbonate, in an inert solvent such as dimethylformamide or acetone, preferably dimethylformamide. The reaction is carried out at a temperature of 0 ° C to 50 ° C, preferably around 25 ° C. Reaction time: 1 to 48 hours, preferably around 16 hours. The compounds of formula I having a basic nature can form a wide range of different salts with various organic or inorganic acids. Although these 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 as a pharmaceutically unacceptable salt and then simply convert it into the compound in free base form. by treatment in an alkaline reagent, and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base-form compounds of this invention are readily prepared by treating the compound in base form 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 compounds in the base form of this invention are those which form non-toxic acid addition salts, ie, salts which contain pharmacologically acceptable anions, such as hydrochloride. hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or citrate acid, tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [ie 1, 1 '-methyl-bis- (2-hydroxy-3-naphthoate)] salts. The compounds of formula I which are also acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of these salts include 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 described herein of formula I. These non-toxic base salts include those derived from pharmaceutically cations. acceptable such as sodium, potassium, calcium and magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.

Alternatively, they can also be prepared by mixing the lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of reagents are preferably employed in order to guarantee the integrity of the reaction and maximum yields of the product. The ability of the compounds of formula I or their pharmaceutically acceptable salts, (hereinafter also referred to as compounds of the present invention) to inhibit mammalian metalloproteinases or reprolysin and, consequently, demonstrate their efficacy in treating diseases characterized by metalloproteinase or factor production of tumor necrosis is demonstrated by the following in vitro assays.

BIOLOGICAL TESTS 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. Trypsin and collagenase are incubated at room temperature for 10 minutes and then a five-fold excess (50 mg / 10 mg trypsin) of the soybean trypsin inhibitor is added. Stock solutions (10 mM) of the inhibitors are prepared in dimethylsulfoxide and then diluted using the following scheme: 10 mM? 120 μM? 12 μM? 1.2 μM? 0.12 μM. Then 25 μl of each concentration is added in triplicate to 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 and without inhibitor) are created in wells D7-D12 and negative controls (without enzyme and without inhibitor) in wells D1-D6. Collagenase-1 is diluted to 240 ng / ml and then 25 ml is added to appropriate wells of the microfluor plate. The final concentration of collagenase in the assay is 60 ng / ml. Substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) is prepared as a 5mM stock solution in dimethyl sulfoxide and then diluted to 20 μM in pH buffer. The assay is initiated by adding 50 ml of substrate per well of the microfluor plate to give a final concentration of 10 mM. Fluorescence readings are taken (excitation at 360 nm, emission at 460 nm) 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 mean of the data is calculated for triplicate determinations). Choose a time point 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 values Cl50. Zero time is used as a target for each compound at each concentration and these values are subtracted from the data at 120 minutes. The data is plotted as inhibitor concentration versus% control (fluorescence of the inhibitor divided by the fluorescence of collagenase alone x 100). The CI5o values are determined from the concentration of inhibitor that gives a signal that is 50% of the control. If it turns out that the IC 50 values are less than 0.03 mM, then the inhibitors are tested at concentrations of 0.3 mM, 0.03 mM and 0.003 mM.

Inhibition of gelatinase (MMP-2) Recombinant human 72 KD gelatinase (MMP-2, gelatinase A) is activated for 16-18 hours with 1 mM p-aminophenyl-mercuric acetate (from a 100 mM stock solution freshly prepared in 0.2 N NaOH) at 4 ° C, with gentle rolling. Stock solutions of inhibitors in 10 mM dimethylsulfoxide are serially diluted in pH buffer (50 mM TRIS, pH 7.5, 200 mM NaCl, CaCl2 5 mM, ZnCI2 20 μM and 0.02% (v / v) of BRIJ-35 using the following scheme: 10 mM? 120 μM? 12 μM? 1.2 μM? 0.12 μM. If necessary, additional dilutions are prepared following this same scheme. In each test, a minimum of four inhibitor concentrations are used for each compound. Then, 25 μl of each concentration is added to triplicate wells of a microfluor plate with 96 black wells 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, etc.). A blank (without enzyme and without inhibitor) and an enzyme positive control (with enzyme and without inhibitor) are also prepared in triplicate. The activated enzyme is diluted to 100 ng / ml in pH regulator, 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 in 5 mM dimethylsulfoxide substrate (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2) is diluted. in pH regulator at 20 μM. The assay is started by adding 50 μl of diluted substrate giving a final concentration of 10 μM substrate assay. At time zero, a fluorescence reading is taken (excitation at 320, emission at 390) immediately and subsequent readings are taken every fifteen minutes at room temperature with a PerSeptive Biosystems CytoFluor multiwell plate reader, with gain at 90 units . The average fluorescence value of the enzyme and the blank against time are plotted. One of the first time points of the linear part of this curve is chosen to make the IC50 determinations. The zero time point for each compound at each dilution is subtracted from the last time point and the data is then expressed as a percentage of the enzyme control (fluorescence of the inhibitor divided by fluorescence of the positive control in enzyme x 100). The data is plotted as concentration of inhibitor against percentage of enzyme control. Cl50 values are defined as the concentration of inhibitor that gives a signal that is 50% of the enzyme positive 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. Stock solutions in 10 mM dimethylsulfoxide inhibitors are serially diluted in pH buffer (50 mM TRIS, pH 7.5, 150 mM NaCl, 10 mM CaC and 0.05% BRIJ-35 (v / v)) using the following scheme: 10 mM? 120 μM? 12 μM? 1.2 μM? 0.12 μM. If necessary, additional dilutions are prepared following this same scheme. In each test, a minimum of four inhibitor concentrations are used for each compound. Then 25 μl of each concentration is added to triplicate wells of a microfluor plate with 96 black bottom U wells. As the final assay volume is 100 μl, the final inhibitor concentrations are the result of an additional 1: 4 dilution ( that is, 30 μM, 3 μM, 0.3 μM, 0.03 μM, etc.). A blank (without enzyme and without inhibitor) and an enzyme positive control (with enzyme and without inhibitor) are also prepared in triplicate. The activated enzyme is diluted to 200 ng / ml in pH regulator, 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 pH buffer to 6 μM. The assay is initiated by the addition of 50 μl of diluted substrate giving a final concentration of 3 μM substrate assay. At time zero, a fluorescence reading is taken (excitation at 320, emission at 390) immediately and subsequent readings are taken every fifteen minutes at room temperature with a PerSeptive multi-well plate reader Biosystems CytoFluor, with the gain to 90 units. The average fluorescence value of the enzyme and the blank against time are plotted. One of the first time points of the linear part of this curve is chosen to make the Cl50 determinations. The zero time point for each compound at each dilution is subtracted from the last time point and the data is then expressed as a percentage of the enzyme control (fluorescence of the inhibitor divided by fluorescence of the positive control in enzyme x 100). The data is plotted as concentration of inhibitor against percentage of enzyme control. The IC50 values are defined as the concentration of inhibitor that gives a signal that is 50% of the positive control in enzyme.

Inhibition of MMP-13 Human recombinant 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 pH buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mM calcium chloride, 20 mM zinc chloride, 0.02% BRIJ 35). 25 μl of diluted enzyme is added per well of a 96-well microfluor plate. The enzyme is then diluted in a 1: 4 ratio in the assay by addition of inhibitor and substrate to give a final concentration in the assay of 60 ng / ml.

Stock solutions (10 mM) of inhibitors are prepared in dimethylsulfoxide and then diluted in pH regulator, following the dilution scheme of inhibitor for inhibition of human collagenase 1 (MMP-1): 25 μl of each concentration is added in triplicate to the microfluor plate. The final concentrations in the assay are 30 mM, 3 mmM, 0.3 mmM and 0.03 mmM. Substrate is prepared (Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) as for the inhibition of human collagenase (MMP-1) and 50 μl is added to each well to give a final assay concentration of 10 μM. Fluorescence readings are taken (excitation at 360 nM, emission at 450 nM) at time 0 and every 5 minutes for 1 hour. Positive controls and negative controls are established in triplicate, as indicated in the MMP-1 assay. The Cl 50 values are determined as for the inhibition of human collagenase (MMP-1). If it turns out that IC50's are less than 0.03 mM, then the inhibitors are tested at final concentrations of 0.3 mM, 0.03 mM, 0.03 mmM, 0.003 mmM and 0.0003 mM.

Inhibition of TNF production The ability of the compounds or their pharmaceutically acceptable salts to inhibit TNF production and, consequently, demonstrate their efficacy in treating diseases involving the production of TNF, is demonstrated by the following in vitro assay: Human mononuclear cells were isolated from anti-coagulated human blood using a Ficoll-hypaque separation technique in one step. (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 10 6 / ml in HBSS containing 1% BSA The differential counts determined using the Abbott analyzer Cell Dyn 3500 indicated that monocytes fluctuated from 17 to 24% of the total cells in these preparations. Aliquots of 180 μl of the cell suspension were distributed in 96-well flat bottom plates (Costar). Additions of compounds and LPS (100 ng / ml final concentration) gave a final volume of 200 μl. All conditions were performed in triplicate. After four hours of 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 separated and assayed to determine TNFa using the R & D ELISA kit.

Inhibition of the production of soluble TNF-α The ability of the compounds or their pharmaceutically acceptable salts to inhibit the cellular release of TNF-a and, consequently, demonstrate their efficacy in treating diseases involving the dis-regulation of soluble TNF-a it is indicated by the following in vitro test: METHOD FOR THE EVALUATION OF ACTIVITY OF RECOMBINANT ENZYME THAT BECOMES TNF-a Expression of recombinant TACE A DNA fragment that encodes the signal sequence, the preprodomain, the prodomain and the catalytic domain of TACE (amino acids 1-473), can be amplified by polymerase chain reaction using a human lung cDNA library with mold. The amplified fragment is then cloned in pFastBac vector. The DNA sequence of the insert is confirmed for the two chains. A bacmid prepared using pFastBac in E. coli DHIOBac is transfected into SF9 insect cells. Then, the virus particles are amplified to P1, P2 and P3 phases. The P3 virus is infected in both Df9 and High Five insect cells and spreads at 27 ° C for 48 hours. The medium is collected and used for testing and further purification.

Fluorescent Extinction Substrate Preparation: A model peptide TNF-α substrate is prepared (LY-Leucine-Alanine-Glutamine-Alanine-Valine-Arginine-Serine-Serine-Lysine (CTMR) -Arginine (LY = Lucifer yellow; CTMR = carboxitetramethyl- rhodamine)) and the concentration is estimated by the absorbance at 560 nm (E56o, 60,000 M-1CM-1) according to the method of Geoghegan, KF, "Improved method for converting an unmodified peptide to an energy-transfer substrate for proteinase "Bioconjuqate Chem. 7, 385-391 (1995). This peptide encompasses the cleavage site in pro-TNF that is cleaved in vivo by TACE.

Expression of recombinant TACE A DNA fragment encoding the signal sequence, the preprodomain, the prodomain, and the catalytic domain of TACE (amino acids 1-473), can be amplified by polymerase chain reaction using a lung cDNA library human as a mold. The amplified fragment is then cloned in pFastBac vector. The DNA sequence of the insert is confirmed for the two chains. A bacmid prepared using pFastBac in E. coli DHIOBac is transfected into SF9 insect cells. Then, the virus particles are amplified to P1, P2 and P3 phases. The P3 virus is infected in both Df9 and High Five insect cells and spreads at 27 ° C for 48 hours. The medium is collected and used for testing and further purification.

Enzymatic Reaction The reaction, carried out in a 96-well plate (Dynatech), comprises 70 μl of pH buffer solution (25 mM Hepes-HCl, pH 7.5, plus 20 μM ZnCl 2), 10 μl of fluorescent extinguished substrate 100 μM , 10 μl of a solution (5%) in DMSO of test compound and an amount of r-TACE enzyme that will cause 50% excision in 60 minutes - in a total volume of 100 μl. The specificity of the enzymatic cleavage in the amido bond between alanine and valine is verified by HPLC and mass spectrometry. Initial cleavage rates are monitored by measuring the rate of increase in fluorescence at 530 nm (excitation at 409 nm) over 30 minutes. The experiment is controlled as follows: 1) as regards the background fluorescence of the substrate; 2) as regards the fluorescence of the completely excised substrate; 3) as regards the extinction or increase of the fluorescence of solutions containing test compound. The data is analyzed as follows. The rates of the "control" reactions containing non-test compound were averaged to establish 100% of the value. The rate of the reaction in the presence of test compound was compared to the rate in the absence of compound and tabulated as "percentage relative to the control containing non-test compound". The results are plotted as "% of control" versus log of the concentration of compound and a semi-maximum point or IC 50 value is determined. All compounds of the invention have IC 50 less than 1 μM, preferably less than 50 nM. The most preferred compounds of the invention are at least 100 times less potent against MMP-1 than in the previous TACE assay.

Assay as human monocytes Human mononuclear cells were isolated from anti-coagulated human blood using a Ficoll-hypaque separation technique in one step. (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 10 6 / ml in HBSS containing 1% BSA The differential counts determined using the Abbott analyzer Cell Dyn 3500 indicated that monocytes fluctuated from 17 to 24% of the total cells in these preparations. 180 m aliquots of the cell suspension were divided into 96-well flat bottom plates (Costar). Additions of compounds and LPS (100 ng / ml final concentration) gave a final volume of 200 μl.

All conditions were performed in triplicate. After four hours of 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 separated and assayed for TNFa using the R &D ELISA kit.

Aggrecanase Assay Primary porcine chondrocytes from joint cartilage are isolated by sequential digestion with trypsin and collagenase followed by digestion with collagenase overnight, and plated at 2 × 10 5 cells per well in 48-well plates with 5 μCi / ml of 35S (1000 Ci / mmol) -sulfur 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 an atmosphere with 5% CO2 .

The night before starting the assay, the chondrocyte monolayers are washed twice in DMEM / 1% PSF / G and then allowed to incubate in DMEM / 1% FBS overnight. The next morning, the chondrocytes are washed once in DMEM / 1% PSF / G. The final wash is allowed to settle on the plates in the incubator while the dilutions are being made. Media and dilutions can be made as described in the following table.

The plates are marked and only the 24 inner wells of the plate are used. On one of the plates, several columns are designated as IL-1 (without drug) and Witness (without IL-1 and without drug). These control columns are counted periodically to monitor the release of 35S-proteoglycan. The control and IL-1 media followed by compound (50 μl) are added to the wells (450 μl) in order to start the assay. The plates are incubated at 37 ° C, with an atmosphere containing 5% CO2. When the release is 40-50% (when CPM of the IL-1 medium is 4-5 times that of the control medium) as estimated by liquid scintillation counting (LSC) of medium samples, the test is completed (9-12 hours). The medium is removed from all wells and placed in scintillation tubes. Scintillation material is added and radioactive counts (LSC) are acquired. To solubilize the cell layers, 500 μl of papain digestion buffer (0.2 M Tris, pH 7.0, 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. The scintillation material is then added and the samples (LSC) are counted. The percentage of counts released from the total present in each well is determined. The averages of the triplicates are made, subtracting from each well the witness background. The percent compound inhibition 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 range of conventional routes, including oral, parenteral (eg intravenous, intramuscular or intramuscular) can be used. subcutaneous), buccal, anal and topical. In general, the compounds of the invention (also hereinafter referred to as the active compounds) will be administered at daily doses between about 0.1 and 25 mg / kg body weight of the subject to be treated, preferably 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 being treated. The person responsible for the administration will determine, in any case, the appropriate dose for each particular subject. The compounds of the present invention can be administered in a wide range of different dosage forms, in general the therapeutically active compounds of this invention are present in said dosage forms at concentration levels ranging from about 5.0% to about 70% in weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, with various disintegrants such as starch (and preferably corn starch, potato or tapioca), alginic acid may be employed. and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic.

Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. 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, colorants, and, if desired, emulsifying and / or suspending agents, together with diluents such as water, ethanol , propylene glycol, glycerin and various similar combinations thereof. In the case of animals, they are advantageously contained in an animal feed or in the drinking water at a concentration of 5-5,000 ppm, preferably from 25 to 500 ppm. For parenteral administration (intramuscular, intraperitoneal, subcutaneous or 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 either sesame or peanut oil or in aqueous propylene glycol. The solutions will have to be adjusted and adjusted to the pH appropriately, 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 intraarticular, intramuscular, and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily carried out by classical 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 about 0.1 to 50 mg / kg / day, advantageously 0.2 to 10 mg / kg / day given in a single dose or in up to 3 divided doses. The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., which contain 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 provided in the form of a solution or suspension from a pump spray container that is tightened or pumped by the patient, or as an aerosol spray presentation to the patient. from a pressurized container or nebulizer, with the use of a suitable propellant, eg dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol, the dosage unit can be determined by providing a valve to provide a measured quantity. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made of, for example, gelatin) can be formulated for use in an inhaler or insufflator, containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. The following examples illustrate the preparation of the compounds of the present invention. Melting points are given without correction. The NMR data are given in parts per million (d) and with reference to the typical deuterium signal in the solvent of the sample (deuterochloroform unless otherwise indicated). The commercial reagents were used without further purification. THF means tetrahydrofuran. DMF means N.N-dimethylformamide. Chromatography means column chromatography performed using 32-63 mm of silica gel and runs under conditions of nitrogen pressure (flash chromatography). The temperature of the room or room designates 20-25 ° C. All non-aqueous reactions were carried out under a nitrogen atmosphere for convenience and to maximize yields. Concentration at reduced pressure means that a rotary evaporator was used.

EXAMPLE 1 (2R, 4S) -4- (4-methoxyphenyl) -5-oxopyrrolidine-2-carboxylic acid hydroxyamide Step A: (5R) -3-bromo-5- (tert-butyldimethylsilylanymethyl) -2-oxo-2,5-dihydro-pyrrol-1-carboxylic acid tert-butyl ester A solution of 2- (tert-Butyldimethylsilanyloxymethyl) -5-oxopyrrolidone-1-carboxylic acid tert -butyl ester (16.5 grams, 50 mmol) in tetrahydrofuran (800 ml) was cooled in a bath at -78 ° C. A 1M solution of lithium bis (trimethylsilyl) amide of tetrahydrofuran (100 mL, 100 mmol) was slowly added. After stirring for 2 hours, a solution of phenylsenylbromide (14.16 grams, 60 mmol) in tetrahydrofuran (100 ml) was added and, after 15 minutes, a solution of 1,2-di-bromotetrachloroethane (19.5 grams) was added. , 60 mmol) in tetrahydrofuran (100 ml). The reaction mixture was stirred for an additional 1.5 hours while cooling to -78 ° C and the reaction was quenched by the addition of a saturated solution of ammonium chloride. Water and diethyl ether were added. The aqueous phase was separated and extracted with diethyl ether. The combined organic layers were concentrated in an orange oil which was dissolved in methylene chloride (1000 ml). A 30% w / v aqueous solution of hydrogen peroxide (20 ml) was added and the mixture was stirred vigorously overnight. Water (50 ml) was added. The aqueous layer was separated and extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate and concentrated to an orange oil.

The title compound (12.0 grams, 59%) was isolated by flash chromatography on silica gel eluting first with a 1: 1 mixture of hexane and methylene chloride and then with methylene chloride alone. 1 H NMR (CDCl 3): d 7.31 (d, J = 2.3 Hz, 1 H), 4.56-4.53 (m, 1 H), 4.08 (dd, J = 3.4, 10.0 Hz, 1H), 3.74 (dd, J = 6.2, 10.0 Hz, 1 H), 1.53 (s, 9H), 0.83 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H). 13 C NMR (CDCl 3): d 164.0, 149.1, 146.3, 118.2, 83.6, 62.8, 61.8, 28.0, 25.6, 18.0, -5.6, -5.7.

Step B: (5R) -5- (tert-Butyl-dimethylsilamino-oxy-3- (4-methoxyphenyl) -2-oxo-2,5-dihydropyrrol-1-carboxylic acid tert-butyl ester The diethanolamine complex of 4-methoxyphenylboronic acid (2.5 grams, 11 mmol) was stirred in a mixture of diisopropyl ether (50 ml) and 1.5 M aqueous hydrochloric acid solution (30 ml) for 2 hours, after separation of the aqueous layer was added toluene (50 ml) and the mixture was concentrated to remove most of the diisopropyl ether, (5R) -3-bromo-5- (tert-butyl-dimethylsilanyloxymethyl) -2-oxo-2-tert-butyl ester was added. , 5-dihydropyrrol-1-carboxylic acid (3.0 grams, 7.38 mmol), toluene (150 ml), and a solution of sodium carbonate (850 mg, 8 mmol) in water (20 ml) After purging the oxygen solution , tetrakis (triphenylphosphene) palladium (0) (250 mg) was added and the mixture was heated to reflux for 2.5 hours, the mixture was cooled and diluted with toluene and water. poured, washed with brine, dried over magnesium sulfate and concentrated to give a brown oil. The title compound (1.7 grams, 53%) was isolated by flash chromatography on silica gel eluting with methylene chloride. 1 H NMR (CDCl 3): d 7.74 (d, J = 8.9 Hz, 2H), 7.24 (d, J = 2.5 Hz, 1 H), 6.88 (d, J = 8.9 Hz, 2 H), 4.57-4.54, (m, 1 H), 4.17 (dd, J = 3.6, 9.6 Hz, 1 H), 3. 79 (s, 3H), 3.72 (dd, J = 6.6, 9.6 Hz, 1H), 1.55 (s, 9H), 0.82 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H).

Step C: (3S, 5R) -5-Hydroxymethyl-3- (4-methoxyphenyl) -2-oxopyrrolidine-1-carboxylic acid tert-butyl ester A solution of (5R) -5-tert-butyl ester - (tert-butyl-d-methylolysilyloxymethyl) -3- (4-methoxy-phenyl) -2-oxo-2,5-di-1-pyrrolid-1-carboxylic acid (1.7 grams, 3.9 mmol ) in ethanol (100 ml) was treated with palladium black (300 mg) and hydrogenated on a Parr ™ shaker at 3 atmospheres pressure overnight. The catalyst was removed by filtration and the solvent was evaporated to give 3S-tert-butyl ester., 5R) -5- (tert-butyl-dimethylsilanyloxy-methyl) -3- (4-methoxyphenyl) -2-oxopyrrolidine-1-carboxylic acid as an oil. This was dissolved in tetrahydrofuran (40 ml) and treated with an aqueous solution of 0.5 M hydrochloric acid (7.2 ml). The resulting mixture was stirred at room temperature overnight, quenched with a saturated sodium carbonate solution and extracted twice with methylene chloride. The combined organic extracts were dried over magnesium sulfate and concentrated to give an oil. The title compound (551 mg, 48%) was isolated by flash chromatography on silica gel eluting with hexane at % in ethyl acetate. 1 H NMR (CDCl 3): d 7.15 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.18-4.13 (m, 1 H), 3.81-3.65 (m, 4H), 3.76 (s, 3H, overlapped), 2.58-2.51 (m, 1 H), 1.96-1.87 (m, 1 H), 1.52 (s, 9H).

Step D: (2R, 4S) -4- (4-methoxyphenyl) -5-oxopyrrolidine-1,2-dicarboxylic acid tert-butyl ester A stock solution containing 12.0 grams of periodic acid and chromium trioxide was prepared (24) mg) in wet acetonitrile (0.75% by volume of water). A portion of this solution (9.6 ml) was added to a solution of (3S, 5R) -5-hydroxymethyl-3- (4-methoxyphenyl) -2-oxopyridine-1-carboxylic acid tert -butyl ester (510 mg, 1.58 mmol) in wet acetonitrile (0.75% by volume of water) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 hours and then the reaction was quenched by the addition of a solution of sodium dibasic phosphate (1.2 grams) in water (20 ml). The mixture was extracted with ethyl acetate and the organic extract was washed with aqueous sodium bisulfite solution and brine. After drying over magnesium sulfate, the solvent was evaporated to give the title compound as a white solid, 518 mg (98%). 1 H NMR (CDCl 3): d 8.56 (broad s, 1 H), 7.13 (d, J = 8.6 Hz, 2H), 6. 82 (d, J = 8.6 Hz, 2H), 4.58 (apparent t, J = 8.3 Hz, 1 H), 3.78-3.73 (m, 1H), 3. 73 (s, 3H), 2.86-2.79 (m, 1 H), 2.13-2.05 (m, 1 H), 1.45 (s, 9H). 13 C NMR (CDCl 3): d 176.2, 173.2, 159.0, 149.4, 129.2, 129.0, 114.2, 84.3, 56.8, 55.2, 47.9, 30.2, 27.8. MS: m / z 334 (M-1), 234. MQ = + 4.4 ° (c = 1.12, CHCl3).

Step E: (3S, 5R) -5-Benzyloxycarbamoyl-3- (4-methoxyphenyl) -2-oxopyrrolidine-1-carboxylic acid tert-butyl ester To a solution of 1-tert-butyl acid ester ( 2R, 4S) -4- (4-methoxyphenyl) -5-pyrrolidine-1,2-dicarboxylic acid (305 mg, 0.91 mmol), diisopropylethylamine (0.35 mL, 2.0 mmol) and O-benzylhydroxylamine hydrochloride (160 mg, 1.0 mmol) in methylene chloride (20 ml) was added (benzotriazol-1-yloxy) tris (dimethylamino) -phosphonip hexafluoroborate (443 mg, 1.0 mmol) .The reaction was stirred at room temperature overnight. of the dilution with methylene chloride, the mixture was washed with saturated aqueous sodium bicarbonate solution, water and brine, The solution was dried over magnesium sulfate and concentrated to a white solid, from which the compound was isolated. of title (294 mg, 73%) by flash chromatography eluting with 25% hexane in ethyl acetate MS: m / z 439 (M-1), 339.

Step F: (2R, 4S) -4- (4-Methoxyphenyl) -5-oxopyrrolidine-2-dicarboxylic acid benzyloxy acid. Hydrogen chloride gas was bubbled in for 3 minutes through a solution of 3-tert-butyl acid ester (3S). , 5R) -5-benzyloxycarbamoyl-3- (4-methoxyphenyl) -2-oxopyrrolidine-1-carboxylic acid (270 mg, 0.61 mmol) in methylene chloride (40 ml). After stirring for a further 10 minutes, the solvent was evaporated to leave a white foam. The title compound (169 mg, 80%) was isolated by flash chromatography (eluting with ethyl acetate) and recrystallization from a mixture of ethyl acetate and hexane. 1 H NMR (CDCl 3): d 10.40 (broad s, 1 H), 7.30-7.23 (m, 5H), 7.15 (broad s, 1 H), 7.04 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 4.79-4.72 (m, 2H), 3.89 (apparent t, J = 7.3 Hz, 1 H), 3.70 (s, 3H), 3.45 (t aprente, J = 9.6 Hz, 1H) , 2.77-2.69 (m, 1 H), 2.06-1.98 (m, 1 H). 13 C NMR (CDCl 3): d 179.1, 169.3, 158.8, 134.9, 130.0, 129.3, 129.2, 128.7, 128.5, 114.2, 78.1, 55.2, 53.9, 46.6, 34.6. MS: m / z 341 (M + 1). [ato = + 39.9 ° (c = 0.91, CHCI3).

Hydroxyamide (2R. 4S) -4- (4-methoxyphenyl) -5-oxopyrrolidine-2-carboxylic acid A solution of benzyloxyamide of (2R, 4S) -4- (4-methoxyphenyl) -5-oxopyrrolidine- 2-carboxylic acid (150 mg, 0.44 mmol) in methanol (15 ml) was treated with 5% palladium on barium sulfate (40 mg) and hydrogenated on a Parr ™ shaker at 3 atmospheres pressure for 2.5 hours. The catalyst was removed by filtration and the solvent was evaporated to give a solid. The title compound (106 mg, 96%) was isolated by crystallization from a mixture of ethyl acetate and hexane. 1 H NMR (DMSO-de): d 10.77 (broad s, 1H), 8.97 (broad s, 1H), 8.01 (broad s, 1 H), 7.14 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 3.91 (apparent t, J = 7.8 Hz, 1 H), 3.69 (s, 3H), 3.53 (apparent t, J = 7.8 Hz, 1 H), 2.67-2.58 (m, 1 H), 1.92-1.84 (m, 1 H). MS: m / z 249 (M-1).

EXAMPLE 2 (2R, 4S) -4-r4- (4-fluorophenoxy) -phenyl-5-oxopyrrolidine-2-carboxylic acid hydroxyamide It is prepared according to the method of Example 1 starting from the complex of 4- (4-fluorophenoxy) phenylboronic acid with diethanolamine. 1 H NMR (DMSO-d 6): d 10.78 (s broad, 1 H), 8.98 (s broad 1 H), 8.06 (s, 1 H), 7.23 (d, J = 8.7 Hz, 2 H), 7.19-7.15 (m , 2H), 7.02-6.98 (m, 2H), 6.89 (d, J = 8.7 Hz, 2H), 3.91 (apparent t, J = 7.8 Hz, 1 H), 3.59 (apparent t, J = 9.8 Hz, 1H ), 2.67-2.60 (m, 1 H), 1.94-1.86 (m, 1 H). 13 C NMR (DMSO-de): d 176.0, 167.8, 157.6 (d, J = 240 Hz), 155.2, 152. 3, 134.8, 129.4, 119.9 (d, J = 9 Hz), 117.5, 116.0 (d, J = 23 Hz), 51.4, 45.5 33.6. MS: m / z 329 (M-1).

WD = + 24.3 ° (c = 1.14, MeOH).

EXAMPLE 3 (2R, 4S) -4- (4'-Fluorobiphenyl-4-yl) -5-oxo-pyrrolidine-2-carboxylic acid hydroxyamide It is prepared according to the method of example 1 starting from the complex of 4'-fIuorobifen-4-ylboronic acid with diethanolamine. Recrystallized from methanol, m.p .: 193-202 ° C. 1 H NMR (DMSO-de): d 10.77 (broad s, 1 H), 8.97 (broad s 1 H), 8. 08 (s, 1 H), 7.67-7.63 (m, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.24 (apparent t, J = 8.8 Hz , 2H), 3.95 (apparent t, J = 7.8 Hz, 1 H), 3.65 (apparent t, J = 9.7 Hz, 1 H), 2.71-2.64 (m, 1 H), 2.00-1.93 (m, 1 H ). MS: m / z 313 (M-1). Analysis calculated for C17H15FN2? 3.1 / 2H2O: C, 63.15; H, 4.99; N, 8.66. Found: C, 62.83; H, 5.48; N, 8.39.

EXAMPLE 4 (2R, 4S) -4-r3- (4-Fluorophenoxy) -phen p-5-oxo-pyrrolidine-2-carboxylic acid hydroxyamide It is prepared according to the method of Example 1 starting from the complex of 3- (4-fluorophenoxy) phenylboronic acid with diethanolamine. Recrystallized from ethyl acetate, m.p .: 151-152 ° C. 1 H NMR (DMSO-de): d 10.79 (s, 1 H), 8.98 (s, 1 H), 8.08 (s, 1 H), 7.28 (apparent t, J = 7.9 Hz, 1 H), 7.22-7.18 (m, 2H), 7.04-7.01 (m, 3H), 6.93 (s, apparent, 1 H), 6.78 (dd, J = 2.5, 8.3 Hz, 1 H), 3.91 (apparent t, J = 7.6 Hz, 1H), 3.62 (apparent t, J = 9.8 Hz, 1 H), 2.69-2.62 (m, 1 H), 1.95-1.87 (m, 1 H). MS: m / z 329 (M-1). [a] D = + 17.9 ° (c = 1.00, MeOH). Analysis calculated for C? 7H? 5FN2O4: C, 61.82; H, 4.58; N, 8.48. Found: C, 61.85; H, 4.59; N, 8.40.

EXAMPLE 5 (2R, 4S) -4-naphthalen-2-yl-5-oxo-pyrrolidine-2-carboxylic acid hydroxyamide It is prepared according to the method of Example 1 starting from 2-naphthylboronic acid. Recrystallized from ethyl acetate / methanol, m.p .: 197-199 ° C. 1 H NMR (DMSO-de): d 10.82 (broad s, 1H), 9.00 (s 1 H), 8.14 (s, 1H), 7.86-7.83 (m, 3H), 7.75 (s, apparent, 1 H) 7.46-7.42 (m, 3H), 4.00 (apparent t, J = 7.6 Hz, 1H), 3.80 (apparent t, J = 9.6 Hz, 1H), 2.77-2.72 (m, 1H), 2. 10-2.03 (m, 1 H). MS: m / z 269 (M-1). MD = 0o (c = 0.33, MeOH). Analysis calculated for C? 5H? 4N2O3: C, 66.66; H, 5.22; N, 10.36. Found: C, 66.43; H, 5.41; N, 10.10.

EXAMPLE 6 (2R, 4S) -5-Oxo-4- (4-phenethylphenyl) -pyrrolidine-2-carboxylic acid hydroxyamide It is prepared according to the method of Example 1 starting from 4-styrylphenylboronic acid. (The styryl double bond is reduced to a phenethylphenyl group at the same time that the double bond of 2-oxo-2,5-dihydropyrrole is hydrogenated). 1 H NMR (DMSO-de): d 10.78 (broad s, 1 H), 8.97 (s 1 H), 8.03 (s, 1H), 7.24-7.22 (m, 4H), 7.14 (apparent s, 5H), 3.92 (apparent t, J = 7.4 Hz, 1 H), 3.55 (apparent t, J = 9.9 Hz, 1 H), 2.82 (apparent s, 4H), 2.67-2.60 (m, 1H), 1.95-187 (m, 1 HOUR). MS m / z 325 (M + 1).

EXAMPLE 7 (2R, 4S) -4- (4-Benzyloxyphenyl) -5-oxo-pyrrolidine-2-carboxylic acid hydroxyamide Step A: (5R) -3- (4-Benzyloxy-phenyl) -5- (tert-butyldimethylsilaminoxymethyl) -2-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester 4-phenethylphenylboronic acid with diethanolamine (8.25 g, 27.8 mmol) was stirred in a mixture of diethyl ether (165 ml) and aqueous 3 M HCl solution (66 ml) for 3 hours. toluene (100 ml) was added and the mixture was concentrated to remove most of the diethyl ether (5R) -3-bromo-5- (tert-butyl-dimethylsilanyloxymethyl) -2-oxo-tert-butyl ester. 2, 5-dihydropyrrole-1-carboxylic acid (7.5 g, 18.5 mmol) and a solution of Na2CO3 (1.25 g, 11.8 mmol) in water (25 mL). After purging the oxygen solution, tetrakis (triphenylphosphene) palladium (0) (424 mg) was added and the mixture was heated to reflux for 18 h. The mixture was cooled and diluted with toluene and water. The organic layer was separated, washed with brine, dried over MgSO and concentrated to give a dark oil. The title compound (5.5 g, 58%) was isolated as a pale yellow solid by flash chromatography on silica gel eluting with 15% diethyl ether in hexane.

Step B: (3S, 5R) -3 - ('4-benzyloxyphenyl) -5- (tert-butyldimethylsilaminoxyethyl) -2-oxo pyrrolidine-1-carboxylic acid tert-butyl ester A solution of ester ter- butyl (5R) -3- (4-encyloxy-phenyl) -5- (tert-butyldimethylsilanyloxymethyl) -2-oxo-2,5-dihydro-pyrrole-1-carboxylic acid butyl ester (2.0 g, 3.92 mmol) in Ethyl acetate (40 ml) and hexane (40 ml) was treated with 20% palladium hydroxide on carbon (200 mg) and hydrogenated on a Parr ™ shaker at 3 atmospheres pressure for 2 hours. The catalyst was removed by filtration and the solvent was evaporated to give the title compound as a yellow oil (2.0 g, 100%).

Step C: (3S, 5R) -3- (4-Benzyloxyphenyl) -5-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester A solution of 3S-tert-butyl acid ester (3S, 5R) -3- (4-benzyloxyphenyl) -5-hydroxymethyl-2-oxo-pyrrolidin-1-carboxylic acid 5R) -3- (4-benzyloxyphenyl) -5- (tert-butyldimethylsilanyloxymethyl) -2-oxo-pyrrolidine-1-carboxylic acid (2.0 g, 3.91 mmol) in tetrahydrofuran (45 ml) was cooled in an ice bath. An aqueous solution of 0.5 M HCl (7.8 mL, 3.9 mmol) was added and the resulting mixture was allowed to warm to room temperature while stirring overnight. After a total reaction time of 24 hours, a saturated aqueous solution of NaHC 3 was added. The mixture was extracted twice with diethyl ether and the combined organic phases were washed with brine, dried over MgSO and concentrated to an oil. The title compound, a colorless oil (1.02 g, 65%), was isolated by flash chromatography on silica gel eluting with ethyl acetate 50% in hexane.

Step D: (2R, 4S) -4- (4-benzyloxyphenyl) -5-oxo-pyrrolidine-2-carboxylic acid A solution containing 6.0 g of periodic acid and chromium trioxide (13 mg) in wet acetonitrile (60 mg) was prepared. ml; 0.75% by volume of water). A portion of this solution (15 ml) was added dropwise to a solution of (3S, 5R) -3- (4-benzyloxyphenyl) -5-hydroxymethyl-2-oxo-tert-butyl ether. pyrrolidine-1-carboxylic acid (1.02 g, 2.57 mmol) in wet acetonitrile (15 ml, 0.75% by volume water) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 hours. At that time, more solution of periodic acid / chromium trioxide (5 ml) was added. Stirring was continued at 0 ° C for an additional 1 hour. After quenching the reaction with a solution of sodium dibasic phosphate (720 mg) in water (12 ml), the mixture was extracted twice with diethyl ether. The combined organic extracts were washed with aqueous sodium bisulfite solution (440 mg in 10 ml of water and brine). After drying over MgSO, the solvent was evaporated to give a yellow solid which was taken up in methylene chloride (100 ml) and cooled in an ice bath. Hydrogen chloride gas was bubbled through the cold solution for 2 minutes and the resulting mixture was stirred at ° C for 1 hour. The solvent and HCl were evaporated to give a solid from which the title compound, 226 mg (28%) was isolated, by trituration with a mixture of methylene chloride, diethyl ether and ethyl acetate. The filtrate from the trituration was dissolved in a saturated aqueous solution of NaHCO 3 and washed twice with diethyl ether. After careful acidulation with an aqueous solution of 6 M HCl, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated to give more of the title compound, 123 mg (15%).

Step E: (2R, 4S) -4- (4-benzyloxyphenyl) -5-oxo-pyrrolidine-2-carboxylic acid (2R, 4S) -4- (trimethylsilylethylethoxy) acid ester To a solution of (2R, 4S) -4- (4- benzyloxyphenyl) -5-oxo-pyrrolidine-2-carboxylic acid (330 mg, 1.06 mmol), N-methylmorpholine (0.25 mL, 2.3 mmol) and O- (2-trimethylsilylethyl) hydroxylamine hydrochloride (220 mg, 1.30 mmol) in CH2Cl2 (20 ml) was added (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluoroborate (560 mg, 1.27 mmol). The reaction was stirred at room temperature for 6 hours. After diluting with CH2CI2, the mixture was washed sequentially with 0.5 M HCl aqueous solution, water, saturated aqueous solution of NaHCO3 and brine. The solution was dried over MgSO4 and concentrated to a white solid which was triturated with ethyl acetate and set aside. The filtrate from the trituration was concentrated and chromatographed on silica gel eluting with 5% methanol in chloroform. The fractions containing the title compound were combined and concentrated to give a white solid which was combined with the solid obtained directly from the crude mixture of the product. The sample was stirred in water overnight. The title compound was collected by filtration and dried. The yield was 194 mg (43%).

Step F: (2R, 4S) -4- (4-benzyloxyphenyl) -5-oxo-pyrrolidine-2-carboxylic acid To a suspension of (2R, 2-trimethylalanylethoxy) acid amide (2R, 4S) -4- (4-benzyloxyphenyl) -5-oxo-pyrrolidine-2-carboxylic acid (95 mg, 0.22 mmol) in methylene chloride, boron trifluoride etherate (0.86 μl, 0.68 mmol) was added. The mixture was stirred at room temperature for 75 minutes. During this period, the suspended solid dissolved completely and the product precipitated. The reaction was quenched by the addition of saturated aqueous solution of NH CI. The title compound was collected by filtration, washing well with ethyl acetate and water, and dried. The yield was 56 mg (78%). 1 H NMR (DMSO-de): d 10.74 (broad s, 1 H), 8.95 (broad s, 1 H), 8.00 (broad s, 1 H), 7.70-7.27 (m, 5H), 7.13 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 5.04 (apparent s, 2H), 3.89 (apparent t, J = 7.7 Hz, 1 H), 3.51 (apparent t, J = 9.7 Hz , 1 H), 2.64-2.57 (m, 1 H), 1.91-1.83 (m, 1H). MS: m / z 325 (M-1).

Claims (19)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula: wherein R 1 is alkyl (Ci-Cß), aryl (Ce-Cι), heteroaryl (C 2 -Cg), aryl (Ce-Cι) alkyl (Ci-Cβ), aryl (C 6 -C) or aryl (C 6) C? O), aryl (C6-C? 0) heteroaryl (C2-C9), heteroaryl (C2-C9) alkyl (Ci-Cß), heteroaryl (C2-C9) aryl (C6-C? 0), heteroaryl ( C2-C9) heteroaryl (C2-C9), aryloxy (C6-C? 0) alkyl (C? -C6), aryloxy (C6-C? 0) aryl (C6-C? O), aryloxy (C6-C? o) heteroaryl (C2-C9), heteroaryloxy (C2-Cg) alkyl (C1-C6), heteroaryloxy (C2-C9) aryl (C6-C? o), heteroaryloxy (C2-C9) heteroaryl (C2-C9), aryl (C6-C? o) alkyl (C? -C6) aryl (C6-C? 0), aryl (C6-C? 0) alkyl- (CrC6) heteroaryl (C2-C9), aryl (C6-C? 0) (C 6 -C 6) alkoxy (C 6 -C 0) aryl, (C 6 -C 6) aryl (C 6 -C 6) alkoxy (C 2 -C 9), aryloxy (C 6 -C 0) alkyl (C 6) ? -C6) aryl (C6-C? 0), aryloxy (C6-C? O) alkyl- (C? -C6) heteroaryl (C2-C9), heteroaryl (C2-C9) -alkyl (C6) aryl ( C6-C? O), heteroaryl (C2-C9) alkyl (C? -C6) -heteroaryl (C2-C), heteroaryl (C2-C9) alkoxy (C6-C6) aryl (C6-C? 0), heteroaryl ( C2-C9) (C6) alkoxy heteroaryl (C 2-C9), heteroaryloxy (C2-C9) alkyl (C6-6) aryl (C6-C6), heteroaryloxy (C2-C8) alkyl- (C6-C) heteroaryl (C2-C9), aryl ( C6-C? 0) aryl (C6-C? 0) alkyl (d-Cß) or aryl (C6-C? 0) alkoxy (Ci-C?) Alkyl (Ci-C?), Where each of said aryl residues ( C6-C 0) or heteroaryl (C-Cg) is optionally substituted, with one or more substituents per ring, at any of the ring carbon atoms that are capable of forming an additional bond, said substituents being independently selected from fluoro, chloro , bromine, alkyl (C? -C6), alkoxy (C? -C6), perfluoroalkyl (C1-C3), perlfuoroalkoxy (C1-C3) and aryloxy (C6-C? 0); and R2 and R3 are independently selected from H, alkyl (CrC6) and CH2-aryl (C6-C? 0); or one of its pharmaceutically acceptable salts.

2. A compound according to claim 1, wherein R1 is aryl (Ce-Cio), aryloxy (C6-C? 0) aryl (C6-C? 0), aryl (C6-C? 0) aryl (C6) -C? 0), aryloxy (Cedo) heteroaryl (C2-C9), heteroaryl (C2-C9), heteroaryl (C2-C9) heteroaryl (C2-C9), aryl (C6-C? O) alkoxy (Ci-Cβ) ) aryl (C6-C? o), heteroaryloxy (C2-Cg) aryl. { Cß-C10), aryl (C6-C? 0) alkoxy (Ci-Cß) heteroaryl (C2-Cg), heteroaryloxy (C2-Cg) heteroaryl (C2-C9), aryl (Ce-Cio) heteroaryl (C2-C9) ), heteroaryl (C2-C) aryl (Cß-C10), heteroaryl (C-Cg) alkoxy (CrC6) aryl (C6-C? 0), or heteroaryl (C2-Cg) alkoxy (C-C6) heteroaryl (C2) -C9), wherein each of said aryl moieties (C6-C? 0) or heteroaryl (C2-C9) of said aryl (C6-C? 0), aryloxy (C6-C? O) aryl (C6-) C? 0), aryl (Cß-C10) aryl (C6-C? 0), aryloxy (C6-C? 0) heteroaryl (C2-Cg), heteroaryl (C2-C9), aryl (C6-C or) alkoxy (C? -C6) aryl (C6-C? 0), heteroaryloxy (C2-Cg) aryl (C6-C? 0), aryl (Cd-Cio) alkoxy (Ci-Cd) he-teroaryl (C2-C8) , (C2-C8) heteroaryloxy (C2-C9) heteroaryl, (C6-C6) aryl (C2-C9) heteroaryl, (C2-C9) heteroaryl (C6-C10) aryl, (C2-C8) heteroaryl alkoxy ( C -C6) aryl (C6-C? 0), or heteroaryl (C2-Cg) alkoxy (d-C) heteroaryl (C2-C9), is optionally substituted, with one or more substituents per ring that are capable of forming a additional link, selecting independent said substituents between fluoro, chloro, bromo, alkyl (C? -C6), alkoxy (C? -C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy (Ce-Cio); or one of its pharmaceutically acceptable salts.

3. A compound of formula I with the stereochemistry: r

4. - A compound according to claim 3, wherein R 1 is aryl (Ce-Cι) optionally substituted.

5. A compound according to claim 3, wherein R1 is optionally substituted aryl (C6-C? O) aryl (Ce-Cio).

6. A compound according to claim 3, wherein R1 is optionally substituted heteroaryloxy (C2-Cg) aryl (Ce-Cio).

7. A compound according to claim 3, wherein R1 is aryl (C6-C10) alkoxy (C6C6) aryl (Ce-Cio) optionally substituted.

8. A compound according to claim 3, wherein said optional substituent of R1 is hydrogen, fluoro, chloro, alkyl (C-C6) or alkoxy (C6-C6).

9. - A compound according to claim 3, wherein said optional substituent of R1 is in the para position of the terminal ring.

10. A compound according to claim 3, wherein R1 is in the ortho position of the terminal ring.

11. A compound according to claim 3, wherein R2 and R3 are hydrogen.

12. A compound according to claim 3, wherein one or both of R2 and R3 are independently selected from alkyl (C? -C6) and CH2 - aryl (C6-C? O).

13. A compound according to claim 3, wherein said compound is selected from the group consisting of: (2R, 4S) -4- (4-methoxyphenyl) -5-oxopyrrolidine-2-carboxylic acid hydroxyamide, acid hydroxyamide (2R, 4S) -4- [4- (4-fluorophenoxy) -phenyl] -5-oxopyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -5-oxo-4- (4-phenoxyphenyl) -pyrrolidine -2-carboxylic acid hydroxyamide (2R, 4S) -4- [4 - (4-chlorophenoxy) -phenyl] -5-oxopyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -4- [3- (4-chlorophenoxy) -phenyl-5-oxopyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -4- [3- (4-fluorophenoxy) -phenyl-5-oxopyrrolidine-2-carboxylic acid hydroxyamide ( 2R, 4S) -5-oxo-4- [4- (4-pyridin-4-yloxy) -phenyl] pyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -4-biphenyl-4- il-5-oxo-pyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -4- (4'-fluorobiphenyl-4-yl) -5-oxopyrrolidine-2-carboxylic acid hydroxyamide ( 2R, 4S) -4- (4-benzyloxyphenyl) -5-oxopyrroli dina-2-carboxylic acid, hydroxyamide (2R, 4S) -5-oxo-4- (4-phenethylphenyl) -pyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -4- [4 - (4-Fluorobenzyloxy) -phenyl] -5-oxopyrrolidone-2-carboxylic acid hydroxyamide (2R, 4S) -4- [4- (3,5-difluorobenzyl-oxy) phenyl] - 5-Oxopyrroline-2-carboxylic acid, (2R, 4S) -4- (4-methoxybenzyl) -5-oxopyrrolidine-2-carboxylic acid hydroxyamide, (2R, 4S) -4- (4'-) hydroxyamide fluorobiphenyl-4-ylmethyl) -5-oxopyrrolidine-2-carboxylic acid, (2R, 4S) -4-naphthalen-2-yl-5-oxo-pyrrolidine-2-carboxylic acid hydroxyamide, (2R, 4S) hydroxyamide -4- [4- (4-fluorophenoxy) -phenyl] -2,4-dimethyl-5-oxo-pyrrolidine-2-carboxylic acid hydroxyamide (2R, 4S) -4- [4 - (4 - fluorophenoxy) -phenyl] -4-methyl-5-oxo-pyrrolidine-2-carboxylic acid (2R, 4R) -4-benzyl-5-oxo-4- (4-phenoxyphenyl) -pyrrolidine-2-carboxylic acid hydroxyamide , hydroxyamide of (2R, 4S) -4- [4- (4-chlorophenoxy) -phenyl] -4-methyI-5-oxo-pyrrolidine-2-carboxylic acid, and hyd (2R, 4S) -4- [4- (4-chlorophenoxy) -phenyl] -2,4-dimethyl-5-oxo-pyrrolidine-2-carboxylic acid oxyamide.

14. 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, organ transplantation toxicity , cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, bullous epidermolysis, osteoporosis, artificial joint implants detachment, atherosclerosis (including rupture of the atherosclerotic plaque), aortic aneurysm (included 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 on, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition improvement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis and septic shock in a mammal, including a human being, comprising an amount of a compound of claim 1 effective in such treatments and a pharmaceutically acceptable carrier.

15. The use of a compound according to 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 bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, artificial joint implant detachment, atherosclerosis (including rupture of atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia , head 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 cognition improvement, sclerosis lateral amyotrophic, escle multiple rosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis and septic shock in a mammal, including a human being.

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

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

18. The use of a compound of claim 1 for the manufacture of a medicament for the inhibition of matrix metalloproteinases in a mammal, including a human.

19. The use of a compound of claim 1 for the manufacture of a medicament for the inhibition of a mammalian reprolysin in a mammal, including a human.