MXPA00009903A - Process for alkylating hindered sulfonamides useful in the production of matrix metalloproteinase inhibitors - Google Patents

Abstract

The present invention relates to a process for the preparation of compounds of formula (b), in which a compound of formula (V) is reacted with a compound of formula (VI). The resulting compound of formula (IV) is reduced to a compound of formula (III) which is hydrolysed to a compound of formula (b). Alternatively, a compound of formula (IV) is hydrolysed to a compound of formula (a) which is reduced to a compound of formula (b). Compounds of formula (IV) are novel. In the formulae the variables are as defined in the claims. Compounds of formula (b) are useful as intermediates in the preparation of matrix metalloproteinase inhibitors.

Description

PROCEDURE FOR THE RENT OF SULFONAMIDES IMPAIRED ESTERICALLY USEFUL IN THE PRODUCTION OF MATRIX METALOPROTEINASE INHIBITORS The present application claims priority under section 35 USC 1 19 (e) of provisional application of United States 60/081: 310 filed on April 10, 1988, the text of which is incorporated herein by reference In its whole. The text and claims of the United States utility model application entitled "Process for the alkylation of sterically hindered sulfonamides" filed on April 9, 1999 and bearing the express mail label EE645346913 E.U.A. it is incorporated as a reference in its entirety in this document.

BACKGROUND OF THE INVENTION The present invention relates to a process for the alkylation of sterically hindered sulfonamides by addition of Michael to propiolates and to novel intermediates prepared in said process. The products of the aforesaid reaction can be converted into inhibitors of the matrix metalloproteinase. Matrix metalloproteinase inhibitors (MMPs) are known to be useful 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, insufficiency syndrome acute respiratory disease, asthma, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, vesicular epidermolysis, osteoporosis, joint loosening in artificial implants, atherosclerosis (including rupture of the atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and cerebral aortic aneurysm), cogestive heart failure, myocardial infarction, stroke, cerebral ischemia, head injury, spinal cord damage, disorders neurodegenerati you (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pains, cerebral amyloid angiopathy, cognitive or nootropic improvement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal damage, degeneration macular, abnormal healing of wounds, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, sclerotitis, AIDS, sepsis, septic shock and other diseases characterized by the inhibition of metalloproteinase or by the expression of ADAM (including TNF-alpha). In addition, the products that can be prepared from compounds and methods of the present invention can be used in combination therapies with conventional non-steroidal anti-inflammatory drugs (hereinafter NSAIDs), COX-2 inhibitors and analgesics for the treatment of arthritis, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, in the treatment of cancer. The alkylsulfonamides that can be prepared by the methods of the present invention are described in the literature. PCT publications WO 96/27583 and WO 98/076697, published March 7, 1996 and February 26, 1998, respectively, refer to arylsulfonylhydroxamic acids. The above references refer to processes for the preparation of sulfonamides using processes other than those described in the present invention. Each of the above mentioned publications is incorporated herein by reference in its entirety.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula wherein R1 is optionally substituted alkyl (C? -C6) or benzyl; R2 and R3 are independently (C -? - C6) alkyl or R2 and R3 are taken together to form a cycloalkyl of three to seven members, a pyran-4-yl ring or a bicyclic ring of formula wherein the asterisk indicates the carbon atom common to R2 and R3; Q is alkyl (C -? - C6), aryl (C6-C? O), heteroaryl (C2-C9), aryl (C6-C10) alkyl (C? -6), heteroaryl (C2-C9) alkyl (C C6), (C6-C10) aryloxy (C6) alkyl, (C6-C6O) aryl (C6-C6O) aryloxy, (C6-C6o) heteroaryl (C2-) aryloxy C9), aryl (C6-C10) aryl (C6-C? O), aryl (C6-C10) heteroaryl (C2-C9), ari Ce-CioJari Ce-C-ioJalkyl (d-Ce), aryl (C6-) C? O) aryl (C6-C10) aryl (C6-C10), aryl (C6-C? O) aryl (C6-C10) heteroaryl (C2-C9), heteroaryl (C2-C9) aryl (C6-C or ), heteroaryl (C2-C9) heteroaryl (C2-C9), aryl (C6-C? o) alkoxy (C? -C6) alkyl (Ct-C6), aryl (C6-C? o) (C 6 -C 6) alkoxy (C 6 -C 6) aryl, (C 6 -C 6) alkoxy (C 6 -C 6) heteroaryl (C 2 -C 9), heteroaryloxy (C 2 -C 9) alkyl (C? -C6), heteroaryloxy (C2-C9) aryl (C6-C? 0), heteroaryloxy (C2-C9) heteraryl (C2-C), heteroaryl (C2-C9) alkoxy (C? -C6) alkyl (C? -C6), heteroaryl (C2-C9) alkoxy (C1-C6) aryl (C? -Cio) or heteroaryl (C2-C9) alkoxy (C? -C6) heteroaryl (C2-Cg) ); wherein each aryl (C? -C-io) or heteroaryl (C2-Cg) moiety of said aryl (C6-C10), heteroaryl (C2-Cg), aryl (C6-C? 0) alkyl (C? -C6), heteroaryl (C2-C9) alkyl (C? -C6), aryloxy (C6-C? O) alkyl (C? -C6), aryloxy (C6-C10) aryl (C6-C10), arylox (C6-C? O) heteroaryl (C2-C9), aryl (C6-C? O) aryl (C6-C10), arIl (C6-C10) heteroaryl (C2-C9), aryl (C6-C) (a) aryl (C6-C10) alkyl (Ci-Ce), aryl (C6-C? o) aryl (C6-C10) aryl (C6-C10), aryl (C6-C1o) aryl (C6) -C1o) heteroaryl (C2-C9), heteroaryl (C2-C9) aryl (C6-C? 0), heteroaryl (C2-C9) heteroaryl (C2-C9), aryl (C6-C? O) alkoxy ( C6C6) alkyl (C6C6), aryl (C6-C6) alkoxy (C1-C6) aryl (C6-C10), aryl (C6-C6) alkoxy (C6-C6) heteroaryl (C2-Cg), heteroaryloxy (C2-Cg) alkyl (C? -C6), heteroaryloxy (C2-Cg) aryl (C6-C? 0), heteroaryloxy (C2-C9) heteroaryl (C2-C9), heteroaryl (C2-C9) alkoxy (C? -C6) alkyl (CiC?), heteroaryl (C2-Cg) alkoxy (C-? -C? aryl (C? -Cio) or heteroaryl (C2-Cg) alkoxy (C ? -C6) heteroaryl (C2-C9) is optionally substituted on some of the carbon atoms of the ring capable of forming an additional bond with one or more substituents per ring independently selected from fluorine, chlorine, bromine, alkyl (Ci-Ce), alkoxy (CiC?), perfluoroalkyl (C1-C3), perfluoroalkoxy (Ct-C3) and aryl (C6-C10); and Y is hydrogen, (C -? - C6) alkyl or a suitable protecting group. Preferred compounds of formula IV are those in which R2 and R3 are taken together to form a cyclobutyl, cyclopentyl, pyran-4-yl ring or a bicyclic ring of formula wherein the asterisk indicates the carbon atom common to R2 and R3; and wherein Q is 4- (4-fluorophenoxy) phenyl. The present invention also relates to a process for the preparation of a compound of formula R wherein R1, R2, R3, Q and Y are as defined above; which comprises reacting a compound of formula wherein R1 is optionally substituted benzyl; and R2, R3 and Q are as defined above; with a compound of formula wherein Y is alkyl (C-i-C-?); in the presence of a base, such as tetrabutylammonium fluoride, potassium carbonate, tertiary amines and cesium carbonate, preferably tetrabutylammonium fluoride, and a polar solvent, such as tetrahydrofuran, acetonitrile, tert-butanol, t-amyl alcohols and N, N-dimethylformamide, preferably tetrahydrofuran.

The present invention also relates to a process comprising reducing said compounds of formula wherein R1, R2, R3 Q and Y are as defined above; with a reducing agent such as a palladium catalyst and a source of hydrogen, preferably palladium-on-carbon hydrogen, in a solvent such as alcohols or tetrahydrofuran, preferably ethanol, to form a compound of formula wherein R is hydrogen; and R2, R3, Q and Y are as defined above. The present invention also relates to a process further comprising reacting said compound of formula III, wherein R4 is hydrogen, with amines such as dicyclohexylamine to form amine salts such as the dicyclohexylammonium salt of the compound of formula III. The term "protecting group" as a substituent for Y is as described in Greene and Wutus, Protective Groups in Orqanic Synthesis, (John Wiley & amp; amp;; Sons, Inc., Wiley Interscience Second Edition, 1991). The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having linear, branched or cyclic moieties, or combinations thereof. The term "alkoxy," as used herein, includes O-alkyl groups in which "alkyl" is as defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl or naphthyl. The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of a hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl. , imidazolyl, benzoimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, soquinolyl, benzofuryl, sobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl. Preferred heteroaryls include pyridyl, furyl, thienyl, isothiazolyl, pyrazinyl, pyrimidyl, pyrazolyl, isoxasolyl, thiazolyl and oxazolyl. More preferred heteroaryls include pyridyl, furyl or thienyl. The term "acyl", as used herein, includes, unless otherwise indicated, a radical of the general formula R- (C = O) - wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkoxy and the terms "alkyl" or "aryl" are as defined above. The term "acyloxy," as used herein, includes O-acyl groups in which "acyl" is as defined above. The serpentine line, that is: wherein formula IV indicates that the group can be either in cis configuration or in trans configuration. The compounds of formula I-V may have chiral centers and thus exist in different diastereomeric or enantiomeric forms. The present invention relates to all optical isomers, tautomers and stereoisomers of the compounds of formula I-V and mixtures thereof. Preferably, the compounds of formula I 'are presented as the exo isomer of formula Improved synthesis routes with higher yields The present invention also relates to improved methodologies for the preparation of compounds such as those of structure (formula) I in Scheme I (see detailed description of the invention below), and to new process intermediates useful in this respect. The compounds of structure I have valuable pharmacological activities. Accordingly, preferred intermediate compounds are provided according to the aforementioned structure IV, wherein R1 is [(A?) CH2] c [(A2) CH2] b [(A3) CH2] aC-, wherein a, b and c are each 1; and each A-i, A2 and A3 is independently selected from the group consisting of H, alkyl (CrC5) and substituted phenyl. In a preferred example Ri is t-butyl; and thus A1, A2 and A3 are each hydrogen.

As described in full detail below, the arrangement of such intermediates facilitates high yields in the synthesis of pharmaceutical compounds of the present invention. Briefly, it has been determined that the Michael addition reaction (see below, for use in the preliminary synthetic steps of the present document) in which a compound of formula it is reacted with a compound of formula it brings surprising and substantial advantages if the group R1 is defined according to this particular example of the invention (R1 is [(A?) CH] c [(A2) CH2] b [(A3) CH2] aC-, wherein a, b and c are each 1, each Ai, A2 and A3 is independently selected from the group consisting of H, (C1-C5) alkyl and phenyl or substituted phenyl), as compared to other examples of R1 as defined in the present disclosure, including for example the benzyl group. The present invention therefore provides processes for the preparation of compounds such as wherein R1 is [(A1) CH2] c [(A2) CH2] b [(A3) CH2] aC-, wherein a, b and c are each 1; and each A-i, A2 and A3 is independently selected from the group consisting of H, (C1-C5) alkyl and substituted phenyl or phenyl and methods for the subsequent use thereof. These procedures include the reduction of said compound IV wherein R1 is [(A1) CH2] c [(A2) CH2] b [(A3) CH2] aC-, wherein a, b and c are each 1; and each Ai, A2 and A3 is independently selected from the group consisting of H, alkyl (C ^ Cs) and phenyl or substituted phenyl and R2, R3, Q and Y are as defined above, with a reducing agent to form a compound of formula In a further aspect of the present invention, said methodology further comprises the hydrolysis of the above compound, wherein R1, R2, R3, Q and Y are as defined above, under acidic conditions to form a compound of formula wherein R2, R3, Q and Y are as defined above. In an alternative embodiment of the present invention, a compound of formula wherein R1, R2, R3, Q and Y are as defined above, are first subjected to hydrolysis under acidic conditions to form a compound of formula wherein R2, R3, Q and Y remain as defined above; and then subjected to a second step in which the compound (a) is treated with a reducing agent to form a compound of formula where R} 2, D R3, Q and Y are as defined above.

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, Q and Z in the reaction schemes and in the discussion that follows are defined as above. SCHEME 1 IV SCHEME 1 continuation Scheme 1 refers to the preparation of matrix metalloproteinase inhibitor compounds of formula I. Referring to scheme 1, the compounds of said formula I are prepared from the compounds of formula II by reaction with a silylated hydroxylamine formed in situ followed by treatment with an acid. Specifically, the silylated hydroxylamine compounds formed in situ are prepared by reaction of hydroxylamine hydrochloride or hydroxylamine sulfate, preferably hydroxylamine hydrochloride with a (C 1 -C) alkylsilyl halide in the presence of a base to form O- trimethylsilylhydroxylamine, N, Obistrimethylsilylhydroxylamine or combinations thereof. Suitable bases include pyridine, 2-6-lutidine or diisopropylethylamine, preferably pyridine. The reaction is carried out at a temperature from about 0 ° C to about 22 ° C (i.e., at room temperature) for a period of about 1 to about 12 hours, preferably about 1 hour. Suitable acids include hydrochloric or sulfuric, preferably hydrochloric. The compounds of said formula II, preferably not isolated, are prepared from the compounds of formula III, wherein R4 is hydrogen, by reaction with oxalyl chloride or thionyl chloride, preferably oxalyl chloride, and a catalyst, preferably about 2% N, N-dimethylformamide in an inert solvent such as methylene chloride or toluene. The reaction is carried out at a temperature from about 0 ° C to about 22 ° C (i.e., at room temperature) for a period of about 1 to about 12 hours, preferably about 1 hour. The compounds of formula III, wherein R4 is hydrogen, can be prepared from the compounds of formula IV, wherein R1 is optionally substituted benzyl, by reduction in a polar solvent. Suitable reducing agents include palladium catalyst with a hydrogen source, such as hydrogen on palladium, palladium on carbon hydrogen or palladium on carbon hydroxide, preferably palladium on carbon hydrogen. Suitable solvents include tetrahydrofuran, methanol, ethanol and isopropanol and mixtures thereof, preferably ethanol. The aforesaid reaction is carried out at a temperature of about 22 ° C (i.e., at room temperature) for a period of 1 to 7 days, preferably about 2 days. The compounds of formula III, wherein R5 is other than hydrogen, such as a protonated amine (such as a primary amine, secondary amine or protonated tertiary amine), alkali metal or alkaline earth metal can be prepared from compounds of formula III. , wherein R5 is hydrogen, by treatment with an aqueous or alkanolic solution containing an acceptable cation (eg, sodium, potassium, dicyclohexylamine, calcium and magnesium, preferably dicyclohexylamine), and then evaporating the resulting solution to dryness, preferably under conditions of reduced pressure or filtering the precipitate, preferably the precipitate of dicyclohexylamine salt. Compounds of formula IV, wherein R1 is optionally substituted alkyl (CiC?) Or benzyl, can be prepared from compounds of formula V, wherein R1 is optionally substituted benzyl, by addition of Michael to an propiolate ester at presence of a base in a polar solvent. Suitable propiolates are those of formula H-C? C-CO2Y, where Y is alkyl (CrC6). The compounds of formula H-C? C-CO2Y are commercially available or can be prepared by methods well known to those skilled in the art. Suitable bases include tetrabutylammonium fluoride, potassium carbonate, tertiary amines and cesium carbonate, preferably tetrabutylammonium fluoride. Suitable solvents include tetrahydrofuran, acetonitrile, tert-butanol, t-amyl alcohols and N, N-d-methylformamide, preferably tetrahydrofuran. The aforesaid reaction is carried out at a temperature of about -10 ° C to about 60 ° C, preferably varying between 0 ° C and about 22 ° C (i.e., room temperature). The compounds of formula IV are obtained as samples of geometric isomers around the olefinic double bond (ie, cis and trans isomers); the separation of the isomers is not necessary. The compounds of the aforementioned formula I in which Y is (C6-C? 0) alkyl can be saponified to the free acid (ie, Y is hydrogen) using a base such as sodium hydroxide in a protic solvent such as ethanol, methanol or water or a mixture such as water and ethanol, water and toluene, or water and THF. The preferred solvent system is water and toluene. The reaction is carried out for a period of 30 minutes to 24 hours, preferably about 2 hours. Compounds of formula V, wherein R 1 is optionally substituted benzyl can be prepared according to procedures well known in the art. The alkylsulfonamides which can be prepared by the processes of the present invention and the starting materials of formula V are also described in the literature. PCT publications WO 96/27583 and WO 98/07697, published March 7, 1996 and February 26, 1998, respectively, refer to arylsulfonylhydroxamic acids. Each of the above mentioned publications is incorporated herein by reference in its entirety. The compounds of formula V in which R2 and R3 are tetrahydropyran-4-yl or a bicyclic ring of formula wherein the asterisk indicates the carbon atom common to R and R p, can be prepared according to procedures analogous to those of examples 2 and 3. The compounds of formula I which are basic in nature are capable of forming a wide variety of different salts with different organic and inorganic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert it to the free base compound by treatment with a alkaline reagent, and then converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treatment of the basic compound with a substantially equivalent amount of the chosen organic or mineral acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. With careful evaporation of the solvent, the desired solid salt is obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of the present invention are those which form non-toxic acid addition salts, ie, salts containing pharmaceutically acceptable anions, such as hydrochloride salts, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate; acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, maleate, fumarate, giuconate, saccharate, benzoate, methanesulfate and pamoate [ie 1, 1'-methylene-bis- (2-hydroxy-3) -naftoato)]. Those compounds of formula I which are also acidic in nature, are capable of forming basic salts with various pharmaceutically acceptable cations. Examples of such salts include the alkali metal salts or alkaline earth metal salts and in particular, the potassium and sodium salts. These salts are prepared by conventional techniques. The chemical bases which are used as reagents for preparing the pharmaceutically acceptable basic salts of the present invention are those which form non-toxic basic salts with the acidic compounds described herein. These non-toxic basic salts include those derived from cations. pharmaceutically acceptable as sodium, potassium, calcium, and magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmaceutically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure conditions. Alternatively, they can be prepared by mixing lower alkanol solutions of the acidic compounds and the desired alkali metal alkoxide, followed by evaporation of the resulting solution to dryness in the same manner. In both cases, stoichiometric amounts of the reagents are preferably employed to ensure that the reaction is complete and that a maximum yield of product is obtained. The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter also known as active compounds) to inhibit matrix metalloproteinase or ADAMs (such as those that inhibit the production of tumor necrosis factor (TNF)) ), thus demonstrating its efficacy in treating diseases characterized by matrix metalloproteinase or ADAM (such as tumor necrosis factor) can be determined in accordance with in vitro assays well known to those skilled in the art. An example of an assay recognized as demonstration of the final products obtained according to the methods of the invention is the Human Collagenase inhibition assay.

Other Preferred Examples of the Invention The present invention also relates to an improved methodology for preparing compounds such as those of the structure (formula) I in Scheme I (see detailed description of the invention below) and to new process intermediates useful in this respect. The compounds of structure I have valuable pharmacological activities. Accordingly, preferred intermediate compounds are provided according to structure IV mentioned above wherein R1 is [(A?) CH2] c [(A2) CH2] b [(A3) CH2] aC-, each of a, b and c 1 being; and each of Ai, A2, and A3 being independently selected from the group consisting of H, (C 1 -C 5) alkyl, and phenyl or substituted phenyl. In a preferred example, R1 is t-butyl; therefore, each of Ai, A2, and A3 are hydrogen.

The arrangement of such intermediates facilitates the synthesis with high yield of pharmaceutical compounds of the invention. It has been determined that in the Michael addition reaction (see below, for use in the present prior synthesis steps) of the present document in which a compound of formula is reacted with a compound of formula substantial and surprising advantages are obtained if the group R1 is defined according to this particular example of the invention (ie, R1 is [(A?) CH2] c [(A2) CH2] b [(A3) CH2] aC-, each of a, b, and c, each being selected from Ai, A2, and A3 independently of the group consisting of H, (C1-C5 alkyl) and substituted phenyl.) This can be seen by comparing it with other examples of R1 as those defined by the present description, including for example, the optionally substituted benzyl or benzyl group, Accordingly, the use of, for example, t-butyl as R 1 is preferred over very useful groups such as benzyl, for example.

The benzyl and substituted benzyl groups are very useful as R1 according to the practice of the present invention. For example, with respect to the structure the reaction conditions can be chosen (see above) so that in one step, not only the carbon-carbon double bond is reduced, but the benzyl group is separated from the carboxyl group. Although this would be apparently advantageous, it appears that the presence of benzyl or substituted benzyl in R1 allows side reactions which may decrease the total yield of the desired Michael addition. Although the practice of the invention is not limited to any theory, it seems that improving the effectiveness of Michael's reaction, even at the expense of simplifying the later stages, can be of significant importance in determining the effectiveness of the overall synthesis scheme. Thus, the present example provides an alternative to another useful technology of the invention. Again without being bound by any theory, it may be that R1 groups such as t-butyl interfere with the side reactions (such as by steric hindrance) more than other R groups such as benzyl during the Michael addition. This effect may be more important for the success of the total reaction than the effectiveness of the direct coupling. Accordingly, the practice of the present invention includes an alternative effective means for generating the intermediate compounds necessary for the efficient production of the active pharmaceutical compounds. The present invention therefore provides methods for preparing compounds such as wherein R1 is [(A) CH2] c [(A2) CH2] b [(A3) CH2] aC-, each of a, b and c 1; and each of Ai, A2 and A3 being selected independently from the group consisting of H, (C1-C5 alkyl) or phenyl or substituted phenyl, and methods for the subsequent use thereof. With reference to the selection of the R1 groups herein, it is expected to be able to use additional groups having the effect of t-butyl or other discovered groups, based on the general descriptions set forth herein. Accordingly, one skilled in the art will appreciate that it falls within the practice of the present invention to use as R1 any group which, with respect to benzyl, reduces the rate of side reactions during the Michael addition. Said additional methods include reducing said compound IV wherein R1 is [(A?) CH2] c [(A2) CH2] b [(A3) CH2] aC-, each of a, b and c 1 being; and each being selected from Ai, A2 and A3 independently of the group consisting of H, (C1-C5 alkyl) and phenyl or substituted phenyl, and R2, R3, Y, and Q are as defined above, with a reducing agent, to form a compound of formula In another aspect of the invention, said methodology further comprises hydrolyzing the above compound, wherein R1, R2, R3, Y and Q are as defined above, under acidic conditions to form a compound of formula wherein R2, R3 and Q are as defined above. In relation to the selection of the groups and for the practice of the present invention, it is appreciated that Y is preferably selected as hydrogen or C? -C6 alkyl in the compounds of the invention. With respect to the aforementioned processes (consider the conversion of structure (i) in structure (ii) above), it is especially preferred that Y is C? -C6 alkyl. The alkyl group Ci-C? it possesses a particularly valuable property because although it is labile to hydrolysis under alkaline conditions, it is resistant to hydrolysis under acid conditions which is useful in the practice of the invention. Thus, when R1 is t-butyl, for example, a preferential hydrolysis can be carried out under mild acid conditions (see for example example 4) and the t-butyl group removed, leaving the Y residue in its position as a functional group. Since the group Y (CC? Alkyl), in comparison with the carboxyl group just discussed, is resistant to the formation of the acid chloride and to the subsequent introduction of the hydroxamic acid, the final chemistry of the invention can be directed to the appropriate carbonyl group when you want It is within the practice of the present invention to use other moieties, in addition to the C C alkyl group? to achieve this same functional result. In a further embodiment of the invention, a compound of formula is first subjected to wherein R1, R2, R3, Y and Q are as defined above, to hydrolysis under acidic conditions to form a compound of formula wherein R2, R3 and Q are as defined above; and then subjecting it to a second step in which the compound (a) is treated with a reducing agent to form a compound of formula wherein R2, R3, Y and Q are as defined above. In relation to the aforementioned reactions, it can be appreciated that hydrolysis under acidic conditions may involve the use of various acids. Among the mineral acids, mention may be made of HCl, HBr and H2SO. Appropriate carboxylic acids such as formic acid and trifluoroacetic acid may also be used. Without limitation, an additional class of useful acids includes sulfonic acids such as p-toluene sulphonic acids and methanesulfonic acids. With respect to the reduction conditions cited as useful in accordance with the practice of this aspect of the invention, the following is appreciated. Suitable catalytic conditions are achieved when the reducing agent is hydrogen on a catalyst which is selected from the group consisting of platinum oxide or Raney nickel, or a supported catalyst which is selected from the group consisting of palladium on carbon or platinum on carbon. Again it is appreciated that it is up to the technicians in the field to identify equally effective agents and conditions.

BIOLOGICAL ESSAYS Inhibition of human colaqenase (MMP-1) Recombinant human collagenase is activated with trypsin using the following ratio: 10 μg of trypsin per 100 μg of collagenase. Trypsin and collagenase are incubated at room temperature for 10 minutes and then a soybean trypsin inhibitor (50 μg / 10 μg) is added in a five-fold excess. mM standard solutions of inhibitors are prepared in dimethyl sulfoxide and then diluted according to the following scheme: 10 mM - - - > 120? M - - - > 12? M - - - > 1.2? M - - - >; 0.12 μM 25 ml of each concentration are then added in triplicate in appropriate wells of a 96-well microfluorescence plate. The final inhibitor concentration will be a 1: 4 dilution after the addition of the enzyme and the substrate. Positive controls are made (with enzyme, without inhibitor) in wells D1-D6 and white (non-enzyme, non-inhibitory) in wells D7-D12. The collagenase was diluted to 400 ng / ml and then 25 μl was added to the appropriate wells of the microfluorescence plate. The final concentration of collagenase in the assays is 100 ng / ml. The substrate is prepared (DNO-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH2) as a 5 mM stock solution in dimethyl sulfoxide and then diluted to 20 mM in assay buffer. The assay is started with the addition of 50 μl of substrate per well of the microfluorescence plate to give a final concentration of 10 μM. The fluorescence readings (excitation at 360 nM, emission at 460 nm) were carried out at time 0 and then at 20 minute intervals. The test was carried out at room temperature with a typical test time of 3 hours. The fluorescence was plotted against time for the blank and the samples containing collagenase (the data from triplicate determinations of averaging). A point is chosen that provides a good signal (the target) and that is not a linear part of the curve (usually in a tone of 120 minutes) to determine the IC 50 values. Zero time is used as a target for each compound at each concentration and these values are extracted from the data for 120 minutes. Data are plotted as inhibitor concentration versus% control (fluorescence of the inhibitor divided by collagen fluorescence alone x 100). IC50's are determined from the concentration of inhibitor that gives a signal that is 50% of the control. If the IC50 are recorded as less than 0.03 μM then the inhibitors are tested at concentrations of 0.3 μM, 0.03 μM, 0.03 μM and 0.003 μM. The following examples illustrate the preparation of the compounds of the present invention. The melting points are uncorrected. The NMR data (nuclear magnetic resonance) are given in parts per million (?) And refer to the deuterium signal of the sample solvent (deuteriochloroform, unless otherwise specified). Commercial reagents are used without further purification. THF refers to tetrahydrofuran. DMF refers to N, N-dimethylformamide. Chromatography refers to a chromatographic column mounted using 32-63 mm of silica gel and operating under nitrogen atmosphere conditions (flash chromatography). Ambient temperature refers to 20 - 25 ° C. All non-aqueous reactions are carried out under a nitrogen atmosphere for convenience and for the maximization of yields. Concentration at reduced pressure means that a rotary evaporator was used.

EXAMPLE 1 Acid 3rr4- (4-fluorophenoxy) benzenesulfonyl? - (1-hydroxycarbamoyl-cyclopentiP-aminol-propionic acid To the benzyl ester of 1-a4- (4-fluorophenoxy) benzenesulfonylamino] -cyclopentanecarboxylic acid To a mixture of 12.41 g (0.032 mole) of 1-aminociclopentanecarboxylic acid benzyl ester, toluene-4-sulfonic acid salt (can be prepared according to with literature procedures such as those described in U.S. Patent No. 4,745,124) and 10.0 g (0.035 moles, 1.1 equivalents) of 4- (4-fluorophenoxy) benzenesuiphenyl chloride (prepared according to Preparation 3) in 1 13 ml of toluene, 1.0 ml was added (0.079 moles, 2.5 equivalents) of triethylamine. The resulting mixture was stirred at room temperature overnight, washed with 2 N hydrochloric acid (2 x 100 ml) and brine (100 ml), dried over sodium sulfate and concentrated to 30 ml. 149 ml of hexane was added dropwise over three hours to give a solid precipitate which was granulated at 0 ° C for one hour and filtered, yielding 12.59 g (85%) of benzyl ester of 1- [4- (4- fluorophenoxy) -benzenesulfonylaminoj-cyclopentane-carboxylic acid. 1 H NMR (CDCl 3)? 7.78-7.82 (m, 2H), 7.30-7.39 (m, 5H), 7.06-7.12 (m, 2H), 6.99-7.04 (m, 2H), 6.93-6.97 (m, 2H), 5.15 (s, 1 H), 5.02 (s, 2H), 2.04-2.13 (m, 2H), 1.92-1.98 (m, 2H), 1.62-1.69 (m, 4H). A 4.0 g sample was granulated in a mixture of 4 ml of ethyl acetate and 40 ml of hexanes overnight, giving 3.72 g (93% recovery) of 1 - [4- (4-fluorophenoxy) benzyl ester) -benzenesulfonyl-aminoj-cyclopentanecarboxylic in the form of light brown solids, e.g. F. 97.0-97.5 ° C.

B) Benzyl ester of 1 - acid. { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) -benzenesulfonin-amino >; -cyclopentanecarboxylic acid A solution of 25.0 g (53.2 mmol) of benzyl ester of 1 - [4- (4-fluorophenoxy) -benzenesulfonylamino] -cyclopentanecarboxylic acid ester and 10.8 ml (106 mmol, 2 equivalents) of ethyl propiolate in 200 ml of dry tetrahydrofuran. at 1 ° C was treated with 53.2 ml (53.2 mmol, 1 equivalent) of a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M) for 45 minutes. The resulting solution was allowed to warm slowly to room temperature and stirred overnight. The tetrahydrofuran was displaced with toluene under reduced pressure and the toluene solution was washed with water and brine, diluted to 600 ml with toluene, stirred with 90 g of silica gel for three hours, filtered and concentrated to 25.14 g. (83%) benzyl ester of 1 - acid. { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) -benzenesulfonyl] -amino} -cyclopentanecarboxylic acid in the form of an orange oil. 1 H NMR (CDCl 3) indicated a 1.5: 1 ratio of trans / cis isomers. Trans? 7.74-7.78 (m, 2H), 7.72 (d, J = 14 Hz, 1 H), 7.26-7.36 (m, 5H), 6.96-7.12 (m, 4H), 6.78-6.84 (m, 2H), 5.44 (d, J = 14 Hz, 1 H), 5.1 1 (s, 2H), 4.12 (q, J = 7.1 Hz, 2), 2.08-2.43 (m, 4H), 1.63-1.80 (m, 4H), 1.24 (t, J = 7. 1 Hz, 3H). Cis? 7.68-7.72 (m, 2H), 7.26-7.36 (m, 5H), 6.96-7.12 (m, 4H), 6.86-6.91 (m, 2H), 6.47 (d, J = 8.1 Hz, 1 H), 5.90 (d, J = 8.1 Hz, 1 H), 5.1 1 (s, 2H), 3.93 (1, J = 7.2 Hz, 2H), 2.08-2.43 (m, 4H), 1 .63-1.80 (m , 4H), 1 .17 (t, J = 7. 2 Hz, 3H).

C) Acid 1 -. { (2-ethoxycarbonylethyl-4H-4- (4-fluorophenoxy) -benzenesulfonin-amino) cyclopentanecarboxylic acid A solution of 2.50 g (4.4 mmol) of benzyl ester of the acid 1-. { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) -benzenesulfonyl] amino} Cyclopentanecarboxylic acid in 25 ml of ethanol was treated with 2.5 g of 10% palladium on carbon catalyst moistened with 50% water and stirred at 365.42 kPa of hydrogen for 21 hours. The catalyst was removed by filtration and washed with ethanol (4 x 25 ml). The filtrate and washing liquids were combined and concentrated in vacuo to 1.74 g (82%) of 1- acid. { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) -benzenesulfonyl] -amino} crude cyclopentanecarboxylic acid in the form of a viscous oil. 1 H NMR (CDCl 3)? 7.78-7.82 (m, 2H), 6.94-7.09 (m, 6H), 4.09 (q, J = 7.2 Hz, 2), 3.56-3.60 (m, 2H), 2.75-2.79 (m, 2H), 2.33- 2.39 (m, 2H), 1.93-2.03 (m, 2H), 1.69-1.76 (m, 2H), 1.56-1.63 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H).

D) 1 - ((2-Ethoxycarbonylethyl) H 4 - (4-fluorophenoxy) -benzenesulfonyl-amino) -cyclopentanecarboxylic acid dicyclohexylamino acid A solution of 3.10 g (6.5 mmole) of 1- (2-ethoxycarbonylethyl) acid ) - [4- (4-fluorophenoxy) -benzenesulfonyl] -aminojcyclopentanecarboxylic acid in 30 ml of ethanol was treated with 1.28 ml (6.5 mmol, 1 equivalent) of dithiohexylamine at room temperature, producing solids in five minutes. ambient temperature overnight and then at 0 ° C for five hours.The white solids were isolated by filtration, washed with 10 ml of cold ethanol and air-dried to give 2.89 g (67%) of the dicyclohexylamino acid salt. -. {(2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) -benzenesulfonyl] -amino} - cyclopentanecarboxylic acid 1 H NMR (CDCl 3)? 7.86-7.91 (m, 2H), 6.99-7.09 (m , 4H), 6.90-6.94 (m, 2H), 5.3 (sa, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.54-3.59 (m, 2H), 2.88-2.95 (m, 4H), 2.31 -2.38 (m, 2H), 1.95-2.22 (m, 6H), 1 .68-1.77 (m, 6H, 1.53-1.60 (m, 4H), 1 .40-1.50 (m, 4H), 1 .21 (t, J = 7.1 Hz, 3H), 1.14-1 .22 (m , 6H). P.f. 164.5-165.9 ° C.

E) Acid 1-Y2-ethoxycarbonylethyl-4,4- (4-fluorophenoxy) -benzenesulfonyl-aminol-cyclopentanecarboxylic acid A solution of 3.0 g (4.5 mmoles) of the dicyclohexylamino salt of 1 - acid. { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) -benzenesulfonyl] -amino} -cyclopentanecarboxylic acid in 30 ml of dichloromethane was treated with 30 ml of 2 N hydrochloric acid at room temperature causing immediate precipitation of solids. This mixture was stirred at room temperature for three hours. The solids were filtered, the aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, dried over sodium sulfate and concentrated in vacuo to 2.2 g (100%) of 1 - acid. { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) -benzenesulfonyl] -amino} -cyclopentanecarboxylic acid in the form of a clear oil. 1 H NMR (DMSO-cfe)? 12.68 (sa, 1 H), 7.76-7.80 (m, 2), 7.25-7.31 (m, 2H), 7.16-7.21 (m, 2H), 7.03-7.08 (m, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.48-3.54 (m, 2H), 2.64-2.70 (m, 2H), 2.13-2.21 (m, 2H), 1.90-1.98 (m, 2H), 1.52-1.59 (m, 4H) , 1.14 (t, J = 7.1 Hz, 3H).

F) 3 - ((1-Chlorocarbonyl-cyclopentyl) -f4- (4-fluorophenoxy-benzene-sulfonyl-amino-propionic acid) ethyl ester A solution of 7.26 g (15.1 mmol) of 1 -. {(2-ethoxycarbonylethyl)) - [4- (4-fluorophenoxy) -benzenesulfonyl] -amino} - cyclopentanecarboxylic acid in 73 ml of dichloromethane was treated with 1.4 ml (17 mmol, 1.1 equivalents) of oxalyl chloride and 0.02 ml (0.3 mmol, 0.02 equivalents) of dimethylformamide at room temperature, causing the appearance of some bubbles, and stirred overnight The resulting solution of 3- (1-chlorocarbonyl-cyclic pentyl) - [4- (4-fluorophenoxy) -benzenesulfonyl] - ethyl ester - amino propionic acid was used for the preparation of 3 - [[4- (4-fluorophenoxy) -benzenesulfonyl] - (1-hydroxycarbamoylcyclopentyl) -amino] propionic acid ethyl ester without isolation. -. (1-Chlorocarbonylcyclopentyl) - [4- (4-fluorophenoxy) -bezenesulfonyl] -propionic acid prepared from similar form was concentrated in vacuo until an oil was obtained. 1 H NMR (CDCl 3)? 7.84-7.87 (m, 2H), 6.98-7.12 (m, 6H), 4.10 (q, J = 7.2 Hz, 2H), 3.55-3.59 (m, 2H), 2.68-2.72 (m, 2H), 2.47-2.53 (m, 2H ), 1.95-2.02 (m, 2), 1.71 -1.76 (m, 4H), 1.24 (t, J = 7.2 Hz, 3H).

G) 3-rr4- (4-fluorophenoxy-benzenesulfonyl) - (1-hydroxycarbamoyl-cyclo-pentiD-aminolpropionic acid ethyl ester) A solution of 1.37 g (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 ml (14 mmoles, 7.5 equivalents) of dry pyridine at 0 ° C was treated with 5.8 ml (45 mmol, 3.0 equivalents) of trimethylsilyl chloride causing the precipitation of white solids.The mixture was allowed to warm to room temperature overnight.This mixture was then cooled at 0 ° C and treated with a solution of 7.54 g (15.1 mmol) of ethyl 3- (1-chlorocarbonylcyclopentyl) - [4- (4-fluorophenoxy) -benzenesulfonyl] -amino} propionic acid ethyl ester. in 73 ml of dichloromethane, prepared as described above, without isolation, causing an exotherm to about 8 ° C. This mixture was stirred at 0 ° C. for 30 minutes and at room temperature for about one hour. with 50 ml of hydrochloric acid or aqueous 2 N and stirred at room temperature for one hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2 x 50 ml) and water (50 ml). This solution of 3 - [[4- (4-fluorophenoxy) -benzenesulfonyl] - (1-hydroxycarbamoylcyclopentyl) -aminojpropionic acid ethyl ester in dichloromethane was used for the preparation of 3 - [[4- (4-fluorine -phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoylcyclopentyl) -aminojpropionic acid without isolation. An aliquot was concentrated until a foam was obtained. 1 H NMR (DMSO-c 6)? 10.37 (s, 1 H), 8.76 (s, 1 H), 7.74-7.79 (m, 2H), 7.24-7.30 (m, 2H), 7.14-7.20 (m, 2H), 7.01 -7.05 (m, 2H) ), 3.99 (q, J = 7.1 Hz, 2H), 3.42-3.47 (m, 2H), 2.62-2.67 (m, 2), 2.16-2.23 (m, 2), 1.77-1.85 (m, 2H), 1.43-1.52 (m, 4), 1.13 (t, J = 7.1 Hz, 3H). A solution prepared in a similar manner was concentrated in vacuo to 6.71 g (89%) of 3 - [[4- (4-fluorophenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclopentyl) -amino] propionic acid ethyl ester in the form of a hard dry foam.

H) 3-rr4- (4 - (, fluorophenoxy) -benzenesulfonyl-1- (1-hydroxycarbamoyl-cyclopentone-aminopropionic acid) A solution of 7.48 g (15.1 mmol) of 3 - [[4- (4- (fluorophenoxy)] ethyl ester ) -benzenesulfonyl] - (1-hydroxycarbamoylcyclopentyl) -aminojpropionic acid in dichloromethane was concentrated by rotary evaporation with the addition of 75 ml of toluene.This solution was treated with 75 ml of water, cooled to 0 ° C and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide granules for 10 minutes with vigorous stirring, this mixture was stirred for 15 minutes at 0 ° C and was heated at room temperature for one hour. separated, diluted with 7.5 ml of tetrahydrofuran, cooled to 0 ° C and treated with 33 ml of 6 N aqueous hydrochloric acid for 20 minutes.This mixture was stirred with 75 ml of 0 ° C ethyl acetate at the temperature The ethyl acetate phase was separated and washed with water. ethyl was treated slowly with 150 ml of hexanes at room temperature causing the precipitation of solids, and stirred overnight. Filtration yielded 5.01 g of 3 - [[4- (4-fluorophenoxy) -benzenesulfonyl] - (1-hydroxycarbamoylcyclopentyl) -aminojpropionic acid as a white solid (71% yield from acid 1 -. { (2-Ethoxycarbonylethyl) - [4- (4-fluorophenoxy) -benzenesulfonyl] -amino} - cyclopentanecarboxylic acid 1 H NMR (DMSO-? E)? 12.32 (s, 1 H), 10.43 (s, 1 H ), 8.80 (s, 1 H), 7.82 (d, J = 8.6 Hz, 2H), 7.28-7.35 (m, 2H), 7.20-7.26 (m, 2), 7.08 (d, J = 8.9 Hz, 2H ), 3.44-3.49 (m, 2H), 2.61-2.66 (m, 2H), 2.24-2.29 (m, 2H), 1 .86-1.90 (m, 2H), 1.54-1.55 (m, 4H); pf 162.9-163.5 ° C (dec).

EXAMPLE 2 3-rf4- (4-Fluoro-phenoxy) -benzenesulfonyl- (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino-1-propionic acid A) 4- (N-diphenylmethylene) amino-tetrahydropyran-4-carboxylic acid benzyl ester To a suspension of sodium hydride (6.56 grams, 0.164 moles) in ethylene glycol dimethyl ether (150 ml) at 0 ° C was added dropwise by means of an addition funnel a solution of the benzyl ester of N- (diphenylmethylene) glycine (0.07398 mol) in dimethyl ether of ethylene glycol (50 ml). Then a solution of 2-bromoethyl of ethylene glycol (50 ml) was added, in 10 ml portions for approximately 5 minutes, to the solution of ethylene glycol dimethyl ether. The ice bath was removed and the reaction was stirred at room temperature for 16 hours. The mixture was diluted with diethyl ether and washed with water. The aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated, yielding the crude product. Chromatography on silica gel eluting first with 4 I of 5% ethyl acetate / hexane followed by 4 liters of 10% ethyl acetate / hexane afforded 4- [N- (diphenylmethylene) -amino] benzyl ester. tetrahydropyran-4-carboxylic acid in the form of a transparent yellow oil.

B) 4-Aminotetrahydropyran-4-carboxylic acid benzyl ester To a solution of 4- [N- (diphenylmethylene) -aminojtetrahydropyran-4-carboxylic acid benzyl ester (0.047 mol) in diethyl ether (120 ml) was added a solution aqueous 1 M hydrochloric acid (100 ml). The mixture was stirred vigorously at room temperature for 16 hours. The layers were separated and the aqueous layer was washed with diethyl ether. The aqueous layer was brought to pH 10 with a dilute aqueous ammonium hydroxide solution and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated to give the 4-aminotetrahydropyran-4-carboxylic acid benzyl ester.

C) Benzyl ester of 4-r4- (4-fluorophenoxy-benzenesulfonylamino-tetrahydropyran-4-carboxylic acid) To a solution of 4-aminotetrahydropyran-4-carboxylic acid benzyl ester (0.0404 mol) in N, N-dimethylformamide (40 ml) ) triethylamine (5.94 ml, 0.043 mole) was added.Solid 4- (4-fluorophenoxy) -benzenesulfonyl chloride (12.165 grams, 0.0424 mole) was added to the above solution in portions The resulting mixture was stirred at room temperature for 15 minutes. After removing most of the solvent by evaporation in vacuo, the residue was partitioned between saturated sodium bicarbonate solution and dichloromethane.The aqueous layer was separated and extracted with dichloromethane.The combined organic layers were washed with brine and dried The solvent was evaporated in vacuo to give the crude 4- [4- (4-fluorophenoxy) -benzenesulfonylamino] tetrahydropyran-4-carboxylic acid benzyl ester. to ultra-flash on silica gel, eluting with 25% ethyl acetate / hexane followed by 50% ethyl acetate / hexane, gave the benzyl ester of 4- [4- (4-fluorophenoxy) -benzenesulfonylamino] tetrahydropyran-4-benzyl ester -carboxylic D) 4- Benzyl ester of acid. { (2-ethoxycarbonyl-vinyl) - [4- (4-fluoro-phenoxy) -benzenesulfonin-amino > tetrahydro-pyran-4-carboxylic acid A solution of (53.2 mmol) of the product from the previous step and 10.8 ml (106 mmol, 2 equivalents) of ethyl propiolate in 200 ml of dry tetrahydrofuran at 1 ° C was treated with 53.2 ml (53.2 mmol, 1 equivalent) of a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M) for 45 minutes. The resulting solution was allowed to warm slowly to room temperature and stirred overnight. The tetrahydrofuran was displaced with toluene under reduced pressure and the toluene solution was washed with water and brine, diluted to 600 ml with toluene, stirred with 90 g of silica gel for three hours, filtered and concentrated, giving the composed of the title.

E) 4 - ((2-Ethoxy-cyclin-ethyl) -r4-fluoro-phenoxy) -benzenesulfon-n-amino) -tetrahydro-pyran-4-carboxylic acid A solution of (4.4 mmol) of the product from step D in ml of ethanol was treated with 2.5 g of 10% palladium on carbon catalyst moistened with 50% water and stirred at 365.42 kPa of hydrogen for 21 hours. The catalyst was removed by filtration and washed with ethanol (4 x 25 ml). The filtrate and washing liquids were combined and concentrated in vacuo to give the crude product.

F) 3 - ((4-Chlorocarbonyl-tetrahydro-pyran-4-yl) -r4- (4-fluoro-phenoxy) -benzenesulfonyl) -amino) -propionic acid ethyl ester A solution of (15.1 mmol) of the product of step E in 73 ml of dichloromethane was treated with 1.4 ml (17 moles, 1.1 equivalents) of oxalyl chloride and 0.02 ml (0.3 mmoles, 0.02 equivalents) of dimethylformamide at room temperature, causing the appearance of some bubbles, and He stirred for one night. The resulting solution of the title compound was used in step G without further isolation.

G) 3-yr- (4-Fluoro-phenoxy) -benzenesulfonyl- (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino-1-propionic acid ethyl ester A solution of (19.7 mmol, 1.3 equivalents) ) of hydroxylamine hydrochloride in 9.2 ml (14 mmoles, 7.5 equivalents) of dry pyridine at 0 ° C was treated with 5.8 ml (45 mmoles 3.0 equivalents) of trimethylsilyl chloride, causing the precipitation of white solids. The mixture was allowed to warm to room temperature overnight. This mixture was then cooled to 0 ° C and treated with a solution of 15.1 mmol of the product of step F in 73 ml of dichloromethane causing an exotherm to about 8 ° C. This mixture was stirred at 0 ° C for 30 minutes and at room temperature for about one hour. Then, the reaction was treated with 50 ml of 2N aqueous hydrochloric acid and stirred at room temperature for one hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2 x 50 ml) and water (50 ml). This solution of the title compound in dichloromethane was used in the next step. ? -n 3-rr4- (4-Fluoro-phenoxy) -benzenesulfonyl- (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino-1-propionic acid A solution of 15.1 mmoles of the product from step G in dichloromethane was concentrated by rotary evaporation with the addition of 75 ml of toluene. This solution was treated with 75 ml of water, cooled to 0 ° C and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide granules for 10 minutes with vigorous stirring. This mixture was stirred for 15 minutes at 0 ° C and was heated at room temperature for one hour. The aqueous phase was separated, diluted with 7.5 ml of tetrahydrofuran, cooled to 0 ° C and treated with 33 ml of 6 N aqueous hydrochloric acid for 20 minutes. This mixture was stirred with 75 ml of ethyl acetate at 0 ° C to room temperature and the ethyl acetate phase was separated and washed with water. The ethyl acetate solution was concentrated, yielding the title compound.

EXAMPLE 3 3-rr4- (4-Fluoro-phenoxy) -benzenesulfonin- (3-hydroxycarbamoyl-8-oxa-bicyclo3.2.noct-3-yl) -aminol-propionic acid A) 3- (Benzhydrylideneamino) -8-oxabicycloic-3,2-octane-3-carboxylic acid benzyl ester To a suspension of sodium hydride (0.41 grams, 17.1 mmol) in N, N-dimethylformamide (50 ml) at 0 ° C a solution of N- (diphenylmethylene) -glycine benzyl ester (7.8 mmoies) in NN-dimethylformamide (50 ml) was added dropwise. After stirring for 30 minutes at room temperature, a solution of cis-2,5-bis (hydroxymethyl) -tetrahydrofuran ditosylate (4.1 grams, 9.3 mmol) (prepared by literature procedures such as those described in JOC) was added dropwise. , 47, 2429-2435 (1932)) in NN-dimethylformamide (50 ml). The reaction mixture was gradually heated to 100 ° C in an oil bath and stirred at this temperature overnight. The solvent was evaporated in vacuo and the residue was taken up in water and extracted twice with diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to a crude product.

B) 3-Amino-8-oxabicyclo3.2.noctane-3-carboxylic acid benzyl ester hydrochloride A two-phase mixture of benzyl 3- (benzhydryldenamene) -8-oxabicyclo [3.2.1] ] octane-3-carboxylic acid (3.9 mmol) in an aqueous solution of 1 N hydrochloric acid (100 ml) and diethyl ether (100 ml) was stirred at room temperature overnight. The aqueous layer was concentrated to provide the title compound.

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

D) 3 - ((2-Ethoxycarbonyl-vinylH 4 - (4-fluoro-phenoxy) -benzenesulfonyl] -amino> -8-oxa-bicyclof3.2.1-octane-3-carboxylic acid benzyl ester A solution of 53.2 mmoles of the product from the previous step and 10.8 ml (106 mmoles, 2 equivalents) of ethyl propiolate in 200 ml of dry tetrahydrofuran at 1 ° C was treated with 53.2 ml (53.2 mmoles, 1 equivalent) of a solution of tetrabutylammonium fluoride in tetrahydrofuran ( 1 M) for 45 minutes The resulting solution was allowed to warm slowly to room temperature and stirred overnight.Thromhydrofuran was displaced with toluene under reduced pressure and the toluene solution was washed with water and brine, diluted to 600 ml with toluene, stirred with 90 g of silica gel for three hours, filtered and concentrated to give the title compound.

E) 3 - ((2-Ethoxycarbonyl-ethyl) - [4- (4-fluoro-phenoxy) -benzenesulfonin-amino) -8-oxa-bicyclo3.2.noctane-3-carboxylic acid A solution of 4.4 mmol of the product from step D in 25 ml of ethanol was treated with 2.5 g of 10% palladium on carbon catalyst moistened with 50% water and stirred at 365.42 kPa of hydrogen for 48 hours. The catalyst was removed by filtration and washed with ethanol (4 x 25 ml). The filtrate and washing liquids were combined and concentrated in vacuo to give the crude product.

F) 3- 3-Chlorocarbonyl-8-oxa-bicichlor3.2.1.joct-3-yl) - [4- (4-fluoro-phenoxy) -benzenesulfonyl-1-amino) -propionic acid ethyl ester A solution of 15.1 mmoles of the product from step E in 73 ml of dichloromethane was treated with 1.4 ml (17 mmol, 1.1 equivalents) of oxalyl chloride and 0.02 ml (0.3 mmol, 0.02 equivalents) of dimethylformamide at room temperature, causing the formation of some bubbles, and stirred overnight. The resulting solution of the title compound was used in step G without isolation.

G) 3-R4- (4-Fluoro-phenoxy) -benzenesulfonyl- (3-hydroxycarbamoyl-8-oxa-bicichlor3.2.1.1oct-3-yl) -amino-1-propionic acid ethyl ester A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 ml (114 mmol, 7.5 equivalents) of dry pyridine at 0 ° C was treated with 5.8 ml (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing precipitation of white solids. The mixture was allowed to warm to room temperature overnight. This mixture was then cooled to 0 ° C and treated with a solution of 15.1 mmol of the product of step F in 73 ml of dichloromethane causing an exotherm to about 8 ° C. This mixture was stirred at 0 ° C for 30 minutes and at room temperature for about one hour. Then, the reaction was treated with 50 ml of 2N aqueous hydrochloric acid and stirred at room temperature for one hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2 x 50 ml) and water (50 ml). This solution of the title compound in dichloromethane was used in the next step.

H) 3-IT4- (4-Fluoro-phenoxy) -benzenesulfonyl] - (3-hydroxycarbamoyl-8-oxa-bicichlor3.2.1 oct-3-yl) -amino-1-propionic acid A solution of 15.1 mmoles of the product of Stage G in dichloromethane was concentrated by rotary evaporation with the addition of 75 ml of toluene. This solution was treated with 75 ml of water, cooled to 0 ° C and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide granules for 10 minutes with vigorous stirring. This mixture was stirred for 15 minutes at 0 ° C and was heated at room temperature for one hour. The aqueous phase was separated, diluted with 7.5 ml of tetrahydrofuran, cooled to 0 ° C and treated with 33 ml of 67 N aqueous hydrochloric acid for 20 minutes. This mixture was stirred with 75 ml of ethyl acetate at 0 ° C to room temperature and the ethyl acetate phase was separated and washed with water. The ethyl acetate solution was concentrated, yielding the title compound.

PREPARATION 1 4- (4-fluorophenoxy) benzenesulfonic acid 4-fluorophenyl ester A solution of 14.68 g (0.131 mol, 2.0 equivalents) of potassium tert-butoxide in 27 ml of dry N-methylpyrrolidinone was treated with a solution of 15.39 g (0.137 moles, 2.1 equivalents) of 4-fluorophenol in 27 ml of N-methylpyrrolidinone. Methylpyrrolidinone dried at room temperature causing a slight exotherm up to 45 ° C. A solution of 13.81 g (0.065 mol) of 4-chlorobenzenesulfonyl chloride in 27 ml of dry N-methylpyrrolidinone was slowly added to the dark reaction mixture, causing a slight exotherm to 44 ° C. The resulting mixture was stirred at room temperature for one hour and then at 130 ° C for 11 hours. The cooled reaction mixture was treated with 162 ml of water, seeded with a small amount of 4- (4-fluorophenoxy) benzenesulfonic acid 4-fluorophenic ester and granulated at room temperature overnight. The resulting solids were filtered, yielding 20.24 g (85%) of 4- (4-fluorophenoxy) benzenesulfonic acid 4-fluorophenic ester. 1 H NMR (CDCl 3)? 7.74 (dd, J = 7.0, 2.0 Hz, 2H), 7.14-6.97 (m, 10H). p.f. 78-83 ° C.

PREPARATION 2 Sodium salt of 4- (4-fluorophenoxy) benzenesulfonic acid To a suspension of 47.43 g (0.131 mol) of 4- (4-fluorophenoxy) benzenesulfonic acid 4-fluorophenyl ester in 475 ml of ethanol was added 13.09 g (0.327 mol, 2.5 equivalents) of sodium hydroxide granules. This mixture was refluxed for three hours and stirred overnight at room temperature. The resulting solids were filtered, yielding 37.16 g (98%) of the sodium salt of 4- (4-fluorophenoxy) benzenesulfonic acid. 1H NMR (CD3OD)? 7.73-7.78 (m, 2H), 7.05-7.13 (m, 2H), 6.99-7.05 (m, 2H), 6.90-6.95 (m, 2H).

PREPARATION 3 4- (4-fluorophenoxy) benzenesulfonyl chloride To a suspension of 1.50 g (0.052 mole) of 4- (4-fluorophenoxy) benzenesulfonic acid sodium salt in 150 ml of dry toluene was added 1.3 ml (0.155 mole, 3 equivalents) of thionyl chloride and 0.04 ml (0.5 mmol, 0.01 equivalents) of dimethylformamide. The resulting mixture was stirred at room temperature for 48 hours, filtered through diatomaceous earth and concentrated under reduced pressure to 40 ml. This solution was used without further purification to prepare the benzyl ester of 1- [4- (4-fluorophenoxy) benzenesulfonylamino] cyclopentanecarboxylic acid. A 5.0 ml portion of this solution was concentrated to 1.77 g of 4- (4-fluorophenoxy) benzenesulfonyl chloride in the form of an oil, corresponding to a yield of 96%. 1 H NMR (CDCl 3)? 7.92-7.97 (m, 2H), 7.01-7.13 (m, 6H). A portion of oil prepared in a similar manner crystallized from hexane, m.p. 80 ° C.

EXAMPLE 4 PREPARATION 1 1-r4- (4-Fluoro-phenoxy) -benzenesulfonylamino-1-cyclopentanecarboxylic acid 1 - [4- (4-Fluoro-phenoxy) -benzenesulfonylamino-cyclopentanecarboxylic acid benzyl ester (15 g, 32 mmol) in 75 ml of THF was combined with 75 ml (150 mmol) of 2 N aqueous sodium hydroxide and stirred at reflux for 1 hour. The reaction was cooled to room temperature and diluted with 100 mL of water and 100 mL of ethyl acetate. The pH of the aqueous phase was adjusted to pH 1.2 and the ethyl acetate layer was separated. The ethyl acetate layer was washed with 100 ml of water and dried over magnesium sulfate. The ethyl acetate was distilled under vacuum and replaced with 75 ml of methyl tert-butyl ether. The product was filtered and dried to yield 11.16 g (92%) of 1 - [4- (4-fIuoro-phenoxy) benzenesulfonylamino] -cyclopentanecarboxylic acid. 1 H NMR (CDCl 3)? 7.71-7.78 (m, 2H), 6.88-7.04 (m, 6H), 5.04 (s, 1 H), 2.01-2.13 (m, 2H), 1.92-1.98 (m, 2H), 1.44-1.68 ( m, 4H).

PREPARATION 2 1-r4- (4-Fluoro-phenoxy) -benzenesulfonylamino-1-cyclopentanecarboxylic acid tert-butyl ester In a solution of 1 - [4- (4-fIuoro-phenoxy) benzenesulfonylamino] -cyclopentanecarboxylic acid (10.22 g, 27 mmol) in 100 ml of methylene chloride at -78 ° C was condensed 40 ml of isobutylene. Concentrated sulfuric acid (0.3 ml) was added and the mixture was allowed to warm to room temperature and stirred for 22 hours. Then, the mixture was washed with 3x50 ml of 2 N NaOH and the organic layer was dried over magnesium sulfate and evaporated, giving 1.1 g (95%) of tert-butyl ester of 1- [4- ( 4-fluoro-phenoxy) -benzenesulfonylamino] -cyclopentanecarboxylic acid. 1 H NMR (CDCl 3)? 7.74-7.77 (m, 2H), 6.85-7.13 (m, 6H), 4.95 (s, 1 H), 1.92-2.02 (m, 2H), 1.78-1.88 (m, 2H), 1.50-1. 65 (m, 4H), 1.35 (s, 9H). The person skilled in the art will recognize numerous other strategies for the synthesis of the reaction intermediates described herein.

For example, esterification with isobutylene can be carried out on a molecule such as followed by sulfonation with, for example, a QSO2CI residue. Alternatively, it will be appreciated that, for example, the t-butyl esters of the above structures are easily prepared or can be purchased commercially.

PREPARATION 3 1 - (2-Ethoxycarbonyl-vinyl) -r 4 - (4-fluoro-phenoxy) -benzenesulfonin-amino-tert-butyl ester -cyclopentanecarboxylic To a mixture of 1- [4- (4-fluoro-phenoxy) -benzenesulfonylamino-cyclopentanecarboxylic acid tert -butyl ester (1.0 g, 2.3 mmol) in 10 ml of THF and 2.3 ml (2.3 mmol) of tetrabutylammonium fluoride 1 M in THF was added 0.23 ml (2.3 mmoles) of ethyl propiolate at room temperature. After stirring for 1 hour, the completion of the reaction was determined by HPLC and distilled to dryness in vacuo. The residue was dissolved in 20 ml of ethyl acetate and washed with 2x10 ml of water and the organic solution was distilled to an oil. This oil was chromatographed on silica gel, eluting with 10% ethyl acetate / hexane, yielding 0.95 g (77% yield) of 1-tert-butyl ester. { (2-ethoxycarbonyl-vinyl) - [4- (4-fluoro-phenoxy) -benzenesulfonyl] -amino} -cyclopentanecarboxylic acid in the form of a colorless oil. 1 H NMR (CDCl 3) indicated a 1.5: 1 ratio of trans / cis isomers. Trans? 7.79-7.83 (m, 2H), 7.63 (d, J = 14 Hz, 1 H), 6.89-7.05 (m, 4H), 5.44 (d, J = 14 Hz, 1 H), 4.08 (q, J = 7.1 Hz, 1 H), 2.08-2.43 (m, 4H), 1.63-1.80 (m, 4H), 1.39 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H). Cis 7.62-7.69 (m, 2H), 6.91-6.85 (m, 2H), 6.55 (d, J = 8.1 Hz, 1 H), 5.85 (d, J = 8.1 Hz, 1 H), 3.81 (q, J) = 7.2 Hz, 2H), 2.08-2.43 (m, 4H), 1.19-1.25 (m, 4H), 1.49 (s, 9H), 1.1 1 (q, J = 7.2 Hz, 3H).

PREPARATION 4 Tert-butyl ester of acid 1 -. { (2-ethoxycarbonyl-ethyl) -r4- (4-fluoro-phenoxy-benzenesulfonyl-amino) -cyclopentanecarboxylic acid A solution of 1-tert-butyl ester. { (2-ethoxycarbonyl-venyl) - [4- (4-fluoro-phenoxy) -benzenesulfonyl] -amino} Cyclopentanecarboxylic acid (1.23 g, 2.3 mmol) in 50 ml of ethanol with 723 mg of 5% Pd / C catalyst was hydrogenated at room temperature until HPLC indicated that the reaction was complete. The catalyst was filtered and the filtrate was evaporated, yielding an oil which was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane. The tert-butyl ester of acid 1 -. { (2-ethoxycarbonyl-ethyl) - [4- (4-fluoro-phenoxy) -benzenesulfonyl] -amino} - Cyclopentanecarboxylic acid was isolated as a colorless oil (875 mg, 71% yield). 1 H NMR (CDCl 3)? 7.75-7.80 (m, 2H), 6.86-7.01 (m, 6H), 4.09 (q, J = 7.2, 2H), 3.44-3.48 (m, 2H), 2.66-2.72 (m, 2H), 2.09-2.15 (m, 2H), 1.52-1.74 (m, 4H), 1.43 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H).

PREPARATION 5 1-f (2-Ethoxycarbonyl-ethylH4- (4-fl-oro-phenoxy) -benzenesulfon-amino-g-cyclopentanecarboxylic acid dicyclohexylamino acid salt A solution of 1-tert-butyl ester. { (2-ethoxycarbonyl-ethyl) - [4- (4-fluoro-phenoxy) -benzenesulfonyl] -amino} Cyclopentanecarboxylic acid (0.225 g, 0.42 mmol) in 4 ml of toluene was treated with methanesulfonic acid (0.06 ml, 0.84 mmol) for 18 hours at room temperature. The solution was washed with aqueous sodium bicarbonate solution and evaporated to a colorless oil. The oil was dissolved in 2 ml of ethanol and treated with dicyclohexylamine (0.084 ml, 0.42 mmol). The product, the dicyclohexyl-amino salt of the acid 1-. { (2-Ethoxycarbonyl-ethyl) - [4- (4-fluoro-phenoxy) -benzenesulfonyl] -aminoj-cyclopentanecarboxylic acid, filtered and dried, over 223 mg (80% yield) of a white solid having a time of HPLC retention and an NMR identical to a sample prepared by the benzyl ester route.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula wherein R1 is [(A?) CH2] c [(A2) CH2] b [(A3) CH2] aC-, wherein a, b and c are each 1; and each A-i, A2 and A3 is independently selected from the group consisting of H, alkyl (C ^ Cs) and phenyl or substituted phenyl; R2 and R3 are independently alkyl (CI-C?) Or R2 and R3 are taken together to form a cycloalkyl of three to seven members, a pyran-4-yl ring or a bicyclic ring of formula wherein the asterisk indicates the carbon atom common to R2 and R3; Q is alkyl (CrC6), aryl (C6-C? 0), heteroaryl (C2-C9), aryl (C6-C? 0) alkyl (C? -6), heteroaryl (C2-C9) alkyl (C? C6), aryloxy (C6-C? O) alkyl (CC?), Aryloxy (C6-C? 0) aryl (C6-C? 0), aryloxy (C6-C? 0) heteroaryl (C2-C9), aryl (C6-C? 0) aryl (C6-C? 0), arIl (C6-C? O) heteroaryl (C2-C9), aryl (C6-C? O) aryl (C6-C or) alkyl ( C? -C6), aryl (C6-C? O) aryl (C6-C? O) aryl (C6-C? O), arIl (C6-C1o) aryl (C6-C? O) heteroaryl (C2) -C9), heteroaryl (C2-C9) aryl (C6-C? O), heteroaryl (C2-C9) heteroaryl (C2-C9), aryl (C6-C? O) alkoxy (C Ce) alkyl ( C? -C6), aryl (C6-C? 0) alkoxy (C? -C6) aryl (C6-C? O), aryl (C6-C? O) alkoxy (Ci-C?) Heteroaryl (C2-C9) ), heteroaryloxy (C2-Cg) alkyI (C-C6), heteroaryloxy (C2-C9) aryl (Ce-Cio), heteroaryloxy (C2-C9) heteroaryl (C2-Cg), heteroaryl (C2-C9) alkoxy ( CrC6) alkyl (C? -C6), heteroaryl (C2-C9) alkoxy (Ci-Ce) aryl (C6-C? O) or heteroaryl (C2-C9) alkoxy (CC?) Heteroaryl (C2-C9); wherein each aryl moiety (C? -CIO) or heteroaryl (C2-Cg) of the aforementioned aryl (C6-C? o), heteroaryl (C2-C9), aryl (C6-C10) alkyl (C ^ Ce) , heteroaryl (C2-C9) alkyl (C-C?), aryloxy (C6-C? o) alkyl (C? -C6), aryloxy (C6-C? 0) aryl (C? -CIO), aryloxy (C6) -C?) Heteroaryl (C2-C9), aryl (C6-C? O) aryl (C-6-C o), aryl (C & C? O) heteroaryl (C2-C9), aryl (C6-) C? O) aryl (C6-C10) alkyl (C6-C0), aryl (C6-C? O) aryl (C6-C? O) aryl (C6-C? 0), aryl (C6-C? 0 ) aryl (C6-C? 0) heteroaryl (C2-Cg), heteroaryl (C2-Cg) aryl (C6-C? 0), heteroaryl (C2-Cg) heteroaryl (C2-C9), aryl (C6-) C? O) alkoxy (C? -C6) alkyl (C? Ce), aryl (C6-C? 0) alkoxy (C? -C6) aryl (C6-C? 0), aryl (C6-C or) alkoxy (C -C6) heteroaryl (C2-Cg), heteroaryloxy (C2-Cg) alkyl (Ci-C?), Heteroaryloxy (C2-C8) aryl (C6-C? 0), heteroaryloxy (C2-Cg) heteroaryl ( C2-C8), heteroaryl (C2-C9) alkoxy (C6-6) alkyl (C6-6), heteroaryl (C2-Cg) alkoxy (Ci-C6) aryl (C6-C6) or heteroaryl ( C2-C9) (C6-6) alkoxy heteroaryl (C2-C9) is optionally substituted on some or of the carbon atoms of the ring capable of forming an additional bond with one or more substituents per ring independently selected from fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (C? -C6), perfluoroalkyl (C1-) C3), perfluoroalkoxy (C1-C3) and aryloxy (C6-C10); and Y is hydrogen or alkyl (Ci-C?).

2. The compound of claim 1 wherein R2 and R3 are taken together to form a cyclobutyl, cyclopentyl, pyran-4-yl ring or a bicyclic ring of formula wherein the asterisk indicates the carbon atom common to R2 and R3.

3. The compound of claim 1 wherein Q is 4- (4-fluorophenoxy) phenyl.

4. A process for the preparation of a compound of formula wherein R1 is [(A?) CH2] c [(A2) CH2] b [(A3) CH2] aC-, wherein a, b and c are each 1; and each Ai, A2 and A3 is independently selected from the group consisting of H, (C1-C5) alkyl and phenyl or substituted phenyl; R2 and R3 are independently (C1-C6) alkyl or R2 and R3 are taken together to form a cycloalkyl of three to seven members, a pyran-4-yl ring or a bicyclic ring of formula wherein the asterisk indicates the carbon atom common to R2 and R3; Q is alkyl (C -C6), aryl (C6-C? 0), heteroaryl (C2-C9), aryloxy (C6-C? O) alkyl (C? -C6), aryloxy (C6-C? O) aryl (C6-C? o), aryloxy (C6-C? o) heteroaryl (C2-C9), aryl (C6-C? o) alkyl (C? -C6), aryl (C6-C? 0) aryl ( C6-C 0), aryl (C6-C? 0) heteroaryl (C2-C9), arii (C6-C? O) aryl (C6-C? O) alkyl (C? -C6), aryl (C6-C) ? o) aryl (C6-C? o) aryl (C6-C? 0), aryl (C6-C? 0) aryl (C6-C? 0) heteroaryl (C2-C9), heteroaryl (C2-C9) alkyl (C6-6), heteroaryl (C2-C9) aryl (C2-C9), heteroaryl (C2-C9) heteroaryl (C2-C9), aryl (C6-C6-) alkoxy (C? -C6) alkyl (C? -C6), aryl (C6-C? O) alkoxy (C? -C6) aryl (C6-C? 0), aryl (C6-C? O) alkoxy (C ? -C6) heteroaryl (C2-C9), heteroaryloxy (C2-C9) alkyl (C? -C6), heteroaryloxy (C2-C9) aryl (C6-C or), heteroaryloxy (C2-C9) heteroaryl (C2-C8) ), heteroaryl (C2-C9) alkoxy (CrC6) alkyl (C? -C6), heteroaryl (C2-C9) alkoxy (C6) C6 aryl (C6-C? 0) or heteroaryl (C2-Cg) alkoxy (C? -C6) heteroaryl (C -C9); wherein each aryl moiety (C6-C? 0) or heteroaryl (C2-Cg) of the aforementioned aryl (C? -C 0), heteroaryl (C2-Cg), aryloxy (C6-C? 0) alkyl (C) ^ Ce), aryloxy (C6-C? 0) aryl (C6-C10), aryloxy (C6-C? 0) heteroaryl (C2-C9), aryl (C6-C? 0) alkyl (C? -C6), aryl (C6-C? o) aryl (C6-C0), aryl (C6-C10) heteroaryl (C2-C9), aryl (C6-C? 0) ar1 (C6-C10) alkyl (C ^ Ce) ), aryl (C6-C? 0) aryl (C6-C? 0) aryl (C6-C? 0), aryl (C6-C? 0) aryl (C6-C? o) heteroaryl (C2-C9), heteroaryl (C2-C9) alkyl (C? -C6), heteroaryl (C2-Cg) aryl (C6-C? o), heteroaryl (C2-C9) heteroaryl (C2-Cg), aryl (C6-C0) alkoxy (C6C6) alkyl (C6), aryl (C6-C6) alkoxy (d-CeJaryl (C6-C6), aryl (C6) alkoxy (C6) heteroaryl (C2-C9) , (C2-C9) heteroaryloxy (C? -C6) alkyl, (C2-C9) heteroaryloxy (C6-C? o) aryl, (C2-Cg) heteroaryloxy (C2-C9) heteroaryl, (C2-C9) heteroaryl ) alkoxy (C? -C6) (C2-C9) heteroaryl (C? -C6) alkoxy (C6-C? 0) alkoxy or (C2-C8) heteroaryl (C? -C6) heteroaryl (C2-) alkoxy C9) is optionally substituted on any of the atoms carbon atoms of the ring capable of forming an additional bond with one or more substituents per ring independently selected from fluorine, chlorine, bromine, alkyl (C? -C6), alkoxy (C-C6), perfluoroalkyl (C1-C3), perfluoroalkoxy (C1-C3) and aryloxy (C6-C10); and Y is hydrogen or alkyl (C -C6); which comprises reacting a compound of formula wherein R1, R2, R3 and Q are as defined above; with a compound of formula wherein Y is alkyl (Ci-C?); in the presence of a base and a polar solvent.

5. The process according to claim 4, wherein said base is tetrabutylammonium fluoride.

6. The process according to claim 4, wherein said solvent is tetrahydrofuran.

7. - The process according to claim 4, further comprising the step of reducing said compound of formula wherein R1, R2, R3 Y and Q are as defined in claim 4, with a reducing agent to form a compound of formula wherein R1, R2, R3 Y and Q are as defined above.

8. The process according to claim 7, wherein said reducing agent is hydrogen on a catalyst selected from the group consisting of platinum oxide or Raney nickel, or a supported catalyst selected from the group consisting of palladium on carbon, or platinum on carbon.

9. The process according to claim 7, wherein the reduction is carried out in ethanol as solvent.

10. - The process according to claim 7, further comprising the hydrolysis of said compound of formula wherein R1, R2, R3 Y and Q are as defined in claim 7, under acidic conditions to form a compound of the formula wherein R1, R2, R3 Q and Y are as defined above. 1. The process according to claim 7, comprising: (a) a first step of hydrolysis of said compound of formula wherein R1, R2, R3 Y and Q are as defined in claim 4, under acidic conditions to form a compound of formula wherein R2, R3 Q and Y are as defined above; and (b) a second step of reducing said compound (a) with a reducing agent to form a compound of formula wherein R2, R3 Q and Y are as defined above. 12. The process according to claim 1, wherein the reducing agent is hydrogen on a catalyst that is selected from the group consisting of platinum oxide or Raney nickel, or a supported catalyst selected from the group consisting of palladium. on carbon, or platinum on carbon. SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of compounds of formula (b) wherein a compound of formula (V) it is reacted with a compound of formula (VI) the resulting compound of the formula (IV) is reduced to a compound of formula (III) which is hydrolyzed to a compound of formula (b); alternatively, a compound of formula (IV) is hydrolyzed to a compound of formula (a) which is reduced to a compound of formula (b); the compounds of formula (IV) are novel; in the formulas the variables are as defined in the claims; The compounds of the formula (b) are useful as intermediates in the preparation of the matrix metalloproteinase inhibitors. PFIZER / MP / ¡gp * rcp * osu * cgm * kra * jvc * sff * aom * P00 / 1343F