The present invention relates to dioxocyclopentyl hydroxamide derivatives of the formula ##STR1## PA1 wherein X, Z and Q are as defined in the specification, and to pharmaceutical compositions and methods of treatment thereof.

BACKGROUND OF THE INVENTION
 The present invention relates to dioxocyclopentyl hydroxamide derivatives,
 and to pharmaceutical compositions comprising such derivatives and to the
 use of such derivatives in the treatment of arthritis, cancer and other
 diseases.
 The compounds of the present invention are inhibitors of zinc
 metalloendopeptidases, especially those belonging to the matrix
 metalloproteinase (also called MMP or matrixin) and reprolysin (also known
 as adamylsin) subfamilies of the metzincins (Rawlings, et al., Methods in
 Enzymology, 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). The MMP's are most well
 known for their role in regulating the turn-over of extracellular matrix
 proteins and as such play important roles in normal physiological
 processes such as reproduction, development and differentiation. In
 addition, the MMP's are expressed in many pathological situations in which
 abnormal connective tissue turnover is occurring. For example, MMP-13 an
 enzyme with potent activity at degrading type II collagen (the principal
 collagen in cartilage), has been demonstrated to be overexpressed in
 osteoarthritic cartilage (Mitchell, et al., J. Clin. Invest., 97, 761
 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also
 overexpressed in osteoarthritic cartilage and inhibition of some or all of
 these MMP's is expected to slow or block the accelerated loss of cartilage
 typical of joint diseases such as osteoarthritis or rheumatoid arthritis.
 The mammalian reprolysins are known as ADAMs (A Disintegrin And
 Metalloproteinase) (Wolfberg, et al., J. Cell Biol., 131, 275-278 (1995))
 and contain a disintegrin domain in addition to a metalloproteinase-like
 domain. To date twenty-three distinct ADAM's have been identified.
 ADAM-17, also known as tumor necrosis factor-alpha converting enzyme
 (TACE), is the most well known ADAM. ADAM-17 (TACE) is responsible for
 cleavage of cell bound tumor necrosis factor-alpha (TNF-.alpha., also
 known as cachectin). TNF-.alpha. is recognized to be involved in many
 infectious and autoimmune diseases (W. Friers, FEBS Letters, 285, 199
 (1991)). Furthermore, it has been shown that TNF-.alpha. is the prime
 mediator of the inflammatory response seen in sepsis and septic shock
 (Spooner, et al., Clinical Immunology and Immunopathology, 62 S11 (1992)).
 There are two forms of TNF-.alpha., a type II membrane protein of relative
 molecular mass 26,000 (26 kD) and a soluble 17 kD form generated from the
 cell bound protein by specific proteolytic cleavage. The soluble 17 kD
 form of TNF-.alpha. is released by the cell and is associated with the
 deleterious effects of TNF-.alpha.. This form of TNF-.alpha. is also
 capable of acting at sites distant from the site of synthesis. Thus,
 inhibitors of TACE prevent the formation of soluble TNF-.alpha. and
 prevent the deleterious effects of the soluble factor.
 Select compounds of the invention are potent inhibitors of aggrecanase, an
 enzyme important in the degradation of cartilage aggrecan. Aggrecanase is
 also believed to be 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 inhibition of aggrecanase is
 expected to slow or block the loss of cartilage 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's
 10, 12 and 15 (Wu, et al., Biochem. Biophys. Res. Comm., 235, 437-442,
 (1997)). As knowledge of the expression, physiological substrates and
 disease association of the ADAM's increases the full significance of the
 role of inhibition of this class of enzymes will be appreciated.
 The compounds of the invention are useful in the treatment of arthritis
 (including osteoarthritis and rheumatoid arthritis), inflammatory bowel
 disease, Crohn's disease, emphysema, acute respiratory distress syndrome,
 asthma, chronic obstructive pulmonary disease, Alzheimer's disease, organ
 transplant toxicity, cachexia, allergic reactions, allergic contact
 hypersensitivity, cancer (such as solid tumor cancer including colon
 cancer, breast cancer, lung cancer and prostrate cancer and hematopoietic
 malignancies including leukemias and lymphomas), tissue ulceration,
 restenosis, periodontal disease, epidermolysis bullosa, osteoporosis,
 loosening of artificial joint implants, atherosclerosis (including
 atherosclerotic plaque rupture), aortic aneurysm (including abdominal
 aortic aneurysm and brain aortic aneurysm), congestive heart failure,
 myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord
 injury, neuro-degenerative disorders (acute and chronic), autoimmune
 disorders, Huntington's disease, Parkinson's disease, migraine,
 depression, peripheral neuropathy, pain, cerebral amyloid angiopathy,
 nootropic or cognition enhancement, amyotrophic lateral sclerosis,
 multiple sclerosis, ocular angiogenesis, corneal injury, macular
 degeneration, abnormal wound healing, burns, diabetes, tumor invasion,
 tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis,
 or septic shock.
 The compounds of the present invention are also useful in the treatment of
 diseases in which inhibition of MMP's and/or ADAM's will provide
 therapeutic benefit, such as those characterized by matrix
 metalloproteinase or ADAM expression.
 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 therefore.
 It is recognized that different combinations of MMP's and ADAM's are
 expressed in different pathological situations. Accordingly, inhibitors
 with specific selectivities for individual ADAM's and/or MMP's may be
 preferred for individual diseases. For example, rheumatoid arthritis is an
 inflammatory joint disease characterized by excessive TNF levels and the
 loss of joint matrix constituents. In this case, a compound that inhibits
 TACE and aggrecanase as well as MMP's such as MMP-13 may be the preferred
 therapy. In contrast, in a less inflammatory joint disease such as
 osteoarthritis, compounds that inhibit matrix degrading MMP's such as
 MMP-13 but not TACE may be preferred.
 The present inventors have also discovered that it is possible to design
 inhibitors with differential metalloprotease activity. Specifically, for
 example, the inventors have been able to design molecules which
 selectively inhibit matrix metalloprotease-13 (MMP-13) preferentially over
 MMP-1.
 SUMMARY OF THE INVENTION
 The present invention relates to compounds of the formula
 ##STR2##
 wherein
 X is &gt;CR.sup.3 R.sup.4 or &gt;C.dbd.O;
 Z is &gt;CH.sub.2 or &gt;NR.sup.1 ;
 R.sup.1 is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl or a group of the formula
 ##STR3##
 n is an integer from one to six;
 R.sup.2 is hydrogen or (C.sub.1 -C.sub.6)alkyl;
 R.sup.3 is hydrogen or (C.sub.1 -C.sub.6)alkyl;
 R.sup.4 is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1
 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.2
 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl,
 (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.6
 -C.sub.10)aryl(C.sub.2 -C.sub.9)heteroaryl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.6 -C.sub.10)aryl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.2 -C.sub.9)heteroaryl, (C.sub.6
 -C.sub.10)aryloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.6
 -C.sub.10)aryloxy(C.sub.6 -C.sub.10)aryl, (C.sub.6
 -C.sub.10)aryloxy(C.sub.2 -C.sub.9)heteroaryl, (C.sub.2
 -C.sub.9)heteroaryloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.2
 -C.sub.9)heteroaryloxy(C.sub.6 -C.sub.10)aryl, (C.sub.2
 -C.sub.9)heteroaryloxy(C.sub.2 -C.sub.9)heteroaryl, (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl(C.sub.6 -C.sub.10)aryl, (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl(C.sub.2 -C.sub.9)heteroaryl,
 (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.6 -C.sub.10)aryl,
 (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.2
 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryloxy(C.sub.1
 -C.sub.6)alkyl(C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryloxy(C.sub.1
 -C.sub.6)alkyl(C.sub.2 -C.sub.9)heteroaryl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl(C.sub.6 -C.sub.10)aryl,
 (C.sub.2 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl(C.sub.2
 -C.sub.9)heteroaryl, (C.sub.2 -C.sub.9)heteroaryl(C.sub.1
 -C.sub.6)alkoxy(C.sub.6 -C.sub.10)aryl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkoxy(C.sub.2 -C.sub.9)heteroaryl,
 (C.sub.2 -C.sub.9)heteroaryloxy(C.sub.1 -C.sub.6)alkyl(C.sub.6
 -C.sub.10)aryl, (C.sub.2 -C.sub.9)heteroaryloxy(C.sub.1
 -C.sub.6)alkyl(C.sub.2 -C.sub.9)heteroaryl, (C.sub.6
 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl or (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, wherein
 each of said (C.sub.6 -C.sub.10)aryl or (C.sub.2 -C.sub.9)heteroaryl
 moieties is optionally substituted on any of the ring carbon atoms capable
 of forming an additional bond by one or more substituents per ring,
 independently selected from fluoro, chloro, bromo, (C.sub.1
 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, perfluoro(C.sub.1
 -C.sub.3)alkyl, perfluoro(C.sub.1 -C.sub.3)alkoxy and (C.sub.6
 -C.sub.10)aryloxy;
 Q is (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.2
 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl,
 (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.6
 -C.sub.10)aryl(C.sub.2 -C.sub.9)heteroaryl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.6 -C.sub.10)aryl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.2 -C.sub.9)heteroaryl, (C.sub.6
 -C.sub.10)aryloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.6
 -C.sub.10)aryloxy(C.sub.6 -C.sub.10)aryl, (C.sub.6
 -C.sub.10)aryloxy(C.sub.2 -C.sub.9)heteroaryl, (C.sub.2
 -C.sub.9)heteroaryloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.2
 -C.sub.9)heteroaryloxy(C.sub.6 -C.sub.10)aryl, (C.sub.2
 -C.sub.9)heteroaryloxy(C.sub.2 -C.sub.9)heteroaryl, (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl(C.sub.6 -C.sub.10)aryl, (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl(C.sub.2 -C.sub.9)heteroaryl,
 (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.6 -C.sub.10)aryl,
 (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.2
 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryloxy(C.sub.1
 -C.sub.6)alkyl(C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryloxy(C.sub.1
 -C.sub.6)alkyl(C.sub.2 -C.sub.9)heteroaryl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl(C.sub.6 -C.sub.10)aryl,
 (C.sub.2 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl(C.sub.2
 -C.sub.9)heteroaryl, (C.sub.2 -C.sub.9)heteroaryl(C.sub.1
 -C.sub.6)alkoxy(C.sub.6 -C.sub.10)aryl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkoxy(C.sub.2 -C.sub.9)heteroaryl,
 (C.sub.2 -C.sub.9)heteroaryloxy(C.sub.1 -C.sub.6)alkyl(C.sub.6
 -C.sub.10)aryl, (C.sub.2 -C.sub.9)heteroaryloxy(C.sub.1
 -C.sub.6)alkyl(C.sub.2 -C.sub.9)heteroaryl, (C.sub.6
 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl or (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, wherein
 each of said (C.sub.6 -C.sub.10)aryl or (C.sub.2 -C.sub.9)heteroaryl
 moieties is optionally substituted on any of the ring carbon atoms capable
 of forming an additional bond by one or more substituents per ring,
 independently selected from fluoro, chloro, bromo, (C.sub.1
 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, perfluoro(C.sub.1
 -C.sub.3)alkyl, perfluoro(C.sub.1 -C.sub.3)alkoxy and (C.sub.6
 -C.sub.10)aryloxy;
 with the proviso that when X is &gt;C.dbd.O and Z is &gt;NR.sup.1, then R.sup.1
 must be hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1
 -C.sub.6)alkyl or (C.sub.2 -C.sub.9)heteroaryl (C.sub.1 -C.sub.6)alkyl;
 or the pharmaceutically acceptable salts thereof.
 The term "alkyl", as used herein, unless otherwise indicated, includes
 saturated monovalent hydrocarbon radicals having straight, branched or
 cyclic moieties or combinations thereof.
 The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl"
 is as defined above.
 The term "aryl", as used herein, unless otherwise indicated, includes an
 organic radical derived from an aromatic hydrocarbon by removal of one
 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 one hydrogen, such as pyridyl, furyl, pyrroyl, thienyl,
 isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl,
 pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl,
 pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl,
 thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl. Preferred heteroaryls
 include pyridyl, furyl, thienyl, isothiazolyl, pyrazinyl, pyrimidyl,
 pyrazolyl, isoxazolyl, thiazolyl or oxazolyl. Most preferred heteroaryls
 include pyridyl, furyl or thienyl.
 The term "terminal ring" refers to the ring furthest from the point of
 attachment of the substituent (i.e. the terminal ring in the group
 (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl(C.sub.2 -C.sub.9)heteroaryl
 is aryl).
 The compound of formula I may 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 wherein the bicyclo [3.3.0] ring system is cis fused.
 Other compounds of the invention relate to a compound of formula I, wherein
 X is --CH.sub.2 -- and Z is --CH.sub.2 --.
 Other compounds of the invention also relate to a compound of formula I,
 wherein X is &gt;C.dbd.O and Z is --CH.sub.2 --.
 Preferred compounds of the invention relate to a compound of formula I
 wherein Z is &gt;NR.sup.1, more preferably wherein R.sup.1 is hydrogen,
 (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl or
 (C.sub.2 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl.
 Other preferred compounds of the invention relate to a compound of formula
 I wherein X is --CH.sub.2 -- and Z is &gt;NR.sup.1, more preferably wherein
 R.sup.1 is hydrogen, (C.sub.1 -C.sub.8)alkyl, (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl or (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl.
 Other preferred compounds of the invention relate to a compound of formula
 I wherein X is &gt;C.dbd.O and Z is &gt;NR.sup.1, more preferably wherein
 R.sup.1 is hydrogen, (C.sub.1 -C.sub.8)alkyl, (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl or (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl.
 More preferred compounds of the present invention relate to a compound of
 formula I, wherein Q is optionally substituted (C.sub.6 -C.sub.10)aryl,
 (C.sub.6 -C.sub.10)aryloxy(C.sub.6 -C.sub.10)aryl, (C.sub.2
 -C.sub.9)heteroaryloxy(C.sub.6 -C.sub.10)aryl or (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.6 -C.sub.10)aryl, preferably
 substituted with zero to three substituents (most preferably zero, one or
 two substituents) independently selected from hydrogen, fluoro, chloro,
 (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy. 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:
 [3aR-(3a.beta.,5.alpha.,
 6a.beta.]-5-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-cyclope
 nta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 [3aS-(3a.alpha., 5.alpha.,
 6a.alpha.]-5-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-cyclop
 enta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 [3aR-(3a.beta., 5.alpha.,
 6a.beta.]-5-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-cyclope
 nta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 [3aS-(3a.alpha.,5.alpha.,
 6a.alpha.]-5-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-cyclop
 enta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 [3aR-(3a.beta.,5.alpha.,
 6a.beta.]-5-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-2-oxo-tetrahydro-c
 yclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 [3aS-(3a.alpha., 5.alpha.,
 6a.alpha.]-5-(4-Benzyloxy-benzenesulfonylamino)-tetrahydro-cyclopenta[1,3]
 dioxole-5-carboxylic acid hydroxyamide and
 [3aS-(3a.alpha., 5.alpha.,
 6a.alpha.]-5-[4-(4-Fluoro-benzyloxy)-benzenesulfonylamino]-tetrahydro-cycl
 openta[1,3]dioxole-5-carboxylic acid hydroxyamide.
 Other compounds of formula I are selected from the group consisting of:
 5-[4-(4-Chloro-benzyloxy)-benzenesulfonylamino]-tetrahydro-cyclopenta[1,3]d
 ioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Methyl-benzyloxy)-benzenesulfonylamino]-tetrahydro-cyclopenta[1,3]d
 ioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Fluoro-2-methyl-benzyloxy)-benzenesulfonylamino]-tetrahydro-cyclope
 nta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(5-Fluoro-2-methyl-benzyloxy)-benzenesulfonylamino]-tetrahydro-cyclope
 nta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-4-yloxy)-benzenesulfonylamino]-tetrahydro-cyclopenta[1,3]diox
 ole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-3-yloxy)-benzenesulfonylamino]-tetrahydro-cyclopenta[1,3]diox
 ole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-2-yloxy)-benzenesulfonylamino]-tetrahydro-cyclopenta[1,3]diox
 ole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-cyclopenta[1,3]d
 ioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Pyridin-4-yl-ethoxy)-benzenesulfonylamino]-tetrahydro-cyclopenta[1,
 3]dioxole-5-carboxylic acid hydroxyamide,
 5-{4-[2-(4-Fluoro-phenyl)-ethoxy]-benzenesulfonylamino}-tetrahydro-cyclopen
 ta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Thiazol4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-cyclopenta[1,3]d
 ioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Chloro-thiazol4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-cyclope
 nta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-(4'-Fluoro-biphenyl-4-sulfonylamino)-tetrahydro-cyclopenta[1,3]dioxole-5-
 carboxylic acid hydroxyamide,
 5-[4-(Benzothiazol-2-yloxy)-benzenesulfonylamino]-tetrahydro-cyclopenta[1,3
 ]dioxole-5-carboxylic acid hydroxyamide,
 5-[5-(4-Fluoro-phenoxy)-furan-2-sulfonylamino]-tetrahydro-cyclopenta[1,3]di
 oxole-5-carboxylic acid hydroxyamide,
 5-(5-Pyridin-2-yl-thiophene-2-sulfonylamino)-tetrahydro-cyclopenta[1,3]diox
 ole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Chloro-phenoxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclopenta[1
 ,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Fluoro-benzyloxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclopenta
 [1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Chloro-benzyloxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclopenta
 [1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2,5-Difluoro-benzyloxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclop
 enta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Methyl-benzyloxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclopenta
 [1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Fluoro-2-methyl-benzyloxy)-benzenesulfonylamino]-2-oxo-tetrahydro-c
 yclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(5-Fluoro-2-methyl-benzyloxy)-benzenesulfonylamino]-2-oxo-tetrahydro-c
 yclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-4-yloxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclopenta[1,
 3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-3-yloxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclopenta[1,
 3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-2-yloxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclopenta[1,
 3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-4-ylmethoxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclopent
 a[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Pyridin-4-yl-ethoxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclope
 nta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-{4-[2-(4-Fluoro-phenyl)-ethoxy]-benzenesulfonylamino}-2-oxo-tetrahydro-cy
 clopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Thiazol-4-ylmethoxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclopent
 a[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Chloro-thiazol-4-ylmethoxy)-benzenesulfonylamino]-2-oxo-tetrahydro-
 cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-(4'-Fluoro-biphenyl-4-sulfonylamino)-2-oxo-tetrahydro-cyclopenta[1,3]diox
 ole-5-carboxylic acid hydroxyamide,
 5-[4-(Benzothiazol-2-yloxy)-benzenesulfonylamino]-2-oxo-tetrahydro-cyclopen
 ta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[5-(4-Fluoro-phenoxy)-furan-2-sulfonylamino]-2-oxo-tetrahydro-cyclopenta[
 1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-(5-Pyridin-2-yl-thiophene-2-sulfonylamino)-2-oxo-tetrahydro-cyclopenta[1,
 3]dioxole-5-carboxylic acid hydroxyamide,
 3-[[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-(5-hydroxycarbamoyl-tetrahydro-cy
 clopenta[1,3]dioxol-5-yl)-amino]-propionic acid,
 3-[[4-(4-Chloro-phenoxy)-benzenesulfonyl]-(5-hydroxycarbamoyl-tetrahydro-cy
 clopenta[1,3]dioxol-5-yl)-amino]-propionic acid,
 3-[[4-(4-Fluoro-benzyloxy)-benzenesulfonyl]-(5-hydroxycarbamoyl-tetrahydro-
 cyclopenta[1,3]dioxol-5-yl)-amino]-propionic acid,
 3-[[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-(5-hydroxycarbamoyl-tetrahydro-
 cyclopenta[1,3]dioxol-5-yl)-amino]-propionic acid,
 3-[[4-(2,5-Difluoro-benzyloxy)-benzenesulfonyl]-(5-hydroxycarbamoyl-tetrahy
 dro-cyclopenta[1,3]dioxol-5-yl)-amino]-propionic acid,
 3-[[4-(2-Methyl-benzyloxy)-benzenesulfonyl]-(5-hydroxycarbamoyl-tetrahydro-
 cyclopenta[1,3]dioxol-5-yl)-amino]-propionic acid,
 3-[[4-(4-Fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-(5-hydroxycarbamoyl-te
 trahydro-cyclopenta[1,3]dioxol-5-yl)-amino]-propionic acid,
 3-[[4-(5-Fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-(5-hydroxycarbamoyl-te
 trahydro-cyclopenta[1,3]dioxol-5-yl)-amino]-propionic acid,
 5-[[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-(3-methyl-butyl)-amino]-tetrahydr
 o-cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-{[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-thiazol-4-ylmethyl-amino}-tetrahy
 dro-cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-{[4-(4-Fluoro-benzyloxy)-benzenesulfonyl]-thiazol-4-ylmethyl-amino}-tetra
 hydro-cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-{(4-Fluoro-benzenesulfonyl)-[2-(4-fluoro-phenyl)-ethyl]-amino}-tetrahydro
 -cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[[4-(2-Pyridin-4-yl-ethoxy)-benzenesulfonyl]-(3-methyl-butyl)-amino]-tetr
 ahydro-cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Fluoro-phenoxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,3]di
 oxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Chloro-phenoxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,3]di
 oxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Fluoro-benzyloxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,3]
 dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Chloro-benzyloxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,3]
 dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2,5-Difluoro-benzyloxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[
 1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Methyl-benzyloxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,3]
 dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Fluoro-2-methyl-benzyloxy)-benzenesulfonylmethyl]-tetrahydro-cyclop
 enta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(5-Fluoro-2-methyl-benzyloxy)-benzenesulfonylmethyl]-tetrahydro-cyclop
 enta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin4-yloxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,3]diox
 ole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-3-yloxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,3]dio
 xole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-2-yloxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,3]dio
 xole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin4-ylmethoxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,3]
 dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Pyridin-4-yl-ethoxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1
 ,3]dioxole-5-carboxylic acid hydroxyamide,
 5-{4-[2-(4-Fluoro-phenyl)-ethoxy]-benzenesulfonylmethyl}-tetrahydro-cyclope
 nta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Thiazol-4-ylmethoxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,3
 ]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Chloro-thiazol-4-ylmethoxy)-benzenesulfonylmethyl]-tetrahydro-cyclo
 penta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-(4'-Fluoro-biphenyl-4-sulfonylmethyl)-tetrahydro-cyclopenta[1,3]dioxole-5
 -carboxylic acid hydroxyamide,
 5-[4-(Benzothiazol-2-yloxy)-benzenesulfonylmethyl]-tetrahydro-cyclopenta[1,
 3]dioxole-5-carboxylic acid hydroxyamide,
 5-[5-(4-Fluoro-phenoxy)-furan-2-sulfonylmethyl]-tetrahydro-cyclopenta[1,3]d
 ioxole-5-carboxylic acid hydroxyamide,
 5-(5-Pyridin-2-yl-thiophene-2-sulfonylmethyl)-tetrahydro-cyclopenta[1,3]dio
 xole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Fluoro-phenoxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclopenta[
 1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Chloro-phenoxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclopenta[
 1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Fluoro-benzyloxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclopent
 a[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Chloro-benzyloxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclopent
 a[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2,5-Difluoro-benzyloxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclo
 penta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Methyl-benzyloxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclopent
 a[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Fluoro-2-methyl-benzyloxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-
 cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(5-Fluoro-2-methyl-benzyloxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-
 cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-4-yloxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclopenta[1
 ,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-3-yloxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclopenta[1
 ,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-2-yloxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclopenta[1
 ,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Pyridin-4-ylmethoxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclopen
 ta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Pyridin-4-yl-ethoxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclop
 enta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-{4-[2-(4-Fluoro-phenyl)-ethoxy]-benzenesulfonylmethyl}-2-oxo-tetrahydro-c
 yclopenta[3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(Thiazol-4-ylmethoxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclopen
 ta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(2-Chloro-thiazol-4-ylmethoxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro
 -cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-(4'-Fluoro-biphenyl-4-sulfonylmethyl)-2-oxo-tetrahydro-cyclopenta[1,3]dio
 xole-5-carboxylic acid hydroxyamide,
 5-[4-(Benzothiazol-2-yloxy)-benzenesulfonylmethyl]-2-oxo-tetrahydro-cyclope
 nta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 2-Benzyl-5-[4-(2,4-difluorobenzyloxy)-benzenesulfonylamino]tetrahydrocyclop
 enta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 2-(2-Methoxyethyl)-5-[4-(quinolin-5-ylmethoxy)-benzenesulfonylamino]-tetrah
 ydrocyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Fluorophenoxy)-benzenesulfonylamino]-2-(2-methoxyethyl)-tetrahydroc
 yclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(5-Chloropyridin-2-yloxy)-benzenesulfonylamino]-2-furan-2-ylmethyl-2-m
 ethyl-tetrahydrocyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide,
 5-[4-(4-Chlorophenoxy)-benzenesulfonylmethyl]-2-ethoxymethyltetrahydrocyclo
 penta-[1,3]dioxole-5-carboxylic acid hydroxyamide,
 3-[(5-Hydroxycarbamoyl-2-phenethyltetrahydrocyclopenta[1,3]dioxol-5-yl)-(4-
 phenoxybenzenesulfonyl)-amino]-propionic acid,
 5-[5-(4-Fluoro-phenoxy)-furan-2-sulfonylmethyl]-2-oxo-tetrahydro-cyclopenta
 [1,3]dioxole-5-carboxylic acid hydroxyamide, and
 5-(5-Pyridin-2-yl-thiophene-2-sulfonylmethyl)-2-oxo-tetrahydro-cyclopenta[1
 ,3]dioxole-5-carboxylic acid hydroxyamide.
 The present invention also relates to the pharmaceutically acceptable acid
 addition salts of compounds of the formula I. The acids which are used to
 prepare the pharmaceutically acceptable acid addition salts of the
 aforementioned base compounds of this invention are those which form
 non-toxic acid addition salts, i.e., salts containing pharmacologically
 acceptable anions, such as the 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 [i.e.,
 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
 The invention also relates to base addition salts of formula I. The
 chemical bases that may be used as reagents to prepare pharmaceutically
 acceptable base salts of those compounds of formula I that are acidic in
 nature are those that form non-toxic base salts with such compounds. Such
 non-toxic base salts include, but are not limited to those derived from
 such pharmacologically acceptable cations such as alkali metal cations
 (e.g., potassium and sodium) and alkaline earth metal cations (e.g.,
 calcium and magnesium), ammonium or water-soluble amine addition salts
 such as N-methylglucamine-(meglumine), and the lower alkanolammonium and
 other base salts of pharmaceutically acceptable organic amines.
 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, acute respiratory distress syndrome,
 asthma, chronic obstructive pulmonary disease, Alzheimer's disease, organ
 transplant toxicity, cachexia, allergic reactions, allergic contact
 hypersensitivity, cancer (such as solid tumor cancer including colon
 cancer, breast cancer, lung cancer and prostrate cancer and hematopoietic
 malignancies including leukemias and lymphomas), tissue ulceration,
 restenosis, periodontal disease, epidermolysis bullosa, osteoporosis,
 loosening of artificial joint implants, atherosclerosis (including
 atherosclerotic plaque rupture), aortic aneurysm (including abdominal
 aortic aneurysm and brain aortic aneurysm), congestive heart failure,
 myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord
 injury, neuro-degenerative disorders (acute and chronic), autoimmune
 disorders, Huntington's disease, Parkinson's disease, migraine,
 depression, peripheral neuropathy, pain, cerebral amyloid angiopathy,
 nootropic or cognition enhancement, amyotrophic lateral sclerosis,
 multiple sclerosis, ocular angiogenesis, corneal injury, macular
 degeneration, abnormal wound healing, burns, diabetes, tumor invasion,
 tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis
 and septic shock in a mammal, including a human, comprising an amount of a
 compound of formula I or a pharmaceutically acceptable salt thereof
 effective in such treatments and a pharmaceutically acceptable carrier.
 The present invention also relates to a pharmaceutical composition for the
 treatment of diseases characterized by metalloproteinase activity and
 other diseases characterized by mammalian reprolysin activity in a mammal,
 including a human, comprising an amount of a compound of formula I or a
 pharmaceutically acceptable salt thereof effective in such treatments and
 a pharmaceutically acceptable carrier.
 The present invention also relates to a pharmaceutical composition for the
 inhibition of (a) matrix metalloproteinases or other metalloproteinases
 involved in matrix degradation, or (b) a mammalian reprolysin (such as
 aggrecanase or ADAM's 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, acute respiratory distress syndrome, asthma, chronic
 obstructive pulmonary disease, Alzheimer's disease, organ transplant
 toxicity, cachexia, allergic reactions, allergic contact hypersensitivity,
 cancer (such as solid tumor cancer including colon cancer, breast cancer,
 lung cancer and prostrate cancer and hematopoietic malignancies including
 leukemias and lymphomas), tissue ulceration, restenosis, periodontal
 disease, epidermolysis bullosa, osteoporosis, loosening of artificial
 joint implants, atherosclerosis (including atherosclerotic plaque
 rupture), aortic aneurysm (including abdominal aortic aneurysm and brain
 aortic aneurysm), congestive heart failure, myocardial infarction, stroke,
 cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative
 disorders (acute and chronic), autoimmune disorders, Huntington's disease,
 Parkinson's disease, migraine, depression, peripheral neuropathy, pain,
 cerebral amyloid angiopathy, nootropic or cognition enhancement,
 amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis,
 corneal injury, macular degeneration, abnormal wound healing, burns,
 diabetes, tumor invasion, tumor growth, tumor metastasis, corneal
 scarring, scleritis, AIDS, sepsis and septic shock in a mammal, including
 a human, comprising administering to said mammal an amount of a compound
 of formula I or a pharmaceutically acceptable salt thereof effective in
 treating such a condition.
 The present invention also relates to the treatment of diseases
 characterized by matrix metalloproteinase activity and other diseases
 characterized by mammalian reprolysin activity in a mammal, including a
 human, comprising administering to said mammal an amount of a compound of
 formula I or a pharmaceutically acceptable salt thereof effective in
 treating such a condition.
 The present invention also relates to a method for the inhibition of (a)
 matrix metalloproteinases or other metalloproteinases involved in matrix
 degradation, or (b) a mammalian reprolysin (such as aggrecanase or ADAM's
 TS-1, 10, 12, 15 and 17, preferably ADAM-17) in a mammal, including a
 human, comprising administering to said mammal an effective amount of a
 compound of formula I or a pharmaceutically acceptable salt thereof.
 This invention also encompasses pharmaceutical compositions containing
 prodrugs of compounds of the formula I. This invention also encompasses
 methods of treating or preventing disorders that can be treated or
 prevented by the inhibition of matrix metalloproteinases or the inhibition
 of mammalian reprolysin comprising administering prodrugs of compounds of
 the formula I. Compounds of formula I having free amino, amido, hydroxy or
 carboxylic groups can be converted into prodrugs. Prodrugs include
 compounds wherein an amino acid residue, or a polypeptide chain of two or
 more (e.g., two, three or four) amino acid residues which are covalently
 joined through peptide bonds to free amino, hydroxy or carboxylic acid
 groups of compounds of formula I. The amino acid residues include the 20
 naturally occurring amino acids commonly designated by three letter
 symbols and also include, 4-hydroxyproline, hydroxylysine, demosine,
 isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric
 acid, citrulline, homocysteine, homoserine, ornithine and methionine
 sulfone. Prodrugs also include compounds wherein carbonates, carbamates,
 amides and alkyl esters, which are covalently bonded to the above
 substituents of formula I through the carbonyl carbon prodrug sidechain.
 One of ordinary skill in the art will appreciate that the compounds of the
 invention are useful in treating a diverse array of diseases. One of
 ordinary skill in the art will also appreciate that when using the
 compounds of the invention in the treatment of a specific disease that the
 compounds of the invention may be combined with various existing
 therapeutic agents used for that disease.
 For the treatment of rheumatoid arthritis, the compounds of the invention
 may be combined with agents such as TNF-.alpha. inhibitors such as
 anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules
 (such as Enbrel.RTM.), low dose methotrexate, lefunimide,
 hydroxychloroquine, d-penicilamine, auranofin or parenteral or oral gold.
 The compounds of the invention can also be used in combination with
 existing therapeutic agents for the treatment of osteoarthritis. Suitable
 agents to be used in combination include standard non-steroidal
 anti-inflammatory agents (hereinafter NSAID's) such as piroxicam,
 diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,
 ketoprofen and ibuprofen, fenamates 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 synvisc.
 The compounds of the present invention may 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 may also be used in combination with
 cardiovascular agents such as calcium channel blockers, lipid lowering
 agents such as statins, fibrates, beta-blockers, Ace inhibitors,
 Angiotensin-2 receptor antagonists and platelet aggregation inhibitors.
 The compounds of the present invention may also be used in combination with
 CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian
 drugs (such as deprenyl, L-dopa, requip, mirapex, MAOB inhibitors such as
 segeline and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors,
 dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists,
 Dopamine agonists and inhibitors of neuronal nitric oxide synthase), and
 anti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors,
 propentofylline or metryfonate.
 The compounds of the present invention may also be used in combination with
 osteoporosis agents such as roloxifene, droloxifene or fosomax and
 immunosuppressant agents such as FK-506 and rapamycin.
 DETAILED DESCRIPTION OF THE INVENTION
 The following reaction Scheme illustrates the preparation of the compounds
 of the present invention. Unless otherwise indicated, n, X, Z, Q and
 R.sup.1, R.sup.2, R.sup.3, and R.sup.4 in the reaction Schemes and the
 discussion that follows is defined as above.
 ##STR4##
 ##STR5##
 ##STR6##
 ##STR7##
 Scheme 1 refers to the preparation of compounds of the formula I, wherein Z
 is &gt;NR.sup.1, and R.sup.1 is hydrogen. Referring to Scheme 1, compounds of
 formula I are prepared from compounds of formula II by activation of the
 carboxylic acid moiety in compounds of formula II followed by treatment of
 the activated acid with hydroxylamine or a protected hydroxylamine
 equivalent that is then deprotected to form the hydroxamic acid.
 Activation of the carboxyl group of formula II is achieved through the
 action of a suitable activating agent such as dialkyl carbodiimides,
 benzotriazol-1-yloxyl)tris(dialkylamino)-phosphonium salts, or oxalyl
 chloride in the presence of a catalytic amount of N,N-dimethylformamide
 (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
 is preferred). Generally, the hydroxylamine or protected hydroxylamine
 equivalent is generated in situ from a salt form, such as hydroxylamine
 hydrochloride, in the presence of an amine base such as triethylamine, or
 N,N-diisopropylethylamine. Suitable protected hydroxylamines include
 O-tert-butylhydroxylamine, O-allylhydroxylamine,
 O-tert-butyldimethylsilylhydroxylamine,
 O-trimethylsilylethylhydroxylamine, O-benzylhydroxylamine, or
 N,O-bistrimethylsilylhydroxylamine. Removal of the protecting group is
 carried out by hydrogenolysis in the instance where O-benzylhydroxylamine
 is used (5% palladium on barium sulfate is the preferred catalyst) or by
 treatment with a strong acid such as trifluoroacetic acid in the situation
 where O-tert-butylhydroxylamine or O-trimethylsilylethylhydroxylamine is
 used. When O-allylhydroxylamine is employed, the allyl group is preferably
 removed by treatment with ammonium formate in the presence of a catalytic
 amount of tetrakis(triphenylphosphine)palladium(0) in aqueous acetonitrile
 at 60.degree. C. or by treatment with piperidine in the presence of a
 catalytic amount of allylpalladium chloride dimer and
 diphenylphosphinoethane in tetrahydrofuran (THF) at about 0.degree. C. to
 about 35.degree. C., preferably about 23.degree. C. In the case where
 N,O-bis-trimethylsilylhydroxylamine is used (preferably generated in situ
 from trimethylsilylchloride and hydroxylamine hydrochloride in pyridine at
 about 0.degree. C.), the silyl protective groups are removed by treatment
 with dilute aqueous acid such as 1 N hydrochloric acid. Suitable solvents
 for the aforesaid activation and hydroxylamine reaction include
 dichloromethane, N,N-dimethylformamide, or tetrahydrofuran, preferably
 dichloromethane. The aforesaid activation and hydroxylamine reactions are
 run at temperatures between about 0.degree. C. to about 60.degree. C.
 (23.degree. C. is preferred) for periods of time between about 1 hour and
 about 20 hours (4 hours is preferred).
 Compounds of formula II are prepared from compounds of formula III by
 removal of the protective group PG.sup.1 to form a carboxylic acid. In
 cases where the protecting group PG.sup.1 is methyl or ethyl, this
 conversion is achieved by saponification with a suitable source of
 hydroxide such as sodium or lithium hydroxide (lithium hydroxide is
 preferred). Preferably the saponification is conducted with stirring, in
 an aqueous solvent mixture such as tetrahydrofuran-methanol-water or
 1,4-dioxane-methanol-water at a temperature between about 0.degree. C. to
 near the boiling point of the solvent system (about 60.degree. C. is
 preferred). In cases where the protecting group PG.sup.1 is benzyl, the
 conversion is achieved by hydrogenolysis of the benzyl group. The
 hydrogenolysis is carried out in a suitable solvent such as ethanol,
 methanol, or ethyl acetate under an atmosphere of hydrogen, in the
 presence of a catalyst such a 10% palladium on carbon. Generally,
 reactions involving the removal of protecting group PG.sup.1 are run for
 periods of time between about 30 minutes to about 8 hours, preferably
 about 4 hours. Unless otherwise mentioned, the aforesaid reactions are
 performed at a temperature from about 0.degree. C. to about 25.degree. C.,
 preferably about 23.degree. C.
 Alternatively compounds of formula III can be converted directly to
 compounds of formula I through the action of hydroxylamine. Preferably,
 the protecting group PG.sup.1 is methyl. Suitable solvents include
 methanol, ethanol, or 2-propanol, preferably methanol. For this reaction
 the preferred method for generating the hydroxylamine is by treatment of
 hydroxylamine hydrochloride with potassium hydroxide. The reaction is
 performed at a temperature between about 0.degree. C. to about 23.degree.
 C. (0.degree. C. is preferred) for a period of time from about 10 minutes
 to about 4 hours (2 hours is preferred).
 Compounds of formula III are prepared from compounds of formula IV by the
 reaction of the cis diol moiety in compounds of formula IV with a source
 of active methylene, active carbonyl or a compound of the formula R.sup.3
 R.sup.4 C.dbd.O. Sources of active methylene include formaldehyde,
 dimethoxymethane, and dibromomethane. Active carbonyl sources include
 phosgene, 1,1'-carbonyldiimidazole, and triphosgene
 (bis(trichloromethyl)carbonate). The preferred method of preparing
 compounds of formula III, wherein X is CH.sub.2, is by reaction of
 compounds of formula IV with dimethoxymethane in the presence of a strong
 acid such as p-toluenesulfonic acid, camphorsulfonic acid, or
 Amberlsyt.RTM. 15 (Amberlyst.RTM. 15 is preferred). Preferably this
 methylenation reaction is conducted in a solvent such as benzene or
 dichloromethane (dichloromethane is preferred) at a temperature between
 about 23.degree. C. to the boiling point of the solvent mixture
 (preferably 40.degree. C.) for a period of around 2 hours to about 24
 hours, preferably about 17 hours. Preferably the aforesaid reaction is
 conducted with the use of a Dean-Stark trap charged with 4 angstrom sieves
 (.ANG.). The preferred method of preparing compounds of formula III,
 wherein X is CO, is by reaction of compounds of formula IV with
 1,1-carbonyldiimidazole. Preferably this carbonylation reaction is
 performed in a solvent such as toluene, dichloromethane, or
 tetrahydrofuran (dichloromethane is preferred), at a temperature between
 about 0.degree. C. to about 35.degree. C. (about 23.degree. C. is
 preferred) for a period of time from about 1 hour to about 2 days hours (1
 day is preferred). The preferred methods for preparing compounds of the
 formula III, wherein X is &gt;CR.sup.3 R.sup.4 and wherein one of R.sup.3 or
 R.sup.4 is other than hydrogen, is by reaction of compounds of the formula
 IV with an aldehyde or ketone compound of the formula R.sup.3 R.sup.4
 C.dbd.O in the presence of an acid, such as p-toluene sulfonic acid, under
 dehydrating conditions such as refluxing the reaction mixture in a high
 boiling solvent such as toluene or benzene in the presence of a Dean-Stark
 trap or 4 .ANG. molecular sieves. Aldehydes or ketones of the formula
 R.sup.3 R.sup.4 C.dbd.O are commercially available or can be made by
 methods well known to those of ordinary skill in the art.
 Compounds of the formula IV are prepared from compounds of the formula V by
 bis-hydroxylation. Preferably the bis-hydroxylation reaction is performed
 using osmium tetroxide in a suitable solvent or solvent mixture such as
 pyridine, acetone-water, or tetrahydrofuran-water. The use of a catalytic
 amount of osmium tetroxide and a stoichiometric amount of a co-oxidant
 such as 4-methylmorpholine N-oxide or trimethyl amine N-oxide in a mixture
 of tetrahydrofuran-water is preferred. The aforesaid reaction is run at a
 temperature between about 0.degree. C. to about 35.degree. C., preferably
 at about 23.degree. C. for a time period of about 1 hour to about 8 hours
 (2 hours is preferred). Compounds of formula IV produced in this way are
 obtained as mixture of diastereomers, which can be separated by
 crystallization, chromatographic means, or by chemical methods. Chemical
 methods include subjecting the mixture of diastereomers to lactonization
 conditions, followed by chromatographic separation of the resulting
 lactone and the remaining diol isomer. The preferred method of
 lactonization involves heating of the mixture of diastereomers of formula
 IV in toluene at reflux in the presence of p-toluenesulfonic acid or
 Amberlyst.RTM. 15 for a period of about 20 hours, using a Dean-Stark trap
 charged with 4 angstrom sieves.
 Compounds of formula V, wherein PG.sup.1 is methyl, ethyl, or benzyl, are
 prepared from compounds of formula VI by reaction with compounds of the
 formula QSO.sub.2 Cl. Preferably the aforesaid reaction is run in a
 suitable solvent such as dichloromethane, tetrahydrofuran,
 N,N-dimethylformamide. Suitable bases include triethylamine,
 N,N-diisopropylethylamine. The use of dichloromethane as solvent and
 N,N-diisopropylethylamine as the base in the presence of a catalytic
 amount of 4-(dimethylamino)pyridine are preferred. The reaction is stirred
 at a temperature between about 0.degree. C. to about 35.degree. C.,
 preferably at about 23.degree. C., for a time period between about 2 hours
 to about 1 day, preferably about 12 hours. Compounds of formula VI wherein
 PG.sup.1 is methyl, ethyl or benzyl are known in the literature (Park,
 K.-H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63, 113-117 see
 also Kotha, S.; Sreenivasachary, N. Bioorg. Med. Chem. Lett. 1998, 8,
 257-260) or can be prepared in an analogous way. Compounds of the formula
 QSO.sub.2 Cl are known, and can be prepared according to methods described
 in PCT publication WO 98/07697, published Feb. 26, 1998, or and PCT
 publication WO 98/33768 published Aug. 6, 1998, are commercially
 available, or can be made by methods well known to those of ordinary skill
 in the art.
 Scheme 2 refers to the preparation of compounds of formula I, wherein Z is
 &gt;CH.sub.2. Referring to Scheme 2, a compound of the formula I is prepared
 from a compound of the formula VII by oxidation of the sulfur. Suitable
 oxidants include meta-chloroperbenzoic acid, hydrogen peroxide, sodium
 perborate, or Oxone.RTM. (Oxone.RTM. is preferred). Preferably the
 reaction is conducted in a suitable solvent or solvent mixture such as
 methanol-water, dioxane-water, tetrahydrofuran-water, methylene chloride,
 or chloroform, preferably methanol-water. Suitable temperatures for the
 aforesaid reaction range from about 0.degree. C. to about 60.degree. C.,
 preferably the temperature may range from about 20.degree. C. to about
 25.degree. C. (i.e. room temperature). The reaction is complete within
 about 0.5 hours to about 24 hours, preferably about 16 hours.
 Compounds of the formula VII are prepared from compounds of the formulas
 VIII as described in Scheme 1 for the preparation of compounds of formula
 I.
 Compounds of formula VIII, wherein X is &gt;CO, can be prepared from compounds
 of formula IX by removal of the protective group P, followed by cyclic
 carbonate formation. Removal of the preferred protective group, P equal to
 &gt;CMe.sub.2, is achieved by a hydrolysis reaction. Preferably this
 hydrolysis is conducted with aqueous hydrochloric acid in a mixture of
 tetrahydrofuran and water at a temperature of about 23.degree. C.
 Formation of the cyclic carbonate is conducted as described in preparation
 1. Compounds of the formula VIII wherein X is &gt;CR.sup.3 R.sup.4 can be
 prepared from compounds of the formula IX by methods analogous to the
 methods of Scheme 1 for the conversion of compounds of formula IV to
 formula III. Compounds of formula IX, wherein P is CH.sub.2, are compounds
 of formula VIII, wherein X is CH.sub.2, and thus can be converted directly
 to compounds of formula VII as described above.
 Compounds of the formula IX can be prepared from compounds of the formula X
 by reaction with a compound of the formula QSH, wherein Q is as defined
 above, in the presence of a strong base in an aprotic polar solvent.
 Suitable bases include sodium hydride, lithium diisopropylamide, potassium
 t-butoxide, sodium amide or potassium hydride, preferably sodium hydride.
 Suitable solvents include ethers (such as THF, diethyl ether or
 1,2-dimethoxyethane), or N,N-dimethylformamide, preferably the solvent is
 THF. The aforesaid reaction is conducted at about -78.degree. C. to about
 0.degree. C., preferably at about 22.degree. C. for a period of 30 minutes
 to about 24 hours, preferably about 2 hours.
 Compounds of the formula X are prepared from compounds of the formula XI by
 dehydration in the presence of a tertiary amine base, preferably
 triethylamine, optionally in the presence of 4-(dimethylamino)pyridine,
 and a dehydrating agent in an inert solvent. Suitable dehydrating agents
 include trifluoromethanesulfonic anhydride, methanesulfonic anhydride,
 methanesulfonyl chloride, p-toluenesulfonyl chloride or benzenesulfonyl
 chloride, preferably benzenesulfonyl chloride. Suitable solvents include
 diethyl ether or dichloromethane. The reaction is performed at a
 temperature from about -80.degree. C. to about 0.degree. C., preferably
 about 0.degree. C. The reaction is carried out for about 10 minutes to 4
 hours, preferably 1 about hour.
 The compounds of the formula XI are prepared from a compound of formula
 XII, wherein PG.sup.2 is methyl or ethyl, by saponification with a base,
 such as lithium hydroxide, in a solvent mixture. Suitable solvent mixtures
 include water and methanol or water, methanol and THF. The reaction is
 performed at a temperature from about 60.degree. C. to about 120.degree.
 C., preferably at about the reflux temperature of the solvent mixture
 used. The reaction is carried out for about 30 minutes to 24 hours,
 preferably about 16 hours.
 Compounds of formula XII are prepared from compounds of formula XIII by a
 reduction reaction. In general, a solution of a compound of formula XIII
 is dissolved in an inert aromatic solvent, preferably benzene or toluene,
 and cooled at about -40.degree. C. to -20.degree. C., preferably about
 -40.degree. C. To the cold solution is added a suitable hindered reducing
 agent, preferably diisobutylaluminum hydride, in an inert aromatic
 solvent, maintaining the temperature below -25.degree. C. After the
 addition is complete, the reaction is maintained below 0.degree. C. for
 about 3 hours. At about -15.degree. C., a protic solvent, preferably
 ethanol, is added. After stirring at about -15.degree. for about 1 hour,
 sodium borohydride is added and the reaction is allowed to warm to about
 room temperature while stirring for a period of 2 to 24 hours, preferably
 about 16 hours. Compounds of formula XII produced in this way are obtained
 as a mixture of diastereomers and can be separated by crystallization,
 chromatography, or chemical methods.
 Compounds of formula XIII, wherein P is a diol protective group, are
 prepared from compounds of formula XIV by reaction with a suitable
 protective group agent. Suitable protective group agents include
 dimethoxymethane, dimethoxypropane, benzaldehyde and 2-methoxypropene. The
 preferred method of preparing compounds of formula XIII, wherein P is
 CH.sub.2, is by reaction of compounds of formula XIV with dimethoxymethane
 in the presence of a strong acid such as p-toluenesulfonic acid,
 camphorsulfonic acid, or Amberlsyt.RTM. 15 (Amberlyst.RTM. 15 is
 preferred). Preferably this methylenation reaction is conducted in a
 solvent such as benzene or dichloromethane (dichloromethane is preferred)
 at a temperature between 23.degree. C. to the boiling point of the solvent
 mixture (preferably 40.degree. C.) for a period of around 2 hours to about
 24 hours, preferably about 17 hours. Preferably the aforesaid reaction is
 conducted with the use of a Dean-Stark trap charged with 4 angstrom
 sieves. The preferred protective group P, when P is not CH.sub.2, is the
 acetonide or isopropylidene ketal (P is &gt;CMe.sub.2 in formula XIII). The
 preferred method of preparing compounds of formula XIII, wherein P is
 &gt;CMe.sub.2, is by reaction of compounds of formula XIV with
 2-methoxypropene and p-toluenesulfonic acid. Preferably the aforesaid
 reaction is conducted in a solvent such as benzene, toluene, or
 dichloromethane (dichloromethane is preferred), for a period of time from
 about 30 minutes to about 24 hours at a temperature from about 0.degree.
 C. to about 35.degree. C. (about 23.degree. C. is preferred).
 The compounds formula XIV, wherein PG.sup.2 is ethyl or methyl, are
 prepared from compounds of the formula XV, by a bis-hydroxylation
 reaction. Preferably the bis-hydroxylation reaction is performed using
 osmium tetroxide in a suitable solvent or solvent mixture such as
 pyridine, acetone-water, or tetrahydrofuran-water. The use of a catalytic
 amount of osmium tetroxide and a stoichiometric amount of a co-oxidant
 such as 4-methyl morpholine N-oxide or trimethyl amine N-oxide in a
 mixture of tetrahydrofuran-water is preferred. The aforesaid reaction is
 run at a temperature between about 0.degree. C. to 23.degree. C.,
 preferably at 23.degree. C. for a time period of about 1 hour to about 8
 hours (2 hours is preferred).
 Compounds of formula XV are commercially available (Frinton Labs, P.O. Box
 2428, Vineland, N.J., 08360), or are known in the literature (Depres,
 J.-P.; Greene, A. E. J. Org. Chem. 1984, 49, 928-931; Chang, S.; Jones II,
 L.; Chunming, W., Lawrence, H. M.; Grubbs, R. H. Organometallics 1998,
 3460-3465; Nugent, W. A.; Feldman, J.; Calabrese, J. C. J. Am. Chem. Soc.
 1995, 117, 8992-8998).
 Compounds of the formula QSH can be prepared by reaction of an alkyl or
 aryl halide with sodium sulfhydride as described in Jerry March, Advanced
 Organic Chemistry, 360 and 589 (3rd ed., 1985). Alternatively, compounds
 of the formula QSH can also be prepared by reaction of an aryl diazonium
 salt with sodium sulfhydride as described in March id. at 601.
 Alternatively, compounds of the formula QSH can also be prepared by
 reaction of a Grignard reagent with sulfur as described in March id. at
 550. Alternatively, compounds of the formula QSH can also be prepared by
 reduction of a sulfonyl chloride, sulfonic acid or disulfide as described
 in March id. at 1107 and 1110.
 Scheme 3 refers to the preparation of compounds of the formula I, wherein Z
 is NR.sup.1 and R.sup.1 is (C.sub.1 -C.sub.6)alkyl, (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl or a group of the formula
 --(CH.sub.2).sub.n CO.sub.2 R.sup.2, wherein n is 1, 3, 4, 5, or 6 and
 R.sup.2 is (C.sub.1 -C.sub.6)alkyl.
 Referring to Scheme 3, compounds of the formula I, wherein X is CH.sub.2
 and Z is NR.sup.1 and R.sup.1 is (C.sub.1 -C.sub.6)alkyl, (C.sub.6
 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.2
 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl or a group of the formula
 --(CH.sub.2).sub.n CO.sub.2 R.sup.2, wherein n is 1, 3, 4, 5, or 6 and
 R.sup.2 is (C.sub.1 -C.sub.6)alkyl, are prepared from compounds of the
 formula XVI as described in Scheme 1 for the preparation of compounds of
 formula I from compounds of the formula II.
 The compound of formula XVI is prepared from a compound of the formula XVII
 by removal of the benzyl protecting group. Specifically, the benzyl
 protecting group is removed by hydrogenolysis using palladium or palladium
 on carbon in a solvent such as methanol or ethanol, for a period from
 about 30 minutes to about 48 hours, preferably 16 hours, at a temperature
 of about 20.degree. C. to about 25.degree. C. (i.e., room temperature).
 The compound of formula XVII is prepared from a compound of the formula
 III, wherein PG.sup.1 is benzyl, by reaction with a reactive derivative of
 an alcohol of the formula R.sup.1 OH such as the methanesulfonate,
 tosylate, chloro, bromo or iodo derivative, preferably the iodo
 derivative, in the presence of a base such as potassium carbonate or
 sodium hydride, preferably sodium hydride, and a polar solvent, such as
 N,N-dimethylformamide. The reaction mixture is stirred at room temperature
 for a time period between about 60 minutes to about 48 hours, preferably
 about 16 hours.
 The compounds of formula III, wherein PG.sup.1 is benzyl, are prepared
 according to the methods of Scheme 1.
 Scheme 4 refers to the preparation of compounds of formula I, wherein
 X.dbd.CH.sub.2, Z is &gt;NR.sup.1, R.sup.1 is a group of the formula
 --(CH.sub.2).sub.2 CO.sub.2 R.sup.2 (i.e. n is 2) and R.sup.2 is (C.sub.1
 -C.sub.6)alkyl.
 Referring to Scheme 4, compounds of said formula I are prepared from
 compounds of the formula XVIII, wherein R.sup.2 is (C.sub.1
 -C.sub.6)alkyl, by reaction with oxalyl chloride or thionyl chloride,
 preferably oxalyl chloride, and a catalyst, preferably about 2% of
 N,N-dimethylformamide, in an inert solvent, such as methylene chloride, to
 form an in situ acid chloride that is subsequently reacted with
 O-trimethylsilylhydroxylamine in the presence of a base, such as pyridine,
 4-N,N-dimethylaminopyridine or triethylamine, preferably pyridine. The
 reaction is performed at a temperature of about 22.degree. C. (i.e., room
 temperature) for about 1 to about 12 hours, preferably about 1 hour.
 Compounds of the formula XVIII, wherein R.sup.2 is (C.sub.1 -C.sub.6)alkyl,
 can be prepared from compounds of the formula XIX, wherein R.sup.2 is
 (C.sub.1 -C.sub.6)alkyl, by reduction in a polar solvent. Suitable
 reducing agents include hydrogen over palladium and hydrogen over
 palladium on carbon, preferably hydrogen over palladium on carbon.
 Suitable solvents include methanol, ethanol and isopropanol, preferably
 ethanol. The aforesaid reaction is performed at a temperature of about
 22.degree. C. (i.e., room temperature) for a period of about 1 to about 7
 days, preferably about 2 days.
 Compounds of the formula XIX, wherein R.sup.2 is (C.sub.1 -C.sub.6)alkyl,
 can be prepared from compounds of the formula III, wherein PG.sup.1 is
 benzyl, by Michael addition to a propiolate ester in the presence of a
 base in a polar solvent. Suitable propiolates are of the formula
 H--C.tbd.C--CO.sub.2 R.sup.2, wherein R.sup.2 is (C.sub.1 -C.sub.6)alkyl.
 Suitable bases include tetrabutylammonium fluoride, potassium carbonate,
 and cesium carbonate, preferably tetrabutylammonium fluoride. Suitable
 solvents include tetrahydrofuran, acetonitrile, tert-butanol and
 N,N-dimethylformamide, preferably tetrahydrofuran. The aforesaid reaction
 is performed at a temperature of about -10.degree. C. to about 60.degree.
 C., preferably ranging between 0.degree. C. and about 22.degree. C. (i.e.,
 room temperature). The compounds of formula XIX are obtained as mixtures
 of geometric isomers about the olefinic double bond; separation of the
 isomers is not necessary.
 Compounds of the formula III, wherein PG.sup.1 is benzyl, can be prepared
 according to the methods of Scheme 1.
 Compounds of said formula I, wherein X is CH.sub.2, Z is &gt;NR.sup.1, R.sup.1
 is a group of the formula --(CH.sub.2).sub.n CO.sub.2 R.sup.2, n is 1 to 6
 and R.sup.2 is hydrogen are prepared from compounds of formula I, wherein
 Z is &gt;NR.sup.1, R.sup.1 is a group of the formula --(CH.sub.2).sub.n
 CO.sub.2 R.sup.2, n is 1 to 6 and R.sup.2 is (C.sub.1 -C.sub.6)alkyl, by
 saponification 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 ethanol. The reaction is conducted for a period of 30 minutes to 24
 hours, preferably about 2 hours.
 The compounds of the formula I which are basic in nature are capable of
 forming a wide variety of different salts with various inorganic and
 organic acids. Although such salts must be pharmaceutically acceptable for
 administration to animals, it is often desirable in practice to initially
 isolate a compound of the formula I from the reaction mixture as a
 pharmaceutically unacceptable salt and then simply convert the latter back
 to the free base compound by treatment with an alkaline reagent, and
 subsequently convert the free base to a pharmaceutically acceptable acid
 addition salt. The acid addition salts of the base compounds of this
 invention are readily prepared by treating the base compound with a
 substantially equivalent amount of the chosen mineral or organic acid in
 an aqueous solvent medium or in a suitable organic solvent such as
 methanol or ethanol. Upon 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 base compounds of this invention are those which
 form non-toxic acid addition salts, i.e., salts containing
 pharmacologically acceptable anions, such as hydrochloride, hydrobromide,
 hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate,
 acetate, lactate, citrate or acid citrate, tartrate or bitartrate,
 succinate, maleate, fumarate, gluconate, saccharate, benzoate,
 methanesulfonate and pamoate [i.e.,
 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
 Those compounds of the formula I which are also acidic in nature, are
 capable of forming base salts with various pharmacologically acceptable
 cations. Examples of such salts include the alkali metal or alkaline-earth
 metal salts and particularly, the sodium and potassium salts. These salts
 are all prepared by conventional techniques. The chemical bases which are
 used as reagents to prepare the pharmaceutically acceptable base salts of
 this invention are those which form non-toxic base salts with the herein
 described acidic compounds of formula I. These non-toxic base salts
 include those derived from such pharmacologically acceptable cations as
 sodium, potassium, calcium and magnesium, etc. These salts can easily be
 prepared by treating the corresponding acidic compounds with an aqueous
 solution containing the desired pharmacologically acceptable cations, and
 then evaporating the resulting solution to dryness, preferably under
 reduced pressure.
 Alternatively, they may also be prepared by mixing lower alkanolic
 solutions of the acidic compounds and the desired alkali metal alkoxide
 together, and then evaporating the resulting solution to dryness in the
 same manner as before. In either case, stoichiometric quantities of
 reagents are preferably employed in order to ensure completeness of
 reaction and maximum product yields.
 The ability of the compounds of formula I or their pharmaceutically
 acceptable salts (hereinafter also referred to as the compounds of the
 present invention) to inhibit metalloproteinases or mammalian reprolysin
 and, consequently, demonstrate their effectiveness for treating diseases
 characterized by metalloproteinase or the production of tumor necrosis
 factor is shown by the following in vitro assay tests.
 Biological Assay
 Inhibition of Human Collagenase (MMP-1)
 Human recombinant collagenase is activated with trypsin. The amount of
 trypsin is optimized for each lot of collagenase-1 but a typical reaction
 uses the following ratio: 5 .mu.g trypsin per 100 .mu.g of collagenase.
 The trypsin and collagenase are incubated at room temperature for 10
 minutes then a five fold excess (50 mg/10 mg trypsin) of soybean trypsin
 inhibitor is added.
 Stock solutions (10 mM) of inhibitors are made up in dimethylsulfoxide and
 then diluted using the following scheme:
EQU 10 mM.fwdarw.120 .mu.M.fwdarw.12 .mu.M.fwdarw.1.2 .mu.M.fwdarw.0.12 .mu.M
 Twenty-five microliters of each concentration is then added in triplicate
 to appropriate wells of a 96 well microfluor plate. The final
 concentration of inhibitor will be a 1:4 dilution after addition of enzyme
 and substrate. Positive controls (enzyme, no inhibitor) are set up in
 wells D7-D12 and negative controls (no enzyme, no inhibitors) are set in
 wells D1-D6.
 Collagenase-1 is diluted to 240 ng/ml and 25 ml is then added to
 appropriate wells of the microfluor plate. Final concentration of
 collagenase in the assay is 60 ng/ml.
 Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH.sub.2) is made as a
 5 mM stock in dimethylsulfoxide and then diluted to 20 .mu.M in assay
 buffer. The assay is initiated by the addition of 50 ml substrate per well
 of the microfluor plate to give a final concentration of 10 mM.
 Fluorescence readings (360 nM excitation, 460 nm emission) are taken at
 time 0 and then at 20 minute intervals. The assay is conducted at room
 temperature with a typical assay time of 3 hours.
 Fluorescence versus time is then plotted for both the blank and collagenase
 containing samples (data from triplicate determinations is averaged). A
 time point that provides a good signal (at least five fold over the blank)
 and that is on a linear part of the curve (usually around 120 minutes) is
 chosen to determine IC.sub.50 values. The zero time is used as a blank for
 each compound at each concentration and these values are subtracted from
 the 120 minute data. Data is plotted as inhibitor concentration versus %
 control (inhibitor fluorescence divided by fluorescence of collagenase
 alone.times.100). IC.sub.50 's are determined from the concentration of
 inhibitor that gives a signal that is 50% of the control.
 If IC.sub.50 's are reported to be less than 0.03 mM then the inhibitors
 are assayed at concentrations of 0.3 mM, 0.03 mM, and 0.003 mM.
 Inhibition of Gelatinase (MMP-2)
 Human recombinant 72 kD gelatinase (MMP-2, gelatinase A) is activated for
 16-18 hours with 1 mM p-aminophenyl-mercuric acetate (from a freshly
 prepared 100 mM stock in 0.2 N NaOH) at 4.degree. C., rocking gently.
 10 mM dimethylsulfoxide stock solutions of inhibitors are diluted serially
 in assay buffer (50 mM TRIS, pH 7.5, 200 mM NaCl, 5 mM CaCl.sub.2, 20
 .mu.M ZnCl.sub.2 and 0.02% BRIJ-35 (vol./vol.)) using the following
 scheme:
EQU 10 mM.fwdarw.120 .mu.M.fwdarw.12 .mu.M.fwdarw.1.2 .mu.M.fwdarw.0.12 .mu.M
 Further dilutions are made as necessary following this same scheme. A
 minimum of four inhibitor concentrations for each compound are performed
 in each assay. 25 .mu.L of each concentration is then added to triplicate
 wells of a black 96 well U-bottomed microfluor plate. As the final assay
 volume is 100 .mu.L, final concentrations of inhibitor are the result of a
 further 1:4 dilution (i.e. 30 .mu.M.fwdarw.3 .mu.M.fwdarw.0.3
 .mu.M.fwdarw.0.03 .mu.M, etc.). A blank (no enzyme, no inhibitor) and a
 positive enzyme control (with enzyme, no inhibitor) are also prepared in
 triplicate.
 Activated enzyme is diluted to 100 ng/mL in assay buffer, 25 .mu.L per well
 is added to appropriate wells of the microplate. Final enzyme
 concentration in the assay is 25 ng/mL (0.34 nM).
 A five mM dimethylsulfoxide stock solution of substrate
 (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH.sub.2) is diluted in assay buffer to
 20 .mu.M. The assay is initiated by addition of 50 .mu.L of diluted
 substrate yielding a final assay concentration of 10 .mu.M substrate. At
 time zero, fluorescence reading (320 excitation; 390 emission) is
 immediately taken and subsequent readings are taken every fifteen minutes
 at room temperature with a PerSeptive Biosystems CytoFluor Multi-Well
 Plate Reader with the gain at 90 units.
 The average value of fluorescence of the enzyme and blank are plotted
 versus time. An early time point on the linear part of this curve is
 chosen for IC.sub.50 determinations. The zero time point for each compound
 at each dilution is subtracted from the latter time point and the data
 then expressed as percent of enzyme control (inhibitor fluorescence
 divided by fluorescence of positive enzyme control.times.100). Data is
 plotted as inhibitor concentration versus percent of enzyme control.
 IC.sub.50 's are defined as the concentration of inhibitor that gives a
 signal that is 50% of the positive enzyme control.
 Inhibition of Stromelysin Activity (MMP-3)
 Human recombinant 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 in 0.2 N NaOH) at 37.degree. C.
 10 mM dimethylsulfoxide stock solutions of inhibitors are diluted serially
 in assay buffer (50 mM TRIS, pH 7.5, 150 mM NaCl, 10 mM CaCl.sub.2 and
 0.05% BRIJ-35 (vol./vol.)) using the following scheme:
EQU 10 mM.fwdarw.120 .mu.M.fwdarw.12 .mu.M.fwdarw.1.2 .mu.M.fwdarw.0.12 .mu.M
 Further dilutions are made as necessary following this same scheme. A
 minimum of four inhibitor concentrations for each compound are performed
 in each assay. 25 .mu.L of each concentration is then added to triplicate
 wells of a black 96 well U-bottomed microfluor plate. As the final assay
 volume is 100 .mu.L, final concentrations of inhibitor are the result of a
 further 1:4 dilution (i.e. 30 .mu.M.fwdarw.3 .mu.M.fwdarw.0.3
 .mu.M.fwdarw.0.03 .mu.M, etc.). A blank (no enzyme, no inhibitor) and a
 positive enzyme control (with enzyme, no inhibitor) are also prepared in
 triplicate.
 Activated enzyme is diluted to 200 ng/mL in assay buffer, 25 .mu.L per well
 is added to appropriate wells of the microplate. Final enzyme
 concentration in the assay is 50 ng/mL (0.875 nM).
 A ten mM dimethylsulfoxide stock solution of substrate
 (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH.sub.2) is diluted in
 assay buffer to 6 .mu.M. The assay is initiated by addition of 50 .mu.L of
 diluted substrate yielding a final assay concentration of 3 .mu.M
 substrate. At time zero, fluorescence reading (320 excitation; 390
 emission) is immediately taken and subsequent readings are taken every
 fifteen minutes at room temperature with a PerSeptive Biosystems CytoFluor
 Multi-Well Plate Reader with the gain at 90 units.
 The average value of fluorescence of the enzyme and blank are plotted
 versus time. An early time point on the linear part of this curve is
 chosen for IC.sub.50 determinations. The zero time point for each compound
 at each dilution is subtracted from the latter time point and the data
 then expressed as percent of enzyme control (inhibitor fluorescence
 divided by fluorescence of positive enzyme control.times.100). Data is
 plotted as inhibitor concentration versus percent of enzyme control.
 IC.sub.50 's are defined as the concentration of inhibitor that gives a
 signal that is 50% of the positive enzyme control.
 Inhibition of MMP-13
 Human recombinant MMP-13 is activated with 2 mM APMA (p-aminophenyl
 mercuric acetate) for 2.0 hours, at 37.degree. C. and is diluted to 240
 ng/ml in assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mM
 calcium chloride, 20 mM zinc chloride, 0.02% brij 35). Twenty-five
 microliters of diluted enzyme is added per well of a 96 well microfluor
 plate. The enzyme is then diluted in a 1:4 ratio in the assay by the
 addition of inhibitor and substrate to give a final concentration in the
 assay of 60 ng/ml.
 Stock solutions (10 mM) of inhibitors are made up in dimethylsulfoxide and
 then diluted in assay buffer as per the inhibitor dilution scheme for
 inhibition of human collagenase-1 (MMP-1): Twenty-five microliters 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 (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH.sub.2) is prepared
 as for inhibition of human collagenase (MMP-1) and 50 .mu.l is added to
 each well to give a final assay concentration of 10 .mu.M. Fluorescence
 readings (360 nM excitation; 450 nM emission) are taken at time 0 and
 every 5 minutes for 1 hour.
 Positive controls and negative controls are set up in triplicate as
 outlined in the MMP-1 assay.
 IC.sub.50 's are determined as per inhibition of human collagenase (MMP-1).
 If IC.sub.50 's are reported to be less than 0.03 mM, inhibitors are then
 assayed at final concentrations of 0.3 mM, 0.03 mmM, 0.003 mmM and 0.0003
 mM.
 Inhibition of TNF Production
 The ability of the compounds or the pharmaceutically acceptable salts
 thereof to inhibit the production of TNF and, consequently, demonstrate
 their effectiveness for treating diseases involving the production of TNF
 is shown by the following in vitro assay:
 Human mononuclear cells were isolated from anti-coagulated human blood
 using a one-step Ficoll-hypaque separation technique. (2) The mononuclear
 cells were washed three times in Hanks balanced salt solution (HBSS) with
 divalent cations and resuspended to a density of 2.times.10.sup.6 /ml in
 HBSS containing 1% BSA. Differential counts determined using the Abbott
 Cell Dyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of
 the total cells in these preparations.
 180 .mu.l of the cell suspension was aliquoted into flat bottom 96 well
 plates (Costar). Additions of compounds and LPS (100 ng/ml final
 concentration) gave a final volume of 200 .mu.l. All conditions were
 performed in triplicate. After a four hour incubation at 37.degree. C. in
 an humidified CO.sub.2 incubator, plates were removed and centrifuged (10
 minutes at approximately 250.times.g) and the supernatants removed and
 assayed for TNFa using the R&D ELISA Kit.
 Inhibition of Soluble TNF-.alpha. Production
 The ability of the compounds or the pharmaceutically acceptable salts
 thereof to inhibit the cellular release of TNF-.alpha. and, consequently,
 demonstrate their effectiveness for treating diseases involving the
 disregulation of soluble TNF-.alpha. is shown by the following in vitro
 assay:
 Human Monocyte Assay
 Human mononuclear cells are isolated from anti-coagulated human blood using
 a one-step Ficoll-hypaque separation technique. (2) The mononuclear cells
 are washed three times in Hanks balanced salt solution (HBSS) with
 divalent cations and resuspended to a density of 2.times.10.sup.6 /ml in
 HBSS containing 1% BSA. Differential counts determined using the Abbott
 Cell Dyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of
 the total cells in these preparations.
 180 m of the cell suspension was aliquoted into flat bottom 96 well plates
 (Costar). Additions of compounds and LPS (100 ng/ml final concentration)
 gave a final volume of 200 .mu.l. All conditions were performed in
 triplicate. After a four hour incubation at 37.degree. C. in an humidified
 CO.sub.2 incubator, plates were removed and centrifuged (10 minutes at
 approximately 250.times.g) and the supernatants removed and assayed for
 TNF-.alpha. using the R&D ELISA Kit.
 Aggrecanase Assay
 Primary porcine chondrocytes from articular joint cartilage are isolated by
 sequential trypsin and collagenase digestion followed by collagenase
 digestion overnight and are plated at 2.times.10.sup.5 cells per well into
 48 well plates with 5 .mu.Ci/ml .sup.35 S (1000 Ci/mmol) sulphur in type I
 collagen coated plates. Cells are allowed to incorporate label into their
 proteoglycan matrix (approximately 1 week) at 37.degree. C., under an
 atmosphere of 5% CO.sub.2.
 The night before initiating the assay, chondrocyte monolayers are washed
 two times in DMEM/1% PSF/G and then allowed to incubate in fresh DMEM/1%
 FBS overnight.
 The following morning chondrocytes are washed once in DMEM/1%PSF/G. The
 final wash is allowed to sit on the plates in the incubator while making
 dilutions.
 Media and dilutions can be made as described in the Table below.

Control Media DMEM alone (control media)
 IL-1 Media DMEM + IL-1 (5 ng/ml)
 Drug Dilutions Make all compounds stocks at 10 mM in DMSO.
 Make a 100 uM stock of each compound in DMEM in
 96 well plate.
 Store in freezer overnight.
 The next day perform serial dilutions in DMEM with
 IL-1 to 5 uM, 500 nM, and 50 nM.
 Aspirate final wash from wells and add 50 ul of
 compound from above dilutions to 450 ul of IL-1 media
 in appropriate wells of the 48 well plates.
 Final compound concentrations equal 500 nM, 50 nM,
 and 5 nM.
 All samples completed in triplicate with Control and
 IL-1 alone samples on each plate.
 Plates are labeled and only the interior 24 wells of the plate are used. On
 one of the plates, several columns are designated as IL-1 (no drug) and
 Control (no IL-1, no drug). These control columns are periodically counted
 to monitor 35S-proteoglycan release. Control and IL-1 media are added to
 wells (450 ul) followed by compound (50 ul) so as to initiate the assay.
 Plates are incubated at 37.degree. C., with a 5% CO.sub.2 atmosphere.
 At 40-50% release (when CPM from IL-1 media is 4-5 times control media) as
 assessed by liquid scintillation counting (LSC) of media samples, the
 assay is terminated (9-12 hours). Media is removed from all wells and
 placed in scintillation tubes. Scintillate is added and radioactive counts
 are acquired (LSC). To solubilize cell layers, 500 ul of papain digestion
 buffer (0.2 M Tris, pH 7.0, 5 mM EDTA, 5 mM DTT, and 1 mg/ml papain) is
 added to each well. Plates with digestion solution are incubated at
 60.degree. C. overnight. The cell layer is removed from the plates the
 next day and placed in scintillation tubes. Scintillate is then added, and
 samples counted (LSC).
 The percent of released counts from the total present in each well is
 determined. Averages of the triplicates are made with control background
 subtracted from each well. The percent of compound inhibition is based on
 IL-1 samples as 0% inhibition (100% of total counts).
 All of the compounds that were tested had IC.sub.50 of less than 30 nM in
 at least one of the above assays. Preferred compounds of the invention had
 IC.sub.50 of less than 10 nM in at least one of the above assays.
 For administration to mammals, including humans, for the inhibition of
 matrix metalloproteinases or mammalian reprolysin, a variety of
 conventional routes may be used including oral, parenteral (eg.,
 intravenous, intramuscular or subcutaneous), buccal, anal and topical. In
 general, the compounds of the invention (hereinafter also known as the
 active compounds) will be administered at dosages between about 0.1 and 25
 mg/kg body weight of the subject to be treated per day, preferably from
 about 0.3 to 5 mg/kg. Preferably the active compound will be administered
 orally or parenterally. However, some variation in dosage will necessarily
 occur depending on the condition of the subject being treated. The person
 responsible for administration will, in any event, determine the
 appropriate dose for the individual subject.
 The compounds of the present invention can be administered in a wide
 variety of different dosage forms, in general, the therapeutically
 effective compounds of this invention are present in such dosage forms at
 concentration levels ranging from about 5.0% to about 70% by weight.
 For oral administration, tablets containing various excipients such as
 microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium
 phosphate and glycine may be employed along with various disintegrants
 such as starch (and preferably corn, potato or tapioca starch), alginic
 acid and certain complex silicates, together with granulation binders like
 polyvinylpyrrolidone, sucrose, gelation and acacia. 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 may also be employed as fillers in gelatin capsules;
 preferred materials in this connection also include lactose or milk sugar
 as well as high molecular weight polyethylene glycols. When aqueous
 suspensions and/or elixirs are desired for oral administration, the active
 ingredient may be combined with various sweetening or flavoring agents,
 coloring matter or dyes, and, if so desired, emulsifying and/or suspending
 agents as well, together with such diluents as water, ethanol, propylene
 glycol, glycerin and various like combinations thereof. In the case of
 animals, they are advantageously contained in an animal feed or drinking
 water in a concentration of 5-5000 ppm, preferably 25 to 500 ppm.
 For parenteral administration (intramuscular, intraperitoneal, subcutaneous
 and intravenous use) a sterile injectable solution of the active
 ingredient is usually prepared. Solutions of a therapeutic compound of the
 present invention in either sesame or peanut oil or in aqueous propylene
 glycol may be employed. The aqueous solutions should be suitably adjusted
 and buffered, preferably at a pH of greater than 8, if necessary and the
 liquid diluent first rendered isotonic. These aqueous solutions are
 suitable intravenous injection purposes. The oily solutions are suitable
 for intraarticular, intramuscular and subcutaneous injection purposes. The
 preparation of all these solutions under sterile conditions is readily
 accomplished by standard pharmaceutical techniques well known to those
 skilled in the art. In the case of animals, 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 up
 to 3 divided doses.
 The active compounds of the invention may also be formulated in rectal
 compositions such as suppositories or retention enemas, e.g., containing
 conventional suppository bases such as cocoa butter or other glycerides.
 For intranasal administration or administration by inhalation, the active
 compounds of the invention are conveniently delivered in the form of a
 solution or suspension from a pump spray container that is squeezed or
 pumped by the patient or as an aerosol spray presentation from a
 pressurized container or a nebulizer, with the use of a suitable
 propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
 dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the
 case of a pressurized aerosol, the dosage unit may be determined by
 providing a valve to deliver a metered amount. The pressurized container
 or nebulizer may contain a solution or suspension of the active compound.
 Capsules and cartridges (made, for example, from gelatin) for use in an
 inhaler or insufflator may be formulated containing a powder mix 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 uncorrected. NMR data are reported
 in parts per million (.delta.) and are referenced to the deuterium lock
 signal from the sample solvent (deuteriochloroform unless otherwise
 specified). Commercial reagents were utilized without further
 purification. THF refers to tetrahydrofuran. DMF refers to
 N,N-dimethylformamide. Chromatography refers to column chromatography
 performed using 32-63 mm silica gel and executed under nitrogen pressure
 (flash chromatography) conditions. Room or ambient temperature refers to
 20-25.degree. C. All non-aqueous reactions were run under a nitrogen
 atmosphere for convenience and to maximize yields. Concentration at
 reduced pressure means that a rotary evaporator was used.
 EXAMPLE 1
 [3aR-(3a.beta.,5.alpha.,6a.beta.]-5-[4-(4-Fluoro-phenoxy)-benzenesulfonylam
 ino]-tetrahydro-cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide

##STR10##
 This compound was prepared according to the same procedure as Example 1,
 starting with 4-(4-chlorophenoxy)benzenesulfonyl chloride in step A. The
 requisite [1.alpha.,3.alpha.R,
 4.alpha.S]-1-[4-(4-chloro-phenoxy)-benzenesulfonyamino]-3,4-dihydroxy-cycl
 opentanecarboxylic acid ethyl ester diol isomer was obtained by
 lactonization of a diol mixture (step C) and chromatographic isolation of
 the remaining diol isomer.
 MS: m/z 453 (M-1).
 EXAMPLE 4
 [3aS-(3a.alpha.,5.alpha.,6a.alpha.]-5-[4-(4-Chloro-phenoxy)-benzenesulfonyl
 amino]-tetrahydro-cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide

##STR11##
 This compound was prepared in an analogous manner to Example 2, starting
 with 4-(4-chlorophenoxy)benzenesulfonyl chloride in step A. The requisite
 [1.alpha.,3.beta.S,4.beta.R]-1-[4-(4-chloro-phenoxy)-benzenesulfonylamino]
 -3,4-dihydroxy-cyclopentanecarboxylic acid ethyl ester diol isomer
 crystallized out in pure form in step B.
 MS: m/z 455 (M+1).
 EXAMPLE 5
 [3aR-(3a.beta.,5.alpha.,6a.beta.]-5-[4-(4-Fluoro-phenoxy)-benzenesulfonylam
 ino]-2-oxo-tetrahydro-cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide

##STR13##
 This compound was prepared in an analogous manner to Example 2, starting
 with 4-(4-benzyloxy)-benzenesulfonyl chloride in step A. The requisite
 [1.alpha.,3.alpha.S,4.alpha.R]-1-[4-(4-benzyloxy)-benzenesulfonylamino]-3,
 4-dihydroxy-cyclopentanecarboxylic acid ethyl ester diol isomer
 crystallized out in pure form in step B.
 MS: m/z 435 (M+1).
 EXAMPLE 7
 [3aS-(3a.alpha.,5.alpha.,6a.alpha.]-5-[4-(4-Fluoro-benzyloxy-benzenesulfony
 lamino]-tetrahydro-cyclopenta[1,3]dioxole-5-carboxylic acid hydroxyamide

##STR15##
 This compound was prepared in an analogous manner to Example 7, except that
 2,5-difluorobenzyl bromide was used in step B.
 MS: m/z 469 (M-1).