Heterocyclic substituted compounds having the general structure:

This invention is directed to compounds which are useful in treating diseases associated with metalloprotease activity, particularly zinc metalloprotease activity. The invention is also directed to pharmaceutical compositions comprising the compounds, and to methods of treating metalloprotease-related maladies using the compounds or the pharmaceutical compositions.
A number of structurally related metalloproteases effect the breakdown of structural proteins. These metalloproteases often act on the intercellular matrix, and thus are involved in tissue breakdown and remodeling. Such proteins are referred to as metalloproteases or MPs.
There are several different families of MPs, classified by sequence homology, disclosed in the art. These MPs include Matrix-Metallo Proteases (MMPs); zinc metalloproteases; many of the membrane bound metalloproteases; TNF converting enzymes; angiotensin-converting enzymes (ACEs); disintegrins, including ADAMs (see Wolfsberg et al, 131 J. Cell Bio. 275-78 Oct., 1995); and the enkephalinases. Examples of MPs include human skin fibroblast collagenase, human skin fibroblast gelatinase, human sputum collagenase, aggrecanse and gelatinase, and human stromelysin. Collagenases, stromelysin, aggrecanase and related enzymes are thought to be important in mediating the symptomatology of a number of diseases.
Potential therapeutic indications of MP inhibitors have been discussed in the literature. See, for example, U.S. Pat. No. 5,506,242 (Ciba Geigy Corp.) and U.S. Pat. No. 5,403,952 (Merck and Co.); the following PCT published applications: WO 96/06074 (British Bio Tech Ltd.); WO 96/00214 (Ciba Geigy), WO 95/35275 (British Bio Tech Ltd.), WO 95/35276 (British Bio Tech Ltd.), WO 95/33731 (Hoffman-LaRoche), WO 95/33709 (Hoffman-LaRoche), WO 95/32944 (British Bio Tech Ltd.), WO 95/26989 (Merck), WO 5 9529892 (DuPont Merck), WO 95/24921 (Inst. Opthamology), WO 95/23790 (SmithKline Beecham), WO 95/22966 (Sanofi Winthrop), WO 95/19965 (Glycomed), WO 95 19956 (British Bio Tech Ltd), WO 95/19957 (British Bio Tech Ltd.), WO 95/19961 (British Bio Tech Ltd.), WO 95/13289 (Chiroscience Ltd.), WO 95/12603 (Syntex), WO 95/09633 (Florida State Univ.), WO 95/09620 (Florida State Univ.), WO 95/04033 (Celitech), WO 94/25434 (Celitech), WO 94/25435 (Celltech); WO 93/14112 (Merck), WO 94/0019 (Glaxo), WO 93/21942 (British Bio Tech Ltd.), WO 92/22523 (Res. Corp. Tech Inc.), WO 94/10990 (British Bio Tech Ltd.), WO 93/09090 (Yamanouchi); British patents GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd.); published European Patent Applications EP 95/684240 (Hoffman LaRoche), EP 574758 (Hoffman LaRoche) and EP 575844 (Hoffman LaRoche); published Japanese applications JP 08053403 (Fujusowa Pharm. Co. Ltd.) and JP 7304770 (Kanebo Ltd.); and Bird et al., J. Med. Chem., vol. 37, pp. 158-69 (1994).
Examples of potential therapeutic uses of MP inhibitors include rheumatoid arthritisxe2x80x94Mullins, D. E., et al., Biochim. Biophys. Acta. (1983) 695:117-214; osteoarthritisxe2x80x94Henderson, B., et al., Drugs of the Future (1990) 15:495-508; cancerxe2x80x94Yu, A. E. et al., Matrix Metalloproteinasesxe2x80x94Novel Targets for Directed Cancer Therapy, Drugs and Aging, Vol. 11(3), p. 229-244 (September 1997), Chambers, A. F. and Matrisian, L. M., Review: Changing Views of the Role of Matrix Metalloproteinases in Metastasis, J. of the Nat""l Cancer Inst., Vol. 89(17), p. 1260-1270 (September 1997), Bramhall, S. R., The Matrix Metalloproteinases and Their Inhibitors in Pancreatic Cancer, Internat""l J. of Pancreatology, Vol. 4, p. 1101-1109 (May 1998), Nemunaitis, J. et al., Combined Analysis of Studies of the Effects of the Matrix Metalloproteinase Inhibitor Marimastat on Serum Tumor Markers in Advanced Cancer: Selection of a Biologically Active and Tolerable Dose for Longer-term Studies, Clin. Cancer Res., Vol 4, p. 1101-1109 (May 1998), and Rasmussen, H. S. and McCann, P. P, Matrix Metalloproteinase Inhibition as a Novel Anticancer Strategy: A Review with Special Focus on Batimastat and Marimastat, Pharmacol. Ther., Vol 75(1), p. 69-75 (1997); the metastasis of tumor cellsxe2x80x94ibid, Broadhurst, M. J., et al., European Patent Application 276,436 (published 1987), Reich, R., et al., Cancer Res., Vol. 48, p. 3307-3312 (1988); multiple sclerosisxe2x80x94Gijbels et al., J. Clin. Invest., vol. 94, p. 2177-2182 (1994); and various ulcerations or ulcerative conditions of tissue. For example, ulcerative conditions can result in the cornea as the result of alkali burns or as a result of infection by Pseudomonas aeruginosa, Acanthamoeba, Herpes simplex and vaccinia viruses. Other examples of conditions characterized by undesired metalloprotease activity include periodontal disease, epidermolysis bullosa, fever, inflammation and scleritis (e.g., DeCicco et al., PCT published application WO 95/29892, published Nov. 9, 1995).
In view of the involvement of such metalloproteases in a number of disease conditions, attempts have been made to prepare inhibitors to these enzymes. A number of such inhibitors are disclosed in the literature. Examples include U.S. Pat. No. 5,183,900, issued Feb. 2, 1993 to Galardy; U.S. Pat. No. 4,996,358, issued Feb. 26, 1991 to Handa et al.; U.S. Pat. No. 4,771,038, issued Sep. 13, 1988 to Wolanin et al.; U.S. Pat. No. 4,743,587, issued May 10, 1988 to Dickens et al., European Patent Publication No. 575,844, published Dec. 29, 1993 by Broadhurst et al.; International Patent Publication No. WO 93/09090, published May 13, 1993 by Isomura et al.; World Patent Publication 92/17460, published Oct. 15, 1992 by Markwell et al.; and European Patent Publication No. 498,665, published Aug. 12, 1992 by Beckett et al.
It would be advantageous to inhibit these metalloproteases in treating diseases related to unwanted metalloprotease activity. Though a variety of MP inhibitors have been prepared, there is a continuing need for potent matrix metalloprotease inhibitors useful in treating diseases associated with metalloprotease activity.
The invention provides compounds which are potent inhibitors of metalloproteases and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention relates to compounds having a structure according to the following Formula (I):
where J, M, Q, T, W, X, Z, R1, R2, R3, R4, R4xe2x80x2, R5, R6, R6xe2x80x2, R7, m, and n have the meanings described in the Detailed Description section below. This invention also includes optical isomers, diastereomers and enantiomers of the formula above, and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof.
The compounds of the present invention are useful for the treatment of diseases and conditions which are characterized by unwanted metalloprotease activity. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for metalloprotease-related maladies.
I. Terms and Definitions
The following is a list of definitions for terms used herein:
The following is a list of definitions for terms used herein.
xe2x80x9cAcylxe2x80x9d or xe2x80x9ccarbonylxe2x80x9d is a radical formed by removal of the hydroxy from a carboxylic acid (i.e., Rxe2x80x94C(xe2x95x90O)xe2x80x94). Preferred acyl groups include (for example) acetyl, formyl, and propionyl.
xe2x80x9cAlkylxe2x80x9d is a saturated hydrocarbon chain having 1 to 15 carbon atoms, preferably 1 to 10, more preferably 1 to 4 carbon atoms. xe2x80x9cAlkenexe2x80x9d is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and having 2 to 15 carbon 3 atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms. xe2x80x9cAlkenexe2x80x9d is a hydrocarbon chain having at least one (preferably only one) carbon-carbon triple bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms. Alkyl, alkene and alkyne chains (referred to collectively as xe2x80x9chydrocarbon chainsxe2x80x9d) may be straight or branched and may be unsubstituted or substituted. Preferred branched alkyl, alkene and alkyne chains have one or two branches, preferably one branch. Preferred chains are alkyl. Alkyl, alkene and alkyne hydrocarbon chains each may be unsubstituted or substituted with from 1 to 4 substituents; when substituted, preferred chains are mono-, di-, or tri-substituted. Alkyl, alkene and alkyne hydrocarbon chains each may be substituted with halo, hydroxy, aryloxy (e.g., phenoxy), heteroaryloxy, acyloxy (e.g., acetoxy), carboxy, aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioketo, cyano, or any combination thereof. Preferred hydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl, and exomethylenyl.
Also, as referred to herein, a xe2x80x9clowerxe2x80x9d alkyl, alkene or alkyne moiety (e.g., xe2x80x9clower alkylxe2x80x9d) is a chain comprised of 1 to 6, preferably from 1 to 4, carbon atoms in the case of alkyl and 2 to 6, preferably 2 to 4, carbon atoms in the case of alkene and alkyne.
xe2x80x9cAlkoxyxe2x80x9d is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., xe2x80x94O-alkyl or xe2x80x94O-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.
xe2x80x9cArylxe2x80x9d is an aromatic hydrocarbon ring. Aryl rings are monocyclic or fused bicyclic ring systems. Monocyclic aryl rings contain 6 carbon atoms in the ring. Monocyclic aryl rings are also referred to as phenyl rings. Bicyclic aryl rings contain from 8 to 17 carbon atoms, preferably 9 to 12 carbon atoms, in the ring. Bicyclic aryl rings include ring systems wherein one ring is aryl and the other ring is aryl, cycloalkyl, or heterocycloakyl. Preferred bicyclic aryl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Aryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Aryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamyl, haloalkyl, methylenedioxy, heteroaryloxy, or any combination thereof. Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl. The most preferred aryl ring radical is phenyl.
xe2x80x9cAryloxyxe2x80x9d is an oxygen radical having an aryl substituent (i.e., xe2x80x94O-aryl). Preferred aryloxy groups include (for example) phenoxy, napthyloxy, methoxyphenoxy, and methylenedioxyphenoxy.
xe2x80x9cCycloalkylxe2x80x9d is a saturated or unsaturated hydrocarbon ring. Cycloalkyl rings are not aromatic. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 9 carbon atoms, preferably from 3 to 7 carbon atoms, in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings comprise 4-, 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Cycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred typically are chloro and fluoro, especially fluoro.
xe2x80x9cHaloalkylxe2x80x9d is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred are C1-C12 haloalkyls; more preferred are C1-C6 haloalkyls; still more preferred still are C1-C3 haloalkyls. Preferred halo substituents are fluoro and chloro. The most preferred haloalkyl is trifluoromethyl.
xe2x80x9cHeteroatomxe2x80x9d is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
xe2x80x9cHeteroalkylxe2x80x9d is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more to preferably 2 to 5. For example, alkoxy (i.e., xe2x80x94O-alkyl or xe2x80x94O-heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or tri-substituted. Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amido, keto, thioketo, cyano, or any combination thereof.
xe2x80x9cHeteroarylxe2x80x9d is an aromatic ring containing carbon atoms and from 1 to about 6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings contain from about 5 to about 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms, in the ring. Bicyclic heteroaryl rings contain from 8 to 17 member atoms, preferably 8 to 12 member atoms, in the ring. Bicyclic heteroaryl rings include ring systems wherein one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. Preferred bicyclic heteroaryl ring systems comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Heteroaryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Heteroaryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy, or any combination thereof. Preferred heteroaryl rings include, but are not limited to, the following:
xe2x80x9cHeteroaryloxyxe2x80x9d is an oxygen radical having a heteroaryl substituent (i.e., xe2x80x94O-heteroaryl). Preferred heteroaryloxy groups include (for example) pyridyloxy, furanyloxy, (thiophene)oxy, (oxazole)oxy, (thiazole)oxy, (isoxazole)oxy, pyrmidinyloxy, pyrazinyloxy, and benzothiazolyloxy.
xe2x80x9cHeterocycloalkylxe2x80x9d is a saturated or unsaturated ring containing carbon atoms and from 1 to about 4 (preferably 1 to 3) heteroatoms in the ring. Heterocycloalkyl rings are not aromatic. Heterocycloalkyl rings are monocyclic, or are fused, bridged, or spiro bicyclic ring systems. Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (carbon and heteroatoms), preferably from 5 to 7 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from about 7 to about 17 ring atoms, preferably from 7 to 12 ring atoms. Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems. Preferred bicyclic heterocycloalkyl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Heterocycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Heterocycloalkyl may be substituted with halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy or any combination thereof. Preferred substituents on heterocycloalkyl include halo and haloalkyl. Preferred heterocycloalkyl rings include, but are not limited to, the following:
As used herein, xe2x80x9cmammalian metalloproteasexe2x80x9d refers to the proteases disclosed in the xe2x80x9cBackgroundxe2x80x9d section of this application. The compounds of the present invention are preferably active against xe2x80x9cmammalian metalloproteasesxe2x80x9d, including any metal-containing (preferably zinc-containing) enzyme found in animal, preferably mammalian, sources capable of catalyzing the breakdown of collagen, gelatin or proteoglycan under suitable assay conditions. Appropriate assay conditions can be found, for example, in U.S. Pat. No. 4,743,587, which references the procedure of Cawston, et al., Anal. Biochem. (1979) 99:340-345; use of a synthetic substrate is described by Weingarten, H., et al., Biochem. Biophy. Res. Comm. (1984) 139:1184-1187. See also Knight, C. G. et al., xe2x80x9cA Novel Coumarin-Labelled Peptide for Sensitive Continuous Assays of the Matrix Metalloproteasesxe2x80x9d, FEBS Letters, Vol. 296, pp. 263-266 (1992). Any standard method for analyzing the breakdown of these structural proteins can, of course, be used. The present compounds are more preferably active against metalloprotease enzymes that are zinc-containing proteases which are similar in structure to, for example, human stromelysin or skin fibroblast collagenase. The ability of candidate compounds to inhibit metalloprotease activity can, of course, be tested in the assays described above. Isolated metalloprotease enzymes can be used to confirm the inhibiting activity of the invention compounds, or crude extracts which contain the range of enzymes capable of tissue breakdown can be used.
xe2x80x9cSpirocyclexe2x80x9d is an alkyl or heteroalkyl diradical substituent of alkyl or heteroalkyl wherein said diradical substituent is attached geminally and wherein said diradical substituent forms a ring, said ring containing 4 to 8 member atoms (carbon or heteroatom), preferably 5 or 6 member atoms.
While alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups may be substituted with hydroxy, amino, and amido groups as stated above, the following are not envisioned in the invention:
1. Enols (OH attached to a carbon bearing a double bond).
2. Amino groups attached to a carbon bearing a double bond (except for vinylogous amides).
3. More than one hydroxy, amino, or amido attached to a single carbon (except where two nitrogen atoms are attached to a single carbon atom and all three atoms are member atoms within a heterocycloalkyl ring).
4. Hydroxy, amino, or amido attached to a carbon that also has a heteroatom attached to it.
5. Hydroxy, amino, or amido attached to a carbon that also has a halogen attached to it.
A xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d is a cationic salt formed at any acidic (e.g., hydroxamic or carboxylic acid) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published Sep. 11, 1987 incorporated by reference herein. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like.
Such salts are well understood by the skilled artisan, and the skilled artisan is able to prepare any number of salts given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt over another for reasons of solubility, stability, formulation ease and the like. Determination and optimization of such salts is within the purview of the skilled artisan""s practice.
A xe2x80x9cbiohydrolyzable amidexe2x80x9d is an amide of a hydroxamic acid-containing (i.e., R1 in Formula (1) is xe2x80x94NHOH) metalloprotease inhibitor that does not interfere with the inhibitory activity of the compound, or that is readily converted in vivo by an animal, preferably a mammal, more preferably a human subject, to yield an active metalloprotease inhibitor. Examples of such amide derivatives are alkoxyamides, where the hydroxyl hydrogen of the hydroxamic acid of Formula (1) is replaced by an alkyl moiety, and acyloxyamides, where the hydroxyl hydrogen is replaced by an acyl moiety (i.e., Rxe2x80x94C(xe2x95x90O)xe2x80x94).
A xe2x80x9cbiohydrolyzable hydroxy imidexe2x80x9d is an imide of a hydroxamic acid-containing metalloprotease inhibitor that does not interfere with the metalloprotease inhibitory activity of these compounds, or that is readily converted in vivo by an animal, preferably a mammal, more preferably a human subject to yield an active metalloprotease inhibitor. Examples of such imide derivatives are those where the amino hydrogen of the hydroxamic acid of Formula (1) is replaced by an acyl moiety (i.e., Rxe2x80x94C (xe2x95x90O)xe2x80x94).
A xe2x80x9cbiohydrolyzable esterxe2x80x9d is an ester of a carboxylic acid-containing (i.e., R1 in Formula (I) is xe2x80x94OH) metalloprotease inhibitor that does not interfere with the metalloprotease inhibitory activity of these compounds or that is readily converted by an animal to yield an active metalloprotease inhibitor. Such esters include lower alkyl esters, lower acyloxy-alkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methylcarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and alkyl acylamino alkyl esters (such as acetamidomethyl esters).
A xe2x80x9csolvatexe2x80x9d is a complex formed by the combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See J. Honig et al., The Van Nostrand Chemist""s Dictionary, p. 650 (1953). Pharmaceutically-acceptable solvents used according to this invention include those that do not interfere with the biological activity of the metalloprotease inhibitor (e.g., water, ethanol, acetic acid, N,N-dimethylformamide and others known or readily determined by the skilled artisan).
The terms xe2x80x9coptical isomerxe2x80x9d, xe2x80x9cstereoisomerxe2x80x9d, and xe2x80x9cdiastereomerxe2x80x9d have the standard art recognized meanings (see, e.g., Hawley""s Condensed Chemical Dictionary, 11th Ed.). The illustration of specific protected forms and other derivatives of the compounds of the instant invention is not intended to be limiting. The application of other useful protecting groups, salt forms, etc. is within the ability of the skilled artisan.
II. Compounds
The subject invention involves compounds having a structure according to Formula (I)
wherein
(A) X is selected from xe2x80x94OH and xe2x80x94NHOH; or when J is xe2x80x94Dxe2x80x94(CR14R14xe2x80x2), R15 where is D is xe2x80x94Oxe2x80x94, as defined below, X can optionally be a covalent bond which joins with J to form a 5 to 9 membered ring; (preferably X is xe2x80x94OH)
(B) W is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R32)xe2x80x94, xe2x80x94C(R32)xe2x95x90C(R32xe2x80x2)xe2x80x94, xe2x80x94Nxe2x95x90C(R32)xe2x80x94, and xe2x80x94Nxe2x95x90Nxe2x80x94 (preferably xe2x80x94Sxe2x80x94 or xe2x80x94C(R32)xe2x95x90C(R32xe2x80x2)xe2x80x94), where R32 and R32xe2x80x2 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (preferably hydrogen);
(C) R1 is selected from hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and halogen (preferably hydrogen or alkyl, more preferably hydrogen);
(D) R2 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl (preferably hydrogen or alkyl, more preferably hydrogen);
(E) T is xe2x80x94(CR8R8xe2x80x2)pxe2x80x94Axe2x80x94(CR8xe2x80x3R8xe2x80x2xe2x80x3)qR9 where
(1) p is from 0 to about 4 (preferably 0 or 1);
(2) q is from 0 to about 4 (preferably 0 or 1);
(3) each R8, R8xe2x80x2, R8xe2x80x3, and R8xe2x80x2xe2x80x3 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl (preferably hydrogen);
(4) R9 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and halogen (preferably hydrogen, lower alkyl or aryl); and
(5) A is selected from a covalent bond; xe2x80x94Oxe2x80x94; xe2x80x94SOrxe2x80x94, where r is 0, 1 or 2 (preferably 0 or 2); and xe2x80x94NR10xe2x80x94 where R10 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (preferably lower alkyl), or R10 can join with R9 to form a ring with 5 to 8 members (preferably 5 or 6) and 1 to 3 heteroatoms (preferably 1or 2); provided that when p is 0, A is a covalent bond;
(F) R3 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl (preferably hydrogen or lower alkyl);
(G) each R4 and R4xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy (preferably hydrogen); and n is from 0 to about 4 (preferably 0 or 1, more preferably 0);
(H) R5 is xe2x80x94(CR11R11xe2x80x2)sR12 where
(1) s is from 0 to about 4 (preferably 0 or 1);
(2) each R11 and R11xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl (preferably hydrogen); and
(3) R12 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halogen, and GR13 where G is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and Rxe2x80x94is selected from hydrogen, alkyl, and aryl;
(I) J is xe2x80x94Dxe2x80x94(CR14R14xe2x80x2)tR15 where
(1) t is from 0 to about 4 (preferably 0 or 1);
(2) D is selected from xe2x80x94Oxe2x80x94; xe2x80x94SOuxe2x80x94 where u is from 0 to 2 (preferably 0 or 2); and xe2x80x94NR16xe2x80x94 where R16 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (preferably lower alkyl), or R16 can join with R15 to form a ring with 5 to 8 members (preferably 5 or 6) and 1 to 3 heteroatoms (preferably 1 or 2);
(3) each R14 and R14xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl (preferably hydrogen); and
(4) R15 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl (preferably hydrogen, lower alkyl, aryl, and heteroaryl); or R15 can join with R13 to form an optionally substituted ring with 5 to 9 members of from 2 to 3 are heteroatoms;
(J) each R6 and R6xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy (preferably hydrogen); and m is from 0 to about 4 (preferably 0 or 1, more preferably 0);
(K) R7 is xe2x80x94(CR17R17xe2x80x2)vR18 where
(1) v is from 0 to about 4 (preferably 0 or 1 );
(2) R17 and R17xe2x80x2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl (preferably hydrogen); and
(3) R18 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and halogen (preferably hydrogen or lower alkyl);
(L) M is xe2x80x94Exe2x80x94(CR19R19xe2x80x2)wR20 where
(1) w is from 0 to about 4 (preferably 0 or 1);
(2) E is selected from a xe2x80x94Oxe2x80x94; xe2x80x94SOxxe2x80x94 where x is from 0 to 2 (preferably 0 or 2); and xe2x80x94NR21xe2x80x94 where R21 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (preferably lower alkyl), or R21 can join with R20 to form a ring with 5 to 8 members (preferably 5 or 6) and 1 to 3 heteroatoms (preferably 1 or 2);
(3) each R19 and R19xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl (preferably hydrogen); and
(4) R20 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl (preferably lower alkyl, aryl or heteroaryl);
(M) Q is xe2x80x94Gxe2x80x2xe2x80x94(CR22R22xe2x80x2)yR23 where
(1) y is from 0 to about 4 (preferably 0 or 1)
(2) Gxe2x80x2 is selected from a covalent bond; xe2x80x94Oxe2x80x94; xe2x80x94SOzxe2x80x94 where z is from 0 to 2 (preferably 0 or 2); and xe2x80x94NR24xe2x80x94 where R24 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (preferably lower alkyl), or R24 can join with R22 to form a ring with 5 to 8 members (preferably 5 or 6) and 1 to 3 heteroatoms (preferably 1 or 2);
(3) each R22 and R22xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl (preferably hydrogen); and
(4) R23 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl (preferably hydrogen, lower alkyl, aryl or heteroaryl), or R23 can join with R20 to form a ring having from 5 to 8 members (preferably 5 or 6) with 1 to 3 heteroatoms (preferably 1 or 2); and
(N) Z is selected from
(1) cycloalkyl and heterocycloalkyl;
(2) xe2x80x94Dxe2x80x2xe2x80x94(CR25R25xe2x80x2)aR26 where
(a) a is from 0 to about 4 (preferably 0 or 1);
(b) when a is from 0 to about 4 then Dxe2x80x2 is selected from xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94, and when a is from 1 to about 4, then D is selected from xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94and xe2x80x94SO2xe2x80x94 (preferably xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94);
(c) each R25 and R25xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy (preferably hydrogen or lower alkyl); and
(d) R26 is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl (preferably aryl, heteroaryl, heterocycloalkyl or cycloalkyl); and, if Dxe2x80x2 is xe2x80x94Cxe2x89xa1Cxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94, then R26 may also be selected from xe2x80x94CONR27R27xe2x80x2 where (i) R27 and R27xe2x80x2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R27 and R27xe2x80x2, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) ring atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms;
(3) xe2x80x94NR28R28xe2x80x2 where
(a) R28 and R28xe2x80x2 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl (preferably hydrogen, alkyl or aryl) and xe2x80x94C(O)xe2x80x94Qxe2x80x2xe2x80x94(CR29R29xe2x80x2)bR30 where
(i) b is from 0 to about 4 (preferably 0 or 1);
(ii) Qxe2x80x2 is selected from a covalent bond and xe2x80x94NR31xe2x80x94 (preferably a covalent bond); and
(iii)each R29 and R29xe2x80x2 is independently selected from hydrogen, alkyl alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy (preferably hydrogen or lower alkyl, R30 and R31 (i) each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R30 and R31, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) ring atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms (preferably R30 is alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl); or R28 and R31, together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 2 to 3 are heteroatoms; or
(b) R28 and R28xe2x80x2, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) ring atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms; and
(4) where
(a) Exe2x80x2 and Y are independently selected from xe2x80x94CHxe2x80x94 and xe2x80x94Nxe2x80x94;
(b) L is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R35)xe2x80x94, xe2x80x94C(R35)xe2x95x90C(R35xe2x80x2)xe2x80x94, xe2x80x94Nxe2x95x90C(R35)xe2x80x94, and xe2x80x94Nxe2x95x90Nxe2x80x94 [preferably xe2x80x94Nxe2x95x90C(R35)xe2x80x94or xe2x80x94C(R35)xe2x95x90C(R35xe2x80x2)xe2x80x94], where R35 and R35xe2x80x2 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (preferably hydrogen or lower alkyl);
(c) c is from 0 to about 4 (preferably 0 or 1);
(d) each R33 and R33xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy (preferably hydrogen or lower alkyl);
(e) Axe2x80x2 is selected from a covalent bond, xe2x80x94Oxe2x80x94, xe2x80x94SOdxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR36xe2x80x94, xe2x80x94NR36xe2x80x94, and xe2x80x94NR36C(O)xe2x80x94 [preferably xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, SO2xe2x80x94, xe2x80x94C(O)NR36xe2x80x94, xe2x80x94NR36xe2x80x94, and xe2x80x94NR36C(O)xe2x80x94; more preferably xe2x80x94Oxe2x80x94]; where d is from 0 to 2 and R36 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, haloalkyl (preferably lower alkyl or aryl); and
(f) Txe2x80x2 is xe2x80x94(CR37R37xe2x80x2)exe2x80x94R38 where e is from 0 to about 4 (preferably 0or 1); each R37 and R37xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy (preferably hydrogen or lower alkyl); and R38 is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (preferably lower alkyl or aryl); or R36 and R38, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) atoms of which 1 to 3 (preferably 1 or 2) are heteroatoms; or R35 and R38, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) atoms of which 1 to 3 (preferably 1 or 2) are heteroatoms;
or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.
III. Compound Preparation
The compounds of the invention can be prepared using a variety of procedures.
The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. Particularly preferred syntheses are described in the following general reaction schemes. (The R groups used to illustrate the reaction schemes do not necessarily correlate to the respective R groups used to describe the various aspects of the Formula I compounds. That is, for example, R1 in Formula (I) does not represent the same moiety as R1 here.) Specific examples for making the compounds of the present invention are set forth in Section VIII, below.
In Scheme 1, the acetate S1a depicted as starting material can be prepared from commercially available sources and converted to the corresponding allyl derivative such as S1b as described in Tetrahedron Lett. 1994, 35 (22), 3669.
Further functionalization of the alkene can be accomplished using methods well known to the skilled artisan. Such a process can be used to access a wide range of functionalities including but not limited to the epoxide S1d depicted in Scheme 1. Some form of nucleophilic addition to the epoxide ring can then occur, using well known methodology to produce the lactone S1e.
If desired, the ester functionality in compounds of type S1e can be transesterified, saponified to an acid or treated with basic hydroxyl amine to give the hydroxamic acid.
In Scheme 2, the allyl glycine S2a is converted to the aldehyde S2d using known methodology (Kurokawa et al, Tetrahedron, 1993, 49, 6195.). The aldehyde can then be transformed using known protecting group methods to the corresponding acetal, animal, or thioacetal S2e. The amine protecting group can then be removed and the sulfonamide group can be added. The lactone can then be transformed to the desired carboxylic acid S2g.
Nucleophilic additions of the anion generated from amino acid condensate S3a to various electrophiles are a well known method for generating amino acids of type S3c in an asymmetric way (Myers et al, J. Am. Chem. Soc. 1997, 119, 656.). These can then be functionalized according to known methods and carried forward as described above to generate a variety of compounds which fall within the scope of this invention.
The oxazolidinone S4a can be transformed to the aluminum enolate which can then react with the corresponding epoxide S4b to produce the alcohol S4c using known methodology (Smith et al, J. Am. Chem. Soc. 1995, 117, 11113.). The alcohol S4c can then be further elaborated to amino acid S4d using well described techniques. Final elaboration of the compound to produce S4e can occur in a manner analogous to that described above in Scheme 1.
A variety of compounds can be generated in a similar fashion, using the guidance of the schemes above.
It is recognized that it is preferable to use a protecting group for any reactive functionality such as a carboxyl, hydroxyl and the like, during the formation of the sultamester. This is standard practice, well within the normal practice of the skilled artisan.
In the above scheme, where R is alkoxy or alkylthio, the corresponding hydroxy or thiol compounds are derived from the final compounds by using a standard dealkylating procedure (Bhatt, et al., xe2x80x9cCleavage of Ethersxe2x80x9d, Synthesis, 1983, pp. 249-281).
These steps may be varied to increase yield of desired product. The skilled artisan will recognize the judicious choice of reactants, solvents, and temperatures is an important component in any successful synthesis. Determination of optimal conditions, etc. is routine. Thus the skilled artisan can make a variety of compounds using the guidance of the schemes above.
It is recognized that the skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction; that is, it is well within the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations of hydroxyls and the like, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. Examples of these manipulations are discussed in standard texts such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) and other art that the skilled artisan is aware of.
The skilled artisan will also readily appreciate that certain reactions are best carried out when another potentially reactive functionality on the molecule is masked or protected, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene, Protecting Groups in Organic Synthesis. Of course, amino acids used as starting materials with reactive side chains are preferably blocked to prevent undesired side reactions.
The compounds of the invention may have one or more chiral centers. As a result, one may selectively prepare one optical isomer, including diastereomer and enantiomer, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers may be separated using known methods, such as chiral salts, chiral chromatography and the like.
In addition, it is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantionmers, or stereoisomers substantially free of the other are disclosed and claimed as well.
IV. Methods of Use
Metalloproteases (MPs) found in the body operate, in part, by breaking down the extracellular matrix, which comprises extracellular proteins and glycoproteins. Inhibitors of metalloproteases are useful in treating diseases caused, at least in part, by the breakdown of such proteins and glycoproteins. These proteins and glycoproteins play an important role in maintaining the size, shape, structure and stability of tissue in the body. Thus, MPs are intimately involved in tissue remodeling.
As a result of this activity, MPs have been said to be active in many disorders involving either the: (1) breakdown of tissues including opthalmic diseases; degenerative diseases, such as arthritis, multiple sclerosis and the like; and metastasis or mobility of tissues in the body; or (2) remodeling of tissues including cardiac disease, fibrotic disease, scarring, benign hyperplasia, and the like.
The compounds of the present invention prevent or treat disorders, diseases and/or unwanted conditions which are characterized by unwanted or elevated activity by MPs. For example, the compounds can be used to inhibit MPs which:
1. destroy structural proteins (i.e. the proteins that maintain tissue stability and structure);
2. interfere in inter/intracellular signaling, including those implicated in cytokine up-regulation, and/or cytokine processing and/or inflammation, tissue degradation and other maladies [Mohler K M, et al, Nature 370 (1994) 218-220, Gearing A J H, et al, Nature 370 (1994) 555-557 McGeehan G M, et al, Nature 370 (1994) 558-561]; and
3. facilitate processes which are undesired in the subject being treated, for example, the processes of sperm maturation, egg fertilization and the like.
As used herein, an xe2x80x9cMP related disorderxe2x80x9d or xe2x80x9cMP related diseasexe2x80x9d is one that involves unwanted or elevated MP activity in the biological manifestation of the disease or disorder; in the biological cascade leading to the disorder; or as a symptom of the disorder. This xe2x80x9cinvolvementxe2x80x9d of the MP includes:
1. The unwanted or elevated MP activity as a xe2x80x9ccausexe2x80x9d of the disorder or biological manifestation, whether the activity is elevated genetically, by infection, by autoimmunity, trauma, biomechanical causes, lifestyle [e.g. obesity] or by some other cause;
2. The MP as part of the observable manifestation of the disease or disorder. That is, the disease or disorder is measurable in terms of the increased MP activity. From a clinical standpoint, unwanted or elevated MP levels indicate the disease, however, MPs need not be the xe2x80x9challmarkxe2x80x9d of the disease or disorder; or
3. The unwanted or elevated MP activity is part of the biochemical or cellular cascade that results or relates to the disease or disorder. In this respect, inhibition of the MP activity interrupts the cascade, and thus controls the disease.
The term xe2x80x9ctreatmentxe2x80x9d is used herein to mean that, at a minimum, administration of a compound of the present invention mitigates a disease associated with unwanted or elevated MP activity in a mammalian subject, preferably in humans. Thus, the term xe2x80x9ctreatmentxe2x80x9d includes: preventing an MP-mediated disease from occurring in a mammal, particularly when the mammal is predisposed to acquiring the disease, but has not yet been diagnosed with the disease; inhibiting the MP-mediated disease; and/or alleviating or reversing the MP-mediated disease. Insofar as the methods of the present invention are directed to preventing disease states associated with unwanted MP activity, it is understood that the term xe2x80x9cpreventxe2x80x9d does not require that the disease state be completely thwarted. (See Webster""s Ninth Collegiate Dictionary.) Rather, as used herein, the term preventing refers to the ability of the skilled artisan to identify a population that is susceptible to MP-related disorders, such that administration of the compounds of the present invention may occur prior to onset of the disease. The term does not imply that the disease state be completely avoided. For example, osteoarthritis (OA) is the most common rhueumatological disease with some joint changes radiologically detectable in 80% of people over 55 years of age. Fife, R. S., xe2x80x9cA Short History of Osteoarthritisxe2x80x9d, Osteoarthritis: Diagnosis and Medical/Surgical Management, R. W. Moskowitz, D. S. Howell, V. M. Goldberg and H. J. Mankin Eds., p 11-14 (1992). A common risk factor that increases the incidence of OA is traumatic injury of the joint. Surgical removal of the meniscus following knee injury increases the risk of radiographically detectable OA and this risk increases with time. Roos, H et al. xe2x80x9cKnee Osteoarthritis After Menisectomy: Prevalence of Radiographic Changes After Twenty-one Years, Compared with Matched Controls.xe2x80x9d Arthritis Rheum., Vol. 41, pp 687-693; Roos, H et al. xe2x80x9cOsteoarthritis of the Knee After Injury to the Anterior Cruciate Ligament or Meniscus: The Influence of Time and Age.xe2x80x9d Osteoarthritis Cartilege., Vol. 3, pp 261-267 (1995). Thus, this patient population is identifiable and could receive administration of a compound of the present invention before progression ef the disease. Thus, progression of OA in such individuals would be xe2x80x9cpreventedxe2x80x9d.
Advantageously, many MPs are not distributed evenly throughout the body. Thus, the distribution of MPs expressed in various tissues are often specific to those tissues. For example, the distribution of metalloproteases implicated in the breakdown of tissues in the joints is not the same as the distribution of metalloproteases found in other tissues. Though not essential for activity or efficacy, certain diseases, disorders, and unwanted conditions preferably are treated with compounds that act on specific MPs found in the affected tissues or regions of the body. For example, a compound which displays a higher degree of affinity and inhibition for an MP found in the joints (e.g. chondrocytes) would be preferred for treatment of a disease, disorder, or unwanted condition found there than other compounds which are less specific.
In addition, certain inhibitors are more bioavailable to certain tissues than others. Choosing an MP inhibitor which is more bioavailable to a certain tissue and which acts on the specific MPs found in that tissue, provides for specific treatment of the disease, disorder, or unwanted condition. For example, compounds of this invention vary in their ability to penetrate into the central nervous system. Thus, compounds may be selected to produce effects mediated through MPs found specifically outside the central nervous system.
Determination of the specificity of an inhibitor of a specific MP is within the skill of the artisan in that field. Appropriate assay conditions can be found in the literature. Specifically, assays are known for stromelysin and collagenase. For example, U.S. Pat. No. 4,743,587 references the procedure of Cawston, et al., Anal Biochem (1979) 99:340-345. See also, Knight, C. G. et al., xe2x80x9cA Novel Coumarin-Labelled Peptide for Sensitive Continuous Assays of the Matrix Metalloproteasesxe2x80x9d, FEBS Letters, Vol. 296, pp. 263-266 (1992). The use of a synthetic substrate in an assay is described by Weingarten, H., et al., Biochem Biophy Res Comm (1984) 139:1184-1187. Any standard method for analyzing the breakdown of structural proteins by MPs can, of course, be used. The ability of compounds of the invention to inhibit metalloprotease activity can, of course, be tested in the assays found in the literature, or variations thereof. Isolated metalloprotease enzymes can be used to confirm the inhibiting activity of the invention compounds, or crude extracts which contain the range of enzymes capable of tissue breakdown can be used.
The compounds of this invention are also useful for prophylactic or acute treatment. They are administered in any way the skilled artisan in the fields of medicine or pharmacology would desire. It is immediately apparent to the skilled artisan that preferred routes of administration will depend upon the disease state being treated and the dosage form chosen. Preferred routes for systemic administration include administration perorally or parenterally.
However, the skilled artisan will readily appreciate the advantage of administering the MP inhibitor directly to the affected area for many diseases, disorders, or unwanted conditions. For example, it may be advantageous to administer MP inhibitors directly to the area of the disease, disorder, or unwanted condition such as in the area affected by surgical trauma (e. g., angioplasty), scarring, burning (e.g., topical to the skin), or for opthalmic and periodontal indications.
Because the remodeling of bone involves MPs, the compounds of the invention are useful in preventing prosthesis loosening. It is known in the art that over time prostheses loosen, become painful, and may result in further bone injury, thus demanding replacement. The need for replacement of such prostheses includes those such as in, joint replacements (for example hip, knee and shoulder replacements), dental prosthesis, including dentures, bridges and prosthesis secured to the maxilla and/or mandible.
MPs are also active in remodeling of the cardiovascular system (for example, in congestive heart failure). It has been suggested that one of the reasons angioplasty has a higher than expected long term failure rate (reclosure over time) is that MP activity is not desired or is elevated in response to what may be recognized by the body as xe2x80x9cinjuryxe2x80x9d to the basement membrane of the vessel. Thus regulation of MP activity in indications such as dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis and aortic aneurysm may increase long term success of any other treatment, or may be a treatment in itself.
In skin care, MPs are implicated in the remodeling or xe2x80x9cturnoverxe2x80x9d of skin. As a result, the regulation of MPs improves treatment of skin conditions including but not limited to, wrinkle repair, regulation and prevention and repair of ultraviolet induced skin damage. Such a treatment includes prophylactic treatment or treatment before the physiological manifestations are obvious. For example, the MP may be applied as a pre-exposure treatment to prevent ultraviolet damage and/or during or after exposure to prevent or minimize post-exposure damage. In addition, MPs are implicated in skin disorders and diseases related to abnormal tissues that result from abnormal turnover, which includes metalloprotease activity, such as epidermolysis bullosa, psoriasis, scleroderma and atopic dermatitis. The compounds of the invention are also useful for treating the consequences of xe2x80x9cnormalxe2x80x9d injury to the skin including scarring or xe2x80x9ccontractionxe2x80x9d of tissue, for example, following burns. MP inhibition is also useful in surgical procedures involving the skin for prevention of scarring, and promotion of normal tissue growth including in such applications as limb reattachment and refractory surgery (whether by laser or incision).
In addition, MPs are related to disorders involving irregular remodeling of other tissues, such as bone, for example, in otosclerosis and/or osteoporosis, or for specific organs, such as in liver cirrhosis and fibrotic lung disease. Similarly in diseases such as multiple sclerosis, MPs may be involved in the irregular modeling of blood brain barrier and/or myelin sheaths of nervous tissue. Thus regulating MP activity may be used as a strategy in treating, preventing, and controlling such diseases.
MPs are also thought to be involved in many infections, including cytomegalovirus [CMV]; retinitis; HIV, and the resulting syndrome, AIDS.
MPs may also be involved in extra vascularization where surrounding tissue needs to be broken down to allow new blood vessels such as in angiofibroma and hemangioma.
Since MPs break down the extracellular matrix, it is contemplated that inhibitors of these enzymes can be used as birth control agents, for example in preventing ovulation, in preventing penetration of the sperm into and through the extracellular milieu of the ovum, implantation of the fertilized ovum and in preventing sperm maturation.
In addition they are also contemplated to be useful in preventing or stopping premature labor and delivery.
Since MPs are implicated in the inflammatory response and in the processing of cytokines, the compounds are also useful as anti-inflammatories, for use in disease where inflammation is prevalent including, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, pancreatitis, diverticulitis, asthma or related lung disease, rheumatoid arthritis, gout and Reiter""s Syndrome.
Where autoimmunity is the cause of the disorder, the immune response often triggers MP and cytokine activity. Regulation of MPs in treating such autoimmune disorders is a useful treatment strategy. Thus MP inhibitors can be used for treating disorders including, lupus erythmatosis, ankylosing spondylitis, and autoimmune keratitis. Sometimes the side effects of autoimmune therapy result in exacerbation of other conditions mediated by MPs, here MP inhibitor therapy is effective as well, for example, in autoimmune-therapy-induced fibrosis.
In addition, other fibrotic diseases lend themselves to this type of therapy, including pulmonary disease, bronchitis, emphysema, cystic fibrosis, acute respiratory distress syndrome (especially the acute phase response).
Where MPs are implicated in the undesired breakdown of tissue by exogenous agents, these can be treated with MP inhibitors. For example, they are effective as rattle snake bite antidote, as anti-vessicants, in treating allergic inflammation, septicemia and shock. In addition, they are useful as antiparasitics (e.g., in malaria) and antiinfectives. For example, they are thought to be useful in treating or preventing viral infection, including infection which would result in herpes, xe2x80x9ccoldxe2x80x9d (e.g., rhinoviral infection), meningitis, hepatitis, HIV infection and AIDS.
MP inhibitors are also thought to be useful in treating Alzheimer""s disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, complications resulting from or arising out of diabetes, especially those involving loss of tissue viability, coagulation, Graft vs. Host disease, leukemia, cachexia, anorexia, proteinuria, and perhaps regulation of hair growth.
For some diseases, conditions or disorders MP inhibition is contemplated to be a preferred method of treatment. Such diseases, conditions or disorders include, arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially the prevention or arrest of tumor growth and metastasis), ocular disorders (especially corneal ulceration, lack of corneal healing, macular degeneration, and pterygium), and gum disease (especially periodontal disease, and gingivitis)
Compounds preferred for, but not limited to, the treatment of arthritis (including osteoarthritis and rheumatoid arthritis) are those compounds that are selective for the matrix metalloproteases and the disintegrin metalloproteases.
Compounds preferred for, but not limited to, the treatment of cancer (especially the prevention or arrest of tumor growth and metastasis) are those compounds that preferentially inhibit gelatinases or type IV collagenases.
Compounds preferred for, but not limited to, the treatment of ocular disorders (especially corneal ulceration, lack of corneal healing, macular degeneration, and pterygium) are those compounds that broadly inhibit metalloproteases. Preferably these compounds are administered topically, more preferably as a drop or gel.
Compounds preferred for, but not limited to, the treatment of gum disease (especially periodontal disease, and gingivitis) are those compounds that preferentially inhibit collagenases.
V. Compositions
The compositions of the invention comprise:
(a) a safe and effective amount of a compound of the invention; and
(b) a pharmaceutically-acceptable carrier.
As discussed above, numerous diseases are known to be mediated by excess or undesired metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, skin inflammation, ulcerations, particularly of the cornea, reaction to infection, periodontitis and the like. Thus, the compounds of the invention are useful in therapy with regard to conditions involving this unwanted activity.
The invention compounds can therefore be formulated into pharmaceutical compositions for use in treatment or prophylaxis of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., latest edition.
A xe2x80x9csafe and effective amountxe2x80x9d of a Formula (I) compound is an amount that is effective, to inhibit metalloproteases at the site(s) of activity, in an animal, preferably a mammal, more preferably a human subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific xe2x80x9csafe and effective amountxe2x80x9d will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the solubility of the Formula (I) compound therein, and the dosage regimen desired for the composition.
In addition to the subject compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term xe2x80x9cpharmaceutically-acceptable carrierxe2x80x9d, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to an animal, preferably a mammal, more preferably a human. The term xe2x80x9ccompatiblexe2x80x9d, as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably a mammal, more preferably a human being treated.
Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens(copyright); wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
If the subject compound is to be injected, the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with blood-compatible suspending agent, the pH of which has been adjusted to about 7.4.
In particular, pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable carrier, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition.
The compositions of this invention are preferably provided in unit dosage form. As used herein, a xe2x80x9cunit dosage formxe2x80x9d is a composition of this invention containing an amount of a Formula (I) compound that is suitable for administration to an animal, preferably a mammal, more preferably a human subject, in a single dose, according to good medical practice. These compositions preferably contain from about 5 mg (milligrams) to about 1000 mg, more preferably from about 10 mg to about 500 mg, more preferably from about 10 mg to about 300 mg, of a Formula (I) compound.
The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the Formula (I) compound. The amount of carrier employed in conjunction with the Formula (I) compound is sufficient to provide a practical quantity of material for administration per unit dose of the Formula (I) compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, Chapters 9 and 10 (Banker and Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).
Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of the Formula (I) compound. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents. flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration are well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents. such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve low characteristics of the powder mixture. Coloring agents, suh as the FDandC dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.
Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, Avicelxe2x80x3 RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitxe2x80x3 coatings, waxes and shellac.
Compositions of the subject invention may optionally include other drug actives.
Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
The compositions of this invention can also be administered topically to a subject, e.g., by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a xe2x80x9cpatchxe2x80x9d. Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a sat an effective amount, usually at least about 0.1%, and preferably from about 1% to about 5%, of the Formula (I) compound. Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein the Formula (I) compound. The carrier may include pharmaceutically-acceptable emolients, emulsifiers, thickening agents, solvents and the like.
VI. Methods of Administration
This invention also provides methods of treating or preventing disorders associated with excess or undesired metalloprotease activity in a human or other animal subject, by administering a safe and effective amount of a Formula (I) compound to said subject. As used herein, a xe2x80x9cdisorder associated with excess or undesired metalloprotease activityxe2x80x9d is any disorder characterized by degradation of matrix proteins. The methods of the invention are useful in treating or preventing disorders described above.
Compositions of this invention can be administered topically or systemically. Systemic application includes any method of introducing Formula (I) compound into the tissues of the body, e.g., intra-articular (especially in treatment of rheumatoid arthritis), intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration. The Formula (I) compounds of the present invention are preferably administered orally.
The specific dosage of inhibitor to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific Formula (I) compound used, the treatment indication, the ability of the Formula (I) compound to reach minimum inhibitory concentrations at the site of the metalloprotease to be inhibited, the personal attributes of the subject (such as weight), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.
Typically, for a human adult (weighing approximately 70 kilograms), from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg, of Formula (I) compound are administered per day for systemic administration. It is understood that these dosage ranges are by way of example only and that daily administration can be adjusted depending on the factors listed above.
A preferred method of administration for treatment of rheumatoid arthritis is oral or parenterally via intra-articular injection. As is known and practiced in the art, all formulations for parenteral administration must be sterile. For mammals, especially humans, (assuming an approximate body weight of 70 kilograms) individual doses of from about 10 mg to about 1000 mg are preferred.
A preferred method of systemic administration is oral. Individual doses of from about 10 mg to about 1000 mg, preferably from about 10 mg to about 300 mg are preferred.
Topical administration can be used to deliver the Formula (I) compound systemically, or to treat a subject locally. The amounts of Formula (I) compound to be topically administered depends upon such factors as skin sensitivity, type and location of the tissue to be treated, the composition and carrier (if any) to be administered, the particular Formula (I) compound to be administered, as well as the particular disorder to be treated and the extent to which systemic (as distinguished from local) effects are desired.
The inhibitors of the invention can be targeted to specific locations where the metalloprotease is accumulated by using targeting ligands. For example, to focus the inhibitors to metalloprotease contained in a tumor, the inhibitor is conjugated to an antibody or fragment thereof which is immunoreactive with a tumor marker as is generally understood in the preparation of immunotoxins in general. The targeting ligand can also be a ligand suitable for a receptor which is present on the tumor. Any targeting ligand which specifically reacts with a marker for the intended target tissue can be used. Methods for coupling the invention compound to the targeting ligand are well known and are similar to those described below for coupling to carrier. The conjugates are formulated and administered as described above.
For localized conditions, topical administration is preferred. For example, to treat ulcerated cornea, direct application to the affected eye may employ a formulation as eyedrops or aerosol. For corneal treatment, the compounds of the invention can also be formulated as gels, drops or ointments, or can be incorporated into collagen or a hydrophilic polymer shield. The materials can also be inserted as a contact lens or reservoir or as a subconjunctival formulation. For treatment of skin inflammation, the compound is applied locally and topically, in a gel, paste, salve or ointment. For treatment of oral diseases, the compound may be applied locally in a gel, paste, mouth wash, or implant. The mode of treatment thus reflects the nature of the condition and suitable formulations for any selected route are available in the art.
In all of the foregoing, of course, the compounds of the invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
Some of the compounds of the invention also inhibit bacterial metalloproteases. Some bacterial metalloproteases may be less dependent on the stereochemistry of the inhibitor, whereas substantial differences are found between diastereomers in their ability to inactivate the mammalian proteases. Thus, this pattern of activity can be used to distinguish between the mammalian and bacterial enzymes.
VII. Preparation and Use of Antibodies
Metalloproteases active at a particularly undesired location (e.g., an organ or certain types of cells) can be targeted by conjugating the compounds of the invention to a targeting ligand specific for a marker at that location such as an antibody or fragment thereof or a receptor ligand. Conjugation methods are known in the art.
The invention is also directed to various other processes which take advantage of the unique properties of these compounds. Thus, in another aspect, the invention is directed to the compounds of Formula (I) conjugated to solid supports. These conjugates can be used as affinity reagents for the purification of a desired metalloprotease.
In another aspect, the invention is directed to the compounds of Formula (I) conjugated to label. As the compounds of the invention bind to at least one metalloprotease, the label can be used to detect the presence of relatively high levels of metalloprotease in vivo or in vitro cell culture.
In addition, the compounds of Formula (I) can be conjugated to carriers which permit the use of these compounds in immunization protocols to prepare antibodies specifically immunoreactive with the compounds of the invention. Typical conjugation methods are known in the art. These antibodies are then useful both in therapy and in monitoring the dosage of the inhibitors.
The invention compounds can also be coupled to labels such as scintigraphic labels, e.g., technetium 99 or I-131, using standard coupling methods. The labeled compounds are administered to subjects to determine the locations of excess amounts of one or more metalloproteases in vivo. The ability of the inhibitors to selectively bind metalloprotease is thus taken advantage of to map the distribution of these enzymes in situ. The techniques can also be employed in histological procedures and the labeled invention compounds can be used in competitive immunoassays.

Abstract: which are inhibitors of metalloproteases and which are effective in treating conditions characterized by excess activity of these enzymes.


A single hoisting mechanism is positioned on a turret of either an external or an internal turret mooring system for a FSO or FPSO vessel and is releasably securable to each of a plurality of anchor leg chains. The mechanism is mounted for angular rotation about the center-line of the turret in order that the hoist can be angularly aligned and selectively engaged with each of the anchor leg chains or riser/umbilicals spaced around the turret.

1. Field of this Invention
This invention relates to chain tensioning arrangements for use during anchor leg tensioning of a turret moored vessel.
2. Description of the Prior Art
FIG. 1 shows a typical prior art permanently connected turret mooring system in a partial cross-section through the internal turret section of the vessel. Such system includes a vessel V having a well W in which a lower turret 10 is rotatably supported with respect to vessel V at deck D by means of bearings 12. An upper turret 14 is secured to lower turret 10. A plurality of anchor legs 16, (formed at least partially with chains) are secured to the turret in order to substantially secure the lower turret 10 and upper turret 14 to the sea floor. The anchor legs 16 run through chain tubes 18 and via sheave 20 and winch/windlass 22 to a chain locker 24 all located on the upper turret 14. A separate windlass 22 and sheave 20 is provided for each anchor leg. Such windlass/sheave assemblies are arranged about the upper turret 14.
Other prior art arrangements have provided a simple winch on the deck of the vessel where the vessel must be rotated with respect to the turret and to a particular anchor chain for tensioning such a chain. Rotation of the vessel requires either a dynamic positioning system or tugboats to orient the vessel against waves, currents and wind or a hydraulic motor and bull gear arrangement for rotating the vessel with respect to the turret. In such arrangements large sheave assembles must be placed at different angular positions on the turret to align with the chain tube and the winch for different angular orientations of the winch with respect to the turret. Large diameter wire rope is required for retrieving anchor leg chains and fluid risers. The possibility of a wire rope breaking poses a great risk to personnel working on the vessel deck where the wire rope passes through several sheave assemblies.
The prior art""s placement of an anchor chain winch on the vessel deck requires that a the vessel deck structure be stiffened to accept the large loads of the winch itself and the forces required to tension an anchor leg. Such stiffening requires increased costs associated with increased steel and vessel design work.
The winch on the deck of such prior art arrangements is usually placed several meters from the turret center-line in order to accommodate proper wire rope spooling. Such placement puts the winch operator at a disadvantage during anchor chain tensioning because of the equipment noise and distance between the winch operator and workmen within the turret.
3. Identification of Objects of this Invention
A primary object of this invention is to provide a chain tensioning arrangement for a turret mooring system that reduces the weight and cost of vessel structures associated with the turret mooring.
Another object of the invention is to provide a chain tensioning system which reduces installation time for tensioning an anchor chain of a turret mooring system.
Another object of the invention is to provide a winch and turret arrangement which reduces hazards to personnel during chain tensioning of a permanently connected turret mooring system;
Another object of the invention is to provide a winch and turret arrangement which reduces the number of support vessels required to tension anchor chains of the turret mooring system.
The objects identified above along with other features and advantages are incorporated in a chain tensioning system for a turret mooring system in which only a single winch is placed on the turret at its center-line and is rotatable with respect to the turret so as to angularly align it with anchor chains spread about the circumference of the turret. Anchor leg tensioning operations can be conducted without regard to vessel heading by rotating the winch with respect to the turret until it is aligned with an anchor chain that is to be tensioned. The invention can be used with external or internal turret mooring systems. A flapper style/ratcheting chain support is provided on the turret for each anchor chain so that mooring leg retrieval operations can continuously be conducted until the desired chain tension is achieved.

Chain tensioning arrangement for turret moored vessel


A universal serial bus stack may use an emulation layer to grant a non-universal serial bus device access to universal serial bus drivers and applications. The universal serial bus stack may exchange a device communication at an emulation layer. The universal serial bus stack may translate between a universal serial bus communication and the device communication at the emulation layer, and then may exchange the universal serial bus communication at a universal serial bus client interface.

Universal Serial Bus (USB) is a protocol for exchanging data and power between a peripheral device and a client device. A peripheral device is a separate device that may communicate with the client device. Examples of a peripheral device may include a mouse, keyboard, a printer, or other devices, both separated from and integrated with the client device. A universal serial bus port may allow the client device to communicate with the peripheral device or to transmit power to the peripheral device.


An active exercise and therapeutic system for promoting physical motion, balance and coordination and importantly a variety of therapeutic modalities to a user's foot or feet. The system includes a training apparatus having a stationary base member operatively interconnected with first and second rotating platforms mounted thereon. The first and second rotating platforms are adapted to receive, respectively, the foot of an individual to stand thereon such that each foot can rotate independently about a separate axis. Stationary base member with rotating platforms mounted thereon can further be positioned upon a specialized mount operative to impart a further range of motion or specific orientation. In further embodiments, the rotating platforms may be provided with a variety of functional modalities, such as calorie counting, distance travelled, and the like, or a therapeutic modality, such as heat, cold or pressure sensation to impart a therapeutic effect to the user's feet.

Numerous exercise devices have been developed to promote a wide range of physical conditioning and enhance the ability of an individual to play a particular sport or perform a specific sports-type motion. With respect to the latter, it is well-known that proper form, coupled with appropriate balance and coordination, is crucial for sports such as golfing, tennis, bowling, pitching baseball/softball, and the like. Developing strength and conditioning, along with improved balance and coordination, is also extremely important when incorporated as part of a physical rehabilitation regimen where it is often crucial to develop muscle strength and range of motion so as to regain health and mobility.
Among the devices that have proven to be exceptionally effective in developing balance and coordination, along with strength and conditioning, include certain training apparatuses and methods of using such apparatuses as disclosed in U.S. Pat. No. 6,790,166B2 issued Sep. 14, 2004 to Broudy entitled BALANCE AND COORDINATION TEACHING METHOD, the teachings of which are expressly incorporated herein by reference. The apparatus disclosed in such reference, as well as the methods of using such apparatus, are exceptionally effective in developing balance and coordination via the use of first and second rotating platform members mounted on a planar base, each platform member being operative to receive the foot of a user. Each foot of the user is operative to rotate independently about a separate axis and can be utilized to properly perform certain motions that are crucial to properly performing any of a variety of sports, and in particular golf, tennis, skiing, surfing, martial arts and baseball, among others. The commercial embodiment of the apparatus and the use of such apparatus are sold under the trademark 8BOARD®, and marketed and distributed by Grail Sports, Inc. of Carlsbad, Calif.
Despite the exceptionally effectiveness of such apparatus, and the methods of using such apparatus to facilitate development of balance and coordination, and physical conditioning, such apparatus and the use of such apparatus have certain limitations. Specifically, the apparatus and the methods of using such apparatus typically require that the apparatus remain in stationary position on level ground. While such placement is optimal for performing certain motions specific to several sports, such as serving a tennis ball or swinging a golf club, the use of such apparatus is limited by the fact that the rotating platforms are maintained in generally parallel relation to the ground or other flat surface and the rotational movement of each respective platform extends about a perpendicularly extending axis. There is thus no ability for the user to experience dynamic or non-level orientations as would be encountered if, for example, the rotating platform surfaces were positioned on an incline or a surface operative to rock back and forth. Such added dimensions would be operative to provide additional challenges to the user, particularly with respect to balance and coordination, and would further enhance the ability of such apparatus to be used in training for skiing, surfing, or skateboarding, or any of a variety of dynamic activities that involve slopes, inclined surfaces, jostling motions and the like.
There are likewise numerous shortcomings associated with the apparatus and training methods of U.S. Pat. No. 6,790,166B2 due to the inability of such devices to impart any type of therapeutic effect to a user of such devices. While rehabilitation is among the many uses associated with such apparatus, such apparatus was originally designed to be utilized while the user is wearing shoes or other foot coverings, and thus incapable of imparting a therapeutic modality to the feet of a user, such as heat or cold, or provide a texturized surface that can be applied to the feet in order to provide a massaging effect. Such enhanced functionality has not heretofore been available with respect to the current use of the subject apparatus having rotational platforms and hence have limited functionality.
Indeed, the functionality of the subject apparatus could otherwise have benefited greatly due to a variety of modalities currently in use, such as a calorie counter, heart rate monitor, timer, sound/lighting/motivational modalities, monitors for measuring distance, respiration, and the like, and the ability to interface with computers or other portable electronic devices, which are currently in use and readily available to those skilled in the art. Along those lines, it is contemplated that the rotational platforms could benefit greatly by being individually manipulated so as to increase resistance and/or limit the range of rotational motion, so as to impart a selective range of motion or strengthening, as may be desired. Currently, there is a substantial need in the art for such enhancements that could be incorporated with such exercise apparatus and methods of using the same.

Combination therapeutic and exercise system


A homogeneous mass of particulate manganese dioxide which has been heat-treated to reduce its moisture content and treated with an organic solvent which substantially fills the pores of the manganese dioxide thereby reducing its affinity for absorbing moisture when exposed to a moisture environment for a fixed time period. The invention also relates to a process for producing the manganese dioxide.

The development of high energy battery systems requires the compatibility of an electrolyte possessing desirable electrochemical properties with highly reactive anode materials, such as lithium, sodium and the like, and the efficient use of high energy density cathode materials, such as manganese dioxide. The use of aqueous electrolytes is precluded in these systems since the anode materials are sufficiently active to react with water chemically. It has therefore been necessary, in order to realize the high energy density obtainable through use of these highly reactive anodes and high energy density cathodes, to turn to the investigation of nonaqueous electrolyte systems and more particularly to nonaqueous organic electrolyte systems.
The term "nonaqueous organic electrolyte" in the prior art refers to an electrolyte which is composed of a solute, for example, a salt or complex salt of Group I-A, Group II-A or Group III-A elements of the Periodic Table, dissolved in an appropriate nonaqueous organic solvent. Conventional solvents include propylene carbonate, ethylene carbonate or y-butyrolactone. The term "Periodic Table" as used herein refers to the Periodic Table of the Elements as set forth on the inside back cover of the Handbook of Chemistry and Physics, 48th Edition, the Chemical Rubber Co., Cleveland, Ohio, 1967-1968.
Although manganese dioxide has been mentioned as a cathode for cell applications, manganese dioxide inherently contains an unacceptable amount of water, both of the absorbed and bound (adsorbed) types, which is sufficient to cause anode (lithium) corrosion along with its associated hydrogen evolution. This type of corrosion that causes gas evolution is a serious problem in sealed cells, particularly in miniature type button cells. In order to maintain overall battery-powered electronic devices as compact as possible, the electronic devices are usually designed with cavities to accommodate the miniature cells as their power source. The cavities are usually made so that a cell can be snugly positioned therein, thus making electronic contact with appropriate terminals within the device. A major potential problem in the use of cell-powered devices of this nature is that if the gas evolution causes the cell to bulge then the cell could become wedged within the cavity. This could result in damage to the device. Also, if electrolyte leaks from the cell it could cause damage to the device. Thus it is important that the physical dimensions of the cell's housing remain constant during discharge and that the cell will not leak any electrolyte into the device being powered.
U.S. Pat. No. 4,133,856 discloses a process of producing an MnO.sub.2 electrode (cathode) for nonaqueous cells whereby the MnO.sub.2 is initially heated within a range of 350.degree. to 430.degree. C. so as to substantially remove both the absorbed and bound water and then, after being formed into an electrode with a conductive agent and binder, it is further heated in a range of 200.degree. to 350.degree. C. prior to its assembly into a cell. British Pat. No. 1,199,426 also discloses the heat treatment of MnO.sub.2 in air at 250.degree. to 450.degree. C. to substantially remove its water component.
It has been found that heat-treated manganese dioxide has an affinity for absorbing water and thus after the water has been substantially removed, it is necessary to take precautions to insure that the manganese dioxide will not absorb moisture from the environment prior to its use as an active material for electrochemical cells.
It is an object of the present invention to provide a homogeneous mass of particulate manganese dioxide that will have a reduced capacity for moisture absorption when exposed to a moisture environment for a fixed time period.
It is another object of the present invention to provide a homogeneous mass of particulate manganese dioxide that has its pores substantially filled with an organic solvent.
It is another object of the present invention to provide a treatment for heat-treated manganese dioxide so as to decrease its affinity or propensity for absorbing moisture.
It is another object of the present invention to employ a homogeneous mass of particulate manganese dioxide that has been treated with an organic solvent as an active material for electrochemical cells, such as nonaqueous cells.
The foregoing and additional objects will become more fully apparent from the following description.

Heat-treated, organic solvent-treated manganese dioxide


Initially, customer time series credit files are acquired. The credit files are organized in a data mart environment for supporting a query system. Time series utilization attributes are created and a neural network time series segmentation process is applied and Nxc3x97N dimension segments are generated for analysis. The chart may be modified to more accurately depict profitable credit revolvers. Credit data from each potential new customer is processed in a similar fashion by the neural network segmentation process. Profitable credit revolvers are identified by having credit utilization patterns belonging to profitable segments previously identified.

1. Technical Field
The present invention is related to consumer credit. More particularly the present invention is a system, method and instruction for identifying which potential customers are credit revolvers for card issuers.
2. Description of Related Art
Strong competition in credit card industry has driven banks and credit card issuers to compete for a few profitable customers. Credit card issuers make their profit out of approximately 20% of total portfolio customers; most of them are revolvers. The major portion of profits for credit card issuers is from higher interest rates charged to credit revolvers. Credit revolvers or revolvers are customers who carry a balance on their credit card accounts from month to month. In general, revolvers are more profitable customers than those who do not carry a monthly balance on their credit card accounts.
Credit card utilization is the percentage of total available credit being utilized by a customer. Neither very high nor very low revolving utilization is considered to be good by credit card issuers. Revolvers with very high credit utilization are considered to be high-risk customers by most credit card issuers. Very high credit utilization may indicate that a customer is in the midst of financial difficulty. Very high credit utilization may put the credit card issuers at high risk for charge-off, or bankruptcy.
Another undesirable credit utilization pattern is an explosive growth pattern. Explosive credit utilization patterns may also lead to delinquency, charge-off, or bankruptcy because the pattern is indicative of a deleterious change in a customer""s financial state. Therefore, credit card issuers must also avoid all potential customers, including revolvers, who demonstrate explosive credit utilization growth unless they have very good strategy to manage high risk customers.
Conversely, most customers with low or even zero utilization do not represent a credible risk to credit card issuers immediately, however, neither do these customers contribute to the credit card issuers"" profits. Customers that maintain credit card accounts merely for the convenience of having instant credit available while shopping are known as convenient users. Normally these customers immediately pay their purchases off. Credit issuers must cover relatively high operation costs for administering customer accounts.
It would be advantageous to provide credit card issuers with the means to filter out unprofitable customers from targeting groups. It would further be advantageous to provide credit card issuers with the means to filter out high-risk customers. It would still further be advantageous to provide a system, method and instructions for objectively filtering out unprofitable customers while acquiring profitable customers.
The present invention relates to a method, system and instructions for generating a stable, time series segmentation credit utilization chart and identifying profitable revolvers from that chart. The process begins by acquiring customer time series credit files. The credit files are organized in a data mart environment that supports a query system. Time series utilization attributes are created first. Then a neural network time series segmentation algorithm is applied to the data. A resultant Nxc3x97N dimension segments chart is generated for analyses. The chart may be further modified to more accurately depict profitable credit revolvers. Profitable credit revolvers are identified by having credit utilization patterns belonging to one or more of the segments in the Nxc3x97N chart previously identified.

Method and system for identifying consumer credit revolvers with neural network time series segmentation

International Business Machines Corporation