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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
  • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/72—Two oxygen atoms, e.g. hydantoin
  • C07D233/80—Two oxygen atoms, e.g. hydantoin with hetero atoms or acyl radicals directly attached to ring nitrogen atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• This invention is directed to compounds that 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.
• 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.
• MPs Matrix-Metallo Proteases
• ACEs angiotensin-converting enzymes
• ADAMs See Wolfsberg et al, 131 J. Cell Bio. 275-78 October, 1995
• 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.
• MP inhibitors examples include rheumatoid arthritis - Mullins, D. E., et al., Biochim. Biophys. Acta. (1983) 695:117-214; osteoarthritis - Henderson, B., et al., Drugs of the Future (1990) 15:495-508; cancer - Yu, A. E. et al., Matrix Metalloproteinases - Novel Targets for Directed Cancer Therapy, Drugs & Aging, Vol. 11(3), p. 229-244 (Sept. 1997), Chambers, A.F.
• ulcerative conditions can result in the cornea as the result of alkali bums or as a result of infection by Pseudomonas aeruginosa, Acanthamoeba, Herpes simplex and vaccinia viruses.
• conditions characterized by undesired metalloprotease activity include periodontal disease, epidermolysis bullosa, fever, inflammation and scleritis (e.g., DeCicco et al., World Patent Publication WO 95/29892 published November 9, 1995).
• the invention provides compounds which are potent inhibitors of metalloproteases and which are effective in treating conditions characterized by excess activity of these enzymes.
• the present invention relates to compounds having a structure according to the following Formula (I):
• R 1 is selected from -OH and -NHOH
• R 2 is selected from hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and halogen;
• R is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
• R 4 is -(CR 7 R 7 VX-(CR 8 R 8' )/-E-A where:
• (1 ) A is from 0 to about 4;
• (2) / is from 0 to about 4;
• each of R 7 , R 7 , R 8 , and R 8 when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl;
• each R 9 and R 9' when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, -arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R 9 and R 9 , together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; (5) E is selected from a covalent bond, -O
• A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or (b) A, together with R 7 , R 7' , R 8 , R 8' , R 9 , R 9' , R 10 , or R 10' , join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
• 5 D is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
• R 6 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl; provided that when k > 0, R 6 is -OH and when k — 0, R 6 is not -OH;
• (a) a is from 0 to about 4;
• each R and R when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; and
• R 15 and R 15 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and -C(O)-Q-(CR 16 R 16 >R 17 where:
• b is from 0 to about 4;
• Q is selected from a covalent bond and -N(R 18 )-;
• each R 16 and R 16 when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl,
• each R and R is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or R 17 and R 18 , together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; or R and R , 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
• R 15 and R 15 together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
• E' and M' are independently selected from -CH- and -N-;
• each R and R when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy;
• A' is selected from a covalent bond, -O-, -SO ⁇ r, -C(O)-,
• R 21 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; and (f) G' is -(CR 22 R 22' ) e -R 23 where e is from 0 to about 4; each R 22 and
• R 22 when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; and R 23 is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and
• 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. DETAILED DESCRIPTION OF THE INVENTION
• Preferred acyl groups include (for example) acetyl, formyl, and propionyl.
• Alkyl is a saturated hydrocarbon chain having 1 to 15 carbon atoms, preferably 1 to 10, more preferably 1 to 4 carbon atoms.
• Alkene is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms.
• Alkyne 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 "hydrocarbon chains”) 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.
• a “lower” alkyl, alkene or alkyne moiety 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.
• Alkoxy is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.
• Aryl 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, methylenedioxy, heteroaryloxy, or any combination thereof.
• Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl.
• the most preferred aryl ring radical is phenyl.
• Aryloxy is an oxygen radical having an aryl substituent (i.e., -O-aryl).
• Preferred aryloxy groups include (for example) phenoxy, napthyloxy, methoxyphenoxy, and methylenedioxyphenoxy.
• Cycloalkyl 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.
• Halo or "halogen” is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred typically are chloro and fluoro.
• Haloalkyl is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred are Cj-C ⁇ haloalkyls; more preferred are Cj-Cg haloalkyls; still more preferred still are C1-C3 haloalkyls. Preferred halo substituents are fluoro and chloro.
• Heteroatom is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
• Heteroalkyl 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 preferably 2 to 5. For example, alkoxy (i.e., -O-alkyl or -O-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.
• Heteroaryl 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:
• Heteroaryloxy is an oxygen radical having a heteroaryl substituent (i.e., -O- heteroaryl).
• Preferred heteroaryloxy groups include (for example) pyridyloxy, furanyloxy, (thiophene)oxy, (oxazole)oxy, (thiazole)oxy, (isoxazole)oxy, pyrmidinyloxy, pyrazinyloxy, and benzothiazolyloxy.
• Heterocycloalkyl 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:
• Oxirane Aziridine Oxetane Azetidine Tetrahydrofuran Pyrrolidine 1 ,4-Oxathiane
• mammalian metalloprotease refers to the proteases disclosed in the "Background” section of this application.
• the compounds of the present invention are preferably active against “mammalian metalloproteases", including any metal- containing (preferably zinc-containing) enzyme found in animal, preferably mammalian,
• the present compounds are more preferably active against metalloprotease enzymes that are zinc-containing proteases which are similar in structure to, for example, human i5 stromelysin or skin fibroblast collagenase.
• metalloprotease enzymes that are zinc-containing proteases which are similar in structure to, for example, human i5 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.
• Spirocycle 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.
• alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups may be5 substituted with hydroxy, amino, and amido groups as stated above, the following are not envisioned in the invention:
• a “pharmaceutically-acceptable salt” 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.
• acidic e.g., hydroxamic or carboxylic acid
• anionic salt formed at any basic (e.g., amino) group.
• 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 “biohydrolyzable amide” is an amide of a hydroxamic acid-containing (i.e., R 1 in Formula (I) is -NHOH) 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.
• amide derivatives are alkoxyamides, where the hydroxyl hydrogen of the hydroxamic acid of Formula (I) is replaced by an alkyl moiety, and acyloxyamides, where the hydroxyl hydrogen is replaced by an acyl moiety (i.e., R-C(O)-).
• a “biohydrolyzable hydroxy imide” 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.
• a “biohydrolyzable ester” is an ester of a carboxylic acid-containing (i.e., R 1 in Formula (I) is -OH) 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.
• 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 methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and alkyl acylamino alkyl esters (such as acetamidomethyl esters).
• lower alkyl esters such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters
• lactonyl esters such as phthali
• a “solvate” is a complex formed by the combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water).
• a solute e.g., a metalloprotease inhibitor
• a solvent e.g., water
• 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 subject invention involves compounds of Formula (I):
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , G and Z have the meanings described above.
• the following provides a description of particularly preferred moieties, but is not intended to limit the scope of the claims.
• R 1 is selected from -OH and -NHOH; preferably -OH.
• R 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.
• R 3 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; preferably hydrogen or alkyl, more preferably hydrogen.
• R 4 is -(CR 7 R 7 VX-(CR 8 R 8' ) / -E-A.
• A: and / is independently selected from
• R 8 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen and haloalkyl; preferably all are hydrogen.
• X is selected from -O-, -S-, -S(O)-, -S(O 2 )-, -N(R 9 )-, -N(COR 9 )-, -N(CO 2 R 9 )-, - N(CONR 9 R 9' )-, and -N(SO 2 R 9 )-, where each R 9 and R 9' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl (preferably each R 9 and R 9 is hydrogen), or (ii) R 9 and R 9 together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from ,5 to 8 ring atoms of which from 1 to 3 are heteroatoms.
• X is -O-, -S
• R 9 is preferably lower alkyl or aryl.
• each R 10 and R 10' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl (preferably each R 10 and R 10 is hydrogen), or (ii) R 10 and R 10 together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms.
• E is covalent bond, -O-, -S-, -N(SO 2 R 10 )-, -N(COR 10 ), or -N(CO 2 R 10 )-, where R 10 is preferably lower alkyl or aryl.
• R 10 is preferably lower alkyl or aryl.
• A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; preferably A is alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
• R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; preferably hydrogen or lower alkyl; more preferably hydrogen.
• R 6 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl; preferably aryl, heteroaryl or hydroxyl.
• Each R u and R 11 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; preferably at least one of R ⁇ and R n is hydrogen, more preferably both are hydrogen.
• Z is selected from cycloalkyl and heterocycloalkyl; -L-(CR I2 R 12' ) fl -R 13 ; -NR 15 R 15' ;
• Z is cycloalkyl or heterocycloalkyl, preferred is where Z is an optionally substituted piperidine or piperazine.
• Each R 12 and R 12 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and
• each R is hydrogen and each R is independently hydrogen or lower alkyl.
• R 13 is selected from aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; preferably R 13 is aryl, heteroaryl, heterocycloalkyl or cycloalkyl.
• R 13 may also be selected from - C(O)NR 14 R 14 where (i) R 14 and R 14 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R 14 and R 14 , 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.
• R 15 and R 15 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, and -C(O)-Q-(CR I 6 R 16 VR 17 ; preferably R 15 and R 15' are independently selected from hydrogen, alkyl, aryl and -C(O)-Q-(CR 16 R 16' ) 6 -R 17 .
• R 15 and/or R 15' is -C(O)-Q- (CR 16 R 16 VR 17
• b is 0, 1, 2, 3 or 4; b is preferably 0 or 1.
• Q is selected from a covalent bond and -NR 18 -; Q is preferably a covalent bond.
• Each R 16 and R 16 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; preferably each R 16 is hydrogen and each R 16 is independently hydrogen or lower alkyl.
• R 17 and R 18 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (preferably one is aryl); or R 17 and R 18 , 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; preferably R 17 is alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl.
• R 15 and R 18 together with the nitrogen 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.
• R 15 and R 15 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.
• Z is (referred to herein as Formula (A))
• E' and M' are independently selected from -CH- and -N-; preferred is where E' is -CH and
• M' is -CH.
• R 20 and R 20' each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; preferably hydrogen or lower alkyl.
• c is 0, 1, 2, 3 or 4, preferably 0 or
• Each R 19 and R 19 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; preferably each R 19 is hydrogen and each R 1 is independently hydrogen or lower alkyl.
• A' is selected from a covalent bond, -O-, -SO ⁇ r, -C(O)-, -C(O)N(R 21 )-, -
• R 21 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; R 21 is preferably lower alkyl or aryl.
• G' is -(CR 22 R 22 ) e -
• R . e is 0, 1, 2, 3 or 4, preferably 0 or 1.
• Each R and R is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; preferably each R 22 is hydrogen and each R 22 is independently hydrogen or lower alkyl.
• R 23 is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; preferably R 3 is lower alkyl or aryl.
• R 21 and R 23 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.
• R 20 and R 23 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.
• the compounds of the invention can be prepared using a variety of procedures.
• the aldehyde Sla is a commercially available material. Its synthetic utility has widely been recognized and several conditions have been developed for its stereoselective reactions with nucleophiles. This way, various aryl or alkyl R ! groups can be introduced to form alcohols Sib, and the syn/anti stereochmistry can be controlled depending on the reaction conditions.
• the newly formed hydroxyl group of Sib can, in turn, be functionalized by a wide variety of alkylating agents using methods well known to the skilled artisan to introduce substituent R 2 .
• the product Sic can then be converted to the target carboxylic acid using methods well documented in the chemical literature.
• the Boc and the acetonide protective groups of Sic can be removed under acidic conditions to obtain the aminoalcohol Sid.
• the amino group of this intermediate can selectively be derivatized by an appropriate aryl sulfonyl chloride using standard Shott and Bouman conditions to give sulfonamide Sle. Further elaboration of the aryl group R 3 may be performed at this stage using, for example, the Suzuki coupling method. Finally, the alcohol function is converted to the carboxylic acid using standard oxidation methods to produce the target molecule Slf.
• carboxylic acid functionality in compounds of type Slf can be converted to the hydroxamic acid by coupling with hydroxylamine using a mixed anhydride method or by forming of an intermediate acid chloride.
• the aziridine S2e which can be obtained from S2d upon treatment with triphenylphosphine, has been shown in chemical literature to be a highly versatile electrophile capable of undergoing ring opening reactions with various sulfur-, oxygen- and nitrogen-based nucleophiles.
• the free amino group can then be derivatized with various sulfonyl chlorides to give sulfonamide esters S2g. If necessary, a more complex aryl sulfonyl group can be introduced in a sequence of several synthetic steps. Finally, the ester function is converted to the carboxylic acid using one of the standard hydrolysis methods to produce the target molecule S2h.
• ester functionality in compounds of type S2g can be converted to the hydroxamic acid by reaction with hydroxylamine under alkaline conditions.
• the free amino group of S3d can then be derivatized with various sulfonyl chlorides to give the target inhibitors S3e. If necessary, a more complex aryl sulfonyl groups can be introduced in a sequence of several synthetic steps. If desired, the carboxylic acid functionality in compounds of type S3e can be converted to the hydroxamic acid by coupling with hydroxylamine using a mixed anhydride method or by forming of an intermediate acid chloride. 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.
• the compounds of the invention may have one or more chiral centers.
• one optical isomer including diastereomer and enantiomer
• another optical starting materials for example by chiral starting materials, catalysts or solvents
• both stereoisomers or both optical isomers including diastereomers and enantiomers at once (a racemic mixture).
• 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.
• optical isomer including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other.
• optical isomers including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
• 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.
• 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 that are characterized by unwanted or elevated activity by MPs.
• the compounds can be used to inhibit MPs which:
• an "MP related disorder” or “MP related disease” 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 "involvement" of the MP includes: 1. The unwanted or elevated MP activity as a "cause” 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 "hallmark" of the disease or disorder; or
• the unwanted or elevated MP activity is part of the biochemical or cellular cascade that results or relates to the disease or disorder.
• inhibition of the MP activity interrupts the cascade, and thus controls the disease.
• treatment is used herein to mean that, at a minimum, administration of a compound of the present invention mitigates a disease associated with unwanted or eleveated MP activity in a mammalian subject, preferably in humans.
• treatment 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 the MP-mediated disease.
• the methods of the present invention are directed to preventing disease states associated with unwanted MP activity, it is understood that the term “prevent” does not require that the disease state be completely thwarted.
• 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.
• osteoarthritis OA
• R.S. "A Short History of Osteoarthritis", Osteoarthritis: Diagnosis and Medical/Surgical Management, R.W. Moskowitz, D.S. Howell, V.M. Goldberg and H.J.
• MPs are not distributed evenly throughout the body.
• the distribution of MPs expressed in various tissues are often specific to those tissues.
• 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.
• 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.
• a compound which displays a higher degree of affinity and inhibition for an MP found in the joints e.g. chondrocytes
• 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.
• 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.
• 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.
• 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.
• 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.
• surgical trauma e. g., angioplasty
• scarring e.g., topical to the skin
• burning e.g., topical to the skin
• opthalmic and periodontal indications e.g., angioplasty
• 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,
• 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 "injury" 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.
• MPs are implicated in the remodeling or "turnover" of skin.
• 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.
• the MP may be applied as a pre- exposure treatment to prevent ultaviolet damage and/or during or after exposure to prevent or minimize post-exposure damage.
• 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 "normal" injury to the skin including scarring or “contraction” 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).
• 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.
• MPs may be involved in the irregular modeling of blood brain barrier and/or myelin sheaths of nervous tissue.
• 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.
• CMV cytomegalovirus
• MPs may also be involved in extra vascularization where surrounding tissue needs to be broken down to allow new blood vessels such as in angiof ⁇ broma 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.
• 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.
• MP inhibitors can be used for treating disorders including, lupus erythmatosis, ankylosing spondylitis, and autoimmune keratitis.
• MP inhibitor therapy is effective as well, for example, in autoimmune-therapy-induced fibrosis.
• MPs are implicated in the undesired breakdown of tissue by exogenous agents, these can be treated with MP inhibitors.
• they are effective as rattle snake bite antidote, as anti-vessicants, in treating allergic inflammation, septicemia and shock.
• they are useful as antiparasitics (e.g., in malaria) and antiinfectives.
• they are thought to be useful in treating or preventing viral infection, including infection which would result in herpes, "cold” (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 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, 5 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 are those compounds that are selective for the matrix metalloproteases and the disintegrin metalloproteases.
• Compounds preferred for, ⁇ o but not limited to, the treatment of cancer are those compounds that preferentially inhibit gelatinases or type IV collagenases.
• Compounds preferred for, but not limited to, the treatment of ocular disorders are those compounds that broadly inhibit metalloproteases. Preferably i5 these compounds are administered topically, more preferably as a drop or gel.
• Compounds preferred for, but not limited to, the treatment of gum disease are those compounds that preferentially inhibit collagenases.
• compositions V. Compositions:
• compositions of the invention comprise:
• the compounds of the invention are useful in therapy with regard to conditions involving this unwanted activity.
• a "safe and effective amount" 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 "safe and effective amount” 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.
• compositions of the subject invention contain a pharmaceutically-acceptable carrier.
• pharmaceutically-acceptable carrier 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.
• compatible 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 subject being treated. The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is determined in-part by the way the compound is to be administered.
• 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®; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free
• Pharmaceutically-acceptable carriers for systemic adminisitration 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.
• the pharmaceutically-acceptable carrier, in compositions for parenteral administration comprises at least about 90% by weight of the total composition. If the subject compound is to be injected, the preferred pharmaceutically- acceptable carrier is sterile, physiological saline, with a blood-compatible suspending agent, the pH of which has preferably been adjusted to about 7.4.
• compositions of this invention are preferably provided in unit dosage form.
• a "unit dosage form” 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.
• 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.
• 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.
• 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/or 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.
• Such liquid dose forms will optionally contain 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; and lubricants such as magnesium stearate, stearic acid and talc.
• Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
• Coloring agents such as the FD&C 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.
• typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, Avicel® RC-591, tragacanth and sodium alginate;
• typical wetting agents include lecithin and polysorbate 80;
• typical preservatives include methyl paraben and sodium benzoate.
• Peroral liquid compositions may also contain one or more components such as the sweeteners, flavoring agents and colorants disclosed above.
• 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.
• dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit® 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.
• 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 "patch".
• Such compositions include, for example, lotions, creams, solutions, gels and solids.
• These topical compositions preferably comprise a safe and 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.
• the carrier is organic in nature and capable of having dispersed or dissolved therein the Formula (I) compound.
• the carrier may include pharmaceutically-acceptable emollients, emulsifiers, thickening agents, solvents and the like.
• This invention also provides methods of treating 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.
• a "disorder associated with excess or undesired metalloprotease activity" is any disorder characterized by degradation of matrix proteins. The methods of the invention are useful in treating 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 compound 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.
• a human adult weighing approximately 70 kilograms
• of Formula (I) compound are administered per day for systemic administration.
• 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 parenteral dosing 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 compounds of the invention can be targeted to specific locations where the metalloprotease is accumulated by using targeting ligands.
• the compound 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 carriers.
• the conjugates are formulated and administered as described below.
• topical administration is preferred.
• direct application to the affected eye may employ a formulation as eyedrops or aerosol.
• 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.
• the compound is applied locally and topically in a gel, paste, salve or ointment.
• 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.
• 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.
• Metalloproteases active at a particularly undesired location 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.
• 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.
• the invention is directed to the compounds of Formula (I) conjugated to label.
• the label can be used to detect the presence of relatively high levels of metalloprotease in vivo or in vitro cell culture.
• 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 1-131, 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.
• THF tetrahydrofuran
• benzophenone diisopropylamine is distilled from calcium hydride and all other solvents are purchased as the appropriate grade.
• Chromatography is performed on silica gel (70 - 230 mesh; Aldrich) or (230 - 400 mesh; Merk) as appropriate.
• Thin layer chromatography analysis (TLC) is performed on glass mounted silica gel plates (200 - 300 mesh; Baker) and visualized with UV or 5% phosphomolybdic acid in ethanol (EtOH).
• the resulting mixture is stirred at room temperature for 3 hours and then the reaction is quenched by the addition of isopropanol. A green precipitate forms after the mixture is stirred for 30 minutes.
• the solution is then filtered through celite with the aid of acetone. The filtrate is concentrated to an oil under reduced pressure. The oil is dissolved in methanol and then an ethereal solution of diazomethane is added. The mixture becomes slightly yellow when excess diazomethane is added. The mixture is concentrated to a light yellow solid. Purification of the solid is accomplished by chromatography on silica gel using 8/2 hexane/EtOAc as the eluent to provide the product as a yellow solid.
• (2S,3S)- 4'-Methoxy-biphenyl-4-sulfonic acid (2-benzothiazol-2-yl-l- hydroxymethyl-2-methoxy-ethyl)-amide.
• the (2S,3S)-N-(2-benzothiazol-2-yl- 1 - hydroxymethyl-2-methoxy-ethyl)-4-bromo-benzenesulfonamide 3d (505 mg, 1.10 mmol) and 4-methoxyphenylboronic acid (252 mg, 1.65 mmol) are taken up in 10 mL of benzene, 1.5 mL of EtOH and 1.5 mL of water in the presence of Pd(PPh 3 ) 4 (38 mg, 0.03 mmol) and 225 mg of Na 2 CO 3 and brought to reflux for 18 hours.
• the oil is dissolved in methanol and then an ethereal solution of diazomethane is added.
• the mixture becomes slightly yellow when excess diazomethane is added.
• the mixture is concentrated to a light yellow solid. Purification of the solid is accomplished by chromatography on silica gel using 8/2 hexane/EtOAc as the eluent to provide the product as a white solid.
• Examples 6-36 are prepared from the corresponding thiol and S2e using procedures described for Example 4 or 5.
• Examples 40-43 are prepared from methyl (2S,3R)-(-)-3-phenylaziridine-2- carboxylate using procedures described for Example 4 or 5.
• the cooling bath is removed and the reaction mixture is stirred for 2.5 hr.
• the reaction mixture is cooled to -78°C, benzyloxyacetaldehyde (898 mg, 5.98 mmol) is added and, after stirring for 10 min, the mixture is warmed up to 0°C and stirred for 3 hr.
• the reaxtion mixture is diluted with ether, washed with IN aq KHSO 4 and solvents are removed under vacum. The residue is dissolved in methanol (10 mL), cooled to 0°C and 30% hydrogen peroxide (5 mL) is added. The cooling bath is removed and the mixture is stirred at room temperature for 2 hr. Saturated aq.
• Example 45-68 are prepared using a corresponding aldehyde and S3a following the procedure described for Example 44.
• compositions for the treatment of ailments associated with unwanted MP activity.
• compositions and methods of the invention do not limit the invention, but provide guidance to the skilled artisan in preparing and using the compounds, compositions and methods of the invention. In each case, other compounds within the invention may be substituted for the example compound shown below to provide substantially similar results. The skilled practitioner will appreciate that the examples provide guidance and may be varied based on the condition being treated and the patient. The following abbreviations are used:
• EDTA ethylenediaminetetracetic acid
• SDA synthetically denatured alcohol
• USP United States Pharmacopoeia
• Example A tablet composition for oral administration, according to the present invention, is made comprising:
• the patient is examined and is found to have reduced inflammation and improved mobility without concomitant pain.
• a capsule for oral administration is made comprising: Component Amount (%w/w)
• the patient is examined via x-ray, arthroscopy and/or MRI, and found to have no further advancement of erosion/fibrillation of the articular cartilage.
• a saline-based composition for local administration is made comprising:
• Component Amount (%w/w)
• a patient having deep corneal abrasion applies a drop of the composition to each eye twice a day. Healing is speeded, with no visual sequelae.
• Example D A topical composition for local administration, according to the present invention, is made comprising:
• Component Composition (% w/v)
• Purified water q.s. Total 100.00
• a patient suffering from chemical burns applies the composition at each dressing change (b.i.d.). Scarring is substantially diminished.
• An inhalation aerosol composition comprising:
• Component Composition (% w/v
• a topical opthalmic composition comprising:
• NATROSOL M Hydroxyethylcellulose 0.50 Sodium metabisulfite 0.10 5 Sodium chloride (0.9%) q.s.
• a human male subject weighing 90 kg (198 lbs), suffering from corneal ulcerations, is treated by a method of this invention. Specifically, for 2 months, a saline solution containing 10 mg of the compound of Example 16 is administered to saido subject's affected eye twice-daily.
• Example G
• composition for parenteral administration comprising:
• the above ingredients are mixed, forming a suspension.
• Approximately 2.0 mL of the suspension is administered, via injection, to a human subject with a premetastatic tumor.
• the injection site juxtaposes the tumor. This dosage is repeated twice daily, for approximately 30 days. After 30 days, symptoms of the disease subside, and dosage is gradually decreased to maintain the patient.
• a mouthwash composition is prepared:
• a lozenge composition is prepared:
• a patient uses the lozenge to prevent loosening of an implant in the maxilla.
• Example J gum composition is prepared, comprising the :
• Flavor 1.0 A patient chews the gum to prevent loosening of dentures.
• the composition is prepared by first mixing 80 kg of glycerin and all of the benzyl alcohol and heating to 65°C, then slowly adding and mixing together methylparaben, propylparaben, water, xanthan gum, and guar gum. These ingredients are mixed for about 12 minutes with a Silverson in-line mixer. The following ingredients are then added in the following order: remaining glycerin, sorbitol, antifoam C, calcium carbonate, citric acid, and sucrose. The flavors and coolants are separately combined and then are slowly added to the other ingredients. The mixture is mixed for about 40 minutes. The patient takes the formulation to prevent flare up of colitis.
• An obese human female subject who is determined to be prone to osteoarthritis, is administered the capsule described in Example B to prevent the symptoms of osteoarthritis. Specifically, a capsule is administered daily to the subject.
• the patient is examined via x-ray, arthroscopy and/or MRI, and found to have no significant advancement of erosion/fibrillation of the articular cartilage.
• Example M A human male subject weighing 90 kg (198 lbs.), who suffers a sports injury, is administered the capsule described in Example B to prevent the symptoms of osteoarthritis. Specifically, a capsule is administered daily to the subject.
• the patient is examined via x-ray, arthroscopy and/or MRI, and found to have no significant advancement of erosion/fibrillation of the articular cartilage.

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