WO2005032541A1 - Substituted heterocyclic mercaptosulfide inhibitors - Google Patents

Substituted heterocyclic mercaptosulfide inhibitors Download PDF

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Publication number
WO2005032541A1
WO2005032541A1 PCT/US2004/031847 US2004031847W WO2005032541A1 WO 2005032541 A1 WO2005032541 A1 WO 2005032541A1 US 2004031847 W US2004031847 W US 2004031847W WO 2005032541 A1 WO2005032541 A1 WO 2005032541A1
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hydrogen
heterocyclo
hydrocarbyl
formula
composition
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PCT/US2004/031847
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French (fr)
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Martin A. Schwartz
Yonghao Jin
Douglas R. Hurst
Qing-Xiang Sang
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Florida State University Research Foundation, Inc.
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Publication of WO2005032541A1 publication Critical patent/WO2005032541A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention is directed to novel substituted heterocyclic mercaptosulfide compounds, precursors, and derivatives as well as the methods for the preparation and pharmaceutical compositions of these compounds.
  • Many of these compounds are designed, synthesized, characterized, and tested to be potent, and some of them, selective inhibitors of matrix metalloproteinases (MMPs), in particular, membrane type 1 matrix metalloproteinase, gelatinase B, gelatinase A, collagenases, matrilysins, metalloelastase, and stromelysin-1.
  • MMPs matrix metalloproteinases
  • physiological and pathological processes and disease conditions include the prevention and treatment of cancer invasion, angiogenesis, and metastasis; stroke and cardiovascular diseases such as myocardial infarction, atherosclerosis, and restensosis; respiratory diseases such as bronchitis and emphysema; neuro-inflammatory diseases; arthritic diseases; periodontal disease; multiple sclerosis; spinal cord injury; inflammation; pain; corneal ulceration and other eye diseases; diabetic retinopathy and other diabetic complications; obesity; wound healing and regeneration; kidney diseases such as glomerulonephritis; neurodegenerative diseases; acquired immunodeficiency syndrome (AIDS); organ preservation for transplantation; the control of fertility and reproductive capabilities such as fertilization, implantation, uterine bleeding, birth control and contraception; blister formation; bone remodeling; male and female osteoporosis; allergic reactions; asthma; emphysema; bacterial meningitis; anti-rheumatic disorders; connective tissue degradation; bacterial infections, anti-toxins such as lethal factor
  • Matrix metalloproteinases are a family of zinc-endopeptidases that are believed to participate in angiogenesis, embryonic development, morphogenesis, reproduction, tissue resorption and remodeling, arthritis, and tumor growth, progression, invasion, and metastasis through breakdown of the extracellular matrix (ECM), cell surface proteins, processing growth factors, cytokines, or chemokines (Brinckerhoff, C. E. and Matrisian, L. M. Matrix metalloproteinases: a tail of a frog that became a prince. Nature Rev. Mol. Cell. Biol. 2002; 3, 207-214; Egeblad, M. and Werb, Z.
  • ECM extracellular matrix
  • CM matrix metalloproteinase substrate binding domains, modules, and exosites. Molec. Biotech. 2002; 22, 51-86). At least twenty three human MMPs have been reported and even more have been reported in vertebrates. Many MMPs such as membrane type 1 matrix metalloproteinase (MT1-MMP) are reported to play multiple functions in ECM remodeling, development, growth, morphogenesis and disease conditions.
  • MMPs membrane type 1 matrix metalloproteinase (MT1-MMP) are reported to play multiple functions in ECM remodeling, development, growth, morphogenesis and disease conditions.
  • MTI-MMP- deficient mice develop dwarfism, osteopenia, arthritis, craniofacial dysmorphism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues (Holmbeck, K., Bianco, P., Caterina, J., Yamada, S., Kromer, M., Kuznetsov, S.A., Mankani, M., Robey, P.G., Poole, A.R., Pidoux, I., Ward, J.M., and Birkedal-Hansen, H.
  • MTI-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover.
  • MT1-MMP is a key enzyme essential for promoting 3-dimensional tumor growth and invasion in vitro and in vivo (Hotary, K.B., Allen, E.D., Brooks, P.C., Datta, N.S., Long, M.W., and Weiss, S.J. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell, 2003; 114, 33-45.) Selective inhibition of certain MMP enzymes, specifically those modulating physiological and disease conditions, is highly desirable.
  • novel substituted heterocyclic mercaptosulfide inhibitors and the salts thereof are novel substituted heterocyclic mercaptosulfide inhibitors and the salts thereof.
  • the inhibitors correspond to Formula 1 :
  • R 20 , R 21 , R 27 and R 28 are independently hydrogen, hydrocarbyl or substituted hydrocarbyl;
  • the X ring is a 5-7 membered saturated heterocyclic ring comprising X 2 ;
  • X 1 is a cation, hydrogen or acyl;
  • X 3 and X 4 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo, or X 3 and X 4 in combination with the carbon atom to which they are attached form a carbocyclic or heterocyclo ring;
  • X 5 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or -NX 51 X 52 ;
  • X 6 and X 7 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo, or X 6 and X 7 in combination with the carbon atom to which they are
  • the present invention is further directed to pharmaceutical compositions comprising such compounds or the salts thereof and the use of such compositions in a method of treatment of a disease or condition mediated by an MMP enzyme.
  • pharmaceutical compositions comprising such compounds or the salts thereof and the use of such compositions in a method of treatment of a disease or condition mediated by an MMP enzyme.
  • the present invention is directed to a compound corresponding to Formula 1 or a salt thereof:
  • R 20 , R 21 , R 27 , R 28 , X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as previously defined.
  • the "X" ring contains X 2 , two carbon atoms substituted by R 20 , R 21 , R 27 , and R 28 , and two carbon atoms in the alpha position relative to the two carbon atoms substituted by R 20 , R 21 , R 27 , and R 28 .
  • X 1 is a cation, hydrogen, or acyl.
  • X 1 is hydrogen.
  • X 1 may be an alkali metal; for example, X 1 may be sodium or potassium.
  • X 1 may be an alkaline earth metal; for example, X 1 may be magnesium or calcium. In other embodiments, X 1 may be aluminum or ammonium.
  • X 1 may be acyl; for example, X 1 may be RC(O)-, wherein R is R 1 , R 1 O-, R 1 R 2 N-, or R 1 S-, wherein R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R 2 is hydrogen, hydrocarbyl or substituted hydrocarbyl.
  • X 1 is -SX 11 , wherein X 11 is hydrocarbyl, substituted hydrocarbyl, heterocyclo or acyl.
  • X is a five-, six- or seven-membered saturated ring and X 2 is oxygen.
  • X is a five-, six- or seven-membered saturated ring and X 2 is sulfone.
  • X is a five-, six- or seven-membered saturated ring and X 2 is -N(X 20 )- wherein X 20 is as previously defined.
  • the oxygen, sulfur or nitrogen atom is covalently bonded directly to the carbon atoms substituted by R 20 , R 21 , R 27 , and R 28 .
  • the X 2 oxygen, sulfur or nitrogen atom is covalently bonded directly to one of the two carbon atoms substituted by R 20 , R 21 , R 27 , and R 28 and indirectly bonded to the other (by means of another ring atom).
  • the X 2 oxygen, sulfur or nitrogen atom is covalently bonded indirectly to each of the two carbon atoms substituted by R 25 , R 26 , R 27 , and R 28 (by means of two other ring atoms). In each of these embodiments, the X ring is fully saturated.
  • X 2 is -N(X 20 )-
  • X 20 may be selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, acyl, -OX 21 , and -NX 23 X 24 . In one embodiment, X 20 is hydrogen.
  • X 20 is acyl; for example, X 20 may be X 200 C(O)- wherein X 200 is alkyl, substituted alkyl, R 1 R 2 N-, RO-, or -NH 2 , where R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R 2 is hydrogen, hydrocarbyl or substituted hydrocarbyl.
  • X 20 may be X 200 C(O)- wherein X 200 is a heterocyclo ring such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl and the like.
  • Exemplary substituents for X 200 where X 200 is a heterocyclo include, but are not limited to, hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy and acyl.
  • X 20 may be -OX 21 wherein X 21 is hydrocarbyl, substituted hydrocarbyl, heterocyclo, or aryl.
  • X 20 may be -NX 23 X 24 wherein X 23 and X 24 are independently hydrocarbyl, substituted hydrocarbyl, heterocyclo, or aryl; or X 23 and X 24 in combination with the nitrogen atom to which they are attached form a heterocyclo ring such as morpholine, azepine, piperdine, pyrrolidine.
  • X 3 and X 4 may be independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and heterocyclo. In one such embodiment, X 3 and X 4 are hydrogen. In another such embodiment, X 3 is hydrogen and X 4 is hydrocarbyl or substituted hydrocarbyl.
  • X 3 may be hydrogen when X 4 is alkyl or alkaryl.
  • X 3 may be hydrogen when X 4 is methyl, ethyl or a C3-C6 straight, branched or cycloalkyl.
  • X 3 may be hydrogen when X 4 is a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 may be hydrogen when X 4 is alkyl or alkaryl.
  • X 3 may be hydrogen when X 4 is optionally substituted alkaryl, e.g., benzyl (-CH 2 C 6 H 5 ) wherein the substituents are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • alkaryl e.g., benzyl (-CH 2 C 6 H 5 ) wherein the substituents are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl
  • X 3 may be hydrogen when X 4 is heterocyclo, e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • heterocyclo e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl
  • X 3 and X 4 in combination with the carbon atom to which they are attached may form a hydrocarbyl, substituted hydrocarbyl or heterocyclo ring.
  • X 3 and X 4 in combination with the carbon atom to which they are attached may form furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl.
  • X 5 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and -NX 51 X 52 wherein X 51 and X 52 are (i) independently hydrocarbyl, substituted hydrocarbyl, heterocyclo, or acyl; or (ii) X 51 and X 52 in combination with the nitrogen atom to which they are attached form a heterocyclo ring.
  • X 5 is hydrogen.
  • X 5 is alkyl; for example X 5 may be optionally substituted methyl, ethyl, or C3-C6 straight, branched or cycloalkyl wherein the substituents are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, dialkylamino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • substituents are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, dialkyla
  • X 5 is -NX 51 X 52 wherein X 51 and X 52 are independently hydrocarbyl, substituted hydrocarbyl, heterocyclo, or acyl.
  • X 6 and X 7 may be independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and heterocyclo. In one such embodiment, X 6 and X 7 are hydrogen. In another such embodiment, X 6 is hydrogen and X 7 is hydrocarbyl or substituted hydrocarbyl. For example, X 6 may be hydrogen when X 7 is alkyl or alkaryl.
  • X 6 may be hydrogen when X 7 is methyl, ethyl or a C3-C6 straight, branched or cycloalkyl.
  • X 6 may be hydrogen when X 7 is a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 6 may be hydrogen when X 7 is alkyl or alkaryl.
  • X 6 may be hydrogen when X 7 is optionally substituted alkaryl, e.g., benzyl (-CH 2 C 6 H 5 ) wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, hexyl, and a heterocyclo ring such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl.
  • X 6 may be hydrogen when X 7 is heterocyclo, e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • heterocyclo e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl
  • X 6 and X 7 in combination with the carbon atom to which they are attached may form a hydrocarbyl, substituted hydrocarbyl or heterocyclo ring.
  • X 6 and X 7 in combination with the carbon atom to which they are attached may form furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl.
  • X 8 and X 9 are hydrogen.
  • X 8 is hydrogen and X 9 is alkyl; for example, X 8 may be hydrogen and X 9 may be optionally substituted methyl, ethyl, or C3-C6 straight, branched or cyclic alkyl.
  • X 8 is hydrogen and X 9 is optionally substituted aryl; for example, X 8 may be hydrogen and X 9 may be optionally substituted phenyl.
  • X 8 may be hydrogen and X 9 may be methyl.
  • X 8 may be hydrogen and X 9 may be para-methoxyphenyl.
  • the substituents may be selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 8 and X 9 in combination with the nitrogen atom to which they are attached may form a heterocyclo ring.
  • X 8 and X 9 in combination with the nitrogen atom to which they are attached may form piperidine, pyrrolidine, morpholine, or azepine.
  • the compound corresponds to Formula 1
  • the X ring is a 5- membered saturated ring and X 2 is -N(X 20 )-.
  • the compound may correspond to Formula 2n:
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1 and the hydrogen atoms shown have the ⁇ stereochemical orientation and the sulfur atoms shown have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1 , and the hydrogen atoms shown have the stereochemical orientation and the sulfur atoms shown have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1 , and X 4 and X 7 have the ⁇ stereochemical orientation and X 3 and X 6 have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1 ; and X 4 and X 7 have the ⁇ stereochemical orientation, X 3 and X 6 have the ⁇ stereochemical orientation, the hydrogen atoms shown have the ⁇ stereochemical orientation and the sulfur atoms shown have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3- C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as previously defined in connection with Formula 1.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is a
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1 and the hydrogen atoms shown have the ⁇ stereochemical orientation and the sulfur atoms shown have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1 , and X 4 and X 7 have the ⁇ stereochemical orientation and X 3 and X 6 have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1 ; and X 4 and X 7 have the ⁇ stereochemical orientation, X 3 and X 6 have the ⁇ stereochemical orientation, the hydrogen atoms shown have the ⁇ stereochemical orientation, and the sulfur atoms shown have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3- C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is any suitable for a compound that corresponds to Formula 9o.
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as previously defined in connection with Formula 1.
  • R 20 , R 2 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1 and the hydrogen atoms shown have the ⁇ stereochemical orientation and the sulfur atoms shown have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is any suitable for a compound that corresponds to Formula 9s.
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1 , and X 4 and X 7 have the ⁇ stereochemical orientation and X 3 and X 6 have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 20 are as previously defined in connection with Formula 1 ;
  • X 4 and X 7 have the ⁇ stereochemical orientation,
  • X 3 and X 6 have the ⁇ stereochemical orientation,
  • the hydrogen atoms shown have the ⁇ stereochemical orientation, and the sulfur atoms shown have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • heterocyclo e.g., furyl, thienyl, pyridyl
  • the X ring is a six membered saturated ring and X 2 is directly bonded to one of the two carbon atoms substituted by R 20 , R 21 , R 27 , and R 28 and indirectly bonded to the other as depicted in Formulae 10 and 11 :
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as previously defined in connection with Formula 1 ;
  • X 25 is -C(R 22 )(R 23 )-, oxygen or -N(R 24 )-; and
  • R 22 , R 23 and R 24 are independently an hydrogen, hydrocarbyl, or substituted hydrocarbyl.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • the X ring is a six membered saturated ring and X 2 is directly bonded to one of the two carbon atoms substituted by R 20 , R 21 , R 27 , and R 28 and indirectly bonded to the other as depicted in Formulae 10a and 11a:
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as previously defined in connection with Formula 1 ;
  • X 25 is -C(R 22 )(R 23 )-, oxygen or -N(R 24 )-; and
  • R 22 , R 23 and R 24 are independently an hydrogen, hydrocarbyl, or substituted hydrocarbyl and the hydrogen atoms shown have the ⁇ stereochemical orientation and the sulfur atoms shown have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • the X ring is a six membered saturated ring and X 2 is directly bonded to one of the two carbon atoms substituted by R 20 , R 21 , R 27 , and R 28 and indirectly bonded to the other as depicted in Formulae 10b and 11b:
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as previously defined in connection with Formula 1;
  • X 25 is -C(R 22 )(R 23 )-, oxygen or -N(R 24 )-; and
  • R 22 , R 23 and R 24 are independently an hydrogen, hydrocarbyl, or substituted hydrocarbyl; and X 4 and X 7 have the ⁇ stereochemical orientation and X 3 and X 6 have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • the X ring is a six membered saturated ring and X 2 is directly bonded to one of the two carbon atoms substituted by R 20 , R 21 , R 27 , and R 28 and indirectly bonded to the other as depicted in Formulae 10c and 11c:
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as previously defined in connection with Formula 1 ;
  • X 25 is -C(R 22 )(R 23 )-, oxygen or -N(R 24 )-; and
  • R 22 , R 23 and R 24 are independently an hydrogen, hydrocarbyl, or substituted hydrocarbyl; and
  • X 4 and X 7 have the ⁇ stereochemical orientation, X 3 and X 6 have the ⁇ stereochemical orientation, the hydrogen atoms shown have the ⁇ stereochemical orientation, and the sulfur atoms shown have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 In another embodiment in which the compound corresponds to Formula 10 or 11 R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • the compound corresponds to Formula 10 or 11 X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals,
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • heterocyclo e.g., furyl, thienyl, pyridyl
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , and X 20 are as previously defined in connection with Formula 1; and R 22 , R 23 and R 24 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, ace
  • heterocyclo e.g., furyl, thienyl, pyridyl, oxazolyl, pyr
  • X 2 is indirectly bonded to each of the carbon atoms substituted by R 20 , R 21 , R 27 , and R 28 through another ring atom selected from carbon and nitrogen.
  • the compound corresponds to Formula 13:
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as previously defined in connection with Formula 1 ;
  • two of X 25 , X 26 and X 27 are selected from -C(R 22 )(R 23 )- and X 2 (i.e., oxygen, sulfone, or -N(X 20 )-), provided, however at least one of X 25 and X 27 is -C(R 22 )(R 23 )-; and
  • each R 22 and R 23 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3- C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is a seven membere
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as previously defined in connection with Formula 1 ;
  • two of X 25 , X 26 and X 27 are selected from -C(R 22 )(R 23 )- and X 2 (i.e., oxygen, sulfone, or -N(X 20 )-), provided, however, at least one of X 25 and X 27 is -C(R 22 )(R 23 )-;
  • each R 22 and R 23 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and the hydrogen atoms shown have the ⁇ stereochemical orientation and the sulfur atoms shown have the ⁇ stereochemical orientation.
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is a seven
  • R 20 , R 21 , R 27 , R 28 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are as previously defined in connection with Formula 1 ;
  • two of X 25 , X 26 and X 27 are selected from -C(R 22 )(R 23 )- and X 2 (i.e., oxygen, sulfone, or -N(X 20 )-), provided, however, at least one of X 25 and X 27 is -C(R 22 )(R 23 )-; and
  • each R 22 and R 23 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and
  • X 4 and X 7 have the ⁇ stereochemical orientation and X 3 and X 6 have the ⁇ stereochemical orientation.
  • R 20 corresponds to Formula 13b
  • R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • the X ring is a seven
  • R 20 , R 21 , R 27 , and R 28 are each hydrogen.
  • X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 , X 3 , X 5 , X 6 , and X 8 are each hydrogen.
  • R 20 , R 21 , R 27 , R 28 are independently hydrocarbyl or substituted hydrocarbyl.
  • X 3 , X 5 , X 6 , and X 8 are hydrogen and X 4 , X 7 , and X 9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • X 3 , X 5 , X 6 , and X 8 may be hydrogen when X 4 , X 7 , and X 9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers).
  • heterocyclo e.g., furyl, thienyl, pyridyl
  • the compounds of the present invention have several asymmetric carbons, it is known to those skilled in the art that the compounds of the present invention having asymmetric carbon atoms may exist in diastereometric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes the enantiomers, diastereomers, racemic mixtures, and other optically active mixtures of the compounds disclosed herein. Synthesis MMPs of the general Formula 1 may be obtained according to the following scheme:
  • Boc terf-butoxycarbonyl; mCPBA, meta-chloroperbenzoic acid; Ph, phenyl; Et, ethyl; t-Bu, ferf-butyl; Me, methyl; DEAD, diethyl azodicarboxylate; THF, tetrahydrofuran;Ac, acetyl; DMF, dimethylformamide; HOBT, 1- hydroxybenzotriazole; EDCI, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • the S-acyl group is modified into the S-Boc group, then the alcohol functionality is replaced by a second acylthio group, with cis stereochemistry, using a variant of the Mitsunobu reaction with a thiolcarboxylic acid such as thiolacetic acid.
  • the S-acetyl group is selectively cleaved using a base in alcohol solvent, and the resulting deblocked thiol is S-alkylated with an ⁇ -bromocarboxylic acid in the presence of a mild base such as potassium carbonate in a solvent such as N,N- dimethylformamide.
  • ⁇ -bromocarboxylic acids are readily available, or are prepared from the corresponding ⁇ -amino acids by treatment with NaNO 2 in cold aqueous HBr.
  • the resulting c/s-substituted S-Boc protected heterocyclic -thiocarboxylic acids are obtained as an approximately 1 :1 mixture of diastereomers.
  • the carboxylic acids are coupled with readily available ⁇ -amino acid amides using a carbodiimide such as EDCI in the presence of an activating agent such as HOBT and a base such as triethylamine, to yield the c/s- substituted S-Boc protected heterocyclic mercaptosulfide inhibitors as an approximately 1 :1 mixture of diastereomers.
  • a carbodiimide such as EDCI
  • an activating agent such as HOBT
  • a base such as triethylamine
  • the diastereomers are separated by chromatography if desired, then the S-Boc group is selectively cleaved by treatment with a strong acid such as HCI, in a non-aqueous solvent such as acetic acid, to afford the deblocked substituted heterocyclic mercaptosulfide inhibitors of general Formula 1.
  • a strong acid such as HCI
  • a non-aqueous solvent such as acetic acid
  • MMP selective inhibitors utilized in the present invention may be in the form of free bases or pharmaceutically acceptable acid addition salts thereof.
  • pharmaceutically-acceptable salts are salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt may vary, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds for use in the present methods may be prepared from an inorganic acid or from an organic acid.
  • organic acids examples include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cycl
  • Suitable pharmaceutically-acceptable base addition salts of compounds of use in the present methods include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N.N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound of any formula set forth herein.
  • MMP inhibitors have been described previously in other MMP inhibitor patents, including but not limited to: Purchase, Jr. et al., United States Patent No. US 6,624,196 B2, Benzene butyric acids and their derivatives as inhibitors of matrix metalloproteinases; and Schwartz et al. United States Patent No. 5,455,262, Mercaptosulfide metalloproteinase inhibitors.
  • MMPs are the major endopeptidases that hydrolyze multiple connective tissue proteins and are likely to be targets for controlling pathological catabolism of ECM proteins.
  • Applications of the compounds of the present invention may include, but are not limited to, control multiple physiological and pathological processes and conditions.
  • MMP inhibitors Egeblad, M. and Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2002; 2, 163-175; Nemeth, J.A., Yousif, R., Herzog, M., Che, M., Upadhyay, J., Shekarriz, B., Bhagat, S., Mullins, C, Fridman, R., and Cher, M.L. Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis. J. Natl. Cancer Inst.
  • angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J. 2002; 16, 2-14).
  • the compounds described herein may be used for the prevention and treatment of cardiovascular diseases such as restenosis, cardiac hypertrophy, atherosclerotic plaque rupture, aortic aneurysm, and heart attacks (Loftus, I.M.
  • MMP matrix metalloproteinases
  • Vase. Med. 2002 7,117-133
  • Cardiovascular diseases are the leading causes of death in Western society.
  • Extracellular matrix (ECM) turnover mediated by MMPs is important in many cardiovascular pathologies, such as arterial remodeling, plaque rupture, restenosis, aneurysm formation and heart failure.
  • MMP inhibitors are likely to be useful in the development of pharmacological approaches to reduce cardiovascular death, considering the positive outcomes after usage of MMP inhibitors in restenosis and arterial remodeling (Sierevogel, M.J., Pasterkamp, G., De Kleijn, D.P., and Strauss, B.H. Matrix metalloproteinases: a therapeutic target in cardiovascular disease. Curr.
  • MMP expression has been detected in the atherosclerotic plaque, and activation of MMPs appears to be involved in the vulnerability of the plaque. Circulating MMP levels are elevated in patients with acute myocardial infarction and unstable angina. Increased MMP expression is also observed after coronary angioplasty, which is related to late loss index after the procedure. These observations suggest that MMP expression may be not only related to instability of the plaque, but also to the formation of restenotic lesions. The development of therapeutic drugs targeted specifically against MMPs may be useful in the prevention of atherosclerotic lesion development, plaque rupture, and restenosis (Ikeda, U. and Shimada, K.
  • MMP blocks in-stent intimal hyperplasia and offers a novel approach to prevent in-stent restenosis (Li, C, Cantor, W.J., Nili, N., Robinson, R., Fenkell, L., Tran, Y.L., Whittingham, H.A., Tsui, W., Cheema, A.N., Sparkes, J.D., Pritzker, K., Levy, D.E., and Strauss, B.H. Arterial repair after stenting and the effects of GM6001 , a matrix metalloproteinase inhibitor. J. Am. Coll. Cardiol. 2002; 39,1852-1858).
  • MMP inhibitors may be used to treat degenerative aortic disease associated with thinning of the medial aortic wall. Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurisms and aortic stenosis (Vine, N. and Powell, J. T. Metalloproteinases in degenerative aortic diseases. Clin. Sci., 1991 ; 81,233- 239). MMPs are involved in the pathogenesis of cardiovascular disease, including atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction.
  • MMP inhibitors are potential therapeutic agents for prevention and treatment of heart failure.
  • MMP inhibitors may also be used for coating stents to timely release MMP inhibitors to prevent restenosis.
  • MMPs inhibitors To prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA) and/or stenting of atherosclerotic stenosed arteries, two water-soluble MMPs inhibitors have already been designed and developed by other groups (Masuda, T, and Nakayama, Y. Development of a water-soluble matrix metalloproteinase inhibitor as an intra-arterial infusion drug for prevention of restenosis after angioplasty. J. Med. Chem. 2003; 46, 3497-3501 ). Myocardial infarction (Ml) is associated with early metalloproteinase (MMP) activation and extracellular matrix (ECM) degradation.
  • MMP early metalloproteinase
  • ECM extracellular matrix
  • Preserving the original ECM of the infarcted left ventricle (LV) by use of early short-term doxycycline (DOX) treatment preserves cardiac structure and function.
  • Early MMP inhibition after Ml yields preservation of LV structure and global as well as scar area passive function, supporting the concept that preserving the original ECM early after coronary occlusion lessens ventricular remodeling (Villarreal, F.J., Griffin, M., Omens, J., Dillmann, W., Nguyen, J., and Covell, J,.
  • Early short-term treatment with doxycycline modulates postinfarction left ventricular remodeling. Circulation. 2003;108, 1487-1492. Epub 2003 Sep 02).
  • Congestive heart failure is a leading cause of death in developed countries and its prevalence is increasing throughout the world. Progressive left ventricular dilation and contractile dysfunction cause most cases of CHF. MMPs are not only associated with ventricular dilation, but may actually mediate the dilation process. Because these enzymes are extracellular and are pharmacologic targets, MMP inhibition is a novel potential therapy for delaying or preventing heart failure (Lindsey, M., and Lee, R.T. MMP inhibition as a potential therapeutic strategy for CHF. Drug News Perspect. 2000; 13, 350-354). Metalloproteinase inhibitors may be used to treatment many other types of cardiovascular diseases.
  • Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke.
  • Metalloproteinase inhibitors may be used to preserve organs for transplantation and prevent hemorrhagic stroke.
  • a new report has described systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy (Yamani, M.H.,
  • metalloproteinase inhibitors may be useful for kidney and other organ transplantation (Marti, H.P. The role of matrix metalloproteinases in the activation of mesangial cells. Transpl. Immunol. 2002; 9, 97-100).
  • the compounds described herein may be useful for the treatment of different types of arthritis.
  • MMP inhibition are useful to treatment osteoarthritis in animal models (Janusz, M.J., Hookfin, E.B., Heitmeyer, S..A, Woessner, J.F., Freemont, A.J., Hoyland, J.A., Brown, K.K., Hsieh, L.C., Almstead, N.G., De, B., Natchus, M..G, Pikul, S., and Taiwo, Y.O. Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors. Osteoarthritis Cartilage.
  • stromelysin and collagenase in synovial fluid from patients with rheumatoid arthritis and post-traumatic knee injury Detection of stromelysin and collagenase in synovial fluid from patients with rheumatoid arthritis and post-traumatic knee injury.
  • Rheumatoid arthritis and osteoarthritis are chronic diseases that result in cartilage degradation and loss of joint function.
  • drugs are predominantly directed towards the control of pain and/or the inflammation associated with joint synovitis but they do little to reduce joint destruction. It will be important to have drugs such as metalloproteinase inhibitors that prevent the structural damage caused by bone and cartilage breakdown (Elliott, S., and Cawston, T. The clinical potential of matrix metalloproteinase inhibitors in the rheumatic disorders.
  • Metalloproteinase inhibitors have been used to treat periodontal diseases (Ramamurthy, N.S., Rifkin, B.R., Greenwald, R.A., Xu, J.W., Liu, Y., Turner, G., Golub, L.M., and Vernillo, A.T. Inhibition of matrix metalloproteinase-mediated periodontal bone loss in rats: a comparison of 6 chemically modified tetracyclines. J. Pehodontol. 2002; 73, 726-734; and Ciancio, S.G. Systemic medications: clinical significance in periodontics. J. Clin. Pehodontol. 2002; Suppl 2, 17-21).
  • metalloproteinase inhibitors may also control the progression of macular degeneration (Musarella, M.A. Molecular genetics of macular degeneration. Doc. OphthalmoL 2001; 102, 165-177).
  • Metalloproteinase inhibitors may prevent human immunodeficiency virus-induced neurodegeneration (Zhang, Kdon McQuibban, G.A., Silva, C, Butler, G.S., Johnston, J.B., Holden, J., Clark-Lewis, I., Overall, CM., and Power, C. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nat Neurosci. 2003; 6,1064-1071.
  • inhibitors may be used to treat spinal cord injury and promote wound healing (Goussev, S., Hsu, J.Y., Lin, Y., Tjoa, T., Maida, N., Werb, Z., and Noble-Haeusslein, L.J. Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing. J. Neurosurg. 2003; 99(2 Suppl): 188-197).
  • Gelatinases belonging to the matrix metalloproteases, contribute to tissue destruction in inflammatory demyelinating disorders of the central nervous system such as multiple sclerosis. Gijbels et al.
  • EAE experimental autoimmune encephalomyelitis
  • GM 6001 hydroxamate matrix metalloprotease inhibitor
  • GM 6001 hydroxamate matrix metalloprotease inhibitor
  • Metalloproteinase inhibitors may have multiple functions against multiple diseases (Supuran, C.T., Casini, A., and Scozzafava, A. Protease inhibitors of the sulfonamide type: anticancer, antiinflammatory, and antiviral agents. Med. Res. Rev. 2003; 23, 535-558).
  • MMP inhibitors many potential therapeutic applications have been summarized and listed (Whittaker, M., Floyd, CD., Brown, P., and Gearing, A.J.H. Design and Therapeutic Application of Matrix Metalloproteinase Inhibitors. Chem. Rev. 1999; 99, 2735 -2776).
  • Metalloproteinase inhibitors including the inhibitors inhibit both MMPs and adamalysins/ADAMs have the potential utility in the prevention and treatment of multiple diseases, including but not limited to cancer, inflammation, arthritis, restensosis, aortic aneurysm, glomerulonephritis, Guillain Barre syndrome, Bacterial Meningitis, Uveoretinitis, Graft-versus-host disease (GVHD), noninsulin-dependent diabetes mellitus, and other diseases and conditions.
  • GVHD Graft-versus-host disease
  • the migration of leucocytes through connective tissues, tissue destruction, remodeling, and angiogenesis observed in inflammatory diseases mirror similar MMP-driven processes in cancer.
  • TNF-converting enzyme TNF-converting enzyme
  • BB-1101 MMP inhibitors
  • MMP inhibitors have been shown to be effective in a number of animal models of inflammatory disease.
  • Glomerulonephritis is a nephritic syndrome which results in destruction and fibrosis of the kidney.
  • BB-1101 given prior to disease induction significantly reduced the inflammatory response and kidney damage.
  • EAE experimental autoimmune encephalomyelitis
  • MS multiple sclerosis
  • rodents are immunized with myelin or one of its protein components in adjuvant, resulting in an autoimmune inflammation of the brain and spinal cord.
  • Adoptive transfer of activated myelin-specific T cells can also result in a similar disease with recurrent episodes of paralysis.
  • An MS-like lesion can also be induced in the brain by the generation of a delayed-type hypersensitivity response (DTH).
  • DTH delayed-type hypersensitivity response
  • GBS Guillain Barre syndrome
  • GBS is an acute inflammatory paralytic disease of the peripheral nervous system in which leucocytes infiltrate nerves causing demyelination and edema.
  • EAN experimental autoimmune neuritis
  • Inhibitor BB-1101 given from initiation in EAN prevented the development of symptoms and reduced the inflammation, demyelination, and weight loss.
  • Animal models of stroke usually involve clipping or blocking the mid-cerebral artery to give either permanent or temporary occlusion and reperfusion.
  • injection of blood or bacterial collagenase into the brain can cause a local hemorrhage.
  • An inflammatory infiltrate is associated with the damaged region in these models.
  • Inhibitor BB-1101 reduces the early phases of blood-brain barrier leakage in an ischemia reperfusion model in the rat and the secondary brain edema which occurs following hemorrhage.
  • rodents can develop bacterial meningitis following infection with bacteria.
  • Batimastat was effective in reducing intracranial pressure and blood-brain barrier breakdown in a model of meningococcal meningitis.
  • Uveoretinitis is an autoimmune inflammatory disease of the eye.
  • Rodent models of uveitis involve immunization with retinal antigens in adjuvant. Treatment with inhibitor BB-1101 was shown to reduce retinal damage in experimental autoimmune uveitis.
  • GVHD graft-versus-host disease
  • TNF- tumor necrosis factor-alpha
  • Fas ligand release by KB- R7785.
  • TNF- tumor necrosis factor-alpha
  • KB-R7785 exerts its antidiabetic effect by ameliorating insulin sensitivity through the inhibition of TNF- production.
  • Airway inflammation and remodeling are key features of asthma. MIVIPs and their inhibitors are thought to contribute to the pathogenesis of asthma via their influence on the function and migration of inflammatory cells as well as matrix deposition and degradation (Kelly, E.A., Jarjour, N.N. Role of matrix metalloproteinases in asthma. Curr. Opin. Pulm. Med. 2003; 9, 28-33 and Chiappara, G., Gagliardo, R., Siena, A, Bonsignore, M.R., Bousquet, J., Bonsignore, G., and Vignola, A.M. Airway remodeling in the pathogenesis of asthma. Curr. Opin. Allergy Clin. Immunol. 2001; 1 , 85-93).
  • Metalloproteinase inhibitors may modulate wound healing process (Armstrong, D.G., and Jude, E.B. The role of matrix metalloproteinases in wound healing. J. Am. Podiatr. Med. Assoc. 2002; 92, 12-18). These inhibitors may be beneficial to prevention and treatment of stroke (Lapchak, P.A., Araujo, D.M. Reducing bleeding complications after thrombolytic therapy for stroke: clinical potential of metalloproteinase inhibitors and spin trap agents. CNS Drugs. 2001 ; 75, 819-829). Neuroinflammation, which occurs in response to brain injury or autoimmune disorders, has been shown to cause destruction of healthy tissues.
  • Neuroinflammatory mechanisms are involved in many acute and chronic neurodegenerative disorders, including stroke, multiple sclerosis, head trauma, and Alzheimer's disease (McGeer, E. G. and McGeer, P. L., Neurodegeneration and the immune system. In: Calne D. B., ed. Neurodegenerative Diseases, W. B. Saunders, 1994; pp277-300). Other diseases that may implicate neuroinflammatory mechanisms include amyotrophic lateral sclerosis (Leigh, P. N., Pathogenic mechanisms in amyotrophic lateral sclerosis and other motor neuron disorders. In: Calne D. B., ed., Neurodegenerative Diseases, W. B.
  • Leukocyte Biol., 1994; 56:387-388 Parkinson's disease, Huntington's disease, prion diseases, and certain disorders involving the peripheral nervous system, such as myasthenia gravis and Duchenne's muscular dystrophy, as well as Alzheimer's disease ( Aisen P. S., "Anti- inflammatory therapy for Alzheimer's disease,” Dementia, 1995;9:173-82).
  • Metalloproteinase inhibitors may modulate these processes and slow the disease progression.
  • MMPs and metalloproteinases play extremely important roles in reproduction and the control of fertility and reproductive capabilities (e.g. contraception/birth control).
  • Fertilization, menstrual cycle, embryo implantation, uterine bleeding, and many other normal and pathological reproductive processes are controlled by metalloproteinases and their inhibitors (Bischof, P., Campana, A. Molecular mediators of implantation. Baillieres Best Pract. Res. Clin. Obstet. Gynaecol. 2000; 14, 801-814 and Dong, J.C., Dong, H., Campana, A., and Bischof, P. Matrix metalloproteinases and their specific tissue inhibitors in menstruation. Reproduction. 2002; 123, 621-631).
  • cardiovascular diseases, inflammation, pain and arthritis other conditions may be prevented and treated by these inhibitors, for example, control of corneal ulceration; diabetic retinopathy and other diabetic complications; wound healing; osteoporosis; kidney diseases; neurodegenerative diseases including, Alzheimer's disease, spinal cord injury, head trauma, AIDS, Parkinson's disease, Huntington's disease, prion diseases; the control of fertility and reproductive capabilities (e.g.
  • contraception/birth control regulation of blister formation; regulation of allergy; modulation of bone remodeling and regeneration; control of asthma; or other inflammatory or autoimmune disorders relying on tissue invasion by different types of cells including white blood cells, and many types of diseases involved in the immuno-system in the body (Whittaker, M., Floyd, CD., Brown, P., and Gearing, A.J.H. Design and Therapeutic Application of Matrix Metalloproteinase Inhibitors. Chem. Rev. 1999; 99, 2735 -2776; and Stemlicht, M.D. and Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001 ;17, 463-516. Review).
  • Metalloproteinase inhibitors may have anti-bacterial activities (Scozzafava, A., Supuran, CT. Protease inhibitors - part 5. Alkyl/arylsulfonyl- and arylsulfonylureido- arylureido- glycine hydroxamate inhibitors of Clostridium histolyticum collagenase. Eur. J. Med. Chem. 2000; 35, 299-307. Metalloproteinase inhibitors may be used in sun screens and skin lotions to prevent ultra violet (UV) irradiation damage to the skin and prevent skin aging. UV irradiation acts as a broad activator of cell surface growth factor and cytokine receptors.
  • UV irradiation acts as a broad activator of cell surface growth factor and cytokine receptors.
  • UV-enhanced matrix degradation is accompanied with decreased collagen production.
  • Several alterations to skin connective tissue that occur during aging are mediated by mechanisms that are similar to those that occur in response to UV irradiation.
  • skin aging is associated with increased AP-1 activity, increased MMP expression, impaired TGF-beta signaling, enhanced collagen degradation, and decreased collagen synthesis.
  • Knowledge gained from examining molecular responses of human skin to UV irradiation provides a framework for understanding mechanisms involved in skin aging and may help in development of new clinical strategies to impede chronological and UV-induced skin aging (Rittie, L, Fisher, G.J. UV-light-induced signal cascades and skin aging. Ageing Res. Rev. 2O02; 1 , 705-720).
  • Metalloproteinase inhibitors may be used for industrial manufacturing of extracellular matrix/collagen products, cosmetics, beauty, and skin protection and medication products. These inhibitors can be used for the prevention and treatments of conditions in human beings and in animals, such as dogs, horses, cats, pigs, birds, sheep, and cattle, as well as other organisms.
  • Formulation Compounds of the instant invention are preferably administered in the form of a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of the present invention or a salt thereof in combination with at least one pharmaceutically or pharmacologically acceptable carrier.
  • the carrier also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is any substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the therapeutic efficacy of the anti-viral compounds.
  • the carrier is "pharmaceutically or pharmacologically acceptable” if it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate.
  • the pharmaceutical compositions of the present invention may be formulated in any conventional manner.
  • compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route.
  • Suitable routes of ad ministration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrastemal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration.
  • compositions of the present invention are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular anti-viral compound used, and its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the composition; the subject, its age, size and general condition; and the route of administration. Suitable carriers are readily determined by one of ordinary skill in the art (see, for example, J. G. Nairn, in: Remington's Pharmaceutical Science (A. Gennaro, ed.), IVlack Publishing Co., Easton, Pa., (1985), pp. 1492-1517, the contents of which are incorporated herein by reference).
  • compositions may be formulated as tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, or any other dosage form which can be administered orally.
  • Techniques and compositions for making oral dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).
  • compositions for oral administration comprise a compound of the present invention, or a salt thereof, in a pharmaceutically acceptable carrier.
  • suitable carriers for solid dosage forms include sugars, starches, and other conventional substances including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid.
  • Such solid dosage forms may be uncoated or may be coated by known techniques; e.g., to delay disintegration and absorption.
  • the compounds of the present invention may also be formulated for parenteral administration, e.g., formulated for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrastemal routes.
  • the compositions of the invention for parenteral administration comprise an effective amount of the compound or a salt thereof in a pharmaceutically acceptable carrier.
  • Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally.
  • Suitable carriers used in formulating liquid dosage forms for oral or parenteral administration include nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable liquid.
  • nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable liquid.
  • Suitable nonaqueous, pharmaceutically-acceptable solvents include, but are not limited to, alcohols (e.g., ⁇ -glycerol formal, ⁇ -glycerol formal, 1 , 3-butyleneglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzy
  • esters e.g., 1-methyl-2-pyrrolidinone, 2- pyrrolid ⁇ none, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di, or tri-gly
  • each of these components will for the most part impart properties which enhance retention of the anti-viral compound at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the anti-viral compound into pharmaceutical formulations, and the like.
  • each of these components is individually present in less than about 15 weight % of the total composition, more typically less than about 5 weight %, and still more typically less than about 0.5 weight % of the total composition.
  • Some components, such as fillers or diluents, can constitute up to 90 wt.% of the total composition, as is well known in the formulation art.
  • Such additives include cryoprotective agents for preventing reprecipitation of the anti-viral compound surface active, wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylene stearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cet
  • Dosage form administration by these routes may be continuous or intermittent, depending, for example, upon the patient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to and assessable by a skilled practitioner.
  • Dosage and regimens for the administration of the pharmaceutical compositions of the invention can be readily determined by those with ordinary skill in the field of anti-viral therapy. It is understood that the dosage of the compositions will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the actual amount of the compound delivered, as well as the dosing schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on such factors as the bioavailability of the compound, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to those of skill in the art.
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect the desired therapeutic response in the animal over a reasonable period of time.
  • an effective amount of the compound, whether administered orally or by another route is any amount which would result in a desired therapeutic response when administered by that route.
  • the concentration of the compound of the present invention or salt thereof in a liquid pharmaceutical composition may be between about 0.01 mg and about 10 mg per ml of the composition.
  • the concentration of the compound or salt thereof in a solid pharmaceutical composition for oral administration may be between about 5 wt % and about 50 wt %, based on the total weight of the composition; in one embodiment, it may be between about 8 wt % and about 40 wt %, and, in another embodiment, between about 10 wt % and about 30 wt %.
  • solutions for oral administration are prepared by dissolving a compound of the present invention or salt thereof in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution. An appropriate volume of a carrier is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration to a patient.
  • powders or tablets for oral administration are prepared by dissolving the compound or salt thereof in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution.
  • the solvent can optionally be capable of evaporating when the solution is dried under vacuum.
  • An additional carrier can be added to the solution prior to drying.
  • the resulting solution is dried under vacuum to form a glass.
  • the glass is then mixed with a binder to form a powder.
  • the powder can be mixed with fillers or other conventional tableting agents and processed to form a tablet for oral administration to a patient.
  • the powder can also be added to any liquid carrier as described above to form a solution, emulsion, suspension or the like for oral administration.
  • Emulsions for parenteral administration can be prepared by dissolving the compound or salt thereof in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution.
  • An appropriate volume of a carrier which is an emulsion is added to the solution while stirring to form a pharmaceutically acceptable emulsion for parenteral administration to a patient.
  • Solutions for parenteral administration can be prepared by dissolving a compound or salt thereof in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution.
  • An appropriate volume of a carrier is added to the solution while stirring to form a pharmaceutically acceptable solution for parenteral administration to a patient.
  • the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials or other conventional containers in concentrated form and diluted with any pharmaceutically acceptable liquid, such as saline, to form an acceptable concentration prior to use as is known in the art.
  • hydrocarbon and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
  • substituted hydrocarbyl moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom.
  • substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
  • the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
  • aryl or “ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
  • amino as used herein alone or as part of another group denotes the moiety -NR 1 R 2 wherein R 1 and R 2 are hydrocarbyl, substituted hydrocarbyl or heterocyclo.
  • halogen or “halo” as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
  • heterocyclo or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
  • the heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom.
  • heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.
  • substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • heteroaromatic as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
  • the heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom.
  • Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.
  • substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • acyl denotes the moiety formed by removal of the hydroxyl group from the group -COOH of an organic carboxylic acid, e.g., RC(O) ⁇ , wherein R is R 1 , R 1 O-, R 1 R 2 N-, or R 1 S-, R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R 2 is hydrogen, hydrocarbyl or substituted hydrocarbyl.
  • DEAD denotes the moiety diethylazodicarboxylate.
  • pharmaceutically acceptable is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product; that is the "pharmaceutically acceptable” material is relatively safe and/or non-toxic, though not necessarily providing a separable therapeutic benefit by itself.
  • Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal salts, alkaline earth metal salts and other physiologically acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences.
  • Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N.N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine.
  • Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.
  • the following examples illustrate the invention.
  • fra ⁇ s-3-BocS-(Py-Boc)-4-OH To a stirred solution of fra ⁇ s-3-BzS-(Py-Boc)-4-OH (1.22 g, 3.74 mmol) in absolute ethanol (3 mL) at 0 ° C was added a solution of potassium t- butoxide (0.46 g, 4.1 mmol) in ethanol (4 mL) dropwise. After 20 min a solution of B0C2O (0.90 g, 4.1 mmol) in a minimum amount of CH2CI2 was added and stirring was continued at 0 ° C for 1 h. After removal of the ethanol under reduced pressure the residue was dissolved in ethyl acetate.
  • MMPs matrix metalloproteinases
  • MMP- 1/human fibroblast collagenase HFC
  • MMP-2/human fibroblast gelatinase HSG
  • MMP- 8/human neutrophil collagenase HNC
  • MMP-9/human neutrophil gelatinase HNG
  • MMP-7/human matrilysin MN
  • MMP-3/human fibroblast stromelysin-1 HFS
  • human recombinant catalytic domain of membrane-type 1 matrix metalloproteinase cdMT1- MMP
  • catalytic domain of MMP-12/metalloelastase cdMET
  • the active concentrations of MMPs were determined by titration with GM6001 , a tight-binding MMP inhibitor, as described previously (Park, H.I., Turk, B.E., Gerkema, F.E., Cantley, L.C., and Sang, Q.-X.A. Peptide substrate specificities and protein cleavage sites of human endometase/matrilysin-2/matrix metalloproteinase-26. J. Biol. Chem. 2002; 277, 35168-35175). Determination of Mercaptosulfide Inhibitor Concentration.
  • the active inhibitor concentrations were estimated by titrating the mercapto group with 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB; Ellman's reagent) as described previously (Ellman, G.L. A colorimetric method for determining low concentrations of mercaptans. Arch. Biochem. Biophys. 1958; 74, 443-450; Ellman, G.L. Tissue sulfhydryl groups. Arch. Biochem. Biophys. 1959; 82, 70-77; Riddles, P.W., Blakeley, R.L., and Zerner, B. Ellman's reagent: 5,5'-dithiobis(2-nitrobenzoic acid)--a reexamination.
  • DTNB 5,5'-dithiobis(2-nitrobenzoic acid)
  • the release of product was monitored by measuring fluorescence (excitation and emission wavelengths of 328 nm and 393 nm, respectively) with a Perkin Elmer Luminescence Spectrophotometer LS 50B connected to a temperature controlled water bath. All stock solutions of inhibitors were in methanol. For inhibition assays, 10 ⁇ l of inhibitor stock solution, 176 ⁇ l of assay buffer, and 10 ⁇ l of enzyme stock solution were mixed and incubated for 30 to 60 minutes prior to initiation of the assay, which was accomplished by adding and mixing 4 ⁇ l of the substrate stock solution. Enzyme concentrations ranged from 0.2 to 7 nM during the assay.
  • K, app Apparent inhibition constant (K, app ) values were calculated by fitting the kinetic data to the Morrison equation for tight- binding inhibitors (Morrison, J.F. Kinetics of the reversible inhibition of enzyme-catalyzed reactions by tight-binding inhibitors. Biochim. et Biophys. Acta 1969; 185, 269-286.), where v, and v 0 are the initial rates with and without inhibitor respectively, and [E] 0 and [/] 0 are the initial (total) enzyme and inhibitor concentrations respectively.

Abstract

Novel substituted heterocyclic mercaptosulfide compounds, precursors, and derivatives, the methods for the preparation, and pharmaceutical compositions of these compounds are described in this invention. These compounds are developed and tested to be potent and relatively selective inhibitors of matrix metalloproteinases (MMPs), e.g. membrane type 1 MMP, gelatinase B, gelatinase A, collagenases, matrilysins, metalloelastase, and stromelysin-1. These inhibitors will be used for the control of physiological and pathological processes in which metalloproteases play a significant role. These inhibitors can be used for human beings, animals, and other organisms.

Description

SUBSTITUTED HETEROCYCLIC MERCAPTOSULFIDE IN HIBITORS
BACKGROUND OF THE INVENTION In general, the present invention is directed to novel substituted heterocyclic mercaptosulfide compounds, precursors, and derivatives as well as the methods for the preparation and pharmaceutical compositions of these compounds. Many of these compounds are designed, synthesized, characterized, and tested to be potent, and some of them, selective inhibitors of matrix metalloproteinases (MMPs), in particular, membrane type 1 matrix metalloproteinase, gelatinase B, gelatinase A, collagenases, matrilysins, metalloelastase, and stromelysin-1. These compounds are used for the control of physiological and pathological processes and disease conditions in which matrix metalloproteinases play a significant role (Sternlicht, M.D. and Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. (20) 17, 463-516; Mercer, B. et al., Journal of Biol. Chem. 2004 (279) 17, 17690 - 696J. For example, such physiological and pathological processes and disease conditions include the prevention and treatment of cancer invasion, angiogenesis, and metastasis; stroke and cardiovascular diseases such as myocardial infarction, atherosclerosis, and restensosis; respiratory diseases such as bronchitis and emphysema; neuro-inflammatory diseases; arthritic diseases; periodontal disease; multiple sclerosis; spinal cord injury; inflammation; pain; corneal ulceration and other eye diseases; diabetic retinopathy and other diabetic complications; obesity; wound healing and regeneration; kidney diseases such as glomerulonephritis; neurodegenerative diseases; acquired immunodeficiency syndrome (AIDS); organ preservation for transplantation; the control of fertility and reproductive capabilities such as fertilization, implantation, uterine bleeding, birth control and contraception; blister formation; bone remodeling; male and female osteoporosis; allergic reactions; asthma; emphysema; bacterial meningitis; anti-rheumatic disorders; connective tissue degradation; bacterial infections, anti-toxins such as lethal factor and other bacterial toxins; anti-viral proteases; anti-snake venom toxins; and in the industrial manufacturing of extracellular matrix/collagen products, cosmetics, and beauty products. Matrix metalloproteinases (MMPs, matrixins) are a family of zinc-endopeptidases that are believed to participate in angiogenesis, embryonic development, morphogenesis, reproduction, tissue resorption and remodeling, arthritis, and tumor growth, progression, invasion, and metastasis through breakdown of the extracellular matrix (ECM), cell surface proteins, processing growth factors, cytokines, or chemokines (Brinckerhoff, C. E. and Matrisian, L. M. Matrix metalloproteinases: a tail of a frog that became a prince. Nature Rev. Mol. Cell. Biol. 2002; 3, 207-214; Egeblad, M. and Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2002; 2, 163-175; Overall, CM. Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites. Molec. Biotech. 2002; 22, 51-86). At least twenty three human MMPs have been reported and even more have been reported in vertebrates. Many MMPs such as membrane type 1 matrix metalloproteinase (MT1-MMP) are reported to play multiple functions in ECM remodeling, development, growth, morphogenesis and disease conditions. For example, MTI-MMP- deficient mice develop dwarfism, osteopenia, arthritis, craniofacial dysmorphism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues (Holmbeck, K., Bianco, P., Caterina, J., Yamada, S., Kromer, M., Kuznetsov, S.A., Mankani, M., Robey, P.G., Poole, A.R., Pidoux, I., Ward, J.M., and Birkedal-Hansen, H. MTI-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell, 1999; 99, 81-92). Furthermore, MT1-MMP is a key enzyme essential for promoting 3-dimensional tumor growth and invasion in vitro and in vivo (Hotary, K.B., Allen, E.D., Brooks, P.C., Datta, N.S., Long, M.W., and Weiss, S.J. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell, 2003; 114, 33-45.) Selective inhibition of certain MMP enzymes, specifically those modulating physiological and disease conditions, is highly desirable.
SUMMARY OF THE INVENTION Among the various aspects of the present invention are novel substituted heterocyclic mercaptosulfide inhibitors and the salts thereof. In one embodiment, the inhibitors correspond to Formula 1 :
Figure imgf000003_0001
wherein: R20, R21, R27 and R28 are independently hydrogen, hydrocarbyl or substituted hydrocarbyl; the X ring is a 5-7 membered saturated heterocyclic ring comprising X2; X1 is a cation, hydrogen or acyl; X2 is sulfone (-S(=O)2-), oxygen, or -N(X20)-; X3 and X4 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo, or X3 and X4 in combination with the carbon atom to which they are attached form a carbocyclic or heterocyclo ring; X5 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or -NX51X52; X6 and X7 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo, or X6 and X7 in combination with the carbon atom to which they are attached form a carbocyclic or heterocyclo ring; X8 and X9 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, -OX83, -NX81X82, -C(=NH2 +)NH2, -NH-C(=NH)NH2, provided, however, X8 and X9 are not each -NX81X82, -C(=NH2 +)NH2, -OX83, or -NH-C(=NH)NH2, or X8 and X9 in combination with the nitrogen atom to which they are attached form a heterocyclo ring; X20 is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, acyl, -OX21, or -NX23X24; X21 is hydrocarbyl, substituted hydrocarbyl, heterocyclo, or acyl; X23 and X24 are independently hydrocarbyl, substituted hydrocarbyl, heterocyclo, or acyl; orX23 and X24 in combination with the nitrogen atom to which they are attached form a heterocyclo ring; X51 and X52 are independently hydrocarbyl, substituted hydrocarbyl, heterocyclo, or acyl; or X51 and X52 in combination with the nitrogen atom to which they are attached form a heterocyclo ring; X81 and X82 are independently hydrocarbyl, substituted hydrocarbyl, or heterocyclo, or X81 and X82 in combination with the nitrogen atom to which they are attached form a heterocyclo ring; and X83 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo. The present invention is further directed to pharmaceutical compositions comprising such compounds or the salts thereof and the use of such compositions in a method of treatment of a disease or condition mediated by an MMP enzyme. Other aspects and objects of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Compounds In one embodiment, the present invention is directed to a compound corresponding to Formula 1 or a salt thereof:
Figure imgf000005_0001
wherein: R20, R21, R27, R28, X, X1, X2, X3, X4, X5, X6, X7, X8, and X9 are as previously defined. As depicted in Formula 1 , the "X" ring contains X2, two carbon atoms substituted by R20, R21, R27, and R28, and two carbon atoms in the alpha position relative to the two carbon atoms substituted by R20, R21, R27, and R28. The single dashed lines linking X2 to the two carbons substituted by R20, R21, R27, and R28 indicate that X2 may be directly bonded to each of these carbon atoms (in which case the X ring is five membered) or that X2 may be indirectly bonded to these carbon atoms by means of another ring atom (in which case the X ring is a six or seven membered ring). In general, X1 is a cation, hydrogen, or acyl. Typically, X1 is hydrogen. In another embodiment, X1 may be an alkali metal; for example, X1 may be sodium or potassium. In a further embodiment, X1 may be an alkaline earth metal; for example, X1 may be magnesium or calcium. In other embodiments, X1 may be aluminum or ammonium. In a further embodiment X1 may be acyl; for example, X1 may be RC(O)-, wherein R is R1, R1O-, R1R2N-, or R1S-, wherein R1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R2 is hydrogen, hydrocarbyl or substituted hydrocarbyl. In another embodiment X1 is -SX11, wherein X11 is hydrocarbyl, substituted hydrocarbyl, heterocyclo or acyl. As previously noted, X2 may be oxygen, sulfone (-S(=0)2-) or -N(X20)-. In one embodiment, X is a five-, six- or seven-membered saturated ring and X2 is oxygen. In another embodiment, X is a five-, six- or seven-membered saturated ring and X2 is sulfone. In another embodiment, X is a five-, six- or seven-membered saturated ring and X2 is -N(X20)- wherein X20 is as previously defined. In each of these embodiments, when the X ring is a five-membered saturated ring, the oxygen, sulfur or nitrogen atom is covalently bonded directly to the carbon atoms substituted by R20, R21, R27, and R28. When the X ring is a six-membered saturated ring, the X2 oxygen, sulfur or nitrogen atom is covalently bonded directly to one of the two carbon atoms substituted by R20, R21, R27, and R28 and indirectly bonded to the other (by means of another ring atom). When the X ring is a seven-membered saturated ring, the X2 oxygen, sulfur or nitrogen atom is covalently bonded indirectly to each of the two carbon atoms substituted by R25, R26, R27, and R28 (by means of two other ring atoms). In each of these embodiments, the X ring is fully saturated. When X2 is -N(X20)-, X20 may be selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, acyl, -OX21, and -NX23X24. In one embodiment, X20 is hydrogen. In another embodiment, X20 is acyl; for example, X20 may be X200C(O)- wherein X200 is alkyl, substituted alkyl, R1R2N-, RO-, or -NH2, where R1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R2 is hydrogen, hydrocarbyl or substituted hydrocarbyl. By way of further example, X20 may be X200C(O)- wherein X200 is a heterocyclo ring such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl and the like. Exemplary substituents for X200 where X200 is a heterocyclo include, but are not limited to, hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy and acyl. In another embodiment, X20 may be -OX21 wherein X21 is hydrocarbyl, substituted hydrocarbyl, heterocyclo, or aryl. In another embodiment, X20 may be -NX23X24 wherein X23 and X24 are independently hydrocarbyl, substituted hydrocarbyl, heterocyclo, or aryl; or X23 and X24 in combination with the nitrogen atom to which they are attached form a heterocyclo ring such as morpholine, azepine, piperdine, pyrrolidine. In general, X3 and X4 may be independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and heterocyclo. In one such embodiment, X3 and X4 are hydrogen. In another such embodiment, X3 is hydrogen and X4 is hydrocarbyl or substituted hydrocarbyl. For example, X3 may be hydrogen when X4 is alkyl or alkaryl. By way of further example, X3 may be hydrogen when X4 is methyl, ethyl or a C3-C6 straight, branched or cycloalkyl. By way of further example, X3 may be hydrogen when X4 is a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. X3 may be hydrogen when X4 is alkyl or alkaryl. By way of further example, X3 may be hydrogen when X4 is optionally substituted alkaryl, e.g., benzyl (-CH2C6H5) wherein the substituents are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. By way of further example, X3 may be hydrogen when X4 is heterocyclo, e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. Alternatively, X3 and X4 in combination with the carbon atom to which they are attached may form a hydrocarbyl, substituted hydrocarbyl or heterocyclo ring. For example, X3 and X4 in combination with the carbon atom to which they are attached may form furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl. In general, X5 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and -NX51X52 wherein X51 and X52 are (i) independently hydrocarbyl, substituted hydrocarbyl, heterocyclo, or acyl; or (ii) X51 and X52 in combination with the nitrogen atom to which they are attached form a heterocyclo ring. In one embodiment, X5 is hydrogen. In another embodiment, X5 is alkyl; for example X5 may be optionally substituted methyl, ethyl, or C3-C6 straight, branched or cycloalkyl wherein the substituents are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, dialkylamino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment, X5 is -NX51X52 wherein X51 and X52 are independently hydrocarbyl, substituted hydrocarbyl, heterocyclo, or acyl. X6 and X7 may be independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and heterocyclo. In one such embodiment, X6 and X7 are hydrogen. In another such embodiment, X6 is hydrogen and X7 is hydrocarbyl or substituted hydrocarbyl. For example, X6 may be hydrogen when X7 is alkyl or alkaryl. By way of further example, X6 may be hydrogen when X7 is methyl, ethyl or a C3-C6 straight, branched or cycloalkyl. By way of further example, X6 may be hydrogen when X7 is a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. X6 may be hydrogen when X7 is alkyl or alkaryl. By way of further example, X6 may be hydrogen when X7 is optionally substituted alkaryl, e.g., benzyl (-CH2C6H5) wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, hexyl, and a heterocyclo ring such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl. By way of further example, X6 may be hydrogen when X7 is heterocyclo, e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. Alternatively, X6 and X7 in combination with the carbon atom to which they are attached may form a hydrocarbyl, substituted hydrocarbyl or heterocyclo ring. For example, X6 and X7 in combination with the carbon atom to which they are attached may form furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl. In general, X8 and X9 may be independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, -OX83, -NX81X82, -C(=NH2 +)NH2, and -NHC(=NH)NH2, provided, however, X8 and X9 are not each -NX81X82, -C(=NH2 +)NH2, -OX83, or -NHC(=NH)NH2. In one embodiment, X8 and X9 are hydrogen. In another embodiment, X8 is hydrogen and X9 is alkyl; for example, X8 may be hydrogen and X9 may be optionally substituted methyl, ethyl, or C3-C6 straight, branched or cyclic alkyl. In another embodiment, X8 is hydrogen and X9 is optionally substituted aryl; for example, X8 may be hydrogen and X9 may be optionally substituted phenyl. In another embodiment, X8 may be hydrogen and X9 may be methyl. In still another embodiment, X8 may be hydrogen and X9 may be para-methoxyphenyl. In each of these embodiments, the substituents may be selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. Alternatively, X8 and X9 in combination with the nitrogen atom to which they are attached may form a heterocyclo ring. For example, X8 and X9 in combination with the nitrogen atom to which they are attached may form piperidine, pyrrolidine, morpholine, or azepine. In one embodiment, the compound corresponds to Formula 1 , the X ring is a 5- membered saturated ring and X2 is -N(X20)-. For example, in this embodiment the compound may correspond to Formula 2n:
Figure imgf000009_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1. In one such embodiment in which the compound corresponds to Formula 2n, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 2n, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 2n, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 2n, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 2n, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 2n, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a saturated 5-membered ring, X2 is -N(X20)-, and the compound corresponds to Formula 4n:
Figure imgf000010_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1 and the hydrogen atoms shown have the β stereochemical orientation and the sulfur atoms shown have the α stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 4n, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 4n, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 4n, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 4n, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 4n, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 4n, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a saturated 5-membered ring, X2 is -N(X20)-, and the compound corresponds to Formula 5n:
Figure imgf000011_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1 , and the hydrogen atoms shown have the stereochemical orientation and the sulfur atoms shown have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 5n, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 5n, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 5n, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 5n, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 5n, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 5n, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a saturated 5-membered ring, X2 is -N(X20)-, and the compound corresponds to Formula 6n:
Figure imgf000012_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1 , and X4 and X7 have the α stereochemical orientation and X3 and X6 have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 6n, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 6n, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 6n, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 6n, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 6n, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 6n, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a saturated 5-membered ring, X2 is -N(X20)-, and the compound corresponds to Formula 7n:
Figure imgf000013_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1 ; and X4 and X7 have the α stereochemical orientation, X3 and X6 have the β stereochemical orientation, the hydrogen atoms shown have the α stereochemical orientation and the sulfur atoms shown have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 7n, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 7n, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 7n, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 7n, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 7n, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3- C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 7n, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a 5-membered saturated ring, X2 is oxygen and the compound corresponds to Formula 6o:
Figure imgf000014_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, and X9 are as previously defined in connection with Formula 1. In one such embodiment in which the compound corresponds to Formula 6o, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 6o, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 6o, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 6o, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 6o, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 60, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a 5-membered saturated ring, X2 is oxygen and the compound corresponds to Formula 7o:
Figure imgf000015_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1 and the hydrogen atoms shown have the α stereochemical orientation and the sulfur atoms shown have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 7o, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 7o, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 7o, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 7o, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 7o, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 7o, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a 5-membered saturated ring, X2 is oxygen and the compound corresponds to Formula 8o:
Figure imgf000016_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1 , and X4 and X7 have the α stereochemical orientation and X3 and X6 have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 8o, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 8o, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 8o, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 8o, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 8o, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 8o, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a 5-membered saturated ring, X2 is oxygen and the compound corresponds to Formula 9o:
Figure imgf000017_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1 ; and X4 and X7 have the α stereochemical orientation, X3 and X6 have the β stereochemical orientation, the hydrogen atoms shown have the α stereochemical orientation, and the sulfur atoms shown have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 9o, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 9o, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 9o, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to
Formula 9o, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 9o, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3- C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 9o, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a 5-membered saturated ring, X2 is sulfone (-S(=0)2-) and the compound corresponds to Formula 8s:
Figure imgf000018_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, and X9 are as previously defined in connection with Formula 1. In one such embodiment in which the compound corresponds to Formula 8s, R20, R2 , R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 8s, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 8s, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 8s, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 8s, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 8s, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a 5-membered saturated ring, X2 is sulfone (-S(=O)2-) and the compound corresponds to Formula 9s:
Figure imgf000019_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1 and the hydrogen atoms shown have the α stereochemical orientation and the sulfur atoms shown have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 9s, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 9s, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 9s, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 9s, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 9s, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 9s, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a 5-membered saturated ring, X2 is sulfone (-S(=O)2-) and the compound corresponds to Formula 10s:
Figure imgf000020_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1 , and X4 and X7 have the α stereochemical orientation and X3 and X6 have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 10s, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10s, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10s, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10s, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 10s, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 10s, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a 5-membered saturated ring, X2 is sulfone (-S(=O)2-) and the compound corresponds to Formula 11s:
Figure imgf000021_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as previously defined in connection with Formula 1 ; X4 and X7 have the α stereochemical orientation, X3 and X6 have the β stereochemical orientation, the hydrogen atoms shown have the α stereochemical orientation, and the sulfur atoms shown have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 10s, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 11s, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 11s, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 11s, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 11 s, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 11s, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In a further embodiment, the X ring is a six membered saturated ring and X2 is directly bonded to one of the two carbon atoms substituted by R20, R21, R27, and R28 and indirectly bonded to the other as depicted in Formulae 10 and 11 :
Figure imgf000022_0001
Figure imgf000022_0002
wherein: R20, R21, R27, R28, X1, X2, X3, X4, X5, X6, X7, X8, and X9 are as previously defined in connection with Formula 1 ; X25 is -C(R22)(R23)-, oxygen or -N(R24)-; and R22, R23 and R24 are independently an hydrogen, hydrocarbyl, or substituted hydrocarbyl. In one such embodiment in which the compound corresponds to Formula 10 or 11 , R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10 or 11 , X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10 or 11 , R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In a further embodiment, the X ring is a six membered saturated ring and X2 is directly bonded to one of the two carbon atoms substituted by R20, R21, R27, and R28 and indirectly bonded to the other as depicted in Formulae 10a and 11a:
Figure imgf000023_0001
wherein: R20, R21, R27, R28, X1, X2, X3, X4, X5, X6, X7, X8, and X9 are as previously defined in connection with Formula 1 ; X25 is -C(R22)(R23)-, oxygen or -N(R24)-; and R22, R23 and R24 are independently an hydrogen, hydrocarbyl, or substituted hydrocarbyl and the hydrogen atoms shown have the α stereochemical orientation and the sulfur atoms shown have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 10a or 11a, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10a or 11a, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10a or 11a, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In a further embodiment, the X ring is a six membered saturated ring and X2 is directly bonded to one of the two carbon atoms substituted by R20, R21, R27, and R28 and indirectly bonded to the other as depicted in Formulae 10b and 11b:
Figure imgf000024_0001
Figure imgf000024_0002
wherein: R20, R21, R27, R28, X1, X2, X3, X4, X5, X6, X7, X8, and X9 are as previously defined in connection with Formula 1; X25 is -C(R22)(R23)-, oxygen or -N(R24)-; and R22, R23 and R24 are independently an hydrogen, hydrocarbyl, or substituted hydrocarbyl; and X4 and X7 have the α stereochemical orientation and X3 and X6 have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 10b or 11b, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10c or 11 c, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10b or 11 b, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In a further embodiment, the X ring is a six membered saturated ring and X2 is directly bonded to one of the two carbon atoms substituted by R20, R21, R27, and R28 and indirectly bonded to the other as depicted in Formulae 10c and 11c:
Figure imgf000025_0001
Figure imgf000025_0002
wherein: R20, R21, R27, R28, X1, X2, X3, X4, X5, X6, X7, X8, and X9 are as previously defined in connection with Formula 1 ; X25 is -C(R22)(R23)-, oxygen or -N(R24)-; and R22, R23 and R24 are independently an hydrogen, hydrocarbyl, or substituted hydrocarbyl; and X4 and X7 have the α stereochemical orientation, X3 and X6 have the β stereochemical orientation, the hydrogen atoms shown have the α stereochemical orientation, and the sulfur atoms shown have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 10b or 11b, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10c or 11c, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10c or 11c, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10 or 11 , R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 10 or 11 R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 10 or 11 X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 10 or 11 , X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). For example, when the X ring is a six membered saturated ring, the compound may correspond to any of Formulae 12cn, 12nc, 12nn, 12co, 12no, 12oc, or 12on:
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
wherein: R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9, and X20 are as previously defined in connection with Formula 1; and R22, R23 and R24 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo. In one such embodiment in which the compound corresponds to Formula 12cn, 12nc, 12nn, 12co, 12no, 12oc, 12on, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 12cn, 12nc, 12nn, 12co, 12no, 12oc, 12on, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 12cn, 12nc, 12nn, 12co, 12no, 12oc, 12on, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 12cn, 12nc, 12nn, 12co, 12no, 12oc, 12on, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 12cn, 12nc, 12nn, 12co, 12no, 12oc, 12on, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 12cn, 12nc, 12nn, 12co, 12no, 12oc, 12on, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). When the X ring is a seven-membered saturated ring, X2 is indirectly bonded to each of the carbon atoms substituted by R20, R21, R27, and R28 through another ring atom selected from carbon and nitrogen. In one embodiment, therefore, when the X ring is a seven membered saturated ring, the compound corresponds to Formula 13:
Figure imgf000029_0001
Formula 13
wherein: (i) R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, and X9, are as previously defined in connection with Formula 1 ; (ii) two of X25, X26 and X27 are selected from -C(R22)(R23)- and X2 (i.e., oxygen, sulfone, or -N(X20)-), provided, however at least one of X25 and X27 is -C(R22)(R23)-; and (iii) each R22 and R23 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo. In one such embodiment in which the compound corresponds to Formula 13, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 13, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3- C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 13, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In one embodiment when the X ring is a seven membered saturated ring, the compound corresponds to Formula 13a:
Formula 13a wherein: (i) R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, and X9, are as previously defined in connection with Formula 1 ; (ii) two of X25, X26 and X27 are selected from -C(R22)(R23)- and X2 (i.e., oxygen, sulfone, or -N(X20)-), provided, however, at least one of X25 and X27 is -C(R22)(R23)-; and (iii) each R22 and R23 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and the hydrogen atoms shown have the α stereochemical orientation and the sulfur atoms shown have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 13a, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13a, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13a, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13a, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 13a, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 13a, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In one embodiment when the X ring is a seven membered saturated ring, the compound corresponds to Formula 13b:
Figure imgf000031_0001
Formula 13b
wherein: (i) R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, and X9, are as previously defined in connection with Formula 1 ; (ii) two of X25, X26 and X27 are selected from -C(R22)(R23)- and X2 (i.e., oxygen, sulfone, or -N(X20)-), provided, however, at least one of X25 and X27 is -C(R22)(R23)-; and (iii) each R22 and R23 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and X4 and X7 have the α stereochemical orientation and X3 and X6 have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 13b, R20,
R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13b, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13b, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13b, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 13b, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 13b, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). In one embodiment when the X ring is a seven membered saturated ring, the compound corresponds to Formula 13c:
Figure imgf000032_0001
Formula 13c wherein: (i) R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, and X9, are as previously defined in connection with Formula 1 ; (ii) two of X25, X26 and X27 are selected from -C(R 2)(R23)- and X2 (i.e., oxygen, sulfone, or -N(X20)-), provided, however at least one of X25 and X27 is -C(R22)(R23)-; and (iii) each R22 and R23 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and X4 and X7 have the α stereochemical orientation, X3 and X6 have the β stereochemical orientation, the hydrogen atoms shown have the α stereochemical orientation, and the sulfur atoms shown have the β stereochemical orientation. In one such embodiment in which the compound corresponds to Formula 13c, R20, R21, R27, and R28 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13c, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13c, R20, R21, R27, R28, X3, X5, X6, and X8 are each hydrogen. In another embodiment in which the compound corresponds to Formula 13c, R20, R21, R27, R28 are independently hydrocarbyl or substituted hydrocarbyl. In another embodiment in which the compound corresponds to Formula 13c, X3, X5, X6, and X8 are hydrogen and X4, X7, and X9 are independently a substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl wherein the substituent(s) are selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. In another embodiment in which the compound corresponds to Formula 13c, X3, X5, X6, and X8 may be hydrogen when X4, X7, and X9 are independently alkyl, alkaryl, or heterocyclo (e.g., furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl or isoquinolinyl, wherein the heterocyclo is optionally substituted with substituents selected from the group consisting of heterocyclo, alkenyl, alkynyl, aryl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, alkoxycarbonyl, aminocarbonyl, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers). Since the compounds of the present invention have several asymmetric carbons, it is known to those skilled in the art that the compounds of the present invention having asymmetric carbon atoms may exist in diastereometric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes the enantiomers, diastereomers, racemic mixtures, and other optically active mixtures of the compounds disclosed herein. Synthesis MMPs of the general Formula 1 may be obtained according to the following scheme:
Figure imgf000034_0001
Abbreviations: Boc, terf-butoxycarbonyl; mCPBA, meta-chloroperbenzoic acid; Ph, phenyl; Et, ethyl; t-Bu, ferf-butyl; Me, methyl; DEAD, diethyl azodicarboxylate; THF, tetrahydrofuran;Ac, acetyl; DMF, dimethylformamide; HOBT, 1- hydroxybenzotriazole; EDCI, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
Readily available five, six, or seven-membered heterocyclic alkenes, where X = O, suitably blocked N, or SO2, are transformed into the corresponding epoxides using an oxidizing agent such as mefø-chloroperbenzoic acid. Reaction of the epoxide with a thiolcarboxylic acid, such as thiolbenzoic acid, in the presence of alumina catalyst gives the trans acylthio-substituted heterocyclic alcohol. The S-acyl group is modified into the S-Boc group, then the alcohol functionality is replaced by a second acylthio group, with cis stereochemistry, using a variant of the Mitsunobu reaction with a thiolcarboxylic acid such as thiolacetic acid. The S-acetyl group is selectively cleaved using a base in alcohol solvent, and the resulting deblocked thiol is S-alkylated with an α-bromocarboxylic acid in the presence of a mild base such as potassium carbonate in a solvent such as N,N- dimethylformamide. The required α-bromocarboxylic acids are readily available, or are prepared from the corresponding α-amino acids by treatment with NaNO2 in cold aqueous HBr. The resulting c/s-substituted S-Boc protected heterocyclic -thiocarboxylic acids are obtained as an approximately 1 :1 mixture of diastereomers. The carboxylic acids are coupled with readily available α-amino acid amides using a carbodiimide such as EDCI in the presence of an activating agent such as HOBT and a base such as triethylamine, to yield the c/s- substituted S-Boc protected heterocyclic mercaptosulfide inhibitors as an approximately 1 :1 mixture of diastereomers. If the X group is suitably blocked N, the N blocking group is 20 selectively removed and replaced by the requisite X group. The diastereomers are separated by chromatography if desired, then the S-Boc group is selectively cleaved by treatment with a strong acid such as HCI, in a non-aqueous solvent such as acetic acid, to afford the deblocked substituted heterocyclic mercaptosulfide inhibitors of general Formula 1. Completely analogous procedures are used to prepare MMP inhibitors of general
Formulae 10, 11 , or 13, where X is -O- or -NR )-, starting from the corresponding suitably-blocked heterocyclic alkenes. Salts The MMP selective inhibitors utilized in the present invention may be in the form of free bases or pharmaceutically acceptable acid addition salts thereof. The term "pharmaceutically-acceptable salts" are salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt may vary, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds for use in the present methods may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of use in the present methods include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N.N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound of any formula set forth herein.
Treatment of Conditions The use of MMP inhibitors have been described previously in other MMP inhibitor patents, including but not limited to: Purchase, Jr. et al., United States Patent No. US 6,624,196 B2, Benzene butyric acids and their derivatives as inhibitors of matrix metalloproteinases; and Schwartz et al. United States Patent No. 5,455,262, Mercaptosulfide metalloproteinase inhibitors. MMPs are the major endopeptidases that hydrolyze multiple connective tissue proteins and are likely to be targets for controlling pathological catabolism of ECM proteins. Applications of the compounds of the present invention may include, but are not limited to, control multiple physiological and pathological processes and conditions. Prevention and treatments of cancer cell invasion, angiogenesis, and metastasis may be achieved by selective MMP inhibitors (Egeblad, M. and Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2002; 2, 163-175; Nemeth, J.A., Yousif, R., Herzog, M., Che, M., Upadhyay, J., Shekarriz, B., Bhagat, S., Mullins, C, Fridman, R., and Cher, M.L. Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis. J. Natl. Cancer Inst. 2002; 94,17-25; Lein, M., Jung, K., Ortel, B., Stephan, C, Rothaug, W., Juchem, R., Johannsen, M., Deger, S., Schnorr, D., Loening, S., Krell, H.W. The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model. Oncogene. 2002; 21, 2089-2096). MMP inhibitors have also shown some efficacy in tumor angiogenesis models (Benelli R., Adatia R., Ensoli B., Stetler-Stevenson W. G., Santi L, and Albini A. Inhibition of AIDS-Kaposi's sarcoma cell induced endothelial cell invasion by TIMP-2 and a synthetic peptide from the metalloproteinase propeptide: implications for an anti-angiogenic therapy. Oncol. Res., 1994; 6, 251-257; Brown, PD., and Giavazzi, R. Matrix metalloproteinase inhibition: a review of anti-tumour activity. Ann. Oncol. 1995; 6, 967-974. Review; Gatto, C, Rieppi, M., Borsotti, P., Innocenti, S., Ceruti, R., Drudis. T. Scanziani. E., Casazza, A.M., Taraboletti, G., and Giavazzi, R. BAY 12-9566, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity. Clin. Cancer Res. 1999; 5, 3603-3607; Tosetti, F., Ferrari, N., De Flora, S., and Albini, A. Angioprevention: angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J. 2002; 16, 2-14). The compounds described herein may be used for the prevention and treatment of cardiovascular diseases such as restenosis, cardiac hypertrophy, atherosclerotic plaque rupture, aortic aneurysm, and heart attacks (Loftus, I.M. and Thompson, M.M. The role of matrix metalloproteinases in vascular disease. Vase. Med. 2002; 7,117-133). Cardiovascular diseases are the leading causes of death in Western society. Extracellular matrix (ECM) turnover mediated by MMPs is important in many cardiovascular pathologies, such as arterial remodeling, plaque rupture, restenosis, aneurysm formation and heart failure. MMP inhibitors are likely to be useful in the development of pharmacological approaches to reduce cardiovascular death, considering the positive outcomes after usage of MMP inhibitors in restenosis and arterial remodeling (Sierevogel, M.J., Pasterkamp, G., De Kleijn, D.P., and Strauss, B.H. Matrix metalloproteinases: a therapeutic target in cardiovascular disease. Curr. Pharm. Des. 2003;9, 1033-1040). Enhanced MMP expression has been detected in the atherosclerotic plaque, and activation of MMPs appears to be involved in the vulnerability of the plaque. Circulating MMP levels are elevated in patients with acute myocardial infarction and unstable angina. Increased MMP expression is also observed after coronary angioplasty, which is related to late loss index after the procedure. These observations suggest that MMP expression may be not only related to instability of the plaque, but also to the formation of restenotic lesions. The development of therapeutic drugs targeted specifically against MMPs may be useful in the prevention of atherosclerotic lesion development, plaque rupture, and restenosis (Ikeda, U. and Shimada, K. Matrix metalloproteinases and coronary artery diseases. Clin. Cardiol. 2003; 26, 55-59). Compared to placebo, a potent and broad spectrum MMP inhibitor GM6001 significantly inhibited intimal hyperplasia and intimal collagen content, and it increased lumen area in stented arteries without effects on proliferation rates. Stenting causes a more vigorous ECM and MMP response than balloon angioplasty, which involves all layers of the vessel wall. Inhibition by MMP blocks in-stent intimal hyperplasia and offers a novel approach to prevent in-stent restenosis (Li, C, Cantor, W.J., Nili, N., Robinson, R., Fenkell, L., Tran, Y.L., Whittingham, H.A., Tsui, W., Cheema, A.N., Sparkes, J.D., Pritzker, K., Levy, D.E., and Strauss, B.H. Arterial repair after stenting and the effects of GM6001 , a matrix metalloproteinase inhibitor. J. Am. Coll. Cardiol. 2002; 39,1852-1858). MMP inhibitors may be used to treat degenerative aortic disease associated with thinning of the medial aortic wall. Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurisms and aortic stenosis (Vine, N. and Powell, J. T. Metalloproteinases in degenerative aortic diseases. Clin. Sci., 1991 ; 81,233- 239). MMPs are involved in the pathogenesis of cardiovascular disease, including atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction. Administration of synthetic MMP inhibitors in experimental animal models of these cardiovascular diseases significantly inhibits the progression of, respectively, atherosclerotic lesion formation, neointima formation, left ventricular remodeling, pump dysfunction, and infarct healing. MMP inhibitors are potential therapeutic agents for prevention and treatment of heart failure. (Creemers, E.E., Cleutjens, J.P., Smits, J.F., Daemen, M.J. Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ. Res. 2001; 89, 201-210). MMP inhibitors may also be used for coating stents to timely release MMP inhibitors to prevent restenosis. To prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA) and/or stenting of atherosclerotic stenosed arteries, two water-soluble MMPs inhibitors have already been designed and developed by other groups (Masuda, T, and Nakayama, Y. Development of a water-soluble matrix metalloproteinase inhibitor as an intra-arterial infusion drug for prevention of restenosis after angioplasty. J. Med. Chem. 2003; 46, 3497-3501 ). Myocardial infarction (Ml) is associated with early metalloproteinase (MMP) activation and extracellular matrix (ECM) degradation. Preserving the original ECM of the infarcted left ventricle (LV) by use of early short-term doxycycline (DOX) treatment preserves cardiac structure and function. Early MMP inhibition after Ml yields preservation of LV structure and global as well as scar area passive function, supporting the concept that preserving the original ECM early after coronary occlusion lessens ventricular remodeling (Villarreal, F.J., Griffin, M., Omens, J., Dillmann, W., Nguyen, J., and Covell, J,. Early short-term treatment with doxycycline modulates postinfarction left ventricular remodeling. Circulation. 2003;108, 1487-1492. Epub 2003 Sep 02). Congestive heart failure (CHF) is a leading cause of death in developed countries and its prevalence is increasing throughout the world. Progressive left ventricular dilation and contractile dysfunction cause most cases of CHF. MMPs are not only associated with ventricular dilation, but may actually mediate the dilation process. Because these enzymes are extracellular and are pharmacologic targets, MMP inhibition is a novel potential therapy for delaying or preventing heart failure (Lindsey, M., and Lee, R.T. MMP inhibition as a potential therapeutic strategy for CHF. Drug News Perspect. 2000; 13, 350-354). Metalloproteinase inhibitors may be used to treatment many other types of cardiovascular diseases. Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke. Metalloproteinase inhibitors may be used to preserve organs for transplantation and prevent hemorrhagic stroke. A new report has described systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy (Yamani, M.H.,
Starling, R.C., Cook, D.J., Tuzcu, E.M., Abdo, A., Paul, P., Powell, K., Ratliff, N.B., Yu, Y., McCarthy, P.M., and Young, J.B. Donor Spontaneous Intracerebral Hemorrhage Is Associated With Systemic Activation of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 and Subsequent Development of Coronary Vasculopathy in the Heart Transplant Recipient. Circulation. 2003 Oct 7; 108(14): 1724-8. Epub 2003 Sep 15. Furthermore, metalloproteinase inhibitors may be useful for kidney and other organ transplantation (Marti, H.P. The role of matrix metalloproteinases in the activation of mesangial cells. Transpl. Immunol. 2002; 9, 97-100). The compounds described herein may be useful for the treatment of different types of arthritis. MMP inhibition are useful to treatment osteoarthritis in animal models (Janusz, M.J., Hookfin, E.B., Heitmeyer, S..A, Woessner, J.F., Freemont, A.J., Hoyland, J.A., Brown, K.K., Hsieh, L.C., Almstead, N.G., De, B., Natchus, M..G, Pikul, S., and Taiwo, Y.O. Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors. Osteoarthritis Cartilage. 2001 ; 9,751-760; Vincenti, M.P., Clark, I.M., Brinckerhoff, C.E. Using inhibitors of metalloproteinases to treat arthritis. Easier said than done? Arthritis. Rheum. 1994; 37,1115-1126). Increased expression of stromelysin and collagenase in synovial fluids from osteo- and rheumatoid arthritis patients as compared to controls has been reported (Walakovits, L. A., Moore, V. L., Bhardwaj, N., Gallick, G. S., and Lark ,M. W. Detection of stromelysin and collagenase in synovial fluid from patients with rheumatoid arthritis and post-traumatic knee injury. Arthritis Rheum., 1992; 35, 35-42). Rheumatoid arthritis and osteoarthritis are chronic diseases that result in cartilage degradation and loss of joint function. Currently available drugs are predominantly directed towards the control of pain and/or the inflammation associated with joint synovitis but they do little to reduce joint destruction. It will be important to have drugs such as metalloproteinase inhibitors that prevent the structural damage caused by bone and cartilage breakdown (Elliott, S., and Cawston, T. The clinical potential of matrix metalloproteinase inhibitors in the rheumatic disorders. Drugs Aging. 2001 ; 18, 87-99 and Bigg, H.F., Rowan, A.D. The inhibition of metalloproteinases as a therapeutic target in rheumatoid arthritis and osteoarthritis. Curr. Opin. Pharmacol. 2001 ; 1, 314-320). Human gingival fibroblast collagenase and stromelysin levels were correlated to the severity of gum disease (Overall, C. M., Wiebkin, O. W., and Thonard, J. C, Demonstrations of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingival. J. Periodontal Res., 1987; 22, 81-88). Metalloproteinase inhibitors have been used to treat periodontal diseases (Ramamurthy, N.S., Rifkin, B.R., Greenwald, R.A., Xu, J.W., Liu, Y., Turner, G., Golub, L.M., and Vernillo, A.T. Inhibition of matrix metalloproteinase-mediated periodontal bone loss in rats: a comparison of 6 chemically modified tetracyclines. J. Pehodontol. 2002; 73, 726-734; and Ciancio, S.G. Systemic medications: clinical significance in periodontics. J. Clin. Pehodontol. 2002; Suppl 2, 17-21). Hydrolysis of ECM proteins was reported in corneal ulceration following alkali burns (Brown, S. I., Weller, C. A., and Wasserman, H. E., Collagenolytic activity of alkali burned corneas. Arch. OphthalmoL, 1969; 81 ,370-373). Thiol-containing peptide inhibitors block the collagenase isolated from alkali-burned rabbit corneas (Bums, F. R., Stack, M. S., Gray, R. D., and Paterson, C. A. Invest. OphthalmoL, 1989; 30,1569-1575). Thus, MMP inhibitors can be used to treat corneal ulceration. Moreover, metalloproteinase inhibitors may also control the progression of macular degeneration (Musarella, M.A. Molecular genetics of macular degeneration. Doc. OphthalmoL 2001; 102, 165-177). Metalloproteinase inhibitors may prevent human immunodeficiency virus-induced neurodegeneration (Zhang, K„ McQuibban, G.A., Silva, C, Butler, G.S., Johnston, J.B., Holden, J., Clark-Lewis, I., Overall, CM., and Power, C. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nat Neurosci. 2003; 6,1064-1071. Epub 2003 Sep 21). These inhibitors may be used to treat spinal cord injury and promote wound healing (Goussev, S., Hsu, J.Y., Lin, Y., Tjoa, T., Maida, N., Werb, Z., and Noble-Haeusslein, L.J. Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing. J. Neurosurg. 2003; 99(2 Suppl): 188-197). Gelatinases, belonging to the matrix metalloproteases, contribute to tissue destruction in inflammatory demyelinating disorders of the central nervous system such as multiple sclerosis. Gijbels et al. used experimental autoimmune encephalomyelitis (EAE) as an animal model to evaluate the effect of a hydroxamate matrix metalloprotease inhibitor (GM 6001 ) on inflammatory demyelination. When administered daily either from the time of disease induction or from the onset of clinical signs, GM 6001 suppressed the development or reversed clinical EAE in a dose- dependent way, respectively. This effect appears to be mediated mainly through restoration of the damaged blood-brain barrier in the inflammatory phase of the disease (Gijbels, K., Galardy, R.E., and Steinman, L. Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases. J. Clin. Invest. 1994; 94, 2177-2182). Metalloproteinase inhibitors may have multiple functions against multiple diseases (Supuran, C.T., Casini, A., and Scozzafava, A. Protease inhibitors of the sulfonamide type: anticancer, antiinflammatory, and antiviral agents. Med. Res. Rev. 2003; 23, 535-558). In a recent review paper, many potential therapeutic applications of MMP inhibitors have been summarized and listed (Whittaker, M., Floyd, CD., Brown, P., and Gearing, A.J.H. Design and Therapeutic Application of Matrix Metalloproteinase Inhibitors. Chem. Rev. 1999; 99, 2735 -2776). Metalloproteinase inhibitors including the inhibitors inhibit both MMPs and adamalysins/ADAMs have the potential utility in the prevention and treatment of multiple diseases, including but not limited to cancer, inflammation, arthritis, restensosis, aortic aneurysm, glomerulonephritis, Guillain Barre syndrome, Bacterial Meningitis, Uveoretinitis, Graft-versus-host disease (GVHD), noninsulin-dependent diabetes mellitus, and other diseases and conditions. The migration of leucocytes through connective tissues, tissue destruction, remodeling, and angiogenesis observed in inflammatory diseases mirror similar MMP-driven processes in cancer. There is now a considerable body of evidence that inflammatory leucocytes in culture and inflamed tissues in vivo express multiple MMPs. The inhibition of the TNF- converting enzyme (TACE, ADAM-17) also confers an added antiinflammatory potential to some MMP inhibitors, such as metalloproteinase inhibitor BB-1101. MMP inhibitors have been shown to be effective in a number of animal models of inflammatory disease. Glomerulonephritis is a nephritic syndrome which results in destruction and fibrosis of the kidney. BB-1101 given prior to disease induction significantly reduced the inflammatory response and kidney damage. In experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), rodents are immunized with myelin or one of its protein components in adjuvant, resulting in an autoimmune inflammation of the brain and spinal cord. Adoptive transfer of activated myelin-specific T cells can also result in a similar disease with recurrent episodes of paralysis. An MS-like lesion can also be induced in the brain by the generation of a delayed-type hypersensitivity response (DTH). Guillain Barre syndrome (GBS) is an acute inflammatory paralytic disease of the peripheral nervous system in which leucocytes infiltrate nerves causing demyelination and edema. An animal model of GBS, experimental autoimmune neuritis (EAN), is induced in rodents by immunization with peripheral nerve myelin. This results in a T cell-dependent inflammation in peripheral nerves leading to paralysis. Inhibitor BB-1101 given from initiation in EAN prevented the development of symptoms and reduced the inflammation, demyelination, and weight loss. When given from onset of symptoms, the compound significantly reduced disease severity. Animal models of stroke usually involve clipping or blocking the mid-cerebral artery to give either permanent or temporary occlusion and reperfusion. Alternatively, injection of blood or bacterial collagenase into the brain can cause a local hemorrhage. An inflammatory infiltrate is associated with the damaged region in these models. Inhibitor BB-1101 reduces the early phases of blood-brain barrier leakage in an ischemia reperfusion model in the rat and the secondary brain edema which occurs following hemorrhage. As regard to the treatment of bacterial meningitis, rodents can develop bacterial meningitis following infection with bacteria. Batimastat was effective in reducing intracranial pressure and blood-brain barrier breakdown in a model of meningococcal meningitis. Uveoretinitis is an autoimmune inflammatory disease of the eye. Rodent models of uveitis involve immunization with retinal antigens in adjuvant. Treatment with inhibitor BB-1101 was shown to reduce retinal damage in experimental autoimmune uveitis. Graft-versus-host disease (GVHD) can be a major complication following allogeneic bone marrow transplantation. In a mouse model of lethal acute GVHD administration of inhibitor KB-R7785 reduced mortality. This effect was attributed to the inhibition of both tumor necrosis factor-alpha (TNF-) and Fas ligand release by KB- R7785. TNF- is a key mediator of insulin resistance in noninsulin-dependent diabetes mellitus. In a mouse model of insulin resistance, administration of KB-R7785 resulted in a significant decrease in both plasma glucose and insulin levels. It is suggested that KB- R7785 exerts its antidiabetic effect by ameliorating insulin sensitivity through the inhibition of TNF- production. Airway inflammation and remodeling are key features of asthma. MIVIPs and their inhibitors are thought to contribute to the pathogenesis of asthma via their influence on the function and migration of inflammatory cells as well as matrix deposition and degradation (Kelly, E.A., Jarjour, N.N. Role of matrix metalloproteinases in asthma. Curr. Opin. Pulm. Med. 2003; 9, 28-33 and Chiappara, G., Gagliardo, R., Siena, A, Bonsignore, M.R., Bousquet, J., Bonsignore, G., and Vignola, A.M. Airway remodeling in the pathogenesis of asthma. Curr. Opin. Allergy Clin. Immunol. 2001; 1 , 85-93). Metalloproteinase inhibitors may modulate wound healing process (Armstrong, D.G., and Jude, E.B. The role of matrix metalloproteinases in wound healing. J. Am. Podiatr. Med. Assoc. 2002; 92, 12-18). These inhibitors may be beneficial to prevention and treatment of stroke (Lapchak, P.A., Araujo, D.M. Reducing bleeding complications after thrombolytic therapy for stroke: clinical potential of metalloproteinase inhibitors and spin trap agents. CNS Drugs. 2001 ; 75, 819-829). Neuroinflammation, which occurs in response to brain injury or autoimmune disorders, has been shown to cause destruction of healthy tissues. Neuroinflammatory mechanisms are involved in many acute and chronic neurodegenerative disorders, including stroke, multiple sclerosis, head trauma, and Alzheimer's disease (McGeer, E. G. and McGeer, P. L., Neurodegeneration and the immune system. In: Calne D. B., ed. Neurodegenerative Diseases, W. B. Saunders, 1994; pp277-300). Other diseases that may implicate neuroinflammatory mechanisms include amyotrophic lateral sclerosis (Leigh, P. N., Pathogenic mechanisms in amyotrophic lateral sclerosis and other motor neuron disorders. In: Calne D. B., ed., Neurodegenerative Diseases, W. B. Saunders, 1994; pp473-488), cerebral amyloid angiopathy (Mandybur, T. I. and Baiko, G., Cerebral amyloid angiopathy with granulomatous angiitis ameliorated by steroid-cytoxan treatment, Clin. Neuropharm., 1992;15, 241-247), AIDS (Gendelman, H. E. and Tardieu, M., Macrophages/microglia and the pathophysiology of CNS injuries in AIDS. J. Leukocyte Biol., 1994; 56:387-388), Parkinson's disease, Huntington's disease, prion diseases, and certain disorders involving the peripheral nervous system, such as myasthenia gravis and Duchenne's muscular dystrophy, as well as Alzheimer's disease ( Aisen P. S., "Anti- inflammatory therapy for Alzheimer's disease," Dementia, 1995;9:173-82). Metalloproteinase inhibitors may modulate these processes and slow the disease progression. MMPs and metalloproteinases play extremely important roles in reproduction and the control of fertility and reproductive capabilities (e.g. contraception/birth control). Fertilization, menstrual cycle, embryo implantation, uterine bleeding, and many other normal and pathological reproductive processes are controlled by metalloproteinases and their inhibitors (Bischof, P., Campana, A. Molecular mediators of implantation. Baillieres Best Pract. Res. Clin. Obstet. Gynaecol. 2000; 14, 801-814 and Dong, J.C., Dong, H., Campana, A., and Bischof, P. Matrix metalloproteinases and their specific tissue inhibitors in menstruation. Reproduction. 2002; 123, 621-631). In addition to control cancer, cardiovascular diseases, inflammation, pain and arthritis, other conditions may be prevented and treated by these inhibitors, for example, control of corneal ulceration; diabetic retinopathy and other diabetic complications; wound healing; osteoporosis; kidney diseases; neurodegenerative diseases including, Alzheimer's disease, spinal cord injury, head trauma, AIDS, Parkinson's disease, Huntington's disease, prion diseases; the control of fertility and reproductive capabilities (e.g. contraception/birth control); regulation of blister formation; regulation of allergy; modulation of bone remodeling and regeneration; control of asthma; or other inflammatory or autoimmune disorders relying on tissue invasion by different types of cells including white blood cells, and many types of diseases involved in the immuno-system in the body (Whittaker, M., Floyd, CD., Brown, P., and Gearing, A.J.H. Design and Therapeutic Application of Matrix Metalloproteinase Inhibitors. Chem. Rev. 1999; 99, 2735 -2776; and Stemlicht, M.D. and Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001 ;17, 463-516. Review). Metalloproteinase inhibitors may have anti-bacterial activities (Scozzafava, A., Supuran, CT. Protease inhibitors - part 5. Alkyl/arylsulfonyl- and arylsulfonylureido- arylureido- glycine hydroxamate inhibitors of Clostridium histolyticum collagenase. Eur. J. Med. Chem. 2000; 35, 299-307. Metalloproteinase inhibitors may be used in sun screens and skin lotions to prevent ultra violet (UV) irradiation damage to the skin and prevent skin aging. UV irradiation acts as a broad activator of cell surface growth factor and cytokine receptors. UV-enhanced matrix degradation is accompanied with decreased collagen production. Several alterations to skin connective tissue that occur during aging are mediated by mechanisms that are similar to those that occur in response to UV irradiation. Thus, skin aging is associated with increased AP-1 activity, increased MMP expression, impaired TGF-beta signaling, enhanced collagen degradation, and decreased collagen synthesis. Knowledge gained from examining molecular responses of human skin to UV irradiation provides a framework for understanding mechanisms involved in skin aging and may help in development of new clinical strategies to impede chronological and UV-induced skin aging (Rittie, L, Fisher, G.J. UV-light-induced signal cascades and skin aging. Ageing Res. Rev. 2O02; 1 , 705-720). Metalloproteinase inhibitors may be used for industrial manufacturing of extracellular matrix/collagen products, cosmetics, beauty, and skin protection and medication products. These inhibitors can be used for the prevention and treatments of conditions in human beings and in animals, such as dogs, horses, cats, pigs, birds, sheep, and cattle, as well as other organisms.
Formulation Compounds of the instant invention are preferably administered in the form of a pharmaceutical composition comprising an effective amount of a compound of the present invention or a salt thereof in combination with at least one pharmaceutically or pharmacologically acceptable carrier. The carrier, also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is any substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the therapeutic efficacy of the anti-viral compounds. The carrier is "pharmaceutically or pharmacologically acceptable" if it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate. The pharmaceutical compositions of the present invention may be formulated in any conventional manner. Proper formulation is dependent upon the route of a ministration chosen. The compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route. Suitable routes of ad ministration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrastemal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration. Pharmaceutically acceptable carriers for use in the compositions of the present invention are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular anti-viral compound used, and its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the composition; the subject, its age, size and general condition; and the route of administration. Suitable carriers are readily determined by one of ordinary skill in the art (see, for example, J. G. Nairn, in: Remington's Pharmaceutical Science (A. Gennaro, ed.), IVlack Publishing Co., Easton, Pa., (1985), pp. 1492-1517, the contents of which are incorporated herein by reference). The compositions may be formulated as tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, or any other dosage form which can be administered orally. Techniques and compositions for making oral dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976). In general, compositions for oral administration comprise a compound of the present invention, or a salt thereof, in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, starches, and other conventional substances including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid. Further, such solid dosage forms may be uncoated or may be coated by known techniques; e.g., to delay disintegration and absorption. The compounds of the present invention may also be formulated for parenteral administration, e.g., formulated for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrastemal routes. The compositions of the invention for parenteral administration comprise an effective amount of the compound or a salt thereof in a pharmaceutically acceptable carrier. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally. Techniques and compositions for making parenteral dosage forms are known in the art. Suitable carriers used in formulating liquid dosage forms for oral or parenteral administration include nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable liquid. Suitable nonaqueous, pharmaceutically-acceptable solvents include, but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerol formal, 1 , 3-butyleneglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, -(β- hydroxyethyl)-lactamide, N, N-dimethylacetamide-amides, 2-pyrrolidinone,
1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidinone, 2- pyrrolidϊnone, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di, or tri-glycerides, fatty acid esters such as isopropyl myristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG- hydroxystearate, N-methyl pyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesters such as poly(ethoxylated)30.60 sorbitol poly(oleate)2.4 poly(oxyethylene)15.20 monooleate, poly(oxyethylene)15.20 mono 12-hydroxystearate, and poly(oxyethylene)15.20 mono ricinoleate, polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas, Wilmington, DE, polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution), saccharide fatty acid esters (i.e., the condensation product of a monosaccharide (e.g., pentoses such as ribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses such as glucose, fructose, galactose, mannose and sorbose, trioses, tetroses, heptoses, and octoses)), disaccharide (e.g., sucrose, maltose, lactose and trehalose) or oligosaccharide or mixture thereof with a C4-C22 fatty acid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid), or steroidal esters); alkyl, aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral, vegetable, animal, essential or synthetic origin (e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil, vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, persic and peanut oil and glycerides such as mono-, di- or triglycerides, animal oils such as fish, marine, sperm, cod-liver, haliver, squalene, squalane, and shark liver oil, oleic oils, and polyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate. Other pharmaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art, and are identified in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, D.C, and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds., )(MarceI Dekker, Inc., New York, New York, 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, PA, 2000), A.J. Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products, JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, No. 10, pp. 917-927 (1963). Additional minor components may be included in pharmaceutical compositions of the present invention for a variety of purposes well known in the pharmaceutical industry. These components will for the most part impart properties which enhance retention of the anti-viral compound at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the anti-viral compound into pharmaceutical formulations, and the like. Typically, each of these components is individually present in less than about 15 weight % of the total composition, more typically less than about 5 weight %, and still more typically less than about 0.5 weight % of the total composition. Some components, such as fillers or diluents, can constitute up to 90 wt.% of the total composition, as is well known in the formulation art. Such additives include cryoprotective agents for preventing reprecipitation of the anti-viral compound surface active, wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylene stearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes, flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g., bentonϊtes), adhesives, bulking agents, flavorings, sweeteners, adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannitol, or sorbitol, cellulose, or calcium phosphate), diluents (e.g., water, saline, electrolyte solutions), binders (e.g., starches such as maize starch, wheat starch, rice starch, or potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents (e.g., starches such as maize starch, wheat starch, rice starch, potato starch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc, stearic acid or salts thereof such as magnesium stearate, or polyethylene glycol), coating agents (e.g., concentrated sugar solutions including gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide), and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols, and thiophenols). Dosage form administration by these routes may be continuous or intermittent, depending, for example, upon the patient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to and assessable by a skilled practitioner. Dosage and regimens for the administration of the pharmaceutical compositions of the invention can be readily determined by those with ordinary skill in the field of anti-viral therapy. It is understood that the dosage of the compositions will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. For any mode of administration, the actual amount of the compound delivered, as well as the dosing schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on such factors as the bioavailability of the compound, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to those of skill in the art. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect the desired therapeutic response in the animal over a reasonable period of time. Preferably, an effective amount of the compound, whether administered orally or by another route, is any amount which would result in a desired therapeutic response when administered by that route. The concentration of the compound of the present invention or salt thereof in a liquid pharmaceutical composition may be between about 0.01 mg and about 10 mg per ml of the composition. The concentration of the compound or salt thereof in a solid pharmaceutical composition for oral administration may be between about 5 wt % and about 50 wt %, based on the total weight of the composition; in one embodiment, it may be between about 8 wt % and about 40 wt %, and, in another embodiment, between about 10 wt % and about 30 wt %. In one embodiment, solutions for oral administration are prepared by dissolving a compound of the present invention or salt thereof in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution. An appropriate volume of a carrier is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration to a patient. In another embodiment, powders or tablets for oral administration are prepared by dissolving the compound or salt thereof in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution. The solvent can optionally be capable of evaporating when the solution is dried under vacuum. An additional carrier can be added to the solution prior to drying. The resulting solution is dried under vacuum to form a glass. The glass is then mixed with a binder to form a powder. The powder can be mixed with fillers or other conventional tableting agents and processed to form a tablet for oral administration to a patient. The powder can also be added to any liquid carrier as described above to form a solution, emulsion, suspension or the like for oral administration. Emulsions for parenteral administration can be prepared by dissolving the compound or salt thereof in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution. An appropriate volume of a carrier which is an emulsion is added to the solution while stirring to form a pharmaceutically acceptable emulsion for parenteral administration to a patient. Solutions for parenteral administration can be prepared by dissolving a compound or salt thereof in a pharmaceutically acceptable solvent capable of dissolving the compound to form a solution. An appropriate volume of a carrier is added to the solution while stirring to form a pharmaceutically acceptable solution for parenteral administration to a patient. If desired, the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials or other conventional containers in concentrated form and diluted with any pharmaceutically acceptable liquid, such as saline, to form an acceptable concentration prior to use as is known in the art.
DEFINITIONS The terms "hydrocarbon" and "hydrocarbyl" as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms. The "substituted hydrocarbyl" moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers. Unless otherwise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. Unless otherwise indicated, the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. Unless otherwise indicated, the alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. The terms "aryl" or "ar" as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl. The term "amino" as used herein alone or as part of another group denotes the moiety -NR1R2 wherein R1 and R2 are hydrocarbyl, substituted hydrocarbyl or heterocyclo. The terms "halogen" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine. The terms "heterocyclo" or "heterocyclic" as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. T e term "heteroaromatic" as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. The term "acyl," as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group -COOH of an organic carboxylic acid, e.g., RC(O)~, wherein R is R1, R1O-, R1R2N-, or R1S-, R1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R2 is hydrogen, hydrocarbyl or substituted hydrocarbyl. The term "DEAD" as used herein denotes the moiety diethylazodicarboxylate. The term "pharmaceutically acceptable" is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product; that is the "pharmaceutically acceptable" material is relatively safe and/or non-toxic, though not necessarily providing a separable therapeutic benefit by itself. Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal salts, alkaline earth metal salts and other physiologically acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N.N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like. The following examples illustrate the invention.
Example 1 Synthesis of Heterocyclic Mercaptosulfide Inhibitors
Figure imgf000057_0001
(Py-Boc)-3,4-oxide. To a stirred solution of Λ/-Boc-3-pyrroline (Okada, T.; Sato,k H.; Tsuji, T.; Tsushima, T.; Nakai, H.; Yoshida, T.; Matsuura, S. Chem. Pharm. Bull. 1993, 41 , 132-138; Jin, Y.; Ghaffari, M. A.; Schwartz, M.A. Tetrahedron Lett. 2002, 43, 7319-7321.) (1.69 g, 10 mmol) in CH2CI2 (20 mL) was added a solution of MCPBA (-85% purity, 5.2 g) in CH2CI2 (20 mL) dropwise and stirring was continued at rt overnight. The mixture was extracted with sat. NaHC03, sat. Na2S03 and sat. NaHCO3 solutions successively. The organic layer was dried over Na2Sθ4 and filtered. After evaporation of the solvent, the residue was purified by flash chromatography (20% ethyl acetate in hexane) to give N- Boc-pyrroline-3,4-oxide as an oil (1.54 g, 82%): ""H NMR (300 MHz, CDCI3) δ 3.77 (dd, J=22, 13 Hz, 2H), 3.66 (br s, 2H), 3.31 (dd, J=13, 3 Hz, 2H), 1.44 (s, 9H).
Figure imgf000058_0001
frans-3-BzS-(Py-Boc)-4-OH. To a stirred slurry of alumina (200-300 mesh, 108 g) in dry ethyl ether (120 mL) was added thiolbenzoic acid (16.4 g, 119 mmol). After 10 min (Py- Boc)-3,4-oxide (4.30 g, 23.0 mmol) was added and stirring was continued at rt for 2 h. The alumina was filtered and was washed several times with ether until no additional product was eluted (TLC). The combined filtrate was washed with sat. aqueous NaHCO3, dried over Na2S04 and evaporated to give ifrans-3-benzoylthio-4-hydroxy-Λ/-Boc- pyrrolidine which was used without further purification (7.0 g, 94%): 1 H NMR (300 MHz, CDCI3) δ 7.93 (d, J=8 Hz, 2H), 7.60 (t, J=8 Hz, 1 H), 7.46 (t, J=8 Hz, 2H), 4.36 (m, 1 H), 4.04 (s, 1 H), 4.01 (t, J=7 Hz, 1 H), 3.72 (m, 1 H), 3.47 (m, 2H), 2.90 (br s, 1 H), 1.47 (s, 9H).
Figure imgf000058_0002
fraπs-3-BocS-(Py-Boc)-4-OH. To a stirred solution of fraπs-3-BzS-(Py-Boc)-4-OH (1.22 g, 3.74 mmol) in absolute ethanol (3 mL) at 0 °C was added a solution of potassium t- butoxide (0.46 g, 4.1 mmol) in ethanol (4 mL) dropwise. After 20 min a solution of B0C2O (0.90 g, 4.1 mmol) in a minimum amount of CH2CI2 was added and stirring was continued at 0 °C for 1 h. After removal of the ethanol under reduced pressure the residue was dissolved in ethyl acetate. The solution was washed with sat. NaHCO3 and with brine, and was dried over Na2Sθ4. After filtration and evaporation of the solvent, the residue was purified by flash chromatography (20% ethyl acetate in hexane) to give trans-3-t- butoxycarbonylthio-4-hydroxy-Λ/-Boc-pyrrolidine as an oil (0.96 g, 80%): 1 H NMR (300 MHz, CDCI3) δ 4.28 (m, 1 H), 3.87 (m, 1 H), 3.74-3.60 (m, 2H), 3.43-3.26 (m, 2H), 2.16 (s, 1 H), 1.48 (s, 9H), 1.43 (s, 9H).
Figure imgf000059_0001
c/s-3-BocS-(Py-Boc)-4-SAc. To a stirred solution of PhsP (2.53 g, 9.64 mmol) in THF (20 mL) at 0 °C was added diethyl azodicarboxylate (1.50 mL, 9.64 mmol) dropwise. After 30 min a solution of thiolacetic acid (0.48 mL, 9.64 mmol) and frar?s-3-BocS-(Py-Boc)-4-OH (1.54 g, 4.82 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at rt for 4 h, then it was evaporated under reduced pressure. The residue was purified by flash chromatogra phy (10% ethyl acetate in hexane) to give c/s-3-£-butoxycarbonylthio-4-acetylthio- Λ/-Boc-pyrrolϊdine as a solid which was recrystallized from ether/hexane (1.73 g, 94%): mp 51 -52 °C; H NMR (300 MHz, CDCI3) δ 4.31 (q, J=6 Hz, 1 H), 4.09 (m, 1 H), 3.90-3.72 (m, 2H), 3.52-3.27 (m, 2H), 2.35 (s, 3H), 1.49 (s, 9H), 1.45 (s, 9H). Anal. Calcd for C16H27NO5S2: C, 50.90; H, 7.21 ; N, 3.71 ; S, 16.99. Found: C, 51.02; H, 7.21 ; N, 3.80; S, 17.09.
eu)
Figure imgf000059_0002
c/s-3-BocS-(Py-Boc)-4-(S-D-Leu). To a stirred solution of c/s-3-BocS-(Py-Boc)-4-SAc (377 mg, 1.00 mmol) in ethanol (2 mL) was added 40% aqueous methylamine (300 μL) and stirring was continued at rt for 30 min. The solvents were evaporated and the residue was dried under high vacuum. To the residue was added DMF (2 mL), Br-L-Leu [(2S)-2- bromo-5-methylpentanoic acid] (195 mg, 1.00 mmol) and K2CO3 (277 mg, 2.00 mmol) successively, and the mixture was stirred at rt under N2 overnight. The reaction mixture was poured into water (20 mL), acidified to pH 2 with 1/V HCI, and extracted with ethyl acetate. The combined organic layer was washed with water and with brine, and then was dried over Na2Sθ4. After filtration and evaporation, the residue was purified by flash chromatography (25% ethyl acetate in hexane) to give c/s-3-BocS-(Py-Boc)-4-(S-D-Leu) as a mixture of diastereomers (370 mg, 82%): 1H NMR (300 MHz, CDCI3) δ 4.15-4.00 (m, 1 H), 3.83-3.20 (m, 6H), 1.85-1.65 (m, 2H), 1.50 (s, 4.5H), 1.48 (s, 4.5), 1.45 (s, 4.5H), 1.43 (S. 4.5H), 1.35-1.15 (m, 1 H).
Figure imgf000060_0001
c;s-3-BocS-(Py-Boc)-4-(S-D-Leu) c;s-3-BocS-(Py-Boc)-4-(S-D-Leu)-P e-NH e
c/s-3-BocS-(Py-Boc)-4-(S-D-Leu)-Phe-NHMe. To a stirred solution of c/s-3-BocS-(Py- Boc)-4-(S-D-Leu) (466 mg, 1.04 mmol), PheNHMe (203 mg, 1.14 mmol) and 1- hydroxybenzotriazole hydrate (141 mg, 1.04 mmol) in CH2CI2 (10 mL) at 0 °C was added triethylamine (180 μL, 1 ,15 mmol) and EDCI [1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride] (228 mg, 1.19 mmol), and the mixture was stirred at rt overnight. The reaction mixture was extracted with 10% aqueous citric acid, sat.
NaHCθ3, and with brine, then it was dried over Na2S04. After evaporation of the solvent the residue was purified by flash chromatography (20% ethyl acetate in hexane) to give c/s-3-BocS-(Py-Boc)-4-(S-D-Leu)-Phe-NHMe (554 mg, 88%) as a diastereomeric mixture: 1H NMR (300 MHz, CDCI3) δ 7.32-7.20 (m, 5H), 7.15-6.50 (m, 1 H), 5.90 (m, 1 H), 4.66 (m, 1H), 3.99 (m, 0.5H), 3.78 (m, 0.5H), 3.70-3.00 (m, 8H), 2.74 (d, J=5 Hz, 3H), 1.71-1.51 (m, 3H), 1.50 (s, 4.5H), 1.48 (s, 4.5H), 1.45 (s, 0.45H), 1.44 (s, 4.5H), 0.90-0.80 (m, 6H); MS calc'd for (M+Na): m/e 632.2804; found 632.2815.
Figure imgf000061_0001
c/s-3-BocS-(Py-Boc)-4-(S-D-Leu)-Phe-NHMe
Figure imgf000061_0002
(3R)-BocS-(Py-CONH2)-(4S)-(S-D-Leu)-Phe-NHMe & (3S)-BocS-(Py-CONH2)-(4R)-(S- D-Leu)-Phe-NH e. To a stirred solution of 1.5M HCI in anhydrous ethyl acetate was added c/s-3-BocS-(Py-Boc)-4-(S-D-Leu)-Phe-NHMe (183 mg, 0.3 mmol) and stirring was continued at rt until starting material was no longer detected by TLC. The solvent was evaporated under reduced pressure and the residue was dissolved in CH2CI2. The solution was cooled with stirring to 0 °C and triethylamine (46 μl) and trimethylsilyl isocyanate (100 μL, 0.74 mmol) were added successively, and the mixture was stirred at rt overnight. The reaction mixture was extracted with water and brine, and was dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (5% methanol in ethyl acetate) to give first the less-polar diastereomer (3R)-BocS-(Py-CONH2)-(4S)-(S-D-Leu)-Phe-NHMe (57 mg, 34%) as a solid which was recrystallized from ethyl acetate/hexane: mp 123-124 °C; 1 H NMR (300 MHz, CDCI3) δ 7.96 (br s, 1 H), 7.24 (m, 5H), 6.32 (br s, 1 H), 5.07 (br s, 2H), 4.67 (q, J=8 Hz, 1 H), 3.92 (m, 1 H), 3.76 (m, 2H), 3.46 (m, 2H), 3.35 (m, 2H), 3.07 (m, 2H), 2.72 (m, 5H), 1.68 (m, 1 H), 1.50 (m, 2H), 1.48 (s, 9H), 0.86 (d, J=7 Hz, 3H), 0.84 (d, J=7 Hz, 3H); MS calc'd for (M+Na): m/e 575.2338, found 575.2310; [α]D20 +11.5° (c=0.55, MeOH). Anal. Calcd for C26H40N4O5S2: C, 56.50; H, 7.29; N, 10.14; S, 11.60. Found: C, 56.25; H, 7.40; N, 9.80; S, 11.07. Further elution of the column then gave the more-polar diastereomer (3S)-BocS- (Py-CONH2)-(4 ?)-(S-D-Leu)-Phe-NHMe (63 mg, 38%) as a solid which was recrystallized from ethyl acetate/hexane: mp 173-175 °C; H NMR (300 MHz, CDCI3) δ 8.10 (br s, 1 H), 7.24 (m, 5H), 6.60 (br s, 1 H), 5.40 (br s, 2H), 4.72 (dd, J=15, 8 Hz, 1 H), 4.07 (m, 1 H), 3.73 (dd, J=12, 6 Hz, 1 H), 3.62 (m, 2H), 3.45 (m, 1 H), 3.40 (dd, J=8, 6 Hz, 1 H), 3.14 (dd, J=14, 7 Hz, 1 H), 3.01 (m, 2H), 2.76 (d, J=5 Hz, 3H), 1.70 (m, 1 H), 1.49 (s, 9H), 1.39 (m, 2H), 0.81 (d, J=7 Hz, 6H); MS calc'd for (M+Na): m/e 575.2338, found 575.2330; [α]D20 +82.6° (c=0.50, MeOH). Anal. Calc'd for C26H4θN4θδS2»1/4H2θ: C, 56.04; H, 7.28; N, 10.06; S, 11.51. Found: C, 55.91 ; H, 7.23; N, 9.88; S, 11.30. Crystals deposited by slow evaporation of the NMR solution were subjected to x-ray crystallographic analysis, which confirmed the assigned structure and stereochemistry.
(3f?)-HS-(Py-CONH2)-(4S)-(S-D-Leu)-Phe-NHMe (3R)-BocS-(Py-CONH2)-(4S)-(S-D- Leu)-P e-NHMe (40 mg) was dissolved in 2/V HCI in acetic acid (1 mL) and the solution was stirred at rt for 2 h. Lyophilization of the solution gave (3R)-HS-(Py-CONH2)-(4S)-(S- D-Leu)-Phe-NHMe as a white solid (33 mg, 100%) which was recrystallized from CH2Cl2/hexane: mp 98-100 °C; 1 H NMR (300 MHz, CD3OD) δ 7.30-7.10 (m, 5H), 4.68 (dd, J=10, 6 Hz, 1 H), 3.80-3.32 (m, 7H), 3.10 (dd, J=14, 6 Hz, 1 H), 2.86 (dd, J=14, 10 Hz, 1 H), 2.71 (s, 3H), 1.56 (m, 1 H), 1.33-1.10 (m, 2H), 0.76 (d, J=6 Hz, 6H); MS calc'd for (M+Na): m/e 475.1814, found 475.1833; [ ]D20 +54.4° (c=0.50, MeOH). Anal. Calc'd for C2lH32N4θ3S2*H2θ: C, 53.59; H, 7.28; N, 11.90; S, 13.63. Found: C, 53.89; H, 7.12; N, 11.62; S, 13.23. (3S)-HS-(Py-CONH2)-(4 ?)-(S-D-Leu)-Phe-NHMe By the same procedure, (3S)-BocS- (Py-CONH2)-(4R)-(S-D-Leu)-Phe-NHMe afforded (3S)-HS-(Py-CONH2)-(4R)-(S-D-Leu)- Phe-NHMe: mp 128-130 °C; 1 H NMR (300 MHz, CD3OD) δ 7.30-7.16 (m, 5H), 4.68 (dd, J=10, 6 Hz, 1 H), 3.79 (m, 1 H), 3.71-3.41 (m, 5H), 3.22 (t, J=9 Hz, 1 H), 3.10 (dd, J=14, 5 Hz, 1 H), 2.86 (dd, J=14, 10 Hz, 1 H), 2.71 (s, 3H), 1.59 (m, 1 H), 1.36-1.20 (m, 2H), 0.79 (d, J=6 Hz, 3H), 0.78 (d, J=6 Hz, 3H); MS calc'd for (M+Na): m/e 475.1814, found 475.1823; [α]D20 +38.5° (c=0.40, MeOH); Anal. Calc'd for C2l H32N4θ3S2»H2θ: C, 53.59; H, 7.28; N, 11.90; S, 13.63. Found: C, 53.97; H, 7.08; N, 11.60; S, 13.14.
Example 2
Figure imgf000063_0001
(S)-2-bromo-4-phenylbutanoic acid. To a stirred mixture of 896 mg (5.01 mmol) of L- homophenylalanine in 20 mL of 3/V aqueous HBr at -10 °C was added 1.04 g (15.0 mmol) of NaNO2 portion wise, then stirring was continued at -10 °C for 3 h. The mixture was extracted with ethyl ether. The ether layer was washed with water and with brine, then it was dried over Na2Sθ4. Evaporation of the solvent gave 1.15 g (4.73 mmol, 94%) of the bromoacid as an oil which was used without further purification: 1H NMR (300 MHz, CDCI3) d 9.45 (br s, 1 H), 7.35-7.18 (m, 5H), 4.20 (dd, J=8, 6 Hz, 1 H), 2.91-2.71 (m, 2H), 2.47-2.25 (m, 2H); [ ]25 D -66.2° © = 0.20, CHCI3) (Iwasaki, G.; Kimura, R; Numao, N.; Kondo, K. Chem. Pharm. Bull. 1989, 37, 280-283).
S-D-hPhe)
Figure imgf000063_0002
cιs-3-BocS-(Py-Boc)-4-(S-D-hPhe). To a stirred solution of c/s-3-BocS-(Py-Boc)-4-SAc (1.24 g, 3.28 mmol) and (S)-2-bromo-4-phenylbutanoic acid (0.80 g, 3.29 mmol) in dry ethanol (4 mL) at 0 °C was added a solution of potassium t-butoxide (0.748 g, 6.66 mmol) in dry ethanol (4 mL) dropwise, and the mixture was stirred at rt overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate, acidified to pH 2 with 1/V HCI, and extracted with ethyl acetate. The combined organic layer was washed with water and brine, and was dried over Na2SO4. After filtration and evaporation, the residue was purified by flash chromatography (25% ethyl acetate in hexane) to give c/s-3-BocS-(Py-Boc)-4-(S-D-hPhe) (1.35g, 83%) as a mixture of diastereomers: 1 H NMR (300 MHz, CDCI3) δ 7.32-7.17 (m, 5H), 4.09 (m, 1 H), 3.82-3.20 (m, 6H), 2.77 (t, J=7 Hz, 2H), 2.20 (m, 1 H), 1.98 (m, 1 H), 1.49 (s, 4.5H), 1.18 (s, 4.5H ), 1.46 (s, 4.5H), 1.44 (s, 4.5H).
Figure imgf000064_0001
c/s-3-BocS-(Py-Boc)^(S-D-hPhe)-Leu-NHPl 4-OMe
c s-3-BocS-(Py-Boc)-4-(S-D-hPhe)-Leu-NHPh-4-OMe. To a stirred solution of c/s-3- BocS-(Py-Boc)-4-(S-D-hPhe) (249 mg, 0.5 mmol), Leu-NHPh-4-OMe (236 mg, 1.0 mmol) and 1-hydroxybenzotriazole hydrate (135 mg, 1.0 mmol) in CH2CI2 (10 mL) at 0 °C was added diisopropylethylamine (350 μL, 1.0 mmol) and EDCI (192 mg, 1.0 mmol), and the mixture was stirred at rt overnight. The reaction mixture was extracted with 10% aqueous citric acid, sat. NaHC03, and with brine, then it was dried over Na2S04. After evaporation of the solvent the residue was purified by flash chromatography to give c/s-3- BocS-(Py-Boc)-4-(S-D-hPhe)-Leu-NHPh-4-OMe (352 mg, 98%) as a mixture of diastereomers: 1 H NMR (300 MHz, CDCI3) δ 8.2 (br m, 1 H), 7.40 (d, J=9 Hz, 1 H), 7.38 (d, J=9 Hz, 1 H), 7.28-7.03 (m, 6H), 6.81 (d, J=9 Hz, 1 H), 6.80 (d, J=9 Hz, 1 H), 4.56 (m, 1 H), 4.15 (m, 0.5H), 4.00 (m, 0.5H), 3.76 (s, 1.5H), 3.75 (s, 1.5H), 3.76-3.15 (m, 6H), 2.72 (t, J=7 Hz, 2H), 2.25 (m, 1H), 2.09-1.6 (m, 4H), 0.97 (m, 6H); MS calc'd for (M+Na): m/e 738.3223, found 738.3257.
Figure imgf000065_0001
c/s-3-BocS-(Py-CONH2)-4-(S-D-hPhe)-Leu-NHPh-4-OMe, Dip & Dmp. To a stirred solution of 1.5M HCI in anhydrous ethyl acetate was added c/s-3-BocS-(Py-Boc)-4-(S-D- hPhe)-Leu-NHPh-4-OMe (215 mg, 0.3 mmol) and stirring was continued at rt until starting material was no longer detected by TLC. The solvent was evaporated under reduced pressure and the residue was dissolved in CH2CI2. The solution was cooled with stirring to 0 °C and triethylamine (46 μL) and trimethylsilyl isocyanate (100 μL, 0.74 mmol) were added successively, and the mixture was stirred at rt overnight. The reaction mixture was extracted with water and brine, and was dried over Na2Sθ4. After evaporation of solvent, the residue was purified by flash chromatography (5% methanol in ethyl acetate) to give c/s-3-BocS-(Py-CONH2)-4-(S-D-hPhe)-Leu-NHPh-4-OMe (148 mg, 75%) as a mixture of two diastereomers. The diastereomers were separated by preparative HPLC (19 x 150 mm C18 column; flow rate 7mL/min; 70% MeOH, 30% H2O). The first fraction collected was concentrated under reduced pressure to remove most of MeOH, then it was lyophilized to give the first diastereomer (Dip): mp 112-113 °C (CH2CI2-hexane); 1H NMR (300 MHz, CD3OD) δ 7.50 (d, J=9 Hz, 2H), 7.30-7.7.13 (m, 5H), 6.87 (d, J=9 Hz, 2H), 4.57 (dd, J=10, 5 Hz, 1 H), 4.06 (q, J=5 Hz, 1 H), 3.84 (q, J=6 Hz, 1 H), 3.78-3.65 (m, 2H), 3.76 (s, 3H), 3.50-3.39 (m, 2H), 3.38-3.20 (m, 1 H), 2.69 (t, J=8 Hz, 2H), 2.15 (m, 1 H), 1.99 (m, 1 H), 1.80-1.53 (m, 3H), 1.44 (s, 9H), 1.01 (d, J=2 Hz, 3H), 0.99 (d, J=2 Hz, 3H); MS calc'd for (M+Na): m/e 681.2757, found 681.2753; [α]D 20 -42.1° (c=0.24, CHCI3). Anal. Calc'd for C33H46N4θ6S2»1/4H2O : C, 59.47; H, 7.06; N, 8.45; S, 9.67. Found: C, 59.74; H, 7.02; N, 8.30; S, 9.54. The second fraction was concentrated under reduced pressure to remove most of
MeOH, then it was lyophilized to give the second diastereomer (Dmp): mp 171-172 °C (CH2CI2-hexane); 1 H NMR (300 MHz, CD3OD) δ 7.33 (d, J=9 Hz, 2H), 7.20-7.00 (m, 5H), 6.77 (d, J=9 Hz, 2H), 4.49 (dd, J=10, 5 Hz, 1 H), 4.12 (m, 1 H), 3.80-3.45 (m, 4H), 3.66 (s, 3H), 3.41 (dd, J=9, 7 Hz, 1 H), 3.30 (t, J=10 Hz, 1 H), 2.58 (t, J=8 Hz, 2H), 1.99 (m, 1 H), 1.83 (m, 1 H), 1.63 (m, 2H), 1.52 (m, 1 H), 1.39 (s, 9H), 0.91 (d, J=2 Hz, 3H), 0.89 (d, J=2 Hz, 3H); MS calc'd for (M+Na): m/e 681.2757, found 681.2753; [α]D 20 +17.2° (c=0.25, CHCI3).
c/s-3-HS-(Py-CONH2)-4-(S-D-hPhe)-Leu-NHPh-4-OMe, Dip (YHJ-74). c/s-3-BocS-(Py- CONH2)-4-(S-D-hPhe)-Leu-NHPh-4-OMe, Dip (18.0 mg, 27.3 μmol) was dissolved in 2/V HCI in acetic acid (1 mL) and the solution was stirred at rt for 2 h. Lyophilization of the solution gave c/s-3-HS-(Py-CONH2)-4-(S-D-hPhe)-Leu-NHPh-4-OMe, Dip as a white solid (15.3 mg, 100%): mp 174-175 °C; 1H NMR (300 MHz, CDCI3) δ 7.44 (d, J=9 Hz, 2H), 7.33-7.10 (m, 5H), 6.87 (d, J=9 Hz, 2H), 4.58 (dd, J=10, 5 Hz, 1 H), 3.76 (s, 3H), 3.80-3.60 (m, 4H), 3.50-3.31 (m, 3H), 2.68 (t, J=8 Hz, 2H), 2.13 (m, 1 H), 1.97 (m, 1 H), 1.82-1.56 (m, 3H), 1.00 (d, J=6 Hz, 3H), 0.99 (d, J=6 Hz, 3H); MS calc'd for (M+Na): m/e 581.2232, found 581.2253; [α]D 20 +2.4° (c=0.50, CDCI3). Anal. Calc'd for C28H38N4θ4S2*H20: C, 58.31 ; H, 6.99; N, 9.71 ; S, 11.12. Found: C, 58.79; H, 6.74; N, 9.53; S, 10.95.
c s-3-HS-(Py-CONH2)-4-(S-D-hPhe)-Leu-NHPh-4-OMe, Dmp (YHJ-75). By the same procedure c.s-3-BocS-(Py-CONH2)-4-(S-D-hPhe)-Leu-NHPh-4-OMe, Dmp (17.6 mg, 26.7 μmol) was converted to c/s-3-HS-(Py-CONH2)-4-(S-D-hPhe)-Leu-NHPh-4-OMe, Dmp (14.9 mg, 100%): mp 105-106 °C; 1H NMR (300 MHz, CD3OD) δ 7.44 (d, J=9 Hz, 2H), 7.32-7.10 (m, 5H), 6.87 (d, J=9 Hz, 2H), 4.58 (dd, J=10, 5 Hz, 1 H), 3.82-3.62 (m, 4H), 3.76 (s, 3H), 3.48 (dd, J=9, 6 Hz, 2H), 3.26 (m, 1 H), 2.69 (t, J=8 Hz, 2H), 2.13 (m, 1 H), 1.98 (m, 1 H), 1.80-1.50 (m, 3H), 1.00 (d, J=6 Hz, 3H), 0.99 (d, J=6 Hz, 3H); MS calc'd for (M+Na): m/e 581.2232, found 581.2233; [α]D 20 -35.4° (c=0.24, CHCI3). Anal. Calc'd for C28H38N4θ4S2»H20: C, 58.31 ; H, 6.99; N, 9.71 ; S, 11.12. Found: C, 58.46; H, 6.62; N, 9.44; S, 10.86. Example 3
The procedures described in Examples 1 and 2 were repeated, but either no N- acylating agent, or other acylating agents, were substituted for the trimethylsilyl isocyanate (TMSI) of Examples 1 and 2 to prepare the series of compounds in the following table, confirmed by included characterizing data:
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Example 4 Table I
Figure imgf000071_0001
Figure imgf000071_0002
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000074_0001
Figure imgf000074_0002
Inhibitor cdMT1 cdMET HNC HFC HNG HFG HFS MLN *Dmp (1.2) (10) (0.57) (8.8) (1.1 ) (0.7) (6) (6.5) (430) (560) (110) (1900) (122) (90) (1100) (670)
Figure imgf000075_0001
YHJ-132 (*Dmp) YHJ-133 (*Dlp)
*Dlp (3.7) (5.1 ) (190) (0.35) (1.8) (13) (250)
Figure imgf000075_0002
YHJ-223 (1 1)
Figure imgf000076_0001
Abbreviations: Dip, or Dmp, faster-eluting, or slower-eluting, diastereomer (chromatography); Me; methyl; Ph, phenyl; Pmp, para methoxyphenyl
The following protocol was used to collect the data found in the preceding table I.
Materials: The fluorescent peptide substrates for matrix metalloproteinases (MMPs) used were purchased from Bachem Chem. Co. The metal salts and Brij-35 were purchased from Fisher Scientific Inc. All other chemicals were purchased from Sigma-Aldrich Chem. Co. The sources and biochemical characterizations of multiple MMPs, including MMP- 1/human fibroblast collagenase (HFC), MMP-2/human fibroblast gelatinase (HFG), MMP- 8/human neutrophil collagenase (HNC), and MMP-9/human neutrophil gelatinase (HNG), MMP-7/human matrilysin (MLN), MMP-3/human fibroblast stromelysin-1 (HFS), human recombinant catalytic domain of membrane-type 1 matrix metalloproteinase (cdMT1- MMP), catalytic domain of MMP-12/metalloelastase (cdMET) were described previously (Sang, Q.X., Birkedal-Hansen, H., and Van Wart, H.E. Proteolytic and non-proteolytic activation of human neutrophil progelatinase B. Biochim. Biophys. Acta. 1995;1251 , 99- 108; Sang, Q.A., Bodden, M.K., and Windsor, L.J. Activation of human progelatinase A by collagenase and matrilysin: activation of procollagenase by matrilysin. J. Protein. Chem. 1996; 15, 243-253; Li, H., Bauzon, D.E., Xu, X., Tschesche, H., Cao, J., and Sang, Q.-X.A. Immunological characterization of cell-surface and soluble forms of membrane type 1 matrix metalloproteinase in human breast cancer cells and in fibroblasts. Molec. Carcinog.1998; 22, 84-94; Park, H.I., Ni, J., Gerkema, F.E., Liu, D., Belozerov, V.E., and Sang, Q.-X.A. Identification and characterization of human endometase (Matrix metalloproteinase-26) from endometrial tumor. J. Biol. Chem., 2000; 275, 20540-20544). The active concentrations of MMPs were determined by titration with GM6001 , a tight-binding MMP inhibitor, as described previously (Park, H.I., Turk, B.E., Gerkema, F.E., Cantley, L.C., and Sang, Q.-X.A. Peptide substrate specificities and protein cleavage sites of human endometase/matrilysin-2/matrix metalloproteinase-26. J. Biol. Chem. 2002; 277, 35168-35175). Determination of Mercaptosulfide Inhibitor Concentration. The active inhibitor concentrations were estimated by titrating the mercapto group with 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB; Ellman's reagent) as described previously (Ellman, G.L. A colorimetric method for determining low concentrations of mercaptans. Arch. Biochem. Biophys. 1958; 74, 443-450; Ellman, G.L. Tissue sulfhydryl groups. Arch. Biochem. Biophys. 1959; 82, 70-77; Riddles, P.W., Blakeley, R.L., and Zerner, B. Ellman's reagent: 5,5'-dithiobis(2-nitrobenzoic acid)--a reexamination. Anal. Biochem. 1979; 94, 75-81). Briefly, the reaction of DTNB with the mercapto group produces 2-nitro- 5-thiobenzoic acid (TNB). The concentration of TNB is then measured by monitoring the absorbance at 412 nm. Cysteine was used to generate the standard cun e with a molar extinction coefficient of 14,000 ± 500 M~1 cm-1, which is close to the value in the literature (Riddles, P.W., Blakeley, R.L., and Zerner, B. Ellman's reagent: 5,5'-dithiobis(2- nitrobenzoic acid)-a reexamination. Anal. Biochem. 1979; 94, 75-81).
Enzyme Kinetic Assays and Inhibition of MMPs. The substrate Mca-PLGLDpaAR-NH2 was used to measure inhibition constants
(Knight, C.G., Willenbrock. F., and Murphy, G. A novel coumarin-Iabeled peptide for sensitive continuous assays of the matrix metalloproteinases. FEBS Lett. 1992; 296, 263- 266). Enzymatic assays were performed at 25 °C in 50 mM HEPES buffer at pH 7.5 in the presence of 10 mM CaCI2, 0.2 M NaCl, and 0.01% or 0.05% Brij-35 with substrate concentrations of 1 μM. The release of product was monitored by measuring fluorescence (excitation and emission wavelengths of 328 nm and 393 nm, respectively) with a Perkin Elmer Luminescence Spectrophotometer LS 50B connected to a temperature controlled water bath. All stock solutions of inhibitors were in methanol. For inhibition assays, 10 μl of inhibitor stock solution, 176 μl of assay buffer, and 10 μl of enzyme stock solution were mixed and incubated for 30 to 60 minutes prior to initiation of the assay, which was accomplished by adding and mixing 4 μl of the substrate stock solution. Enzyme concentrations ranged from 0.2 to 7 nM during the assay. Apparent inhibition constant (K,app) values were calculated by fitting the kinetic data to the Morrison equation for tight- binding inhibitors (Morrison, J.F. Kinetics of the reversible inhibition of enzyme-catalyzed reactions by tight-binding inhibitors. Biochim. et Biophys. Acta 1969; 185, 269-286.), where v, and v0 are the initial rates with and without inhibitor respectively, and [E]0 and [/]0 are the initial (total) enzyme and inhibitor concentrations respectively. More detailed experimental design and methods have been described in previous reports (Park, H.I., Jin, Y., Hurst, D.R., Monroe, C.A., Lee, S., Schwartz, M.A., and Sang, Q.-X. The intermediate S1' pocket of the endometase/matrilysin-2 active site revealed by enzyme inhibition kinetic studies, protein sequence analyses, and homology modeling. J. Biol. Chem. 2003 Dec 19; 278(51): 51646-53. Epub 2003 Oct 07. Hurst, D.R., Schwartz, M.A., Ghaffari, M.A., Jin, Y., Tschesche, H., Fields, G.B., and Sang, Q.-X. Catalytic- and ecto-domains of membrane type 1 -matrix metalloproteinase have similar inhibition profiles but distinct endopeptidase activities. Biochem. J. 2004 Feb 1 ; 377(Pt 3): 775-9.)

Claims

WHAT IS CLAIMED IS:
1. A composition corresponding to Formula 1 or a salt thereof:
Figure imgf000080_0001
wherein: R20, R21, R27 and R28 are independently hydrogen, hydrocarbyl or substituted hydrocarbyl; the X ring is a 5-7 membered saturated heterocyclic ring comprising X2; X1 is a cation, hydrogen or acyl; X2 is sulfone (-S(=0)2-), oxygen, or -N(X20)-; X3 and X4 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; or X3 and X4 in combination with the carbon atom to which they are attached form a carbocyclic or heterocyclo ring; X5 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or -NX51X52; X6 and X7 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; or X6 and X7 in combination with the carbon atom to which they are attached form a carbocyclic or heterocyclo ring; X8 and X9 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, -OX83, -NX81X82, -C(=NH2 +)NH2, or -NH-C(=NH)NH2, provided, however, X8 and X9 are not each -NX81X82, -C(=NH2 +)NH2, -OX83, or -NH-C(=NH)NH2; or X8 and X9 in combination with the nitrogen atom to which they are attached form a heterocyclo ring; X20 is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, acyl, -OX21, or
_Nχ23χ24.
X21 is hydrocarbyl, substituted hydrocarbyl, heterocyclo, or acyl; X23 and X24 are independently hydrocarbyl, substituted hydrocarbyl, heterocyclo, or acyl; or X23 and X24 in combination with the nitrogen atom to which they are attached form a heterocyclo ring; X51 and X52 are independently hydrocarbyl, substituted hydrocarbyl, heterocyclo, or acyl; or X51 and X52 in combination with the nitrogen atom to which they are attached form a heterocyclo ring; X81 and X82 are independently hydrocarbyl, substituted hydrocarbyl, or heterocyclo; or X81 and X82 in combination with the nitrogen atom to which they are attached form a heterocyclo ring; and X83 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
2. The composition of claim 1 wherein X2 is -NX20 and X20 is as defined in claim 1.
3. The composition of claim 1 wherein the X ring is a 5-membered saturated heterocyclic ring.
4. The composition of claim 3 wherein X2 is sulfone (-S(=0)2-).
5. The composition of claim 3 wherein X2 is oxygen.
6. The composition of claim 3 wherein X2 is -NX20 and X20 is as defined in claim 1.
7. The composition of claim 1 wherein the composition corresponds to Formulae 10 or 11 :
Figure imgf000082_0001
Figure imgf000082_0002
wherein: R20, R21, R27, R28, X1, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in claim 1 ; X25 is -C(R22)(R23)-, oxygen or -N(R24)-; and R22, R23 and R24 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.
8. The composition of claim 7 wherein X2 is sulfone (-S(=0)2-).
9. The composition of claim 7 wherein X2 is oxygen.
10. The composition of claim 7 wherein X2 is -N(X20)- and X20 is as defined in claim
11. The composition of claim 1 wherein the composition corresponds to Formula
13:
Figure imgf000083_0001
Formula 13
wherein: (i) R20, R21, R27, R28, X1, X3, X4, X5, X6, X7, X8, X9 and X20 are as defined in claim 1 ; (ii) X25, X26 and X27 are selected from -C(R22)(R23)-, oxygen, sulfone, and -N(X20)-, provided, however, at least one of X25 and X27 is -C(R22)(R23)-; and (iii) each R22 and R23 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
12. The composition of any of claims 1-11 wherein R20, R21, R27 and R28 are hydrogen.
13. The composition of any of claims 1-11 wherein X1 is hydrogen.
14. The composition of any of claims 1-11 wherein X3 is hydrogen.
15. The composition of any of claims 1-11 wherein X5 is hydrogen.
16. The composition of any of claims 1-11 wherein X6 is hydrogen.
17. The composition of any of claims 1-11 wherein X8 is hydrogen.
18. The composition of any of claims 1-11 wherein X4, X7, and X9 are independently an optionally substituted methyl, ethyl or a C3-C6 straight, branched or cycloalkyl.
19. The composition of any of claims 1 -11 wherein X4, X7, and X9 are independently an optionally substituted alkyl, alkaryl, or heterocyclo.
20. A method of treating a condition mediated by a matrix metalloproteinase, the method comprising administering to an individual a composition of any of claims 1-19.
21. A process for the preparation of a compound corresponding to any of claims 1- 19, the process comprising transforming a heterocyclic epoxide to the corresponding heterocyclic alcohol using a thiolcarboxylic acid in the presence of alumina catalyst wherein the epoxide has the formula:
Figure imgf000084_0001
and the heterocyclic alcohol has the formula:
Figure imgf000084_0002
wherein R , R , R27, R28 and X2 are as defined in claim 1 and Ac is acyl.
22. The process of claim 21 wherein the process additionally comprises the step of replacing the acyl group of the heterocyclic alcohol with a protecting group to form a protected heterocyclic alcohol wherein the protected heterocyclic alcohol has the formula:
Figure imgf000085_0001
wherein R20, R21, R27, R28 and X2 are as defined in claim 1 and P1 is a protecting group.
23. The process of claim 22 wherein the process additionally comprises the step of replacing the hydroxy group of the protected heterocyclic alcohol with an S-acyl group by treating the protected heterocyclic alcohol with a thiolcarboxylic acid to form an S-acyl heterocycle having the formula:
Figure imgf000085_0002
wherein R20, R21, R27, R28 and X2 are as defined in claim 1 , P1 is a protecting group, and Ac is acyl.
24. The process of claim 23 wherein the S-acyl heterocycle is alkylated by cleaving the acyl group, Ac, and alkylating the deacylated sulfur atom with an alkylating agent.
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Cited By (2)

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US8362068B2 (en) 2009-12-18 2013-01-29 Idenix Pharmaceuticals, Inc. 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors
US8404866B2 (en) 2008-09-03 2013-03-26 Florida State University Research Foundation Substituted heterocyclic mercaptosulfonamide metalloprotease inhibitors

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* Cited by examiner, † Cited by third party
Title
JIN Y. ET AL.: "A practical synthesis of differentially-protected cis-1,2-cyclopentanedithiols and cis-3,4-pyrrolidinedithiols", TETRAHEDRON LETTERS, vol. 43, October 2002 (2002-10-01), pages 7319 - 7321, XP004389284 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8404866B2 (en) 2008-09-03 2013-03-26 Florida State University Research Foundation Substituted heterocyclic mercaptosulfonamide metalloprotease inhibitors
US8362068B2 (en) 2009-12-18 2013-01-29 Idenix Pharmaceuticals, Inc. 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors
US9187496B2 (en) 2009-12-18 2015-11-17 Idenix Pharmaceuticals Llc 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors

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