WO1995029892A1 - Hydroxamic acid and amino acid derivatives and their use as anti-arthritic agents - Google Patents

Hydroxamic acid and amino acid derivatives and their use as anti-arthritic agents Download PDF

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Publication number
WO1995029892A1
WO1995029892A1 PCT/US1995/005012 US9505012W WO9529892A1 WO 1995029892 A1 WO1995029892 A1 WO 1995029892A1 US 9505012 W US9505012 W US 9505012W WO 9529892 A1 WO9529892 A1 WO 9529892A1
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Prior art keywords
substituted
alkyl
methyl
hydroxyamino
methyl amide
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PCT/US1995/005012
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French (fr)
Inventor
Carl Peter Decicco
Irina Cipora Jacobson
Ronald L. Magolda
David John Nelson
Robert Joseph Cherney
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The Du Pont Merck Pharmaceutical Company
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Priority to AU23947/95A priority Critical patent/AU2394795A/en
Publication of WO1995029892A1 publication Critical patent/WO1995029892A1/en

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    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • 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
    • C07D403/10—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 aromatic rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • MMP-3 stromelysin
  • MMP metalloproteinases
  • OA and RA Osteo- and Rheumatoid Arthritis
  • stromelysin a matrix metalloproteinase (MMP-3)
  • MMP-3 matrix metalloproteinase
  • osteoarthritis osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth.
  • Tumour necrosis factor is a cytokine which is produced initially as a cell-associated 28kD precusor. It is released as an active, 17kD form, which can mediate a large number of deleterious effects in vivo . When administered to animals or humans it causes inflammation, fever, cardiovascular effects,
  • AA is an amino acid, as inhibitors of matrix metallproteinase mediated diseases.
  • PCT International Publication No. WO 94/02446 discloses metalloproteinase inhibitors which are natural amino acid derivatives of general formula:
  • the compounds of the current invention inhibit the production of TNF, a cytokine implicated in inflammatory diseases.
  • TNF a cytokine implicated in inflammatory diseases.
  • the hydroxamic and carboxylic acids and derivatives thereof of the present invention have been further found to be orally bioavailable.
  • hydroxamic and carboxylic acids and derivatives described herein have a distinct advantage in this regard, in that they do not contain readily cleavable peptide bonds, are of low molecular weight, and can be hydrophilic yet still inhibit matrix metalloproteinases.
  • the present invention relates to a class of novel hydroxamic acids and carbocyclic acids and derivatives thereof that inhibit stromelysin and other matrix metalloproteinases, and also inhibit the production of tumor necrosis factor (TNF), and are therefore useful for the treatment of arthritis and other related inflammatory diseases.
  • TNF tumor necrosis factor
  • R 2 is selected from:
  • R 3 is selected from: OR 11 , NHCH(R 12 )COR 13 ,
  • R 4 is selected from:
  • R 5 and R 6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered carbocyclic or heterocyclic ring, wherein said heterocyclic ring contains one or two N, O or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R 18 ;
  • R 8 is a substituent on nitrogen and is selected from hydrogen
  • R 9 is selected from:
  • R 9a is selected from H, OR 17 , SR 17 or NR 10 R 10a ,
  • R 9 and R 9a can be taken together to form a 3-7 membered carbocyclic or heterocyclic ring, said heterocyclic ring containing 1-2 heteroatoms selected from N, O or S, optionally substituted on carbon with keto;
  • R 10 is selected from:
  • R 10a is selected from hydrogen or C 1 -C 4 alkyl
  • R 10 and R 10a can alternatively join to form -(CH 2 ) 4 -,
  • R 11 is H, benzyl, or C 1 -C 4 alkyl;
  • R 12 is selected from:
  • R 13 is C 1 -C 4 alkyl
  • R 14 and R 15 are independently selected from H or C 1 -C 4 alkyl
  • R 16 is hydrogen or methyl
  • R 17 is selected from:
  • R 17a is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ; R 17b is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, .isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ;
  • R 18 when a substituent on carbon, is selected from one or more of the following:
  • -NR 10 R 10a C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, -S(O) m R 11 , -NHSO 2 R 11 , phenyl, optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -cyalkoxy, hydroxy, or -NR 10 R 10a , a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperid
  • R 18 when a substituent on nitrogen, is selected from one or more of the following:
  • R 19 when a substituent on carbon, is selected from one or more of the following:
  • -NR 10 R 10a C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, -S(O) m R 11 , -NHSO 2 R 11 , a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl
  • R 19 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with
  • R 19 when a substituent on nitrogen, is selected from one or more of the following:
  • R 20 is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ;
  • One embodiment of the present invention relates to a novel class of compounds embodied within the class of compounds of Formula I and
  • R 1 is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl,
  • thiazolidinyl isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ;
  • R 1a is selected from H, NR 10 R 10a , OR 17 or S(O) m R 17
  • R 1 and R la can be taken together to form a
  • heterocyclic ring 3-7 membered carbocyclic or heterocyclic ring, said heterocyclic ring containing 1-2 hetero-atoms selected from N, O, and S;
  • R 2 is selected from:
  • R 3 is -NR 10 R 10a
  • R 4 is selected from:
  • R 5 and R 6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered
  • carbocyclic or heterocyclic ring wherein the heterocyclic ring contains one to two N, O, or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R 18 ;
  • R 8 is a substituent on nitrogen and is selected from
  • R 10 is selected from:
  • R 10a is selected from hydrogen or C 1 -C 4 alkyl
  • R 10 and R 10a can alternatively join to form -(CH 2 ) 4 -, -(CH 2 ) 5 -, -CH 2 CH 2 N(R 16 )CH 2 CH 2 -, or -CH 2 CH 2 OCH 2 CH 2 -;
  • R 11 is H, benzyl, or C 1 -C 4 alkyl
  • R 12 is selected from:
  • R 13 is C 1 -C 4 alkyl
  • R 14 and R 15 are independently selected from H or C 1 -C 4 alkyl;
  • R 16 is hydrogen or methyl;
  • R 17 is selected from:
  • R 17a is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ;
  • R 17b is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ;
  • R 18 when a substituent on carbon, is selected from one or more of the following:
  • -NR 10 R 10a C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, -S(O) m R 11 , -NHSO 2 R 11 , phenyl, optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy or NR 10 R 10a , a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidiny
  • R 18 when a substituent on nitrogen, is selected from one or more of the following:
  • R 19 when a substituent on carbon, is selected from one or more of the following:
  • -NR 10 R 10a C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, -S(O) m R 11 , -NHSO 2 R 11 , a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl
  • R 19 when a substituent on nitrogen, is selected from one or more of the following:
  • R 20 is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ; with the following proviso:
  • R 2 is not hydrogen, C 3 -C 10 alkyl or (C 1 -C 4 alkyl)aryl.
  • preferred compounds of this embodiment are compounds of Formula II wherein:
  • R 1 is selected from:
  • R 2 is selected from:
  • R 8 is hydrogen
  • R 10 is selected from:
  • R 5 is selected from:
  • R 6 is hydrogen; with the proviso that R 8 is absent when Z is O.
  • a second embodiment of the present invention relates to a class of novel compounds also embodied within the class of compounds of Formula I and to pharmaceutical compositions and methods of use of these novel compounds for the inhibition of stromelysin and other matrix metalloproteinases, for the inhibition of the production of tumor necrosis factor (TNF) and in the treatment of Osteo and Rheumatoid Arthritis (OA and RA) and related diseases.
  • TNF tumor necrosis factor
  • OA and RA Osteo and Rheumatoid Arthritis
  • Q is selected from: a C 5 -C 14 carbocyclic ring system substituted with 0-4 groups selected from R 5 , R 6 , R 18 or
  • R 2 is selected from
  • R 3 is NR 10 R 10a ;
  • R 4 is selected from:
  • heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or
  • R 4a is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ;
  • R 5 and R 6 are independently selected from:
  • R 5 and R 6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered
  • carbocyclic or heterocyclic ring wherein the heterocyclic ring contains one or two N, O or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R 18 ;
  • R 8 is a substituent on nitrogen and is selected from hydrogen
  • R 9 is selected from:
  • R 10 is selected from:
  • R 10a is selected from hydrogen or C 1 -C 4 alkyl
  • R 10 and R 10a can alternatively join to form -(CH 2 ) 4 -,
  • R 11 is H, benzyl, or C 1 -C 4 alkyl
  • R 13 is C 1 -C 4 alkyl
  • R 14 and R 15 are independently selected from H or C 1 -C 4 alkyl;
  • R 16 is hydrogen or methyl;
  • R 17 is selected from:
  • R 17a is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ;
  • R 17b is selected from:
  • R 18 when a substituent on carbon, is selected from one or more of the following:
  • -NR 10 R 10a C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, -S(O) m R 11 , -NHSO 2 R 11 , phenyl, optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy or NR 10 R 10a ;
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ; or R 18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or
  • R 18 when a substituent on nitrogen, is selected from one or more of the following:
  • R 19 when a substituent on carbon, is selected from one or more of the following:
  • R 19 when a substituent on nitrogen, is selected from one or more of the following:
  • R 20 is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ;
  • R 2 is selected from
  • Z is N or O; with the proviso that R 8 is absent when Z is O.
  • Specifically preferred compounds of the second embodiment are selected from:
  • a third embodiment of the present invention relates to a class of novel compounds also embodied within the class of compounds of Formula I and to pharmaceutical compositions and methods of use of these novel compounds for the inhibition of stromelysin and other matrix metalloproteinases, for the inhibition of the production of tumor necrosis factor (TNF) and in the treatment of Osteo and Rheumatoid Arthritis (OA and RA) and related diseases.
  • TNF tumor necrosis factor
  • OA and RA Osteo and Rheumatoid Arthritis
  • Q is selected from:
  • R 2 is selected from
  • R 3 is NR 10 R 10a ;
  • R 4 is selected from:
  • heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or
  • R 4a is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ; R 5 and R 6 are independently selected from:
  • R 5 and R 6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains one or two N, O or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R 18 ;
  • R 8 is a substituent on nitrogen and is selected from hydrogen,
  • R 9 is selected from:
  • R 9a is selected from H, OR 17 , NR 10 R 10a or S(O) n R 17 , Alternately R 9 and R 9a can be taken together to form a 3-7 membered carbocyclic or heterocyclic ring said heterocyclic ring containing 1-2 heteroatoms selected from N, O or S; R 10 is selected from:
  • R 10a is selected from hydrogen or C 1 -C 4 alkyl
  • R 10 and R 10a can alternatively join to form -(CH 2 ) 4 -,
  • R 11 is H, benzyl, or C 1 -C 4 alkyl
  • R 12 is selected from:
  • R 13 is C 1 -C 4 alkyl
  • R 14 and R 15 are independently selected from H or C 1 -C 4 alkyl
  • R 17a is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ; R 17b is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ; R 18 , when a substituent on carbon, is selected from one or more of the following: phenoxy, benzy
  • -NR 10 R 10a C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, -S(O) m R 11 , -NHSO 2 R 11 , phenyl, optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy or NR 10 R 10a ;
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ; or R 18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or
  • R 18 when a substituent on nitrogen, is selected from one or more of the following:
  • R 19 when a substituent on carbon, is selected from one or more of the following:
  • -NR 10 R 10a C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, -S(O) m R 11 , -NHSO 2 R 11 , a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl
  • R 19 when a substituent on nitrogen, is selected from one or more of the following:
  • R 20 is selected from:
  • a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R 19 ;
  • Z is N or O; with the proviso that R 8 is absent when Z is O.
  • a fourth embodiment of the invention provides compounds of formula IIa or pharmaceutically acceptable salts or prodrug forms thereof which are useful in the method of treating Osteo and Rheumatoid arthritis (OA and RA) and related inflammatory diseases which uses a stromelysin or related matrix metalloproteinase
  • R 2 is selected from:
  • R 3 is selected from OR 11 , NHCH(R 12 )COR 13 , NR 10 R 10a ,
  • R 10 and R 10a are each independently selected from
  • the present invention also provides methods for the treatment of osteo- and rheumatoid arthritis and other related inflammatory diseases by administering to a host a pharmaceutically or therapeutically effective or acceptable amount of a compound of formula (I) as described above.
  • therapeutically effective amount it is meant an amount of a compound of the present invention effective to inhibit stromelysin or related matrix metalloproteinases and the production of TNF or to treat the symptoms of osteo- or rheumatoid arthritis or related inflammatory diseases in a host.
  • the compounds of the present invention can also be administered in combination with one or more additional therapeutic agents.
  • Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each.
  • a lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
  • terapéuticaally effective amount it is meant an amount of a compound of Formula I that when
  • stromelysin administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to inhibit stromelysin so as to prevent or ameliorate the inflamatory disease condition or the progression of the disease.
  • administered in combination or “combination therapy” it is meant that the compound of Formula I and one or more additional therapeutic agents are
  • each component may be administered concurrently to the mammal being treated.
  • each component may be administered at the same time or sequentially in any order at different points in time.
  • each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
  • any variable for example R 1 through R 20 , R 10a , n, m, Z, X, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • said group may optionally be substituted with up to three R 17 and R 17 at each occurrence is selected independently from the defined list of possible R 17 .
  • substituent may be bonded to any atom on the ring.
  • piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formula I via any atom in such piperazinyl, piperidinyl, tetrazolyl group.
  • stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • substituted means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic
  • bicycloalkyl is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane,
  • alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
  • Alkylcarbonyl is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to the residue of the compound at the designated location.
  • Alkylcarbonylamino is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to an amino bridge, where the bridge is attached to the residue of the compound at the designated location.
  • Alkylcarbonyloxy is intended to include an alkyl group of an indicated number of carbon atoms attached to a carbonyl group, where the carbonyl group is attached through an oxygen atom to the residue of the compound at the designated location.
  • alkylene alkenylene, phenylene, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I.
  • alkylene alkenylene, phenylene, and the like, may alternatively and equivalently be denoted herein as "-(alkyl)-", “-(alkyenyl)-” and “-(phenyl)-”, and the like.
  • arylalkyl represents an aryl group attached through an alkyl bridge.
  • carbocycle or “carbocyclic residue” or “carbocyclic ring system” is intended to mean any stable 3- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • heteroaryl or “heterocyclic” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may
  • heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting
  • heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,
  • quinuclidinyl morpholinyl or oxazolidinyl.
  • fused ring and spiro compounds containing, for example, the above heterocycles.
  • amino acid as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids, modified and unusual amino acids, as well as amino acids which are known to occur
  • Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids,
  • amino acid residue means that portion of an amino acid (as defined herein) that is present in a peptide.
  • peptide as used herein means a compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond.
  • peptide also includes compounds containing both peptide and non-peptide components, such as
  • pseudopeptide or peptide mimetic residues or other non-amino acid components Such a compound containing both peptide and non-peptide components may also be referred to as a "peptide analog”.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula I are prepared by modifying
  • Prodrugs include compounds of Formula I wherein
  • hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I, phosphate esters, dimethylglycine esters,
  • aminoalkylbenzyl esters aminoalkyl esters
  • the pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formula I formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
  • salicylic sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with
  • the pharmaceutically acceptable salts of the acids of Formula I with an appropriate amount of a base such as an alkali or alkaline earth metal hydroxide e.g.
  • an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e
  • dibenzylethylenediamine trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
  • pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount-of the
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
  • novel compounds of Formula I may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the educt molecule must be
  • R is an ester protecting group
  • R 1 and R 2 are defined as provided in the preceding Summary of the Invention in connection with formula I, with an
  • the condensation is carried out using any of the many methods for the formation of amide bonds known to one skilled in the art of organic synthesis. These methods include but are not limited to conversion of acid (V) to the corresponding acid chloride (Va), or use of standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide,
  • the preferred method is treatment of the cyclic amine with the acid chloride prepared from (V).
  • Methods for conversion of carboxylic acids to acid chlorides are described in (J. March, Adv. Org. Chem. 1985, p. 1146, J. Wiley & Son, USA) and include, for example,
  • Compounds of Formula I wherein A is HONHCOCH(R 1 ) and Q is aryl or heteroaryl are prepared by treatment of the acid chloride (Va) prepared from acid (V) with a metallated aryl or heteroaryl as shown in Scheme 2, where R, R 1 and R 2 are defined as above, Ar represents an aryl or heteroaryl group and M is lithium, magnesium bromide or trialkyl or triaryltin.
  • the organometallic species, Ar—M are obtained by treatment of an aryl or heteroaryliodide or bromide with an alkyl or aryl lithium reagent, magnesium or a trialkyltin reagent to give the corresponding lithium, magnesium bromide or tin species using methods well known to one skilled in the art.
  • the condensation of a trialkyltin species with acid chlorides in the presence of a catalytic amount of a palladium(0) catalyst has been reviewed by Stille (Angew. Chem. Int. Ed. Engl., 1986 25:508).
  • the heteroaryl species is sufficiently reactive, either direct metallation or direct condensation of the unactivated heteroaryl compound with the acid chloride is possible. (See B. Oddo, Gazz. Chim. Ital., 1911, 41:234.)
  • the intermediate ester is then converted to the target hydroxamic acid as described above.
  • an ⁇ -bromoester of formula (XI) is treated with the potassium salt of dibenzyl malonate to give triester (XII).
  • Methods for the preparation of ⁇ -bromoesters of amino esters are well known to one skilled in the art of organic
  • Suitable nucleophiles include, but are not limited to alkyllithiums, alkylmagnesium halides, thiols and alkoxides, and the like.
  • Unsubstituted piperazic acid esters of formula (XV) may be prepared as described by Adams et al. (Synth. Commun. 1988, 18, 2225) or by the general synthetic routes shown in Scheme 4.
  • benzylchloroformate in the presence of a suitable base such as aqueous sodium hydroxide followed by exposure to isobutylene under acid catalysis.
  • a suitable base such as aqueous sodium hydroxide followed by exposure to isobutylene under acid catalysis.
  • Piperazic esters (XV) are coupled with acids of formula (V) to give amides of formula (VI) as described above.
  • the reagents of choice are hydrogenation conditions using hydrogen at atmospheric pressure or in a Parr apparatus at elevated hydrogen pressure, or cyclohexene or
  • Alkylating agents include alkyl halides, mesylates, tosylates, etc.
  • Suitable bases are
  • alkylcarbonyl are prepared by treating deprotected (VII) with an acyl halide such as acetyl chloride.
  • compound (XV) can be replaced with other N- heterocycles or aryl or heteroaryl derivatives to give additional compounds of Formula III.
  • Carboxylic acid (XXII) is converted to the acid fluoride by the method dexcribed by Carpino (vide supra) using cyanuric fluoride. Treatment with Cbz-protected piperazic acid provides the coupled compounds XXIII. The acid is subsequently converted to an amide by activation as described above to give compounds of formula XXIV. Removal of the Cbz protecting group by catalytic hydrogenation followed by deprotection of the t-butyl ester with trifluoroacetic acid provides compounds of formula IVa.
  • the functional groups of the constituent amino acids must be protected during the coupling reactions to avoid undesired bonds being formed.
  • the protecting groups that can be used are listed in Greene,
  • (+)-(S)-4-benzyloxazolidinone 66.56 g, 0.376 mol
  • tetrahydrofuran 900 ml
  • n-butyl lithium 164 ml, 2.29 M in hexanes
  • the acid chloride pre-cooled to -78° C in a jacketed addition funnel
  • the cooling bath was then removed, and the solution allowed to continue stirring over 18 h.
  • the reaction was quenched with 10% citric acid (400 ml) and water (600 ml).
  • a solution of lithium diisopropyl amide wa first prepared as follows; Diisopopylamine (0.801 mol, 112.3 ml in 250 ml tetrahydrofuran) was cooled to 0° C and treated with n-BuLi (2.5M in hexanes, 0.785 mol, 314 ml) and allowed to stir for 20 min. The solution was then cooled to -78 and the compound of Procedure 1A (250 g, 0.735 mol) in 625 ml THF was added at such a rate as to maintain the internal temperature of the reaction mixture at or below -70° C. Upon completion of the addition, the mixture was allowed to stir an additional 2 h at -78° C. A solution of di-tert-butyl
  • Example 1B The compound of Example 1B was dissolved in
  • Example 1C The compound of Example 1C (210 mg, 0.47 mmol) was combined with N-methylmorpholine (0.056 ml) in dry methylene chloride (15 ml) and cooled to -20oC under N 2 . Isobutylchloroformate (0.061 ml, 0.47 mmol) was added, and the solution was allowed to stir for 1h. A solution of O-benzylhydroxylamine hydrochloride (77 mg) and N-methylmorpholine (0.056 ml) in methylene chloride (3 ml) was added with washing with methylene chloride, and the mixture was allowed to stir at room temperature for 18 h. The mixture was then diluted with methylene chloride, washed with 10% citric acid (1 ⁇ 20 ml), brine and then dried over anhydrous magnesium sulfate.
  • the bis-Cbz protected intermediate was hydrogenated with H 2 Pd-C in ethanol for 4 h at 1 atm.
  • (+)-(S)-4-(phenylmethyl)-oxazolidinone (8.83 g, 53.5 mmol) in tetrahydrofuran (100 ml), cooled to -78° C, was added n-butyl lithium (21.4 ml, 2.5 M in hexanes) over 1h with stirring.
  • the compound of Part A (14 g, 41.5 mmol) was dissolved in 150 ml anhydrous THF and cooled to -78 under N 2 .
  • LDA (41.5 mmol) was added over 10 min., and the solution was stirred at -78 for 30 additional minutes.
  • Tert-butyl bromoacetate (8.1 g, 41.5 mmol) dissolved in 30 ml THF was added over 20 min, and the resulting mixture was allowed to stir at -78 for 30 min then warmed to ambient temperature by removal of the cooling bath. After 1 h, the solution was concentrated on a rotary evaporator to 1/4 volume. Ethyl acetate was added followed by washing with 10% citric acid, water then brine and dried over MgSO4.
  • the acyl hydrazide (8.5 g) was dissolved in methylene chloride. At 0oC, N-methylmorpholine (2.5 ml, 19.9 mmol) was added followed by isobutylchloroformate (2.5 ml, 19.2 mmol). After this mixture was stirred at 0oC for 30 mm, 40% aqueous methylamine (6.2 g) was added. The mixture was warmed to room temperature and was stirred overnight. The reaction was quenched and washed with saturated NaHCO 3 solution. The aqueous layer was dried, filtered, and concentrated. Flash chromatography of the resulting oil gave the desired amide (3.0 g, 5.5 mmol, 33%) as a white foam: MS-CI (m/z) 539 (M + + 1, 49%).
  • MMP-3 inhibitory activity of the compounds of the present invention is demonstrated using assays of MMP-3 activity, for example, using the assay described below for assaying inhibitors of MMP-3 activity.
  • the compounds of the present invention are bioavailable in vivo as demonstrated, for example, using the ex vivo assay described below.
  • the compounds of formula I have the ability to suppress/inhibit cartilage degradation in vivo, for example, as demonstrated using the animal model of acute cartilage degradation described below.
  • the compounds provided by this invention are also useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit MMP-3. These would be provided in commercial kits comprising a compound of this invention.
  • Matrixmetalloproteinases have also been implicated in the degradation of basement membrances to allow infiltration of cancer cells into the circulation and subsequent penetration into other tissues leading to tumor metastasis. (Stetler-Stevenson, Cancer and
  • the compounds of the present invention would also have utility for the prevention and treatment of
  • inflammatory, infectious, immunological or malignant diseases include, but are not limited to inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, an acute infection, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, crohn's disease,
  • the compounds of the present invention have been shown to inhibit TNF production in lipopolysacharride stimulated mice, for example, using the assay for TNF Induction in Mice described below.
  • ⁇ g denotes microgram
  • mg denotes milligram
  • g denotes gram
  • ⁇ L denotes microliter
  • mL denotes milliliter
  • L denotes liter
  • nM denotes nanomolar
  • ⁇ M denotes micromolar
  • mM denotes millimolar
  • M denotes molar
  • nm denotes
  • a compound is considered to be active if it has an IC 50 or K i value of less than about 1 mM for the
  • a high capacity enzymatic assay was developed to detect potential inhibitors of MMP-3.
  • the assay uses a derivative of a peptide substrate, substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met), which is cleaved by MMP-3 exclusively at the glutamine-phenylalanine bond.
  • substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met
  • MMP-3 exclusively at the glutamine-phenylalanine bond.
  • fluorimetric method of product detection The production of the hydrolysis product, substance P 7-11, is measured by reaction with fluorescamine, a fluorogenic compound which reacts with the primary amine of this fragment.
  • the substance P substrate is bisacetylated to block the primary amines of the intact substrate.
  • fluorescence represents generation of product (7-11 peptide) formed upon cleavage by MMP-3, and is
  • concentrations of the compound were added to control plasma, the plasma was extracted by the same method, and then assayed in the MMP-3 enzymatic assay.
  • a standard curve was prepared that related percent inhbition in the MMP-3 assay to the concentration of drug added in the spiked samples. Based on the percent inhibition in the presence of plasma from dosed rats, the concentration of compound was determined using the standard curve.
  • Table B shows the results of dosing of representative compounds of the invention orally in rats at 100 mg/kg.
  • An in vivo model of acute cartilage degradation in rats has been characterized as a method to determine the proteoglycan content in the synovial fluid after the induction of cartilage degradation.
  • Experimental groups exhibit increased levels of proteoglycan content in their synovial fluid versus control rats.
  • the criteria to demonstrate a compound's activity in this model is the ability to inhibit the demonstration of cartilage degradation, as measured by increased proteoglycan content in the synovial fluid of rats after compound administration.
  • Indomethacin a non-steroidal anti-inflammatory drug is inactive in this model.
  • Test compounds are administered to mice either I.P. or P.O. at time zero. Immediately following compound administration, mice receive an I.P. injection of 20 mg of D-galactosamine plus 10 ⁇ g of lipopolysaccharide. One hour later, animals are anesthetized and bled by cardiac puncture. Blood plasma is evaluated for TNF levels by an ELISA specific for mouse TNF.
  • the compounds of the present invention can be administered orally using any pharmaceutically
  • the active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions.
  • the active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier.
  • a valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.
  • the compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an antiinflammatory and antiarthritic agent.
  • the compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action, MMP-3, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with
  • compositions either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard
  • the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70 kg of body weight, this translates into a dosage of 70 to 1400 mg/day.
  • the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;
  • an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like
  • the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as
  • cholesterol cholesterol, stearylamine, or phosphatidylcholines .
  • Such polymers can include
  • polyhydroxyethylaspartamidephenol or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon
  • caprolactone polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of
  • Dosage forms suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch,
  • cellulose derivatives magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • suitable stabilizing agents such as sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite
  • bisulfite, sodium sulfite, or ascorbic acid are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain
  • preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • Capsules are prepared by conventional procedures so that the dosage unit is 500 milligrams of active
  • a large number of unit capsules may also prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • the final volume is brought up to 100% by the addition of distilled water.
  • Active Ingredient 10 Sodium Saccharin 0.01
  • Keltrol ® Food Grade Xanthan Gum
  • Xanthan gum is slowly added into distilled water before adding the active ingredient and the rest of the formulation ingredients.
  • the final suspension is passed through a homogenizer to assure the elegance of the final products.

Abstract

The present invention relates to a class of novel hydroxamic acids and carbocyclic acids and derivatives thereof that inhibit stromelysin, and are therefore useful for the treatment of arthritis. The class of compounds useful in this method of treatment is represented by Formula (I).

Description

TITLE
HYDROXAMIC ACID AND AMINO ACID DERIVATIVES AND THEIR USE AS ANTI-ARTHRITIC AGENTS
CROSS-REFERENCE TO EARLIER FILED APPLICATION
This application is a continuation-in-part of DM-6717, U.S. Serial Number 08/234,195 filed on April 28, 1994.
FIELD OF THE INVENTION
The present invention relates to small molecules which inhibit matrix metalloproteinases and/or the production of tumor necrosis factor (TNF),
pharmaceutical preparations containing them and to their use as pharmaceutical agents. BACKGROUND OF THE INVENTION
There is now a body of evidence that stromelysin (MMP-3) and other metalloproteinases (MMP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to
resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion;
periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of
extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of matrix metalloproteinase), which form inactive complexes with the MMP's. Osteo- and Rheumatoid Arthritis (OA and RA
respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and
metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of
articullar cartillage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al . Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition,
immunohistochemical studies (Okada et al. Ann. Rheum. 48, 1989, 645) have demonstrated that stromelysin is synthesized and secreted by synovial lining cells in RA. Also, higher than normal levels of stromelysin in chondrocytes was detected in 90% of OA cartilage where stromelysin staining correlated with histological scores of pathology and with proteoglycan depletion (Okada et al. Lab Invest. 66, 1992, 680).
Therefore stromelysin, a matrix metalloproteinase (MMP-3), has been implicated as one of the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the
administration of MMP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990). Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as stromelysin, collagenase, and gelatinase are potentially useful for the treatment or prophylaxis of conditions involving such tissue
breakdown, for example rheumatoid arthritis,
osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth.
Tumour necrosis factor (TNF or TNF-α) is a cytokine which is produced initially as a cell-associated 28kD precusor. It is released as an active, 17kD form, which can mediate a large number of deleterious effects in vivo . When administered to animals or humans it causes inflammation, fever, cardiovascular effects,
haemorrhage, coagulation, similar to those seen during acute infections and shock states.
There is considerable evidence from animal model studies that blocking the effects of TNF with specific antibodies can be beneficial in acute infections, shock states, graft versus host reactions and autoimmune disease. TNF is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal haematopoiesis in patients with these tumours.
Compounds which inhibit the production or action of TNF are therefore potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis, radiation damage, and hyperoxic alveolar injury. Since excessive TNF production has been noted in several diseases or conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may have particular advantages in the treatment or prophylaxis of diseases or conditions in which both mechanisms are involved.
PCT International Publication No. WO 92/213260 describes N-carboxyalkylpeptidyl compounds of general formula:
Figure imgf000006_0001
wherein AA is an amino acid, as inhibitors of matrix metallproteinase mediated diseases.
PCT International Publication No. WO 90/05716 discloses hydroxamic acid based collagenase inhibitors having the general formula:
Figure imgf000006_0002
PCT International Publication No. WO 92/13831 describes related hydroxamic acids having collagenase inhibiting activity with the general formula:
Figure imgf000006_0003
PCT International Publication No. WO 94/02446 discloses metalloproteinase inhibitors which are natural amino acid derivatives of general formula:
Figure imgf000007_0002
PCT International Publication No. WO 93/09097 discloses piperazinic acid derivatives of general formula:
Figure imgf000007_0001
having inhibiting activity against type IV collagenase useful as a cancer metastasis suppressants.
Ogita et al. (J. Anti. 1992, 45, 1723-1732) report the isolation of a structurally related class of microbial metabolites, the matlystatins, which were identified through screening for inhibitors of Type IV collagenases and share the general formula shown below.
Figure imgf000008_0002
European Patent Application Publication No. 574,758 Al, discloses hydroxamic acid derivatives as collagenase inhibitors having the general formula:
Figure imgf000008_0001
The compounds of the current invention act as inhibitors of stromelysin and other matrix
metalloproteinases, thereby preventing cartilage loss and destruction. In addition, the compounds of the current invention inhibit the production of TNF, a cytokine implicated in inflammatory diseases. The hydroxamic and carboxylic acids and derivatives thereof of the present invention have been further found to be orally bioavailable. A number of the compounds reported to be inhibitors of metalloproteinases, such as
collagenase, have suffered from lack of adequate
bioavailability and are thus not useful as therapeutic agents, particularly if oral administration is desired. Poor oral activity has been ascribed to relatively high molecular weight, to inadequate solubility properties, and to the presence of peptide bonds, which are
vulnerable to cleavage by mammalian proteases in vivo and which generally cause the molecules to be
extensively bound in human serum. The hydroxamic and carboxylic acids and derivatives described herein have a distinct advantage in this regard, in that they do not contain readily cleavable peptide bonds, are of low molecular weight, and can be hydrophilic yet still inhibit matrix metalloproteinases.
SUMMARY OF THE INVENTION
The present invention relates to a class of novel hydroxamic acids and carbocyclic acids and derivatives thereof that inhibit stromelysin and other matrix metalloproteinases, and also inhibit the production of tumor necrosis factor (TNF), and are therefore useful for the treatment of arthritis and other related inflammatory diseases. The class of compounds useful in this method of treatment is represented by
Formula I below:
Figure imgf000009_0001
or pharmaceutically acceptable salts or prodrug forms thereof, wherein: A is selected from -N(R8)CH(R9)CO2H or
-CH(R11)C(R9a)(R9)CO2H, -C (R1)(R1a)CONHOH; Q is selected from: a C5-C14 carbocyclic ring system substituted with 0-4 groups selected from R5, R6, R18 or
-C(=O)R3, or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-4 groups selected from R5, R6, R8, R19 or -C(=O)R3;
R1 is selected from:
H, halogen
C1-C10 alkyl substituted with 0-3 R4,
C2-C10 alkenyl substituted with 0-3 R4,
C2-C10 alkynyl substituted with 0-3 R4,
C6-C10 aryl,
C3-C6 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or
pyridazinyl, pyrrolidinyl, triazolidinyl, oxadiazolidinyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R1a is selected from H, R1, NR10R10a, OR17 or S(O)mR17
Alternately R1 and R1a can be taken together to form a 3-7 membered carbocyclic or a 5-7 membered, saturated heterocyclic ring, said heterocyclic ring containing 1-2 heteroatoms selected from N, O, and S, and optionally substituted at carbon with keto;
R2 is selected from:
C2-C10 alkyl substituted with 0-3 R17b,
(-CH2)nO-(C1-C8 alkyl) -R20, or
(-CH2)nS-(C1-C8 alkyl) -R20,
-(CH2)nOR20, -(CH2)nSR20,
-(CH2)nS-(C1-C6) alkyl, or
-(CH2)nO-(C1-C6) alkyl; n=0-8
R3 is selected from: OR11, NHCH(R12)COR13,
NHCH(R12)COOR11, NHCH (R12) CONR14R15, NR10R10a; R4 is selected from:
-OR17a, -SOmR17a, -CO2R12, -CONR10R10a,
-NR8R10, -NHC(=NR8)N(R8)R10,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R18;m=0-2; R4a is selected from:
-OR17, -SOmR17, -CO2R12, -CONR10R10a,
C1-C4 alkyl,
aryl substituted with 0-5 R18,
C1-C4 alkylcarbonyl,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl , thiazolinyl, thiazolidinyl, isothiazolinyl , piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R5 and R6 are independently selected from:
hydrogen,
hydroxy,
C1-C6 alkyl substituted with 0-3 R20,
phenyl,
C7-C14 arylalkyl,
C7-C14 arylalkoxy,
C1-C4 alkylcarbonyl,
C7-C14 arylalkoxycarbonyl,
C1-C4 alkoxy, -NR14R15, -COOR11,
C1-C4 alkoxycarbonyl , hydroxymethyl, -CH2OR13, C1-C4 alkylaminocarbonyl, -C(=NOH)R14,
=0, =S, or a ketal or thioketal form thereof when R5 or R6 are attached to a saturated carbon atom, or = 0 when R5 or R6 is attached to sulfur;
R5 and R6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered carbocyclic or heterocyclic ring, wherein said heterocyclic ring contains one or two N, O or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R18;
R8 is a substituent on nitrogen and is selected from hydrogen,
C1-C6 alkyl substituted with 0-3 R20,
C1-C6-alkylcarbonyl, alkoxycarbonyl,
arylalkoxycarbonyl,
alkylaminocarbonyl,
arylsulfonyl,
heteroarylalkoxycarbonyl,
cycloalkoxycarbonyl,
heteroarylsulfonyl,
alkyesulfonyl,
cycloalkylsulfonyl,
R9 is selected from:
H,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a;
R9a is selected from H, OR17, SR17 or NR10 R10a,
Alternately R9 and R9a can be taken together to form a 3-7 membered carbocyclic or heterocyclic ring, said heterocyclic ring containing 1-2 heteroatoms selected from N, O or S, optionally substituted on carbon with keto; R10 is selected from:
hydrogen,
C1-C4 alkoxy,
C1-C6 alkyl substituted with 0-4 R4 or
C1-C6 alkylcarbonyl;
R10a is selected from hydrogen or C1-C4 alkyl;
R10 and R10a can alternatively join to form -(CH2)4-,
-(CH2)5-, -CH2CH2N(R16)CH2CH2-, or -CH2CH2OCH2CH2-;
R11, is H, benzyl, or C1-C4 alkyl; R12 is selected from:
H,
C1-C4 alkyl substituted with 0-3 R4,
C2-C4 alkenyl substituted with 0-3 R4,
C2-C4 alkynyl substituted with 0-3 R4;
R13 is C1-C4 alkyl;
R14 and R15 are independently selected from H or C1-C4 alkyl;
R16 is hydrogen or methyl;
R17 is selected from:
hydrogen,
C1-C6 alkyl substituted with 0-3 R17A
C1-C6 alkylcarbonyl substituted with 0-3 R17A, C1-C6 alkoxycarbonyl substituted with 0-3 R17A, phenoxycarbonyl substituted with 0-3 R18;
R17a is selected from:
H,
C1-C4 alkyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; R17b is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, .isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R18, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, phenyl, optionally substituted with halogen, C1-C4 alkyl, C1-cyalkoxy, hydroxy, or -NR10R10a, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a, =O or =S when attached to a saturated carbon atom, or =O when attached to sulfur;
R18, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;
R19, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl,
oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R19 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a;
R19, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl; and
R20 is selected from:
aryl substituted with 0-5 R18,
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; One embodiment of the present invention relates to a novel class of compounds embodied within the class of compounds of Formula I and to pharmaceutical compositions and methods of use of these novel compounds for the inhibition of stromelysin and other matrix metalloproteinases, for the inhibition of the production of tumor necrosis factor (TNF) and in the treatment of Osteo and Rheumatoid Arthritis (OA and RA). These novel compounds are represented by Formula II below:
Figure imgf000018_0001
or pharmaceutically acceptable salts or prodrug forms thereof, wherein: Q is selected from:
a C5-C14 carbocyclic ring system substituted with 0-4 groups selected from R5, R6, R18 or
-C(=O)R3, or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-4 groups selected from R5, R6, R8, R19 or -C(=O)R3;
R1 is selected from:
H, halogen
C1-C10 alkyl substituted with 0-3 R4,
C2-C10 alkenyl substituted with 0-3 R4,
C2-C10 alkynyl substituted with 0-3 R4,
C6-C10 aryl,
C3-C6 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl,
thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R1a is selected from H, NR10R10a, OR17 or S(O)mR17
Alternately R1 and Rla can be taken together to form a
3-7 membered carbocyclic or heterocyclic ring, said heterocyclic ring containing 1-2 hetero-atoms selected from N, O, and S;
R2 is selected from:
C2-C10 alkyl substituted with 0-3 R17b,
(-CH2)nO-(C1-C8 alkyl) -R20, or
(-CH2)nS-(C1-C8 alkyl) -R2°,
-(CH2)nOR20,
-(CH2)nSR20,
-(CH2)nS-(C1-C6) alkyl, or
-(CH2)nO-(C1-C6) alkyl; n=0-6
R3 is -NR10R10a
R4 is selected from:
OR17, SOmR17, -CO2R12, -CONR10R10a,
-NR8R10, -NHC(=NR8)N(R8)R10,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; m=0-2; R5 and R6 are independently selected from:
hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 R20, phenyl, C7-C14 arylalkyl, C7-C14 arylalkoxy, C1-C4 alkylcarbonyl, C7-C14 arylalkoxycarbonyl, C1-C4 alkoxy, -NR14R15, -COOR11, C1-C4 alkoxycarbonyl, hydroxymethyl,
-CH2OR13, C1-C4 alkylaminocarbonyl,
-C(=NOH)R14;
R5 and R6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered
carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains one to two N, O, or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R18;
R8 is a substituent on nitrogen and is selected from
hydrogen,
C1-C6 alkyl substituted with 0-3 R20,
C1-C6-alkylcarbonyl,
alkoxycarbonyl,
arylalkoxycarbonyl,
arylsulfonyl, heteroarylsulfonyl,
cycloakoxycarbonyl,
keteroarylalkoxycarbonyl,
alkylsulfonyl, or
cycloalkylsulfonyl;
R10 is selected from:
hydrogen,
C1-C4 alkoxy,
C1-C6 alkyl substituted with 0-4 R4;
R10a is selected from hydrogen or C1-C4 alkyl;
R10 and R10a can alternatively join to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R16)CH2CH2-, or -CH2CH2OCH2CH2-;
R11, is H, benzyl, or C1-C4 alkyl;
R12 is selected from:
H,
C1-C4 alkyl substituted with 0-3 R4,
C2-C4 alkenyl substituted with 0-3 R4,
C2-C4 alkynyl substituted with 0-3 R4; R13 is C1-C4 alkyl;
R14 and R15 are independently selected from H or C1-C4 alkyl; R16 is hydrogen or methyl;
R17 is selected from:
hydrogen,
C1-C6 alkyl substituted with 0-3 R17A
C1-C6 alkylcarbonyl substituted with 0-3 R17A, C1-C6 alkoxycarbonyl substituted with 0-3 R17A, phenoxycarbonyl substituted with 0-3 R18; R17a is selected from:
H,
C1-C4 alkyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R17b is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R18, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, phenyl, optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy or NR10R10a, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a =0 or =S when attached to a saturated carbon atom, or =O when attached to sulfur;
R18, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1-
C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl; R19, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R19 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a;
R19, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl; R20 is selected from:
aryl substituted with 0-5 R18,
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; with the following proviso:
when R1 and R1a are both hydrogen and Q is
Figure imgf000025_0001
then R2 is not hydrogen, C3-C10 alkyl or (C1-C4 alkyl)aryl.
Presently, preferred compounds of this embodiment are compounds of Formula II wherein:
Q is a 5-7 membered saturated heterocyclic ring system containing at least one nitrogen and optionally containing an additional heteroatom selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-4 groups selected from R5, R6, R8, R19 or -C(=O)R3;
R1 is selected from:
H, C1-C4 alkyl substituted with 0-3 R4;
R2 is selected from:
C2-C4 alkyl substituted with 0-3 R17b,
-O-.C1-C6 alkyl) -R20,
-S-(C1-C6 alkyl) -R20,
-CH2O-(C1-C5 alkyl) -R20, or
-CH2S-(C1-C5 alkyl) -R20; R8 is hydrogen;
R10 is selected from:
hydrogen,
C1-C6 alkyl substituted with 0-4 R4;
Presently more preferred compounds of this
embodiment are compounds of Formula II wherein:
Q is a heterocycle selected from hexahydro-1- pyridazinyl, 2-tetrahydro-1,2-oxazinyl, 1- morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1- piperazinyl, 4-methylpiperazinyl, tetrahydro-1,4- thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl-1-oxide, tetrahydro-1,4-thiazin-4-yl-1,1-dioxide, 1-oxa-2- piperidinyl, said heterocycle being substituted with 0-3 groups selected from -C(=O)R3, R5, R6, or R8.
Still more preferred compounds of this embodiment are compounds of Formula II wherein:
Q is
Figure imgf000026_0001
; Z is N or O;
R5 is selected from:
hydrogen, phenyl, C7-C14 arylalkyl, C7-C14
arylalkoxy, C1-C4 alkylcarbonyl, or C7-C14 arylalkoxycarbonyl; and R6 is hydrogen; with the proviso that R8 is absent when Z is O.
Specifically preferred compounds of this embodiment are selected from:
[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]- N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-benzylsuccinyl]- N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S- methoxyphenylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S- methoxybenzylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S- methylthiophenylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S- methylthiobenzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-(methylthio-2- thienyl)succinyl]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl acetate]- N2-(S)-piperazic acid-N-methyl amide, [4-(N-hydroxyamino)-2R-isobutyl-3S-methyl
isopropanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl
thioacetate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl
thioisopropanoate]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-(2- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-(3- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-(4- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl thio- tert-butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methylsuccinyl]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S- methoxyphenylsuccinyl]-N2-(S)-piperazic acid-
N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S- methoxybenzylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S- methylthiophenylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide, [4- (N-hydroxyamino) -2R-hexyl-3S- methylthiobenzylsuccinyl] -N2- (S) -piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-(methylthio-2- thienyl)succinyl]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl acetate]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl
isopropanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl
thioacetate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl
thioisopropanoate]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl thio-tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(2- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(3- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(4- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- methylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide, [4-(N-hydroxyamino)-2R-ethylphenyl-3S- benzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- methoxyphenylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- methoxybenzylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- methylthiophenylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- methylthiobenzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S-(methylthio- 2-thienyl)succinyl]-N2-(S)-piperazic acid-N- methyl amide
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- benzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl
acetate]-N2-(S)-piperazic acid-N-methyl amide, [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl
isopropanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl
thioacetate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl
thioisopropanoate]-N2-(S)-piperazic acid-N- methyl amide, [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl thio- tert-butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methylsuccinyl]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S- methylthiophenylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S- methylthiobenzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-(methylthio-2- thienyl)succinyl]-N1-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl acetate]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl
isopropanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl
thioacetate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl
thioisopropanoate]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl thio-tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl-(2- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl-(3- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide, [4-(N-hydroxyamino)-2R-octyl-3S-methyl-(4- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]- N2-(S)-4'(S/R)-benzylpiperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]- N2-(S)-5'(S/R)-benzylpiperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]- N2-(S)-6'(S/R)-benzylpiperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]- N2-(S)-[5',6']benzopiperazic acid-N-methyl amide,
A second embodiment of the present invention relates to a class of novel compounds also embodied within the class of compounds of Formula I and to pharmaceutical compositions and methods of use of these novel compounds for the inhibition of stromelysin and other matrix metalloproteinases, for the inhibition of the production of tumor necrosis factor (TNF) and in the treatment of Osteo and Rheumatoid Arthritis (OA and RA) and related diseases. These compounds are represented by Formula III below:
Figure imgf000032_0001
or pharmaceutically acceptable salts or prodrug forms thereof, wherein:
Q is selected from: a C5-C14 carbocyclic ring system substituted with 0-4 groups selected from R5, R6, R18 or
-C(=O)R3, or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-4 groups selected from R5, R6, R8, R19 or -C(=O)R3;
R2 is selected from
C1-C8 alkyl substituted with 0-3 R17b,
C1-C8 alkenyl substituted with 0-3 R17b,
C1-C8 alkynyl substituted with 0-3 R17b,
-(CH2)n-O-(C1-C8 alkyl),
-(CH2)n-S-(C1-C8 alkyl),
-(CH2)nO-(C1-C8 alkylene)-R20,
(CH2)nS(C1-C8 alkylene)-R20
- (CH2 ) nOR20 , or
-CH2 ) nSR20 n=1-8
R3 is NR10R10a;
R4 is selected from:
-OR17, -SOmR17, -CO2R12, -CONR10R10a,
-NR8R10, -NHC(=NR8)N(R8)R10,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or
pyridazinyl, said heterocyclic ring system being substituted with 0-2 R19; m= 0-2;
R4a is selected from:
-OR17, -SOmR17, -CO2R12, -CONR10R10a,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R5 and R6 are independently selected from:
hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 R20, phenyl, C7-C14 arylalkyl, C7-C14 arylalkoxy, C1-C4 alkylcarbonyl, C7-C14 arylalkoxycarbonyl, C1-C4 alkoxy, -NR14R15, -COOR11, C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13, C1-C4 alkylaminocarbonyl, -C(=NOH)R14, =0, =S, or a ketal or thioketal form thereof when R5 or R6 are attached to a saturated carbon atom, or = 0 when R5 or R6 is attached to sulfur;
R5 and R6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered
carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains one or two N, O or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R18;
R8 is a substituent on nitrogen and is selected from hydrogen,
C1-C6 alkyl substituted with 0-3 R20,
C1-C6-alkylcarbonyl,
alkoxycarbonyl,
arylalkoxycarbonyl,
alkylaminocarbonyl,
arylsulfonyl,
heteroarylsulfonyl,
cycloakoxycarbonyl,
keteroarylalkoxycarbonyl,
alkylsulfonyl, or
cycloalkylsulfonyl;
R9 is selected from:
H,
C1-C5 alkyl substituted with 0-3 R4a,
C2-C5 alkenyl substituted with 0-3 R4a,
C2-C5 alkynyl substituted with 0-3 R4a;
R10 is selected from:
hydrogen,
C1-C4 alkoxy,
C1-C6 alkyl substituted with 0-4 R4;
R10a is selected from hydrogen or C1-C4 alkyl;
R10 and R10a can alternatively join to form -(CH2)4-,
-(CH2)5-, -CH2CH2N(R16)CH2CH2-, or -CH2CH2OCH2CH2-;
R11, is H, benzyl, or C1-C4 alkyl;
R12 is selected from:
H, C1-C8 alkyl substituted with 0-3 R4,
C2-C8 alkenyl substituted with 0-3 R4,
C2-C8 alkynyl substituted with 0-3 R4; R13 is C1-C4 alkyl;
R14 and R15 are independently selected from H or C1-C4 alkyl; R16 is hydrogen or methyl;
R17 is selected from:
hydrogen,
C1-C6 alkyl substituted with 0-3 R17A
C1-C6 alkylcarbonyl substituted with 0-3 R17A, C1-C6 alkoxycarbonyl substituted with 0-3 R17A, phenoxycarbonyl substituted with 0-3 R18;
R17a is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R17b is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R18, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, phenyl, optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy or NR10R10a;
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a, =0 or =S when attached to a saturated carbon atom, or =O when attached to sulfur;
R18, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;
R19, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide,
C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R19 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy,
-NR10R10a; or,
R19, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;
R20 is selected from:
aryl substituted with 0-5 R18,
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
Preferred compounds of the second embodiment are compounds of Formula III wherein:
Q is a heterocycle selected from hexahydro-1- pyridazinyl, 2-tetrahydro-1,2-oxazinyl, 1- morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1- piperazinyl, 4-methylpiperazinyl, tetrahydro-1,4- thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl-1-oxide, tetrahydro-1,4-thiazin-4-yl-1,1-dioxide, said heterocycle being substituted with 0-3 groups selected from -C(=O)R3, R5, R6, or R8;
R2 is selected from
C2-C4 alkyl substituted with 0-3 R17b
-(CH2)nO-(C1-C5 alkyl)-R20, or
-(CH2)nS-(C1-C5 alkyl)-R20; n= 1-5;
R8 is hydrogen; R9 is selected from:
hydrogen,
C1-C5 alkyl substituted with 0-3 R4a;
More preferred compounds of the second embodiment are compounds of Formula III wherein:
Q is
Figure imgf000040_0001
Z is N or O; with the proviso that R8 is absent when Z is O. Specifically preferred compounds of the second embodiment are selected from:
N-[1(R)-carboxy-ethyl]-α-(S)-isobutylglycine-(S)- N2-piperazic acid methyl amide, N-[1(R)-carboxy-ethyl]-α-(S)-hexylglycine-(S)-N2- piperazic acid methyl amide,
N-[1(R)-carboxy-ethyl]-α-(S)-heptylglycine-(S)-N2- piperazic acid methyl amide,
N-[1(R)-carboxy-ethyl]-α-(S)-octylglycine-(S)-N2- piperazic acid methyl amide,
N-[1(R)-carboxy-ethyl]-α-(S)-ethylphenylglycine- (S)-N2-piperazic acid methyl amide,
N-[1(R)-carboxy-ethyl]-α-(S)-propylphenylglycine- (S)-N2-piperazic acid methyl amide,
N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)- isobutylglycine-(S)-N2-piperazic acid methyl amide,
N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)- hexylglycine-(S)-N2-piperazic acid methyl amide,
N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)-ethylphenyl- glycine-(S)-N2-piperazic acid methyl amide, N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)- propylphenyl-glycine-(S)-N2-piperazic acid methyl amide.
N-[1(R)-carboxy-ethyloxybenzyl]-α-(S)- isobutylglycine-(S)-N2-piperazic acid methyl amide,
N-[1(R)-carboxy-ethyloxybenzyl]-α-(S)-hexylglycine- (S)-N2-piperazic acid methyl amide,
N-[1(R)-carboxy-ethyloxybenzyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazic acid methyl amide, N-[1(R)-carboxy-ethyloxybenzyl]-α-(S)-propylphenylglycine-(S)-N2-piperazic acid methyl amide,
N-[1(R)-carboxy-4-(p-toluenesulfonyl)butyl]-α-(S)- phenethylglycyl-(S)-N2-piperazic acid methyl amide, and
N-[1(R)-carboxyethyl]-α-[2-(4-phenylphenoxy)ethyl]- glycyl-(S)-N2-piperazic acid methyl amide. A third embodiment of the present invention relates to a class of novel compounds also embodied within the class of compounds of Formula I and to pharmaceutical compositions and methods of use of these novel compounds for the inhibition of stromelysin and other matrix metalloproteinases, for the inhibition of the production of tumor necrosis factor (TNF) and in the treatment of Osteo and Rheumatoid Arthritis (OA and RA) and related diseases. These compounds are represented by Formula IV below:
Figure imgf000042_0001
or pharmaceutically acceptable salts or prodrug forms thereof, wherein:
Q is selected from:
a C5-C14 carbocyclic ring system substituted with 0-4 groups selected from R5, R6, R18 or
-C(=O)R3, or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-4 groups selected from R5, R6, R8, R19 or -C(=O)R3;
R2 is selected from
C1-C6 alkyl substituted with 0-3 R17b,
-(CH2)n-O-(C1-C8 alkyl),
-(CH2)n-S-(C1-C8 alkyl),
-(CH2)nO-(C1-C8 alkylene)-R20,
(CH2)nS(C1-C8 alkylene)-R20
-(CH2)nOR20, or -CH2)nSR20 n=0-8 R3 is NR10R10a;
R4 is selected from:
-OR17, -SOmR17, -CO2R12, -CONR10R10a,
-NR8R10, -NHC(=NR8)N(R8)R10,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or
pyridazinyl, said heterocyclic ring system being substituted with 0-2 R19; R4a is selected from:
-OR17, -SOmR17, -CO2R12, -CONR10R10a,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; R5 and R6 are independently selected from:
hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 R20, phenyl, C7-C14 arylalkyl, C7-C14 arylalkoxy, C1-C4 alkylcarbonyl, C7-C14 arylalkoxycarbonyl, C1-C4 alkoxy, -NR14R15,
-COOR11, C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13, C1-C4 alkylaminocarbonyl, -C(=NOH)R14, =0, =S, or a ketal or thioketal form thereof when R5 or R6 are attached to a saturated carbon atom, or = 0 when R5 or R6 is attached to sulfur;
R5 and R6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains one or two N, O or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R18; R8 is a substituent on nitrogen and is selected from hydrogen,
C1-C6 alkyl substituted with 0-3 R20,
C1-C6-alkylcarbonyl,
alkoxycarbonyl,
arylalkoxycarbonyl,
alkylaminocarbonyl,
arylsulfonyl,
heteroarylsulfonyl,
cycloakoxycarbonyl,
keteroarylalkoxycarbonyl,
alkylsulfonyl, or
cycloalkylsulfonyl;
R9 is selected from:
H,
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a, C2-C6 alkynyl substituted with 0-3 R4a;
R9a is selected from H, OR17, NR10R10a or S(O)nR17, Alternately R9 and R9a can be taken together to form a 3-7 membered carbocyclic or heterocyclic ring said heterocyclic ring containing 1-2 heteroatoms selected from N, O or S; R10 is selected from:
hydrogen,
C1-C4 alkoxy,
C1-C6 alkyl substituted with 0-4 R4; R10a is selected from hydrogen or C1-C4 alkyl;
R10 and R10a can alternatively join to form -(CH2)4-,
-(CH2)5-, -CH2CH2N(R16)CH2CH2-, or -CH2CH2OCH2CH2-; R11, is H, benzyl, or C1-C4 alkyl;
R12 is selected from:
H,
C1-C8 alkyl substituted with 0-3 R4,
C2-C8 alkenyl substituted with 0-3 R4,
C2-C8 alkynyl substituted with 0-3 R4;
R13 is C1-C4 alkyl; R14 and R15 are independently selected from H or C1-C4 alkyl;
R16 is hydrogen or methyl; R17 is selected from:
hydrogen,
C1-C6 alkyl substituted with 0-3 R17A C1-C6 alkylcarbonyl substituted with 0-3 R17A, C1-C6 alkoxycarbonyl substituted with 0-3 R17A, phenoxycarbonyl substituted with 0-3 R18; R17a is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; R17b is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; R18, when a substituent on carbon, is selected from one or more of the following: phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, phenyl, optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy or NR10R10a;
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a, =0 or =S when attached to a saturated carbon atom, or =O when attached to sulfur;
R18, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl,
-CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;
R19, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R19 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a; or,
R19, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;
R20 is selected from:
aryl substituted with 0-5 R18,
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
Preferred compounds of the third embodiment are compounds of Formula IV wherein:
Q is a heterocycle selected from hexahydro-1- pyridazinyl, 2-tetrahydro-1,2-oxazinyl, 1- morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1- piperazinyl, 4-methylpiperazinyl, tetrahydro-1,4- thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl-1-oxide, tetrahydro-1,4-thiazin-4-yl-1,1-dioxide, said heterocycle being substituted with 0-3 groups selected from -C(=O)R3, R5, R6, or R8; R2 is selected from
C2-C4 alkyl substituted with 0-3 R17b
-(CH2)nO-(C1-C5 alkyl) -R20, or
-(CH2)nS-(C1-C5 alkyl) -R20; n= 0-6;
R8 is hydrogen; R9 is selected from:
hydrogen,
C1-C4 alkyl substituted with 0-3 R4a;
More preferred compounds of the third embodiment are compounds of Formula IV wherein:
Q is
Figure imgf000050_0001
Z is N or O; with the proviso that R8 is absent when Z is O.
Specifically preferred compounds of the third embodiment are compounds selected from the group
consisting of:
2-[2(R)-[2-[(1,1'-biphenyl)yl]ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[(1,1'-biphenyl)yl]ethyl]-4-methyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[(1,1'-biphenyl)yl]propyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-(4-propylphenyl)ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-(4-butylphenyl)ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine, 2-[2(R)-[2-(4-t-butylphenyl)ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[4-(4-fluorophenyl)phenyl]ethyl]-4- butyl-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[4-(4-fluorophenyl)phenyl]ethyl]-4- methyl-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-2-n-octyl-4-methyl-4(S)-carboxy-1- oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine.
2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-butyl- 4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-methyl- 4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-[3- (phenylsulfonyl)propyl-4(S)-carboxy-1- oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-(3- phenylpropyl)-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-methyl- 4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-[3- (phenylsulfonyl)propyl-4(S)-carboxy-1- oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine, 2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-(3- phenylpropyl)-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[4-(dimethylamino)methylphenyl]ethyl]-4- butyl-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[4-(dimethylamino)methylphenyl]ethyl]-4- methyl-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[4-(dimethylamino)methylphenyl]ethyl]-4- [3-(phenylsulfonyl)propyl-4(S)-carboxy-1- oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2{R)-[2-[4-(dimethylamino)methylphenyl]ethyl]-4- (3-phenylpropyl)-4(S)-carboxy-1-oxobutyl]- 3(S)-methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-imidazolyl)phenyl]ethyl]-4-butyl- 4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-imidazolyl)phenyl]ethyl]-4-methyl- 4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-imidazolyl)phenyl]ethyl]-4-[3- (phenylsulfonyl)propyl-4(S)-carboxy-1- oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine, and
2-[2(R)-[2-[(4-imidazolyl)phenyl]ethyl]-4-(3- phenylpropyl)-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine.
A fourth embodiment of the invention provides compounds of formula IIa or pharmaceutically acceptable salts or prodrug forms thereof which are useful in the method of treating Osteo and Rheumatoid arthritis (OA and RA) and related inflammatory diseases which uses a stromelysin or related matrix metalloproteinase
inhibitor as a cartilage protecting agent:
Figure imgf000053_0001
wherein :
R2 is selected from:
H,
C3-C10 alkyl, or
aryl-(C1-C4 alkyl)-;
R3 is selected from OR11, NHCH(R12)COR13, NR10R10a,
NHCH(R12)COOR11, or NHCH(R12)CONR14R15; R10 and R10a are each independently selected from
hydrogen, C1-C4 alkyl, or C1-C4 alkoxy;
R11, R12, and R15 are each independently selected from hydrogen or C1-C4 alkyl;
R13 and R14 are C1-C4 alkyl.
DETAILED DESCRIPTION OF THE INVENTION In the present invention it has been discovered that the compounds above are useful as inhibitors of stromelysin and similar matrix metalloproteinases, and the production of TNG and for the treatment of
rheumatoid arthritis, osteoarthritis and similar pathological conditions.
The present invention also provides methods for the treatment of osteo- and rheumatoid arthritis and other related inflammatory diseases by administering to a host a pharmaceutically or therapeutically effective or acceptable amount of a compound of formula (I) as described above. By therapeutically effective amount, it is meant an amount of a compound of the present invention effective to inhibit stromelysin or related matrix metalloproteinases and the production of TNF or to treat the symptoms of osteo- or rheumatoid arthritis or related inflammatory diseases in a host.
The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents. Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
By "therapeutically effective amount" it is meant an amount of a compound of Formula I that when
administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to inhibit stromelysin so as to prevent or ameliorate the inflamatory disease condition or the progression of the disease.
By "administered in combination" or "combination therapy" it is meant that the compound of Formula I and one or more additional therapeutic agents are
administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention may contain asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When any variable (for example R1 through R20, R10a, n, m, Z, X, etc.) occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R17, then said group may optionally be substituted with up to three R17 and R17 at each occurrence is selected independently from the defined list of possible R17.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such
substituent may be bonded to any atom on the ring.
When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formula I, then such substituent may be bonded via any atom in such substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise, said
piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formula I via any atom in such piperazinyl, piperidinyl, tetrazolyl group.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "substituted", as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., =O), then 2 hydrogens on the atom are replaced.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic
hydrocarbon groups having the specified number of carbon atoms (for example, "C1-C10" denotes alkyl having 1 to 10 carbon atoms); "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CvFw where v = 1 to 3 and w = 1 to (2v+D); "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-,bi- or polycyclic ring systems, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl; and
"bicycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
"Alkylcarbonyl" is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to the residue of the compound at the designated location. "Alkylcarbonylamino" is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to an amino bridge, where the bridge is attached to the residue of the compound at the designated location.
"Alkylcarbonyloxy" is intended to include an alkyl group of an indicated number of carbon atoms attached to a carbonyl group, where the carbonyl group is attached through an oxygen atom to the residue of the compound at the designated location.
The terms "alkylene", "alkenylene", "phenylene", and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I. Such
"alkylene", "alkenylene", "phenylene", and the like, may alternatively and equivalently be denoted herein as "-(alkyl)-", "-(alkyenyl)-" and "-(phenyl)-", and the like.
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or naphthyl; the term
"arylalkyl" represents an aryl group attached through an alkyl bridge.
As used herein, "carbocycle" or "carbocyclic residue" or "carbocyclic ring system" is intended to mean any stable 3- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or
"heteroaryl" or "heterocyclic" is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may
optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting
compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,
benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl or
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1 ,5,2-dithiazinyl, thiophenyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,
oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, indolizinyl, isoindolyl, 3H--ndolyl, indolyl, 1H-indazolyl, purinyl, 4.H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,
pyrazolinyl, piperidinyl, piperazinyl,
hexahydropyridazinyl, indolinyl, isoindolinyl,
quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term "amino acid" as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids, modified and unusual amino acids, as well as amino acids which are known to occur
biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The
Peptides. 5: 342-429, the teaching of which is hereby incorporated by reference. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids,
hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, ornithine, 2, 4-diaminobutyric acid,
homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, β-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl- norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine,
4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid,
1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
The term "amino acid residue" as used herein means that portion of an amino acid (as defined herein) that is present in a peptide.
The term "peptide" as used herein means a compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond. The term "peptide" also includes compounds containing both peptide and non-peptide components, such as
pseudopeptide or peptide mimetic residues or other non-amino acid components. Such a compound containing both peptide and non-peptide components may also be referred to as a "peptide analog".
The term "peptide bond" means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound of Formula I is modified by making acid or base salts of the compound of Formula I.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
"Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula I are prepared by modifying
functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
Prodrugs include compounds of Formula I wherein
hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I, phosphate esters, dimethylglycine esters,
aminoalkylbenzyl esters, aminoalkyl esters and
carboxyalkyl esters of alcohol and phenol functional groups in the compounds of formula (I); and the like.
The pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formula I formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic,
salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with
stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
The pharmaceutically acceptable salts of the acids of Formula I with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g.
sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g.,
dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount-of the
appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two;
generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's
Pharmaceutical Sciences. 17th ed., Mack Publishing
Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Synthesis
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of Formula I may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the educt molecule must be
compatible with the reagents and reactions proposed. Not all compounds of Formula I falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are
compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
Compounds of formula I wherein A is HONHCOCH(R1) and Q is a saturated N-heterocycle linked via a N atom in the ring are prepared by condensation of acids of formula (V):
Figure imgf000063_0001
wherein R is an ester protecting group, and R1 and R2 are defined as provided in the preceding Summary of the Invention in connection with formula I, with an
appropriately substituted N-heterocycle to form an amide bond between the carbonyl of (V) and a basic nitrogen in the ring of said heterocycle as shown in Scheme 1.
Figure imgf000064_0001
The condensation is carried out using any of the many methods for the formation of amide bonds known to one skilled in the art of organic synthesis. These methods include but are not limited to conversion of acid (V) to the corresponding acid chloride (Va), or use of standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide,
diisopropylcarbodiimide, or water-soluble carbodiimides) method, active ester (p-nitrophenyl ester, N- hydroxysuccinic imido ester) method, carbonyldiimidazole method, phosphorus reagents such as BOP-Cl. Some of these methods (especially the carbodiimide) can be enhanced by the addition of 1-hydroxybenzotriazole.
The preferred method is treatment of the cyclic amine with the acid chloride prepared from (V). Methods for conversion of carboxylic acids to acid chlorides are described in (J. March, Adv. Org. Chem. 1985, p. 1146, J. Wiley & Son, USA) and include, for example,
treatment of the acid with oxalyl chloride in the presence of a catalytic amount of N,N'- dimethylformamide. Removal of the ester protecting group followed by activation the resulting acid, for example with isobutylchloroformate, and reaction with O- benzylhydroxylamine gives a protected hydroxamic acid. Deprotection gives the hydroxamic acid.
Compounds of Formula I wherein A is HONHCOCH(R1) and Q is aryl or heteroaryl are prepared by treatment of the acid chloride (Va) prepared from acid (V) with a metallated aryl or heteroaryl as shown in Scheme 2, where R, R1 and R2 are defined as above, Ar represents an aryl or heteroaryl group and M is lithium, magnesium bromide or trialkyl or triaryltin. The organometallic species, Ar—M, are obtained by treatment of an aryl or heteroaryliodide or bromide with an alkyl or aryl lithium reagent, magnesium or a trialkyltin reagent to give the corresponding lithium, magnesium bromide or tin species using methods well known to one skilled in the art. The condensation of a trialkyltin species with acid chlorides in the presence of a catalytic amount of a palladium(0) catalyst has been reviewed by Stille (Angew. Chem. Int. Ed. Engl., 1986 25:508). In cases where the heteroaryl species is sufficiently reactive, either direct metallation or direct condensation of the unactivated heteroaryl compound with the acid chloride is possible. (See B. Oddo, Gazz. Chim. Ital., 1911, 41:234.) The intermediate ester is then converted to the target hydroxamic acid as described above.
Figure imgf000065_0001
The acids of formula (V) are prepared as previously described (Crimmin et al Synlett 1993, 137; Tamaki et al Tetrahedron Lett 1993, 34:683) or by the general routes shown in Scheme 3. An appropriately substituted carboxylic acid (VIII) is converted to the chiral oxazolidinone (IX) by the method of Evans. Deprotonation with a strong base followed by treatment with t-butyl bromoacetate, produces intermediate (X).
Transesterification of the chiral auxiliary with LiOBn, followed by acid treatment to remove the tert-butyl protecting group and conversion of the acid to the trichloroethylester gives a compound of formula (Va), where R1 is hydrogen. Alternately, hydrolysis of the chiral auxilliary can be accomplished with alkaline hydrogen peroxide to give acid (Vb).
Alternately, as shown in Route B, an α-bromoester of formula (XI) is treated with the potassium salt of dibenzyl malonate to give triester (XII). Methods for the preparation of α-bromoesters of amino esters are well known to one skilled in the art of organic
synthesis (R. S. Compagnone and H. Rapoport, J. Org. Chem. 1986, 51, 1713.) Removal of the benzyl esters and decarboxylation gives acid (XIII) which can be converted to (Va) by manipulation of the acid functions using standard methodology. Acids (V) where R1 is other than hydrogen are obtained from intermediate (XII) via
Mannich reaction followed by quaternization and
elimination to give the methylene compound (XIV). Once again manipulation of the acid functions gives the desired mono-trichloroethylester. Simple reduction of the alkene gives (V) where R1 is methyl. Compounds with R1 other than hydrogen or methyl are obtained from intermediate (XIV) by 1,4-addition of appropriate nucleophiles to the α,β-unsaturated acid moiety.
Suitable nucleophiles include, but are not limited to alkyllithiums, alkylmagnesium halides, thiols and alkoxides, and the like.
Figure imgf000067_0001
Compounds of formula II, wherein Z is N may be prepared from piperazic acid derivatives of formula (XV), wherein the designations R5, R6, R7 are defined as provided in the preceding Summary of the Invention in connection with formula II.
.
Figure imgf000067_0002
Unsubstituted piperazic acid esters of formula (XV) may be prepared as described by Adams et al. (Synth. Commun. 1988, 18, 2225) or by the general synthetic routes shown in Scheme 4.
Figure imgf000068_0001
Asymmetric addition of di-t-butyl
diazodicarboxylate to a chiral oxazolidinone prepared from an appropriately substituted 5-bromovaleric acid derivative (K. j. Hale, V. M. Delisser, and S.
Manaviazar Tetrahedron Lett., 1992, 33, 7613.) followed by removal of the BOC groups and hydrolysis of the oxazolidinone gives the piperazic acid derivative (XVa). Methods of choice for removal of the BOC groups are trifluoroacetic acid, neat or in dichloromethane, or HCl in dioxane. Hydrolysis of the oxazolidinone is
preferably carried out by treatment with aqueous lithium hydroxide. Compounds of formula (XVa) can be easily converted to a compound of formula (XV) by methods well known to one of ordinary skill in the art of organic synthesis, for example, by treatment with
benzylchloroformate in the presence of a suitable base such as aqueous sodium hydroxide followed by exposure to isobutylene under acid catalysis.
In an alternate method for the preparation of compounds of formula (XV), Diels-Alder cyclization of 4- phenyl-1,2,4-triazoline-3,5-dione with an appropriately substituted diene (Adams, vide supra) yields an adduct which after reduction and alkaline hydrolysis gives piperazic acid derivatives (XVa) which are converted to (XV) as described above. Compounds of Formula II wherein Z is N and R8 is H can be prepared from
piperazic esters of formula (XV) and acids of formula (V) as outlined in Scheme 5.
Figure imgf000069_0001
Piperazic esters (XV) are coupled with acids of formula (V) to give amides of formula (VI) as described above.
For compounds of Formula II wherein Z is N, and R8 is H and R3 is -NR10R10a, the synthesis proceeds by
hydroxylsis of the t-butyl ester of a compound of
Formula (VI), followed by activation of the resulting acid with a coupling reagent chosen from the list of standard procedures above, for example,
isobutylchloroformate, and treatment with an excess of an amine of formula R10(R10a)NH or corresponding alcohol to give the corresponding amide. The trichloroethyl ester is removed by reduction followed by conversion to the hydroxamic acid as previously described. Tbe preferred methods for removal of the TCE ester are reduction with zinc dust or mild base hydrolysis. For removal of the benzyl and Cbz groups in one pot, the reagents of choice are hydrogenation conditions using hydrogen at atmospheric pressure or in a Parr apparatus at elevated hydrogen pressure, or cyclohexene or
ammonium formate over palladium, palladium hydroxide on charcoal or platinum oxide in methanol, ethanol or tetrahydrofuran, or combination of these solvents (P. N. Rylander, Hydrogenation Methods, Academic Press, 1985). For compounds wherein R1 contains sulfur, removal of the benzyl and Cbz protecting groups is carried out by hydrogenation in the presence of Wilkinson's catalyst or by treatment with trimethylsilyliodide.
An alternate route to compounds of Formula II wherein R1 is other than hydrogen or methyl is depicted in Scheme 6. An acid of formula (XIV) is condensed with a compound of formula (XV) using one of the methods described above, to give (XVI). This intermediate is converted as described to acid (XVII). Michael addition of an appropriate nucleophile and conversion of the acid functionality to a hydroxamic acid gives compounds of formula II. This route can be used to prepare other compounds of formula II by replacing compound (XV) in scheme 6 with the heterocycles, aryl and heteroaryl reagents described above
Figure imgf000071_0001
Compounds of Formula II can also be as illustrated in Scheme 7 .
Figure imgf000072_0001
Compounds of Formula II wherein Z is N and R8 is other than hydrogen are prepared as outlined in Scheme 8. Compounds of Formula (VII) are deprotected as
described above followed by alkylation of the resulting free amine with an alkylation agent in the presence of a suitable base. Alkylating agents include alkyl halides, mesylates, tosylates, etc. Suitable bases are
triethylamine, N-methylmorpholine or
diisopropylethylamine. Compounds wherein R8 is
alkylcarbonyl are prepared by treating deprotected (VII) with an acyl halide such as acetyl chloride.
Figure imgf000073_0001
Compounds of formula II wherein Z = O are prepared from hydroxamic acids of formula (XVII) as outlined in Scheme 9.
Figure imgf000073_0002
Hetero-Diels-Alder reaction between hydroxamic acids of formula (XVII) and an appropriately substituted diene in the presence of a suitable oxidant gives compounds of formula (XVIII) which upon reduction give compounds of formula II.
Figure imgf000073_0003
Compounds of Formula I wherein A is -NHCH (R9 ) CO2H are prepared from amino acids (XIX) as by following the steps depicted in Scheme 10 .
Figure imgf000074_0001
An N-protected amino acid (XIX) fluoride (prepared as described by Carpino et al., J. Org. Chem. 1991 56, 2612) is coupled with piperazic esters of formula (XV) in the presence of an organic amine base such as
triethylamine, to give hydrazide (XX). Further
elaboration of the t-Butyl ester as described above and hydrogenation of the Cbz-protecting groups followed by hydrolysis of the BOC group gives an amine of formula (XXI) . Alkylation of XXI with a suitable halide or triflate in the presence of a base such as Hunig's base, followed by deprotection if necessary, provides
compounds of general III. Using methods described above, compound (XV) can be replaced with other N- heterocycles or aryl or heteroaryl derivatives to give additional compounds of Formula III.
Compounds of Formula I wherein A is
-CH(R11)C(R9a) (R9)CO2H are prepared from acids (XXII) as depicted in Scheme 11 using methods described above.
Carboxylic acid (XXII) is converted to the acid fluoride by the method dexcribed by Carpino (vide supra) using cyanuric fluoride. Treatment with Cbz-protected piperazic acid provides the coupled compounds XXIII. The acid is subsequently converted to an amide by activation as described above to give compounds of formula XXIV. Removal of the Cbz protecting group by catalytic hydrogenation followed by deprotection of the t-butyl ester with trifluoroacetic acid provides compounds of formula IVa.
Figure imgf000076_0001
The acids of formula (XXII) are prepared as illustrated in Scheme 12. Reaction of the titanium homoenolate of ethyl bromopropionate, (XXVI) with a suitably protected 4-hydroxybenzaldehyde, such as (XXVII) provides an intermediate lactone which is reduced by catalytic hydrogenation and converted to the Evans chiral oxazolidinone (XXVII). Removal of the silyl protecting group follwed by conversion to the corresponding triflate using standard conditions
(triflic anhydride and pyridine) provides (XXIX). The triflate may then be coupled to aryl boronic acids or aryl zinc reagents to afford biaryl compounds (XXX). Asymmetric Micahel addition of (XXX) to t-butyl acrylate follwed by removal of the chiral auxiliary with lithium hydroxide/hydrogen peroxide gives (XXXI). Dianion formation with 2 equivalents of lithium diisopropyl amide in tetrahydrofuran/DMPU followed by alkylation with an appropriate alkyl iodide gives XXII, suitably functionalized for coupling as described above.
Figure imgf000078_0001
Unusual amino acids used in this invention can be synthesized by standard methods familiar to those skilled in the art ("The Peptides: Analysis, Sythesis, Biology, Vol. 5, pp. 342-449, Academic Press, New York (1981)). N-Alkyl amino acids can be prepared using procedures described in Cheung et al. (Can. J. Chem. 55, 906 (1977)) and Freidinger et al., (J. Org. Chem. 48, 77 (1982)), which are incorporated herein by
reference.
The functional groups of the constituent amino acids must be protected during the coupling reactions to avoid undesired bonds being formed. The protecting groups that can be used are listed in Greene,
"Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Sythesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference.
In a second aspect of this invention, we claim that pharmaceutical preparations of compounds of formula I (with the indicated provisos) are orally bioavailable drugs useful for the treatment of arthritis by their action as cartilage protectants.
The compounds of this invention and their
preparation can be further understood by the following procedures and examples, which exemplify but do not constitute a limit of their invention.
Examples
Abbreviations used in the Examples are defined as follows: "1X" for once, "2X" for twice, "3X" for thrice, "bs" for broad singlet, "°C" for degrees
Celsius, "Cbz" for benzyloxycarbonyl, "d" for doublet, "dd" for doublet of doublets, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, "1H" for proton, "hr" for hour or hours, "m" for multiplet, "M" for molar, "min" for minute or minutes, "mp" for melting point range, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" for triplet, "tlc" for thin layer chromatography, "v/v" for volume to volume ratio. "α", "β, "R" and "S" are stereochemical designations familiar to those skilled in the art.
Procedure 1
Preparation of N1-benzyloxycarbonyl-S-piperazic acid tert-butyl ester
A. [4S- (phenylmethyl ) -2-oxazolidinyl ) ] -5-bromovaleramide
Bromovaleric acid (68g, 0.38 mol) was dissolved in dry methylene chloride (640 ml) and anhydrous DMF (1ml) was added. The solution was cooled to 0° C under an atmosphere of nitrogen. Oxalyl chloride (36.8 ml, 0.413 mol) was added dropwise over 20 min, followed by
continued stirring at 0° C for lh then at room
temperature until gas evolution had ceased (6 h). The solvent was then removed in vacuo to yield the crude acid chloride.
To a solution of of (+)-(S)-4-benzyloxazolidinone (66.56 g, 0.376 mol) in tetrahydrofuran (900 ml), cooled to -78° C, was added n-butyl lithium (164 ml, 2.29 M in hexanes) over lh with mechanical stirring. Following an additional stiring period of 15 min, the acid chloride (pre-cooled to -78° C in a jacketed addition funnel) was added over 45 min. The cooling bath was then removed, and the solution allowed to continue stirring over 18 h. The reaction was quenched with 10% citric acid (400 ml) and water (600 ml). The phases were separated, and the aqueous phase was extracted with ether (3 X 300ml). The combined organics were washed with saturated aqueous sodium bicarbonate solution (2 × 600 ml), 10 % citric acid (2 x 300 ml), water and brine, then dried over anhydrous magnesium sulfate. Filtration and removal of solvent gave the crude product (124.0 g, 97%).
Recrystallization from 10:1 heptane ether provided the pure product in 85% yield, mp 57-59° C. MS m/e 340 (M+H)+. [α]D +81.6.
B. N1,N2-[di-tert-butoxycarbonyl]-S-piperazic acid [4S-(phenylmethyl)-2-oxazolidinonamide]
A solution of lithium diisopropyl amide wa first prepared as follows; Diisopopylamine (0.801 mol, 112.3 ml in 250 ml tetrahydrofuran) was cooled to 0° C and treated with n-BuLi (2.5M in hexanes, 0.785 mol, 314 ml) and allowed to stir for 20 min. The solution was then cooled to -78 and the compound of Procedure 1A (250 g, 0.735 mol) in 625 ml THF was added at such a rate as to maintain the internal temperature of the reaction mixture at or below -70° C. Upon completion of the addition, the mixture was allowed to stir an additional 2 h at -78° C. A solution of di-tert-butyl
diazodicarboxylate (203 g, 0.882 mol) in dry methylene chloride (370 ml) was then added dropwise at such a rate so as to maintain the internal temperature below -70° C, The resulting mixture was stirred for an additional 15 min, followed by addition of tetrabutyl ammonium iodide (40g, 0.110 mol) and continued stirring at -78° C for 5 min. The reaction temperature was then raised to -20 °C and the mixture was allowed to stir for 18 h whereupon HPLC analysis showed complete conversion to product. The crude mixture was poured into a solution of ether (800 ml), water (2 L) , and potassium dihydrogen phosphate (50 g). The organic layer was separated, and the aqueous further extracted with ether. The combined organics were washed with saturated aqueous sodium hydrogen bicarbonate solution (500 ml) and brine followed by drying over anhydrous magnesium sulfate. Filtration and solvent evaporation gave 443 g of product which was purified by MPLC-SiO2 (25% ethyl acetate/hexane) to yield the desired product (417 gm, 91%). MS m/e 507 (M+H)+. [α]D = +35.95 (c 0.370, methanol). A related procedure for the preparation of this compound is detailed in the literature (Hale et al, Tetrahedron Letters 1992, 33, 7613).
C. S-piperazic acid [4S-(phenylmethyl)-2-oxazolidinonimide] dihydrochloride
To a cooled solution of 4N hydrogen chloride in dioxane (100 ml) was added a solution of the compound of Procedure 1B (10 g, 0.02 mol) in dioxane (10 ml). The cooling bath was then removed, and the solution was allowed to stir for 4 h at room temperature. The solvent was removed in vacuo to give the desired
dihydrochloride salt (7.3 g, 98%). MS 290 m/e (M+H), [α]D = +89.29 (c 0.224, methanol), ir 3434, 1782, 1698,
1HNMR(300 MHz) 7.25 (5H, m), 4.81 (1H, dd), 4.40 (1H, m), 4.22 (1H, dd), 3.01 (4H, m), 2.0-1.75 (3H, m), 1.6 (1H, m).
D. N1-(benzyloxycarbonyl)-S-piperazic acid [4S-(phenylmethyl)-2-oxazolidinonimide]
A solution of the compound of Procedure 1C (8.03 g, 22.1 mmol) in DMF (45 ml) cooled to 0° C was treated with Hunigs base (15.8 ml, 90.4 mmol) and allowed to stir for 20 min. Benzyl chloroformate (3.76 g, 22.1 mmol) was added dropwise over 20 min, followed by removal of the cooling bath and continued stirring at 20° C for 18 h. Evaporation of the volatiles left a brown oil that was taken up in ethyl acetate. The white precipitate (diisopropylethylamine hydrochloride) was removed by filtration, and the filtrate was washed with saturated sodium bicarbonate, water and brine, followed by drying over anhydrous magnesium sulfate. Filtration and solvent removal in vacuo gave a semi-solid that was recrystallized from pentane/ethyl acetate to give the desired product (6.36 g, 68%, 1st crop). mp 102-103° C. MS m/e 423 (M+H)+. [α]D=+33.3 (c 0.664, MeOH).
E. N1-(benzyloxycarbonyl)-S-piperazic acid
The compound of Procedure 1D (5 g, 11.8 mmol) was dissolved in a mixture of THF (50 ml) and water (10.2 ml) and cooled to 0° C. Lithium hydroxide monohydrate
(1.16 g) was added, and the disappearance of starting material was monitored by tic (1:1 ether/hexane). Upon completion of reaction (approximately 4h), the reaction was quenched with 10% citric acid and extracted with ethyl acetate. The ethyl acetate phase was then
extracted 5 times with saturated sodium bicarbonate solution. The aqueous base phase was acidified with citric acid, and extracted 4 times with ethyl acetate. The organic phase was then washed with water, brine and dried over anhydrous magnesium sulfate. Solvent
evaporation gave the desired product (2.9 g, 93%) which was used without purification in the next step. MS m/e 282 (M+H)+, [α]D = -31.25 (c 0.0128, MeOH), ir 3200, br, 1750, 1692 1HNMR(300 MHz) 7.28 (5H, m), 5.05 (2H, s), 3.8 (1H, ddd), 3.28 (2H, m), 3.02 (1H, m), 1.85 (1H, m), 1.70 (1H, m), 1.5 (2H, m). F. N1-(benzyloxycarbonyl)-S-piperazic acid tert-butyl ester
To a solution of the the compound of Procedure 1E (11 g) in methylene chloride (100 ml ), was added N,N-diisopropyl-O-tert-butyl imidate●CuCl2 (35 ml of a 3 M solution in methylene chloride), and the whole was allowed to stir at 20° C for 18 h. Acetic acid (20 ml) was added, and the solution was stirred for an
additional 30 min. Filtration, followed by dilution with water (100 ml) and saturated sodium bicarbonate solution until basic (pH 9-10) gave a solution that was stirred vigorously for another 10 min. Separation of the organic phase followed by extraction with methylene chloride gave the product layer which required an additional filtration to remove a blue gelatinous precipitate. The aqueous layer was extracted an additional 3 times with methylene chloride, and the combined organics were washed with water, brine and then dried over anhydrous magnesium sulfate. Solvent removal in vacuo gave an oil that was triturated with hexane and filtered to remove any residual solid. Removal of the hexane gave the desired product as an oil (10.3 g, 88%) that solidified on standing at -20° C. MS m/e 280 (M+H)+, [α]D = -33 (c 0.700, MeOH), ir 1732, 1698.
Procedure 2
Preparation of N1-(benzyloxycarbonyl)-6-phenylpiperazic acid tert-butyl ester
A. 2-Carbomethoxy-5,8-diphenylbicyclo [4.3]-1,6,8-triaza-7,9-dioxonon-3-ene
To a suspension of N-phenyl-3, 4-dioxourazole (9.55 g 54.5 mmol) in methylene chloride (250 ml) was added a solution of methyl 5-phenyl-2,4-pentenoate (10.25g, 54.5 mmol) in methylene chloride (100 ml) over 20 minutes. The mixture was allowed to continue stirring at room temperature for 18h. The solvent was removed by on a rotary evaporator to give a semi-solid that was
triturated with 1:1 ether/hexane. The white crystals were collected by filtration to give the product (12.34 g, 65%). The trituation was repeated on the filtrate to give an additional crop of white cyrstalline product, for a combined yield of 14.16 g (75%). mp. 155-156º C. MS m/e 364 (M+H)+.
B. 2-Carbomethoxy-5, 8-diphenylbicyclo [4.3]-1,6,8-triaza-7,9-dioxononane.
The product of Procedure 2A (14.16g, 39.9 mmol) was diluted with a 3:1 mixture of ethanol/ethyl acetate, and stirred in the presence of 10% palladium on carbon under 1 atm of hydrogen pressure for 18 h. The catalyst was removed by filtration and washed with methylene
chloride. Solvent was removed by evaporation to give a white solid foam (14.2 g, 100%). Trituration of the foam with 1:1:1 Ethyl acetate/ether/hexane, filtration and drying gave the desired product (12.7g, 90%). mp 126-128º C. MS 366 (M+H)+. C. 6-Phenylpiperazic acid dihydrochloride
The compound of Procedure 2B (28.7 g, 78.6 mmol), butanol (210ml) and powdered potassium hydroxide (28.7g, 511 mmol) were combined and heated to reflux for 24h. The mixture was cooled to room temperature and allowed to stir for an additional 24h. Water (225 ml) was added, and the mixture stirred for 30 min. The butanol layer was separated and washed with water (225 ml). The combined aqueous phases were washed once with methylene chloride. The aqueous phase was then acidified to pH 2 using 6N HCl. Evaporation of the volatiles under high vacuum gave a solid that was triturated with methanol. The potassium chloride was filtered off and the solvent was removed to yield the desired product (21.5 g, 96%). MS m/e 207 (M+H)+ of free base.
D. N1-(Benzyloxycarbonyl) piperazic acid
The compound of Procedure 2C (lg, 3.6 mmol) was dissolved in water (15 ml) and adjusted to pH 9-9.5 with 2N sodium hydroxide. The resulting mixture was then cooled to 5º C, and a solution of benzylchloroformate
(0.464 ml, 3.6 mmol) in toluene (2ml) and a solution of sodium hydroxide (3.58 mmol) in water (2ml) were added simultaneously and at equal rates over 5 min. The biphasic solution was allowed to stir for 18h. The solution was then acidified to pH 3 using 1N HCl , and the mixture extracted with ethyl acetate (3X). The organic phase was washed with brine and dried over anhydrous magnesium sulfate. Filtration, followed by solvent evaporation in vacuo gave the title compound (1.16g, 95%). This material was used crude in the next step. MS m/e 341 (M+H)+, 295 (M+-CO2), 251 (M+-benzyl).
E. N1-(benyloxycarbonyl)-6-phenylpiperazic acid t-butyl ester.
A solution of the compound of Procedure 2D (1.22g, 3.6 mmol) in methylene chloride (10 ml), cooled to 0ºC, was treated with N,N-disopropyl- O-tert-butylimidate●CuCl2 (3.5 ml, 3.5M solution). The cooling bath was removed, and the solution was allowed to stir for 4.5 h at room temperature. The material was worked up as described previously in the procedure of Procedure IF. The crude material (1.24g, 86%) was purified by MPLC (SiO2, 4:1 hexane/ethyl acetate) to give the product as a mixture of diastereomers. MS 397 (M+H)+.
Procedure 3
Preparation of (2S,3R)-2'2'2'-Trichloroethyl 3-carboxy- 2,5-dimethylhexanoate
A. (R)-2-Ethenyl-3-(t-butoxycarbonyl)-5-methylhexanoic acid
(R)-Benzyl (2-benzyloxycarbonyl)-3-(tert-butoxycarbonyl)-5-methylhexanoate (2 g, 4.4 mmol) was prepared as described in European Patent Application WO 90/05719) and dissolved in ethanol (40 ml). Ammonium formate (1.4 g, 21.3 mmol) was added followed by 10% Pd-C (500 mg) as an isopropanol slurry. After 90 min, the catalyst was removed by filtration through celite to give a solution of the crude diacid. Piperidine (415 g) was added and the mixture was allowed to stir for 10 min at room temperature. Aqueous formaldehyde (2.1 ml, 40% solution) was added, and the mixture was allowed to stir for an additional 18 h. The solution was then heated to reflux for 90 min, cooled to room temperature, and the solvent evaporated. The crude material was partitioned between ethyl acetate and 10% citric acid solution. The acid layer was extracted with ethyl acetate 3X, and the combined organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. to yield of the title compound (0.87 g, 82%) as a colorless oil. MS m/e 242 (M+H)+; IR 3500-2800, 1730, 1700, 1626 cm-1.
B. 2S-Methyl-3R-(tert-butoxycarbonyl)-5-methylhexanoic acid
To a solution of the compound of Procedure 3A (0.86 g) in methanol (40 ml) was added 10% Pd-C (120 mg), and the heterogeneous mixture was stirred under 1 atm hydrogen gas for 12 h. The catalyst was filtered, and the solvent evaporated to give the saturated product as a colorless oil (9:1 mixture of diastereomers). MS m/e 244 (M+H)+, [α] +18.2 (c 0.406, methanol)
C. 2'2'2'-Trichloroethyl 2S-methyl-3R-(tert-butoxycarbonyl),5-methylhexanoate
The compound of Procedure 3B (4.4 mmol),
trichloroethanol (850 ml, 8.8 mmol), and DMAP (30 mg) were combined in dry methylene chloride (10 ml) and cooled to 0 C. Dicyclohexylcarbodiimide (908 mg (4.4 mmol) was added, the cooling bath removed after 5 min and the solution allowed to stir under a nitrogen atmosphere for 12 h. The dicyclohexylurea precipitate was removed by filtration, followed by washing the organic layer with 10% citric acid and brine.
Evaporation of the solvent gave a semi-solid which was triturated with hexane to give another crop of the urea that was also collected by filtration. The hexane layer was stirred vigorously over an equal volume of water for 2 h to remove excess trichloroethanol. The hexane layer was then separated, washed with brine and dried over
MgSO4. Evaporation of solvent gave a crude oil that was purified by silica gel MPLC (5% ether/hexane) to give the desired pure diastereomer as an oil ( 77 %) . MS m/e 376 (M+H)+, [α]D = +7.43 (c 0.350, methanol).
D. (2S, 3R)-2'2'2'-Trichloroethyl 3-carboxy-2,5-dimethylhexanoate
The product of Procedure 3C (5 g, 3.3 mmol) was added to a 4N soultion of HCl in dioxane (125 ml) and stirred at room temperature for 8 h. The solvent was then removed in vacuo to give the title acid (4.2 g, 98%). MS m/e 319 (M+H)+, [α]D = +9.8 (c 9.8, methanol).
Example 1
[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2- (S)-piperazic acid-N-methyl amide
A. (2R,3S)-[4-(2'2'2'-trichloroethoxy)-2-isobutyl-3-methylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazic acidtert-butyl ester
The compound of Procedure 3D (1 g, 3.1 mmol) was dissolved in dry methylene chloride (30 ml), containing 5 drops of dry N,N-dimethylformamide. The solution was cooled to 0 C under N2 followed by addition of oxalyl chloride (0.297 ml, 3.4 mmol). The solution was allowed to stir 30 min at 0º C and then 1 h at RT. The solvent was evaporated in vacuo 3X with washing with dry
methylene chloride to remove HCl. The crude acid
chloride was dissolved in 15 ml methylene chloride and added to a mixture of the (+/-) -t-butylester of N1-benzyloxycarbonylpiperazic acid (992 mg, 3.1 mmol) and N-methylmorpholine (341 ul, 3.1 mmol) in methylene chloride (20 ml) at 0º C. The mixture was then allowed to stir for 18 h at room temperature, then diluted with 10% citric acid, followed by separation and washing with saturated aqueous sodium bicarbonate, brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give crude material that was purified by silica gel MPLC to give the title compound (0.96 g, 50%) as a 1:1 mixture of diastereomers. MS m/e 623 (M+H)+. IR 1760 cm-1.
B. (2R,3S)-[4-(2'2'2'-trichloroethoxy)-2-isobutyl-3-methylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazic acid N-methyl amide
The compound of example 1A (0.96 g) was added to a solution of 4N HCl/dioxane (35 ml) and allowed to stir for 8 h at room temperature. Solvent removal in vacuo gave the desired acid in quantitative yield. The crude acid was dissolved in methylene chloride (10 ml) was treated with N-methylmorpholine (0.19 ml, 1.7 mmol) and cooled to -20ºC . After stirring for 10 min at -20, isobutylchloroformate ( 0.2 ml, 1.5 mmol) was added dropwise over 5 min, and the solution was allowed to stir for 1 h at that temperature. The resulting mixture was treated with 5 equivalents of 40% aqueous
methylamine, and the solution was allowed to stir for 30 min over which time ambient temperature was reached. The mixture was then diluted with ethyl acetate, washed with 10% citric acid, water and brine then dried over
anhydrous magnesium sulfate. Evaporation of the solvent gave a crude oil that was purified by MPLC (5%
MeOH/methylene chloride) to give the desired amide as a 1:1 mixture of diastereomers (770 mg, 89%). MS m/e 578 (M+H)+, IR 3354, 1752, 1716, 1678, 1544 cm-1.
C. (2R,3S)-[4-hydroxy-2-isobutyl-3-methylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazic acid N-methyl amide
The compound of Example 1B was dissolved in
tetrahydrofuran (26 ml) to which was added 5.2 ml of a 1 M solution of ammonium acetate. The solution was cooled to 0ºC and Zn powder (2.3 g, 3 wt. equivs.) was added. The heterogeneous solution was vigorously stirred for 10 min at 0ºC and an additional 6 h at room temperature. The crude reaction mixture was filtered and washed with ethyl acetate. The solvent was then removed by evaporation, and the crude material was taken up in ethyl acetate and washed with water, 10% citric acid (2x), brine and then dried over anhydrous magnesium sulfate. Filtration and evaporation of solvent, followed by MPLC (10% MeOH/methylene chloride) gave the desired product in a 1:1 mixture of diastereomers as a white foam (330 mg, 57%). MS m/e 465 (M+H)+, IR 3324, 2958, 1712, 1680, 1554 cm-1. D. (2R,3S)-[4-(benzyloxyamino)-2-isobutyl-3-methylsuccinyl]-N2-(N1- yl)-piperazic acid N-methyl amide
The compound of Example 1C (210 mg, 0.47 mmol) was combined with N-methylmorpholine (0.056 ml) in dry methylene chloride (15 ml) and cooled to -20ºC under N2. Isobutylchloroformate (0.061 ml, 0.47 mmol) was added, and the solution was allowed to stir for 1h. A solution of O-benzylhydroxylamine hydrochloride (77 mg) and N-methylmorpholine (0.056 ml) in methylene chloride (3 ml) was added with washing with methylene chloride, and the mixture was allowed to stir at room temperature for 18 h. The mixture was then diluted with methylene chloride, washed with 10% citric acid (1×20 ml), brine and then dried over anhydrous magnesium sulfate.
Evaporation of solvent gave of the O-benzyl protected hydroxamic acid (203 mg, 78%) as a mixture of
diastereomers which were separated by HPLC C18 column, 10% isopropanol/hexane.
Diastereomer A 97 mg (first product to elute)was
converted to the corresponding hydroxamic acid as detailed in Example 1E below.
Diastereomer B 95 mg (second product to elute) was converted to the corresponding hydroxamic acid as detailed in Example 2 below.
E. (R)-[(2R,3S)-4-(N-hydroxyamino)-2-isobutyl-3-methylsuccinyl]-N2-piperazic acid-N-methyl amide Diastereomer A of Example 1D (29 mg, 0.052 mmol) was dissolved in ethanol ( 5 ml) and 10% Pd on C (5 mg) was added. The solution was stirred under a balloon of hydrogen for lh. The heterogeneous mixture was filtered through a microporous filter, and evaporated to dryness to give the title compound (18 mg, quantitative yield). MS m/e 570 (M+H)+, [α]D +54.17 (c 0.216, MeOH), mp 120-130 °C, ir 3224, 1624 br, 1HNMR (400 MHz, COSY, CD3OD)
5.1 (1H, dd), 4.08 (1H, dt), 3.09 (1H, ddd), 2.79 (3H, s) 2.4 (1H, ddd), 2.25 (1H, ddd), 2.19 (1H, dddd), 1.8
(1H, dddd), 1.65 (1H, ddd), 1.55 (2H, m), 1.4 (1H, m),
1.2 (3H, d), 1.19 (1H, m), 0.92 (3H, d), 0.88 (3H,d), 13CNMR (100 MHz, DEPT, CD3OD) 178.7, 174.8, 173.6, 42.9, 41.7, 41.0, 27.5, 27.3, 26.3, 24.2, 22.3, 22.2, 15.5.
Example 2
(S)-[(2R,3S)-4-(N-hydroxyamino)-2-isobutyl-3- methylsuccinyl]-N2-piperazic acid-N-methyl amide Diastereomer B of Example 1D (15 mg) was dissolved in ethanol (5 ml) and 10% Pd on C (5 mg) was added. The solution was stirred under a balloon of hydrogen for 1h. The heterogeneous mixture was filtered through a
microporous filter, and evaporated to dryness to give the title compound (10 mg,). mp 123-127 °C, MS m/e 570 (M+H)+, [COD +6.67 (c 0.009, MeOH), 1HNMR (400 MHz, COSY, CD3OD) 5.15 (1H, dd), 4.0 (1H, m), 3.05 (1H, m),
2.8 (1H, m), 2.79 (1H, s), 2.28 (1H, m), 2.10 (1H, m),
1.9 (1H, m), 1.7-1.5 (3H, m), 1.3 (1H, m), 1.05 (1H, m), 1.04 (3H, d), 0.92 (3H, d), 0.83 (3H, d), 13CNMR (100 MHz, DEPT, CD3OD) 180.8, 179.11, 174.6, 52.4, 42.6, 42.5, 28.1, 27.5, 27.1, 227.0, 26.2, 24.5, 22.4, 17.3, 17.1.
Example 3
N-[1(R)-carboxyethyl]-α-(S)-isobutylglycine-(S)-N1- piperazic acid methyl amide
To a solution of Cbz-L-Leucine (1g, 3.77 mmol) and N,N-dimethylformamide (0.5 ml) in methylene chloride (45 ml) at 0º, was added oxalyl chloride (0.329 ml). The solution was stirred for 1 h at 0 and then 2h at room temperature. The solution was then evaporated in vacuo . The crude acid chloride was then taken up in methylene chloride (45 ml) and cooled to 0 under N2. The compound of Procedure 1F (1.21 mg, 3.77 mmol) and N-methylmorpholine (0.458 ml) in methylene chloride was added to the solution of acid chloride over 10 min , and the whole was allowed to stir for 18h at RT. The mixture was taken up in methylene chloride and washed with 10% citric acid, saturated aqueous sodium bicarbonate, water, brine and then dried over anhydrous magnesium sulfate. Filtration and evaporation of solvent gave the amide as an oil that was purified by MPLC (1.7 g, 79 %) This amide (1.7 mg,2.98 mmol) was treated with trifluoroacetic acid for 4 h at room temperature.
Solvent evaporation gave the intermediate acid which was used without further purification in the next step.
To a -20ºC solution of the crude acid (660 mg, 1.29 mmol) and N-methylmorpholine (0.145 ml, 1.37 mmol) in methylene chloride was added isobutylchloroformate
(0.173 ml, 1.32 mmol). The solution was allowed to stir for 1 h at -20. Aqueous methylamine (40% solution, 5 equiv) was added and the temperature allowed to increase to ambient. After 1h, the solution was quenched with 10% citric acid, diluted with methylene chloride and washed with water and brine folloed by drying over MgSO4.
Filtration and solvent evaporation gave the methyl amide which was purified by MPLC.
The bis-Cbz protected intermediate was hydrogenated with H2 Pd-C in ethanol for 4 h at 1 atm. The
heterogeneous mixture was filtered and evaporated in vacuo to give the corresponding amine. The final product was obtained by performing a reductive amination with benzyl pyruvate as described in the following: The amine in THF was treated with benzyl pyruvate at 20 °C. Sodium cyanoborhydride was added and an equivalent of p-toluenesulfonic acid in THF was titrated in over lh. The solvent was evaporated to approximately 1/3 volume and ethyl acetate and water were added. The organic phase was separated and the aqueous washed an additional 3 times with ethyl acetate. The combined organics were washed with water and brine then dried over MgSO4.
Filtration and solvent evaporation gave the crude amino acid as a mixture of diastereomers which was purified by MPLC (60% MeOH/methylene chloride). MS m/e 327 (M+H)+ Example 45a
(S)-[(2R)-4-(N-hydroxyamino)-2-propylphenyl-succinyl]- N2-piperazic acid-N-methyl amide
A. [4S-(phenylmethyl)-2-oxazolidinyl)]-5-phenylvaleramide
The sodium salt of 5-phenylvaleric acid (53.5 mol) was dissolved in dry THF (100 ml) and anhydrous DMF (lml) was added. The solution was cooled to 0° C under an atmosphere of nitrogen. Oxalyl chloride (4.67 ml) was added dropwise over 20 min, followed by continued stirring at 0° C for 1h then at room temperature until gas evolution had ceased (3 h).
To a solution of of (+)-(S)-4-(phenylmethyl)-oxazolidinone (8.83 g, 53.5 mmol) in tetrahydrofuran (100 ml), cooled to -78° C, was added n-butyl lithium (21.4 ml, 2.5 M in hexanes) over 1h with stirring.
Following an additional stiring period of 15 min, the acid chloride (pre-cooled to -78° C in a jacketed addition funnel) was added over 45 min. The cooling bath was then removed, and the solution allowed to continue stirring over 18 h. The reaction was quenched with 10% citric acid (100 ml) and water (100 ml). The phases were separated, and the aqueous phase was extracted with ether (3 X 300ml). The combined organics were washed with saturated aqueous sodium bicarbonate solution (2 × 600 ml), 10 % citric acid (2 × 300 ml), water and brine, then dried over anhydrous magnesium sulfate. Filtration and removal of solvent gave the crude product which was chromatographed using 20% ethyl acetate/hexane to give 14 g (77%) of the desired product. MS m/e 338 (M+H) . B. [4S-(phenylmethyl)-2-oxazolidinyl)]-2S-(t-butylacetyl)-5-phenylvaleramide.
The compound of Part A (14 g, 41.5 mmol) was dissolved in 150 ml anhydrous THF and cooled to -78 under N2. LDA (41.5 mmol) was added over 10 min., and the solution was stirred at -78 for 30 additional minutes. Tert-butyl bromoacetate (8.1 g, 41.5 mmol) dissolved in 30 ml THF was added over 20 min, and the resulting mixture was allowed to stir at -78 for 30 min then warmed to ambient temperature by removal of the cooling bath. After 1 h, the solution was concentrated on a rotary evaporator to 1/4 volume. Ethyl acetate was added followed by washing with 10% citric acid, water then brine and dried over MgSO4. Solvent evaporation gave an oil that was purified by MPLC 25% ether/hexane to give 10.75 g (57%) of the addition product, mp 73-75 °C, MS m/e 452 (M+H)+, [α]D=+74.3 (c 0.214, methanol).
C. Tert-Butyl-3R-(hydroxycarbonyl)-6-phenylhexanoate
To a cooled solution (0 °C)of the compound of Part B (5 g, 11.1 mmol) dissolved in 60 ml of THF/H2O (4:1) was added hydrogen peroxide (30% solution, 4.5 ml, 44.4 mmol) was followed by aqueous LiOH (425 mg in 30 ml water). The solution was allowed to stir for 5 h at 0, at which time complete consumption of starting material was observed by tic. The THF was removed under reduced pressure, and the resulting aqueous phase washed with methylene chloride. The water phase was then carefully acidified to pH 1 with 10% HCl. The solution was then extracted with ethyl acetate, dried over MgSO4, filtered and evaporated to give the crude product. The material was purified by MPLC 7% methanol/methylene chloride to provide 2.90 g (90%) of purified acid. MS m/e 293
(M+H)+, [α]D=+6.3 (C 0.322, methanol). D. (2R)-[4-(tert-butoxy)-2-(3-phenylpropyl)succinyl]-N2-(N1-benzyloxycarbonyl)-S-piperazic acid
The compound of Part C (2.50 g, 8.56 mmol) was dissolved in 100 ml of anhydrous toluene and cooled to -10 °C. DMF (0.5 ml) was added followed by oxalyl chloride (1.39 g). The resulting solution was allowed to stir for 1h at -10, followed by evaporation of solvent under high vac at -10. Th crude acid chloride was then diluted with 50 ml methylene chloride, and cooled to 0o under N2. In a separate flask, N-benzyloxycarbonyl-S-piperazic acid (2.26g) was dissolved in 35 ml methylene chloride and treated with 3.68 ml of triethylamine.
After 5 min, this solution was transferred to a dropping funnel and added to the aboveover 10 min. Stirring was continued for 1 h at 0 and 1 h at ambient temperature. The reaction was then quenched with 10% citric acid and extracted 3 times with methylene chloride. The organic phase was then washed with water, brine, then dried over MgSO4. Filtration and solvent evaporation followed by
MPLC (7% MeOH / methylene chloride) gave 1.95 g (42%) of the desired product. MS m/e 539 (M+H)+, [α]D=-10.6 (c 1.002, methanol). E. (2R)-[4-(tert-butoxy)-2-(3-phenylpropyl)succinyl]-N2-(N1-benzyloxycarbonyl)-piperazic acid N-methyl amide
To the compound of Part D (1.90 g, 3.53 mmol) dissolved in 40 ml methylene chloride, was added, NMM (413 ul). The solution was cooled to -20, followed by addition of IBCF (459 ul, 3.53 mmol). The mixture was allowed to stir for 1.5 h followed by the addition of 0.6 ml of 40% aqueous methyl amine. The cooling bath was removed and the solution was allowed to stir for 1 h at ambient temperature. The reaction was quenched by the addition of 10% citric acid. The organic phase was separated, washed with water, brine and then dried over MgSO4. Filtration and solvent evaporation gave the crude product which was purified by MPLC (75% MeOH / methylene chloride) to give 1.6 g (82%) of product. MS m/e 552 (M+H)+, [α]D=-29.9 (c 0.166, methanol). F. (2R)-[4-hydroxy-2-(3-phenylpropyl)succinyl]-N2-(N1-benzyloxycarbonyl)-piperazic acid N-methyl amide
1.6 g of the compound of Part E was treated with 50 ml of 4N HCl in dioxane for 2h. The solvent was then evaporated under reduced pressure to give the crude acid, which was purified by MPLC (7% MeOH / methylene chloride ramped to 13% MeOH / methylene chloride) . 930 mg (65%) of pure desired product was obtained. MS m/e 496 (M+H)+, [α]D=-34.8 (c 0.118, methanol) G. (2R)-[4-(benzyloxyamino)-2-(3-phenylpropyl)succinyl]-N2-(N1-benzyloxycarbonyl)-piperazic acid N-methyl amide
In a manner analogous to example 1D the title compound was prepared from 930 mg of compound of Example 45a, Part F to give 620 mg (54%) of the desired product. MS m/e 601 (M-CH3)+, [α]D=-30.7 (c 0.114, methanol).
H. (2R)-[4-(hydroxyamino)-2-(3-phenylpropyl)succinyl]-N2-(N1-benzyloxycarbonyl)-piperazic acid N-methyl amide
In a manner analogous to 1E, the title compound was obtained in 80% yield (40 mg). MS m/e 376 (M+H)+, [α]D=
-12.5 (c0.080, methanol), 1HNMR (MeOH - d4) 7.25-7.15
(5H,m), 5.05 (1H, m), 3.9 (1H, m), 2.95 (1H,m), 2.8
(1H,m), 2.76 (3H,s), 2.6 (2H,m), 2.5 (1H, dd), 2.19 (1H, dd), 2.01 (1H,m), 1.95 (1H,m), 1.7-1.4 (6H,m)
Example 205
S-[2S-((ΙR-Carboxy)ethylamino)-4-phenyl)butanoyl]-N2- piperazic acid, N-methyl amide A. S-[2S-(t-butyloxycarbonylamino)-4-phenylbutanoyl]-[N1-benzyloxycarbonyl]-N2-piperazic acid, mono
methylamide The piperazic acid of Procedure 1, part E ( 4.35 g, 16.5 mmol) was dissolved in methylene chloride prior to the addition of Hunig's base (5.7 ml, 33.1 mmol). This mixture was cooled to 0ºC, and the acid fluoride 1 (4.6 g, 16.5 mmol) in methylene chloride at 0ºC was added dropwise. The reaction was warmed to room temperature and was stirred overnight. The reaction was quenched and washed with 10% aqueous citric acid solution. The organic layer was dried, filtered, and concentrated to give the crude acyl hydrazide (8.5 g), which was carried forward. The acyl hydrazide (8.5 g) was dissolved in methylene chloride. At 0ºC, N-methylmorpholine (2.5 ml, 19.9 mmol) was added followed by isobutylchloroformate (2.5 ml, 19.2 mmol). After this mixture was stirred at 0ºC for 30 mm, 40% aqueous methylamine (6.2 g) was added. The mixture was warmed to room temperature and was stirred overnight. The reaction was quenched and washed with saturated NaHCO3 solution. The aqueous layer was dried, filtered, and concentrated. Flash chromatography of the resulting oil gave the desired amide (3.0 g, 5.5 mmol, 33%) as a white foam: MS-CI (m/z) 539 (M+ + 1, 49%).
B. S-[2S-(t-butyloxycarbonylamino)-4-phenylbutanoyl]-N2-piperazic acid, mono methylamide
The amide of Ex. 205, Part A (3.0 g, 5.5 mmol) was dissolved in methanol prior to the addition of 10% Pd/C (310 mg). The mixture was stirred under a hydrogen atmostphere for 3 hrs. The Pd/C was removed by
filtration, and the resulting solution was concentrated. Flash chromatography provided the desired product (1.86 g, 4.6 mmol, 80%) as a white foam: MS-CI (m/z) 405 (M+ + 1, 100%). C. S-[2S-((1R-benzyloxycarbonyl)ethylamino)-4-phenyl)butanoyl]-N2-piperazic acid, N-methyl amide The compound of Ex. 205, Part B (1.3 g, 3.2 mmol) was dissolved in 4M HCl/dioxane (60 ml) and was stirred overnight. The solution was concentrated to a white solid before saturated Na2CO3 was added. This was extracted with methylene chloride. The organic layer was dried, filtered, and concentrated. This yielded the crude primary amine which was used directly in the next step. Thus, a portion of this primary amine 6 (474.5 mg, 1.56 mmol) was dissolved in methylene chloride and cooled to 0 C prior to the addition of Hunig's base (0.35 ml, 2.0 mmol). This mixture was added to the triflate of benzyl lactate 7 [ produced in si tu from benzyl lactate (365.2 mg), 2,6-lutidine (0.3 ml), and Tf2O (0.4 ml)] in methylene chloride at 0°C. The reaction was warmed to room temperature and was stirred overnight. The reaction was quenched with saturated NaHCO3 solution and was extracted with methylene
chloride. The organic layer was dried, filtered, and concentrated. Flash chromatography provided the desired alkylated amine 8 (87.6 mg, 0.2 mmol, 12%) as a white foam: MS-CI (m/z) 467 (M+ + 1, 100%).
D. S-[2S-((1R-Carboxy)ethylamino)-4-phenyl)butanoyl]-N2-piperazic acid, N-methyl amide
The compound of Ex. 205, Part C (72 mg, 0.15 mmol) was dissolved in methanol prior to the addition of 10% Pd/C (10 mg). The mixture was stirred under a hydrogen atmostphere overnight. The Pd/C was removed by
filtration, and the resulting solution was concentrated. Trituration with ether provided 10 (56 mg, 0.15 mmol, 99%) as a white solid: mp 118-120°C; MS-CI (m/z) 377 (M+ + 1, 100%); 1H NMR (DMSO, 300 MHz, d ppm) 8.02 (m, 1H), 7.3-7.15 (m, 5H), 4.92 (m, 2H), 4.18 (t, 1H), 3.12 (m, 1H), 2.95 (br d, 1H), 2.75-2.5 (m, 5H), 2.04 (br d, 1H), 1.85-1.6 (m, 3H), 1.45 (m, 2H), and 1.19 (d, 3H). Using the procedure of Ex. 205, the following compounds were similarly prepared.
Example 215
S-[2S-((1R-Carboxy-2-phenyl)ethylamino)-4- phenyl)butanoyl]-N2-piperazic acid, N-methyl amide mp 209-211°C; MS-CI (m/z) 453 (M+ + 1, 100%); 1H NMR (DMSO, 300 MHz, d ppm) 7.98 (m, 1H), 7.3-7.02 (m, 10H), 4.9 (br d, 1H), 4.8 (br d, 1H), 3.88 (m, 1H), 3.23 (m, 1H), 2.88-2.7 (m, 3H), 2.6 (d, 3H), 2.5 (m, 1H), 2.4 (m,1H), 1.99 (br d, 1H), 1.82-1.6 (m, 2H), and 1.57-1.35 (m, 3H). Example 216
S-[2S-((1R-Carboxy-3-methyl)butylamino)-4- phenyl)butanoyl]-N2-piperazic acid, N-methyl amide mp 96-99°C; MS-CI (m/z) 419 (M+ + 1, 100%); 1H NMR (CD3OD, 300 MHz, d ppm) 7.3-7.15 (m, 5H), 5.06 (m, 1H), 4.85 (t, 1H), 3.55 (t, 1H), 3.0 (br d, 1H), 2.85-2.7 (m, 6H), 2.3-1.76 (m, 6H), 1.6 (m, 3H), and 0.98 (dd, 6H).
Example 217
S-[2S-((1R-Carboxy-2-phenyl)ethylamino)-4- methyl)pentanoyl]-N2-piperazic acid, N-methyl amide mp 179-180°C; MS-CI (m/z) 329 (M+ + 1, 100%); 1H NMR (CD3OD, 300 MHz, d ppm) 5.03 (m, 1H), 4.8 (m, 1H), 3.54 (q, 1H), 3.03 (br 1, 1H), 2.85 (td, 1H), 2.75 (s, 3H), 2.13-1.95 (m, 2H), 1.82-1.52 (m,5H), 1.8 (d, 3H), and 0.98 (app t, 6H).
Example 402
2-[2(R)-[2-[(1,1'-biphenyl)yl]ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine A. 4-[(1,1'-biphenyl)yl]tetrahydrofuran-2-one
To a stirred solution of ethyl 3-iodopropanoate (2.12 g, 9.32 mmol) in anhydrous toluene (15 ml) and freshly distilled N,N-dimethyl acetamide (1.58 ml), was added Zn-Cu complex (0.98 g). The mixture was heated to 80° C for 4h.
To a separate flask containing Ti(OiPr)4 (2.06 ml) in methylene chloride (2 ml), was added dropwise TiCl4 (2.33 ml, 1M soln). The mixture was stirred 15 min then cooled to -40°C. The ZnCu complex above was cooled to room temperature and cannulated into the TiCl2(OiPr)2 solution and the mixture allowed to stir at -20°C for 20 min and then recooled to -40°C. To this was added 4- phenylbenzaldehyde (1.36 g, 7.46 mmol) in methylene chloride (10 ml) dropwise , and the whole was stirred for 15 min at -40°C then allowed to reach room
temperature over 18h. The mixture was then poured into a mixture of 10% HCl and ether and stirred for 10 min. The solution was extracted with ethyl acetate, washed with water, brine, then dried over MgSO4. Following
filtration, the crude material was recrystallized from ethyl acetate/hexane to afford the desired pure product (1.42 g, 80%). MP 103.5-104°C; EIMS (M+H) 239; IR (KBr) 1766 cm-1.
B. 4-(1,1'-biphenyl)ylbutanoic acid
To a solution of the compound of Ex. 328, Part A (1.06 g, 4.5 mmol) in methanol (20 ml) and ethyl acetate (10 ml), was added 10% Pd-C (0.10 g). The mixture was treated with H2 at 1 atm for 1.5 h. The catalyst was removed by filtration and the filtrate evaporated to give the title acid (1.0 g, 94%). MP 119.5-120.5° C;
CIMS (M+NH4 +) 258; IR (KBr) 1696, 3026 cm-1.
C. 3-[4-(1,1'-biphenyl)yl-1-oxobutyl]-4(S)- (phenylmethyl)oxazolidin-2-one The title compound was obtained as an oil in 74% yield using the method described above in Procedure 1, Part A IR (kBr) 3026, 1766, 1696 cm"1; [α]D = +80.3 (c. 0.36, methanol); HRMS calculated 400.191229, found
400.191814.
D. 3-[4(S)-t-butoxycarbonyl-2(R)-[2-[(1,1'-biphenyl)yl]ethyl]-1-oxobutyl]-4(S)-(phenylmethyl)oxazolidin-2-one
To a stirred solution of TiCl4 (1.88 ml, 1 M) in methylene chloride (9 ml) at 0° C, was added Ti(OiPr)4 (0.9 ml) dropwise over 15 min, followed by
diisopropylethylamine (0.44 ml). After an additional 20 min, the compound of Ex. 328, Part C (0.95g, 2.38 mmol) was added in one portion and the resulting mixture was allowed to stir for 1h at 0° C. Tert-butyl acrylate
(0.52 ml, 3.57 mmol) was added, and the cooling bath was removed, followed by stirring at room temperature for 12 h. The reaction was quenched with saturated aqueous ammonium chloride solution; the aqueous layer was separated and extracted with methylene chloride. The combined organics were then washed again with saturated ammonium chloride solution, water and brine. The
solution was dried over anhydrous magnesium sulfate, filtered and evaporated to give a crude oil which was purified by MPLC (25% ethyl acetate/hexane) to provde tghe Michael addition product as an oil (0.886 g). IR (KBr) 3060, 3028, 1780, 1726, 1694 cm-1; [α]D = +62.3 (c. 0.32, methanol); HRMS calculated 528.274999, found
528.274957.
E. 4(S)-t-butoxycarbonyl-2(R)-[2-[(1,1'-biphenyl)yl]-ethyl]butanoic acid
To a solution of the compound of Ex. 328, Part D (5.71 g, 10.8 mmol) in THF (67 ml) and water (17 ml) cooled to
0° C was added a mixture of 30% H2O2 (8.8 ml) and lithium hydroxide (43.3 mmol). The solution was evaporated after 1.5 h, and the resulting material acidified with 10% citric acid. The organic material was extracted with ethyl acetate, washed with water and brine and dried over anhydrous magnesium sulfate. Filtration and removal of solvent gave a slurry containing 4(S)-phenylmethyloxazolidin-2-one and crude product. Addition of ether and a seed crystal of 4(S)- (phenylmethyl)oxazolidinone followed by cooling to -20, gave a solid precipitate which was removed by
filtration. The product was further purified by
conversion to its dicyclohexylamine salt and
recrystallization from ether. The salt was then treated with 5% KHSO4 to give the acid as a crystalline product that could be used without further purification in the next step.
F. 4(S)-t-butoxycarbonyl-4-butyl-2(R)-[2-[(1,1'-biphenyl)yl]ethyl]butanoic acid
To a stirred, cooled (-78° C) solution of the compund of Ex. 328, Part E (1.01 g, 2.73 mmol) in THF (20 ml)/DMPU(5 ml), was added LDA (5.46 ml, 1 M soln) over 10 min. Following the addition, the solution was allowed to stir for 1 h at -40° C. Butyl iodide (0.31 ml, 2.73 mmol) was added, and the solution allowed to gradually reach room temp over 12 h. The crude material was then poured into 10% citric acid and extracted with ethyl acetate. The combined organics were washed with water, brine and then dried over anhydrous magnesium sulfate. Filtration and removal of the solvent in vacuo gave the desired product as 4:1 mixture of diastereomers which could be separated directly by HPLC on silica gel or alternately, by conversion to the benzyl ester and MPLC purification as described in WO94/12169. [α]D = + 20 (c. 0.20, methanol); IR (kBr) 3028, 1726, 1602; HRMS calculated 425.269185, found 425.269228. G. 2-[2(R)-[2-[(1,1'-biphenyl)yl]ethyl]-4(S)-t-butoxycarbonyl-4-butyl-1-oxobutyl]-hexahydropyridazine
To a stirred, cooled (-20° C; CCI4/CO2) solution of the compound of Ex. 328, Part F, (0.297 grams) and pyridine (56mL) in anhydrous methylene chloride (5 mL) was added cyanuric fluoride (0.19 g) over one minute. The reaction was stirred 1.5 hours at -20°, filtered and washed with ice water. The aqueous was extracted 2X with methylene chloride. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure affording a clear oil (0.301 g). 1H NMR in CDCI3 was consistent with a clean conversion to the acid fluoride which was carried on without further characterization or purification. The acid fluoride thus obtained was dissolved in anhydrous methylene chloride (1 mL) and added to a previously mixed solution of piperazic acid (0.185 g) and diisopropylethylamine (0.24 mL) in
anhydrous methylene chloride (5 mL). The reaction was allowed to stir at room temperature overnight. The reaction was poured into 10% aqueous citric acid and extracted three times with methylene chloride. The combined organic phases were washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and solvent was removed under reduced
pressure. The resulting material was purified via preparative layer chromatography (EM plates, 1mm silica gel with 0.25mm concentration zone) eluting 2X with 2% MeOH in CHCl3 to afford the desired product as an oil (0.060 mg). HRMS calculated 671.369628, found
671.368562, IR (KBr) 3062, 3030, 1724, 1674 cm-1.
H. 2-[2(R)-[2-[(1,1'-biphenyl)yl]ethyl]-4(S)-t-butoxycarbonyl-4-butyl-1-oxobutyl]-3-(methylaminocarbonyl)hexahydropyridazine
To a stirred, cooled (-20 °C) solution of the compound of Ex. 328, Part G (0.059 g) in anhydrous THF (2 mL) was added N-methylmorpholine (10 mL) followed in 15 minutes by isobutylchloroformate (12 mL). The reaction was stirred 35 minutes at -20° C at which time a 40 % aqueous solution of monomethylamine (31 mL) was added. The reaction was stirred 45 minutes at room temperature and then the volatile components were removed under reduced pressure. The residue was taken up in ethyl acetate, washed with 10% aqueous citric acid, water, saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure affording the N-methyl amide (0.050 g). HRMS calculated 684.401262, found
684.399793. I. 2-[2(R)-[2-[(1,1'-biphenyl)yl]ethyl]-4-butyl-4(S)-carboxy-1-oxobutyl]-3(S)-methylaminocarbonylhexahydropyridazine
Trifluoroacetic acid (2 mL) was added to the amide of Ex. 328, Part H ( 0.050 g), and the reaction was stirred for 1 hour at room temperature at which time the volatiles were removed under reduced pressure affording free acid (0.040 g) which was used without further purification.
To a stirred solution of the crude acid (0.039 g) in methanol (2 mL) was added 10 % palladium on carbon
(10-15 mg). The mixture was stirred for one hour undera atm hydrogen (at which time it was filtered and the volatiles were removed under reduced pressure. The residue was chromatographed on 1mm EM preprative chromatography plates with a 0.25 mm concentration zone eluting 2 times in 7.5 % MeOH in CHCl3 to provide the title compound (0.019 grams). HRMS calculated
494.301882, found 494.300034. Using the above-described techniques or variations thereon appreciated by those of skill in the art of chemical synthesis, the compounds of Tables 1-3 (shown below) can also be prepared.
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
UTILITY
The compounds of formula I possess matrix
metalloproteinase and/or TNF inhibitory activity. The MMP-3 inhibitory activity of the compounds of the present invention is demonstrated using assays of MMP-3 activity, for example, using the assay described below for assaying inhibitors of MMP-3 activity. The
compounds of the present invention are bioavailable in vivo as demonstrated, for example, using the ex vivo assay described below. The compounds of formula I have the ability to suppress/inhibit cartilage degradation in vivo, for example, as demonstrated using the animal model of acute cartilage degradation described below.
The compounds provided by this invention are also useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit MMP-3. These would be provided in commercial kits comprising a compound of this invention.
Matrixmetalloproteinases have also been implicated in the degradation of basement membrances to allow infiltration of cancer cells into the circulation and subsequent penetration into other tissues leading to tumor metastasis. (Stetler-Stevenson, Cancer and
Metastasis Reviews, 9, 289-303, 1990.) The compounds of the present invention should be useful for the
prevention and treatment of invasive tumors by
inhibition of this aspect of metastasis.
The compounds of the present invention would also have utility for the prevention and treatment of
osteopenia associated with matrixmetalloproteinase-mediated breakdown of cartilage and bone which occurs in osteoporosis patients.
Compounds which inhibit the production or action of TΝF and/or MMP's are potentially useful for the
treatment or prophylaxis of various inflammatory, infectious, immunological or malignant diseases. These include, but are not limited to inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, an acute infection, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, crohn's disease,
mycobacterial infection, meningitis, psoriasis,
periodontits, gingivitis, congestive heart failure, fibrotic disease, cachexia, and aneroxia, graft
rejection, cancer, corneal ulceration or tumor invasion by secondary metastases, autoimmune disease, osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, and hyperoxic alveolar injury.
The compounds of the present invention have been shown to inhibit TNF production in lipopolysacharride stimulated mice, for example, using the assay for TNF Induction in Mice described below.
As used herein "μg" denotes microgram, "mg" denotes milligram, "g" denotes gram, "μL" denotes microliter, "mL" denotes milliliter, "L" denotes liter, "nM" denotes nanomolar, "μM" denotes micromolar, "mM" denotes millimolar, "M" denotes molar and "nm" denotes
nanometer. "Sigma" stands for the Sigma-Aldrich Corp. of St. Louis, MO.
A compound is considered to be active if it has an IC50 or Ki value of less than about 1 mM for the
inhibition of MMP-3.
Bisacetylated Substance P / MMP-3 fluorescent assay
A high capacity enzymatic assay was developed to detect potential inhibitors of MMP-3. The assay uses a derivative of a peptide substrate, substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met), which is cleaved by MMP-3 exclusively at the glutamine-phenylalanine bond. In order to adapt this assay for high throughput screening, we have developed a fluorimetric method of product detection. The production of the hydrolysis product, substance P 7-11, is measured by reaction with fluorescamine, a fluorogenic compound which reacts with the primary amine of this fragment. The substance P substrate is bisacetylated to block the primary amines of the intact substrate. Thus, the resulting
fluorescence represents generation of product (7-11 peptide) formed upon cleavage by MMP-3, and is
quantitated using a standard curve prepared with known concentrations of 7-11 peptide. Kinetic studies using the bisacetylated substrate yield the following
parameters for MMP-3: Km =769 +/- 52 uM; Vmax = 0.090 +/- 0.003 nmoles 7-11 peptide/min.
To evaluate inhibition of MMP-3, compounds were prepared at a concentration of 10 mM in 100% methanol, and then further diluted to a 20X molar stock. Five microliters of each drug stock was added to the assay in the presence of 20 nM truncated MMP-3 in 67.5 mM tricine (pH 7.5), 10 mM CaCl2, 40 mM NaCl, and 0.005% Brij 35 in a final volume of 100 microliters. Bisacetylated substance P (1000 mM) was added, and the assay was run for 1 hour at 25ºC. The reaction was quenched with EDTA (20 mM) and product was detected fluorometrically following addition of fluorescamine (0.075 mg/ml).
Fluorescence of each sample was converted to an amount of product formed using a substance P 7-11 standard curve. Under these conditions, the assay is linear with respect to MMP-3 amount up to 10 pmoles. Inhibition of MMP-3 was determined by comparing the amount of product generated in the presence and absence of compound.
Activities of representative compounds of the invention in the above assay are shown in Table A below. The Ki values are indicated as follows: +++ = <50 nM; ++ = 50 nM to 100 nM; + = >100nM.
Table A
Ex. No. Ki
73 ++
1E ++ 2 +++
45a +
4 +++
205 +
215 +
216 +
217 +
218 ++
219 ++
402 ++
Ex vivo assay for bioavailability of MMP-3 inhibitors
Blood was collected by cardiac puncture from rats at different times after dosing I.V., I.P., or P.O. with compound in order to determine the levels of inhibitor present. Plasma was extracted with 10% TCA in 95% methanol, and placed on ice for 10 minutes. The plasma was then centrifuged for 15 minutes at 14,000 rpm in an Eppendorf microcentrifuge. The supernatant was removed, recentrifuged, and the resulting supernatant was diluted 1:10 in 50 mM tricine, pH 8.5. The pH of the sample was adjusted to 7.5, and then assayed in the MMP-3 substance P fluorescent enzymatic assay. Plasma from naive rats was extracted by the same method and used as a negative control. This plasma was also used to prepare a spiked plasma curve of the compound of interest . Known
concentrations of the compound were added to control plasma, the plasma was extracted by the same method, and then assayed in the MMP-3 enzymatic assay. A standard curve was prepared that related percent inhbition in the MMP-3 assay to the concentration of drug added in the spiked samples. Based on the percent inhibition in the presence of plasma from dosed rats, the concentration of compound was determined using the standard curve.
Table B shows the results of dosing of representative compounds of the invention orally in rats at 100 mg/kg. Table B
Ex. No. Cmax (μg/ml)
73 3.2
1E 1.8
4 1.7
Acute Cartilage Degradation Rat Model
An in vivo model of acute cartilage degradation in rats has been characterized as a method to determine the proteoglycan content in the synovial fluid after the induction of cartilage degradation. Experimental groups exhibit increased levels of proteoglycan content in their synovial fluid versus control rats. The criteria to demonstrate a compound's activity in this model, is the ability to inhibit the demonstration of cartilage degradation, as measured by increased proteoglycan content in the synovial fluid of rats after compound administration. Indomethacin, a non-steroidal anti-inflammatory drug is inactive in this model.
Indomethacin administration does not inhibit the
demonstration of cartilage degradation in experimental animals. In contrast, administration of a compound of this invention significantly inhibited the demonstration of cartilage degradation in this model. TNF Induction In Mice
Test compounds are administered to mice either I.P. or P.O. at time zero. Immediately following compound administration, mice receive an I.P. injection of 20 mg of D-galactosamine plus 10 μg of lipopolysaccharide. One hour later, animals are anesthetized and bled by cardiac puncture. Blood plasma is evaluated for TNF levels by an ELISA specific for mouse TNF.
Administration of representative compounds of the present invention to mice results in a dose-dependent suppression of plasma TNF levels at one hour in the above assay. Dosage and Formulation
The compounds of the present invention can be administered orally using any pharmaceutically
acceptable dosage form known in the art for such administration. The active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions. The active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier. A valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.
The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an antiinflammatory and antiarthritic agent.
The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action, MMP-3, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with
pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard
pharmaceutical practice.
The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of
administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent
treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the
condition.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70 kg of body weight, this translates into a dosage of 70 to 1400 mg/day.
Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be
administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as
cholesterol, stearylamine, or phosphatidylcholines .
Compounds of the present invention may also be coupled with soluble polymers as targetable drug
carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon
caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of
hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch,
cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium
bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain
preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules
Capsules are prepared by conventional procedures so that the dosage unit is 500 milligrams of active
ingredient, 100 milligrams of cellulose and 10
milligrams of magnesium stearate.
A large number of unit capsules may also prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Syrup
Wt. %
Active Ingredient 10
Liquid Sugar 50
Sorbitol 20
Glycerine 5
Flavor, Colorant and as required
Preservative
Water as required
The final volume is brought up to 100% by the addition of distilled water.
Aqueous Suspension
Wt. %
Active Ingredient 10 Sodium Saccharin 0.01
Keltrol® (Food Grade Xanthan Gum) 0.2 Liquid Sugar 5
Flavor, Colorant and as required
Preservative
Water as required
Xanthan gum is slowly added into distilled water before adding the active ingredient and the rest of the formulation ingredients. The final suspension is passed through a homogenizer to assure the elegance of the final products.
Resuspendable Powder
Wt. %
Active Ingredient 50.0
Lactose 35.0
Sugar 10.0 Acacia 4.7
Sodium Carboxylmethylcellulose 0.3 Each ingredient is finely pulverized and then uniformly mixed together. Alternatively, the powder can be prepared as a suspension and then spray dried.
Semi-Solid Gel
Wt. %
Active Ingredient 10
Sodium Saccharin 0.02
Gelatin 2
Flavor, Colorant and as required
Preservative
Water as required
Gelatin is prepared in hot water. The finely pulverized active ingredient is suspended in the gelatin solution and then the rest of the ingredients are mixed in. The suspension is filled into a suitable packaging container and cooled down to form the gel.
Semi-Solid Paste
Wt. %
Active Ingredient 10
Gelcarin® (Carrageenin gum) 1
Sodium Saccharin 0.01
Gelatin 2
Flavor, Colorant and as required
Preservative
Water as required
Gelcarin® is dissolved in hot water (around 80°C) and then the fine-powder active ingredient is suspended in this solution. Sodium saccharin and the rest of the formulation ingredients are added to the suspension while it is still warm. The suspension is homogenized and then filled into suitable containers. Emulsifiable Paste
Wt. %
Active Ingredient 30
Tween® 80 and Span® 80 6
Keltrol® 0.5
Mineral Oil 63.5 All the ingredients are carefully mixed together to make a homogenous paste.
Soft Gelatin Capsules
A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive
displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active
ingredient. The capsules are washed and dried.
Tablets
Tablets may be prepared by conventional procedures so that the dosage unit is 500 milligrams of active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose and 10 milligrams of magnesium stearate.
A large number of tablets may also be prepared by conventional procedures so that the dosage unit was 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase
palatability or delay absorption. Injectable
A parenteral composition suitable for
administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume
propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized. Suspension
An aqueous suspension is prepared for oral
administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 mL of vanillin.
The compounds of the present invention may be administered in combination with a second therapeutic agent, especially non-steroidal anti-inflammatory drugs (NSAID's). The compound of Formula I and such second therapeutic agent can be administered separately or as a physical combination in a single dosage unit, in any dosage form and by various routes of administration, as described above.
The compound of Formula I may be formulated together with the second therapeutic agent in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.). When the compound of Formula I and the second therapeutic agent are not formulated together in a single dosage unit, the compound of Formula I and the second therapeutic agent may be administered essentially at the same time, or in any order; for example the compound of Formula I may be administered first, followed by administration of the second agent. When not administered at the same time, preferably the administration of the compound of Formula I and the second therapeutic agent occurs less than about one hour apart, more preferably less than about 5 to 30 minutes apart.
Preferably the route of administration of the compound of Formula I is oral. Although it is
preferable that the compound of Formula I and the second therapeutic agent are both administered by the same route (that is, for example, both orally), if desired, they may each be administered by different routes and in different dosage forms (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously).
The dosage of the compound of Formula I when administered alone or in combination with a second therapeutic agent may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of
administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of
treatment, and the effect desired, as described above. Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active
ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of
hydroxypropyl methylcellulose (HPMC) or other
appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to
interaction with the other component.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of osteoarthritis or rheumatoid arthritis, which
comprise one or more containers containing a
pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.
In the present disclosure it should be understood that the specified materials and conditions are
important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the
invention from being realized.
The term "consisting essentially of" where used in the present disclosure is intended to have its customary meaning; namely, that all specified materials and conditions are very important in practicing the
invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.
The foregoing disclosure includes all the
information deemed essential to enable those of skill in the art to practice the claimed invention. Because the cited references may provide further useful information, however, these cited materials are hereby incorporated by reference.
Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.
Various equivalents, changes and modifications may be made without departing from the spirit and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Claims

What is claimed: 1. A method of treating osteoarthritis or rheumatoid arthritis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I:
Figure imgf000132_0001
or pharmaceutically acceptable salts or prodrug forms thereof, wherein:
A is selected from -N(R8)CH(R9)CO2H or
-CH(R11)C(R9a) (R9)CO2H, -C (R1)(R1a)CONHOH; Q is selected from:
a C5-C14 carbocyclic ring system substituted with 0-4 groups selected from R5, R6, R18 or
-C(=O)R3, or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-4 groups selected from R5, R6, R8, R19 or -C(=O)R3;
R1 is selected from:
H, halogen
C1-C10 alkyl substituted with 0-3 R4,
C2-C10 alkenyl substituted with 0-3 R4,
C2-C10 alkynyl substituted with 0-3 R4, C6-C10 aryl,
C3-C6 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or
pyridazinyl, pyrrolidinyl, triazolidinyl, oxadiazolidinyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R1a is selected from H, R1, NR10R10a, OR17 or S(O)mR17
Alternately R1 and R1a can be taken together to form a 3-7 membered carbocyclic or a 5-7 membered, saturated heterocyclic ring, said heterocyclic ring containing 1-2 heteroatoms selected from N, O, and S, and optionally substituted at carbon with keto;
R2 is selected from:
C2-C10 alkyl substituted with 0-3 R17b,
(-CH2)nO-(C1-C8 alkyl)-R20, or
(-CH2)nS-(C1-C8 alkyl) -R20,
-(CH2)nOR20,
-(CH2)nSR20,
-(CH2)nS-(C1-C6) alkyl, or
-(CH2)nO-(C1-C6) alkyl; n=O-8 R3 is selected from: OR11, NHCH(R12)COR13,
NHCH(R12)COOR11, NHCH (R12 ) CONR14R15, NR10R10a;
R4 is selected from:
-OR17a, -SOmR17a, -CO2R12, -CONR10R10a,
-NR8R10, -NHC(=NR8)N(R8)R10,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18, C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R18; m=0-2; R4a is selected from:
-OR17, -SOmR17, -CO2R12, -CONR10R10a,
C1-C4 alkyl,
aryl substituted with 0-5 R18,
C1-C4 alkylcarbonyl,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R5 and R6 are independently selected from:
hydrogen,
hydroxy,
C1-C6 alkyl substituted with 0-3 R20,
phenyl, C7-C14 arylalkyl,
C7-C14 arylalkoxy,
C1-C4 alkylcarbonyl,
C7-C14 arylalkoxycarbonyl,
C1-C4 alkoxy, -NR14R15, -COOR11,
C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13, C1-C4 alkylaminocarbonyl, -C(=NOH)R14,
=0, =S, or a ketal or thioketal form thereof when R5 or R6 are attached to a saturated carbon atom, or = 0 when R5 or R6 is attached to sulfur;
R5 and R6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered carbocyclic or heterocyclic ring, wherein said heterocyclic ring contains one or two N, O or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R18;
R8 is a substituent on nitrogen and is selected from hydrogen,
C1-C6 alkyl substituted with 0-3 R20,
C1-C6-alkylcarbonyl,
alkoxycarbonyl,
arylalkoxycarbonyl,
alkylaminocarbonyl,
arylsulfonyl,
heteroarylalkoxycarbonyl,
cycloalkoxycarbonyl,
heteroarylsulfonyl,
alkyesulfonyl,
cycloalkylsulfonyl,
R9 is selected from:
H,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a; R9a is selected from H, OR17, SR17 or NR10 R10a,
Alternately R9 and R9a can be taken together to form a 3-7 membered carbocyclic or heterocyclic ring, said heterocyclic ring containing 1-2 heteroatoms selected from N, O or S, optionally substituted on carbon with keto; R10 is selected from:
hydrogen,
C1-C4 alkoxy,
C1-C6 alkyl substituted with 0-4 R4 or
C1-C6 alkylcarbonyl;
R10a is selected from hydrogen or C1-C4 alkyl;
R10 and R10a can alternatively join to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R16)CH2CH2-, or -CH2CH2OCH2CH2-;
R11, is H, benzyl, or C1-C4 alkyl;
R12 is selected from:
H,
C1-C4 alkyl substituted with 0-3 R4,
C2-C4 alkenyl substituted with 0-3 R4,
C2-C4 alkynyl substituted with 0-3 R4;
R13 is C1-C4 alkyl;
R14 and R15 are independently selected from H or C1-C4 alkyl;
R16 is hydrogen or methyl;
R17 is selected from:
hydrogen, C1-C6 alkyl substituted with 0-3 R17A
C1-C6 alkylcarbonyl substituted with 0-3 R17A, C1-C6 alkoxycarbonyl substituted with 0-3 R17A, phenoxycarbonyl substituted with 0-3 R18;
R17a is selected from:
H,
C1-C4 alkyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R17b is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; R18, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, phenyl, optionally substituted with halogen, C1-C4 alkyl, C1-cyalkoxy, hydroxy, or -NR10R10a, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused
5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a, =O or =S when attached to a saturated carbon atom, or =O when attached to sulfur;
R18, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl; R19, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R19 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy,
-NR10R10a;
R19, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl; and R20 is selected from:
aryl substituted with 0-5 R18,
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
2 . A compound of Formula II :
Figure imgf000140_0001
or pharmaceutically acceptable salts or prodrug forms thereof, wherein:
Q is selected from:
a C5-C14 carbocyclic ring system substituted with 0-4 groups selected from R5, R6, R18 or
-C(=O)R3, or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-4 groups selected from R5, R6, R8, R19 or -C(=O)R3; R1 is selected from:
H, halogen
C1-C10 alkyl substituted with 0-3 R4,
C2-C10 alkenyl substituted with 0-3 R4,
C2-C10 alkynyl substituted with 0-3 R4,
C6-C10 aryl,
C3-C6 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R1a is selected from H, NR10R10a, OR17 or S(O)mR17
Alternately R1 and R1a can be taken together to form a
3-7 membered carbocyclic or heterocyclic ring, said heterocyclic ring containing 1-2 hetero-atoms selected from N, O, and S;
R2 is selected from:
C2-C10 alkyl substituted with 0-3 R17b,
(-CH2)nO-(C1-C8 alkyl)-R20, or
(-CH2)nS-(C1-C8 alkyl)-R20,
-(CH2)nOR20,
-(CH2)nSR20,
-(CH2)nS-(C1-C6) alkyl, or
-(CH2)nO-(C1-C6) alkyl; n=0-6
R3 is -NR10R10a
R4 is selected from:
OR17, SOmR17, -CO2R12, -CONR10R10a,
-NR8R10, -NHC(=NR8)N(R8)R10,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; m=0-2;
R5 and R6 are independently selected from:
hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 R20, phenyl, C7-C14 arylalkyl, C7-C14 arylalkoxy, C1-C4 alkylcarbonyl, C7-C14 arylalkoxycarbonyl, C1-C4 alkoxy, -NR14R15, -COOR11, C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13, C1-C4 alkylaminocarbonyl,
-C(=NOH)R14;
R5 and R6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains one to two N, O, or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R18;
R8 is a substituent on nitrogen and is selected from hydrogen,
C1-C6 alkyl substituted with 0-3 R20,
C1-C6-alkylcarbonyl,
alkoxycarbonyl,
arylalkoxycarbonyl,
arylsulfonyl,
heteroarylsulfonyl,
cycloakoxycarbonyl,
keteroarylalkoxycarbonyl,
alkylsulfonyl, or
cycloalkylsulfonyl;
R10 is selected from:
hydrogen,
C1-C4 alkoxy,
C1-C6 alkyl substituted with 0-4 R4;
R10a is selected from hydrogen or C1-C4 alkyl;
R10 and R10a can alternatively join to form -(CH2)4-,
-(CH2)5-, -CH2CH2N(R16)CH2CH2-, or -CH2CH2OCH2CH2-;
R11, is H, benzyl, or C1-C4 alkyl;
R12 is selected from:
H,
C1-C4 alkyl substituted with 0-3 R4,
C2-C4 alkenyl substituted with 0-3 R4,
C2-C4 alkynyl substituted with 0-3 R4;
R13 is C1-C4 alkyl; R14 and R15 are independently selected from H or C1-C4 alkyl; R16 is hydrogen or methyl;
R17 is selected from:
hydrogen,
C1-C6 alkyl substituted with 0-3 R17A
C1-C6 alkylcarbonyl substituted with 0-3 R17A, C1-C6 alkoxycarbonyl substituted with 0-3 R17A, phenoxycarbonyl substituted with 0-3 R18;
R17a is selected from:
H,
C1-C4 alkyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R17b is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl,
pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R18, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, phenyl, optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy or NR10R10a, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a =0 or =S when attached to a saturated carbon atom, or =O when attached to sulfur;
R18, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;
R19, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R19 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused
5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a;
R19, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;
R20 is selected from:
aryl substituted with 0-5 R18,
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; with the following proviso:
when R1 and R1a are both hydrogen and Q is
Figure imgf000147_0001
then R2 is not hydrogen, C3-C10 alkyl or (C1-C4 alkyl)aryl.
3. A compound of Claim 2 wherein:
Q is a 5-7 membered saturated heterocyclic ring system containing at least one nitrogen and optionally containing an additional heteroatom selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-4 groups selected from R5, R6, R8, R19 or -C(=O)R3; R1 is selected from:
H,
C1-C4 alkyl substituted with 0-3 R4;
R2 is selected from:
C2-C4 alkyl substituted with 0-3 R17b,
-O-(C1-C6 alkyl)-R20,
-S-(C1-C6 alkyl)-R20.
-CH2O-(C1-C5 alkyl)-R20, or
-CH2S-(C1-C5 alkyl)-R20;
R8 is hydrogen;
R10 is selected from:
hydrogen,
C1-C6 alkyl substituted with 0-4 R4;
4. A compound of Claim 3 wherein:
Q is a heterocycle selected from hexahydro-1- pyridazinyl, 2-tetrahydro-1,2-oxazinyl, 1- morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1- piperazinyl, 4-methylpiperazinyl, tetrahydro-1,4- thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl-1-oxide, tetrahydro-1,4-thiazin-4-yl-1,1-dioxide, 1-oxa-2- piperidinyl, said heterocycle being substituted with 0-3 groups selected from -C(=O)R3, R5, R6, or R8.
5. A compound of claim 4 wherein:
Q is
;
Figure imgf000149_0001
Z is N or O;
R5 is selected from:
hydrogen, phenyl, C7-C14 arylalkyl, C7-C14
arylalkoxy, C1-C4 alkylcarbonyl, or C7-C14 arylalkoxycarbonyl; and
R6 is hydrogen; with the proviso that R8 is absent when Z is O. 6. A compound of Claim 2 selected from the group consisting of:
[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]- N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-benzylsuccinyl]- N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S- methoxyphenylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S- methoxybenzylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide, [4-(N-hydroxyamino)-2R-isobutyl-3S- methylthiophenylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S- methylthiobenzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-(methylthio-2- thienyl)succinyl]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl acetate]- N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl
isopropanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl
thioacetate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl
thioisopropanoate]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-(2- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-(3- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-(4- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl thio- tert-butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methylsuccinyl]-N2- (S)-piperazic acid-N-methyl amide, [4-(N-hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S- methoxyphenylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S- methoxybenzylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S- methylthiophenylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S- methylthiobenzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-(methylthio-2- thienyl)succinyl]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl acetate]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl
isopropanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl
thioacetate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl
thioisopropanoate]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl thio-tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide, [4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(2- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(3- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(4- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- methylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- benzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- methoxyphenylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- methoxybenzylsuccinyl]-N2-(S)-piperazic acid- N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- methylthiophenylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- methylthiobenzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S-(methylthio- 2-thienyl)succinyl]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S- benzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl
acetate]-N2-(S)-piperazic acid-N-methyl amide, [4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl isopropanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl
thioacetate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-ethyIphenyl-3S-methyl
thioisopropanoate]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl thio- tert-butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methylsuccinyl]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S- methylthiophenylsuccinyl] -N2- (S) -piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S- methylthiobenzylsuccinyl]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-(methylthio-2- thienyl)succinyl]-N1-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl acetate]-N2- (S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl
isopropanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl
thioacetate]-N2-(S)-piperazic acid-N-methyl amide, [4-(N-hydroxyamino)-2R-octyl-3S-methyl
thioisopropanoate]-N2-(S)-piperazic acid-N- methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl thio-tert- butanoate]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl-(2- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl-(3- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-octyl-3S-methyl-(4- pyridyl)]-N2-(S)-piperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl] N2-(S)-4'(S/R)-benzylpiperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl] N2-(S)-5'(S/R)-benzylpiperazic acid-N-methyl amide,
[4 -(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl] N2-(S)-6'(S/R)-benzylpiperazic acid-N-methyl amide,
[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl] N2-(S)-[5',
6']benzopiperazic acid-N-methyl amide,
7. A compound of formula III:
Figure imgf000154_0001
or pharmaceutically acceptable salts or prodrug forms thereof, wherein: Q is selected from:
a C5-C14 carbocyclic ring system substituted with 0-4 groups selected from R5, R6, R18 or
-C(=O)R3, or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-4 groups selected from R5, R6, R8, R19 or -C(=O)R3;
R2 is selected from
C1-C8 alkyl substituted with 0-3 R17b,
C1-C8 alkenyl substituted with 0-3 R17b,
C1-C8 alkynyl substituted with 0-3 R17b,
-(CH2)n-O-(C1-C8 alkyl),
-(CH2)n-S-(C1-C8 alkyl),
-(CH2)nO-(C1-C8 alkylene) -R20,
(CH2)nS(C1-C8 alkylene) -R20
-(CH2)nOR20, or
-CH2)nSR20 n=1-8
R3 is NR10R10a;
R4 is selected from:
-OR17, -SOmR17, -CO2R12, -CONR10R10a,
-NR8R10, -NHC(=NR8)N(R8)R10,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl , pyridinyl , morpholinyl , furyl , thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, said heterocyclic ring system being substituted with 0-2 R19; m= 0-2;
R4a is selected from:
-OR17, -SOmR17, -CO2R12, -CONR10R10a,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, .oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R5 and R6 are independently selected from:
hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 R20, phenyl, C7-C14 arylalkyl, C7-C14 arylalkoxy, C1-C4 alkylcarbonyl, C7-C14 arylalkoxycarbonyl, C1-C4 alkoxy, -NR14R15, -COOR11, C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13, C1-C4 alkylaminocarbonyl, -C(=NOH)R14, =O, =S, or a ketal or thioketal form thereof when R5 or R6 are attached to a saturated carbon atom, or = 0 when R5 or R6 is attached to sulfur; R5 and R6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered
carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains one or two N, O or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R18; R8 is a substituent on nitrogen and is selected from hydrogen,
C1-C6 alkyl substituted with 0-3 R20,
C1-C6-alkylcarbonyl,
alkoxycarbonyl,
arylalkoxycarbonyl,
alkylaminocarbonyl,
arylsulfonyl,
neteroarylsulfonyl,
cycloakoxycarbonyl,
keteroarylalkoxycarbonyl,
alkylsulfonyl, or
cycloalkylsulfonyl;
R9 is selected from:
H,
C1-C5 alkyl substituted with 0-3 R4a,
C2-C5 alkenyl substituted with 0-3 R4a,
C2-C5 alkynyl substituted with 0-3 R4a; R10 is selected from:
hydrogen,
C1-C4 alkoxy,
C1-C6 alkyl substituted with 0-4 R4; R10a is selected from hydrogen or C1-C4 alkyl;
R10 and R10a can alternatively join to form -(CH2)4-,
-(CH2)5-. -CH2CH2N(R16)CH2CH2-, or -CH2CH2OCH2CH2-; R11, is H, benzyl, or C1-C4 alkyl;
R12 is selected from: H,
C1-C8 alkyl substituted with 0-3 R4,
C2-C8 alkenyl substituted with 0-3 R4,
C2-C8 alkynyl substituted with 0-3 R4; R13 is C1-C4 alkyl;
R14 and R15 are independently selected from H or C1-C4 alkyl;
R16 is hydrogen or methyl;
R17 is selected from:
hydrogen,
C1-C6 alkyl substituted with 0-3 R17A
C1-C6 alkylcarbonyl substituted with 0-3 R17A, C1-C6 alkoxycarbonyl substituted with 0-3 R17A, phenoxycarbonyl substituted with 0-3 R18; R17a is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; R17b is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R18, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, phenyl, optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy or NR10R10a;
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a, =0 or =S when attached to a saturated carbon atom, or =O when attached to sulfur;
R18, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;
R19, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide,
C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R19 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy,
-NR10R10a; or,
R19, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;
R20 is selected from:
aryl substituted with 0-5 R18,
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
8. A compound of Claim 7 wherein:
Q is a heterocycle selected from hexahydro-1- pyridazinyl, 2-tetrahydro-1,2-oxazinyl, 1- morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1- piperazinyl, 4-methylpiperazinyl, tetrahydro-1,4- thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl-1-oxide, tetrahydro-1,4-thiazin-4-yl-1,1-dioxide, said heterocycle being substituted with 0-3 groups selected from -C(=O)R3, R5, R6, or R8; R2 is selected from
C2-C4 alkyl substituted with 0-3 R17b
-(CH2)nO-(C1-C5 alkyl) -R20, or
-(CH2)nS-(C1-C5 alkyl) -R20; n= 1-5;
R8 is hydrogen;
R9 is selected from:
hydrogen,
C1-C5 alkyl substituted with 0-3 R4a;
9. A compound of Claim 7 wherein: Q is
Figure imgf000162_0001
Z is N or O; with the proviso that R8 is absent when Z is O.
10. A compound of Claim 7 selected from the group consisting of:
N-[1(R)-carboxy-ethyl]-α-(S)-isobutylglycine-(S)- N2-piperazic acid methyl amide,
N-[1(R)-carboxy-ethyl]-α-(S)-hexylglycine-(S)-N2- piperazic acid methyl amide, N-[1(R)-carboxy-ethyl]-α-(S)-heptylglycine-(S)-N2- piperazic acid methyl amide,
N-[1(R)-carboxy-ethyl]-α-(S)-octylglycine-(S)-N2- piperazic acid methyl amide,
N-[1(R)-carboxy-ethyl]-α-(S)-ethylphenylglycine- (S)-N2-piperazic acid methyl amide, N-[1(R)-carboxy-ethyl]-α-(S)-propylphenylglycine- (S)-N2-piperazic acid methyl amide, N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)- isobutylglycine-(S)-N2-piperazic acid methyl amide,
N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)- hexylglycine-(S)-N2-piperazic acid methyl amide,
N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)-ethylphenyl- glycine-(S)-N2-piperazic acid methyl amide, N-[1(R)-carboxy-ethylthiobenzyl]-α-(S)- propylphenyl-glycine-(S)-N2-piperazic acid methyl amide.
N-[1(R)-carboxy-ethyloxybenzyl]-α-(S)- isobutylglycine-(S)-N2-piperazic acid methyl amide,
N-[1(R)-carboxy-ethyloxybenzyl]-α-(S)-hexylglycine- (S)-N2-piperazic acid methyl amide, N-[1(R)-carboxy-ethyloxybenzyl]-α-(S)-ethylphenyl- glycine-(S)-N2-piperazic acid methyl amide, N-[1(R)-carboxy-ethyloxybenzyl]-α-(S)-propylphenyl- glycine-(S)-N2-piperazic acid methyl amide, N-[1(R)-carboxy-4-(p-toluenesulfonyl)butyl]-α-(S)- phenethylglycyl-(S)-N2-piperazic acid methyl amide, or
N-[1(R)-carboxyethyl]-α-[2-(4-phenylphenoxy)ethyl]- glycyl-(S)-N2-piperazic acid methyl amide.
11. A compound of the formula IV:
Figure imgf000164_0001
or pharmaceutically acceptable salts or prodrug forms thereof, wherein:
Q is selected from:
a C5-C14 carbocyclic ring system substituted with 0-4 groups selected from R5, R6, R18 or
-C(=O)R3, or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-4 groups selected from R5, R6, R8, R19 or -C(=O)R3;
R2 is selected from
C1-C6 alkyl substituted with 0-3 R17b,
-(CH2)n-O-(C1-C8 alkyl),
-(CH2)n-S-(C1-C8 alkyl),
-(CH2)nO-(C1-C8 alkylene) -R20,
(CH2)nS(C1-C8 alkylene) -R20
-(CH2)nOR20, or
-CH2)nSR20 n=0-8
R3 is NR10R10a;
R4 is selected from:
-OR17, -SOmR17, -CO2R12, -CONR10R10a,
-NR8R10, -NHC(=NR8)N(R8)R10,
C1-C4 alkyl, C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, said heterocyclic ring system being substituted with 0-2 R19; R4a is selected from:
-OR17, -SOmR17, -CO2R12, -CONR10R10a,
C1-C4 alkyl,
C1-C4 alkylcarbonyl,
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R5 and R6 are independently selected from:
hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 R20, phenyl, C7-C14 arylalkyl, C7-C14 arylalkoxy, C1-C4 alkylcarbonyl, C7-C14 arylalkoxycarbonyl, C1-C4 alkoxy, -NR14R15, -COOR11, C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13, C1-C4 alkylaminocarbonyl,
-C(=NOH)R14, =0, =S, or a ketal or thioketal form thereof when R5 or R6 are attached to a saturated carbon atom, or = 0 when R5 or R6 is attached to sulfur;
R5 and R6 when attached to adjacent atoms on the ring can alternately join to form a 5-7 membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring contains one or two N, O or S atoms, said carbocyclic or heterocyclic ring being substituted with 0-2 R18;
R8 is a substituent on nitrogen and is selected from hydrogen,
C1-C6 alkyl substituted with 0-3 R20,
C1-C6-alkylcarbonyl,
alkoxycarbonyl,
arylalkoxycarbonyl,
alkylaminocarbonyl,
arylsulfonyl,
heteroarylsulfonyl,
cycloakoxycarbonyl,
keteroarylalkoxycarbonyl,
alkylsulfonyl, or
cycloalkylsulfonyl; R9 is selected from:
H,
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 alkynyl substituted with 0-3 R4a;
R9a is selected from H, OR17, NR10R10a or S(O)nR17,
Alternately R9 and R9a can be taken together to form a 3-7 membered carbocyclic or heterocyclic ring said heterocyclic ring containing 1-2 heteroatoms selected from N, O or S; R10 is selected from:
hydrogen,
C1-C4 alkoxy,
C1-C6 alkyl substituted with 0-4 R4;
R10a is selected from hydrogen or C1-C4 alkyl;
R10 and R10a can alternatively join to form -(CH2)4-,
-(CH2)5-, -CH2CH2N(R16)CH2CH2-, or rCH2CH2OCH2CH2-;
R11, is H, benzyl, or C1-C4 alkyl;
R12 is selected from:
H,
C1-C8 alkyl substituted with 0-3 R4,
C2-C8 alkenyl substituted with 0-3 R4,
C2-C8 alkynyl substituted with 0-3 R4;
R13 is C1-C4 alkyl;
R14 and R15 are independently selected from H or C1-C4 alkyl;
R16 is hydrogen or methyl;
R17 is selected from:
hydrogen,
C1-C6 alkyl substituted with 0-3 R17A
C1-C6 alkylcarbonyl substituted with 0-3 R17A, C1-C6 alkoxycarbonyl substituted with 0-3 R17A, phenoxycarbonyl substituted with 0-3 R18;
R17a is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl,
thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R17b is selected from:
aryl substituted with 0-5 R18,
C3-C8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
R18, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, phenyl, optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy or NR10R10a; a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a, =0 or =S when attached to a saturated carbon atom, or =O when attached to sulfur;
R18, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl,
-CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl; R19, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a,
-NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19; or R19 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused
5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a; or,
R19, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl,
-CH2NR10R10a, -NR10R10a, C2-C6 alkoxyalkyl, C1- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1- C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl; R20 is selected from:
aryl substituted with 0-5 R18,
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl,
isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R19;
12. A compound of Claim 11 wherein:
Q is a heterocycle selected from hexahydro-1- pyridazinyl, 2-tetrahydro-1,2-oxazinyl, 1- morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1- piperazinyl, 4-methylpiperazinyl, tetrahydro-1,4- thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl-1-oxide, tetrahydro-1,4-thiazin-4-yl-1,1-dioxide, said heterocycle being substituted with 0-3 groups selected from -C(=O)R3, R5, R6, or R8;
R2 is selected from
C2-C4 alkyl substituted with 0-3 R17b
-(CH2)nO-(C1-C5 alkyl)-R20, or
-(CH2)nS-(C1-C5 alkyl)-R20; n= 0-6; R8 is hydrogen;
R9 is selected from:
hydrogen,
C1-C4 alkyl substituted with 0-3 R4a;
13. A compound of Claim 11 wherein:
Q is
Figure imgf000172_0001
Z is N or O;
14. A compound of Claim 11 selected from the group consisting of:
2-[2(R)-[2-[(1,1'-biphenyl)yl]ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[(1,1'-biphenyl)yl]ethyl]-4-methyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[(1,1'-biphenyl)yl]propyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-(4-propylphenyl)ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-(4-butylphenyl)ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-(4-t-butyIphenyl)ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[4-(4-fluorophenyl)phenyl]ethyl]-4- butyl-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[4-(4-fluorophenyl)phenyl]ethyl]-4- methyl-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-2-n-octyl-4-methyl-4(S)-carboxy-1- oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine . 2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-butyl- 4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-methyl- 4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-[3- (phenylsulfonyl)propyl-4(S)-carboxy-1- oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[(4-thiazolyl)phenyl]ethyl]-4-(3- phenylpropyl)-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-butyl-4(S)- carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-methyl- 4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-[3- (phenylsulfonyl)propyl-4(S)-carboxy-1- oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine,
2-[2(R)-[2-[(4-oxazolyl)phenyl]ethyl]-4-(3- phenylpropyl)-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[4-(dimethylamino)methylphenyl]ethyl]-4- butyl-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[4-(dimethylamino)methyIphenyl]ethyl]-4- methyl-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[4-(dimethylamino)methyIphenyl]ethyl]-4- [3-(phenylsulfonyl)propyl-4(S)-carboxy-1- oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine, 2-[2(R)-[2-[4-(dimethylamino)methyIphenyl]ethyl]-4- (3-phenylpropyl)-4(S)-carboxy-1-oxobutyl]- 3(S)-methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-imidazolyl)phenyl]ethyl]-4-butyl- 4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-imidazolyl)phenyl]ethyl]-4-methyl- 4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine, 2-[2(R)-[2-[(4-imidazolyl)phenyl]ethyl]-4-[3- (phenylsulfonyl)propyl-4(S)-carboxy-1- oxobutyl]-3(S)-methylaminocarbonyl- hexahydropyridazine, and
2-[2(R)-[2-[(4-imidazolyl)phenyl]ethyl]-4-(3- phenylpropyl)-4(S)-carboxy-1-oxobutyl]-3(S)- methylaminocarbonyl-hexahydropyridazine.
15. A method of treating osteoarthritis or rheumatoid arthritis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula IIa:
Figure imgf000174_0001
wherein:
R2 is selected from:
H,
C3-C10 alkyl, or
aryl-(C1-C4 alkyl)-; R3 is selected from OR11, NHCH(R12)COR13, NR10R10a, NHCH(R12)COOR11, or NHCH(R12)CONR14R15;
R10 and R10a are each independently selected from
hydrogen, C1-C4 alkyl, or C1-C4 alkoxy;
R11, R12, and R15 are each independently selected from hydrogen or C1-C4 alkyl; R13 and R14 are C1-C4 alkyl.
16. A pharmacetucal composition comprising a compound of any one of Claims 2 through 14 and a pharmaceutical acceptable carrier.
17. A method of treating diseases mediated by maxtrix metallproteinase and/or tumor necrosis factor in a mammal comprising administering to the mammal an effective amount of a compound of any one of Claims 2 through 14.
18. A method of Claim 17 wherein the disease is one mediated by matrix metalloproteinase.
19. A method of Claim 17 wherein the disease is selected from rheumatoid arthritis, osteoarthritis, periodonitis, gingivitis, corneal ulceration or tumor invasion by secondary metastases.
20. A method of Claim 17 wherein the disease is one mediated by tumor necrosis faxtor.
21. A method of Claim 17 wherein the disease is selected from inflammation, fever, cardiovascular effects, hemmorrhage, coagulation and acute phase response, cachexia and anorexia, an acute infection, a shock state, a graft versus host reaction or autoimmune disease.
PCT/US1995/005012 1994-04-28 1995-04-27 Hydroxamic acid and amino acid derivatives and their use as anti-arthritic agents WO1995029892A1 (en)

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US6683093B2 (en) 2000-05-12 2004-01-27 Pharmacia Corporation Aromatic sulfone hydroxamic acids and their use as protease inhibitors
US6683078B2 (en) 2001-07-19 2004-01-27 Pharmacia Corporation Use of sulfonyl aryl or heteroaryl hydroxamic acids and derivatives thereof as aggrecanase inhibitors
US6689794B2 (en) 2001-05-11 2004-02-10 Pharmacia Corporation Aromatic sulfone hydroxamates and their use as protease inhibitors
US6696456B1 (en) 1999-10-14 2004-02-24 The Procter & Gamble Company Beta disubstituted metalloprotease inhibitors
US6696449B2 (en) 1997-03-04 2004-02-24 Pharmacia Corporation Sulfonyl aryl hydroxamates and their use as matrix metalloprotease inhibitors
US6747027B1 (en) 1996-07-22 2004-06-08 Pharmacia Corporation Thiol sulfonamide metalloprotease inhibitors
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US6800646B1 (en) 1999-02-08 2004-10-05 Pharmacia Corporation Sulfamato hydroxamic acid metalloprotease inhibitor
US6852751B2 (en) 2000-03-21 2005-02-08 The Procter & Gamble Company Difluorobutyric acid metalloprotease inhibitors
US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6869951B1 (en) 1999-07-16 2005-03-22 Pharmacia Corporation Method of changing conformation of a matrix metalloproteinase
US6890937B2 (en) 1997-11-14 2005-05-10 Pharmacia Corporation Aromatic sulfone hydroxamic acid metalloprotease inhibitor
US6949545B2 (en) 2000-03-21 2005-09-27 The Procter & Gamble Company Heterocyclic side chain containing, n-substituted metalloprotease inhibitors
US7115632B1 (en) 1999-05-12 2006-10-03 G. D. Searle & Co. Sulfonyl aryl or heteroaryl hydroxamic acid compounds
US7119203B2 (en) 2002-04-25 2006-10-10 Pharmacia Corporation Piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors
JP2007503422A (en) * 2003-08-23 2007-02-22 ヴァーナリス（オックスフォード）リミテッド Hydroxamic acid derivatives as metalloproteinase inhibitors
JP2008507575A (en) * 2004-07-26 2008-03-13 アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ N-hydroxyamide derivatives and uses thereof
US7524938B2 (en) 2003-04-04 2009-04-28 Yeda Research And Development Co., Ltd. Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins
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US5985911A (en) * 1997-01-07 1999-11-16 Abbott Laboratories C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion
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