WO1995029892A1 - Derives d'acides hydroxamiques et d'acides amines et leur utilisation comme agents antiarthritiques - Google Patents

Derives d'acides hydroxamiques et d'acides amines et leur utilisation comme agents antiarthritiques 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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English (en)
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/fr

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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
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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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    • 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
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    • C07D213/78—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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    • 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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    • 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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    • C07D235/02—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
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    • 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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    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
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    • 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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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

Cette invention se rapporte à une classe de nouveaux acides hydroxamiques et de nouveaux acides carbocycliques, ainsi qu'à des dérivés de ces acides, lesquels inhibent la stromélysine et sont par conséquent utiles pour traiter l'arthrite. La classe des composés utiles dans ce procédé de traitement est représentée par la formule (I).
PCT/US1995/005012 1994-04-28 1995-04-27 Derives d'acides hydroxamiques et d'acides amines et leur utilisation comme agents antiarthritiques WO1995029892A1 (fr)

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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
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US6489349B1 (en) 1996-04-23 2002-12-03 Targacept, Inc. Pharmaceutical compositions for inhibition of cytokine production and secretion
US6747027B1 (en) 1996-07-22 2004-06-08 Pharmacia Corporation Thiol sulfonamide metalloprotease inhibitors
EP0927168B1 (fr) * 1996-08-28 2002-11-06 The Procter & Gamble Company Inhibiteurs 1,3-diheterocycliques de metalloproteases
US5952320A (en) * 1997-01-07 1999-09-14 Abbott Laboratories Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion
US5985911A (en) * 1997-01-07 1999-11-16 Abbott Laboratories C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion
WO1998033788A1 (fr) * 1997-01-31 1998-08-06 Pharmacia & Upjohn S.P.A. Inhibiteurs de metalloproteinases matricielles
US6194451B1 (en) 1997-01-31 2001-02-27 Pharmacia & Upjohn S.P.A. Matrix metalloproteinase inhibitors
US6716844B2 (en) 1997-03-04 2004-04-06 Pharmacia Corporation Aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds
US6794511B2 (en) 1997-03-04 2004-09-21 G. D. Searle Sulfonyl aryl or heteroaryl hydroxamic acid compounds
US6696449B2 (en) 1997-03-04 2004-02-24 Pharmacia Corporation Sulfonyl aryl hydroxamates and their use as matrix metalloprotease inhibitors
US6362183B1 (en) 1997-03-04 2002-03-26 G. D. Searle & Company Aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds
US6476027B1 (en) 1997-03-04 2002-11-05 Monsanto Company N-hydroxy 4-sulfonyl butanamide compounds
US6656954B2 (en) 1997-03-04 2003-12-02 Pharmacia Corporation Sulfonyl divalent aryl or heteroaryl hydroxamic acid compounds
US6638952B1 (en) 1997-03-04 2003-10-28 Pharmacia Corporation Aromatic sulfonyl alpha-cycloamino hydroxamic acid compounds
US5962471A (en) * 1997-05-13 1999-10-05 Hoechst Aktiengesellschaft Substituted 6- and 7-aminotetrahydroisoquinolinecarboxylic acids
EP0878467A1 (fr) * 1997-05-13 1998-11-18 Hoechst Aktiengesellschaft Acids 6- et 7-aminotetrahydroisoquinolinecarboxyliques substitués
US6890937B2 (en) 1997-11-14 2005-05-10 Pharmacia Corporation Aromatic sulfone hydroxamic acid metalloprotease inhibitor
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