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    • 专利摘要:
    PURPOSE: Novel -sulfonyl hydroxamic acids, pharmaceutical compositions containing them, and a method of using them are provided. CONSTITUTION: A compound of formula (I), or pharmaceutical acceptable salts thereof is provided wherein R1 is C4-12 alkyl, C4-12 alkenyl, C4-12 alkynyl, -(CH2)h-C3-8 cycloalkyl, -(CH2)h-aryl or -(CH2)h-het; R2 is C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, -(CH2)h-C3-8 cycloalkyl, -(CH2)h-C3-8 cycloalkenyl, -(CH2)h-aryl, -(CH2)h-het, -(CH2)h-Q, -(CH2)i-X-R4 or -(CH2)iCHR5R6. The compounds are inhibitors of matrix metalloproteinases involved in tissue degradation.
    公开号:KR20000048639A
    申请号:KR1019990702581
    申请日:1997-09-19
    公开日:2000-07-25
    发明作者:마싸 에이. 워페호스키；도널드 이. 하퍼
    申请人:로렌스 티. 마이젠헬더；파마시아 앤드 업존 캄파니；
    IPC主号:
    专利说明:

    Beta-Sulfonyl Hydroxamic Acids As Matrix Metalloproteinases Inhibitors
    Many diseases including osteoarthritis, rheumatoid arthritis, plaque arthritis, osteopenia, such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulcer, skin ulcer, gastric ulcer, inflammation, asthma and other connective tissue degeneration related diseases In the process, the loss of connective tissue itself occurs. In developed countries, the prevalence of these diseases is high, but there is no cure to prevent the development of tissue damage. There is a great deal of scientific evidence indicating that uncontrolled binding matrix metalloproteinase (MMPs) activity causes damage, and as a result, inhibition of these enzymes has been the target of therapeutic intervention (Matricians, L.M. (Matrisian, LM), Bases, Volume 14, pp 445-463 (1992), Emonard, H. et al., Cellular and molecular Biology, 36, pp 131-153 (1990). And Dockerty, AJP et al., Annals of the Rheumatic, Vol. 49, pp 469-479 (1990).
    Hydroxamic acid derivatives are a class of known therapeutically active MMPs inhibitors and numerous literatures in the art disclose various hydroxamic acid derivatives. For example, European Patent Publication No. 0,606,046 A1 discloses arylsulfonamido-substituted hydroxamic acids useful as matrix metalloproteinase inhibitors. WO 95/35275 and WO 95/35276 disclose sulfonamide hydroxamic acid and carboxylic acid derivatives useful as matrix metalloproteinase inhibitors. All of these references relate to sulfonamide hydroxamic acid. The compounds of the present invention are novel and distinguish from all other sulfonamide hydroxamic acids in that they replace ordinary nitrogen atoms with carbon atoms. The present invention provides sulfonyl hydroxamic acid derivatives.
    The compounds of the present invention inhibit various enzymes of the matrix metalloproteinase family, mainly stromelysin and gelatinases, and thus, osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulcers, skin ulcers, gastric ulcers It is useful in the treatment of matrix metallo endoproteinase diseases such as, inflammation, asthma and other connective tissue degeneration related diseases.
    The following documents disclose sulfonyl hydroxamic acid derivatives.
    WO 95/09841 discloses hydroxamic acid compounds useful as inhibitors of TNF and matrix metalloproteinases.
    WO 93/20047 discloses hydroxamic acid compounds useful as producers of tumor necrosis factor and inhibitors of matrix metalloproteinases.
    WO 90/05719 discloses hydroxamic acid compounds useful for the management of diseases including tissue degeneration and / or for promoting wound healing.
    The hydroxamic acid compounds of these documents have essential peptide backbones. The compounds of the present invention are distinguished from these documents in that they do not have a peptide backbone.
    European patent application EP 0780 386 A1 discloses matrix metalloproteinase inhibitors useful for the treatment of mammals in disease states that are alleviated by inhibition of matrix metalloproteinases.
    WO 97/24117 discloses substituted aryl, heteroaryl, particularly useful for inhibiting the production or physiological action of TNF in the treatment of patients suffering from physiologically harmful excessive tumor necrosis factor (TNF) related disease states. Arylmethyl or heteroarylmethyl hydroxamic acid compounds are disclosed.
    <Overview of invention>
    The present invention provides novel compounds of formula (I) or pharmaceutically acceptable salts thereof.
    Where
    R 1 is a) C 4-12 alkyl,
    b) C 4-12 alkenyl,
    c) C 4-12 alkynyl,
    d)-(CH 2 ) h -C 3-8 cycloalkyl,
    e)-(CH 2 ) h -aryl,
    f)-(CH 2 ) h -aryl substituted with C 1-4 alkyl, C 1-4 alkoxy, halo, —NO 2 , —CF 3 , —CN or —N (C 1-4 alkyl) 2 ,
    g)-(CH 2 ) h -het, or
    h) — (CH 2 ) h -hets substituted with C 1-4 alkyl or halo;
    R 2 is a) C 1-12 alkyl,
    b) C 1-12 alkyl substituted with 1 to 3 of halo, —CN, —NO 2 , —CF 3 , —N (R 3 ) 2 , —SR 3 or OH,
    c) C 2-12 alkenyl,
    d) C 2-12 alkenyl substituted with one to three of halo, —CN, —NO 2 or —CF 3 ,
    e) C 2-12 alkynyl,
    f) C 2-12 alkynyl substituted with 1 to 3 of halo, —CN, —NO 2 or —CF 3 ,
    g)-(CH 2 ) h -C 3-8 cycloalkyl,
    h) — (CH 2 ) h —C 3-8 cycloalkyl substituted with one to three of C 1-4 alkyl, C 1-4 alkoxy or halo,
    i)-(CH 2 ) h -C 3-8 cycloalkenyl,
    j) — (CH 2 ) h —C 3-8 cycloalkenyl substituted with one to three of C 1-4 alkyl, C 1-4 alkoxy or halo,
    k)-(CH 2 ) h -aryl,
    l) C 1-4 alkyl, C 1-4 alkoxy, -CF 3 , -OH, -NO 2 , -CN, -N (R 3 ) 2 , -SR 3 , -SO 2 (C 1-4 alkoxy) -(CH 2 ) h -aryl substituted with 1 to 3 of -C (= 0) R 3 or -NC (= 0) R 3 ,
    m)-(CH 2 ) h -aryl substituted with 1 to 5 halo,
    n)-(CH 2 ) h -het,
    o)-(CH 2 ) h -hets substituted with 1 or 2 of C 1-4 alkyl or halo,
    p)-(CH 2 ) h -Q,
    q)-(CH 2 ) h -Q substituted with 1 to 3 of C 1-4 alkyl, C 1-4 alkoxy, halo or phenyl,
    r)-(CH 2 ) i -the chain may be optionally substituted with C 1-4 alkyl or phenyl, which in turn may be substituted with 1 to 3 of halo or C 1-4 alkyl-(CH 2 ) i- XR 4 , or
    s)-(CH 2 ) i CHR 5 R 6 ;
    R 3 is a) H,
    b) C 1-4 alkyl,
    c)-(CH 2 ) h -phenyl, or
    d)-(CH 2 ) h -phenyl substituted with 1 to 3 of C 1-4 alkyl, C 1-4 alkoxy or halo;
    X is a) -O-,
    b) -S (= O) j- ,
    c) -NR 7- ,
    d) -S (= 0) 2 NR 8- , or
    e) -C (= 0)-;
    R 4 is a) H,
    b) C 1-4 alkyl,
    c)-(CH 2 ) h -phenyl,
    d)-(CH 2 ) h -phenyl substituted with 1 to 3 of C 1-4 alkyl, C 1-4 alkoxy, halo, —NO 2 or —CN, or
    e)-(CH 2 ) h -het;
    R 5 is a) C 1-4 alkyl, or
    b) -C (= 0) R 3 ;
    R 6 is a) -C (= 0) R 3 , or
    b) — (CH 2 ) h C (═O) R 3 ;
    R 7 is a) H,
    b) C 1-4 alkyl,
    c)-(CH 2 ) h -phenyl,
    d)-(CH 2 ) h -phenyl substituted with 1 to 3 of C 1-4 alkyl, C 1-4 alkoxy or halo,
    e) -C (= 0) -R 3 ,
    f) -S (= 0) 2 R 3 , or
    g) -C (= 0) OR 3 ;
    R 8 is a) C 1-4 alkyl,
    b)-(CH 2 ) h -phenyl, or
    c)-(CH 2 ) h -phenyl substituted with 1 to 3 of C 1-4 alkyl, C 1-4 alkoxy or halo;
    Aryl is a mono- or di-carbon aromatic moiety;
    Het is a 5-10 membered unsaturated heterocyclic moiety having 1 to 3 atoms selected from the group consisting of oxygen, nitrogen and sulfur;
    Q is a 5-10 membered saturated heterocyclic moiety having 1 or 2 atoms selected from the group consisting of oxygen, nitrogen and sulfur;
    h is 0, 1, 2, 3, 4, 5 or 6;
    i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
    j is 0, 1 or 2.
    The compounds of the present invention are useful for the treatment of matrix metallo endoproteinase diseases by inhibiting various enzymes of the matrix metalloproteinase family, mainly stromelysin and gelatinase.
    The present invention relates to novel β-sulfonyl hydroxamic acids, pharmaceutical compositions containing them and methods of using them. Compounds of the invention are inhibitors of matrix metalloproteinases involved in tissue degeneration.
    For the purposes of the present invention, the carbon content of various hydrocarbon containing moieties is represented by a prefix indicating the minimum and maximum number of carbon atoms in the moieties, ie the prefix C ij is an integer "i" to an integer "j" (both positive numbers) Defines the number of carbon atoms of Thus, C 1-4 alkyl represents alkyl of 1 to 4 (both positive) and carbon, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
    The terms "C 1-4 alkyl", "C 4-8 alkyl", "C 1-12 alkyl" and "C 1-18 alkyl" each represent 1 to 4, 4 to 8, 1 to 12, or Alkyl groups having 1 to 18 carbon atoms; For example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and their isomeric forms, preferably the alkyl group of R 1 Has 1 to 8 carbon atoms and the alkyl group of R 2 has 1 to 8 carbon atoms.
    The terms "C 2-12 alkenyl" and "C 4-8 alkenyl" refer to alkenyl groups of at least one double bond each having 2 to 12 carbon atoms; For example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, heptdienyl, octenyl, octadienyl, octatrienyl, nonenyl, undecenyl, dodecenyl and isomers thereof Form, preferably the alkenyl group of R 1 has 4 to 8 carbon atoms, and the alkenyl group of R 2 has 2 to 8 carbon atoms.
    The term "C 2-12 alkynyl" refers to an alkynyl group of at least one triple bond having 2 to 12 carbon atoms; For example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, octadinyl, octatriinyl, noninyl, nonenedinyl and their isomeric forms, preferably The alkynyl group of R 1 has 4 to 8 carbon atoms and the alkynyl group of R 2 has 2 to 8 carbon atoms.
    The term “C 3-8 cycloalkyl” refers to cycloalkyl having 3 to 8 carbon atoms; For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and isomeric forms thereof are preferred, and cycloalkyl groups have 3 to 6 carbon atoms.
    The term “C 3-8 cycloalkenyl” refers to cycloalkenyl having 3 to 8 carbon atoms; For example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctetyl, and their isomeric forms, preferably cycloalkenyl groups have 5 or 6 carbon atoms .
    The terms "C 1-4 alkoxy", "C 1-6 alkoxy" and "C 1-8 alkoxy" refer to 1 to 4, 1 to 6, or 1 to 8, respectively, attached to the oxygen atom of the hydroxyl group Alkyl group having 2 carbon atoms; For example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms are shown.
    The term "aryl" refers to a monocyclic or bicyclic aromatic moiety; For example, phenyl, naphthyl or biphenyl. Each of these residues may be appropriately substituted. Aryl is preferably phenyl or C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, bromo, —NO 2 , —CF 3 , —N (C 1-4 alkyl) 2 , —C ( Phenyl substituted with ═O) R 3 or —NC (═O) R 3 .
    The term "het" refers to a 5-10 membered unsaturated heterocyclic moiety having one or more atoms selected from the group consisting of oxygen, nitrogen and sulfur; For example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3 -Pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl , 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2 Indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole, Benzoisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrole Rollyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 1-fury Nil, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, preferably pyridyl, quinolinyl, pyrrolyl, thienyl, thiazolyl or indolyl. Each of these moieties may be optionally substituted with one or two of C 1-4 alkyl, —NO 2 , fluoro, chloro or bromo.
    The term "Q" refers to a 5-10 membered saturated heterocyclic moiety having 1 or 2 atoms selected from the group consisting of oxygen, nitrogen and sulfur; For example, piperidinyl, 2-, 3- or 4-piperidinyl, [1,4] piperazinyl, morpholinyl, 2- or 3-morpholinyl, thiomorpholinyl, dioxolanyl , Imidazolidinyl, [1,3] oxathiolanyl, [1,3] oxazolidinyl, pyrrolidinyl, butyrolactonyl, butyrolactamyl, succinimidyl, glutarimidyl, valero Lactamil, 2,5-dioxo- [1,4] -piperazinyl, pyrazolidinyl, 3-oxopyrazolidinyl, 2-oxo-imidazolidinyl, 2,4-dioxo-imidazoli Diyl, 2-oxo- [1,3] -oxazolidinyl, 2,5-dioxo- [1,3] -oxazolidinyl, isoxazolidinyl, 3-oxo-isoxazolidinyl, [1, 3] -thiazolidinyl, 2- or 4-oxo- [1,3] -thiazolidinyl, preferably, butyrolactamyl, succinimidyl, glutarimidyl, valerolactam, 2,5 -Dioxo- [1,4] -piperazinyl, 3-oxopyrazolidinyl, 2-oxo-imidazolidinyl, 2,4-dioxo-imidazolidinyl, 2-oxo- [1,3 ] -Oxazolidinyl, 2,5-dioxo -[1,3] -oxazolidinyl, 3-oxo-isoxazolidinyl, 2- or 4-oxo- [1,3] -thiazolidinyl.
    The term halo represents fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.
    The compounds of the present invention can be appropriately converted to their salts according to conventional methods.
    The term "pharmaceutically acceptable salts" refers to acid addition salts useful for the administration of the compounds of the invention, including hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, Maleate, malate, succinate, tartarate, citrate, 2-hydroxyethyl sulfonate and fumarate, and the like. These salts may be present in hydrated form. Some of the compounds of the present invention may form metal salts such as sodium salts, potassium salts, calcium salts and magnesium salts, which are included within the term “pharmaceutically acceptable salts”.
    The compounds of formula (I) of the present invention have a chiral center at the α-position of hydroxamic acid, and as such there are two enantiomers or racemic mixtures of both. The present invention relates to a mixture comprising both isomers as well as both isomers. In addition, depending on the substituents, there may be additional isomeric centers and other isomeric forms in any of the R 2 groups, and the present invention includes all possible stereoisomers and geometric isoforms in these groups.
    R 1 is preferably n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, phenyl, 4-methylphenyl, 4-ethylphenyl, 4-tert-butylphenyl, 4-isopropylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4 -Ethoxyphenyl, 4-n-butyloxyphenyl, benzyl, 4-phenylbenzyl, 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-chlorobenzyl, 2-, 3- or 4 Bromobenzyl, and 4-ethoxybenzyl. More preferably, R 1 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, phenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-butoxyphenyl, benzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-ethoxybenzyl.
    R 2 is preferably methyl, 1-cyano-1-phenyl methyl, 2-cyano ethyl, 2-phenylethyl, 2-bromo-2-phenylethyl, 2-bromoethyl, propyl, isopropyl, 3-chloropropyl, 3-bromopropyl, n-butyl, isobutyl, 3-methylbutyl, 1-methylpropyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, n-hexadecyl, n-octadecyl, 2-propenyl, 2-propynyl, 3-butenyl, 4-pentenyl, 3-buteninyl, 4-penteninyl, cyclopentyl, cyclo Hexyl, cyclohexylmethyl, 2-cyclohexylethyl, 4-cyclohexylbutyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, phenylaminomethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-bromo Phenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-nitrophenyl, 4-ethoxyphenyl, benzyl, 4-methylbenzyl, 2-fluorobenzyl , 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl Jill, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-ethoxybenzyl, 4-nitrobenzyl , Methylcarbonyl, 1-methylcarbonyl methyl, 2-phenylcarbonyl ethyl, isopropylcarbonyl, methoxycarbonyl, ethoxycarbonyl, 1,1-ethoxycarbonyl methyl, 2,2-ethoxy Carbonyl ethyl, 1,2-ethoxycarbonyl ethyl, 2-methoxycarbonyl propyl, 3-methoxycarbonyl propyl, 1-ethoxycarbonyl methyl, 1-ethoxycarbonyl ethyl, phenylcarbonyl, Phenylcarbonyl methyl, pyridylcarbonyl methyl, pyridylmethyl, pyridylethyl, quinolinylmethyl, pyrrolyl methyl, indolyl methyl, thienyl, thiazolyl, thiethylmethyl, thienylethyl, piperidinyl methyl , Piperazinyl methyl, morpholino methyl, morpholino ethyl, morpholino propyl, thiomorpholino methyl, thiomorpholino propyl, 4-methoxybenzenesulfonyl meth , 3- (4-methoxybenzenesulfonyl) amino propyl, 3- (4-methoxybenzenesulfonyl) propyl, 3-hydroxy, amino, 3-phenoxy propyl, 2-phenyl ethyloxy, (4- Butoxybenzenesulfonyl) methyl, methyl-3- (1,5,5-trimethylhydantoin), methyl-3- (1-butyl-5,5-dimethylhydantoin), (4-methoxybenzenesulfonyl ) Methyl, (4-chlorobenzenesulfonyl) methyl, (4-bromobenzenesulfonyl) methyl, (n-butylsulfonyl) methyl, (n-octylsulfonyl) methyl, 3- (4-methoxybenzene Sulfonyl) propyl, (4-methylbenzenesulfonyl) methyl, (benzenesulfonyl) methyl, methyl-3- (1-methylhydantoin), methyl-3- (1-butylhydantoin) and methyl-3- (5,5-dimethylhydantoin). More preferably, R 2 is (4-methoxybenzenesulfonyl) methyl, (4-chlorobenzenesulfonyl) methyl, (4-bromobenzenesulfonyl) methyl, (n-butylsulfonyl) methyl, ( n-octylsulfonyl) methyl, 3- (4-methoxybenzenesulfonyl) propyl, (4-methylbenzenesulfonyl) methyl, (benzenesulfonyl) methyl, methyl-3- (1-methylhydantoin), Methyl-3- (1-butylhydantoin) and methyl-3- (5,5-dimethylhydantoin).
    Particularly preferred compounds of the present invention are the following compounds:
    (1) N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -3-phenyl-propionamide,
    (2) N-hydroxy-2-[(benzenesulfonyl) methyl] -3-phenyl-propionamide,
    (3) N-hydroxy-2-[(benzenesulfonyl) methyl] -propionamide,
    (4) N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (5) N-hydroxy-2-[(4-chlorobenzenesulfonyl) methyl] -3- (4-chlorobenzenesulfonyl) -propionamide,
    (6) N-hydroxy-2-[(4-bromobenzenesulfonyl) methyl] -3- (4-bromobenzenesulfonyl) -propionamide,
    (7) N-hydroxy-2-[(n-butylsulfonyl) methyl] -3- (n-butylsulfonyl) -propionamide,
    (8) N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (n-octylsulfonyl) -propionamide,
    (9) N-hydroxy-2-[(4-methylbenzenesulfonyl) methyl] -3- (4-methylbenzenesulfonyl) -propionamide,
    (10) N-hydroxy-2-[(benzenesulfonyl) methyl] -3- (benzenesulfonyl) -propionamide,
    (11) N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanamide,
    (12) N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (13) N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (14) N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide,
    (15) N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (16) N-hydroxy-2- [methyl-3- (5,5-dimethylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (17) (+)-N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (18) (-)-N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (19) (+)-N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (20) (-)-N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (21) (+)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide,
    (22) (-)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide,
    (23) (+)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (24) (-)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (25) (+)-N-hydroxy-2- [methyl-3- (5,5-dimethylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide, or
    (26) (-)-N-hydroxy-2- [methyl-3- (5,5-dimethylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide.
    The compound of the present invention can be prepared according to the following method.
    In Scheme I, R 1 and R 2 are the groups as defined above. Substituted malonic esters (2) can be purchased or readily prepared from compounds (1) by methods known to those skilled in the art. For example, the enolate (1) produced by the appropriate base in a suitable solvent is reacted with an alkylating agent R 2 -I (where I is bromo, chloro, tosylate, mesylate, epoxide, etc.) to the desired substitution Malonic acid ester (2). Organic Synthesis, Vol. 1, p 250 (1954); Organic Synthesis, Vol. 3, p 495 (1955). Compound (2) is hydrolyzed to monoacid compound (3) by reacting with a suitable base equivalent of alkali base, such as alkali hydroxide, in a suitable solvent at a temperature between 0 ° C and 30 ° C. Compound (3) is converted to acrylic ester (4) in the presence of formaldehyde and piperidine in suitable solvents such as pyridine, ethanol and dioxane at reflux temperature. In many cases, acrylic esters (4) are commercially available. Thiol (H-SR 1 ) is added to acrylic ester (4) at room temperature in the presence of an alkoxide in a catalytic amount of alcohol solvent or a tertiary amine base in chloroform to give sulfide ester (5). The resulting sulfide (5) is easily oxidized to sulfone (6) by an oxidizing agent such as meta-chloroperbenzoic acid (MCPBA) in a suitable solvent such as methylene chloride or using hydrogen peroxide in acetic acid as a solvent. The ester can be hydrolyzed by procedures known in the art such as using reflux with 6N HCl for 10-20 hours or using iodotrimethylsilane in chloroform to give the free acid (7). The reaction of combining acid (7) with hydroxylamine hydrochloride to form hydroxysamate (9) can be accomplished by several routes known to those skilled in the art. For example, the acid (7) can be activated by chloroethylformate in anhydrous THF or similar compatible solvent, or by a carbodiimide condensing agent such as EDC in the presence or absence of HOBT in DMF and methylene chloride. . In both cases tertiary amines are required. The activated acid (7) is then reacted with hydroxylamine to give the desired hydroxylsamic acid derivative. Alternatively, the acid (7) is condensed with benzyl-protected hydroxylamine hydrochloride using a reagent as described above to produce the protected hydroxylate (8). Compound (8) is often easier to purify and can be readily hydrolytically cleaved into free hydroxamate (9) by a palladium catalyst in alcoholic solvent. Other protected hydroxylamines, such as tert-butyl hydroxylamine, can also be used, which can be treated with trifluoroacetic acid to give free hydroxylates.
    In a second method of preparing the compounds of the present invention, commercially available acrylic acid (10) is used as shown in Scheme II. Acrylic acid is treated with thiol to give compound (11). This reaction can be carried out while refluxing a suitable solvent such as dioxane with piperidine as catalyst. See Annelen, 564, pp 73-78 (1949). A variation of this method is shown in Scheme III, where α-bromomethyl acrylic acid (12) is reacted with 2 moles of thiol to give bis-sulfide (13). The resulting sulfides are oxidized with meta-chloroperbenzoic acid or excess hydrogen peroxide to give compound (7) in Scheme II and compound (14) in Scheme III, respectively. The remaining synthetic steps for preparing compound (9) and compound (15) are similar to the procedure described in Scheme I.
    Schemes IV, V and VI describe methods particularly suitable for the preparation of compounds of formula I in which the R 2 group contains heteroatoms. In Scheme IV, substituent R 4 is as defined above. In compound (16) the group (I) is bromo, chloro, tosylate, mesylate or epoxide, which according to procedures known in the art reagent R 4 -XH (where X is O, NR 7 and May be S, etc.). The remaining synthetic steps for synthesizing compound (18) are similar to the procedure described in Scheme I.
    In Scheme V, suitably protected cysteine (P in compound (19) is a protecting group) can be converted to the corresponding thiol (20). After removing the protecting group, the R 7 group (as defined above) can be introduced to the nitrogen atom as shown in compound (23). The procedure described in Scheme V is discussed in more detail in Synthesis Communication, Vol. 16, No. 5, p.565 (1986). This method can be performed for both racemates and single enantiomers. The enantiomerically rich isomers, following the general procedure as described above, can be used as starting materials to obtain a single enantiomer of the desired R or S.
    In Scheme VI, compound (12) is first reacted with an equivalent of thiol or sulfinate in a suitable solvent, such as toluene, at ambient or reflux temperature, in the presence or absence of a suitable base such as sodium bicarbonate or triethyl amine Compound (25) and Compound (26) are obtained, respectively. Compound (25) is converted to compound (26) at 0 ° C. using an oxidizing agent such as meta-chloroperbenzoic acid in a suitable solvent such as methylene chloride. The intermediate (26) may be reacted with an anionic or conjugate acid W, wherein W is oxygen, in a solvent such as toluene or dimethylformamide, in the presence or absence of a basic catalyst such as sodium bicarbonate or triethyl amine, preferably at reflux temperature. Reacting with a heteroatom such as nitrogen or sulfur to obtain intermediate (7), wherein the R 2 group can be -CH 2 XR 4 , -CH 2 -het or -CH 2 -Q . The remaining synthetic steps for preparing the final hydroxylsam compound (9) are similar to the procedure described in Scheme I.
    In addition to Schemes IV, V and VI, compounds of formula (I) in which the R 2 group contains heteroatoms can also be prepared according to Scheme II using compound (12). In this method, α-bromomethyl acrylic acid (12) is reacted with one equivalent of an anion or conjugate acid W to produce acrylic acid 10 (wherein the R 2 groups are —CH 2 —W where W is as defined above). May be The remaining synthetic steps for preparing the final hydroxylsam compound (9) are similar to the procedure described in Scheme II. When W is thiol or thiolate, the sulfur contained in R 2 can be oxidized to sulfoxide or sulfone, for example to obtain asymmetric bis-sulfonyl hydroxamate.
    The chemical reactions of Schemes I, II, IV and VI proceed through achiral or racemic intermediates, and intermediates (5-9 or 11) are removed by traditional induction methods such as chiral chromatography or chiral salt formation of intermediate (7). The cleavage can yield the pure enantiomer of the final product.
    Pharmaceutical compositions of the invention may be prepared by mixing the compounds of formula (I) of the invention with pharmaceutically acceptable solid or liquid carriers and optionally pharmaceutically acceptable auxiliaries and excipients using conventional standard techniques. Solid form compositions include powders, tablets, dispersible granules, capsules and suppositories. The solid carrier may also be at least one substance that acts as a diluent, flavor, solubilizer, lubricant, suspending agent, binder, tablet disintegrant and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting waxes, cocoa butter and the like. Liquid form compositions include solutions, suspensions, and emulsions. For example, solutions may be provided in which the compounds of the present invention are dissolved in water, water-propylene glycol and water-polyethylene glycol systems, optionally containing conventional colorants, flavors, stabilizers and thickeners.
    Pharmaceutical compositions are provided using conventional techniques. Preferably, the composition is present in unit dosage form containing the active ingredient, i.
    The amount of the active ingredient in the pharmaceutical composition and its unit dosage form, ie the compound of formula (I) according to the invention, can be very different and can be adjusted according to the specific dosage form, the potency of the particular compound and the desired concentration. Generally, the amount of active ingredient will be from 0.5% to 90% by weight of the composition.
    In therapeutic uses to treat patients suffering from or susceptible to diseases including connective tissue degeneration, or to inhibit various enzymes of the family of matrix metalloproteinases including collagenase, stromelysin and gelatinases, The compounds of the present invention or pharmaceutically acceptable compositions thereof may be administered orally, parenterally and in dosages to obtain and maintain a concentration (ie, amount or blood concentration) of an active ingredient effective for inhibiting such enzymes in a patient being treated. (Or) will be administered topically. In general, the effective amount of the active compound will range from about 0.1 to about 100 mg / kg. It will be appreciated that the dosage may vary depending on the needs of the patient, the severity of the connective tissue degeneration to be treated and the particular compound used. In addition, the initial dose to be administered may be rapidly increased above the upper limit to achieve the desired blood concentration, or the initial dose may be less than optimal and the daily dose may be gradually increased during the course of treatment, depending on the specific circumstances. It will be appreciated. If desired, the daily dosage may also be administered in multiple doses, for example, two to four times daily.
    The compounds of the present invention inhibit various enzymes of the matrix metalloproteinase family, mainly stromelysin and gelatinases, thereby reducing osteoarthritis such as osteoarthritis, rheumatoid arthritis, septic arthritis, osteoporosis, tumor metastasis (invasion and Growth), periodontitis, gingivitis, corneal ulcers, skin ulcers, gastric ulcers and other connective tissue degeneration related diseases such as matrix metallo endoproteinases. Such diseases and conditions are well known and can be easily diagnosed by a physician of ordinary skill.
    Pharmaceutical compositions for parenteral administration are generally as soluble salts (acid addition salts or base salts) dissolved in pharmaceutically acceptable liquid carriers such as water for injection and suitably buffered isotonic solutions of pH about 3.5-6. Will contain a pharmaceutically acceptable amount of the compound according to the invention. Suitable buffers include, by way of example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+)-lysine and L (+)-arginine. The compound of formula (I) will generally be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration of about 1 mg / ml to about 400 mg / ml. The resulting liquid pharmaceutical composition will be administered to obtain a dosage of the above-mentioned inhibitory effective amount. The compounds of formula (I) according to the invention are advantageously administered orally in solid and liquid dosage forms.
    The compounds of the present invention and their preparations will be better understood with reference to the following examples, which are intended to be illustrative and are not intended to limit the scope of the present invention.
    Example 1: Preparation of N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -3-phenyl-propionamide
    Step 1: Preparation of Benzyl Malonic Acid Monoethyl Ester
    Benzylmalonic acid diethyl ester (10 g, 40 mmol) in 25 mL of ethanol was cooled to 0 ° C. Potassium hydroxide (2.5 g, 40 mmol) dissolved in 25 ml of ethanol was added dropwise over 50 minutes. The cooling bath was removed and the mixture was stirred for another hour. The solvent volume was reduced by evaporation in vacuo and the residual solution was poured into aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The aqueous phase was acidified with aqueous 10% HCl and extracted twice with ethyl acetate. The organic phase was dried by brine extraction, filtered from anhydrous sodium sulfate and concentrated in vacuo to afford 8.08 g of the title compound as a colorless oil.
    Step 2: Preparation of 2-benzyl-2-propenic acid ethyl ester
    Benzyl malonic acid monoethyl ester (8.0 g, 36 mmol), 7 ml pyridine, 0.36 ml (3.6 mmol) piperidine, and 1.06 g (35 mmol) paraformaldehyde in an oil bath maintained at 130 ° C. Reflux under nitrogen for 1.5 hours. After cooling for 0.5 h, the mixture was partitioned between 100 ml of water and 100 ml of hexane. The aqueous phase was reextracted with 50 mL of hexane. The organic phase was washed with aqueous 10% HCl, water, 1M sodium bicarbonate and brine. It was dried over anhydrous sodium sulfate and concentrated in vacuo to yield 5.8 g of the title compound as a colorless oil.
    Step 3: Preparation of 2-[(4-methoxybenzenethio) methyl] -3-phenyl-propenic acid ethyl ester
    4-methoxybenzenethiol (0.6 mL, 4.7 mmol) in 1 mL of ethanol was cooled in an ice bath with stirring. 0.13 mL (0.34 mmol) of ethanol sodium ethoxide solution was added. After 15 minutes, 1.0 g (5.3 mmol) of 2-benzyl-2-propenoic acid ethyl ester in 1 ml of ethanol was added dropwise over about 2 minutes. The ice bath was removed and the reaction mixture was stirred for 17 hours. The mixture was evaporated in vacuo and partitioned between ethyl acetate and aqueous 5% HCl. The organic phase was concentrated and chromatographed on silica gel eluting with hexanes: acetone (98: 2) to afford 1.04 g of the title compound as a colorless oil.
    Step 4: Preparation of 2-[(4-methoxybenzenesulfonyl) methyl] -3-phenyl-propionic acid ethyl ester
    2.17 g (10 mmol) of solid in a solution of 2-[(4-methoxybenzenethio) methyl] -3-phenyl-propenic acid ethyl ester (1.51 g, 4.6 mmol) in 50 mL of methylene chloride cooled in an ice bath MCPBA was added in portions over 5 minutes. The cold bath was removed and the mixture was stirred at rt overnight. The suspension is filtered and the solid is washed with methylene chloride. The organic solution was extracted with 3 parts of 1M sodium bicarbonate, extracted with brine, dried, filtered from anhydrous sodium sulfate and concentrated. Chromatography on silica gel eluting with methylene chloride: acetone (99: 1) gave 1.31 g of the title compound as a colorless oil.
    Step 5: Preparation of 2-[(4-methoxybenzenesulfonyl) methyl] -3-phenyl-propionic acid
    A mixture of 0.56 g (1.5 mmol) of 2-[(4-methoxybenzenesulfonyl) methyl] -3-phenyl-propionic acid ethyl ester and 8 ml of 6N HCl was heated at 115 ° C. for 17 hours. The mixture was transferred to 100 ml ice-water and extracted with 2 parts of ethyl acetate. The organic phase was extracted three times with 50 mL portions of aqueous 5% sodium bicarbonate. The bicarbonate solution was poured onto ice and acidified with concentrated HCl. The acidified aqueous mixture was extracted three times with 50 mL portions of ethyl acetate and the combined organic extracts were concentrated in vacuo to yield 0.45 g of the title compound as a white solid.
    Step 6: Preparation of N-benzyloxy-2-[(4-methoxybenzenesulfonyl) methyl] -3-phenyl-propionamide
    A solution of 2-[(4-methoxybenzenesulfonyl) methyl] -3-phenyl-propionic acid (1.05 g, 3.14 mmol) and 0.69 mL (6.3 mmol) of NMM in anhydrous THF under nitrogen was cooled in an ice bath. Ethyl chloroformate (0.33 mL, 3.5 mmol) in 7 mL THF was added dropwise over 5 minutes. After the suspension was stirred at 0 ° C. for 10 minutes, several portions of a slurry of O-benzylhydroxylamine hydrochloride (0.64 g, 4 mmol) and NMM (0.44 mL, 4 mmol) in 7 mL THF were introduced. The mixture was stirred for 10 minutes and stored at 10 ° C. overnight. The mixture was allowed to warm to rt for 0.5 h and then partitioned between ethyl acetate and aqueous 10% HCl. The organic phase was washed with water, 3 parts 1M sodium bicarbonate and brine. It was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel eluting with 40% -50% ethyl acetate in hexanes. This gave 1.26 g of the title compound as a colorless oil.
    Step 7: Preparation of N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -3-phenyl-propionamide
    N-benzyloxy-2-[(4-methoxybenzenesulfonyl) methyl] -3-phenyl-propionamide (1.25 g, 2.85 mmol) was dissolved in 45 mL of ethanol. To this was added 0.36 g of palladium hydroxide on carbon (Pearlman catalyst) and the suspension was placed in a shaker under 15 psi of hydrogen for 2.25 hours. The catalyst was filtered off, washed with ethanol and the ethanol solution was concentrated in vacuo to evaporate from methylene chloride to give 0.875 g of the title compound as a white solid.
    Example 2: Preparation of N-hydroxy-2-[(benzenesulfonyl) methyl] -3-phenyl-propionamide
    Following the general procedure described in Example 1 (Steps 3 to 7) and insignificantly changed except using thiophenol as starting material in Step 3, the title compound was obtained as a white solid.
    Example 3: Preparation of N-hydroxy-2-[(benzenesulfonyl) methyl] -propionamide
    Step 1: Preparation of 2-[(benzenesulfonyl) methyl] -propionic acid
    To 1 mmol of 2-[(benzenethio) methyl] -propionic acid in 10 ml of cooled methylene chloride in an ice bath was added 0.5 g (2.3 mmol) of solid MCPBA in portions. The reaction mixture was stirred at rt for 6 h and refrigerated overnight. The suspension was filtered, the filtrate was concentrated and chromatographed on silica gel eluting with 25% ethyl acetate and 0.5% acetic acid in hexanes, followed by 50% ethyl acetate, 0.5% acetic acid in hexanes. Evaporation of the solvent gave 0.225 g of the title compound as a white solid.
    Step 2: Preparation of N-hydroxy-2-[(benzenesulfonyl) methyl] -propionamide
    Following the general procedure described in Example 1 (Steps 6 to 7) and insignificantly changed in Step 6 except using 2-[(benzenesulfonyl) methyl] -propionic acid as the starting material, the title compound Was obtained as a white solid.
    Example 4: Preparation of N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide
    Step 1: Preparation of 2- (4-methoxybenzenethiomethyl) -3- (4-methoxybenzenethio) -propionic acid
    To a stirred mixture of 2-bromomethylacrylic acid (10 g, 60 mmol) in 125 mL of toluene at room temperature is added sodium bicarbonate (15 g, 180 mmol) and 4-methoxybenzenethiol (16.5 mL, 140 mmol) and this mixture Was refluxed overnight. The mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate, and the aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo to afford the title compound as a white solid.
    Step 2: Preparation of 2- (4-methoxybenzenesulfonylmethyl) -3- (4-methoxybenzenesulfonyl) -propionic acid
    A stirred mixture of 2- (4-methoxybenzenethiomethyl) -3- (4-methoxybenzenethio) -propionic acid (18.5 g, 5 mmol) in methylene chloride (250 mL) was cooled in a dry ice / acetone bath and , m-chloroperoxybenzoic acid (MCPBA) (54.5 g, 213 mmol) was added in small portions over about 30 minutes. After stirring for 2 days at ambient temperature and standing for 1 day, the mixture was vacuum filtered on a plug of silica gel 60 (230-400 mesh) and the filtrate was followed by chloroform, followed by chloroform / methyl alcohol / acetic acid (89:10: Eluted with 1). The filtrate was concentrated and triturated with hexanes to afford the title compound as a white solid.
    Step 3: Preparation of N-benzyloxy-2- (4-methoxybenzenesulfonylmethyl) -3- (4-methoxybenzenesulfonyl) -propionamide
    2- (4-methoxybenzenesulfonylmethyl) -3- (4-methoxybenzenesulfonyl) -propionic acid (5.0 g, 12 mmol) in tetrahydrofuran (30 mL), 1- (3-dimethylaminopropyl A mixture of) -3-ethylcarbodiimide hydrochloride (4.3 g, 23 mmol), benzylhydroxylamine hydrochloride (2.3 g, 14 mmol) and distilled water (30 mL) was stirred overnight. The mixture was filtered to give a white precipitate, which was dissolved in chloroform (200 mL) and filtered. The filtrate was extracted with brine (100 mL) and the organic phase was concentrated in vacuo to give N-benzyloxy-2- (4-methoxybenzenesulfonylmethyl) -3- (4-methoxybenzenesulfonyl) -propionamide ( 2.24 g, 36%). The first filtrate reacted overnight was transferred to ethyl acetate, extracted with 10% hydrochloric acid, water, aqueous sodium bicarbonate and brine and concentrated in vacuo to afford the title compound as a white solid.
    Step 4: Preparation of N-hydroxy-2- (4-methoxybenzenesulfonylmethyl) -3- (4-methoxybenzenesulfonyl) -propionamide
    N-benzyloxy-2- (4-methoxybenzenesulfonylmethyl) -3- (4-methoxybenzenesulfonyl) -propionamide (5.0 g, 9.4 mmol), pulman catalyst (0.9 g) and ethyl alcohol ( 50 ml) of the suspension was stirred overnight at room temperature under hydrogen (20 psig). The reaction mixture was filtered through celite and the soluble solid was dissolved with methyl alcohol followed by chloroform / methyl alcohol (9: 1). The combined filtrates were concentrated in vacuo to afford N-hydroxy-2- (4-methoxybenzenesulfonylmethyl) -3- (4-methoxybenzenesulfonyl) -propionamide as a white solid.
    Example 5: Preparation of N-hydroxy-2-[(4-chlorobenzenesulfonyl) methyl] -3- (4-chlorobenzenesulfonyl) -propionamide
    Step 1: Preparation of 2- (4-chlorobenzenesulfonylmethyl) -3- (4-chlorobenzenesulfonyl) -propionic acid
    Following the general procedure of Example 4 (Steps 1 and 2) and insignificantly changed except using 4-chlorothiophenol as starting material in Step 1, the title compound was obtained as a white solid.
    Step 2: Preparation of N-hydroxy-2-[(4-chlorobenzenesulfonyl) methyl] -3- (4-chlorobenzenesulfonyl) -propionamide
    2- (4-Chlorobenzenesulfonylmethyl) -3- (4-chlorobenzenesulfonyl) -propionic acid (0.52 g, 1.1 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol), 1- A mixture of (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.25 g, 1.3 mmol) and hydroxylamine hydrochloride (0.083 g, 1.2 mmol) was stirred in an ice bath for 20 minutes, and dimethylformamide ( 4-methylmorpholine (0.28 mL, 2.5 mmol) in 10 mL) was added. After stirring overnight at ambient temperature, the mixture was partitioned between ethyl acetate and aqueous 10% hydrochloric acid. The organic phase was further extracted with aqueous acid, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was chromatographed on silica gel (230-400 mesh) using chloroform / acetone / acetic acid (79/20/1) and the eluate was concentrated in vacuo to afford the title compound as a white solid.
    Example 6: Preparation of N-hydroxy-2-[(4-bromobenzenesulfonyl) methyl] -3- (4-bromobenzenesulfonyl) -propionamide
    Following the general procedure of Example 5 (Steps 1 and 2) and insignificantly changed except using 4-bromothiophenol as starting material in Step 1, the title compound was obtained as a white solid.
    Example 7: Preparation of N-hydroxy-2-[(n-butylsulfonyl) methyl] -3- (n-butylsulfonyl) -propionamide
    Step 1: Preparation of 2-[(n-butylthio) methyl] -3- (n-butylthio) -propionic acid, ethyl ester
    Surrounding a mixture of 4-bromomethylacrylic acid, ethyl ester (1.0 g, 6.0 mmol), n-butylthiol (1.4 mL, 13 mmol) and potassium carbonate (1.7 g, 13 mmol) in anhydrous ethyl alcohol (25 mL) Stir overnight at temperature. The mixture was transferred to ethyl acetate, extracted with aqueous 10% hydrochloric acid and concentrated in vacuo to afford the title compound as a colorless clear oil.
    Step 2: Preparation of 2-[(n-butylsulfonyl) methyl] -3- (n-butylsulfonyl) -propionic acid, ethyl ester
    After stirring the stirred mixture of 2-[(n-butylthio) methyl] -3- (n-butylthio) -propionic acid, ethyl ester (1.0 g, 3.4 mmol) in methylene chloride (30 mL), the m-chloro Roperoxybenzoic acid (3.0 g, 14. mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo to afford 2-[(n-butylsulfonyl) methyl] -3- (n-butylsulfonyl) -propionic acid, ethyl ester as a colorless transparent oil.
    Step 3: Preparation of 2-[(n-butylsulfonyl) methyl] -3- (n-butylsulfonyl) -propionic acid
    A mixture of 2-[(n-butylsulfonyl) methyl] -3- (n-butylsulfonyl) -propionic acid, ethyl ester (1.0 g, 3.0 mmol) in 6N hydrochloric acid (20 mL) was refluxed overnight. The mixture was transferred to distilled water and extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo to afford the title compound as a colorless clear oil.
    Step 4: Preparation of N-hydroxy-2-[(n-butylsulfonyl) methyl] -3- (n-butylsulfonyl) -propionamide
    Following the general procedure of Example 4 (steps 3 and 4), except in step 3 using 2-[(n-butylsulfonyl) methyl] -3- (n-butylsulfonyl) -propionic acid as starting material And insignificantly changed to afford the title compound as a white solid.
    Example 8: Preparation of N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (n-octylsulfonyl) -propionamide
    Following the general procedure of Example 7 (Steps 1 to 4) and insignificantly changed except using n-octylthiol as starting material in Step 1, the title compound was obtained as a white solid.
    Example 9: Preparation of N-hydroxy-2-[(4-methylbenzenesulfonyl) methyl] -3- (4-methylbenzenesulfonyl) -propionamide
    Step 1: Preparation of 2-[(4-methylbenzenesulfonyl) methyl] -3- (4-methylbenzenesulfonyl) -propionic acid
    A mixture of 2-bromomethylacrylic acid (2.0 g, 12 mmol), p-toluenesulfin sodium salt, monohydrate (6.4 g, 27 mmol) and sodium bicarbonate (1.0 g, 12 mmol) in toluene (50 mL) was prepared. It was refluxed overnight. The mixture was transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid. The organic phase was concentrated in vacuo and triturated with hexanes to afford the title compound as a white solid.
    Step 2: Preparation of N-hydroxy-2-[(4-methylbenzenesulfonyl) methyl] -3- (4-methylbenzenesulfonyl) -propionamide
    To N-methylpyrrolidinone (20 ml) cooled in an ice bath, 2-[(4-methylbenzenesulfonyl) methyl] -3- (4-methylbenzenesulfonyl) -propionic acid (4.4 g, 11 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.2 g, 22 mmol) and hydroxylamine hydrochloride (1.5 g, 22 mmol) were added. After stirring overnight at ambient temperature, the mixture was transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid, distilled water, aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo and triturated from hexanes to afford the title compound as a white solid.
    Example 10 Preparation of N-hydroxy-2-[(benzenesulfonyl) methyl] -3- (benzenesulfonyl) -propionamide
    Following the general procedure of Example 9, and insignificantly changed except in the step 1 using sodium benzenesulfinic acid salt (2.5 g, 15 mmol) as starting material, the title compound was obtained as a white solid.
    Example 11: Preparation of N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanamide
    Step 1: Preparation of 3- (4-methoxybenzenethio) -propylmalonic acid, diethyl ester
    To a stirred mixture of 3-chloropropylmalonic acid, diethyl ester (2.1 g, 8.6 mmol) in dimethylformamide (20 mL) 4-methoxybenzenethiol (1.2 mL, 9.5 mmol) in dimethylformamide (20 mL) And sodium bicarbonate (0.72 g, 8.6 mmol) was added. After stirring at room temperature overnight, the mixture was transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid, distilled water, aqueous sodium bicarbonate and brine and concentrated in vacuo. The concentrate was triturated with hexane, extracted with distilled water, concentrated in vacuo and chromatographed on silica gel using methylene chloride / hexane (9/1) to afford the title compound as a colorless clear oil.
    Step 2: Preparation of 3- (4-methoxybenzenesulfonyl) -propylmalonic acid, diethyl ester
    Cool the stirred mixture of 3- (4-methoxybenzenethio) -propylmalonic acid, diethyl ester (2.4 g, 7.0 mmol) in chloroform (150 mL) and m-chloroperoxybenzoic acid (3.3 g, 15 mmol) Was added in small portions. After stirring overnight at ambient temperature, the mixture was transferred to chloroform / methyl alcohol (9/1), extracted with aqueous sodium bicarbonate and brine and concentrated in vacuo. The concentrate was chromatographed on silica gel using chloroform / methyl alcohol (99.5 / 0.5) and the eluate was concentrated in vacuo to afford the title compound as a colorless clear oil.
    Step 3: Preparation of 3- (4-methoxybenzenesulfonyl) -propylmalonic acid, monoethyl ester
    To a stirred mixture of 3- (4-methoxybenzenesulfonyl) -propylmalonic acid, diethyl ester (2.0 g, 5.4 mmol) in anhydrous ethyl alcohol (50 mL) potassium hydroxide in anhydrous ethyl alcohol (0.41 g, 5.9 mmol) ) Was added. After stirring overnight at ambient temperature, the mixture was partitioned between chloroform / methyl alcohol (9/1) and aqueous sodium hydroxide. The aqueous phase was acidified with concentrated hydrochloric acid, extracted with chloroform / methyl alcohol (9/1) and the organic extracts were concentrated in vacuo to afford the title compound as a colorless clear oil.
    Step 4: Preparation of 2-[(4-methoxybenzenesulfonyl) propyl] -2-propenic acid, ethyl ester
    3- (4-methoxybenzenesulfonyl) -propylmalonic acid, monoethyl ester (1.1 g, 3.2 mmol), paraformaldehyde (0.11 g, 3.5 mmol), piperidine (0.03 mL, 0.32 mmol) and pyridine (20 mL) was refluxed for 3 h. The mixture was transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid, distilled water, aqueous sodium bicarbonate and brine and the organic phase was concentrated in vacuo to afford the title compound as a colorless clear oil.
    Step 5: Preparation of 2-[(4-methoxybenzenethio) methyl] -5- (4-methoxybenzenesulfonyl) -pentanoic acid, ethyl ester
    To a stirred mixture of 4-methoxybenzenethiol (0.30 mL, 2.2 mmol) in anhydrous ethyl alcohol (1 mL) cooled in an ice bath was added sodium ethoxide solution (0.2 mL, 0.22 mmol) and anhydrous within 15 minutes. 2-[(4-methoxybenzenesulfonyl) propyl] -2-propenoic acid, ethyl ester (0.70 g, 2.2 mmol) in ethyl alcohol (2 mL) was added. After stirring overnight at ambient temperature, the mixture was transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid, distilled water, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was triturated with hexanes and the filtered solid was extracted with chloroform and concentrated in vacuo to afford the title compound as a white solid.
    Step 6: Preparation of 2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanoic acid, ethyl ester
    Of 2-[(4-methoxybenzenethio) methyl] -5- (4-methoxybenzenesulfonyl) -pentanoic acid, ethyl ester (0.8 g, 1.8 mmol) in chloroform (50 mL) cooled in an ice bath. To the stirred mixture was added m-chloroperoxybenzoic acid (0.81 g, 3.7 mmol). After stirring at ambient temperature overnight, the mixture was transferred to ethyl acetate, which was extracted with aqueous sodium bicarbonate and brine. The organic phase was concentrated in vacuo, triturated with hexanes, and the filtered solid was dissolved in chloroform. The chloroform mixture was then extracted with aqueous sodium bicarbonate and brine and the organic phase was concentrated in vacuo to afford the title compound as a white solid.
    Step 7: Preparation of 2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanoic acid
    A mixture of 2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanoic acid, ethyl ester (0.70 g, 1.4 mmol) in 6N hydrochloric acid (20 mL) overnight It was refluxed. The mixture was transferred to ethyl acetate and extracted with aqueous sodium bicarbonate. The combined aqueous extracts were acidified with concentrated hydrochloric acid and extracted with ethyl acetate. This organic extract was concentrated in vacuo to afford the title compound as a white solid.
    Step 8: Preparation of N-benzyloxy-2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanamide
    2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanoic acid (0.5 g, 1.1 mmol), benzylhydroxylamine hydrochloride (0.21 g, 1.3 mmol), A mixture of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.42 g, 2.2 mmol) and tetrahydrofuran / water (1/1, 10 mL) was stirred at ambient temperature overnight. The mixture was transferred to ethyl acetate, which was extracted with aqueous 10% hydrochloric acid, distilled water, aqueous sodium bicarbonate and brine. The organic phase was concentrated in vacuo to afford the title compound as a white solid.
    Step 9: Preparation of N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanamide
    N-benzyloxy-2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanamide (0.3 g, 0.5 mmol), pulman catalyst (0.11 g) and anhydrous The mixture of ethyl alcohol was stirred overnight under hydrogen (15 psig) at room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The concentrate was chromatographed on silica gel using chloroform / ethyl acetate / methyl alcohol / acetic acid (50/40/10/1) and the eluate was concentrated in vacuo to afford the title compound as a white solid.
    Example 12 Preparation of N-hydroxy-2- (n-octylsulfonyl) methyl-3- (4-methoxybenzenesulfonyl) -propionamide
    Step 1: Preparation of 2-[(n-octylthio) methyl] -2-propenoic acid
    A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol), n-octylthiol (1.2 mL, 6.6 mmol) and dimethylformamide (10 mL) was refluxed overnight. The mixture was then transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid and distilled water. The organic phase was concentrated in vacuo to afford the title compound as a white solid.
    Step 2: Preparation of 2-[(n-octylthio) methyl] -3- (4-methoxybenzenethio) -propenoic acid
    A mixture of 2-[(n-octylthio) methyl] -2-propenoic acid (1.0 g, 4.3 mmol), 4-methoxybenzenethiol (1.1 mL, 8.6 mmol) and dimethylformamide (25 mL) was refluxed overnight I was. The mixture was partitioned between ethyl acetate and aqueous 10% hydrochloric acid and the organic phase was concentrated in vacuo. The concentrate was chromatographed on silica gel using chloroform / methyl alcohol / acetic acid (98/1/1) and the eluate was concentrated in vacuo to afford the title compound as a white solid.
    Step 3: Preparation of 2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionic acid
    M-chloro to a stirred mixture of 2-[(n-octylthio) methyl] -3- (4-methoxybenzenethio) -propenoic acid (0.6 g, 1.6 mmol) in chloroform (15 mL) cooled in an ice bath. Roperoxybenzoic acid (1.4 g, 6.6 mmol) was added. After stirring overnight at ambient temperature, the mixture was partitioned between hexane and aqueous 10% hydrochloric acid and the aqueous phase was further extracted with hexane and ethyl acetate. The ethyl acetate extract was concentrated in vacuo and chromatographed on silica gel using chloroform / methyl alcohol / acetic acid (98/1/1) to afford the title compound as a white solid.
    Step 4: Preparation of N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide
    Following the general procedure of Example 4 (steps 3 and 4), in step 3 2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionic acid (0.5 g, 1.2 mmol ) Was insignificant except for using as a starting material to give the title compound as a white solid.
    Example 13: Preparation of N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide
    Step 1: Preparation of 2- [methyl-3- (1-methylhydantoin)]-2-propenic acid
    A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol), 1-methylhydantoin (0.85 g, 7.2 mmol), sodium bicarbonate (1.1 g, 13 mmol) and toluene (50 mL) was refluxed overnight. The mixture was transferred to ethyl acetate and extracted with aqueous sodium bicarbonate. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ethyl acetate and chloroform / methyl alcohol (9/1). The organic extract was concentrated to give the title compound as a solid.
    Step 2: Preparation of 2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenethio) -propionic acid
    2-Methenyl-2- [methyl-3- (1-methylhydantoin)]-propenoic acid (1.1 g, 5.5 mmol), 4-methoxybenzenethiol (0.75 mL, 6.0 mmol), sodium bicarbonate (0.92 g , 11 mmol) and toluene (50 mL) were refluxed overnight. The mixture was concentrated in vacuo and chromatographed on silica gel using chloroform / methyl alcohol / acetic acid (97/2/1). The eluate was concentrated in vacuo and triturated with hexanes to afford the title compound as a white solid.
    Step 3: Preparation of 2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionic acid
    A mixture of 2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenethio) -propionic acid (1.0 g, 3.0 mmol) in methylene chloride (50 mL) was cooled and m- Chloroperoxybenzoic acid (1.4 g, 6.3 mmol) was added. After stirring overnight at ambient temperature, the mixture was concentrated in vacuo and chromatographed on silica gel 60 (230-400 mesh) using chloroform / methyl alcohol / acetic acid (94/5/1). The eluate was concentrated in vacuo to afford the title compound as a white solid.
    Step 4: Preparation of N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide
    Following the general procedure of Example 4 (steps 3 and 4), in step 3 2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionic acid (0.6 g , 1.6 mmol) was changed insignificant except using as starting material to afford the title compound.
    Example 14 Preparation of N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide
    Step 1: Preparation of 4-butoxybenzenesulfinic acid sodium salt
    To a stirred mixture of sodium iodide (8.8 g, 59 mmol) in acetone (250 mL) was added 4-butoxybenzenesulfonyl chloride (5.0 g, 20 mmol). After stirring overnight at ambient temperature, the mixture was filtered and the filtered solid was washed with acetone to give the 4-butoxybenzenesulfinic acid sodium salt as a white solid.
    Step 2: Preparation of 2-[(4-butoxybenzenesulfonyl) methyl] -2-propenoic acid
    A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol), 4-butoxybenzenesulfinic acid sodium salt (3.1 g, 13 mmol), sodium carbonate (1.9 g, 18 mmol) and dimethylformamide (20 mL) It was refluxed overnight. The reaction mixture was then partitioned between ethyl acetate and aqueous 10% hydrochloric acid and the organic phase was concentrated in vacuo. The concentrate was chromatographed on silica gel 60 (230-400 mesh) using chloroform / methyl alcohol / acetic acid (94/5/1) and the eluate was concentrated in vacuo to afford the title compound as a white solid.
    Step 3: Preparation of 2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionic acid
    2-[(4-butoxybenzenesulfonyl) methyl] -2-propenoic acid (1.0 g, 3.4 mmol), 1-butylhydantoin (0.78 g, 5.0 mmol), sodium bicarbonate (0.63 g, 7.4 mmol) and The mixture of toluene (50 mL) was refluxed overnight. The reaction mixture was transferred to ethyl acetate, extracted with aqueous 10% hydrochloric acid and concentrated in vacuo. The concentrate was triturated with hexane and diethyl ether to afford the title compound as a white solid.
    Step 4: Preparation of N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide
    Following the general procedure of Example 4 (steps 3 and 4) and in step 3 2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionic acid (0.59 g , 1.3 mmol) was changed insignificant except using as starting material to give the title compound as a white solid.
    Example 15 Preparation of N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide
    Following the general procedure of Example 14 (Steps 1 to 4) and insignificantly changed except using 4-methoxybenzenesulfonyl chloride as starting material in Step 1, the title compound was obtained as a white solid. .
    Example 16: Preparation of N-hydroxy-2- [methyl-3- (5,5-dimethylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide
    Following the general procedure of Example 14 (steps 1 to 4) and insignificantly changed except in the step 3 using 5,5-dimethylhydantoin (1.5 g, 11 mmol) as starting material, the title compound Was obtained as a white solid.
    Example 17: (+)-N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide and (-)-N-hydroxy- Preparation of 2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide
    A racemic mixture of N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -3- (n-octylsulfonyl) propionamide (Example 12) was prepared using chiralpak (anhydrous ethyl alcohol). Chiralpak) eluted on an AD column and the eluates collected at Rf = 13.5 min and Rf = 23.5 min were concentrated in vacuo to give enantiomer (17A) ([α] 25 D = + 4 °) and enantiomer, respectively. (17B) ([a] 25 D = -4 °) was obtained.
    Example 18: (+)-N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide and (-)-N- Preparation of Hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide
    Racemic mixture of N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide (Example 13) using anhydrous ethyl alcohol Elution was carried out on a Chiralpak AD column and the eluate collected at Rf = 8.6 min and Rf = 10.5 min was concentrated in vacuo to give enantiomer 18A and enantiomer 18B, respectively.
    Example 19: (+)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide and (-)-N- Preparation of Hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide
    Racemic mixture of N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide (Example 14) using anhydrous ethyl alcohol Eluted on a Chiralpak AD column and the eluates collected at Rf = 16.5 min and Rf = 17.8 min were concentrated in vacuo to give enantiomer (19A) ([α] 25 D = -3 °) and enantio, respectively. Mer (19B) ([a] 25 D = + 3 °) was obtained.
    Example 20: (+)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide and (-)-N- Preparation of Hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide
    Racemic mixture of N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide (Example 15) using anhydrous ethyl alcohol Eluted on a Chiralpak AD column and the eluates collected at Rf = 13.4 min and Rf = 15.8 min were concentrated in vacuo to give enantiomer (20A) ([a] 25 D = -4 °) and enantio, respectively. Mer (20B) ([a] 25 D = + 4 °) was obtained.
    Example 21 Biological Activity Test
    Inhibitory activity was assessed in vitro using particle concentration fluorescence analysis on one or more MMP enzymes (stromelicin, gelatinase and collagenase). Inhibitors bind to MMP enzymes and prevent degradation of the substrate by stromelysin, gelatinase or collagenase. Fluorescein and biotin residues are attached to the substrate. Thus, the intact substrate binds to the avidin coated particles via biotin residues. Once the particles are washed and dried, a fluorescence signal is generated since the phosphor attaches to the particles. If no inhibitor is present, the substrate is degraded by the MMP enzyme and the fluorescein group is removed, so no fluorescence signal can be detected. After the test compound was dissolved in DMSO at the desired concentration, the solution was diluted 1: 5 with MMP buffer (50 mM Tris-HCl, pH 7.5; 150 mM NaCl; 0.02% NaN 3 ). Serial 2-fold dilutions of each compound were prepared. The concentrated activating enzyme solution was transferred to the plates of each test compound and the mixture was incubated at room temperature for 15 minutes. The thawed MMP substrate was then added to all plates and the plates were incubated for 1 to 3 hours in the dark at room temperature. At this time, the substrate mixture is mixed with 0.1% avidin coated particles. After 15 minutes, the beads were filtered and washed and the fluorescence values were measured. The Ki value was then calculated. Inhibition data for the compounds of the present invention are shown in Table 1 below. Compounds with lower Ki values are expected to be more effective as MMP inhibitors. Compounds with a Ki of less than 15 μM for stromelysin are expected to have a therapeutic effect in connective tissue disorders.



    权利要求:
    Claims (18)
    [1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt thereof.
    <Formula I>

    Where
    R 1 is a) C 4-12 alkyl,
    b) C 4-12 alkenyl,
    c) C 4-12 alkynyl,
    d)-(CH 2 ) h -C 3-8 cycloalkyl,
    e)-(CH 2 ) h -aryl,
    f)-(CH 2 ) h -aryl substituted with C 1-4 alkyl, C 1-4 alkoxy, halo, —NO 2 , —CF 3 , —CN or —N (C 1-4 alkyl) 2 ,
    g)-(CH 2 ) h -het, or
    h) — (CH 2 ) h -hets substituted with C 1-4 alkyl or halo;
    R 2 is a) C 1-12 alkyl,
    b) C 1-12 alkyl substituted with 1 to 3 of halo, —CN, —NO 2 , —CF 3 , —N (R 3 ) 2 , —SR 3 or OH,
    c) C 2-12 alkenyl,
    d) C 2-12 alkenyl substituted with one to three of halo, —CN, —NO 2 or —CF 3 ,
    e) C 2-12 alkynyl,
    f) C 2-12 alkynyl substituted with 1 to 3 of halo, —CN, —NO 2 or —CF 3 ,
    g)-(CH 2 ) h -C 3-8 cycloalkyl,
    h) — (CH 2 ) h —C 3-8 cycloalkyl substituted with one to three of C 1-4 alkyl, C 1-4 alkoxy or halo,
    i)-(CH 2 ) h -C 3-8 cycloalkenyl,
    j) — (CH 2 ) h —C 3-8 cycloalkenyl substituted with one to three of C 1-4 alkyl, C 1-4 alkoxy or halo,
    k)-(CH 2 ) h -aryl,
    l) C 1-4 alkyl, C 1-4 alkoxy, -CF 3 , -OH, -NO 2 , -CN, -N (R 3 ) 2 , -SR 3 , -SO 2 (C 1-4 alkoxy) -(CH 2 ) h -aryl substituted with 1 to 3 of -C (= 0) R 3 or -NC (= 0) R 3 ,
    m)-(CH 2 ) h -aryl substituted with 1 to 5 halo,
    n)-(CH 2 ) h -het,
    o)-(CH 2 ) h -hets substituted with 1 or 2 of C 1-4 alkyl or halo,
    p)-(CH 2 ) h -Q,
    q)-(CH 2 ) h -Q substituted with 1 to 3 of C 1-4 alkyl, C 1-4 alkoxy, halo or phenyl,
    r)-(CH 2 ) i -the chain may be optionally substituted with C 1-4 alkyl or phenyl, which in turn may be substituted with 1 to 3 of halo or C 1-4 alkyl-(CH 2 ) i- XR 4 , or
    s)-(CH 2 ) i CHR 5 R 6 ;
    R 3 is a) H,
    b) C 1-4 alkyl,
    c)-(CH 2 ) h -phenyl, or
    d)-(CH 2 ) h -phenyl substituted with 1 to 3 of C 1-4 alkyl, C 1-4 alkoxy or halo;
    X is a) -O-,
    b) -S (= O) j- ,
    c) -NR 7- ,
    d) -S (= 0) 2 NR 8- , or
    e) -C (= 0)-;
    R 4 is a) H,
    b) C 1-4 alkyl,
    c)-(CH 2 ) h -phenyl,
    d)-(CH 2 ) h -phenyl substituted with 1 to 3 of C 1-4 alkyl, C 1-4 alkoxy, halo, —NO 2 or —CN, or
    e)-(CH 2 ) h -het;
    R 5 is a) C 1-4 alkyl, or
    b) -C (= 0) R 3 ;
    R 6 is a) -C (= 0) R 3 , or
    b) — (CH 2 ) h C (═O) R 3 ;
    R 7 is a) H,
    b) C 1-4 alkyl,
    c)-(CH 2 ) h -phenyl,
    d)-(CH 2 ) h -phenyl substituted with 1 to 3 of C 1-4 alkyl, C 1-4 alkoxy or halo,
    e) -C (= 0) -R 3 ,
    f) -S (= 0) 2 R 3 , or
    g) -C (= 0) OR 3 ;
    R 8 is a) C 1-4 alkyl,
    b)-(CH 2 ) h -phenyl, or
    c)-(CH 2 ) h -phenyl substituted with 1 to 3 of C 1-4 alkyl, C 1-4 alkoxy or halo;
    Aryl is a mono- or di-carbon aromatic moiety;
    Het is a 5-10 membered unsaturated heterocyclic moiety having 1 to 3 atoms selected from the group consisting of oxygen, nitrogen and sulfur;
    Q is a 5-10 membered saturated heterocyclic moiety having 1 or 2 atoms selected from the group consisting of oxygen, nitrogen and sulfur;
    h is 0, 1, 2, 3, 4, 5 or 6;
    i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
    j is 0, 1 or 2.
    [2" claim-type="Currently amended] The compound of claim 1, wherein R 2 is a) C 1-12 alkyl substituted with one to three of halo, —CN, —NO 2 , —CF 3 , —N (R 3 ) 2 , —SR 3 or OH,
    b) C 2-12 alkenyl,
    c) C 2-12 alkenyl substituted with one to three of halo, —CN, —NO 2 or —CF 3 ,
    d) C 2-12 alkynyl,
    e) C 2-12 alkynyl substituted with one to three of halo, —CN, —NO 2 or —CF 3 ,
    f) — (CH 2 ) h —C 3-8 cycloalkyl substituted with one to three of C 1-4 alkyl, C 1-4 alkoxy or halo,
    g)-(CH 2 ) h -C 3-8 cycloalkenyl,
    h) — (CH 2 ) h —C 3-8 cycloalkenyl substituted with one to three of C 1-4 alkyl, C 1-4 alkoxy or halo,
    i) aryl,
    l) C 1-4 alkyl, C 1-4 alkoxy, -CF 3 , -OH, -NO 2 , -CN, -N (R 3 ) 2 , -SR 3 , -SO 2 (C 1-4 alkoxy) Aryl substituted with 1 to 3 of -C (= 0) R 3 or -NC (= 0) R 3 ,
    k)-(CH 2 ) h -het,
    l) — (CH 2 ) h -hets substituted with 1 or 2 of C 1-4 alkyl or halo,
    m)-(CH 2 ) i -Q,
    n) — (CH 2 ) i —Q substituted with one to three of C 1-4 alkyl, C 1-4 alkoxy, halo or phenyl,
    o)-(CH 2 ) i -the chain may be optionally substituted with C 1-4 alkyl or phenyl, which in turn may be substituted with 1 to 3 of halo or C 1-4 alkyl-(CH 2 ) i- XR 4 , or
    p)-(CH 2 ) h CHR 5 R 6 ;
    Wherein R 3 , X, R 4 , R 5 , R 6 , R 7 , R 8 , aryl, het and Q are as defined in claim 1;
    h is 0, 1, 2, 3, 4, 5 or 6;
    i is 1, 2, 3, 4, 5 or 6;
    [3" claim-type="Currently amended] The compound of claim 1, wherein R 2 is a)-(CH 2 ) h -het,
    b) — (CH 2 ) h -hets substituted with 1 or 2 of C 1-4 alkyl or halo,
    c)-(CH 2 ) i -Q,
    d) — (CH 2 ) i —Q substituted with one to three of C 1-4 alkyl, C 1-4 alkoxy, halo or phenyl, or
    e)-(CH 2 ) i -chain may be optionally substituted with C 1-4 alkyl or phenyl, which in turn may be substituted with 1 to 3 of halo or C 1-4 alkyl-(CH 2 ) i- XR 4 ;
    Wherein X, R 4 , R 7 , R 8 , aryl, het and Q are as defined in claim 1;
    h is 0, 1, 2, 3, 4, 5 or 6;
    i is 1, 2, 3, 4, 5 or 6;
    [4" claim-type="Currently amended] The compound of claim 1, wherein R 1 is a) C 4-8 alkyl,
    b)-(CH 2 ) h -phenyl, or
    c)-(CH 2 ) h -phenyl substituted with C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro or bromo;
    R 2 is a) — (CH 2 ) h -pyridyl, quinolinyl, which may optionally be substituted with one to three of C 1-4 alkyl, C 1-4 alkoxy, phenyl, fluoro, chloro or bromo Pyrrolyl, thienyl or thiazolyl or indolyl,
    b)-(CH 2 ) h -piperidinyl, piperazinyl, morpholino, 4-thio, which may optionally be substituted with one to three of C 1-4 alkyl, phenyl, fluoro, chloro or bromo Morpholinyl, butyrolactamyl, 2-oxo-oxazolidinyl or 2,4-dioxo-imidazolidinyl,
    c)-(CH 2 ) i -XR 4 ;
    X is a) -S (= 0) j- ;
    R 4 is a) C 1-8 alkyl,
    b) phenyl, or
    c) phenyl substituted with C 1-4 alkyl, C 1-4 alkoxy or halo;
    h is 0, 1, 2, 3, 4, 5 or 6;
    i is 1, 2, 3, 4, 5 or 6;
    j is 0, 1 or 2;
    [5" claim-type="Currently amended] The compound of claim 1, wherein R 1 is n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, phenyl, 4 -Methylphenyl, 4-ethylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 4-isopropylphenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-methoxy Phenyl, 4-ethoxyphenyl, 4-n-butoxyphenyl, benzyl, 4-phenylbenzyl, 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-chlorobenzyl, 2-, 3 Or 4-bromobenzyl, and 4-ethoxybenzyl.
    [6" claim-type="Currently amended] The compound of claim 1, wherein R 1 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, phenyl, 4-methylphenyl, 4-ethylphenyl, 4-chlorophenyl, 4-bromophenyl , 4-fluorophenyl, 4-methoxyphenyl, 4-n-butoxyphenyl, benzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-ethoxybenzyl Compound.
    [7" claim-type="Currently amended] The compound of claim 1, wherein R 2 is methyl, 1-cyano-1-phenyl methyl, 2-cyano ethyl, 2-phenylethyl, 2-bromo-2-phenylethyl, 2-bromoethyl, propyl, Isopropyl, 3-chloropropyl, 3-bromopropyl, n-butyl, isobutyl, 3-methylbutyl, 1-methylpropyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, n -Heptyl, n-octyl, n-hexadecyl, n-octadecyl, 2-propenyl, 2-propynyl, 3-butenyl, 4-pentenyl, 3-buteninyl, 4-penteninyl, cyclo Pentyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 4-cyclohexylbutyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, phenylaminomethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4 Bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-nitrophenyl, 4-ethoxyphenyl, benzyl, 4-methylbenzyl, 2- Fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chloro Benzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-ethoxybenzyl, 4-nitrobenzyl , Methylcarbonyl, 1-methylcarbonyl methyl, 2-phenylcarbonyl ethyl, isopropylcarbonyl, methoxycarbonyl, ethoxycarbonyl, 1,1-ethoxycarbonyl methyl, 2,2-ethoxy Carbonyl ethyl, 1,2-ethoxycarbonyl ethyl, 2-methoxycarbonyl propyl, 3-methoxycarbonyl propyl, 1-ethoxycarbonyl methyl, 1-ethoxycarbonyl ethyl, phenylcarbonyl, Phenylcarbonyl methyl, pyridylcarbonyl methyl, pyridylmethyl, pyridylethyl, quinolinylmethyl, pyrrolyl methyl, indolyl methyl, thienyl, thiazolyl, thiethylmethyl, thienylethyl, piperidinyl methyl , Piperazinyl methyl, morpholino methyl, morpholino ethyl, morpholino propyl, thiomorpholino methyl, thiomorpholino propyl, 4-methoxybenzenesulfonyl Methyl, 3- (4-methoxybenzenesulfonyl) amino propyl, 3-hydroxy, amino, 3-phenoxy propyl, 2-phenyl ethyloxy, (4-butoxybenzenesulfonyl) methyl, methyl-3- (1,5,5-trimethylhydantoin), methyl-3- (1-butyl-5,5-dimethylhydantoin), (4-methoxybenzenesulfonyl) methyl, (4-chlorobenzenesulfonyl) methyl , (4-bromobenzenesulfonyl) methyl, (n-butylsulfonyl) methyl, (n-octylsulfonyl) methyl, 3- (4-methoxybenzenesulfonyl) propyl, (4-methylbenzenesulfonyl ) Methyl, (benzenesulfonyl) methyl, methyl-3- (1-methylhydantoin), methyl-3- (1-butylhydantoin) and methyl-3- (5,5-dimethylhydantoin) Compound selected from among.
    [8" claim-type="Currently amended] The compound according to claim 1, wherein R 2 is (4-methoxybenzenesulfonyl) methyl, (4-chlorobenzenesulfonyl) methyl, (4-bromobenzenesulfonyl) methyl, (n-butylsulfonyl) methyl, (n-octylsulfonyl) methyl, 3- (4-methoxybenzenesulfonyl) propyl, (4-methylbenzenesulfonyl) methyl, (benzenesulfonyl) methyl, methyl-3- (1-methylhydantoin) , Methyl-3- (1-butylhydantoin) and methyl-3- (5,5-dimethylhydantoin).
    [9" claim-type="Currently amended] The method of claim 1,
    (1) N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -3-phenyl-propionamide,
    (2) N-hydroxy-2-[(benzenesulfonyl) methyl] -3-phenyl-propionamide,
    (3) N-hydroxy-2-[(benzenesulfonyl) methyl] -propionamide,
    (4) N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (5) N-hydroxy-2-[(4-chlorobenzenesulfonyl) methyl] -3- (4-chlorobenzenesulfonyl) -propionamide,
    (6) N-hydroxy-2-[(4-bromobenzenesulfonyl) methyl] -3- (4-bromobenzenesulfonyl) -propionamide,
    (7) N-hydroxy-2-[(n-butylsulfonyl) methyl] -3- (n-butylsulfonyl) -propionamide,
    (8) N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (n-octylsulfonyl) -propionamide,
    (9) N-hydroxy-2-[(4-methylbenzenesulfonyl) methyl] -3- (4-methylbenzenesulfonyl) -propionamide,
    (10) N-hydroxy-2-[(benzenesulfonyl) methyl] -3- (benzenesulfonyl) -propionamide,
    (11) N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanamide,
    (12) N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (13) N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (14) N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide,
    (15) N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (16) N-hydroxy-2- [methyl-3- (5,5-dimethylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (17) (+)-N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (18) (-)-N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (19) (+)-N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (20) (-)-N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (21) (+)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide,
    (22) (-)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide,
    (23) (+)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (24) (-)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (25) (+)-N-hydroxy-2- [methyl-3- (5,5-dimethylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide, or
    (26) A compound which is (-)-N-hydroxy-2- [methyl-3- (5,5-dimethylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide.
    [10" claim-type="Currently amended] The method of claim 1,
    (1) N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (2) N-hydroxy-2-[(4-chlorobenzenesulfonyl) methyl] -3- (4-chlorobenzenesulfonyl) -propionamide,
    (3) N-hydroxy-2-[(4-bromobenzenesulfonyl) methyl] -3- (4-bromobenzenesulfonyl) -propionamide,
    (4) N-hydroxy-2-[(n-butylsulfonyl) methyl] -3- (n-butylsulfonyl) -propionamide,
    (5) N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (n-octylsulfonyl) -propionamide,
    (6) N-hydroxy-2-[(4-methylbenzenesulfonyl) methyl] -3- (4-methylbenzenesulfonyl) -propionamide,
    (7) N-hydroxy-2-[(benzenesulfonyl) methyl] -3- (benzenesulfonyl) -propionamide,
    (8) N-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl] -5- (4-methoxybenzenesulfonyl) -pentanamide,
    (9) N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (10) N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (11) N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide,
    (12) N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (13) N-hydroxy-2- [methyl-3- (5,5-dimethylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (14) (+)-N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (15) (-)-N-hydroxy-2-[(n-octylsulfonyl) methyl] -3- (4-methoxybenzenesulfonyl) -propionamide,
    (16) (+)-N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (17) (-)-N-hydroxy-2- [methyl-3- (1-methylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (18) (+)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide,
    (19) (-)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-butoxybenzenesulfonyl) -propionamide,
    (20) (+)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (21) (-)-N-hydroxy-2- [methyl-3- (1-butylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide,
    (22) (+)-N-hydroxy-2- [methyl-3- (5,5-dimethylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide, or
    (23) A compound which is (-)-N-hydroxy-2- [methyl-3- (5,5-dimethylhydantoin)]-3- (4-methoxybenzenesulfonyl) -propionamide.
    [11" claim-type="Currently amended] A method of inhibiting excessive matrix metalloproteinases, comprising administering an effective amount of the compound according to claim 1 to a patient in need of excessive inhibition of the matrix metalloproteinases.
    [12" claim-type="Currently amended] The method of claim 11, wherein said matrix metalloproteinases comprise stromelysine, collagenase and gelatinase.
    [13" claim-type="Currently amended] A method of treating a person suffering from or susceptible to a disease comprising connective tissue degeneration, comprising administering an effective amount of the compound according to claim 1 to a patient suffering from or susceptible to a disease comprising connective tissue degeneration. .
    [14" claim-type="Currently amended] The method of claim 13, wherein the disease associated with connective tissue degeneration is osteopenia, rheumatoid arthritis, septic arthritis, osteopenia such as osteoporosis, tumor metastasis, invasion and growth, or periodontitis, gingivitis, corneal ulcer or gastric ulcer.
    [15" claim-type="Currently amended] The method of claim 11, wherein the effective amount of the compound of claim 1 is administered orally, parenterally or topically in a pharmaceutical composition.
    [16" claim-type="Currently amended] The method of claim 13, wherein the effective amount of the compound of claim 1 is administered orally, parenterally or topically in a pharmaceutical composition.
    [17" claim-type="Currently amended] The method of claim 11 or 13, wherein the compound is administered in an amount of about 0.1 to about 100 mg / kg body weight / day.
    [18" claim-type="Currently amended] A pharmaceutical composition comprising an excessive amount of matrix metalloproteinase inhibitory compound of claim 1 and a pharmaceutically acceptable carrier.
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    同族专利:
    公开号 | 公开日
    IL128900D0|2000-01-31|
    WO1998013340A1|1998-04-02|
    ID21897A|1999-08-05|
    EP0929519B1|2005-02-23|
    AU4645997A|1998-04-17|
    BR9712134A|1999-08-31|
    HK1022468A1|2005-01-21|
    US5847153A|1998-12-08|
    CN1158254C|2004-07-21|
    AT289590T|2005-03-15|
    EA001460B1|2001-04-23|
    CA2266368A1|1998-04-02|
    EP0929519A1|1999-07-21|
    NO991494D0|1999-03-26|
    JP2001516338A|2001-09-25|
    US6235928B1|2001-05-22|
    ES2236829T3|2005-07-16|
    CZ92399A3|1999-07-14|
    AU726799B2|2000-11-23|
    NO991494L|1999-05-26|
    DE69732571T2|2006-01-12|
    HU0000145A2|2000-07-28|
    NZ334729A|2001-01-26|
    HU0000145A3|2001-12-28|
    CN1230177A|1999-09-29|
    EA199900332A1|1999-12-29|
    PL332509A1|1999-09-13|
    NO312893B1|2002-07-15|
    DE69732571D1|2005-03-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-09-27|Priority to US2684896P
    1996-09-27|Priority to US60/026,848
    1997-09-19|Application filed by 로렌스 티. 마이젠헬더, 파마시아 앤드 업존 캄파니
    2000-07-25|Publication of KR20000048639A
    优先权:
    申请号 | 申请日 | 专利标题
    US2684896P| true| 1996-09-27|1996-09-27|
    US60/026,848|1996-09-27|
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