WO1998034915A1 - N-hydroxy-beta-sulfonyl-propionamide derivatives and their use as inhibitors of matrix metalloproteinases - Google Patents

N-hydroxy-beta-sulfonyl-propionamide derivatives and their use as inhibitors of matrix metalloproteinases Download PDF

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Publication number
WO1998034915A1
WO1998034915A1 PCT/IB1998/000101 IB9800101W WO9834915A1 WO 1998034915 A1 WO1998034915 A1 WO 1998034915A1 IB 9800101 W IB9800101 W IB 9800101W WO 9834915 A1 WO9834915 A1 WO 9834915A1
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Prior art keywords
alkyl
aryl
alkoxy
aryloxy
heteroaryl
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PCT/IB1998/000101
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French (fr)
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Ralph Pelton Robinson
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Pfizer Inc.
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Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to AU54935/98A priority Critical patent/AU5493598A/en
Priority to CA002279863A priority patent/CA2279863A1/en
Priority to EP98900334A priority patent/EP0966438A1/en
Priority to JP10534044A priority patent/JP2000507975A/en
Priority to BR9807824-0A priority patent/BR9807824A/en
Publication of WO1998034915A1 publication Critical patent/WO1998034915A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to arylsulfonylamino hydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor (TNF) and as such are useful in the treatment of a condition selected from the group consisting of arthritis,
  • the compounds of the present invention may be used in combination therapy with standard non- steroidal anti-inflammatory drugs (hereinafter NSAID'S) and analgesics for the treatment of
  • cytotoxic drugs such as ad ⁇ amycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vinc ⁇ stine, in the treatment of cancer
  • This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to pharmaceutical compositions useful therefor 20
  • Matrix-degrading metalloproteinases such as gelatmase, stromelysin and collagenase, are involved in tissue matrix degradation (e g collagen collapse) and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e . 25 osteoarth ⁇ tis and rheumatoid arthritis), tissue uiceration (e g .
  • Tumor necrosis factor is recognized to be involved in many infectious and auto-immune 30 diseases (W Fiers, FEBS Letters. 1991, 285, 199) Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C E Spooner et al , Clinical Immunology and Immunopatholo ⁇ v. 1992, 62 S11) Summarv of the Invention
  • the present invention relates to a compound of the formula
  • R 2 is hydrogen or (C r C 6 )alkyl
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, (C 1 -C ⁇ )alkyl, trifluoromethyl, tnfluoromethyl(C r C 6 )alkyl, (C r C 6 )alkyl(d ⁇ fluoromethylene), (C 1 -C 3 )alkyl(d ⁇ fluoromethylene)(C 1 -C 3 )alkyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl,
  • any of the carbon atoms of said ring, capable of forming an additional bond may be optionally substituted by a substituent (preferably zero to three substituents) independently selected from the group consisting of fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C r C 6 )alkoxy, perfluoro(C r C 3 )alkyl, perfluoro(C 1 -C 3 )alkoxy and (C 6 -C 10 )aryloxy, R is R O or R R N wherein R 6 and R 7 are each independently selected from the group consisting of hydrogen, (C C 6 )alkyl, (C 6 -C 10 )aryl(C C 6 )alkyl or (C 2 -C 9 )heteroaryl(C r C 6 )alkyl, wherein each of said (C 6 -C 10 )aryl and (C 2 -C 9 )heteroaryl moieties of said (C 6 -
  • R 8 is piperazinyl, (C 1 -C 6 )alkylp ⁇ peraz ⁇ nyl, (C 6 -C 10 )arylp ⁇ peraz ⁇ nyl,
  • Q is (C r C 6 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 - C 10 )aryl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryloxy(C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryl, (C 2 - C 9 )heteroaryl(C 2 -C 9 )heteroaryl, (C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, (C 6 - C 10 )aryl(C r C 6 )alkoxy(C 6 -
  • the present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, ]_ ⁇ _, salts containing pharmacologically acceptable anions, such as the hydrochlonde, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate []_e_, 1 ,1'-methylene-b ⁇ s-(2-hydroxy-3- naphthoate)]saltsaltsaltsalt
  • the invention also relates to base addition salts of formula I
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e g . potassium and sodium) and alkaline earth metal cations (e g .
  • ammonium or water- soluble amine addition salts such as N-methylglucam ⁇ ne-(meglum ⁇ ne), t ⁇ methyl-ammonium or diethylammonium, and the lower alkanolammonium salts such t ⁇ s-(hydroxymethyl)- methylammonium and other base salts of pharmaceutically acceptable organic amines
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof
  • alkoxy includes O-alkyl groups wherein “alkyl” is defined above
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl
  • heteroaryl includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroyi, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, py ⁇ midyl, quinolyl, isoquinoly., benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, punnyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl
  • acyl as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkoxy
  • acyloxy includes O-acyl groups wherein "acyl” is defined above
  • the compound of formula I may have chiral centers and therefore exist in different diaste ⁇ ome ⁇ c or enantiome ⁇ c forms
  • This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof
  • Preferred compounds of formula I include those wherein R 1 is OH and R 2 is hydrogen
  • Other preferred compounds of formula I include those wherein both R 3 and R 4 are (C r C 6 )alkyl or R 3 and R 4 are taken together to form an optionally substituted (C 3 -C 6 )cycloalkyl ring or a benzo-fused(C 3 -C 6 )cycloalkyl ring or a group of the formula
  • Other preferred compounds of formula I include those wherein R 1 is hydroxy
  • Other preferred compounds of formula I include those wherein Q is (C 6 -C 10 )aryl or (C ⁇ - C 10 )aryloxy(C 6 -C 10 )aryl, wherein each (C 6 -C 10 )aryl moieties of said is (C 6 -C 10 )aryl or (C 6 - C 10 )aryloxy(C 6 -C 10 )aryl groups may be optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (C r C ⁇ )alkyl, (C r C 6 )alkoxy or perfluoro(C 1 - C 3 )alkyl
  • More preferred compounds of formula I include those wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (C r C 6 )alkyl, (C r C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl, more preferably the substituents are selected from fluoro, chloro, (C r C 6 )alkoxy or (C r C 6 )alkyl, most preferably the substituent is in the 4-pos ⁇ t ⁇ on
  • Specific preferred compounds of formula I include the following (2S)-2,N-d ⁇ hydroxy-3-(4-methoxybenzenesulfonyl)prop ⁇ onam ⁇ de, 3-[4-(4-fluorophenoxy)phenylsulfonyl]-2,N-d ⁇ hydroxyprop ⁇ onam ⁇ de, 2,N-d ⁇ hydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclobutyl]acetam ⁇ de
  • the present invention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, osteoporosis, cancer, synergy with cytotoxic anticancer agents, tissue uiceration, macular degeneration, restenosis, pe ⁇ odontal disease, epidermolysis bullosa, sclentis, in combination with standard NSAID'S and analgesics and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of
  • the present invention also relates to a method for treating a condition selected from the group consisting of arthritis, osteoporosis, cancer, tissue uiceration, macular degeneration, restenosis, pe ⁇ odontal disease, epidermolysis bullosa, sclentis, compounds of formula I may be used in combination with standard NSAID'S and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition
  • TNF tumor necrosis factor
  • Scheme 1 refers to the preparation of compounds of the formula I, wherein R 3 and R 4 are hydrogen
  • a compound of the formula i is prepared from a compound of the formula II by hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction inert solvent
  • Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate
  • Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol
  • the aforesaid reaction may be performed at a pressure from about 1 to about 5 atmospheres, preferably about 3 atmospheres
  • Suitable temperatures for the aforesaid reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature)
  • the reaction is complete within about 0 5 hours to about 5 hours, preferably about 3 hours
  • the compound of formula II is prepared from a compound of formula III by reaction with O-benzylhydroxylamine hydrochlo ⁇ de, an activating agent, and a base in a reaction inert solvent
  • Suitable activating agents include (benzot ⁇ azol-l-yloxy)t ⁇ s(d ⁇ methylam ⁇ no) phosphonium hexafluorophosphate or 1-(3-(d ⁇ methylam ⁇ nopropyl)-3-ethylcarbod ⁇ m ⁇ de hydrochlonde, preferably (benzot ⁇ azol-l-yloxy)t ⁇ s(d ⁇ methylam ⁇ no) phosphonium hexafluorophosphate
  • Suitable bases include tertiary amines such as triethylamine, diisopropylethylamine or 4-N,N-d ⁇ methylam ⁇ nopy ⁇ d ⁇ ne, preferably triethylamine
  • the temperature of the aforesaid reaction may range from about 0°
  • the compound of formula III is prepared from a compound of formula IV by hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction inert solvent
  • Suitable catalysts include palladium or 5-10% palladium on activated charcoal, preferably 10% palladium on activated charcoal
  • Suitable solvents include acetic acid, alcohols such as ethanol, methanol, or isopropanol, preferably ethanol
  • the aforesaid reaction may be performed at a pressure from about 1 to about 5 atmospheres, preferably about 3 atmospheres Suitable temperatures for the aforesaid reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature)
  • the reaction is complete within about 0 5 hours to about 24 hours, preferably about 3 hours
  • Suitable oxidants include meta- chloroperbenzoic acid, hydrogen peroxide or sodium perborate, preferably meta- chloroperbenzoic acid
  • Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride
  • Suitable temperatures for the aforesaid reaction range from about 0°C to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature) The reaction is complete within about 0 5 hours to about 24 hours, preferably about 3 hours
  • Compounds of the formula V, wherein R 1 is hydroxy can be prepared from compounds of the formula VI by reaction with a Gngnard reagent and a thiol of the formula QSH in a reaction inert solvent
  • Gngnard reagents include ethyl magnesium bromide or phenyl magnesium bromide, preferably ethyl magnesium bromide
  • Suitable solvents include ethers such as diethy 1 ether, tetrahydrofuran or 1 ,2-d ⁇ methoxyethane, preferably the solvent is a mixture of tetrahydrofuran and diethyl ether
  • Suitable temperatures for the aforesaid reaction are from about -78°C to about 50°C , preferably from about 0°C to about 25°C (i e room temperature) The reaction is complete in about 1 to about 24 hours, preferably about 3 hours Compounds of the formula V, wherein R 1 is (C 6 -C 10 )aryl(C
  • Compounds of the formula VI can be prepared by methods well known to those of ordinary skill in the art Compounds of the formula VI can also be prepared by peracid oxidation (e g , meta-chloroperbenzoic acid) of the corresponding , ⁇ -unsaturated benzyl esters as described in Jerry March, Advanced Organic Chemistry. 735 (3rd ed , 1985)
  • the corresponding , ⁇ -unsaturated benzyl esters may be prepared by Knovenagel condensation between a malonate monobenzyl ester and paraformaldehyde in the presence of pipendine as described in H O House, Modern Synthetic Reactions. 649-651 (2nd ed , WA Benjamin, Menlo Park, California, 1972)
  • Scheme 2 refers to the preparation of compounds of the formula I, wherein R 2 is hydrogen and R 1 is OH
  • compounds of formula I can be prepared from compounds of the formula VII by hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction inert solvent
  • Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate
  • Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol
  • the aforesaid reaction may be performed at a pressure from about 1 to about 5 atmospheres, preferably about 3 atmospheres
  • Suitable temperatures for the aforesaid reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature)
  • the reaction is complete within about 0 5 hours to about 5 hours, preferably about 3 hours
  • the compound of formula IX is prepared from a compound of the formula X by reaction with an excess of sodium pe ⁇ odate in the presence of catalytic ruthenium trichloride hydrate
  • the aforesaid reaction is conducted at a temperature from about 0°C to about 35°C, preferably from about 20°C to about 25°C (i e room temperature)
  • Suitable solvents include acetone or a mixture of acetonitnle, carbon tetrachlo ⁇ de and water, preferably a 1 1 2 mixture of acetonitile, carbon tetrachlonde and water
  • the reaction is conducted from about 0 5 to about 2 hours, preferably about 1 25 hours
  • the compound of the formula X wherein "P" is pivaloyl, acetyl or benzoyl, is prepared by reaction of a compound of the formula XI with a protecting group reagent in the presence of a base in a reaction inert solvent
  • Suitable protecting group reagents include pivaloyl chloride, pivaloic anhydride, acetyl chloride, acetic anhydride, benzoyl clo ⁇ de or benzoic anhydride, preferably acetic anhydride
  • Suitable bases include tertiary amine bases such as pyridine or 4-N,N-d ⁇ methylam ⁇ nopyr ⁇ d ⁇ ne, preferably 4-N, N-dimethylaminopy ⁇ dine
  • the temperature of the aforesaid reaction is from about 0°C to about 30°C, preferably from about 20°C to about 25°C (i e room temperature)
  • Suitable solvents include halogenated solvents such as methylene chlor
  • the compound of formula XI is prepared from a compound of the formula XII by reaction with 2-furaldehyde and a strong base in a polar aprotic solvent
  • Suitable bases include potassium-tert -butoxide, lithium diisopropylamide, and butyl lithium, preferably 2 5 M n- butyllithium in hexane
  • the temperature of the aforesaid reaction is from about -78°C to about 0°C, preferably about -78°C
  • Suitable solvents include diethyl ether, tetrahydrofuran, or 1,2- dimethoxyethane, preferably the solvent is tetrahydrofuran
  • the reaction is conducted from about 0 25 hours to about 6 hours, preferably about 0 33 hours
  • the compound of formula XII is prepared from a compound of the formula XIII by reaction with an oxidant in a reaction inert solvent Suitable oxidants include meta- chloroperbenzoic acid
  • the compound of the formula XIII is prepared from a compound of the formula XIV by reaction with a thiol of the formula QSH in the presence of a base in an aprotic solvent
  • bases include sodium hydride, ethyl magnesium bromide, lithium diisopropyl amide, potassium hydride, or sodium methoxide, preferably sodium hydride
  • the temperature of the aforesaid reaction is from about 0°C to about 60°C, preferably 20°C to about 25°C (i e room temperature)
  • Suitable solvents include aprotic solvents such as methylene chloride, tetrahydrofuran or N,N-d ⁇ methylformam ⁇ de, preferably N,N-d ⁇ methylformam ⁇ de
  • the reaction is conducted for about 1 hour to about 48 hours, preferably about 16 hours
  • Compounds of the formula XIV and QSH are commercially available or can be made by methods well known to those of ordinary skill in the art
  • Compounds of the formula QSH can also be prepared by reaction of an alkyl or aryl halide with sodium sulfhyd ⁇ de as described in Jerry March, Advanced Organic Chemistry. 360 and 589 (3rd ed , 1985)
  • compounds of the formula QSH can also be prepared by reaction of an aryl diazonium salt with sodium sulfhydnde as described in March ⁇ d_ at 601
  • compounds of the formula QSH can also be prepared by reaction of a Gngnard reagent with sulfur as described in March id.
  • compounds of the formula QSH can also be prepared by reduction of a sulfonyl chloride, sulfonic acid or disulfide as described in March ⁇ d_ at 1107 and 1110
  • Scheme 3 refers to the preparation of compounds of the formula I, wherein R 1 is other than hydroxy and R 2 is hydrogen
  • compounds of the formula I are prepared from compounds of the formula XVII by hydrogenolysis according to methods analogous to the methods described for converting compounds of formula VII to compounds of formula I in Scheme 2
  • compounds of the formula XVII are prepared from compounds of the formula XVI by reaction with O-benzylhydroxylamine hydrochlo ⁇ de in the presence of a catalyst and a base in a reaction inert solvent according to methods analogous to the conversion of compounds of the formula IX to formula VIII as described above in Scheme 2
  • Compounds of the formula XVI are prepared from compounds of the formula XV by reaction with an excess of sodium periodate in the presence of a catalyst according to methods analogous to those used for the conversion of compounds of the formula X to formula IX as described above in Scheme 2.
  • R 1 is (C 6 -C 10 )aryl(C C 6 )alkoxy or (C,-C e )alkoxy
  • R 1a L is a leaving group and R 1a is (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 1 -C ⁇ )alky1, in the presence of a strong base in an aprotic polar solvent.
  • Suitable leaving groups include chloro, fluoro, bromo, mesylate, triflate or tosylate.
  • the leaving group is iodo.
  • Suitable bases include lithium dialkyi amides such as lithium N-isopropyl-N-cyclohexylamide or lithium diisopropyl amide, potassium t-butoxide, sodium amide, potassium hydride or sodium hydride, preferably sodium hydride.
  • Suitable solvents include ethers (such as THF, diethyl ether or 1 ,2-dimethoxyethane), preferably THF. The aforesaid reaction is conducted at about -78°C to about 0°C, preferably at about 0°C.
  • Suitable leaving groups include chloro, fluoro, bromo or (R b )0- (i.e. an anhydride).
  • the leaving group is chloro.
  • Suitable bases include tertiary amine bases such as triethylamine, pyridine or 4-dimethylaminopyridine, preferably triethylamine.
  • the temperature of the aforesaid reaction is from about 0°C to about 30°C, preferably from about 20°C to about 25°C (i.e. room temperature).
  • Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. The reaction is conducted from about 1 hour to about 24 hours, preferably for about 2 hours.
  • Scheme 4 refers to the preparation of compounds of the formula I, wherein R 2 is other than hydrogen and R 3 and R 4 are other than hydrogen.
  • compounds of the formula I are prepared from compounds of the formula XXIII by hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction inert solvent.
  • Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate.
  • Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol
  • the aforesaid reaction may be performed at a pressure from about 1 to about 5 atmospheres, preferably about 3 atmospheres
  • Suitable temperatures for the aforesaid reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature)
  • the reaction is complete within about U 5 hours to about 5 hours, preferably about 3 hours
  • the compound of the formula XXIII is prepared from a compound of the formula XXII by reaction with O-benzylhydroxylamine hydrochlonde in the presence of a catalyst and a base in a reaction inert solvent
  • Suitable catalysts include (benzotr ⁇ azol-1- yloxy)t ⁇ s(d ⁇ methylam ⁇ no)phosphon ⁇ um hexafluorophosphate or 1-(3-(d ⁇ methylam ⁇ nopropyl)-3- ethylcarbodiimide hydrochlonde, preferably (benzot ⁇ azol-l-yloxy)tr ⁇ s(d ⁇ methylam ⁇ no) phosphonium hexafluorophosphate
  • Suitable bases include tertiary amines such as triethylamine diisopropylethylamine or dimethylaminopy ⁇ dine, preferably triethylamine
  • the aforesaid reaction temperature is from about 0° C to about
  • the compound of the formula XXII can be prepared by deprotection of a compound of the formula XXI by reaction with an alkali metal hydroxide in a polar solvent
  • Suitable alkali metal hydroxides include lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide, most preferably about 5 equivalents of the alkali metal hydroxide
  • the aforesaid reaction may conducted at a temperature from about 0°C to about 60°C, preferably from about 20°C to about 25°C (i e room temperature)
  • Suitable solvents include a mixture of water and an alcohol such as methanol or ethanol and, optionally an water miscible ether such as tetrahydrofuran or 1 ,2-d ⁇ methoxyethane
  • the solvent system is methanol/water/tetrahydrofuran
  • the reaction is conducted from about 1 to about 72 hours, preferably about 24 hours
  • Suitable bases include sodium hydride (NaH), potassium-tert -butoxide, lithium d ⁇ sopropylamide, and butyl lithium, preferably 2 5 M n-butyllithium in hexane
  • NaH sodium hydride
  • potassium-tert -butoxide lithium d ⁇ sopropylamide
  • butyl lithium preferably 2 5 M n-butyllithium in hexane
  • the temperature of the aforesaid reaction is from about -78°C to about 0°C, preferably about -78°C
  • Suitable solvents include diethyl ether, tetrahydrofuran, or 1 ,2-d ⁇ methoxyethane, preferably the solvent is tetrahydrofuran
  • the reaction is conducted from about 0 25 hours to about 6 hours, preferably about 0 33 hours
  • compounds of the formula I wherein R 1 is other than hydroxy, R 2 is other than hydrogen and R and R 4 are other than hydrogen, can be prepared from compounds of the formula XXV by methods analogous to the conversion of compounds of the formula XXII to compounds of formula I, as described above in Scheme 4 Compounds of the formula XXV can be prepared from compounds of the formula
  • Suitable catalysts include palladium or 5- 10% palladium on activated charcoal, preferably 10% palladium on activated charcoal
  • Suitable solvents include acetic acid, alcohols such as ethanol, methanol, or isopropanol, preferably ethanol
  • the aforesaid reaction may be performed at a pressure from about 1 to about 5 atmospheres, preferably about 3 atmospheres Suitable temperatures for the aforesaid reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature)
  • the reaction is complete within about 0 5 hours to about 24 hours, preferably about 3 hours
  • (C r C 6 )alkoxy can be prepared from compounds of the formula XXI by reaction with an arylalkyl or alkyl halide in the presence of a base in an aprotic solvent
  • bases include sodium hydride, ethyl magnesium bromide, lithium diisopropyl amide, potassium hydride, or sodium methoxide, preferably sodium hydride
  • the temperature of the aforesaid reaction is from about 0°C to about 60°C, preferably 20°C to about 25°C (i e room temperature)
  • Suitable solvents include aprotic solvents such as methylene chloride, tetrahydrofuran or N,N- dimethylformamide, preferably N,N-d ⁇ methylformam ⁇ de
  • the reaction is conducted for about 1 hour to about 48 hours, preferably about 16 hours
  • Suitable bases include tertiary amines such as triethylamine, dnsopropylethylamine or 4-N,N-d ⁇ methylam ⁇ nopyr ⁇ d ⁇ ne, preferably triethylamine
  • the temperature of the aforesaid reaction may range from about 0°C to about 60°C, preferably about 20°C (room temperature)
  • Suitable solvents include halogenated solvents such as methylene chloride or chloroform, or ethers such as THF or diethyl ether, preferably the solvent is methylene chloride
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, ]_ ⁇ _, salts containing pharmacologically acceptable anions, such as hydrochlonde, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [ ⁇ _e_, 1 ,1'-methylene-b ⁇ s-(2-hydroxy-3- naphthoate)] salts
  • pharmacologically acceptable anions such as hydrochlonde, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate
  • Those compounds of the formula I which are also acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations
  • examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts
  • These salts are all prepared by conventional techniques
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I
  • These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc
  • These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating
  • the compounds of formula I or their pharmaceutically acceptable salts (hereinafter also referred to as the compounds of the present invention) to inhibit matrix metalloproteinases or the production of tumor necrosis factor (TNF) and, consequently, demonstrate their effectiveness for treating diseases characterized by matrix metalloproteinase or the production of tumor necrosis factor is shown by the following yjtro assay tests
  • MMP-1 Human Colla ⁇ enase
  • Human recombinant collagenase is activated with trypsin using the following ratio 10 mg trypsin per 100 mg of collagenase
  • the trypsin and collagenase are incubated at room temperature for 10 minutes then a five fold excess (50 mg/10 mg trypsin) of soybean trypsin inhibitor is added 10 mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then diluted using the following Scheme
  • Collagenase is diluted to 400 ng/ml and 25 ml is then added to appropriate wells of the microfluor plate Final concentration of collagenase in the assay is 100 ng/ml
  • Substrate (DNP-Pro-Cha-Gly-Cys(Me)-H ⁇ s-Ala-Lys(NMA)-NH 2 ) is made as a 5 mM stock in dimethyl sulfoxide and then diluted to 20 mM in assay buffer The assay is initiated by the addition of 50 ml substrate per well of the microfluor plate to give a final concentration of 10 mM
  • Fluorescence readings (360 nM excitation, 460 nm emission) were taken at time 0 and then at 20 minute intervals The assay is conducted at room temperature with a typical assay time of 3 hours
  • Fluorescence vs time is then plotted for both the blank and collagenase containing samples (data from triplicate determinations is averaged)
  • a time point that provides a good signal (the blank) and that is on a linear part of the curve (usually around 120 minutes) is chosen to determine IC 50 values
  • the zero time is used as a blank for each compound at each concentration and these values are subtracted from the 120 minute data
  • Data is plotted as inhibitor concentration vs % control (inhibitor fluorescence divided by fluorescence of collagenase alone x 100)
  • IC 50 's are determined from the concentration of inhibitor that gives a signal that is 50% of the control
  • IC 50 's are reported to be ⁇ 0 03 mM then the inhibitors are assayed at concentrations of 0 3 mM, 0 03 mM, 0 03 mM and 0 003 mM
  • MMP-2 Inhibition of Gelatmase activity is assayed using the Dnp-Pro-Cha-Gly-Cys(Me)-H ⁇ s-Ala- Lys(NMA)-NH 2 substrate (10 mM) under the same conditions as inhibition of human collagenase (MMP-1)
  • 72kD gelatmase is activated with 1 mM APMA (p-aminophenyl mercuric acetate) for 15 hours at 4°C and is diluted to give a final concentration in the assay of 100 mg/ml
  • Inhibitors are diluted as for inhibition of human collagenase (MMP-1) to give final concentrations in the assay of 30 mM, 3 mM, 0 3 mM and 0 03 mM Each concentration is done in triplicate
  • Fluorescence readings (360 nm excitation, 460 emission) are taken at time zero and then at 20 minutes intervals for 4 hours
  • IC 50 's are determined as per inhibition of human collagenase (MMP-1 ) If IC 50 's are reported to be less than 0 03 mM, then the inhibitors are assayed at final concentrations of 0 3 mM, 0 03 mM, 0 003 mM and 0 003 mM
  • MMP-3 Inhibition of Stromelysin Activity
  • Inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingarten and Feder (Wemberg, H and Feder, J , Spectrophotometric Assay for Vertebrate Collagenase, Anal Biochem 147, 437-440 (1985))
  • Hydrolysis of the thio peptolide substrate [Ac-Pro-Leu-Gly-SCH[CH 2 CH(CH 3 ) 2 ]CO-Leu-Gly-OC 2 H 5 ] yields a mercaptan fragment that can be monitored in the presence of Ellman's reagent
  • Human recombinant prostromelysin is activated with trypsin using a ratio of 1 ml of a 10 mg/ml trypsin stock per 26 mg of stromelysin The trypsin and stromeiysin are incubated at 37°C for 15 minutes followed by 10
  • Assays are conducted in a total volume of 250 ml of assay buffer (200 mM sodium chloride, 50 mM MES, and 10 mM calcium chloride, pH 6 0) in 96-well microliter plates
  • Activated stromelysin is diluted in assay buffer to 25 mg/ml
  • Ellman's reagent (3-Carboxy-4- nitrophenyl disulfide) is made as a 1M stock in dimethyl formamide and diluted to 5 mM in assay buffer with 50 ml per well yielding at 1 mM final concentration 10 mM stock solutions of inhibitors are made in dimethyl sulfoxide and diluted serially in assay buffer such that addition of 50 mL to the appropriate wells yields final concentrations of 3 mM, 0 3 mM, 0 003 mM, and 0 0003 mM All conditions are completed in triplicate
  • a 300 mM dimethyl sulfoxide stock solution of the peptide substrate is diluted to 15 mM in assay buffer and the assay is initiated by addition of 50 ml to each well to give a final concentration of 3 mM substrate Blanks consist of the peptide substrate and Ellman's reagent without the enzyme Product formation was monitored at 405 nm with a Molecular Devices
  • MMP-13 Human recombinant MMP-13 is activated with 2mM APMA (p-aminophenyl mercuric acetate) for 1 5 hours, at 37°C and is diluted to 400 mg/ml in assay buffer (50 mM Tns, pH 7 5, 200 mM sodium chloride, 5mM cal ⁇ um chloride, 20mM zinc chloride, 0 02% b ⁇ j) Twenty-five microliters of diluted enzyme is added per well of a 96 well microfluor plate The enzyme is then diluted in a 1 4 ratio in the assay by the addition of inhibitor and substrate to give a final concentration in the assay of 100 mg/ml
  • assay buffer 50 mM Tns, pH 7 5, 200 mM sodium chloride, 5mM cal ⁇ um chloride, 20mM zinc chloride, 0 02% b ⁇ j
  • 10 mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then diluted in assay buffer as per the inhibitor dilution scheme for inhibition of human collagenase (MMP-1) Twenty-five microliters of each concentration is added in triplicate to the microfluor plate The final concentrations in the assay are 30 mM, 3mM, 0 3 mM, and 0 03 mM Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-H ⁇ s-Ala-Lys(NMA)-NH 2 ) is prepared as for inhibition of human collagenase (MMP-1) and 50 ml is added to each well to give a final assay concentration of 10 mM Fluorescence readings (360 nM excitation, 450 emission) are taken at time 0 and every 5 minutes for 1 hour
  • Positive controls consist of enzyme and substrate with no inhibitor and blanks consist of substrate only
  • IC 50 's are determined as per inhibition of human collagenase (MMP-1) If IC 50 's are reported to be less than 0 03 mM, inhibitors are then assayed at final concentrations of 0 3 mM, 0 03 mM, 0 003 mM and 0 0003 mM
  • the active compound will be administered at dosages between about 0 1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0 3 to 5 mg/kg
  • the active compound will be administered orally or parenterally
  • some variation in dosage will necessarily occur depending on the condition of the subject being treated
  • the person responsible for administration will, in any event, determine the appropriate dose for the individual subject
  • the compounds of the present invention can be administered in a wide variety of different dosage forms, in general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5 0% to about 70% by weight
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrro done, sucrose, gelation and acacia Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tablettmg purposes
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules, preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents as well
  • a sterile mjectable solution of the active ingredient is usually prepared Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed The aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered isotonic These aqueous solutions are suitable intravenous injection purposes
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes
  • the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art
  • compounds can be administered intramuscularly or subcutaneously at dosage levels of about 0 1 to 50 mg/kg/day, advantageously 0 2 to 10 mg/kg/day given in a single dose or up to 3 divided doses
  • the active compounds of the invention may also be formulated in rectal compositions such as supposi
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e g .
  • the dosage unit may be determined by providing a valve to deliver a metered amount
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound
  • Capsules and cartridges made, for example, from gelatin
  • an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch
  • Example 4 2.N-DIHYDROXY-2-f1-(4-METHOXYBENZENESULFONYL)CYCLOPENTYL1ACETAMlDE 2,N-Dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclopentyl]acetamide was prepared by a method analogous to that described in Example 3 using 4-methoxybenzenethiol and cyclopentyl bromide as startinc* materials. MS m/z 328 (M-1).
  • DIHYDROXYACETAMIDE 2- ⁇ 1-[4-(4-Fluorophenoxy)benzenesulfonyl]cyclobutyl ⁇ -2,N-dihydroxyacetamide was prepared by a method analogous to that described in Example 3 using 4-(4- fluorophenoxy)benzenethiol and cyclobutyl bromide as starting materials. MS m/z 394 (M-1).
  • 4-(4-Fluorophenoxy)benzenethiol was obtained as follows. Chlorosulfonic acid (26 mL, 0.392 mole) was added dropwise to ice-cooled 4-fluorophenoxybenzene (36.9 grams, 0.196 mole) with mechanical stirring. When addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4-
  • DIHYDROXYACETAMIDE 2- ⁇ 1-[4-(4-Fluorophenoxy)benzenesulfonyl]cyclopentyl ⁇ -2,N-d ⁇ hydroxyacetam ⁇ de was prepared by a method analogous to that described in Example 3 using (4- fluorophenoxy)benzeneth ⁇ ol and cyclopentyl bromide as starting materials MS m/z 408 (M-1)

Abstract

A compound of formula (I) wherein R?1, R2, R3, R4¿ and Q are as defined in the specification, to pharmaceutical compositions containing them and to their medicinal use as matrix metalloproteinases inhibitors and for the production of tumor necrosis factor (TNF).

Description

N-HYDROXY-BETA-SULF0NYL-PR0PI0NAMIDE DERIVATIVES AND THEIR USE AS INHIBITORS OF MATRIX METALLOPROTEINASES
Background of the Invention
The present invention relates to arylsulfonylamino hydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor (TNF) and as such are useful in the treatment of a condition selected from the group consisting of arthritis,
10 osteoporosis, cancer, tissue uiceration, restenosis, peπodontal disease, epidermolysis bullosa, sclentis and other diseases characterized by matrix metalloprotemase activity, such as AIDS, sepsis, or septic shock and other diseases involving the production of TNF In addition, the compounds of the present invention may be used in combination therapy with standard non- steroidal anti-inflammatory drugs (hereinafter NSAID'S) and analgesics for the treatment of
15 arthritis, and in combination with cytotoxic drugs such as adπamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincπstine, in the treatment of cancer
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to pharmaceutical compositions useful therefor 20 There are a number of enzymes which effect the breakdown of structural proteins and which are structurally related metalloproteases Matrix-degrading metalloproteinases, such as gelatmase, stromelysin and collagenase, are involved in tissue matrix degradation (e g collagen collapse) and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e . 25 osteoarthπtis and rheumatoid arthritis), tissue uiceration (e g . corneal, epidermal and gastric uiceration), abnormal wound healing, peπodontal disease, bone disease (e . Paget's disease and osteoporosis), tumor metastasis or invasion, as well as HIV-infection (J Leuk Biol . 52 (2) 244-248, 1992)
Tumor necrosis factor is recognized to be involved in many infectious and auto-immune 30 diseases (W Fiers, FEBS Letters. 1991, 285, 199) Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C E Spooner et al , Clinical Immunology and Immunopatholoαv. 1992, 62 S11) Summarv of the Invention The present invention relates to a compound of the formula
Figure imgf000004_0001
wherein R1 is hydrogen, hydroxy, (C6-C10)aryl(C1-C6)alkoxy, (C C6)alkoxy, (CrC6)alkyl(C=0)0-, (C1-C6)alkoxy(C=0)0-l (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-,
(C6-C10)aryl(C1-C6)alkyl(C=O)O- or (C6-C10)aryl(C1-C6)alkoxy(C=O)O-, wherein said aryl moiety of said (C6-C10)aryl(CrC6)alkoxy, (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-,
(C6-C10)aryl(C1-C6)alkyl(C=O)O- or (C6-C10)aryl(CrC6)alkoxy(C=O)O- groups is optionally substituted by one or more substituents (preferably one to three substituents) independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (CrC6)alkoxy, perfluoro(C1-C3)alkyl, perfluoro(C C3)alkoxy and (C6-C10)aryloxy,
R2 is hydrogen or (CrC6)alkyl,
R3 and R4 are independently selected from the group consisting of hydrogen, (C1-Cβ)alkyl, trifluoromethyl, tnfluoromethyl(CrC6)alkyl, (CrC6)alkyl(dιfluoromethylene), (C1-C3)alkyl(dιfluoromethylene)(C1-C3)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl,
(C6-C10)aryl(CrC6)alkyl, (C2-C9)heteroaryl(CrC6)alkyl, (C6-C10)aryl(C6-C10)aryl,
(C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, hydroxy(C C6)alkyl, (C1-C6)alkyl(C=0)0-(C C6)alkyl, (C1-C6)alkoxy(C=0)0-(CrC6)alkyl, (C6-C10)aryl(C=O)O-(CrC6)alkyl, (C6-C10)aryloxy(C=O)O- (C1-C6)alkyl , (C6-C10)aryl(C1-C6)alkyl(C=O)O-(C C6)alkyl, (C6-C10)aryl(CrC6)alkoxy(C=O)O- (CrC6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryloxy(CrC6)alkyl,
(C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (Cz-O eteroaryKCrCe lkoxytCrC^al yl, amιno(CrC6)alkyl, (C1-C6)alkylamιno(C1-C6)alkyl, [(C1-C6)alkyl]2amιno(C1-C6)alkyl,
(CrC6)alkyl(C=0)NH(C Ce)alkyl, (CrC6)alkoxy(C=0)NH(CrC6)alkyl,
(C6-C10)aryl(C=O)NH(CrC6)alkyl, (C6-C10)aryloxy(C=O)NH(CrC6)alkyl, (C6-C10)aryl(C1-C6)alkyl(C=O)NH(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C=O)NH(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, R5CO(C1-C6)alkyl or R8(CrC6)alkyl, or R3 and R4 may be taken together with the carbon atom to which they are attached to form a (C3-C6)cycloalkyl or benzo-fused(C3-C6)cycloalkyl ring or a group of the formula
Figure imgf000005_0001
wherein the carbon atom bearing the asterisk is the carbon to which R3 and R4 are atttached, "n" and "m" are independently selected from the integers one and two, and X is CF2, O, SOz or NR9, wherein R9 is hydrogen, (CrC6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (Ce-C^ary C C^alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (CrC6)alkylsulfonyl, (C6-C10)arylsulfonyl, (C C6)alkyl(C=0)-, (CrC6)alkoxy(C=0)-, (C6-C10)aryl(C=O)-, (C6-C10)aryloxy(C=O)-, (C6-C10)aryl(CrC6)alkyl(C=O)- or (C6-C10)aryl(C1-C6)alkoxy(C=O)-, wherein each of said (C6-C10)aryl, (C2-C9)heteroaryl or (C3-C6)cycloalkyl moieties of said (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(CrC6)alkyl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C=O)O-(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl(C=O)O-(C1-C6)alkyl,
(C6-C10)aryl(C1-C6)alkoxy(C=O)O-(C1-C6)alkyl, (C6-C10)aryloxy(C1-C6)alkyl,
(Ce-C^Jary Cj^alkoxyCC CsJalkyl, (C2-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl,
(C6-C10)aryl(C=O)NH(CrC6)alkyl, (C6-C10)aryl(C1-C6)alkyl(C=O)NH(C1-C6)alkyl,
(C6-C10)aryl(C1-C6)alkoxy(C=O)NH(C1-C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, (C6-C10)aryl(C=O)-, (C6-C10)aryl(C C6)alkyl(C=O)-,
(C6-C10)aryl(C1-C6)alkoxy(C=O)-, (C3-C6)cycloalkyl, or benzo-fused(C3-C6)cycloalkyl ring may be optionally substituted on any ring atom capable of forming an additional bond by a substituent (preferably one to three substituents per ring) independently selected from the group consisting of fluoro, chloro, bromo, (C-,-C6)alkyl, (CrC6)alkoxy, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)aikoxy and (C6-C10)aryloxy, or when R3 and R4 are taken together with the carbon atom to which they are attached to form a group of the formula
Figure imgf000005_0002
then any of the carbon atoms of said ring, capable of forming an additional bond, may be optionally substituted by a substituent (preferably zero to three substituents) independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl, (CrC6)alkoxy, perfluoro(CrC3)alkyl, perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy, R is R O or R R N wherein R6 and R7 are each independently selected from the group consisting of hydrogen, (C C6)alkyl, (C6-C10)aryl(C C6)alkyl or (C2-C9)heteroaryl(CrC6)alkyl, wherein each of said (C6-C10)aryl and (C2-C9)heteroaryl moieties of said (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl groups may be optionally substituted by one or more substituents independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (C C6)alkoxy, perfluoro^-C^alkyl, perfluoro(CrC3)alkoxy and (C6-C10)aryloxy, or R6 and R7 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle selected from piperazinyl, (CrC6)alkylpιperazιnyl,
(C6-C10)arylpιperazιnyl, (C2-C9)heteroarylpιperazιnyl, (C6-C10)aryl(CrC6)alkylpιperazιnyl,
(C2-C9)heteroaryl(CrC6) alkylpiperazinyl, (CrC6)alkyl(C=0)-pιperazιnyl, (C C6)alkoxy(C=0)- piperazinyl, (C6-C10)aryl(C=O)-pιperazιnyl, (C6-C10)aryl(C C6)alkyl(C=O)-pιperazιnyl,
(C6-C10)aryl(C1-C6)alkoxy(C=O)-pιperazιnyl, morpholinyl, pipeπdinyl, pyrrolidinyl or azetidinyl, wherein each of said piperazinyl, (CrC6)alkylpιperazιnyl, (C6-C10)arylpιperazιnyl,
(C2-C9)heteroarylpιperazιnyl, (C6-C10)aryl(C1-C6)alkylpιperazιnyl, (C C^heteroary C Cs) alkylpiperazinyl, (C1-C6)alkyl(C=0)-pιperazιnyl, (CrC6)alkoxy(C=0)-piperazinyl, (C6-C10)aryl(C=O)-pιperazιnyl, (C6-C10)aryl(CrC6)alkyl(C=O)-pιperazιnyl,
(C6-C10)aryl(C1-C6)alkoxy(C=O)-pιperazιnyl, morpholinyl, pipendinyl, pyrrolidinyl or azetidinyl may be optionally substituted on any ring carbon atom capable of forming an additional bond with a substituent (preferably one to three substituents per ring) independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy, perfluoro(C1-C3)alkyl, or perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy,
R8 is piperazinyl, (C1-C6)alkylpιperazιnyl, (C6-C10)arylpιperazιnyl,
(C2-C9)heteroarylpιperazιnyl, (C6-C10)aryl(C1-C6)alkylpιperazιnyl, (C2-C9)heteroaryl(C1-C6) alkylpiperazinyl, (C C6)alkyl(C=0)-pιperazιnyl, (C C6)alkoxy(C=0)-pιperazιnyl,
(C6-C10)aryl(C=O)-pιperazιnyl, (C6-C10)aryl(C1-C6)alkyl(C=O)-pιperazιnyl, (C6-C10)aryl(CrC6)alkoxy(C=O)-pιperazιnyl, morpholinyl, pipendinyl, pyrrolidinyl, azetidinyl, pipeπdyl, (CrC6)alkylpιperιdyl, (C6-C10)arylpιperιdyl, (C2-C9)heteroarylpιpeπdyl,
(C6-C10)aryl(C1-C6)alkylpιperιdyl, (C2-C9)heteroaryl(C1-C6)alkylpιperιdyl, (CrC6)alkyl(C=0)- pipeπdyl, (C C6)alkoxy(C=0)-pιperιdyl, (C6-C10)aryl(C=O)-pιperιdyl,
(C6-C10)aryl(C1-C6)alkyl(C=O)-piperidyl, or (C6-C10)aryl(C1-C6)alkoxy(C=0)-pιpeπdyl, wherein each of said piperazinyl, (CrC6)alkylpιperazιnyl, (C6-C10)arylpιperazιnyl, (C2-C9)heteroarylpιperazιnyl, (C6-C10)aryl(CrC6)alkylpιperazιnyl, (C2-C9)heteroaryl(CrC6) alkylpiperazinyl, (C1-CP)alkyl(C=0)-ριperazιnyl, (CrC6)alkoxy(C=0)-pιperazιnyl,
(C6-C10)aryl(C=O)-pιperazιnyl, (C6-C10)aryl(C1-C6)alkyl(C=O)-pιperazιnyl,
(C6-C10)aryl(C1-C6)alkoxy(C=O)-pιperazιnyl, morpholinyl, pipendinyl, pyrrolidinyl, azetidinyl, pipendyl, (C C6)alkylpιperιdyl, (C6-C10)arylpιperιdyl, (C2-C9)heteroarylpιperιdyl,
(Ce-C^Jary C CeJalkylpipeπdyl, (C2-C9)heteroaryl(C1-C6)alkylpιperιdyl (CrC6)alkyl(C=0)- pipeπdyl, (CrC6)alkoxy(C=0)-pιpeπdyl, (C6-C10)aryl(C=O)-pιpeπdyl,
(C6-C10)aryl(CrC6)alkyl(C=O)-pιperιdyl, and (C6-C10)aryl(C1-C6)alkoxy(C=O)-pιperιdyl may be optionally substituted on any ring carbon atom capable of forming an additional bond with a substituent (preferably one to three substituents per ring) independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy, perfluoro(C1-C3)alkyl, or perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy,
Q is (CrC6)alkyl, (C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6- C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2- C9)heteroaryl(C2-C9)heteroaryl, (C1-C6)alkyl(C6-C10)aryl, (C1-C6)alkoxy(C6-C10)aryl, (C6- C10)aryl(CrC6)alkoxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C2-
C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl(C2-C9)heteroaryl, (C1-C6)alkoxy(C2-C9)heteroaryl, (C6- C10)aryl(CrC6)alkoxy(C2-C9)heteroaryl, (C2-C9)heteroaryloxy(C2-C9)heteroaryl, (C6-
C10)aryloxy(C1-C6)alkyl, (C2-C9)heteroaryloxy(C1-C6)alkyl, (CrC6)alkyl(C6-C10)aryloxy(C6- C10)aryl, (CrC6)alkyl(C2-C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl(C6-C10)aryloxy(C2-
C9)heteroaryl, (C1-C6)alkoxy(C6-C10)aryloxy(C6-C10)aryl, (CrC6)alkoxy(C2-C9)heteroaryloxy(C6- C10)aryl or (C1-C6)alkoxy(C6-C10)aryloxy(C2-C9)heteroaryl wherein each (C6-C10)aryl or (C2- C9)heteroaryl moieties of said (C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C C6)alkyl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (Cr Cβ)alkyl(Cβ-C10)aryl, (CrC6)alkoxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C6-C10)aryl, (C6- C10)aryl(CrC6)alkoxy(C C6)alkyl, (C2-C9)heteroaryloxy(C6-C10)aryl, (CrC6)alkyl(C2-
C9)heteroaryl, (C1-C6)alkoxy(C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkoxy(C2-C9)heteroaryl, (C2- C9)heteroaryloxy(C2-C9)heteroaryl, (C6-C10)aryloxy(CrC6)alkyl, (C2-C9)heteroaryloxy(C1-C6)alkyl, (CrC6)alkyl(C6-C10)aryloxy(C6-C10)aryl, (C1-C6)alkyl(C2-C9)heteroaryloxy(C6-C10)aryl, (Cr C6)alkyl(C6-C10)aryloxy(C2-C9)heteroaryl, (CrC6)alkoxy(C6-C10)aryloxy(C6-C10)aryl, (C C6)alkoxy(C2-C9)heteroaryloxy(C6-C10)aryl or (CrC6)alkoxy(C6-C10)aryloxy(C2-C9)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or more substituents (preferably one to three substituents) independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (C C6)alkoxy, perfluoro(CrC3)alkyl, perfluoro(C C3)alkoxy and (C6-C10)aryloxy, with the proviso that if either R3 or R4 is hydrogen, or if both R3 and R4 are hydrogen, then R1 and R2 can not both be hydrogen or R1 must be hydroxy, (CrC6)alkoxy, (C6-C10)aryl(C1-C6)alkoxy, (C C6)alkyl(C=0)0-(C1-C6)alkyl, (C C6)alkoxy(C=0)0-(CrC6)alkyl, (C6-C10)aryl(C=O)O-(C1-C6)alkyl, (C6-C10)aryloxy(C=O)O- (C6-C10)arylalkyl(C=O)O-(CrC6)alkyl or (C6-C10)arylalkoxy(C=O)O-(CrC6)alkyl, or a pharmaceutically acceptable salt thereof
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, ]_§_, salts containing pharmacologically acceptable anions, such as the hydrochlonde, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate []_e_, 1 ,1'-methylene-bιs-(2-hydroxy-3- naphthoate)]salts
The invention also relates to base addition salts of formula I The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e g . potassium and sodium) and alkaline earth metal cations (e g . calcium and magnesium), ammonium or water- soluble amine addition salts such as N-methylglucamιne-(meglumιne), tπmethyl-ammonium or diethylammonium, and the lower alkanolammonium salts such tπs-(hydroxymethyl)- methylammonium and other base salts of pharmaceutically acceptable organic amines
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof
The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is defined above
The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl
The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroyi, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyπmidyl, quinolyl, isoquinoly., benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, punnyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl The term "acyl", as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkoxy and the terms "alkyl" or "aryl" are as defined above
The term "acyloxy", as used herein, includes O-acyl groups wherein "acyl" is defined above The compound of formula I may have chiral centers and therefore exist in different diasteπomeπc or enantiomeπc forms This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof
Preferred compounds of formula I include those wherein R1 is OH and R2 is hydrogen Other preferred compounds of formula I include those wherein both R3 and R4 are (CrC6)alkyl or R3 and R4 are taken together to form an optionally substituted (C3-C6)cycloalkyl ring or a benzo-fused(C3-C6)cycloalkyl ring or a group of the formula
Figure imgf000009_0001
wherein the carbon atom bearing the asterisk is the carbon to which R3 and R4 are atttached, "n" and "m" are independently selected from the integers one and two, and X is CF2, O, S02 or NR9, wherein R9 is hydrogen, (CrC6)alkyl, (C6-C10)aryl, (C2-C9)heteroalkyl, (C6- C10)aryl(CrC6)alkyl, (C2-C9)heteroaryl(CrC6)alkyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, (CrC6)alkyl(C=0)-, (CrC6)alkoxy(C=0)-, (C6-C10)aryl(C=O)-, (C6-C10)aryl(CrC6)alkyl(C=O)-, or (C6-C10)aryl(C1-C6)alkoxy(C=O)-, wherein each of said (C6-C10)aryl and (C2-C9)heteroaryl moieties of said (C6-C10)aryl, (C2-C9)heteroalkyl, (C6-C10)aryl(CrC6)alkyl, (C2-C9)heteroaryl(Cr C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)aryl(C=O)-, (C6-C10)aryl(CrC6)alkyl(C=O)-, and (C6-C10)aryl(CrC6)alkoxy(C=O)- groups may be optionally independently substituted with one or more substituents (preferably one to three substituents) independently selected from the group consisting of fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy, perf>uoro(C C3)alkyl, perfluoro(CrC3)alkoxy and (C6-C10)aryloxy More preferred compounds of formula I include those wherein R3 and R4 are taken together to form an optionally substituted (C3-C6)cycloalkyl ring
Other preferred compounds of formula I include those wherein R1 is hydroxy Other preferred compounds of formula I include those wherein Q is (C6-C10)aryl or (Cβ- C10)aryloxy(C6-C10)aryl, wherein each (C6-C10)aryl moieties of said is (C6-C10)aryl or (C6- C10)aryloxy(C6-C10)aryl groups may be optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (CrCβ)alkyl, (CrC6)alkoxy or perfluoro(C1- C3)alkyl
More preferred compounds of formula I include those wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy or perfluoro(C1-C3)alkyl, more preferably the substituents are selected from fluoro, chloro, (CrC6)alkoxy or (CrC6)alkyl, most preferably the substituent is in the 4-posιtιon
Specific preferred compounds of formula I include the following (2S)-2,N-dιhydroxy-3-(4-methoxybenzenesulfonyl)propιonamιde, 3-[4-(4-fluorophenoxy)phenylsulfonyl]-2,N-dιhydroxypropιonamιde, 2,N-dιhydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclobutyl]acetamιde
2,N-dιhydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclopentyl]acetamιde, 2-[1-(4-cyclobutoxybenzenesulfonyl)cyclobutyl]-2,N-dιhydroxyacetamιde, 2-[1-(4-butoxybenzenesulfonyl)cyclobutyl]-2,N-dιhydroxyacetamιde, 2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclobutyl}-2,N-dιhydroxyacetamιde, or 2-{1-t4-(4-fluorophenoxy)benzenesulfonyl]cyclopentyl}-2,N-dιhydroxyacetamιde
Other specific compounds of formula I include the following 2,N-dιhydroxy-2-[1-(4-phenoxybenzenesulfonyl)cyclopentyl]acetamιde, 2,N-dιhydroxy-2-[1-(4-phenoxybenzenesulfonyl)cyclobutyl]acetamιde, acetic acid {1 -[4-(4-fluorophenoxy)benzenesulfonyl]cyclopentyl}hydroxycarbamoyl methyl ester, acetic acid {1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclobutyl}hydroxycarbamoyl methyl ester,
2-{i-[4-(4-fluorophenoxy)benzenesulfonyl]cyclopentyl}-N-hydroxy-2-methoxy- acetamide, 2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclobutyl}-N-hydroxy-2- methoxyacetamide,
2-[ -(4-butoxybenzenesulfonyl)cyclohexyl]-2,N-dιhydroxyacetamιde, 2-[i-(4-butoxybenzenesulfonyl)cyclopentyl]-2,N-dιhydroxyacetamιde, or 2-[i-(4-butoxybenzenesulfonyl)cyclobutyl]-2,N-dιhydroxyacetamιde The present invention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, osteoporosis, cancer, synergy with cytotoxic anticancer agents, tissue uiceration, macular degeneration, restenosis, peπodontal disease, epidermolysis bullosa, sclentis, in combination with standard NSAID'S and analgesics and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier The present invention also relates to a method for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof
The present invention also relates to a method for treating a condition selected from the group consisting of arthritis, osteoporosis, cancer, tissue uiceration, macular degeneration, restenosis, peπodontal disease, epidermolysis bullosa, sclentis, compounds of formula I may be used in combination with standard NSAID'S and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition
Detailed Description of the Invention The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated n, m, R1, R2, R3, R4, R5, R6, R7, R8, Q and X in the reaction Schemes and the discussion that follow are defined as above.
SCHEME 1
Figure imgf000013_0001
VI V
Figure imgf000013_0002
IV
Figure imgf000013_0003
SCHEME 2
Figure imgf000014_0001
Figure imgf000014_0002
XII
XI
Figure imgf000014_0003
x
Figure imgf000014_0004
VII
SCHEME 3
Figure imgf000015_0001
XVII
Figure imgf000015_0002
SCHEME 4
Figure imgf000016_0001
XXIII
Figure imgf000016_0002
Scheme 1 refers to the preparation of compounds of the formula I, wherein R3 and R4 are hydrogen Referring to Scheme I, a compound of the formula i is prepared from a compound of the formula II by hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction inert solvent Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol The aforesaid reaction may be performed at a pressure from about 1 to about 5 atmospheres, preferably about 3 atmospheres Suitable temperatures for the aforesaid reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature) The reaction is complete within about 0 5 hours to about 5 hours, preferably about 3 hours
The compound of formula II is prepared from a compound of formula III by reaction with O-benzylhydroxylamine hydrochloπde, an activating agent, and a base in a reaction inert solvent Suitable activating agents include (benzotπazol-l-yloxy)tπs(dιmethylamιno) phosphonium hexafluorophosphate or 1-(3-(dιmethylamιnopropyl)-3-ethylcarbodιιmιde hydrochlonde, preferably (benzotπazol-l-yloxy)tπs(dιmethylamιno) phosphonium hexafluorophosphate Suitable bases include tertiary amines such as triethylamine, diisopropylethylamine or 4-N,N-dιmethylamιnopyπdιne, preferably triethylamine The temperature of the aforesaid reaction may range from about 0°C to about 60°C, preferably about 20°C (room temperature) Suitable solvents include halogenated solvents such as methylene chloride or chloroform, or ethers such as THF or diethyl ether, preferably the solvent is methylene chloride The reaction is complete in about 4 hours to about 48 hours, preferably about 16 hours
The compound of formula III is prepared from a compound of formula IV by hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction inert solvent Suitable catalysts include palladium or 5-10% palladium on activated charcoal, preferably 10% palladium on activated charcoal Suitable solvents include acetic acid, alcohols such as ethanol, methanol, or isopropanol, preferably ethanol The aforesaid reaction may be performed at a pressure from about 1 to about 5 atmospheres, preferably about 3 atmospheres Suitable temperatures for the aforesaid reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature) The reaction is complete within about 0 5 hours to about 24 hours, preferably about 3 hours
Compounds of the formula IV can be prepared from compounds of the formula V by reaction with an oxidant in a reaction inert solvent Suitable oxidants include meta- chloroperbenzoic acid, hydrogen peroxide or sodium perborate, preferably meta- chloroperbenzoic acid Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride Suitable temperatures for the aforesaid reaction range from about 0°C to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature) The reaction is complete within about 0 5 hours to about 24 hours, preferably about 3 hours
Compounds of the formula V, wherein R1 is hydroxy, can be prepared from compounds of the formula VI by reaction with a Gngnard reagent and a thiol of the formula QSH in a reaction inert solvent Suitable Gngnard reagents include ethyl magnesium bromide or phenyl magnesium bromide, preferably ethyl magnesium bromide Suitable solvents include ethers such as diethy1 ether, tetrahydrofuran or 1 ,2-dιmethoxyethane, preferably the solvent is a mixture of tetrahydrofuran and diethyl ether Suitable temperatures for the aforesaid reaction are from about -78°C to about 50°C , preferably from about 0°C to about 25°C (i e room temperature) The reaction is complete in about 1 to about 24 hours, preferably about 3 hours Compounds of the formula V, wherein R1 is (C6-C10)aryl(CrC6)alkoxy or (C C6)alkoxy, can be prepared from compounds of the formula V, wherein R1 is hydroxy, by reaction with a compound of the formula R1aL, wherein L is a leaving group and R1a is (C6-C10)aryl(C1-C6)alkyl or (C1-C6)alkyl, in the presence of a strong base in an aprotic polar solvent Suitable leaving groups include chloro, fluoro, bromo, mesylate, triflate or tosylate Preferably, the leaving group is lodo Suitable bases include sodium hydride, lithium dialkyi amides such as lithium N- isopropyl-N-cyclohexylamide or lithium dnsopropyl amide, potassium t-butoxide, sodium amide, or potassium hydride, preferably sodium hydride Suitable solvents include ethers (such as THF, diethyl ether or 1 ,2-dιmethoxyethane), preferably THF The aforesaid reaction is conducted at about -78°C to about 0°C, preferably at about 0°C Compounds of the formula V, wherein R1 is (C1-C6)alkyl(C=0)0-, (C1-Cβ)alkoxy-
(C=0)0-, (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-, (C6-C10)aryl(CrC6)alkyl(C=O)O- or (C6-C10)aryl(C1-C6)alkoxy(C=O)O-, can be prepared from compounds of the formula V, wherein R1 is hydroxy, by reaction with a compound of the formula R1 L, wherein is a leaving group and R is (CrC6)alkyl(C=0)-, (CrC6)alkoxy(C=0)-, (C6-C10)aryl(C=O)-, (C6-C10)aryloxy(C=0)-T (C6-C10)aryl(C1-C6)alkyl(C=O)- or (C6-C10)aryl(CrC6)alkoxy(C=O)-, in the presence of a base in a reaction inert solvent Suitable leaving groups include chloro, fluoro, bromo, or R1bO (i e an anhydride) Preferably, the leaving group is chloro Suitable bases include tertiary amine bases such as triethylamine, pyridine or 4-dιmethylamιnopyrιdιne, preferably triethylamine The temperature of the aforesaid reaction is from about 0°C to about 30°C, preferably from about 20°C to about 25°C (i e room temperature) Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride The reaction is conducted from about 1 hour to about 24 hours, preferably for about 2 hours
Compounds of the formula VI can be prepared by methods well known to those of ordinary skill in the art Compounds of the formula VI can also be prepared by peracid oxidation (e g , meta-chloroperbenzoic acid) of the corresponding ,β-unsaturated benzyl esters as described in Jerry March, Advanced Organic Chemistry. 735 (3rd ed , 1985) The corresponding ,β-unsaturated benzyl esters may be prepared by Knovenagel condensation between a malonate monobenzyl ester and paraformaldehyde in the presence of pipendine as described in H O House, Modern Synthetic Reactions. 649-651 (2nd ed , WA Benjamin, Menlo Park, California, 1972)
Compounds of the formula VI, wherein R2 is hydrogen, can also be prepared in racemic or enantiomeπcally pure form by conversion of L-, D-, or D,L-serιne as reported by W Roush and B Brown, J Org Chem . 47, 3387 (1992)
Scheme 2 refers to the preparation of compounds of the formula I, wherein R2 is hydrogen and R1 is OH Referring to Scheme 2, compounds of formula I can be prepared from compounds of the formula VII by hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction inert solvent Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol The aforesaid reaction may be performed at a pressure from about 1 to about 5 atmospheres, preferably about 3 atmospheres Suitable temperatures for the aforesaid reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature) The reaction is complete within about 0 5 hours to about 5 hours, preferably about 3 hours Compounds of the formula VII can be prepared from compounds of the formula VIII by reaction with an alkali metal hydroxide in a polar solvent Suitable alkali metal hydroxides include lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide, most preferably about 5 equivalents of the alkali metal hydroxide The aforesaid reaction may conducted at a temperature from about 0°C to about 60°C, preferably from about 20°C to about 25°C (ι e room temperature) Suitable solvents include a mixture of water and an alcohol such as methanol or ethanol and, optionally an water miscible ether such as tetrahydrofuran or 1 ,2-dιmethoxyethane Preferably, the solvent system is methanol/water/tetrahydrofuran The reaction is conducted from about 1 to about 72 hours, preferably about 24 hours The compound of formula VIII is prepared from a compound of the formula IX by reaction with O-benzylhydroxylamine hydrochloπde in the presence of a catalyst and a base in a reaction inert solvent Suitable catalysts include (benzotrιazol-1- yloxy)trιs(dιmethylamιno)phosphonιum hexafluorophosphate or 1-(3-(dιmethylamιnopropyl)-3- ethylcarbodnmide hydrochloπde, preferably (benzotπazol-l-yloxy)trιs(dιmethylamιno) phosphonium hexafluorophosphate Suitable bases include tertiary amines such as triethylamine diisopropylethylamme or dimethylaminopyπdine, preferably triethylamine The aforesaid reaction temperature is from about 0° C to about 60°C, preferably from about 20° C to about 25°C (i e. room temperature) Suitable solvents include halogenated solvents such as methylene chloride or c.iloroform, preferably methylene chloride The reaction is conducted from about 4 hours to about 48 hours, preferably about 16 hours
The compound of formula IX is prepared from a compound of the formula X by reaction with an excess of sodium peπodate in the presence of catalytic ruthenium trichloride hydrate The aforesaid reaction is conducted at a temperature from about 0°C to about 35°C, preferably from about 20°C to about 25°C (i e room temperature) Suitable solvents include acetone or a mixture of acetonitnle, carbon tetrachloπde and water, preferably a 1 1 2 mixture of acetonitile, carbon tetrachlonde and water The reaction is conducted from about 0 5 to about 2 hours, preferably about 1 25 hours
The compound of the formula X, wherein "P" is pivaloyl, acetyl or benzoyl, is prepared by reaction of a compound of the formula XI with a protecting group reagent in the presence of a base in a reaction inert solvent Suitable protecting group reagents include pivaloyl chloride, pivaloic anhydride, acetyl chloride, acetic anhydride, benzoyl cloπde or benzoic anhydride, preferably acetic anhydride Suitable bases include tertiary amine bases such as pyridine or 4-N,N-dιmethylamιnopyrιdιne, preferably 4-N, N-dimethylaminopyπdine The temperature of the aforesaid reaction is from about 0°C to about 30°C, preferably from about 20°C to about 25°C (i e room temperature) Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride The reaction is conducted from about 1 hour to about 24 hours, preferably for about 2 hours
The compound of formula XI is prepared from a compound of the formula XII by reaction with 2-furaldehyde and a strong base in a polar aprotic solvent Suitable bases include potassium-tert -butoxide, lithium diisopropylamide, and butyl lithium, preferably 2 5 M n- butyllithium in hexane The temperature of the aforesaid reaction is from about -78°C to about 0°C, preferably about -78°C Suitable solvents include diethyl ether, tetrahydrofuran, or 1,2- dimethoxyethane, preferably the solvent is tetrahydrofuran The reaction is conducted from about 0 25 hours to about 6 hours, preferably about 0 33 hours The compound of formula XII is prepared from a compound of the formula XIII by reaction with an oxidant in a reaction inert solvent Suitable oxidants include meta- chloroperbenzoic acid, hydrogen peroxide or sodium perborate, preferably meta- chloroperbenzoic acid Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride Suitable temperatures for the aforesaid reaction range from about 0°C to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature) The reaction is complete within about 0 5 hours to about 24 hours, preferably about 3 hours
The compound of the formula XIII is prepared from a compound of the formula XIV by reaction with a thiol of the formula QSH in the presence of a base in an aprotic solvent Suitable bases include sodium hydride, ethyl magnesium bromide, lithium diisopropyl amide, potassium hydride, or sodium methoxide, preferably sodium hydride The temperature of the aforesaid reaction is from about 0°C to about 60°C, preferably 20°C to about 25°C (i e room temperature) Suitable solvents include aprotic solvents such as methylene chloride, tetrahydrofuran or N,N-dιmethylformamιde, preferably N,N-dιmethylformamιde The reaction is conducted for about 1 hour to about 48 hours, preferably about 16 hours
Compounds of the formula XIV and QSH are commercially available or can be made by methods well known to those of ordinary skill in the art Compounds of the formula QSH can also be prepared by reaction of an alkyl or aryl halide with sodium sulfhydπde as described in Jerry March, Advanced Organic Chemistry. 360 and 589 (3rd ed , 1985) Alternatively, compounds of the formula QSH can also be prepared by reaction of an aryl diazonium salt with sodium sulfhydnde as described in March ιd_ at 601 Alternatively, compounds of the formula QSH can also be prepared by reaction of a Gngnard reagent with sulfur as described in March id. at 550 Alternatively, compounds of the formula QSH can also be prepared by reduction of a sulfonyl chloride, sulfonic acid or disulfide as described in March ιd_ at 1107 and 1110 Scheme 3 refers to the preparation of compounds of the formula I, wherein R1 is other than hydroxy and R2 is hydrogen
Referring to Scheme 3, compounds of the formula I are prepared from compounds of the formula XVII by hydrogenolysis according to methods analogous to the methods described for converting compounds of formula VII to compounds of formula I in Scheme 2 Compounds of the formula XVII are prepared from compounds of the formula XVI by reaction with O-benzylhydroxylamine hydrochloπde in the presence of a catalyst and a base in a reaction inert solvent according to methods analogous to the conversion of compounds of the formula IX to formula VIII as described above in Scheme 2 Compounds of the formula XVI are prepared from compounds of the formula XV by reaction with an excess of sodium periodate in the presence of a catalyst according to methods analogous to those used for the conversion of compounds of the formula X to formula IX as described above in Scheme 2.
Compounds of the formula XV, wherein R1 is (C6-C10)aryl(C C6)alkoxy or (C,-Ce)alkoxy, can be prepared from compounds of the formula XI by reaction with a compound of the formula R1aL, wherein L is a leaving group and R1a is (C6-C10)aryl(C1-C6)alkyl or (C1-Cβ)alky1, in the presence of a strong base in an aprotic polar solvent. Suitable leaving groups include chloro, fluoro, bromo, mesylate, triflate or tosylate. Preferably, the leaving group is iodo. Suitable bases include lithium dialkyi amides such as lithium N-isopropyl-N-cyclohexylamide or lithium diisopropyl amide, potassium t-butoxide, sodium amide, potassium hydride or sodium hydride, preferably sodium hydride. Suitable solvents include ethers (such as THF, diethyl ether or 1 ,2-dimethoxyethane), preferably THF. The aforesaid reaction is conducted at about -78°C to about 0°C, preferably at about 0°C.
Compounds of the formula XV, wherein R1 is (C C6)alkyl(C=0)0-, (C1-C6)alkoxy(C=0)0-l (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-,
(C6-C10)aryl(C1-C6)alkyl(C=O)O- or (C6-C10)aryl(CrC6)alkoxy(C=O)O-, can be prepared from compounds of the formula XI by reaction with a compound of the formula R1bL, wherein L is a leaving group and R is (C1-Cβ)alkyl(C=0)-, (C1-C6)alkoxy(C=0)-l (C6-C10)aryl(C=O)-, (C6-C10)aryloxy(C=O)O-, (C6-C10)aryl(C1-C6)alkyl(C=O)- or (C6-C10)aryl(C C6)alkoxy(C=O)-, in the presence of a base in a reaction inert solvent. Suitable leaving groups include chloro, fluoro, bromo or (R b)0- (i.e. an anhydride). Preferably, the leaving group is chloro. Suitable bases include tertiary amine bases such as triethylamine, pyridine or 4-dimethylaminopyridine, preferably triethylamine. The temperature of the aforesaid reaction is from about 0°C to about 30°C, preferably from about 20°C to about 25°C (i.e. room temperature). Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride. The reaction is conducted from about 1 hour to about 24 hours, preferably for about 2 hours.
Compounds of the formula XI can be made according to the methods of Scheme 2. Scheme 4 refers to the preparation of compounds of the formula I, wherein R2 is other than hydrogen and R3 and R4 are other than hydrogen.
Referring to Scheme 4, compounds of the formula I are prepared from compounds of the formula XXIII by hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction inert solvent. Suitable catalysts include 5% palladium on barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably methanol The aforesaid reaction may be performed at a pressure from about 1 to about 5 atmospheres, preferably about 3 atmospheres Suitable temperatures for the aforesaid reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature) The reaction is complete within about U 5 hours to about 5 hours, preferably about 3 hours
The compound of the formula XXIII is prepared from a compound of the formula XXII by reaction with O-benzylhydroxylamine hydrochlonde in the presence of a catalyst and a base in a reaction inert solvent Suitable catalysts include (benzotrιazol-1- yloxy)tπs(dιmethylamιno)phosphonιum hexafluorophosphate or 1-(3-(dιmethylamιnopropyl)-3- ethylcarbodiimide hydrochlonde, preferably (benzotπazol-l-yloxy)trιs(dιmethylamιno) phosphonium hexafluorophosphate Suitable bases include tertiary amines such as triethylamine diisopropylethylamine or dimethylaminopyπdine, preferably triethylamine The aforesaid reaction temperature is from about 0° C to about 60°C, preferably from about 20° C to about 25°C (i e room temperature) Suitable solvents include halogenated solvents such as methylene chloride or chloroform, preferably methylene chloride The reaction is conducted from about 4 hours to about 48 hours, preferably about 16 hours
The compound of the formula XXII can be prepared by deprotection of a compound of the formula XXI by reaction with an alkali metal hydroxide in a polar solvent Suitable alkali metal hydroxides include lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide, most preferably about 5 equivalents of the alkali metal hydroxide
The aforesaid reaction may conducted at a temperature from about 0°C to about 60°C, preferably from about 20°C to about 25°C (i e room temperature) Suitable solvents include a mixture of water and an alcohol such as methanol or ethanol and, optionally an water miscible ether such as tetrahydrofuran or 1 ,2-dιmethoxyethane Preferably, the solvent system is methanol/water/tetrahydrofuran The reaction is conducted from about 1 to about 72 hours, preferably about 24 hours
Compounds of the formula XXI can be prepared from compounds of the formula XII by reaction with a compound of the formula
Figure imgf000023_0001
XXVII wherein P' is methyl, ethyl or benzyl, and a strong base in a polar aprotic solvent Suitable bases include sodium hydride (NaH), potassium-tert -butoxide, lithium dπsopropylamide, and butyl lithium, preferably 2 5 M n-butyllithium in hexane The temperature of the aforesaid reaction is from about -78°C to about 0°C, preferably about -78°C Suitable solvents include diethyl ether, tetrahydrofuran, or 1 ,2-dιmethoxyethane, preferably the solvent is tetrahydrofuran The reaction is conducted from about 0 25 hours to about 6 hours, preferably about 0 33 hours
Alternatively, compounds of the formula I, wherein R1 is other than hydroxy, R2 is other than hydrogen and R and R4 are other than hydrogen, can be prepared from compounds of the formula XXV by methods analogous to the conversion of compounds of the formula XXII to compounds of formula I, as described above in Scheme 4 Compounds of the formula XXV can be prepared from compounds of the formula
XXIV, wherein P' is benzyl, by hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction inert solvent Suitable catalysts include palladium or 5- 10% palladium on activated charcoal, preferably 10% palladium on activated charcoal Suitable solvents include acetic acid, alcohols such as ethanol, methanol, or isopropanol, preferably ethanol The aforesaid reaction may be performed at a pressure from about 1 to about 5 atmospheres, preferably about 3 atmospheres Suitable temperatures for the aforesaid reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature may range from about 20°C to about 25°C (i e room temperature) The reaction is complete within about 0 5 hours to about 24 hours, preferably about 3 hours Compounds of the formula XXIV, wherein R1 is (C6-C10)aryl(C1-C6)alkoxy,
(CrC6)alkoxy, can be prepared from compounds of the formula XXI by reaction with an arylalkyl or alkyl halide in the presence of a base in an aprotic solvent Suitable bases include sodium hydride, ethyl magnesium bromide, lithium diisopropyl amide, potassium hydride, or sodium methoxide, preferably sodium hydride The temperature of the aforesaid reaction is from about 0°C to about 60°C, preferably 20°C to about 25°C (i e room temperature) Suitable solvents include aprotic solvents such as methylene chloride, tetrahydrofuran or N,N- dimethylformamide, preferably N,N-dιmethylformamιde The reaction is conducted for about 1 hour to about 48 hours, preferably about 16 hours
Alternatively, compounds of the formula XXIV, wherein R1 is (C1-C6)alkyl(C=0)0-, (C C6)alkoxy(C=0)0-, (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-,
(C6-C10)aryl(C1-C6)alkyl(C=O)O- or (C6-C10)aryl(C1-C6)alkoxy(C=O)O-, can be prepared from compounds of the formula XXI by reaction with an arylacyl or acyl halide in the presence of a base in an aprotic solvent Suitable bases include tertiary amines such as triethylamine, dnsopropylethylamine or 4-N,N-dιmethylamιnopyrιdιne, preferably triethylamine The temperature of the aforesaid reaction may range from about 0°C to about 60°C, preferably about 20°C (room temperature) Suitable solvents include halogenated solvents such as methylene chloride or chloroform, or ethers such as THF or diethyl ether, preferably the solvent is methylene chloride The reaction is complete in about 4 hours to about 48 hours, preferably about 16 hours The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol Upon careful evaporation of the solvent, the desired solid salt is obtained
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, ]_§_, salts containing pharmacologically acceptable anions, such as hydrochlonde, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [ι_e_, 1 ,1'-methylene-bιs-(2-hydroxy-3- naphthoate)] salts
Those compounds of the formula I which are also acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts These salts are all prepared by conventional techniques The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields
The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter also referred to as the compounds of the present invention) to inhibit matrix metalloproteinases or the production of tumor necrosis factor (TNF) and, consequently, demonstrate their effectiveness for treating diseases characterized by matrix metalloproteinase or the production of tumor necrosis factor is shown by the following yjtro assay tests
Biological Assay Inhibition of Human Collaαenase (MMP-1)
Human recombinant collagenase is activated with trypsin using the following ratio 10 mg trypsin per 100 mg of collagenase The trypsin and collagenase are incubated at room temperature for 10 minutes then a five fold excess (50 mg/10 mg trypsin) of soybean trypsin inhibitor is added 10 mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then diluted using the following Scheme
10 mM > 120 μM > 12 μM > 1 2 μM > 0 12 μM
Twenty-five microliters of each concentration is then added in triplicate to appropriate wells of a 96 well microfluor plate The final concentration of inhibitor will be a 1 4 dilution after addition of enzyme and substrate Positive controls (enzyme, no inhibitor) are set up in wells D1- D6 and blanks (no enzyme, no inhibitors) are set in wells D7-D12
Collagenase is diluted to 400 ng/ml and 25 ml is then added to appropriate wells of the microfluor plate Final concentration of collagenase in the assay is 100 ng/ml
Substrate (DNP-Pro-Cha-Gly-Cys(Me)-Hιs-Ala-Lys(NMA)-NH2) is made as a 5 mM stock in dimethyl sulfoxide and then diluted to 20 mM in assay buffer The assay is initiated by the addition of 50 ml substrate per well of the microfluor plate to give a final concentration of 10 mM
Fluorescence readings (360 nM excitation, 460 nm emission) were taken at time 0 and then at 20 minute intervals The assay is conducted at room temperature with a typical assay time of 3 hours
Fluorescence vs time is then plotted for both the blank and collagenase containing samples (data from triplicate determinations is averaged) A time point that provides a good signal (the blank) and that is on a linear part of the curve (usually around 120 minutes) is chosen to determine IC50 values The zero time is used as a blank for each compound at each concentration and these values are subtracted from the 120 minute data Data is plotted as inhibitor concentration vs % control (inhibitor fluorescence divided by fluorescence of collagenase alone x 100) IC50's are determined from the concentration of inhibitor that gives a signal that is 50% of the control
If IC50's are reported to be <0 03 mM then the inhibitors are assayed at concentrations of 0 3 mM, 0 03 mM, 0 03 mM and 0 003 mM
Inhibition of Gelatmase (MMP-2) Inhibition of gelatmase activity is assayed using the Dnp-Pro-Cha-Gly-Cys(Me)-Hιs-Ala- Lys(NMA)-NH2 substrate (10 mM) under the same conditions as inhibition of human collagenase (MMP-1) 72kD gelatmase is activated with 1 mM APMA (p-aminophenyl mercuric acetate) for 15 hours at 4°C and is diluted to give a final concentration in the assay of 100 mg/ml Inhibitors are diluted as for inhibition of human collagenase (MMP-1) to give final concentrations in the assay of 30 mM, 3 mM, 0 3 mM and 0 03 mM Each concentration is done in triplicate
Fluorescence readings (360 nm excitation, 460 emission) are taken at time zero and then at 20 minutes intervals for 4 hours
IC50's are determined as per inhibition of human collagenase (MMP-1 ) If IC50's are reported to be less than 0 03 mM, then the inhibitors are assayed at final concentrations of 0 3 mM, 0 03 mM, 0 003 mM and 0 003 mM
Inhibition of Stromelysin Activity (MMP-3) Inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingarten and Feder (Wemgarten, H and Feder, J , Spectrophotometric Assay for Vertebrate Collagenase, Anal Biochem 147, 437-440 (1985)) Hydrolysis of the thio peptolide substrate [Ac-Pro-Leu-Gly-SCH[CH2CH(CH3)2]CO-Leu-Gly-OC2H5] yields a mercaptan fragment that can be monitored in the presence of Ellman's reagent Human recombinant prostromelysin is activated with trypsin using a ratio of 1 ml of a 10 mg/ml trypsin stock per 26 mg of stromelysin The trypsin and stromeiysin are incubated at 37°C for 15 minutes followed by 10 ml of 10 mg/ml soybean trypsin inhibitor for 10 minutes at 37°C for 10 minutes at 37°C to quench trypsin activity
Assays are conducted in a total volume of 250 ml of assay buffer (200 mM sodium chloride, 50 mM MES, and 10 mM calcium chloride, pH 6 0) in 96-well microliter plates Activated stromelysin is diluted in assay buffer to 25 mg/ml Ellman's reagent (3-Carboxy-4- nitrophenyl disulfide) is made as a 1M stock in dimethyl formamide and diluted to 5 mM in assay buffer with 50 ml per well yielding at 1 mM final concentration 10 mM stock solutions of inhibitors are made in dimethyl sulfoxide and diluted serially in assay buffer such that addition of 50 mL to the appropriate wells yields final concentrations of 3 mM, 0 3 mM, 0 003 mM, and 0 0003 mM All conditions are completed in triplicate
A 300 mM dimethyl sulfoxide stock solution of the peptide substrate is diluted to 15 mM in assay buffer and the assay is initiated by addition of 50 ml to each well to give a final concentration of 3 mM substrate Blanks consist of the peptide substrate and Ellman's reagent without the enzyme Product formation was monitored at 405 nm with a Molecular Devices
UVmax plate reader
IC50 values were determined in the same manner as for collagenase
Inhibition of MMP-13 Human recombinant MMP-13 is activated with 2mM APMA (p-aminophenyl mercuric acetate) for 1 5 hours, at 37°C and is diluted to 400 mg/ml in assay buffer (50 mM Tns, pH 7 5, 200 mM sodium chloride, 5mM calαum chloride, 20mM zinc chloride, 0 02% bπj) Twenty-five microliters of diluted enzyme is added per well of a 96 well microfluor plate The enzyme is then diluted in a 1 4 ratio in the assay by the addition of inhibitor and substrate to give a final concentration in the assay of 100 mg/ml
10 mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then diluted in assay buffer as per the inhibitor dilution scheme for inhibition of human collagenase (MMP-1) Twenty-five microliters of each concentration is added in triplicate to the microfluor plate The final concentrations in the assay are 30 mM, 3mM, 0 3 mM, and 0 03 mM Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-Hιs-Ala-Lys(NMA)-NH2) is prepared as for inhibition of human collagenase (MMP-1) and 50 ml is added to each well to give a final assay concentration of 10 mM Fluorescence readings (360 nM excitation, 450 emission) are taken at time 0 and every 5 minutes for 1 hour
Positive controls consist of enzyme and substrate with no inhibitor and blanks consist of substrate only
IC50's are determined as per inhibition of human collagenase (MMP-1) If IC50's are reported to be less than 0 03 mM, inhibitors are then assayed at final concentrations of 0 3 mM, 0 03 mM, 0 003 mM and 0 0003 mM
All of the compounds of the invention that were tested in the Inhibition of MMP-13 assay had IC50's of less than 50nm
Inhibition of TNF Production The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF is shown by the following m vitro assay Human mononuclear cells were isolated from anti-coagulated human blood using a one- step Ficoll-hypaque separation technique (2) The mononuclear cells were washed three times in Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2 x 10 /ml in HBSS containing 1% BSA Differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of the total cells in these preparations
180m of the cell suspension was aliquoted into flat bottom 96 well plates (Costar) Additions of compounds and LPS (100ng/ml final concentration) gave a final volume of 200ml All conditions were performed in triplicate After a four hour incubation at 37°C in an humidified C02 incubator, plates were removed and centπfuged (10 minutes at approximately 250 x g) and the supernatants removed and assayed for TNFα using the R&D ELISA Kit®
For administration to mammals, including humans, for the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF), a variety of conventional routes may be used including oral, parenteral (e g , intravenous, intramuscular or subcutaneous), buccal, anal and topical In general, the active compound will be administered at dosages between about 0 1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0 3 to 5 mg/kg Preferably the active compound will be administered orally or parenterally However, some variation in dosage will necessarily occur depending on the condition of the subject being treated The person responsible for administration will, in any event, determine the appropriate dose for the individual subject The compounds of the present invention can be administered in a wide variety of different dosage forms, in general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5 0% to about 70% by weight
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrro done, sucrose, gelation and acacia Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tablettmg purposes Solid compositions of a similar type may also be employed as fillers in gelatin capsules, preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof In the case of animals, they are advantageously contained in an animal feed or drinking water in a concentration of 5-5000 ppm, preferably 25 to 500 ppm
For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile mjectable solution of the active ingredient is usually prepared Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed The aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered isotonic These aqueous solutions are suitable intravenous injection purposes The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art In the case of animals, compounds can be administered intramuscularly or subcutaneously at dosage levels of about 0 1 to 50 mg/kg/day, advantageously 0 2 to 10 mg/kg/day given in a single dose or up to 3 divided doses The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e_g_, containing conventional suppository bases such as cocoa butter or other glycendes
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e g . dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafiuoroethane, carbon dioxide or other suitable gas In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount The pressurized container or nebulizer may contain a solution or suspension of the active compound Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch
The following Examples illustrate the preparation of the compounds of the present invention Melting points are uncorrected NMR data are reported in parts per million (d) and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform unless otherwise specified) Commercial reagents were utilized without further purification THF refers to tetrahydrofuran DMF refers to N,N-dιmethylformamιde Chromatography refers to column chromatography performed using 32-63 mm silica gel and executed under nitrogen pressure (flash chromatography) conditions Room or ambient temperature refers to 20-25°C All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields Concentration at reduced pressure means that a rotary evaporator was used
Example 1 (2S)-2.N-DIHYDROXY-3-(4-METHOXYBFNZENESULFONYL)PROPIONAMinF
(A) (2S)-2-Hvdroxy-3-(4-methoxyphenylsulfanyl)propιonιc acid benzyl ester A solution of 1 M ethylmagnesium bromide in diethyl ether (16 6 mL, 16 7 mmole) was diluted with tetrahydrofuran (32 mL) and cooled in an ice bath A solution of 4-methoxybenzenethιol (2 3 grams, 16 7 mmole) in anhydrous tetrahydrofuran (5 mL) was added dropwise The resulting mixture was allowed to stir at 0°C for 1 hour and then a solution of benzyl (2S)-glycιdate (2 3 grams, 12 9 mmole) in tetrahydrofuran (5 mL) was added The mixture was stirred at room temperature for 3 hours After quenching with water, the mixture was extracted with ether The aqueous layer was acidified to pH 5 and again extracted with diethyl ether The combined diethyl ether extracts were washed with water and brine, dried over magnesium sulfate and concentrated to an oil The product,
(2SJ-2-hydroxy-3-(4-methoxyphenylsulfanyl)propιonιc acid benzyl ester (36 grams, 88%) was isolated as a light yellow oil by chromatography on silica gel using 1 1 diethyl ether/hexane as eluant
(B) (2S)-2-Hvdroxy-3-(4-methoxybenzenesulfonyl)propιonιc acid benzyl ester A solution of (2SJ-2-hydroxy-3-(4-methoxyphenylsulfanyl)propιonιc acid benzyl ester (3 6 grams, 11 mmole) in methylene chloride (25 mL) was cooled in an ice bath and a solution of 50% m-chloroperbenzoic acid (8 4 grams, 24 mmole) in methylene chloride (75 mL) was added dropwise The resulting mixture was stirred at room temperature for 4 hours After quenching with saturated aqueous sodium bisulfite solution, the mixture was extracted with diethyl ether The extract was washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated to a white solid Recrystallization from 1 1 hexane/ethyl acetate afforded (2SJ-2-hydroxy-3-(4-methoxybenzenesulfonyl)propιonιc acid benzyl ester (3 2 grams, 84%) as a white crystalline solid
(C) (2S)-2-Hvdroxy-3-(4-methoxybenzenesulfonyl)propιonιc acιd A solution of (2SJ-2-hydroxy-3-(4-methoxybenzenesulfonyl)propιonιc acid benzyl ester
(1 0 grams, 2 8 mmole) in methanol (70 mL) was treated with 10% palladium on activated carbon
(100 mg) and hydrogenated at 3 atmospheres pressure for 3 hours in a Parr shaker The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated to afford (2SJ-2-hydroxy-3-(4-methoxybenzenesulfonyl)propιonιc acid as a white foam (729 mg, 100%)
(D) (2S)-N-Benzyloxy-2-hvdroxy-3-(4-methoxyben7enesulfonyl)propinnamirie
To a solution of (2S)-2-hydroxy-3-(4-methoxybenzenesulfonyl)propιonιc acid (800 mg, 3 0 mmole), O-benzylhydroxylamine hydrochlonde (526 mg, 3 3 mmole) and triethylamine (1 2 mL, 9 0 mmole) in methylene chloride (80 mL) was added (benzotrιazol-1-yloxy)trιs(dιmethylamιno)phosphonιum hexafluorophosphate (1 4 grams, 3 3 mmole) The reaction mixture was stirred at room temperature for 16 hours and was then diluted with methylene chloride The solution was washed successively with saturated aqueous sodium bicarbonate solution, water, 0 5 M aqueous hydrochloric acid solution and saturated brine After drying over magnesium sulfate, the solvent was evaporated to afford an oil The desired product, (2S)-N-benzyloxy-2-hydroxy-3-(4-methoxybenzenesulfonyl)propιonamιde (400 mg, 36%), was isolated by flash chromatography on silica gel eluting successively with chloroform, 1% methanol in chloroform and 2% methanol in chloroform
(E) (2S)-2.N-Dιhydroxy-3-(4-methoxybenzenesulfonyl)propιonamιde A solution of (2S)-N-benzyloxy-2-hydroxy-3-(4-methoxybenzenesulfonyl) propionamide
(400 mg, 1 0 mmole) in methanol (30 mL) was treated with 5% palladium on barium sulfate (200 mg) and hydrogenated at 3 atmospheres pressure for 4 hours in a Parr shaker The catalyst was removed by passage through a 0 45 μm nylon filter and the filtrate was concentrated The desired product, (2S)-2,N-dιhydroxy-3-(4-methoxybenzenesulfonyl) propιonamιde(180 mg, 65%), was isolated by flash chromatography on silica gel eluting with 5% methanol in chloroform followed by recrystallization from chloroform/methanol
Melting point 138-144°C, MS m/z 276 (M+1), analysis calculated for C10H13NO6S C, 4363, H, 4 76, N, 5 09 Found C, 43 51 , H, 468, N, 4 95
Example 2 3-[4-(4-FLUOROPHENOXY)PHENYLSULFONYLl-2.N-DIHYDROXYPROPIONAMIDE
3-[4-(4-Fluorophenoxy)phenylsulfonyl]-2,N-dιhydroxypropιonamιde was prepared by a method analogous to that described in Example 1 using (4-fluorophenoxy)phenylthιol as starting material Recrystallized from chloroform
Melting point 129-130°C, MS m/z 356 (M+1), analysis calculated for C15H14FN06S 0 75H20 C, 48 84, H, 4 24, N, 3 80 Found C, 49 03, H, 4 06, N, 3 86
Example 3 ? N-DIHYDROXY-?-f1-(4-METHOXYBENZENESULFONYL)CYCLOBUTYI-1ACETAMIDE
(A) 1-Cyclobutylsulfanyl-4-methoxybenzene 4-Methoxybenzenethιol (5 7 g, 40 7 mmole) was added to a suspension of sodium hydride (1 17 grams, 49 mmole) in dry N,N-dιmethylformamιde (50 mL) After stirring for 1 hour, cyclobutylbromide (6 0 grams, 444 mmole) was added The reaction mixture was stirred for 16 hours and was quenched by addition of saturated aqueous ammonium chloride solution The solvents were evaporated The residue was taken up in diethyl ether and washed successively with 0 5 N aqueous hydrochloric acid solution, water and brine After drying over magnesium sulfate, the diethyl ether was evaporated to afford 1-cyclobutylsulfanyl-4-methoxybenzene as an oil (7 9 grams, 100%)
(B) 1-Cyclobutylsulfonyl-4-methoxybenzene
A solution of 1-cyclobutylsulfanyl-4-methoxybenzene (7 9 grams, 407 mmole) in methylene chloride (50 mL) was cooled in an ice bath and a solution of 57% m-chloroperbenzoic acid (28 grams, 92 mmole) in methylene chloride (100 mL) was added dropwise The resulting mixture was stirred at room temperature for 7 days After quenching with saturated aqueous sodium bisulfite solution, the mixture was filtered to remove a white precipitate and extracted with methylene chloride The extract was washed successively with saturated aqueous sodium bicarbonate solution, water and brine After drying over magnesium sulfate, the solution was concentrated to a white solid Recrystallization from ethyl acetate afforded
1-cyclobutylsulfonyl-4-methoxyhenzene (7 28 grams, 79%) as a white crystalline solid
(C) Furan-2-yl-[1-(4-methoxybenzenesulfonyl)cvclobutyllmethanol
A solution of 1-cyclobutylsulfonyl-4-methoxybenzene (4 0 grams, 17 7 mmole) in dry tetrahydrofuran (80 mL) was cooled to -78°C and a 2 5 M solution of n-butylhthium in hexane was added The mixture was allowed to warm to -50°C and was again cooled to -78°C
2-Furaldehyde (4 mL, 48 mmole) was then added After stirring for 20 minutes at -78°C, the reaction was quenched by addition of saturated aqueous ammonium chloride solution The resulting mixture was extracted with ethyl acetate The organic extract was washed with water and brine and was dried over magnesium sulfate Evaporation of the solvent gave an oil from which furan-2-yl-[1-(4-methoxybenzenesulfonyl)cyclobutyl]-methanol (4 3 grams, 75%) was isolated by flash chromatography on silica gel eluting with 1 3 ethyl acetate/hexane
(D) 2.2-Dιmethy Ipropionic acid furan-2-y l[1 -(4-methoxybenzenesulfonyl)cvclo- butylj-methyl ester A solution of furan-2-yl-[1-(4-methoxybenzenesulfonyl)cyclobutyl]methanol (1 57 grams, 4 9 mmole) and 4-dιmethylamιnopyπdιne (0 89 grams, 7 3 mmole) in methylene chloride (50 mL) was cooled in an ice bath Pivaloyl chloride (0 66 mL, 5 4 mmole) was added The mixture was stnred at 0°C for 2 hours, diluted with methylene chloride and extracted successively with 0 5 N aqueous hydrochloric acid and brine After drying over MgSθ4, the solvent was evaporated to leave an oil from which the desired product, 2,2- dimethylpropionic acid furan-2-yl[1-(4-methoxybenzenesulfonyl)cyclobutyl]methyl ester (1.60 grams, 81%), was isolated by flash chromatography eluting with 16% ethyl acetate in hexane.
(E) 2.2-Dimethylpropionic acid carboxy[1-(4-methoxybenzenesulfonyl)cvclobutyl] methyl ester
To a solution of 2,2-dimethylpropionic acid furan-2-yl[1-(4-methoxybenzenesulfonyl)- cyclobutyl]methyl ester (1.6 grams, 3.94 mmol) in acetonitrile (12 mL), carbon tetrachloride (12 mL) and water (22 mL) at room temperature were added, sequentially, sodium periodate (6.73 grams, 31 mmole) and ruthenium (III) chloride hydrate (21 mg). The mixture was stirred at room temperature for 1.25 hours and was then diluted with water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate to yield the crude product, 2,2-dimethylpropionic acid carboxy[1-(4-methoxybenzenesulfonyl)cyclobutyl]-methyl ester, as an oil.
(F) 2.2-Dimethylpropionic acid benzy loxycarbamoy l-[1 -(4-methoxybenzene sulfonyD-cvclobutyllmethyl ester
The entire crude sample of 2,2-dimethylpropionic acid carboxy[1-(4-methoxybenzene- sulfonyi)cyclobutyl]methyl ester obtained in Step E was dissolved in methylene chloride (60 mL). O-Benzylhydroxylamine hydrochlonde (0.69 grams, 4.3 mmol), triethylamine (1.6 mL, 11.5 mmole) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.91 grams, 4.3 mmole) were then added sequentially. The mixture was stirred at room temperature for 16 hours and was then concentrated under vacuum. The residue was taken up in ethyl acetate and the resulting solution was washed successively with 0.5 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate, the solvent was evaporated to afford an oil. The desired product, 2,2-dimethylpropionic acid benzyloxycarbamoyl-[1 -(4- methoxybenzenesulfonyl)cyclobutyljmethyl ester (0.87 grams, 46%), was isolated by flash chromatography on silica gel eluting with 30% ethyl acetate in hexane.
(G) N-Benzyloxy-2-hvdroxy-2[1-(4-methoxybenzenesulfonyl)cvclobutyll acetamide
To a solution of 2,2-dimethylpropionic acid benzyloxycarbamoyl-[1-(4- methoxybenzenesulfonyl)cyclobutyl]methyl ester (0.87 grams, 1.78 mmol) in methanol (10 mL), tetrahydrofuran (5 mL) and water (5 mL) was added lithium hydroxide hydrate (0.37 grams, 8.8 mmol). The mixture was stirred at room temperature for 24 hours. Methanol- washed Amberlite IR-120 ion exchange resin (6 grams) was then added. After stirring for 15 minutes, the mixture was filtered. The filtrate was concentrated and the residue was taken up in ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated to afford the desired product, N-benzyloxy-2-hydroyy-2[1-(4-methoxybenzenesulfonyl)-cyclobutyl]acetamide, as an oil (0.72 grams, 100%).
(H) 2.N-Dihydroxy-2-f1-(4-methoxybenzenesulfonyl)cvclobutyl]acetamide
A solution of N-benzyloxy-2-hydroxy-2[1-(4-methoxybenzenesulfonyl)- cyclobutyl]acetamide (0.13 grams, 0.32 mmole) in methanol (30 mL) was treated with 5% palladium on barium sulfate (0.07 grams) and hydrogenated at 3 atmospheres pressure for 4 hours in a Parr shaker. The catalyst was removed by passage through a 0.45 μm nylon filter and the filtrate was concentrated. The desired product, 2,N-dihydroxy-2-[1-(4- methoxybenzenesulfonyl)cyclobutyl]acetamide (0.061 grams, 65%), was isolated as a foam by flash chromatography on silica gel eluting successively with chloroform, 1% methanol in chloroform and 2% methanol in chloroform. MS m/z 314 (M-1).
Example 4 2.N-DIHYDROXY-2-f1-(4-METHOXYBENZENESULFONYL)CYCLOPENTYL1ACETAMlDE 2,N-Dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclopentyl]acetamide was prepared by a method analogous to that described in Example 3 using 4-methoxybenzenethiol and cyclopentyl bromide as startinc* materials. MS m/z 328 (M-1).
Example 5 ?-{1.r4-(4-FLUOROPHENOXY)BENZENESULFONYL1CYCLOBUTYL}-2.N-
DIHYDROXYACETAMIDE 2-{1-[4-(4-Fluorophenoxy)benzenesulfonyl]cyclobutyl}-2,N-dihydroxyacetamide was prepared by a method analogous to that described in Example 3 using 4-(4- fluorophenoxy)benzenethiol and cyclobutyl bromide as starting materials. MS m/z 394 (M-1).
4-(4-Fluorophenoxy)benzenethiol was obtained as follows. Chlorosulfonic acid (26 mL, 0.392 mole) was added dropwise to ice-cooled 4-fluorophenoxybenzene (36.9 grams, 0.196 mole) with mechanical stirring. When addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4-
(4-fluorophenoxy)benzenesulfonylchloride (18.6 grams, 33%) was collected by filtration and was dried in the air.
4-(4-Fluorophenoxy)benzene-sulfonylchloride (5.1 grams, 17.7 mmole) was added to an ice-cooled mixture of concentrated sulfuric acid (7 mL) and water (37 mL) with mechanical stirring. Zinc dust (6.2 grams, 95 mmole) was then added in portions. The cooling bath was removed and the mixture was allowed to stir at room temperature for 2 hours and at reflux for 3 hours. After cooling to room temperature, the mixture was quenched by addition of ice. The resulting mixture was extracted with toluene. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and evaporated to afford 4-(4- fluorophenoxy)benzenethιol as a white solid (3 3 grams, 84%)
Example 6 2-{1-[4-(4-FLUOROPHENOXY)BENZENESULFONYl lCYCLOPENTYI }-2 N-
DIHYDROXYACETAMIDE 2-{1-[4-(4-Fluorophenoxy)benzenesulfonyl]cyclopentyl}-2,N-dιhydroxyacetamιde was prepared by a method analogous to that described in Example 3 using (4- fluorophenoxy)benzenethιol and cyclopentyl bromide as starting materials MS m/z 408 (M-1)
Example 7 2-ri-(4-CYCLOBUTOXYBENZENESULFONYL)CYCLOBUTYL1-2.N- DIHYDROXYACETAMIDE
2-[1-(4-Cyclobutoxybenzenesulfonyl)cyclobutyl]-2,N-dιhydroxyacetamιde was prepared by a method analogous to that described in Example 3 using 1-cyclobutoxy-4- cyclobutylsulfanylbenzene as starting material in step B MS 354 (M-1)
Example 8 2-[1-(4-BUTOXYBENZENESULFONYL)CYCLOBUTYLl-2.N-DIHYDROXYACETAMIDE
2-[1-(4-Butoxybenzenesulfonyl)cyclobutyl]-2,N-dιhydroxyacetamιde was prepared by a method analogous to that described in Example 3 using 1-butoxy-4- cyclobutylsulfanylbenzene as starting material as starting material in step B MS 356 (M-1)
Preparation A 4-(4-FLUOROPHENOXY)BENZENESUI FONYLCHLORIDE
Chlorosulfonic acid (26 mL, 0 392 mole) was added dropwise to ice-cooled 4- fluorophenoxy benzene (36 9 grams, 0 196 mole) with mechanical stirring When addition was complete, the mixture was stirred at room temperature for 4 hours The mixture was then poured into ice water The titled compound (18 6 grams, 33%) was collected by filtration and was dried in the air
Preparation B
4-(4-FLUOROPHEN XY^BF.NZENETHIOL
4-(4-Fluorophenoxy)benzene-sulfonylchlorιde (5 1 grams, 17 7 mmole) was added to an ice-cooled mixture of concentrated sulfuric acid (7 mL) and water (37 mL) with mechanical stirring Zinc dust (6 2 grams, 95 mmole) was then added in portions The cooling bath was removed and the mixture was allowed to stir at room temperature for 2 hours and at reflux for
3 hours After cooling to room temperature, the mixture was quenched by addition of ice The resulting mixture was extracted with toluene The organic layer was washed with water and saturated brine, dried over mrgnesium sulfate and evaporated to afford the titled compound as a white solid (3 3 grams, 84%)
Preparation C 4-CYCLOBUTYI SULFANY1 PHFNOI 4-Hydroxybenzenethιol ( 10 0 grams, 79 3 mmole) was added to a suspension of sodium hydride (1 9 grams, 79 2 mmole) in N,N-dιmethylformamιde (50 mL) When evolution of hydrogen was complete and the mixture had cooled to room temperature, cyclobutylbromide (11 4 grams, 84 4 mmole) was added The reaction mixture was stirred at room temperature for 2 5 hours and was then quenched by addition of water and 6 N aqueous hydrochloric acid solution The mixture was extracted with diethyl ether The organic extract was washed with brine, dried over magnesium sulfate and concentrated to afford a yellow oil Roughly half of this material was chromatographed on silica gel eluting with 9 1 1 hexane/ethyl acetate/methylene chloride to afford the titled compound as a clear oil (8 85 grams)
Preparation D 1-CYCLOBUTOXY-4-CYCLOBUTYLSULFANYLBENZENE A 60% suspension of sodium hydride in oil (1 97 grams, 49 mmole) was added to a solution of 4-cyclobutylsulfanylphenol(7 2 grams, 40 mmole) in N,N-dιmethylformamιde (25 mL) After hydrogen evolution was complete, cyclobutylbromide (6 4 grams, 47 mmole) was added The reaction mixture was stirred at room temperature for 4 hours and then at 70°C in an oil bath for 16 hours After cooling and quenching with water, the mixture was extracted with diethyl ether The organic extract was washed with water and brine, dried over magnesium sulfate and concentrated to give an impure sample of the titled compound, an oil This was used without without purification
Preparation E 1-BUTOXY-4-CYCLOBUTYLSULFANYLBENZENE A 60% suspension of sodium hydride in oil (2 2 grams, 55 mole) was added to an ice- cooled solution of 4-cyclobutylsulfanylphenol(8 85 grams, 49 1 mmole) in N,N- dimethylformamide (35 mL) After hydrogen evolution was complete, 1-bromobutane (6 7 mL, 58 9 mmole) was added The reaction mixture was then stirred at room temperature for 16 hours After cooling and quenching with water, the mixture was extracted with diethyl ether The organic extract was washed with water and brine, dried over magnesium sulfate and concentrated to give an impure sample of the titled compound, an oil (11 2 grams) This was used without without purification

Claims

CLAIMS 1. A compound of the formula
Figure imgf000038_0001
wherein R1 is hydrogen, hydroxy, (C6-C10)aryl(C1-C6)alkoxy, (CrC6)alkoxy,
(CrC6)alkyl(C=0)0-, (CrC6)alkoxy(C=0)0-, (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-, (C6-C10)aryl(CrC6)alkyl(C=O)O- or (C6-C10)aryl(CrC6)alkoxy(C=O)O-; wherein said aryl moiety of said (C6-C10)aryl(CrC6)alkoxy, (C6-C10)aryl(C=O)O-, (C6-C10)aryloxy(C=O)O-, (C6-C10)aryl(CrC6)alkyl(C=O)O- or (C6-C10)aryl(C1-C6)alkoxy(C=O)O- groups is optionally substituted by one or more substituents independently selected from fluoro, chloro, bromo, (Cr C6)alkyl, (CrC6)alkoxy, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy; R2 is hydrogen or (CrC6)alkyl;
R3 and R4 are independently selected from the group consisting of hydrogen, (CrC6)alkyl, trifluoromethyl, trifluoromethyl(CrC6)alkyl, (CrC6)alkyl(difluoromethylene), (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl,
(C6-C10)aryl(CrC6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl,
(C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, hydroxy(CrC6)alkyl, (CrC6)alkyl(C=0)0-(CrC6)alkyl, (CrC6)alkoxy(C=0)0-(C C6)alkyl, (C6-C10)aryl(C=O)O-(C1-C6)alkyl, (C6-C10)aryloxy(C=O)O- (CrC6)alkyl , (C6-C10)aryl(C1-C6)alkyl(C=O)O-(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C=O)O- (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryloxy(CrC6)alkyl,
(C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl, amino(CrC6)aikyl, (C1-C6)alkylamino(C1-C6)alkyl, [(CrC6)alkyl]2amino(CrC6)alkyl,
(C1-C6)alkyl(C=0)NH(C1-C6)alkyl, (C1-C6)alkoxy(C=0)NH(C1-C6)alkyl,
(C6-C10)aryl(C=O)NH(CrC6)alkyl, (C6-C10)aryloxy(C=O)NH(CrC6)alkyl, (C6-C10)aryl(C1-C6)alkyl(C=O)NH(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C=O)NH(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl(CrC6)alkyl, R5CO(C1-C6)alkyl or R8(CrC6)alkyl; or R3 and R4 may be taken together with the carbon atom to which they are attached to form a (C3-C6)cycloalkyl or benzo-fused(C3-C6)cycloalkyl ring or a group of the formula
Figure imgf000039_0001
wherein the carbon atom bearing the asterisk is the carbon to which R3 and R4 are atttached, "n" and "m" are independently selected from the integers one and two, and X is CF2, 0, S02 or NR9, wherein R9 is hydrogen, (CrC6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(CrC6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, (C C6)alkylsuϊfonyl, (C6-C10)arylsulfonyl, (C C6)alkyl(C=0)-, (C1-C6)alkoxy(C=0)-, (C6-C10)aryl(C=O)-, (C6-C10)aryloxy(C=O)-, (C6-C10)aryl(CrC6)alkyl(C=O)- or (C6-C10)aryl(C1-C6)alkoxy(C=O)-; wherein each of said (C6-C10)aryl, (C2-C9)heteroaryl or (C3-C6)cycloalkyl moieties of said (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(CrC6)alkyl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(Cl-C6)alkyl, (C6-C10)aryl(C=O)O-(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl(C=O)O-(C1-C6)alkyl,
(C6-C10)aryl(C1-C6)alkoxy(C=O)O-(C1-C6)alkyl, (C6-C10)aryloxy(C1-C6)alkyl,
(C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl,
(C6-C10)aryl(C=O)NH(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl(C=O)NH(C1-C6)alkyl,
(C6-C10)aryl(C1-C6)alkoxy(C=O)NH(C1-C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, (C6-C10)aryl(C=O)-, (C6-C10)aryl(C C6)alkyl(C=O)-,
(C6-C10)aryl(C1-C6)alkoxy(C=O)-, (C3-C6)cycloalkyl, or benzo-fused(C3-C6)cycloalkyl ring may be optionally substituted on any ring atom capable of forming an additional bond by a substituent independently selected from the group consisting of fluoro, chloro, bromo, (CrC6)alkyl, (C-,- C6)alkoxy, perfluoro(C C3)alkyl, perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy; or when R3 and R4 are taken together with the carbon atom to which they are attached to form a group of the formula
Figure imgf000039_0002
then any of the carbon atoms of said ring, capable of forming an additional bond, may be optionally substituted by a substituent independently selected from the group consisting of fluoro, chloro, bromo, (C C6)alkyl, (CrC6)alkoxy, perfluoro(C1-C3)alkyl, perfluoro(CrC3)alkoxy and (C6- C10)aryloxy; R is R O or R R N wherein R and R7 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C C6)alkyl, wherein each of said (C6-C10)aryl and (C2-C9)heteroaryl moieties of said (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(CrC6)alkyl groups may be optionally substituted by one or more substituents independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy, perfluoro(CrC3)alkyl, perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy, or R6 and R7 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle selected from piperazinyl, (CrC6)alkylp╬╣peraz╬╣nyl,
(C6-C10)arylp╬╣peraz╬╣nyl, (C2-C9)heteroarylp╬╣peraz╬╣nyl, (C6-C10)aryl(C1-C6)alkylp╬╣peraz╬╣nyl,
(C CgJheteroary C Ce) alkylpiperazinyl, (C1-C6)alkyl(C=0)-p╬╣peraz╬╣nyl, (CrC6)alkoxy(C=0)- piperazinyl, (C6-C10)aryl(C=O)-p╬╣peraz╬╣nyl, (C6-C10)aryl(C1-C6)alkyl(C=O)-p╬╣peraz╬╣nyl,
(C6-C10)aryl(C1-C6)alkoxy(C=O)-p╬╣peraz╬╣nyl, morpholinyl, pipendinyl, pyrrolidinyl or azetidinyl, wherein each of said piperazinyl, (CrC6)alkylp╬╣peraz╬╣nyl, (C6-C10)arylp╬╣peraz╬╣nyl,
(C2-C9)heteroarylp╬╣peraz╬╣nyl, (C6-C10)aryl(C1-C6)alkylp╬╣peraz╬╣nyl, (C2-C9)heteroaryl(CrC6) alkylpiperazinyl, (C1-C6)alkyl(C=0)-p╬╣peraz╬╣nyl, (CrC6)alkoxy(C=0)-p╬╣peraz╬╣nyl, (C6-C10)aryl(C=O)-p╬╣peraz╬╣nyl, (C6-C10)aryl(C1-C6)alkyl(C=O)-p╬╣peraz╬╣nyl,
(C6-C10)aryl(C1-C6)alkoxy(C=O)-p╬╣peraz╬╣nyl, morpholinyl, pipendinyl, pyrrolidinyl or azetidinyl may be optionally substituted on any ring carbon atom capable of forming an additional bond with a substituent (preferably one to three substituents per ring) independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy, perfluoro(CrC3)alkyl, or perfluoro(CrC3)alkoxy and (C6-C10)aryloxy,
R8 is piperazinyl, (C1-C6)alkylp╬╣peraz╬╣nyl, (C6-C10)arylp╬╣peraz╬╣nyl,
(C2-C9)heteroarylp╬╣peraz╬╣nyl, (C6-C10)aryl(C1-C6)alkylp╬╣peraz╬╣nyl, (C2-C9)heteroaryl(CrC6) alkylpiperazinyl, (CrC6)alkyl(C=0)-p╬╣peraz╬╣nyl, (CrC6)alkoxy(C=0)-p╬╣peraz╬╣nyl,
(C6-C10)aryl(C=O)-pιperazιnyl, (C6-C10)aryl(C1-C6)alkyl(C=O)-pιperazmyl, (C6-C10)aryl(CrC6)alkoxy(C=O)-pιperazιnyl, morpholinyl, pipendinyl, pyrrolidinyl, azetidinyl, pipeπdyl,
Figure imgf000040_0001
(C6-C10)arylpιpeπdyl, (C2-C9)heteroarylpιpeπdyl,
(C6-C10)aryl(CrC6)alkylpιperιdyl, (C2-C9)heteroaryl(CrC6)alkylpιperιdyl, (C C6)alkyl(C=0)- pipendyl, (C1-C6)alkoxy(C=0)-pιpeπdyl, (C6-C10)aryl(C=O)-pιperιdyl,
(C6-C10)aryl(C1-C6)alkyl(C=O)-pιpeπdyl, or (C6-C10)aryl(CrC6)alkoxy(C=O)-pipendyl, wherein each of said piperazinyl, (CrC6)alkylpιperazιnyl, (C6-C10)arylpιperazιnyl, (C2-C9)heteroarylpιperazιnyl, (C6-C10)aryl(C1-C6)alkylpιperazιnyl, (C2-C9)heteroaryl(CrC6) alkylpiperazinyl, (C C6)alkyl(C=0)-pιperazιnyl, (C1-C6)alkoxy(C=0)-pιperazιnyl,
(C6-C10)aryl(C=O)-p╬╣peraz╬╣nyl, (C6-C10)aryl(CrC6)alkyl(C=O)-p╬╣peraz╬╣nyl,
(C6-C10)aryl(C1-C6)alkoxy(C=O)-p╬╣peraz╬╣nyl, morpholinyl, pipendinyl, pyrrolidinyl, azetidinyl, piperidyl, (CrC6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C2-C9)heteroarylpiperidyl,
(C6-C10)aryl(CrC6)alkylpiperidyl, (C2-C9)heteroaryl(C1-C6)alkylpiperidyl (C1-C6)alkyl(C=0)- piperidyl, (CrC6)alkoxy(C=0)-piperidyl, (C6-C10)aryl(C=O)-piperidyl,
(C6-C10)aryl(C1-C6)alkyl(C=O)-piperidyl, and (C6-C10)aryl(C1-C6)alkoxy(C=O)-piperidyl may be optionally substituted on any ring carbon atom capable of forming an additional bond with a substituent independently selected from fluoro, chloro, bromo, (C C6)alkyl, (C1-C6)alkoxy, perfluoro(C1-C3)alkyl, or perfluoro(C C3)alkoxy and (C6-C10)aryloxy;
Q is (CrC6)alkyl, (C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6- C1o)aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2- C9)heteroaryl(C2-C9)heteroaryl, (C C6)alkyl(C6-C10)aryl, (C1-C6)alkoxy(C6-C10)aryl, (C6- C10)aryl(C1-C6)alkoxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C2-
C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl(C2-C9)heteroaryl, (CrC6)alkoxy(C2-C9)heteroaryl, (C6- C1o)aryl(C1-C6)alkoxy(C2-C9)heteroaryl, (C2-C9)heteroaryloxy(C2-C9)heteroaryl, (C6-
C10)aryloxy(C1-C6)alkyl, (C2-C9)heteroaryloxy(C1-C6)alkyl, (CrC6)alkyl(C6-C10)aryloxy(C6- C10)aryl, (C1-C6)alkyl(C2-C9)heteroaryloxy(C6-C10)aryl, (CrC6)alkyl(C6-C10)aryloxy(C2- C9)heteroaryl, (C1-C6)alkoxy(C6-C10)aryloxy(C6-C10)aryl, (CrC6)alkoxy(C2-C9)heteroaryloxy(C6- C10)aryl or (C1-C6)alkoxy(C6-C10)aryloxy(C2-C9)heteroaryl wherein each (C6-C10)aryl or (C2- C9)heteroaryl moieties of said (C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C C6)alkyl(C6-C10)aryl, (C C6)alkoxy(C6-C10)aryl, (C6-C10)aryl(CrC6)alkoxy(C6-C10)aryl, (C6- C10)aryl(CrC6)alkoxy(CrC6)alkyl, (C2-C9)heteroaryloxy(C6-C10)aryl, (C C6)alkyl(C2-
C9)heteroaryl, (CrC6)alkoxy(C2-C9)heteroaryl, (C6-C10)aryl(CrC6)alkoxy(C2-C9)heteroaryl, (C2- C9)heteroaryloxy(C2-C9)heteroaryl, (C6-C10)aryloxy(CrC6)alkyl, (C2-C9)heteroaryloxy(C1-C6)alkyl, (C1-C6)alkyl(C6-C10)aryloxy(C6-C10)aryl, (C C6)alkyl(C2-C9)heteroaryloxy(C6-C10)aryl, (Cr C6)alkyl(C6-C10)aryloxy(C2-C9)heteroaryl, (C1-C6)alkoxy(C6-C10)aryloxy(C6-C10)aryl, (Cr C6)alkoxy(C2-C9)heteroaryloxy(C6-C10)aryl or (C1-C6)alkoxy(C6-C10)aryloxy(C2-C9)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or more substituents independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C C6)alkoxy, perfluoro(CrC3)alkyl. perfluoro(CrC3)alkoxy and (C6-C10)aryloxy; with the proviso that if either R3 or R4 is hydrogen, or if both R3 and R4 are hydrogen, then R1 and R2 can not both be hydrogen or R1 must be hydroxy, (C1-C6)alkoxy,
(C6-C10)aryl(CrC6)alkoxy, (C1-C6)alkyl(C=0)0-(C1-C6)alkyl, (C1-C6)alkoxy(C=0)0-(C1-C6)alkyl,
(C6-C10)aryl(C=O)O-(C1-C6)alkyl, (C6-C10)aryloxy(C=O)O- (C6-C10)arylalkyl(C=O)O-(C1-C6)alkyl or (C6-C10)arylalkoxy(C=O)O-(C1-C6)alkyl; and the pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 , wherein R1 is OH and R2 is hydrogen.
3. A compound according to claim 1 , wherein both R3 and R4 are (CrC6)alkyl or R3 and R4 are taken together with the carbon atom to which they are attached to form an optionally substituted (C3-C6)cycloaikyl ring or benzo-fused(C3-C6)cycloalkyl ring or a group of the formula
Figure imgf000042_0001
wherein "n" and "m" are independently selected from the integers one and two, and X is
CF2, O, S02 or NR9, wherein R9 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C2-C9)heteroalkyl, (C6- C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(CrC6)alkyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, (CrC6)alkyl(C=0)-, (CrC6)alkoxy(C=0)-, (C6-C10)aryl(C=O)-, (C6-C10)aryl(CrC6)alkyl(C=O)-, or (C6-C10)aryl(C1-C6)alkoxy(C=O)-; wherein each of said (C6-C10)aryl and (C2-C9)heteroaryl moieties of said (C6-C10)aryl, (C2-C9)heteroalkyl, (C6-C10)aryl(C1-C6)alkyl, (C C^heteroary C,- C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)aryl(C=O)-, (C6-C10)aryl(CrC6)alkyl(C=O)-, and (C6-C10)aryl(C1-C6)alkoxy(C=O)- groups may be optionally independently substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (Cr C6)alkyl, (C1-C6)alkoxy, perfluoro(CrC3)alkyl, perfluoro(CrC3)alkoxy and (C6-C10)aryloxy.
4. A compound according to claim 2, wherein both R3 and R4 are (CrC6)alkyl or R3 and R4 are taken together with the carbon atom to which they are attached to form a (C3-C6)cycloalkyl ring or benzo-fused(C3-C6)cycloalkyl ring or a group of the formula
(q , CCH2)m
X wherein "n" and "m" are independently selected from the integers one and two, and X is CF2, O, S02 or NR9, wherein R9 is hydrogen, (CrC6)alkyl, (C╬▓-C10)aryl, (C2-C9)heteroalkyl, (C6- C10)aryl(C1-C╬▓)alkyl, (C2-C9)heteroaryl(CrC6)alkyl, (C C6)alkylsulfonyl, (C6-C10)arylsulfonyl, (C6- C10)arylsulfonyl, (CrC6)a╬╣kyl(C=0)-, (CrC6)alkoxy(C=0)-, (C6-C10)aryl(C=O)-,
(C6-C10)aryl(CrC6)alkyl(C=O)-, or (C6-C10)aryl(C C6)alkoxy(C=O)-; wherein each of said (C6- C10)aryl and (C2-C9)heteroaryl moieties of said (C6-C10)aryl, (C2-C9)heteroalkyl, (C6-C10)aryl(C C6)alkyl, (C2-C9)heteroaryl(C C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)aryl(C=O)-,
(C6-C10)aryl(C1-C6)alkyl(C=O)-, and (C6-C10)aryl(CrC6)alkoxy(C=O)- groups may be optionally independently substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy.
5. A compound according to claim 1 , wherein R3 and R4 are taken together to form an optionally substituted (C3-C6)cycloalkyl ring.
6. A compound according to claim 2, wherein R3 and R4 are taken together to form an optionally substituted (C3-C6)cycloalkyl ring.
7. A compound according to claim 1 , wherein Q is (C6-C10)aryl or (C6- C10)aryloxy(C6-C10)aryl, wherein each (C6-C10)aryl moiety of said (C6-C10)aryl or (C6- C10)aryloxy(C6-C10)aryl group may be optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy or perfluoro(C1- C3)alkyl.
8. A compound according to claim 2, wherein Q is (C6-C10)aryl or (C6- C10)aryloxy(C6-C10)aryl, wherein each (C6-C10)aryl moiety of said (C6-C10)aryl or (C6- C╬╣o)aryloxy(C6-C10)aryl group may be optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy or perfluoro(C1- C3)alkyl.
9. A compound according to claim 3, wherein Q is (C6-C10)aryl or (C6- C10)aryloxy(C6-C10)aryl, wherein each (C6-C10)aryl moiety of said (C6-C10)aryl or (C6- C10)aryloxy(C6-C10)aryl group may be optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy or perfluoro(C1- C3)alkyl.
10. A compound according to claim 4, wherein Q is (C6-C10)aryl or (C6- C10)aryloxy(C6-C10)aryl, wherein each (C6-C10)aryl moiety of said (C6-C10)aryl or (C6- C10)aryloxy(C6-C10)aryl group may be optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (CrC6)alkoxy or perfluoro(Cr C3)alkyl.
11. A compound according to claim 5, wherein Q is (C6-C10)aryl or (C6- C10)aryloxy(C6-C10)aryl, wherein each (C6-C10)aryl moiety of said (C6-C10)aryl or (C6- C10)aryloxy(C6-C10)aryl group may be optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy or perfluoro(Cr C3)alkyl.
12. A compound according to claim 1 , wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (C C6)alkyl, (CrC6)alkoxy or perfluoro(C C3)alkyl.
13. A compound according to claim 2, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (CrC6)alkoxy or perfluoro(C C3)alkyl.
14. A compound according to claim 3, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (C C6)alkoxy or perfluoro(CrC3)alkyl.
15. A compound according to claim 4, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (CrC6)alkoxy or perfluoro(CrC3)alkyl.
16. A compound according to claim 5, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (CrC6)alkoxy or perfluoro(CrC3)alkyl.
17. A compound according to claim 8, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, (CrC6)alkyl, (C C6)alkoxy or perfluoro(CrC3)alkyl.
18. A compound according to claim 1, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, (CrC6)alkoxy or (CrC6)alkyl.
19. A compound according to claim 2, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, (CrC6)alkoxy or (CrC6)alkyl.
20. A compound according to claim 5, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, (C C6)alkoxy or (CrC6)alkyl.
21. A compound according to claim 8, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro,
(CrC6)alkoxy or (C C6)alkyl.
22. A compound according to claim 1 , wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, (CrC6)alkoxy or (C1-C6)alkyl and wherein the substituent is in the 4-position.
23. A compound according to claim 2, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, (C1-C6)alkoxy or (CrC6)alkyl and wherein the substituent is in the 4-position.
24. A compound according to claim 5, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, (CrC6)alkoxy or (CrC6)alkyl and wherein the substituent is in the 4-position.
25. A compound according to claim 8, wherein Q is phenyl or phenoxyphenyl optionally substituted with one or more substituents independently selected from fluoro, chloro, (CrC6)alkoxy or (CrC6)alkyl and wherein the substituent is in the 4-position.
26. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
(2S)-2,N-dihydroxy-3-(4-methoxybenzenesulfonyl)propionamide, 3-[4-(4-fluorophenoxy)phenylsulfonyl]-2,N-dihydroxypropionamide, 2,N-dihydroxy-2-[1 -(4-methoxybenzenesuϊfonyl)cyclobutyl]acetamide;
2,N-dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclopentyl]acetamide, 2-[1-(4-cyclobutoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide, 2-[1-(4-butoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide, 2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclobutyl}-2,N-dihydroxyacetamide, and 2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclopentyl}-2,N-dihydroxyacetamide.
27. A pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, osteoporosis, cancer, tissue uiceration, muscular degeneration, restenosis, periodontal disease, epidermolysis bullosa, sderitis, in combination with standard NSAID'S and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier.
28. A method for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of claim 1.
29. A method for treating a condition selected from the group consisting of arthritis, osteoporosis, cancer, tissue uiceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, sderitis, compounds of formula I may be used in combination with standard NSAID'S and analgesics and in combination with cytotoxic anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 , effective in treating such a condition.
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