Classifications

• • 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)

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• 1998
  • 1998-01-27 WO PCT/IB1998/000101 patent/WO1998034915A1/en not_active Application Discontinuation
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