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AP826A - Arysulfonylamino hydroxamic acid derivatives. - Google Patents

Arysulfonylamino hydroxamic acid derivatives. Download PDF

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Publication number
AP826A
AP826A APAP/P/1998/001191A AP9801191A AP826A AP 826 A AP826 A AP 826A AP 9801191 A AP9801191 A AP 9801191A AP 826 A AP826 A AP 826A
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Prior art keywords
aryl
heteroaryl
alkyl
carboxylic acid
aryloxy
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APAP/P/1998/001191A
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AP9801191A0 (en
Inventor
Ralph Pelton Robinson
Kim Francis Mcclure
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Pfizer Prod Inc
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
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    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

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Abstract

A compound of the formula wherein R1, R2 and Q are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, 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 (NSAID'S) and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.

Description

ARYLSULFQNYLAMINO HYDROXAMIC ACID DERIVATIVES
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, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, 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 arthritis, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, 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.
There are a number of enzymes which effect the breakdown of structural proteins and which are structurally related metalloproteases. Matrix-degrading metalloproteinases, such as gelatinase, 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.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Paget's disease and osteoporosis), tumor metastasis or invasion, as well as HIV-infection (J. Leuk. Biol,, 52 (2): 244-248, 1992).
AP/P/ 9 8/011 91
Tumor necrosis factor is recognized to be involved in many infectious and auto30 immune 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 ai., Clinical Immunology and Immunopathology. 1992, 62 S11).
AP 0 0 0 8 2 6
-2The present invention relates to a compound of the formula
H0-NH
II
-CR1
I
-CR!
H
-N S\ // o Q or the pharmaceutically acceptable salts thereof, wherein
R' and R2 are each independently selected from (CT-C^alkyl, trifluoromethyl, trif I u oro met hyl (C,-C6) alkyl, (C,-Ce) alkyl (difiuoro methyl ene), (C, C3)alkyl(difluoromethylene(C1-C3)alkyl, (Ce-C10)aryl, (C2-C9)heteroaryl, (Cg-C^ary^C,- a C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl or R1 and R2 may be taken together to form a (C3C6)cycloalkyl or benzo-fused (C3-C6)cycloalkyl ring or a group of the formula
wherein n and m are independently 1 or 2 and X is CF2, S, O or NR3 wherein R3 is hydrogen, (CrCe)alkyl, (Ce-C10)aryl, (C2-C9)heteroaryl, (Cg-C^arylCC^CgJalkyl, (C2CgjheteroarylfC^Cgjalkyl, (CT-C^alkylsulfonyl, (C6-C10)arylsulfonyi or acyl; and
Qis(C1-Ce)alkyl,(C6-C10)ary!,(Cg-C10)aryloxy(C6-C10)aryl,(C6-C10)aryf(C6-C10)aryl, (C6-Cl0)aryl(C6-C10)aryl(C1-Cg)alkyl, (Cs-C10)aryl(C2-C9)heteroaryl, (C6-Clo)aryloxy(C2C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C2-C9)heteroaryl(C6C10)aryl,(C1-C6)alkyl(C6-C10)aryl1(C,-C6)alkoxy(C6-C10)arylt(Ce-C,0)aryl(C1-Ce)alkoxy(CeC10)aryl, (Cg-C^aryiO^-Cgjalkoxy^-CgJalkyl, (C2-C9)heteroaryloxy(C6-C10)aryl, (C,Ce)alkyl(C2-C9)heteroaryl, (C1-C6)eilkoxy(C2-C9)heteroaryl, (Cg-C^aryl^-C/alkoxytC.,C9)heteroaryl, (C2-Cg)heteroaryloxy(C2-C9)heteroaryl, (Cg-C^Jaryloxy^-CgJalkyl, (C2C9)heteroaryloxy(C,-C6)alkyl, (Cl-Ce)alkyl(Ce-Clo)aryloxy(Ce-C1o)aryl, (C,-Ce)alkyl(C2C9)heteroaryloxy(C6-C10)aryl, (C1-Ce)alkyl(Ce-C10)aryloxy(C2-C9)heteroaryl, (Cr C6)alkoxy(Cg-C10)aryloxy(Cg-C10)aryl, (C1-Ce)alkoxy(C2-C9)heteroaryloxy(Cs-C10)aryl or (C,-Ce)alkoxy(Ce-C10)aryloxy(C2-Cg)heteroaryl wherein each aryl group is optionally substituted byfluoro, chloro, bromo, (C,-Ce)alkyl, (C^C^alkoxy orperfluoro^-C^alkyl.
AP/P/ 9 8/011 91
APO00826
-3The 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 5 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, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyi, (C^CgJalkoxy, (Ce-C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C,-Ce)aikyl.
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, pyroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazoiyl, thiazolyl, oxazolyi, benzthiazolyl br benzoxazolyl, optionally substituted by 1 to 2 substituents selected from the group consisting of fluoro, chloro, trifluoromethyi, (C,-C6)alkoxy, (CeC,0)aryloxy, trifluoromethoxy, difluoromethoxy and (C^-Cgjalkyl.
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 arylalkyloxy 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 enantiomeric 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 and R2 are taken together to form a (C3-C6)cycloalkyl or benzo-fused (C3-C6)cycloalkyl ring or a group of the formula
AP/PZ 9 8/01191
AP ο Ο Ο 8 2 6
wherein η and m are independently 1 or 2 and X is CF2, S, O or NR3 wherein R3 is hydrogen, (C^CJalkyl, (Ce-C10)aryl, (C2-C9)heteroaryl, (Ce-C^aryKCT-CJalkyl, (C2CJheteroaryl^-CJalkyl, (C,-Ce)alkylsulfonyl, (Ce-C10)arylsuifonyl or acyl.
Other preferred compounds of formula I include those wherein R1 and R2 are 10 taken together to form a (C3-C6)cycloalkyl or benzo-fused (C3-Ce)cycloalkyl ring.
Other preferred compounds of formula I include those wherein Q is (C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryloxy(Ce-C10)aryl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryi, (C6-C,0)aryl(C2-C9)heteroaryl, (C2C9)heteroaryl(C6-C10)aryl or (C2-C9)heteroaryloxy(C6-C10)aryl.
Other preferred compounds of formula I include those wherein Q is (CeC10)aryloxy(C6-C10)aryl.‘
Other preferred compounds of formula I include those wherein R1 and R2 are each independently (C,-Ce)alkyl.
More preferred compounds of formula I include those wherein R1 and R2 are 20 taken together to form a (C3-C6)cycloaikyl or benzo-fused (C3-C6)cycloalkyl ring or a group of the formula
AP/P/ 98/011 91 wherein n and m are independently 1 or 2 and X is CF2, S, O or NR3 wherein R3 is hydrogen, (C^CJalkyl, (C6-C10)aryl, (C2-C9)heteroaryl, (Cg-C^aryl^-CJalkyl, (C2CJheteroaryKC^CJalkyl, (C^CJalkylsulfonyl, (Ce-C10)arylsulfonyl or acyl; and Q is (Ce30 C10)aryl, (C6-C10)aryl(Ce-C10)aryl, (Ce-C10)aryloxy(C6-C10)aryl, (C6-C10)aryloxy(CrC9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (Ce-C10)aryl(C2C9)heteroaryl, (C2-C9)heteroaryl(Ce-C10)aryl or (C2-C9)heteroaryloxy(C6-C10)aryl.
AP Ο Ο Ο 8 2 6
-5More preferred compounds of formula I include those wherein R1 and R2 are taken together to form a (C3-Ce)cycloalkyl or benzo-fused (C3-Ce)cycloalkyl ring; and Qis (C6-C,0)aryl, (C6-C10)aryl(Ce-C10)aryl, (Ce-C,0)aryloxy(Ce-C10)aryl, (Ce-C10)aryloxy(C2C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (Ce-C10)aryl(C25 C9)heteroaryl, (C2-C9)heteroaryl(Ce-C10)aryl or (C2-C9)heteroaryloxy(Ce-C10)aryl.
More preferred compounds of formula I include those wherein R1 and R2 are each independently (C^C^alkyl; and Q is (Ce-C10)aryl, (Ce-C10)aryl(Ce-C10)aryl, (CeC,0)aryloxy(Ce-C10)aryl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2C9)heteroaryl(C2-C9)heteroaryl, (C6-C10)aryl{C2-C9)heteroaryI, (C2-C9)heteroaryl(Ce10 C10)aryl or (C2-C9)heteroaryloxy(C6-C10)aryl.
More preferred compounds of formula I include those wherein R1 and R2 are each independently (C,-C6)alkyl; and Q is (C6-C10)aryloxy(Ce-C10)aryl.
Specific preferred compounds of formula I include the following:
3- [4-(4-Fluorophenoxy)benzenesulfonylamino]azetidine-3-carboxylic acid hydroxyamide;
4- [4-(4-Fluorophenoxy)benzenesulfonylamino]piperidine-4-carboxylic acid hydroxyamide;
-[4-(4-Fluorophenoxy)benzenesulfonylamino]cyclopropane-1 -carboxylic acid hydroxyamide;
1 -[4-(4-Chlorophenoxy)benzenesulfonylamino]cyclopropane-1 -carboxylic acid hydroxy amide;
-[4-(4-Fluorophenoxy)benzenesulfonylamino]cyclobutane-1 -carboxylic acid hydroxy amide;
-[4-(4-Chlorophenoxy)benzenesulfonylamino]cyclobutane-1 -carboxylic acid hydroxyamide;
-[4-(4-Fluorophenoxy)benzenesulfonylamino]cyclopentane-1 -carboxylic acid hydroxyamide;
-[4-(4-Fluorophenoxy)benzenesulfonylamino]cyclohexane-1 -carboxylic acid hydroxyamide;
2-[4-(4-Fluorophenoxy)benzenesulfonylamino]-N-hydroxy-2-methylpropionamide;
2-[4-(4-Chlorophenoxy)benzenesulfonylamino]-N-hydroxy-2-methyl-propionamide;
N-Hydroxy-2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)propionamide;
AP/P/ 98/01191
APOΟ 08 2 6
-61 -(5-Pyridin-2-yl-thiophene-2-sulfonylamino)cyclopentane-1 -carboxylic acid hydroxyamide;
-(4,-Fluorobiphenyl-4-sulfonylamino)cyclopropane-1 -carboxylic acid hydroxyamide;
1 -(4'-Fluorobiphenyl-4-siilfonylamino)cyclobutane-1 -carboxylic acid hydroxyamide;
-(4'-Fluorobiphenyl-4-sulfonylamino)cyclopentane-1 -carboxylic acid hydroxy amide;
2-(4-Methoxybenzenesufonylamino)indan-2-carboxylic acid hydroxyamide; and
2-[4-(4-Fluorophenoxy)benzenesulfonylamino]-indan-2-carboxylic acid hydroxy amide.
The present invention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, synergy with cytotoxic anticancer agents, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, 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, cancer, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, 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
AP/P/ 98/01191
AP 0 0 0 8 2 6
-7formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition.
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated R1, R2 and Q in the reaction Schemes and the discussion that follow are defined as above.
Preparation A
AP/P/ 9 8/01191
Vi i
J^GISTRAR OF PAINTS I
AND TRADE MARKS f
JANWdg j ~ PO.tOYCV’?? ί
AP 0 0 0 8 2 6
-8Scheme 1
I
IV
AP/P/ 9 8/01 1 9 1
AP Ο Ο Ο 8 2 6
-9Ιη Reaction 1 of Preparation A, an amino acid of formula III is treated with benzyl alcohol and an acid of the formula HX, wherein X is preferably 4toluenesulfonate, in an inert solvent, such as benzene or toluene (toluene preferred) to obtain the corresponding benzyl ester acid salt of formula V. The reaction is normally carried out for a time period between about 1 hour to about 24 hours, at the boiling temperature of the solvent used. The water formed during the progress of the reaction is normally collected in a Dean-Stark trap.
In Reaction 2 of Preparation A, the compound of formula V is converted to the corresponding compound of formula VI by reacting V with a reactive functional derivative of a sulfonic acid (QSO2OH), such as the sulfonyl chloride (QSO2CI), in the presence of a base, such as sodium hydroxide or triethylamine, and a solvent, such as methylene chloride, tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water. The reaction mixture is stirred at a temperature between about 0°C to about 50°C, preferably at room temperature, for a time period between about
10 minutes to about 2 days, preferably about 60 minutes.
In Reaction 3 of Preparation A, the intermediate compound of formula VI is hydrogenolyzed to provide the intermediate of formula II. The reaction is carried out at in a solvent, such as ethanol, under an atmosphere of hydrogen (preferably at 3 atmospheres pressure) using a catalyst such as 10% palladium on activated carbon.
The reaction mixture is normally agitated at room temperature for a time period between about 30 minutes to about 24 hours, preferably about 1.5 hours.
In reaction 1 of Scheme 1, the amino acid compound offormula III is converted to the corresponding compound of formula II by reacting III with a reactive functional derivative of a sulfonic acid of the formula QSO2OH, wherein Q is as defined above, such as the sulfonyl chloride (QSO2CI), in the presence of a base, such as sodium hydroxide or triethylamine, and a polar solvent such as tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water. The reaction mixture is stirred at a temperature between about 0°C to about 50°C, preferably at room temperature, for a time period between 10 minutes to about 2 days, preferably about 60 minutes.
In reaction 2 of Scheme 1, the carboxylic acid of formula II is converted to the hydroxamic acid compound offormula I by treating II with 1 -(3-dimethylaminopropyl)-3ethylcarbodiimide and 1-hydroxybenztriazoie in a polar solvent, such as N,Ndimethylformamide, followed by the addition of hydroxylamine to the reaction mixture
AP/PI 9 8/01191
AP ο Ο ο 8 2 6
-10after a time period between about 15 minutes to about 1 hour, preferably about 30 minutes. The hydroxyiamine is preferably generated in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as triethylamine. Alternatively, a protected derivative of hydroxylamine or its salt form, where the hydroxyl group is protected as a tert-butyl, benzyl, allyl or 2-trimethylsilylethyl ether, may be used in place of hydroxylamine or a hydroxylamine salt. Removal of the hydroxyl protecting group is carried out by hydrogenolysis for a benzyl protecting group (5% palladium on barium sulfate is the preferred catalyst) or treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyltinhydride and acetic acid in the presence of catalytic bis(triphenylphosphine) pa!ladium(ll)chloride. The 2-trimethylsilylethyl ether may be removed by reaction with a strong acid such as trifluoroacetic acid or by reaction with a fluoride source such as boron trifluoride etherate. The reaction of II with hydroxylamine, a salt of hydroxylamine, a protected derivative of hydroxylamine or a salt of a protected derivative of hydroxylamine may also be carried out the presence of (benztriazol-1-yloxy)triS(dimethylamino)-phosphoniumhexafluorophosphateandabase such as triethylamine in an inert solvent, such as methylene chloride. The reaction mixture is stirred at a temperature between about 0°C to about 50°C, preferably room temperature, for a time period between about 1 hour to about 3 days, preferably about
1 day. The preferred procedure for converting compound II to compound I is to react
II with O-benzylhydroxylamine hydrochloride in the presence of (benztriazol-1 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate and triethylamine using methylene chloride as solvent. Subsequent removal of the O-benzyl protecting group to afford a compound of formula I is then carried out by hydrogenolysis under 3 atmospheres hydrogen at room temperature using 5% palladium on barium sulfate as catalyst. The preferred solvent is methanol. The reaction time may vary from about 1 hour to about 5 hours (3.5 hours preferred).
In certain instances it is preferred to obtain the compound of formula I by reaction of hydroxylamine, a salt of hydroxylamine, a protected derivative of hydroxylamine or a salt of a protected derivative of hydroxylamine with an activated ester of formula IV, as shown in Reaction 3 of Scheme 1. The reaction is carried out in an inert solvent, such as Ν,Ν-dimethyl-formamide at a temperature ranging from about room temperature to about for a time period of f (&GISTRA.R Or PATENTS I AMD TRADE MARKS } .29JANWSC j
I · l
AP/P/ 9 8/01191
AP Ο Ο Ο 8 2 6
-11about 1 hour to about 2 days. If a protected derivative of hydroxylamine or a salt of a protected derivative of hydroxylamine is used, removal of the protecting group is carried out as described above. The activated ester derivative of formula IV is obtained by treatment of the compound of formula II with (benztriazol-1 -yloxy)tris(dimethylamino)5 phosphonium hexafluorophosphate and a base such as triethylamine in an inert solvent, such as methylene chloride (Reaction 4, Scheme 1). The reaction mixture is stirred at a temperature between about 0°C to about 50°C, preferably room temperature, for a time period between about 1 hour to about 3 days, preferably about 1 day.
Pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris(hydroxymethyl)-methylammonium slats.
Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids e.g. hydrochloric acid, methanesulfonic acid, maleic acid, are aiso possible provided a basic group, such as pyridyl, constitutes part of the structure.
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 in vitro assay tests.
Biological Assay
Inhibition of Human Collagenase (MMP-1)
Human recombinant collagenase is activated with trypsin using the following ratio: 10 /zg trypsin per 100 /zg of collagenase. The trypsin and collagenase are incubated at room temperature for 10 minutes then a five fold excess (50 /zg/10 pg 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:
mM--> 120 μΜ---> 12 μΜ-> 1.2 μΜ-> 0.12 μΜ
16110/86 ,'d/dV
APO 00 8 2 6
-12Twenty-five microliters of each concentration is then added in triplicate to appropriate wells of a 96 well microfiuor 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 μ\ is then added to appropriate wells of the microfiuor plate. Final concentration of collagenase in the assay is 100 ng/ml.
Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is made as a5 mM stock in dimethyl sulfoxide and then diluted to 20 μΜ in assay buffer. The assay is initiated by the addition of 50 μΙ substrate per well of the microfiuor plate to give a final concentration of 10μΜ.
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 μΜ then the inhibitors are assayed at concentrations of 0.3 μΜ, 0.03 μΜ, 0.03 μΜ and 0.003 μΜ.
Inhibition of Gelatinase (MMP-2)
Inhibition of gelatinase activity is assayed using the Dnp-Pro-Cha-Gly-Cys(Me)His-Ala-Lys(NMA)-NH2 substrate (10 μΜ) under the same conditions as inhibition of human collagenase (MMP-1).
θθ 72kD gelatinase is activated with 1 mM ΑΡΜΑ (p-aminophenyl mercuric acetate) for Ί5 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
98/01191
APO00826
-13final concentrations in the assay of 30 μΜ, 3 μΜ, 0.3 μΜ and 0.03 μΜ. 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 μΜ, then the inhibitors are assayed at final concentrations of 0.3 μΜ, 0.03 μΜ, 0.003 μΜ and 0.003 μΜ.
Inhibition of Stromelysin Activity (MMP-3)
Inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingarten and Feder (Weingarten, H. and Feder, J., Spectrophotometric Assay for Vertebrate Collagenase, Anal. Biochem. 147. 437-440 (1985)). Hydrolysis of the thio peptolide substrate [Ac-Pro-Leu-GlySCH[CH2CH(CH3)2]CO-Leu-Giy-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 μΙ of a 10 mg/ml trypsin stock per 26 μg of stromelysin. The trypsin and stromelysin are incubated at 37°C for 15 minutes followed by 10 μΙ 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 μΙ 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 μg/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 μΙ per well yielding at 1 mM final concentration.
mM stock solutions of inhibitors are made in dimethyl sulfoxide and diluted serially in assay buffer such that addition of 50 μ\- to the appropriate wells yields final concentrations of 3 μΜ, 0.3 μΜ, 0.003 μΜ, and 0.0003 μΜ. 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 μΙ 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.
AP/F/ 9 8/01191
AP Ο Ο Ο 826
-14Inhibition of MMP-13
Human recombinant MMP-13 is activated with 2mM ΑΡΜΑ (p-aminophenyl mercuric acetate) for 1.5 hours, at 37°C and is diluted to 400 mg/ml in assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5mM calcium chloride, 20μΜ zinc chloride,
0.02% brij). Twenty-five microiiters 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.
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 microiiters of each concentration is added in triplicate to the microfluor plate. The final concentrations in the assay are 30 μΜ, 3μΜ, 0.3 μΜ, and 0.03 μΜ.
Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is prepared asfor inhibition of human collagenase (MMP-1) and 50 μΙ is added to each well to give a final assay concentration of 10 μΜ. 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 IC5Q's are reported to be less than 0.03 μΜ, inhibitors are then assayed at final concentrations of 0.3 μΜ, 0.03 μΜ, 0.003 μΜ and 0.0003 μΜ.
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 in 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.
AP/PZ 9 8/01191
APO 0 0 8 2 6
-15·<>
180μ of the cell suspension was aliquoted into flate bottom 96 well plates (Costar). Additions of compounds and LPS (100ng/ml final concentration) gave a final volume of 200//I. All conditions were performed in triplicate. After a four hour incubation at 37°C in an humidified CO2 incubator, plates were removed and centrifuged (10 minutes at approximately 250 x g) and the supernatants removed and assayed for TNFa using the R&D ELISA Kit.
For administration to mammals, including humans, for the inhibition of matrix metalioproteinases or the production of tumor necrosis factor (TNF), a variety of conventional routes may be used including orally, parenterally and topically. In general, the active compound will be administered orally or parenterally 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. 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 polyvinylpyrrolidone, sucrose, gelation and acacia.
Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting 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
AP/P/ 9 8/01191
AP Ο Ο Ο 8 2 6
-16advantageously contained in an animal feed or drinking water in a concentration of 55000 ppm, preferably 25 to 500 ppm.
For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable 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 present invention is illustrated by the following examples, but it is not limited to the details thereof.
Preparation A
4-(4-Fluorophenoxy)benzenesulfonyl chloride
Chlorosulfonic acid (26 mL, 0.392 mole) was added dropwise to ice-cooled 4fiuorophenoxybenzene (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 dried in the air.
25 Preparation B
Sodium 4-(3-methylbutoxy)benzenesulfonate
A solution of 4-hydroxybenzenesulfonic acid (10.0 grams, 43.1 mmole) and sodium hydroxide (3.3 grams, 83 mmole) in water (40 mL) was mixed with a solution of 1-iodo-3-methylbutane (11.3 mL, 86.4 mmole) in isopropanol (60 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under vaccuum. The titled compound, 10.0 grams (87%), was collected by filtration washing with isopropanol. j»·*®*»-*·.
AP/P/ 9 8/01191
AP Ο Ο Ο 8 2 6
-17Preparatlon C
4-(3-Methylbutoxv)benzenesulfonyl chloride
A mixture of sodium 4-(3-methylbutoxy)benzenesulfonate (2.5 grams, 9.4 mmole), thionyl chloride (10 mL), and 5 drops of Ν,Ν-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was taken up in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated to afford the titled compound as an oil, 2.34 grams (95%).
Preparation D
Sodium 4-(2-cyclopentvlethoxv)benzenesulfonate
A solution of 4-hydroxybenzenesulfonic acid (6.5 grams, 28.2 mmole) and sodium hydroxide (2.2 grams, 55 mmole) in water (15 mL) was mixed with a solution of 2-(bromoethyi)cyclopentane (15.0 grams, 84.7 mmole) in isopropanol (40 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under vaccuum. The titled compound, 4.7 grams (57%), was collected by filtration washing with isopropanol.
Preparation E
4-(3-Methylbutoxv)benzenesulfonyl chloride
A mixture of sodium 4-(2-cyclopentylethoxy)-benzenesulfonate (2.5 grams, 8.6 mmole), thionyl chloride (15 mL), and a few drops of Ν,Ν-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was taken up in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated to afford the titled compound as an oil, 2.24 grams (90%).
Preparation F
4*-Fluorobiphenvlsulfonvl chloride
Chlorosulfonic acid (8.7 mL, 0.13 mole) was added dropwise to 4-fIuorobiphenyl (10.2 grams, 59 mmol) while sirring in an ice bath. Stirring was continued with ice cooling for 0.5 hours and then the reaction mixture was poured onto ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed wHh water and brine, dried over magnesium sulfate and
AF.T,' 3 8/01191
ΑΡ ο ο 0 8 2 6
-18concentrated to afford a white solid. The desired product, 4'-fluorobiphenyisulfonyl chloride (4.3 grams, 27%), was separated from 4'-fluorobiphenyIsulfonic acid (an unwanted side product) by crystallization of the latter from ethyl acetate and crystallization of the remaining material from hexane.
Preparation G
Sodium 4-(4-fluorobenzyloxv)benzenesulfonate
To a solution of 4-hydroxybenzenesuifonic acid (5.13 grams, 22.1 mmole) in 1N aqueous sodium hydroxide solution (23 mL) was added a solution of 4fluorobenzylbromide (3.3 mL, 26.5 mmole) in ethanol (20 mL). The resulting mixture was heated at reflux for 2 days. Upon cooling and standing, a white solid precipitated. The precipitated product, sodium 4-(4-fluorobenzyloxy)benzenesulfonate, 4.95 grams (74%) was collected by filtration washing with ethyl acetate and diethyl ether.
Preparation H
4-(4-Fluorobenzvloxy)benzenesulfonvl chloride
To a slurry of sodium 4-(4-fluorobenzyloxy)benzenesulfonate (0.5 grams, 1.64 mmole), in methylene chloride (5 mL) was added phosphorus pentachloride (275 mg, 1.31 mmole). The resulting mixture was heated at reflux for 7 hours. After cooling in an ice bath and quenching with water (15 mL), the mixture was extracted with ethyl acetate. The organic phase was washed brine, dried over sodium sulfate, and concentrated to afford 4-(4-fluorobenzyloxy)benzenesulfonyl chloride a white solid (130 mg, 26%).
Preparation I
4-(4-Chlorophenoxv)benzenesulfonyl chloride
Chlorosulfonic acid (9.7 mL, 0.147 mole) was added dropwise to 4chlorophenoxybenzene (12.6 mL, 73.4 mmole) at room temperature with stirring. When addition was complete, the mixture was stirred at room temperature for 1 hour and then poured into ice water. The solid was collected by filtration, dried in the air, and recrystallized from petroleum ether and ethyl acetate to give 4-(4chlorophenoxy)benzenesulfonylchloride (7.43 grams, 33%).
AP/P/ 9 8/01191
REGISTRAR OP PATENTS AND TRADE MARKS
2R JAN
PC 1 Τ 7A
AP ο Ο Ο 8 2 6
-19Example 1
1-(4-Methoxvbenzene8ulfonvlamino)cvclopentane-1-carboxvllcacidhvdroxyamide (A) To a solution of 1-aminocyclopentane-1-carboxylic acid (6.0 grams, 46.5 mmole) and triethylamine (14 mL, 100 mmole) in dioxane (90 mL) and water (90 mL) was added 4-methoxybenzenesulfonyl chloride (10.6 grams, 51.3 mmole). The resulting mixture was stirred at room temperature for 4 hours, acidified with aqueous 1N hydrochloric acid solution, and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate and concentrated to leave a tan solid which was triturated with chloroform to afford 1-(410 methoxybenzenesulfonylamino)-cyclopentane-1 -carboxylic acid as a white solid, 5.42 grams (39%).
(B) To a solution of 1-(4-methoxybenzenesulfonylamino)cyclopentane-1carboxylic acid (4.65 grams, 15.2 mmole) and triethylamine (2.5 mL, 17.9 mmole) in methylene chloride (120 mL) was added (benzotriazol-1 15 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (7.4 grams, 16.3 mmole).
The resulting mixture was stirred at room temperature for 2.5 days. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed successively with aqueous 0.5 N hydrochloric acid solution, water and brine. After drying over magnesium sulfate, the solvent was evaporated to afford 1-(420 methoxybenzenesulfonylamino)cyclopentane-carboxylic acid benzotriazol-1 -yl ester as a yellow solid. This was dissolved in N,N-dimethyiformamide (120 mL) and to the resulting solution was added diisopropylethylamine (5.3 mL, 30 mmole) and Obenzylhydroxylamine hydrochloride (3.2 grams, 20 mmole). The mixture was heated in an oil bath at 50°C for 20 hours. The solvent was evaporated and ethyl acetate was added. The mixture was filtered to collect a white solid. The filtrate was washed successively with aqueous 0.5 N hydrochloric acid solution, aqueous saturated sodium bicarbonate solution and brine. Upon evaporation of the solvent, a solid was obtained . which was combined with that isolated by filtration and triturated with ethyl acetate to afford 1 -(4-methoxybenzenesulfonylamino)cyclopentane-1 -carboxylic acid benzyloxyamide as a white solid, 2.92 grams (47%).
. (C) A solution of 1 -(4-methoxybenzenesulfonyiamino)cyclopentane-1 -carboxylic acid benzyloxyamide (1.50 grams, 3.71 mmole) in methanol (200 mL) was treated with
5% palladium on barium sulfate (0.75 grams) and hydrogenated at 3 atmospheres
I 6 U 0 / 8 6 IdidV
AP Ο Ο ο 8 2 6
-20pressure for 3.5 hours in a Parr shaker. The catalyst was removed by passage through a 0.45 pm nylon filter and the filtrate was concentrated to afford 1-(4methoxybenzenesulfonylamino)-cyclopentane-1-carboxylic acid hydroxyamide_as a white solid, 1.13 grams (97%). MS: 313 (M-1).
The titled compounds of Examples 2-8 were prepared by a method analogous to that described in Example 1 using the reagents indicated.
Example 2
1-(4-Methoxvbenzenesulfonvlamino)cyclohexane-1 -carboxylic acid hydroxyamide.
-Aminocyclohexane-1 -carboxylic acid; 4-methoxybenzenesulfonyl chloride. MS:
327 (M-1).
Example 3
-i4-(4-Fluorophenoxv)benzenesulfonvlaminolcyclopentane-1 -carboxylic acid hydroxyamide
-Aminocyclopentane-1 -carboxylic acid; 4-(4-fluorophenoxy)benzenesulfonyl chloride. MS: 393 (M-1). Analysis calculated for C18H19FN205S.0.25 H2O: C 54.19, H 4.93, N 7.02. Found: C 54.20, H 5.13, N 7.08.
Example 4
1-r4-(4-Fluorophenoxy)benzenesulfonylaminoTcyclohexane-1-carboxylic acid hydroxyamide
1-Aminocyclohexane-1-carboxylic acid; 4-(4-fluorophenoxy)benzenesulfonyl chloride. Recrystallized from chloroform. MP: 174°C; MS: 407 (M-1).
Example 5 ~l-r4-(4-Fluorophenoxv)benzenesulfonylamino1cvclopropane-1-carboxylic acid hydroxyamide
1-Aminocyclopropane-1 -carboxylic acid; 4-(4-fluorophenoxy)benzenesulfonyl chloride. MP: 184°C; MS 365 (M-1); Analysis calculated for CieH15FN2O5S: C 52.45, H 4.13, N 7.65. Found: C 52.20, H 4.34, N 7.44.
Example 6
-(4,-Fluorobiphenyl-4-sulfonvlamino)cvclopentane-1 -carboxylic acid hydroxyamide
1-Aminocyclopentane-1-carboxylic acid; 4'-fluorobiphenylsulfonyl chloride.
Recrystallized from chloroform. MP 159 °C; MS: 377 (M-1).
AP/P/ 9 8/01191
AP Ο Ο Ο 8 2 6
-21Example 7
1-f4-(4-Fluorophenoxv)benzenesulfonvlamino1cyclobutane-1-carboxylic acid hydroxyamide
-Aminocyclobutane-1 -carboxylic acid; 4-(fluorophenoxy)benzenesulfonyl 5 chloride. MS: 379 (M-1).
Example 8
1-r4-(4-Fluorobenzvloxv)benzenesulfonvlaminolcyclopropanecarboxvlic acid hydroxyamide
-Aminocyclopropane-1 -carboxylic acid; 4-(4-fluorobenzyloxy)benzenesulfonyl chloride. MS: 379 (M-1).
Example 9
N-Hvdroxv-2-(4-methoxybenzenesulfonvlamino)-2-methvlpropionamide (A) A solution of 2-amino-2-methylpropionic acid benzyl ester hydrochloride (12.0 grams, 52.2 mmole) and 4-methoxybenzenesulfonylchloride (11.9 grams, 57.6 mmole) in dioxane (100 mL) and water (100 mL) was cooled in an ice bath. Triethylamine (18.2 mL, 0.13 mole) was then added. The ice bath was removed and the reaction mixture was allowed to stir at room temperature for 2 days. The solvents were removed under vacuum and the residue was taken up in ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with aqueous saturated sodium bicarbonate solution, aqueous 1 N hydrochloric acid solution, and brine. After drying over sodium sulfate, the solvent was evaporated to leave a yellow oil (19.3 grams) a portion of which (10 grams) was chromatographed on silica gel eluting with 3:7 ethyl acetate/hexane to afford, after recrystallization from ethyl acetate/hexane, 2-(425 methoxybenzenesulfonylamino)-2-methylpropionic acid benzyl ester_as a white solid, 6.59 grams (67%).
(B) A solution of 2-(4-methoxybenzenesulfonyiamino)-2-methylpropionic acid benzyl ester (1.5 grams, 4.13 mmole) in ethanol (80 mL) was treated with 10% palladium on carbon (0.17 grams) and hydrogenated at 3 atmospheres pressure for 1.5 hours in a Parr shaker. The catalyst was removed by passage through a 0.45 μτη nylon filter and the filtrate was concentrated to afford 2-(4-methoxybenzenesulfonylamino)-2methylpropionic acid as a white solid, 1.09 grams (96%).
110/86 :2,'dV
AP Ο Ο Ο 8 2 6
-22(C) A solution of 2-(4-methoxybenzenesulfonylamino)-2-methyipropionic acid (1.08 grams, 3.95 mmole) in methylene chloride (120 mL) was cooled in an ice bath. Triethylamine (2.2 mL, 15.8 mmole), (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (2.6 grams, 5.88 mmole) and O5 benzyihydroxylamine hydrochloride (0.95 grams, 5.95 mmole) were subsequently added. The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed successively with aqueous 1 N hydrochloric acid solution, aqueous saturated sodium bicarbonate solution, water and brine. After drying over sodium sulfate, the solvent was evaporated to afford an oil from which the desired product, Nbenzyloxy-2-(4-methoxybenzenesulfonylamino)-2-methyl-propionamide (1.41 grams, 95%), a white solid, was obtained by chromatography on siiica gel eluting with 1:2 ethyl acetate/hexanes.
(D) A solution of N-benzyloxy-2-(4-methoxybenzenesulfonylamino)-2-methyl15 propionamide (1.40 grams, 3.70 mmole) in methanol (80 mL) was treated with 5% palladium on barium sulfate (0.75 grams) and hydrogenated at 3 atmospheres pressure for 1.5 hours in a Parr shaker. The catalyst was removed by passage through a 0.45 //m nylon filter and the filtrate was concentrated to afford N-hydroxy-2-(4-methoxybenzenesulfonylamino)-2-methylpropionamide as a white solid, 1.06 grams (100%).
MP: 122-125°C. MS: 289 (M+1): Analysis calculated for CnHieN2O5S: C, 45.82; H, 5.59; N, 9.72; Found: C, 45.88; H, 5.60; N, 9.69.
The titled compounds of Examples 10-12 were prepared by a method analogous to that described in Example 9 using the reagents indicated.
Example 10 25 2-f4-(4-Fiuorophenoxy)benzenesulfonylamino1-N-hvdroxv-2-methvl-propionamide
2-Amino-2-methylpropionicacid benzyl esterhydrochloride; 4-(4-fluorophenoxy)benzenesulfonyl chloride. MP: 133-134°C. MS: 369 (M+1), Analysis calculated for C,eH17FN2O5S: C, 52.17; H, 4.65; N, 7.60; Found: C, 52.21; H, 4.83; N, 7.80.
Example 11 33 N-Hvdroxv-2-methvl-2-r4-(3-methvlbutoxv)benzenesulfonvlamino]-propionamide 2 Amino-2-methylpropionic acid benzyl ester hydrochloride; 4-(3-methylbutoxy)benzenesulfonyl chloride. Recrystailized from ethyl acetate/hexane. MP 126.5-128°C.
CO £
CU <
Τ 20 Ο
ΑΡ ο ο Ο 8 2 6
-23MS: 343 (Μ-1), Analysis calculated for C15H24N2O5S: C, 52.31; H, 7.02; N, 8.13; Found: C, 52.30; H, 7.07; N, 8.16.
Example 12
2-f4-(2-Cvclopentvlethoxv)benzenesulfonviamino1-N-hvdroxv-2-methylpropionamide
2-Amino-2-methylpropionic acid benzyl ester hydrochloride; 4-(2cyclopentylethoxy) benzenesulfonyl chloride. Recrystallized from ethyl acetate/hexane. MP 126-127°C. MS: 369 (M-1). Analysis calculated for C17H26N2O5S: C 55.12, H 7.07, N 7.56. Found: C 55.46, H 7.09, N 7.38.
Example 13
N-Hvdroxv-2-methvl-2-(5-pvridin-2-vlthiophene-2-sulfonyIamino)propionamide (A) To a solution of 2-amino-2-methylpropionic acid (2.0 grams, 19.4 mmole) in 1 N aqueous sodium hydroxide solution (45 mL) and dioxane (45 mL) was added 5pyridin-2-ylthiophene-2-sulfonyl chloride (8.41 grams, 32.4 mmole). The resulting mixture was stirred at room temperature for 16 hours. Additional 1 N aqueous sodium hydroxide solution (45 mL) was added to the reaction mixture which was then extracted with diethyl ether. The organic extracts were discarded. The aqueous layer was acidified with 1 N hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate fractions were washed with brine, dried over magnesium sulfate and concentrated to afford 2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)propionic acid as a white solid (2.18 grams, 34%).
(B) To a solution of 2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)propionic acid (1.60 grams, 4.91 mmole) in methylene chloride (160 mL) was added triethylamine (2.3 mL, 16.5 mmole), (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (2.4 grams, 5.41 mmole) and 0-(2trimethylsilylethyl)hydroxylamine hydrochloride (0.92 grams, 5.41 mmole). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed with water, aqueous saturated sodium bicarbonate solution, and brine. After drying over magnesium sulfate, the solvent was evaporated to afford a white foam from which the desired product, 2-methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)-N-(2trimethylsilanylethoxy)-propionamide (220 mg, 10%), a white solid, was isolated by chromatography on silica gel eluting with 3:2 ethyl acetate/hexanes.
AP/P/ 9 8/01 191
APO00826
-24(C) 2-Methyl-2-(5-pyridin-2-ylthiophene-2-sulfonylamino)-N-(2-trimethylsilanylethoxy)propionamide (80 mg, 0.18 mmole) was dissolved in trifiuoroacetic acid and the resulting solution was stirred at room temperature for 16 hours. The trifiuoroacetic acid was evaporated under vacuum, chasing with methanol, to afford N-hydroxy-2-methyl-25 (5-pyridin-2-ylthiophene-2-sulfonylamino)propionamide, a yellow oil (60 mg, 97%) which was crystallized from ethanol. MP 165-166°C. MS: 342 (M+1).
The titled compounds of Examples 14-15 were prepared by a method analogous to that described in Example 13 using the reagent indicated.
Example 14
-(5-Pvridin-2-vl-thiophene-2-sulfonylamino)cvclopentane-1 -carboxylic acid hydroxyamide
-Aminocyciopentane-1 -carboxylic acid; 5-pyridin-2-ylthiophene-2-sulfonyl chloride. MS: 368 (M + 1).
Example 15
-f4-(4-Chiorophenoxv)benzenesuifonvlamino1cyclopropane-1 -carboxylic acid hydroxyamide
-Aminocyclopropane-1 -carboxylic acid; 4-(4-chlorophenoxy)benzenesulfonyl chloride. MS: 381 (M-1).

Claims (8)

1. A compound of the formula
R1
HO·
-NI
H
APO0082fi
-250
II I
-c—c~
H •N
I hi vine now particularly described and a-cviiaineJ mv/our said inventi·? a,.,! d· v hat inn’nk’r the same is to be peribimed bwe de. tare that whal ί/we s. 1.
mu is \// //S\
0 Q or the pharmaceutically acceptable salts thereof, wherein
R1 and R2 are each independently selected from (C,-Ce)alkyl, trifluoromethyl, trifluoromethyl(C,-Ce) alkyl, (C,-Cfl)alkyl(difluoromethylene), (¢,CJalky^drfiuoromethyienelC^CJaJkyi, (Ce-C10)aryf, (C2-C8}heteroaryi, (Ce-C10)aryl(C,Ce)aJkyf, (C2-C9)heteroaryl(C,-Ce)alkyl or R1 and R2 may be taken together to form a (C3Ce)cycfoalkyl or benzo-fused (C3-Ce)cycloalkyf ring or a group of the formula
AP/F. 9 8/01 191 wherein n and m are independently 1 or 2 and X is CF2, S, O or NR3 wherein R3 is hydrogen, (C,-Ce)alkyl, (Ce-C10)aryi, (C2-C9}heteroaryl, (Ce-C,0)aryl(C,-Ce)aJkyl. (C2Cg)heteroaryl(C,-CB)alkyl, {C,-Ce)alkylsulfonyl, (Ce-C10)aryisulfonyl or acyl; and
Qls^,-Ce)alkyl,{Ce-Cw)aryl,(Ce-Ct0)aiyloxy^e-C,0)aryl1(Ce<5w)aryl(Ce^t0)aryl, {Ce-C10)aryl(Ce-C10)aryl(C,-Ce)alkyl, (Ce-C,0)aryi(C2-Ce)heteroary1, (Ce-C10)aryloxy(C2C9)heteroary1, (C2-Ce}heteroaryi, (C2-Ce)heteroaryl(C2-Ce}heteroaryi, (C2-C8)heteroaryl(CeC10)aryi,(^ -Ce)alkyl(Ce-C,0)aryl,{C,-Ce)alkoxy(C6-C,0)aryl.{Ce-C,0)aryl(C,-Ce)alkoxy(CeC10)aryl, {Ce-C10)aryl(C,-C6)aJkoxy(C,-Ce)alky1, (C2-C8)heteroarytoxy{Ce-C10)aryi, (¢,Ce)alkyl(Cz-Ce)heteroaryl, (¢, -Ce)alkoxy(C2-Ce)heteroaryf, (Ce-C, 0)aryl(C,-Ce)alkoxy{C2C9)heteroaryl, (C2-C,)heteroaryloxy(C2-C,)heteroaryl, (Ce-Cw)aryloxy{C,-Ce)alkyl. (C2« C8)heteroaryloxy(C,-C6) alkyl, (C,-Ce)alkyf(Ce-Cw)aryloxy(Ce-C,0)aryl, (C,-Ce}aIkyl(C2C9)heteroaryloxy(Ce-C,0)aryl, (C^CeialkyliCe-C^JaryloxyiCj-CjJheteroaryl, (¢,Ce)alkoxy{Ce-C,0)aryloxy(Ce-Ct0)aryl, (C,-Ce)alkoxy(C2-C9)heteroaryloxy(Ce-C,0)aryl or (C^C^alkoxy(0,,-0,0)aryloxy(Cj-C9)heteroaryl wherein each aryl group is optionally substituted byfluoro, chloro, bromo, (CT-CgJalkyl, (CT-C^alkoxy orperfluoroiC^CjJalkyl.
2. A compound according to claim 1, wherein R’ and R2 are taken together to form a (C3-Ce)cycloalkyl or benzo-fused (C3-C„)cycloalkyl ring or a group of the
5 formula
APOύ0826 wherein n and m are independently 1 or 2 and X is CF2, S, 0 or NR3 wherein R3 is hydrogen, (C^-C^alkyl, (C6-C,0)aryl, (C2-C9)heteroaryl, (Cg-C^aryl^-CJaJkyl, (C2C9)heteroaryl(C,-Ce)alkyl, (C^-C^alkylsulfonyl, (C6-C10)arylsulfonyl or acyl.
3. A compound according to claim 2, wherein R1 and R2 are taken together 15 to form a (C3-Ce)cycloalkyl or benzo-fused (C3-Ce)cycloalkyl ring.
4. A compound according to claim 1, wherein R1 and R2 are each independently (C,-Ce)aikyi.
5. A compound according to any one of claims 1 to 4, wherein Q is (CeC10)aryl, (C6-C10)aryl(Ce-C10)aryl, (Ce-C10)aryioxy(Ce-C10)aryl, (Ce-C10)aryloxy(C220 Cg)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (Ce-C10)aryl(C2¥ C9)heteroaryl, (C2-C9)heteroaryl(Ce-C10)aryl or (C2-C9)heteroaryloxy(Ce-C10)aryl.
6. A compound according to claim 5, wherein Q is (Ce-C1o)aryloxy(CeC10)aryl.
7. A compound according to claim 1, wherein said compound is selected 25 from the group consisting of:
3- [4-(4-Fluorophenoxy)benzenesulfonylamino]azetidine-3-carboxylic acid hydroxyamide;
4- [4-(4-Fluorophenoxy)benzenesulfonylamino}piperidine-4-carboxylic acid hydroxyamide;
30 1-[4-(4-Fluorophenoxy)benzenesulfonylamino]cyclopropane-1 -carboxylic acid hydroxyamide;
1-[4-(4-Chlorophenoxy)benzenesulfonylamino]cyclopropane-1 -carboxylic acid hydroxyamide;
ΑΡ/Γ7 98/01191
AP Ο ύ Ο 8 2 6
-271 -[4-(4-Fluorophenoxy)benzenesulfonyiamino]cyclobutane-1 -carboxylic acid hydroxyamide;
1 -[4-(4-Chlorophenoxy)benzenesulfonylamino]cyclobutane-1 -carboxylic acid hydroxyamide;
5 1-[4-(4-FIuorophenoxy)benzenesulfonylamino]cyclopentane-1-carboxylic acid hydroxyamide;
1 -[4-{4-Fluorophenoxy)benzenesutfonylamino]cyclohexane-1 -carboxylic acid hydroxy amide;
2-[4-(4-Fluorophenoxy)benzenesutfonylamino]-N-hydroxy-2-methylpropionamide;
10 2-[4-(4-Chtorophenoxy)benzenesulfonyiamino]-N-hydroxy-2-methyl-propionamide;
N-Hydroxy-2-methyl-2-(5-pyridin-2-yIthiophene-2-suifonylamino)propionamide;
1 -(5-Pyridin-2-yl-thiophene-2-sulfonylamino)cyclopentane-1 -carboxylic acid hydroxy amide;
1 -(4'-Ftuorobiphenyl-4-sulfonylamino)cyclopropane-1 -carboxylic acid
15 hydroxyamide;
1 -(4'-Fluorobiphenyl-4-sulfonylamino)cyclobutane-1 -carboxylic acid hydroxy amide;
1 -(4'-Fluorobiphenyl-4-sulfonylamino)cyclopentane-1 -carboxylic acid hydroxyamide;
20 2-(4-Methoxybenzenesufonylamino)indan-2-carboxy1ic acid hydroxyamide; and
2-[4-(4-Fluorophenoxy)benzenesulfonylamino]-indan-2-carboxylic acid hydroxy amide.
8. A pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, mucular
25 degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, in combination with standard NSAIDS 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
30 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.
APAP/P/1998/001191A 1997-02-03 1998-01-29 Arysulfonylamino hydroxamic acid derivatives. AP826A (en)

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