Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-08-26
2001-04-10
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S562000, C514S329000, C514S459000, C546S223000, C549S424000, C560S013000, C562S430000
Reexamination Certificate
active
06214872
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to aryloxyarylsulfonylamino hydroxamic acid derivatives. These compounds are selective inhibitors of matrix metalloproteinase-13 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, bone resorption, loosening of artificial joint implants, atherosclerosis, multiple sclerosis, occular angiogenisis (for example macular degeneration) and other diseases characterized by matrix metalloproteinase activity.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to the 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).
Tumor necrosis factor is recognized to be involved in many infectious and auto-immune diseases (W. Friers,
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 Immunopathology,
1992 62 11).
PCT Publication WO 96,27583, published Sep. 12, 1996 refers to certain arylsulfonylamino hydroxamic acids.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula
or the pharmaceutically acceptable salts thereof, wherein
R
1
is (C
1
-C
6
)alkyl;
R
2
is (C
1
-C
6
)alkyl;
or R
1
and R
2
taken together with the carbon atom to which they are attached form a ring selected from (C
5
-C
7
)cycloalkyl, 4-tetrahydropyranyl and 4-piperidinyl;
R
3
is hydrogen or (C
1
-C
6
)alkyl; and
Y is a substituent on any of the carbon atoms of the phenyl ring capable of supporting an additional bond, preferably from 1 to 2 substituents (more preferably one substituent, most preferably one substituent in the 4-position) on the phenyl ring, independently selected from hydrogen, fluoro, chloro, trifluoromethyl, (C
1
-C
6
)alkoxy, trifluoromethoxy, difluoromethoxy and (C
1
-C
6
)alkyl.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term “alkoxy”, as used herein, includes O-alkyl groups wherein “alkyl” is defined above.
The 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, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, enthanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
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.
This invention also encompasses pharmaceutical compositions containing and methods of treating or preventing comprising administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain. Prodrugs also include compounds of formula I in which the hydroxamic acid and carbonyl moiety when taken together form a group of the formula
wherein R
1
, R
2
and Y are as defined in formula I and U and V are independently carbonyl, methylene, SO
2
or SO
3
, and b is an integer from one to three wherein each methylene group is optionally substituted with hydroxy.
Preferred compounds of formula I include those wherein Y is hydrogen, fluoro or chloro, preferably 4-fluoro or 4-chloro.
Other preferred compounds of formula I include those wherein R
1
and R
2
taken together with the carbon atom to which they are attached form a cyclopentyl or 4-tetrahydropyranyl ring.
Other preferred compounds of formula I include those wherein R
1
and R
2
are both methyl.
Other preferred compounds of formula I include those wherein R
3
is hydrogen.
Specific preferred compounds of formula I include the following:
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxy-carbamoylcyclopentyl)amino]-propionic acid ethyl ester,
3-[[4(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxy-carbamoylcyclopentyl)amino]propionic acid,
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoyl-1-methylethyl)amino]propionic acid ethyl ester, and
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxy-carbamoyl-1-methylethyl)amino]propionic acid.
Other compounds of formula I include the following:
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(4-hydroxycarbamoyltetrahydropyran-4-yl)-amino]propionic acid,
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(4-hydroxycarbamoyltetrahydropyran-4-yl)-amino]propionic acid ethyl ester,
3-[[4-(4-chlorophenoxy)benzenesulfonyl]-(4-hydroxycarbamoyltetrahydropyran-4-yl)-amino]propionic acid,
3-[[4-(4-chlorophenoxy)benzenesulfonyl]-(4-hydroxycarbamoyltetrahydropyran-4-yl)-amino]propionic acid ethyl ester,
3-[(4hydroxycarbamoyltetrahydropyran-4-yl)-(4-phenoxybenzenesulfonyl)amino]-propionic acid.
3-[[(4-hydroxycarbamoyltetrahydropyran-4-yl)-(4-phenoxybenzenesulfonyl)amino]propionic acid ethyl ester,
3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(4-hydroxycarbamoylpiperidin-4-yl)-ami
Butterfield Garth
Fan Jane
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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