ZA200100294B - Coadministration of ACAT and MMP inhibitors for the treatment of atherosclerotic lesions. - Google Patents

Coadministration of ACAT and MMP inhibitors for the treatment of atherosclerotic lesions. Download PDF

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ZA200100294B
ZA200100294B ZA200100294A ZA200100294A ZA200100294B ZA 200100294 B ZA200100294 B ZA 200100294B ZA 200100294 A ZA200100294 A ZA 200100294A ZA 200100294 A ZA200100294 A ZA 200100294A ZA 200100294 B ZA200100294 B ZA 200100294B
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acid
methyl
phenyl
biphenyl
hydroxy
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ZA200100294A
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Thomas Michael Andrew Bocan
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Warner Lambert Co
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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Description

“#7 wo oes PCT/US99/13948
COADMINISTRATION OF ACAT AND MMP INHIBITORS FOR THE
TREATMENT OF ATHEROSCLEROTIC LESIONS
3 BACKGROUND OF THE INVENTION 4 Enzymes known as native matrix metalloproteinases (MMP) are classes of naturally occurring enzymes found in most mammals. They are zinc proteases that hydrolyze collagens, proteoglycans, and glycoproteins. The classes include gelatinase A and B, stromelysin-1 and -2, fibroblast collagenase, neutrophil collagenase, matrilysin, metalloelastase, and interstitial collagenase. These enzymes are implicated in a number of diseases which result from breakdown of connective tissues, such as rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, and even tumor metastasis. The expression of MMPs in atherosclerosis is discussed in White A., Bocan T.M.A., Boxer P.A., Peterson J.T.,
Schrier D. Emerging therapeutic advances for the development of second generation matrix metalloproteinase inhibitors. Curr. Pharm. Design 3:45-58 (1997). To date, inhibitors of matrix metalloproteinases have not been utilized with ACAT inhibitors.
United States Patent Application 08/987167 filed December 8, 1997, : teaches MMP inhibitors and their preparation and is hereby incorporated by reference.
Compounds which inhibit acyl-coenzyme A:cholesterol acyltransferase are known as ACAT inhibitors. Certain ACAT inhibitors and the methods for preparing them are taught in United States Patent 5,491,172 and its divisional ) 5,633,287 which are hereby incorporated by reference.
United States Patent 5,756,545 covers MMP inhibitors especially 2-(4’-Bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid. This patent is hereby incorporated by reference.
United States Patent 5,441,975 teaches ACAT inhibitors, especially
N-(2,6-Diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-y1)-2-phenyl-acetamide.
This and other patents in the same patent family: 5,646,170; 5,693,657; and 5,366,987 are hereby incorporated by reference.
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SUMMARY OF THE INVENTION
The instant invention is the coadministration of ACAT and MMP inhibitors for the reduction of both macrophage and smooth muscle cell components of atherosclerotic lesions in a mammal, particularly a human. The lesions are directly reduced, and so, the expansion of existing lesions and the ] development of new ones is impaired.
Certain ACAT inhibitors and certain MMP inhibitors are disclosed as suitable for coadministration.
Pharmaceutical compositions of the inhibitors are also included in the invention.
DETAILED DESCRIPTION OF THE INVENTION
Coadministration of a bioavailable ACAT inhibitor with a matrix metalloproteinase (MMP) inhibitor can blunt the development of atherosclerotic lesions and promote development of a stable plaque morphology. ACAT is inhibitors have been shown to reduce the accumulation of monocyte-macrophages within atherosclerotic lesions of rabbits. In addition, monocyte-macrophages have been reported to secrete such matrix metalloproteinases as MMP-7 and -9 while smooth muscle cells are noted to secrete MMP-1, -2, and -3. Inhibition of ACAT while directly reducing the accumulation of lipid-filled monocyte-macrophages will decrease the source of MMPs. Inhibition of MMPs will also limit the development of atherosclerotic lesions through reducing smooth muscle cell and monocyte migration into the development intima by limiting extracellular matrix remodeling. Coadministration of both agents will limit the development of new lesions by inhibiting cellular accumulation and stabilize the developed lesions by preventing both matrix remodeling and reducing the number of lipid-filled monocyte-macrophages, a source of MMP-7 and -9.
The instant invention is a method for treating and/or preventing atherosclerotic lesions comprising coadministrating one or more MMP inhibitors and one or more ACAT inhibitors.
ay i @ "WoO 00/04892 : PCT/US99/13948
The invention is further a method for preventing plaque rupture and for promoting lesion regression by administering a combination of an ACAT inhibitor and an MMP inhibitor.
The method is practiced by administering a chemical compound effective ) 5 in inhibiting the biological activity of a matrix metalloproteinase such as ; collagenase, stromelysin, gelatinase, or elastase. The numerous compounds known to be matrix metalloproteinase inhibitors are useful in the practice of this invention.
The method is practiced by administering a chemical compound which inhibits the enzyme acyl-coenzyme A:cholesterol acyltransferase. The numerous compounds known as ACAT inhibitors are useful in the practice of this invention.
A “matrix metalloproteinase inhibitor” as used herein is any chemical compound that inhibits by at least five percent the hydrolytic activity of at least one matrix metalloproteinase enzyme that is naturally occurring in a mammal.
Co 15 Such compounds are also referred to as “MMP inhibitors.” Numerous matrix } metalloproteinase inhibitors are known, and all are useful in the method of this oo invention. For example, 4-biarylbutyric and 5-biarylpentanoic acid derivatives are } described in United States Patent Application 339846 filed November 15, 1994, a which is incorporated herein by reference. The compounds are defined generally as (T)xA-B-D-E-G. Over 400 specific compounds are named, and each is oo incorporated herein and can be employed in this invention. Especially preferred compounds to be utilized include the following: [1,1”-Biphenyl]-4-butanoic acid, 4’-chloro-o-(2-methylpropyl)-y-oxo-; : [1,1”-Biphenyl]-4-butanoic acid, 4’-chloro-a-(2-methylpropyl)-y-oxo-, (S)-; [1,1”-Biphenyl]}-4-butanoic acid, 4’-chloro-o-(2-methylpropyl)-y-oxo-, (R)-; [1,1°-Biphenyl]-4-butanoic acid, 4’-chloro-B-(2-methylpropyl)-y-oxo-, (S); (1,1’-Biphenyl]-4-butanoic acid, 4 -chloro-B-(2-methylpropyl)-y-oxo-,
R)-; [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-y-oxo-; [1,1”-Biphenyl]-4-butanoic acid, 4’-bromo-y-oxo-;
[ 1,1’-Biphenyl]-4-butanoic acid, 4’-fluoro-y-0xo-; [1,1’-Biphenyl]-4-butanoic acid, 2’-flucro-y-oxo-; [1,1"-Biphenyl]-4-butanoic acid, 2’-chloro-y-oxo-; {1,17-Biphenylj-4-butanoic acid, 2°,4 -difiuoro-y-oxo-; . [1,1”-Biphenyl}-4-butanoic acid, 3’-chloro-y-oxo-; [1,1’-Biphenyl |-4-butanoic acid, o-(2-methyl-propyl)-y-oxo-; ; [1,1’-Biphenyl]-4-butanoic acid, 4’-bromo-ot-(2-methylpropyl)-y-oxo-; [1,1’-Biphenyl}-4-butanoic acid, 4’-fluoro-a-(2-methylpropyl)-y-oxo-; [1,1”-Biphenyl]-4-butanoic acid, 4’-ethyl-0i-(2-methylpropyl)-y-oxo-; [1,1’-Biphenyl]-4-butanoic acid, 2’-fluoro-ai-(2-methylpropyl)-y-oxo- ; [1,1"-Biphenyl]-4-butanoic acid, 2’-chloro-oi-(2 -methylpropy!)-y-oxo-; [1,1’-Bipheny!]-4-butancic acid, 4’-methoxy-o-(2-methylpropyl)-v-oxo-; [1,1”-Biphenyl]-4-butanoic acid, 2’ 4’-difluoro-o-(2-methylpropyl)-y-oxo-; [1,1’-Bipheny!]-4-butanoic acid, 4’-methyl-o-(2-methylpropyl)-y-oxo-; [1,1"-Biphenyl}-4-butanoic acid, 0-(2-methyl-propyl)-y-oxo-4’-pentyl-; [1,1”-Biphenyl]-4-butanoic acid, 4’-chloro-o-methylene-v-0xo0-; [1,1’-Biphenyl]-4-butanoic acid, 2’-chioro-oi-methylene-y-0xo-; [1,1"-Biphenyl}-4-butanoic acid, 4’-chloro-o-methyl-y-oxo-; [1,1”-Biphenyl}-4-butanoic acid, 4’-chloro-y-oxo-o-pentyl-;
Benzenebutanoic acid, 4-chloro-0i-(2-methylpropyl)-y-oxo-;
Benzenebutanoic acid, 4-methyl-o-methylene-y-oxo-; 2-Butenoic acid, 4-(4’-chloro[1,1’-biphenyl]-4-y1)-4-oxo-, (E)-; 2-Butenoic acid, 4-[4-(4-chlorophenyoxy)-phenyl]-4-oxo, (&)-; [1,1"-Biphenyl}-4-butanoic acid, 4’-hydroxy-o-(2-methylpropyl)-y-oxo-; [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-B-methylene-y-oxo-; {1,1"-Biphenyl]-4-butanoic acid, 4’-chloro-y-hydroxy-o.-(2-methylpropyl)-; [1,1’-Biphenyl}-4-butanoic acid, 4’-chloro-y-hydroxy-o.-(2-methylpropyl)-; 2(3H)-Furanone, 5-(4’-chloro[ 1,1’-biphenyl]-4-y1)dihydro-3- (2-methylpropyl)-; 2(3H)-Furanone, 5-(4’-chlorof 1,1 "-biphenyl]-4-yl)dihydro-3-(2- methylpropyl)-;
) © ta Wo 00/04892 PCT/US99/13948 [1,1’-Biphenyl}-4-butanoic acid, 3’,4’-dichloro-y-oxo-a-(3-phenylpropyl)-; [1,1’-Biphenyl]-4-butanoic acid, 3’,5"-dichloro-y-0xo-a-(3-phenylpropyl)-; [1,1’-Biphenyl]-4-butanoic acid, 4’-(acetyloxy)-y-oxo-0-(3- " phenylpropyl)-;
Benzenepentanoic acid, a-[2-[4-(5-chloro-2-thienyl)phenyl]-2-oxoethyl]-; s 2-Furancarboxylic acid, 5-[4-(3-carboxy-1-0x0-6-phenylhexyl)phenyl]-;
Benzenepentanoic acid, o-[2-0x0-2-[4-(3-pyridinyl)phenyljethyl]-;
Benzenepentanoic acid, o-[2-0x0-2-[4-[6-(pentyloxy)-3-pyridinyl]- phenyl]ethyl]-; [1,1”-Biphenyl]-4-butanoic acid, y-oxo-4’-(pentylthio)-o-(3- phenylpropyl) ; [1,1’-Biphenyl]-4-butanoic acid, 4"-methoxy-y-oxo-0.-(3-phenylpropyl)-; : [1,1’-Biphenyl]-4-butanoic acid, 3’-chloro-4’-fluoro-y-oxo-ot-(3- phenylpropyl)-; | [1 ,1’-Biphenyl]-4-butanoic acid, 4’-ethoxy-y-oxo-a-(3-phenylpropyl)-;
Benzenepentanoic acid, a-[2-0xo0-2-[4-(3-thienyl)phenyl]ethyl]-; [1,1"-Biphenyl]-4-butanoic acid, 2’,4’-dichloro-y-oxo-o-(3-phenylpropyl)-; ) [1,1’-Biphenyl}-4-butanoic acid, 4’-formyl-y-oxo-0-(3-phenylpropyl)-; [1,1’-Biphenyl]-4-butanoic acid, y-oxo-0-(3-phenylpropyl)-3’,5’- bis(trifluoromethyl)-;
Benzenepentanoic acid, o-[2-0x0-2-[4-(2-thienyl)phenyl]ethyl]-; [1,1"-Biphenyl]-4-butanoic acid, y-oxo-a-(3-phenylpropyl)-3’- (trifluoromethyl)-; [1,1’-Biphenyl}-4-butanoic acid, 2’-formyl-y-ox0-0t-(3-phenylpropyl)-; [1,1’-Biphenyl]-4-butanoic acid, 4-hydroxy-y-oxo-0.-(3-phenylpropyl)-; [1,1’-Biphenyl]-4-butanoic acid, y-0x0-0i-(3-phenylpropyl)-4’-propoxy-; [1,1"-Biphenyl]-4-butanoic acid, y-oxo-4’-(pentyloxy)-o-(3- phenylpropyl)-; [1,1"-Biphenyl]-4-butanoic acid, y-oxo-4’-(pentyloxy)-a-(3- phenylpropyl)-, (S)-;
[1,1’-Biphenyl]-4-butanoic acid, y-ox0-4’~(pentyloxy)-o-(3- phenylpropyl)-, (R)-; [1,1°-Biphenyl]-4-butanoic acid, 4’-(hexyl 0Xy)-y-0x0-0i~(3-phenylpropyl)-; i1,1"-Biphenyij-4-butanoic acid, 4’ -butoxy-y-0Xo-0i-(3- phenyipropyi)-; . [1,1-Biphenyl]-4-butanoic acid, y-ox0-4’~(3 -phenylpropoxy)-o- (3-phenylpropyl)-; [1,1’-Biphenyl]-4-butanoic acid, 4’-(1 -methylethoxy)-y-oxo-a- (3-phenylpropyl)-; [1,1”-Biphenyi]-4-butanoic acid, 4’-(heptyioxy)-y-oxo-a.- (3-phenylpropyl)-; [1,1”-Bipheny!]-4-butanoic acid, 4’-(cyclohexyl-methoxy)-y-0x0-0t- (3-phenylpropyl)-; [1,1’-Biphenyl]-4-butanoic acid, 4'-(2-methyl-propoxy)-y-0x0-0i- (3-phenylpropyl)-; i5 [1,1’-Biphenyl]-4-butanoic acid, y-0x0-0-(3 ~-phenylpropyl)-4’- (2-propenyloxy)-; [1,1"-Bipheny!l-4-butancic acid, 4’-chlore-o-heptyl-v-oyo-; [1,1"-Biphenyl]-4-butanoic acid, 4’-chloro-a-decyl-y-oxo-; [1,1"-Biphenyl]-4-butanoic acid, 4’-nitro-y-oxo0-0-(2-phenylethyl)-; [1,1’-Biphenyl]-4-butanoic acid, 4’-cyano-y-0xo0-0i- (2-phenylethyl)-; [1,1V’-Biphenyl]-4-butanoic acid, 4’~chloro-a-[2-(2-iodopheny!)ethyl]-
Y-0X0-; [1,1”-Biphenyl}-4-butanoic acid, 4’~chloro-oi- [2-(3-iodophenyl)ethyl]-
Y-0X0-} [1,1"-Biphenyl}-4-butanoic acid, 4’-chloro-o-[2-(4-iodophenyl)ethyl}-
Y-0X0-; [1,1"-Biphenyl}-4-butanoic acid, 4’-chloro-a-[2-(3,5- dimethoxyphenyl)ethyl]-y-oxo-; [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-y-oxo-0.-phenyl-; [1,1"-Biphenyl]-4-butanoic acid, 4’-chloro-y-oxo-0-(phenylmethyl)-; (1,1"-Biphenyl]-4-butanoic acid, 4’-chloro-y-oxo-a.-(2-phenylethyl)-;
~ ‘a wo 00/04852 © PCT/US99/13948 [1,1-Biphenyl]-4-butanoic acid, 4’~chloro-y-oxo-oi-[(trimethylsilyl)- methyl}-; [1,1”-Biphenyl]-4-butanoic acid, 4’-bromo-y-oxo0-0t-(3 -phenylpropyl)-; . [1,1°-Biphenyl]-4-butanoic acid, -y-oxo-0.-(3-phenylpropyl)-; [1,1 "-Biphenyl]-4-butanoic acid, 4’-amino-y-oxo-o-(2-phenylethyl)-; - [1 1’-Biphenyl}-4-butanoic acid, y-oxo0-0-(2-phenylethyl)-4’- [[(phenylmethoxy)carbonyljamino]-; © [1,1"Biphenyl]-4-butanoic.acid, #-[[(1,1-dimethylethoxy)- carbonyl]amino]-y-oxo-o-(2-phenylethyl)-; | [1,1"-Biphenyl}-4-butanoic acid, 4'-(acetylamino) y-oxo-a.- (2-phenylethyl)-; [1,1’-Biphenyl]-4-butanoic acid, y-oxo-4'-[(1 -oxopentyl)amino]-o- (2-phenylethyl)-; (1,1"-Biphenyl]-4-butanoic acid, 4’-[(3,3 -dimethyl-1-oxobutyl)amino]- y-0x0-0-(2-phenylethyl)-; [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-o0i-[2-[2-(methoxycarbonyl)- phenyl]ethyl]}-y-oxo-; Co [1,1”-Biphenyl]-4-butanoic acid, 0-[2-(2-carboxyphenyl)ethyl]-4’-chloro- - ¥-0X0-} [1,1"-Biphenyl}-4-butanoic acid, 4’-chloro-o-[2-[2-[(diethylamino)- carbonyl]phenyl]ethyl]-y-oxo-; [1,1°-Biphenyl]-4-butanoic acid, 4’-chloro-o-[2-[3- ((diethylamino)carbonyl]phenyl]ethyl]-y-oxo-, (S)-; [1,1"-Biphenyl}-4-butanoic acid, 4’-chloro-o-[2-[3- [(diethylamino)carbonyl]phenyl]ethyl]-y-oxo-, (R)-;
Cyclopentanecarboxylic acid, 2-[(4’-chloro[1,1 "-biphenyl]}-4-yl)carbonyl]- 5-[(phenylmethoxy)methyl]-, (1c.,2B,5B)-;
Cyclopentanecarboxylic acid, 2-[(4’-chloro[1,1’-bipheny]] -4-yl)carbonyl]- 5-(phenoxymethyl)-, (1c,28,5B)-; : Cyclopentanecarboxylic acid, 2-[(benzoyloxy)-methyl]-5-[(4’-chloro[1,1’- biphenyl]-4-yl)carbonyl]-, (1c.,2[3,58)-;
1,2-Benzenedicarboxyiic acid, 1-[[2-carboxy-3-[(4’-chioro[ i ,1’-biphenyi]- 4-yl)carbonyl]cyclopentyl]-methyl]-2-methyl ester, (1 0,203,300);
Cyclopentanecarboxylic acid, 2-[(4’-chloro[1,1 "-biphenyl]-4-yl)carbonyl]- 5-{(2-thienyithicjmethylj-, (1&,23,58)-; .
Cyclopentanecarboxylic acid, 2-[(benzoylamino)methyl]-5-[(4’- chiorof1,1’-biphenyij-4-yl)carbonylj-, (1x,28,5B)-; :
Cyclopentanecarboxylic acid, 2-[(4’-chloro[ 1,1 "-biphenyl]-4-yl)carbonyl}- 5-[[(2-methoxyethoxy)methoxy]methyl]-, (1t,2B,5B)-;
Cyclopentanecarboxylic acid, 2-[(4’-chloro[ 1, ] "-biphenyl]-4-yl)carbonyi]- 5-[[(phenylmethyl)thio}methyl]-, (1c,2B,5B)-;
Cyclopentanecarboxylic acid, 2-[(4’-chloro[1,1 ’-biphenyl]-4-yl)carbonyl]- 5-[(phenylthio)methyl]-, (12,28,58)-;
Cyclopentanecarboxylic acid, 2-[(4’-chloro[1,1 "-biphenyl]-4-yl)carbonyl]- 5-[(propylthio)methyl}-, (10,23,58)-;
Cyclopentanecarboxylic acid, 2-[(2-benzothiazolylthio)methyl]-5-[(4’- chloro[1,1’-biphenyl}-4-yl)carbonyl]-, (10,28,58)-:
Benzoic acid, Z-{[[2-carboxy-3-{(4’-chioro[1,1’-biphenyi]- 4-ylcarbonyl]cyclopentyllmethyl]thio]-, 1-methy] ester, (1,228,300);
Cyclopentanecarboxylic acid, 2-[(4’-chloro{1,1 "-bipheny!]-4-yl)carbonyl]-
S-[[{{phenylmethoxy)carbony!]-amino]methyl}-, (12,2B,58)-;
Benzoic acid, 2-methyi-, [2-carboxy-3-[(4’-chloro[1,1’-biphenyl]- 4-ylcarbonyl]cyclopentyl]methyl ester, (10,2B,301)-;
Benzoic acid, 3-methyl-, [2-carboxy-3-[(4"-chloro[1,1’-biphenyl]- 4-yl)carbonyl]cyclopentyl]methyl ester, (10,228,301);
Benzoic acid, 4-methyl-, [2-carboxy-3-[(4’-chloro[] ,1’-biphenyl]- 4-yl)carbonyljcyclopentyl)methyl ester, (10,2B,30t)-;
Benzoic acid, 2-methoxy-, [2-carboxy-3-{(4’-chloro[1,1’-biphenyl]- 4-yl)carbonyl]cyclopentyljmethy! ester, (10,2B,300)-;
Benzoic acid, 3-methoxy-, [2-carboxy-3-[(4’~chloro[1,1 ‘-biphenyl]- 4-yl)carbonyl]cyclopentyl]methyl ester, (10.,2B,30()-;
} [. eT Woon: -PCT/US99/13948
Benzoic acid, 4-methoxy-, [2-carboxy-3-[(4’-chloro(1,1’-biphenyl]- 4-yl)carbonyl]cyclopentyl]methyl ester, (1a,28,30)-;
Cyclopentanecarboxylic acid, 2-[(2-benzoxazolylthio)methyl]-5-[(4'- . chloro[1,1’-biphenyl}-4-yl)carbonyl]-, (10.,2B,58)-;
Cyclopentanecarboxylic acid, 2-[(4’-chloro[1,1’-bipheny}]-4-yl)carbonyl]- ) 5-[(1,3-dihydro-4-nitro-1,3-dioxo-2H-isoindol-2-yl)methyl}-, (10,,2B,58)-;
Cyclopentanecarboxylic acid, 2-[(4’-chloro[1,1’-biphenyl]-4-yl)carbonyl]- 5-[(1,3-dihydro-5-nitro-1,3-dioxo-2 H-isoindol-2-yl)methyl]-, (1c.,2B,5B)-; 2H-Benz[f]isoindole-2-butanoic acid, o- [2-(4"-ethoxy[ 1 ,1’-biphenyl]-4-yl)- 2-oxoethyl]-1,3-dihydro-1,3-dioxo-; [1,1’-Biphenyl]-4-butanoic acid, o-(acetylamino)-4’-chloro-y-oxo-; 2H-Isoindole-2-hexanoic acid, a-[2-(4’-chloro[ 1,1’-biphenyl]-4-y1)- 2-oxoethyl]-1,3-dihydro-1,3-dioxo-; {1,1"-Biphenyl]-4-butanoic acid, 4’-chloro-ot-[[[3-(methoxycarbonyl)- phenyl]thiolmethyl]-y-oxo0-; [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-o-[[(2,6-(dimethylphenyl)- thio}methyl]-y-oxo-; : [1,1°-Biphenyl]-4-butanoic acid, 4’-chloro-o.-[[[4-fluoro- 2-(methoxycarbonyl)phenyljthio]methyl]-y-oxo-; : [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-a-[[[3-[(diethylamino)- carbonyl}phenyl]thiojmethyl}-y-oxo-; [1,1"-Biphenyl]}-4-butanoic acid, 4’-chloro-a-[[[2-[(dimethylamino)- carbonyl]phenyl]thioJmethyl]-y-oxo-; : [1,1’-Biphenyl}-4-butanoic acid, 4'-chloro-a-[[[3-[(dimethylamino)- carbonyljphenyl]thio]methyl-]-y-oxo-;
Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, 3-[[4’-(pentyloxy)[1,1’- biphenyl]-4-yl]carbonyl}-, (2-endo,3-exo)-; 1-Cyclopentene-1-carboxylic acid, 5-[(4"-chlorof1 ,1’-biphenyl]- 4-yl)carbonyl]-;
Cyclopentanecarboxylic acid, 2-[(4’-chloro[1,1 "-biphenyl]-4-yl)carbonyl)- 5-{(phenylmethyl)thio]-, (1t,2,5)-;
Cyclopentanecarboxylic acid, 2-[(4"-chloro[ 1,1 "-biphenyl-4-yl)carbonyl}- 5-[(phenylmethyl)thio]-, (1ct,2[,58)-; 1-Cyclopentene-1-carboxylic acid, 5-[[4’-(pentyloxy)[1,1 "-biphenyl}- 4-yijcarbonyij-; : 1-Cyclopentene-1-carboxylic acid, 5-[[4’-(hexyloxy)[1,1 ’-biphenyl]- 4-yl)jcarbonyij-; : [1,1°-Biphenyl]-4-butanoic acid, 4’-hydroxy-y-oxo--| (phenylthio)- methyl]-; [1,1’-Biphenyl]-4-butanoic acid, o- [2-[2-[(butylamino)- carbonyl]phenyljethyl]-4’-chloro-y-oxo-; [1,1"-Biphenyl]-4-butanoic acid, a-[2-(3-carboxyphenyl)ethyl]-4’-chloro- ¥-0X0-; [1,1"-Biphenyl]-4-butanoic acid, 4’-chloro-ot-[2-[3-[(diethylamino)- carbonyl]phenyl]ethy!l-v-oxo-; [1,1"-Biphenyl}-4-butanoic acid, o-[2-[3-[(butylamino)carbonyl]}- phenyljethyl]-4’-chloro-y-oxo-;
I1,1"-Biphenyl]-4-butansic acid, 4'-chloro-oi-12-T4-[(diethylaming)- carbonyl]phenyl]ethyl}-y-oxo-; [1,1°-Biphenyl]-4-butanoic acid, ¢- [2-{4-[(butylamino)- carbonylphenyljethyl}-4’-chloro-y-oxo-; [1,1’-Biphenyl}-4-butanoic acid, o-[2-(4-carboxyphenyl)ethyl]-4’-chloro- ¥-0X0-; {1,1’-Biphenyl]-4-butanoic acid, 4’-methoxy-y-oxo-o-(2-phenylethyl)-; [1,1"-Biphenyl]-4-butanoic acid, 4’-hydroxy-y-oxo-ai-(2-phenylethyl)-; [1,1"-Biphenyl]-4-butanoic acid, 4’-ethoxy-y-oxo0-0i-(2-phenylethyl)-; [1,1°-Biphenyl]-4-butanoic acid, Y-0x0-0t-(2-phenylethyl)-4’-propoxy-; [1,1"-Biphenyl]-4-butanoic acid, y-oxo-4’-(pentyloxy)-a-(2-phenylethyl)-; {1,1"-Biphenyl]-4-butanoic acid, 4’-(hexyloxy)-y-oxo-a-(2-phenylethyl)-; [1,1"-Biphenyl}-4-butanoic acid, 4’-butoxy-y-oxo-o-(2-phenylethyl)-; [1,1’-Biphenyl])-4-butanoic acid, y-0x0-0-(2-phenylethyl)-4’- (phenylmethoxy)-;
Te WO 00/04892 © PCT/US99/13948 1 1,1-Biphenyl}-4-butanoic acid, a-[2-(3 -iodophenyl)ethyl]-y-oxo-4'- (pentyloxy)-; [1,1"-Biphenyl]-4-butanoic acid, a-[2-(3-iodophenyl)ethyl]-y-oxo-4’- . (phenylmethoxy)-; [1,1’-Biphenyl]-4-butanoic acid, o- [2-(3-[(diethylamino)carbonyl]- , phenyl]ethyl]-y-oxo0-4’-(pentyloxy)-; : [1,1’-Biphenyl]-4-butanoic acid, o-[2-(3-[(diethylamino)carbonyl]- phenyl]ethyl}-y-oxo0-4’ -(phenylmethoxy)-; 1,2-Pyrrolidinedicarboxylic acid, 3-[(4’-chloro[ 1,1’-biphenyl]- 4-yl)carbonyl]-, 1-(phenylmethyl) ester, 2S-trans)-; ~~ 1,2-Pyrrolidinedicarboxylic acid, 3-[(4"-chloro[ 1,1’-biphenyl]- 4-yl)carbonyl]-, 1-(phenylmethyl) ester, (2'R-trans)-;
L-Proline, 3-[(4’-chloro[1,1’-biphenyl}-4-yl)carbonyl]- 1-[[(phenylmethyl)amino]carbonyl]-, trans-;
L-Proline, 3-[(4’-chloro[1,1’-biphenyl]-4-yl)carbonyl]-1-(1-oxo- 3-phenylpropyl)-, trans-; : L-Proline, 3-[(4’-chloro[1,1’-biphenyl]-4-yl)carbonyl)-1 -(phenylacetyl)-, trans-;
L-Proline, 3-[(4’-chloro[1,1’-biphenyl]-4-yl)carbonyl]-1-(3,3 -dimethyl- 1-oxobutyl)-, trans-; : [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-a-heptyl-y-oxo-; [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-a-decyl-y-oxo-; . . [1,1’-Biphenyl}-4-butanoic acid, 4"-nitro-y-oxo-a-(2-phenylethyl)-; [1,1’-Biphenyl]-4-butanoic acid, 4’-cyano-y-oxo-0-(2-phenylethyl)-; [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-0--[2-(2-iodophenyl)ethyl]-y- 0X0-; : (1,1’-Biphenyl}-4-butanoic acid, 4’-chloro-a-[2-(3 -iodophenyl)ethyl]-y- 0X0-; [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-a- [2-(4-iodophenyl)ethyl]-y- 0X0-;
11,1"-Biphenyi]-4-butanoic acid, 4"-chioro-o-{2~(3,5- dimethoxyphenyl)ethyl]-y-oxo-; [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-y-oxo-ot-phenyl-; [1,1’-Biphenyl}-4-butancic acid, 4’-chioro-v-oxc-gi- {phenyimcthyij-; : [1,1"-Biphenyl]-4-butanoic acid, 4’-chloro-y-oxo-0-(2-phenylethyl)-; [1,1"-Biphenyl}-4-butanoic acid, 4’-chloro-y-ox0-0i-[(trimethyisilyi)- : methyi]-; [1,1’-Biphenyl}-4-butanoic acid, 4’-bromo-y-oxo-o-(3-phenylpropyl)-; {1,1’-Biphenyl]}-4-butanoic acid, 7-0X0-0-(3-phenylpropyl)-; [1,1’-Biphenyl]-4-butanoic acid, 4’-amino-y-oxo-0-(2-phenylethyl)-; [1,1”-Biphenyl]-4-butanoic acid, Y-0x0-0-(2-phenylethyl)-4’- [{(phenylmethoxy)carbonyllamino]-; [1,1"-Biphenyl]-4-butanoic acid, 4"-[[(1,] -dimethylethoxy)- carbonyl]amino]-y-cxo-0-(2-phenylethyl)-; [1,1-Biphenyl]-4-butanoic acid, 4’-(acetylamino)-y-oxo-ot- (2-phenylethyl)-; [1,1-Bipheny!]-4. butancic acid, y-oxe-4'-101 -gxopentyljaming]-o- (2-phenylethyl)-; [1,1"-Biphenyl]-4-butanoic acid, 4’-[(3,3-dimethyl-1 ~oxobutyl)amino]-y- 0x0-0.-(2-phenylethyl)-; [1,1’-Biphenyl]-4-butanocic acid, 4’-chloro-o-[2-[2-methoxycarbonyl)- phenyllethyl]-y-oxo-; [1,1"-Biphenyl]-4-butanoic acid, a-{2-(2-carboxyphenyl)ethyl]-4’-chloro-
Y-0X0-; [1,1"-Biphenyl]-4-butanoic acid, 4’-chloro-a-[2-[2-[(diethylamino)- carbonyl)phenyl]ethyl]-y-oxo-; [1,1’-Biphenyl]-4-butanoic acid, 4’-chloro-0i-[2-[3-[(diethylamino)- carbonyl)phenyl]ethyl]-y-oxo-, (S)-; and [1,1”-Biphenyl]-4-butanoic acid, 4’-chloro-0i-[2-[3-[(diethylamino)- carbonyl)phenyl]ethyl}-y-oxo-, (R)-.
E WO 00/04892 © PCT/US99/13948
Fenbufen and compounds related to fenbufen can be utilized. Such compounds are described in United States Patent Number 3,784,701 and by Child, etal, J. Pharm. Sci., 1977;66:466-476, and Arzneim-Forsch, 1980;30(4A):695- 702, all of which are incorporated herein by reference. Preferred compounds from the fenbufen series to be utilized in this invention have the formula ’ OO) , Where R is 0) :
CCH2CH COOH (fenbufen), COCH=CHCOOH, SO»NH,, COCH>CHCOOH,
CHj3
COCH,CH—COOH © , COCHyCH,S03Na, CH(OH)CH>CH,> COOH,
COCHCHCOOH, COCH»CH>CONHOH, C(=NOH)CH»CH»COOH, and | on
COCH,SCH,COOH.
Numerous peptides are known matrix metalloproteinase inhibitors. Typical of such peptides are those described in United States Patent Number 5,300,501; 5,530,128; 5,455,258; 5,552,419; WO 95/13289; and WO 96/11209, all of which are incorporated herein by reference. Such compounds are illustrated by the formula I 0 rl RZ 0 7
A
RS 0 R3 where each of the variable groups can include hydrogen alkyl, aryl, heteroaryl, alkenyl, alkynyl, carboxy, and the like. Preferred compounds from within this class which can be utilized in the method of this invention include the following:
IN-[2,3-bis-Acetyimercaptopropanoyij-L-ieucyi- L-phenylalanine
N-methylamide;
N-[2-Acetylmercapto-3 -methoxycarbonylpropanoyi]-L-leucyl-L- phenylalanine N-methylamide;
N-[2-Acetylmercapto-4-methoxycarbonylbutanoyl]-L-leucyl-L- phenylalanine N-methylamide; ]
N-[2-Acetyimercapto-5-methoxycarbonylpentanoy! |-L-leucyl-L- phenylalanine N-methylamide;
N-[2-Acetylmercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L- phenylalanine N-methylamide;
N-[2-Acetylmercapto-4-phthalimidobutanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine
N-methylamide; i5 N-[2-Acetylmercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2,3-bis-Mercaptopropanoyli-L-leucyl-L-phenylalanine N-methylamide;
N-{2-Mercapto-3-methoxycarbonyipropanoyi]-L-ieucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-4-methoxycarbonylbutanyol]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-4-methoxycarbonylpentanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-4-phthalimidobutanoyij-L-leucyl-phenyi-alanine
N-methyiamide;
N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-6-phthalimidohexanyoyl}-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Acetylmercapto-5-methoxycarbonylpentanoyl]-L-leucyl-
L-phenylalanine N-methylamide;
> 4 : N .. ‘WO 00/04892 ‘PCT/US99/13948
N-[2-Acetylmercapto-6-methoxycarbonylhexanyol]-L-leucyl-
L-phenylalanine N-methylamide; :
N-[2-Acetylmercapto-6-methoxycarbonylhexanyol]-L-valinyl-
L-phenylalanine N-methylamide;
N-[2-Acetylmercapto-6-methoxycarbonylhexanyol]-L-leucyl-L-tryptophan
N-methylamide; :
N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-valinyl-L-phenylalanine
N-methylamide;
N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-tryptophan
N-methylamide;
N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-[B-(4- thiazolyl)]alaine N-methylamide; 15 . N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-(B-(2- pyridyl)alanine N-methylamide; - N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-5-methyl-L- glutamicacid N-methylamide;
N-[2-Acetylmercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Acetylmercapto-2-(3-phthalimido) phenylacetyl]-L-leucyl-
L-phenylalanine N-methylamide;
N-[2-Mercapto-5-methoxycarbonylpentanoyl]-L-phenylalanine
N-methylamide; Co
N-[2-Mercapto-6-methoxycarbonylhexanyol}-L-leucyl-L-phenylalanine
N-methylamide; . ~~ N- [2-Mercapto-6-methoxycarbonylhexanyol]-L-leucyl-L-trptophan
N-methylamide;
N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-tryptophan
N-methylamide;
N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-| B- (4-thiazolyl)alanine N-methylamide;
N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-[B-(2- pyridyijjaianinc N-mecthylamide; .
N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-5 -methyl-L-glutamic acid N-methylamide; .
N-[2-Mercapto-6-phthalimidohexanoyl}-L-leucyl-L-phenylalanine
N-methylamide;
N- [N-Mercaptoacetyl)-L-leucyl]-L-phenylalanine N-methylamide;
N-[Acetomercaptoacyl)-L-leucyl-L-phenylalanine methylamide; (RS)-2-(Acetylthio)pentanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-(Acetylthio)propanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2~(Acetylthio)-3-methylbutanoyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-(Acetylthio)-2-phenylacetyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-(Acetylthic)-3-phenylpropanoyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-(Acetylthio)-4-phenylbutanoyl-L-leucyl-L-phenylalanine
N-methylamide;
N-(Acetylmercaptoacyl)-L-threonyl-L-phenylalanine methylamide;
N-(Acetylmercaptoacyl)-L-leucyl-L-tryptophan methylamide; (RS)-2-Mercaptopentanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercaptopropanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercapto-3-methylbutanoyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-Mercapto-2-phenylacetyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-Mercapto-3-phenylpropanoyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-Mercapto-4-phenylbutanoyl-L-leucyl-L-phenylalanine
N-methylamide;
~ "a "WO 00/04892 - PCT/US99/13948
N-[N-(Mercaptoacetyl)-L-threonyl]-L-phenylalanine methylamide;
N-[N-(Mercaptoacetyl)-L-leucyl]-L-tryptophan methylamide; [4-(N-Hydroxyamino)-2(R)-cyclohexylmethylsuccinyl]-L-B- cyclohexylalanine-N-(2-phenylethyl)amide; [4-N-(Hydroxyamino)-2R-isobutylsuccinyl]-L-B-cyclohexylalanine-N- } (2-phenylethyl)amide;- [4-(N-hydroxyamino)-2R-phenylpropylsuccinyl]-L-B-cyclohexylalanine- - N-(2-phenylethyl)amide; [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl}-L--cyclohexylalanine-
N-[2-(N,N-dimethyldmino]ethyl)amide; [4-(N -Hydroxyamino)-2R-phenylpropylsuccinyl]-L-B-cyclohexylalanine-
N-[2-(p-sulphonamidophenyl)ethyl)amide; [4-(N -Hydroxyamino)-2R-phenylpropylsuccinyl]-L-B-cyclohexylalanine-
N-(2-(p-sulphonylphenyl)ethyl)amide; © [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-B-cyclohexylalanine-
N-[2-(2-pyridyl)ethyl]amide; [4-(N-Hydroxyamino)-2R-pentylsuccinyl]-L-B-cyclohexylalanine-N- (2-phenylethyl)amide; ~ [4-(N-Hydroxyamino)-2R-isoamylsuccinyl}-L-B-cyclohexylalanine-N- (2-phenylethyl)amide; [4-(N -Hydroxyamino)-2R-phenylbutylsuccinyl]-L-B-cyclohexylalanine-N- (2-phenylethyl)amide; [4-(N -Hydroxyamino)-2R-phenylpropylsuccinyl]-L--cyclohexylalanine-
N-[3-(d-morpholinyl)propyl]amide: Co y [4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-B-cyclohexylalanine- or N-[B-alanine}amide; [4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-B-cyclohexylalanine amide; - [4-(N-Hydroxyamino)-2R-(3-phenylpropyl)succinyl}-L-B- cyclohexylalanine amide; [4-(N-Hydroxyamino)-2R-(3-phenylbutyl)succinyl]-L-f- cyclohexylalanine amide; :
“ ;
-18-
[4-N -(Hydroxyamino)-ZR-phenyiethyisuccinyij-L-leucine-N- (2-phenylethyl)amide;
[4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-leucine-N- (2-phenylethyDamide;
[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl|-L-tryptophan amide; [4-(N-~Hydroxyamino)-2(R)-isobutylsuccinyl]-L-valine amide; {3-Phosphono-2R,S-phenyipropyi- i -oxopropyi] -L--cyclohexylalanine-N-
(2-phenylethyl)amide, dimethylester; [3-Phosphono-2R-phenylpropyl-1 -oxopropyl]-L-B-cyclohexylalanine-N- (2-phenylethyl)amide; [3-Phosphono-2S-phenylpropyl-1 -oxopropyl]-L-B-cyclohexylalanine-B- alanine; [3-Phosphono-2R-phenylpropyi-1 -oxopropyl]-L-f-cyclohexylalanine: [3-Phosphono-2S-phenylpropyl-1 -oxopropyi]-L-B-cyclohexylalanine-j- alanine, methyl ester; [3-Phosphono-2R,S-phenylpropyl-1-oxopropyl] -L-B-cyclohexylalanine-N- (4(3-aminopropyl)morpholinejamide, bromine salt; [3 -Phosphono-2R,S-(4-methylphenyl)propyl- I-oxopropyl]-L-B- cyclohexylalanine-N-(2-phenylethyljamide, diethylester; {3-Phosphono-2R,S-(4-methylphenyl)propyl-1 -oxopropyij-L-B3- cyclohexylalanine-N-(2-phenylethyl)-amide; 4-t-Butoxy-2(R)-[3-(2-phenoxyethyl)succinyl]-L-B-cyclohexylalanine-N- (2-phenylethyl)amide; 4-Hydroxy-2(R)-[3-(2-phenoxyethyl)succinyl]-L-B-cyclohexylalanine-N- (2-phenylethyl)amide; 4-(N-Hydroxyamino-2(R)-[3-(2-phenoxyethyl)succinyl]-L-B- cyclohexylalanine-N-(2-phenylethyl)amide; {4-Hydroxy-2(R)-[3-(4-pyridinium)propyl}succinyl}-L-B- cyclohexylalanine-N-(2-phenylethyl)amide; {4-(N -Hydroxyamino)-2(R)-[3-(4-pyridinium)propyl]succinyl}-L-p- cyclohexylalanine-N-(2-phenylethyl)amide;
hy © WO0.00/04892 PCT/US99/13948 {4-(N-Hydroxyamino)-2(R)-[3-(N-methyl-4-pyridinium)propyl]succinyl } -
L-B-cyclohexylalanine-N-(2-phenylethyl)amide; {4-Hydroxy-2-(R)-[3-(4-methylphenyl)propyl]succinyl }-L-B- } cyclohexylalanine-N- [(2-morpholine-sulphonylamino)ethyl]amide; {4-(N-Hydroxyamino)-2-(R)-[3-(4-methylphenyl)propyl]succinyl}-L-B- } - cyclohexylalanine-N-[(2-morpholinesulphonylamino)ethyl]amide; {4-(N-Hydroxyamino)-2-(R)-[3-(4-chlorophenyl)propyl]succinyl } -L-B- cyclohexylalanine-N-[(2-morpholinesulphonylamino)ethyl Jamide; { 4-N-Hydroxyamino)-2-(R)- [3-(4-methylphenyl)propyl]succinyl}-L-B- cyclohexylalanine-N- [(2-dimethylsulphonylamino)propyl]amide; : [4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl] -L-[S- (methyl)penicillamine]-N-methylamide; [4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl]-L- [S- (methyl)penicillamine]amide; [4-(N -Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyljsuccinyl]-L- penicillamine]amide; {4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl }-L-[S- (methyl)penicillaminesulphone]-N-methylamide; {4-(N -Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L- [S- (methyl)penicillaminesulphoxide]-N-methylamide; {4-(N-Hydroxyamino)-2(R)-[3-(4-chlorophenyl)propyl]succinyl}-L- penicillamine-N-methylamide; [4-(N-Hydroxyamino)-2(R)-3-(2 -methylpropylsuccinyl}-L-[S- methyl)penicillamine]-N-methylamide;
N4-Hydroxy-N 1 -(1-(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-4- (chlorophenylpropyl)succinamide;
N4-Hydroxy-N1-(1-(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4- methylphenylpropyl)succinamide;
N4-Hydroxy-N1-(1 -(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4- methoxyphenylpropyl)succinamide;
N4-Hydroxy-N1-(1-(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4- trifluoromethylphenylpropyl)succinamide;
) ’
N4-Hydroxy-N1-(1-(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4- chloromethylphenylpropyl)succinamide;
N-[N-(Mercaptoacetyl)-L-leucyl]-L-phenylalanine methylamide;
N-{Acetomercaptoacyl)-L-icucyij-L-phenylalanine methylamde; . (RS)-2-(Acetylthio)pentanoyl-L-leucyl-L-phenylalanine N-methylamide; (R5)-2-(Acetylthio)propanoyl-L-leucyl-L-phenylalanine N-methylamide; : (RS)-2-{Acetylthio)-3-methyibutanoyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-(Acetylthio)-2-phenylacetyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-(Acetylthio)-3-phenylpropanoyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-(Acetyithio)-4-phenylbutanoyl-L-leucyl-L-phenylalanine
N-methylamide;
N-(Acetylmercaptoacyl)-L-threcnyl-L-phenylalanine methylamide;
N-(Acetylmercaptoacyl)-L-leucyl-L-tryptophan methylamide; (RS)-2-Mercaptopentancyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercaptopropanoyl-L-leucyl-L-phenylalanine N-methylamide; (RS)-2-Mercapto-3-methylbutanoyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-Mercapto-2-phenylacetyl-L-leucyl-L-phenylalanine
N-methylamide; (RS)-2-Mercapto-3-phenylpropanoyl-L-leucyl-L-phenylalanine :
N-methylamide; (RS)-2-Mercapto-4-phenylbutanoyl-L-leucyl-L~phenylalanine
N-methylamide;
N-[N-(Mercaptoacetyl)-L-threonyl]-L-phenylalanine methylamide; : N-[N-(Mercaptoacetyl)-L-leucyl]-L-tryptophan methylamide;
N-[2,3-bis-Acetylmercaptopropanoyl]-L-leucyl- L-phenylalanine
N-methylamide;
N- [2-Acetylmercapto-3-methoxycarbonylpropanoyl]-L-leucyl-L- phenylalanine N-methylamide;
w te "WO 00/04892 © PCT/US99/13948
N-[2-Acetylmercapto-4-methoxycarbonylbutanoyl]-L-leucyl-L- phenylalanine N-methylamide;
N-[2-Acetylmercapto-5-methoxycarbonylpentanoyl]-L-leucyl-L-
NB phenylalanine N-methylamide;
N-[2-Acetylmercapto-6-methoxycarbonylhexanoyl}-L-leucyl-L- } phenylalanine N-methylamide;
N-[2-Acetylmercapto-4-phthalimidobutanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Acetylmercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine
N-methylamide; :
N-[2,3-bis-Mercaptopropanoyl]-L-leucyl-L-phenylalanine N-methylamide;
N-[2-Mercapto-3-methoxycarbonylpropanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-4-methoxycarbonylbutanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-5-methoxycarbonylpentanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-4-phthalimidobutanoyl]-L-leucyl-L-phenylalanine
N-methylamide; So : CL Gee
N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-6-phthalimidohexanoyl]-L-leucyl- L-phenylalanine
N-methylamide;
N-[2-Acetylmercapto-5-methoxycarbonylpentanoyl]-L-leucyl-L- phenylalanine N-methylamide;
N-[2-Acetylmercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L- phenylalanine N-methylamide;
N-[2-Acetylmercapto-6-methoxycarbonylhexanoyl]-L-valinyl-L- phenylalanine N-methylamide;

Claims (32)

~~ WO 00/04892 : : PCT/US99/13948 5 AA72- oo ® Sooo oJ CLAIMS oe :
1. A method for treating and/or preventing atherosclerotic lesions in a : mammal in need thereof comprising administering to said mammal a . therapeutically effective amount of an ACAT inhibitor witha oo F therapeutically effective amount of a MMP inhibitor. : C
2 A method for preventing plaque rupture and for promoting lesion - regression in a mammal in need of said treatment and/or prevention N comprising administering to said mammal a therapeutically effective - amount of an ACAT inhibitor with a therapeutically effective amount of a MMP inhibitor. :
3. A method according to Claim 1 utilizing a compound of the formula oo : ~ wherein: : A is a bond, CONH Y N vhere Y is CH or N . is a bond, ,or — — ,where YisCH or N; : Rlis alkyl, aryl, halo, amino, substituted or disubstituted amino, or alkoxy; RZ is carboxyalkyl ketone or oxime, carboxyalkylsulfonamide, or -SO»-NHCHCOOH; and SE R3is alkyl, substituted alkyl, amino, substituted or disubstituted amino, or } aryl, and pharmaceutically acceptable salts thereof.
)
4. A method of Claim 3 utilizing a compound of the formula Co | /T\ - ~ oo Y N R* - rl — . SUPERSEDED 16 NOV 2001 Co
® | Cane . i.
5. A method according to Claim 3 employing a compound of the formula . ’ rR! | . ’ . .
6. A method according to Claim 4 employing a compound of the formula =~ : :
Oo. I H 3 S—N—C—COR™ Rr! IIH | Co © R2 wherein: oo R1 is C{-Cg alkyl, halo, nitro, NR4R3, cyano, OR, and COOR%; R2isC 1-Ce alkyl, optionally substituted by phenyl, substituted phenyl, "NR4RS3, ORS, carboxy, carboxamido, HoN-C-NH-, thio, = methylthio, indole, imidazole, phthalimido, phenyl, and substituted “ phenyl; ~. : R3 is OH, OC;-Cg alkyl, or NHOH; th | ’ R4 is hydrogen, C1-Cg alkyl, or C1-Cg alkanoyl; RS is hydrogen or C1-Cg alkyl; and RO is hydrogen, C1-Cs alkyl, C1-Cg alkanoyl, phenyl, or substituted phenyl. Co 7. A method according to Claim 5 employing a compound of the formula : : 0 0 ol al H R S—N—C—COH .. 20 8. A method according to Claim 6 employing 2-(4’-bromobiphenyl- 4-sulfonylamino)-3-methyl-butyric acid. SUPERSEDED :i& iV 2001 | oo
PCT/US99/13948 ~ R%is OH, OC,-C alkyl, or NHOH; R* is hydrogen, C,-C; alkyl, or C;-C alkanoyl, R’® is hydrogen or C,-C, alkyl; and RS is hydrogen, C,-C, alkyl, C,-C, alkanoyl, phenyl, or substituted phenyl.
7. A method according to Claim 6 wherein the compound is of the formula 0 0 OO II Ry
8. A method according to Claim 6 wherein the MMP inhibitor is 2-(4'-bromobiphenyl-4-sulfonylamino)-3-methyl-butyric acid.
9. A method according to Claim 2 wherein the MMP inhibitor is a compound of the formula 2 Ri / rR} R* gq N TS SE “Tg —C—R R rR! R32 Ra AMENDED SHEET
® PCT/US99/13948 wherein R and R' are the same or different and are hydrogen, alkyl, halogen, nitro, cyano, trifluoromethyl, OR’ wherein RS is hydrogen, : alkyl, aryl, arylalkyl, heteroaryl, or cycloalkyl, -N-R¢ wherein RS and R® are the same or different and are I” as defined above for RS, 0 OCR’ wherein R® is as defined above, : 0 Jucx where R® is as defined above, oO [ -S-C-R® wherein R® is as defined above, -SR® wherein RS is as defined above, AMENDED SHEET
PCT/US99/13948 0} -C-R6 wherein RS is as defined above, -CH-OR® wherein RS is as defined above, : -CH»-N-R6 wherein RS and R62 are the same or different R62 and are as defined above for RS, 0 : I CNRS wherein R6 and R62 are the same or different and Rba are as defined above for RS, 0) i -S-R6 wherein R6 is as defined above,
O . cycloalkyl, or heteroaryl, with the proviso that R and R1 are not both hydrogen; R2 is -ORS wherein RS is as defined above, or ARE wherein RS and R62 are the same or different and are R62 as defined above for RS; R3, R32 R4, and R42 are the same or different and are hydrogen, fluorine, : alkyl, -(CHp)p-aryl wherein n is an integer from 1 to 6, -(CHp)p-heteroaryl wherein n is as defined above, -(CHjp)p-cycloalkyl wherein n is as defined above, AMENDED SHEET
PCT/US99/13948
<(CH2)p-X~(CHp)q-aryl wherein X is O, §, SO, SO, or NH, and p and q are each zero or an integer of 1 to 6, and the sum of p + q is not greater than six, «(CH2)p-X~(CHp)g-heteroaryl wherein X, p, and q are as defined above, or (CHp)p-R7 wherein R7 is N-phthalimido, N-2,3-naphthyimido, -ORS wherein RS is as defined above, NRE wherein R6 and R62 are the same or different and Ra are as defined above for RY, -SRS where RS is as defined above, O -S-R6 wherein RS is as defined above, Oo [ -S-R6 wherein RS is as defined above, 0) 0] -0-C-R6 wherein RY is as defined above, (0) I ACRE wherein RS and R62 are the same or different R62 and are as defined above for RS, 0 -S-C-R6 wherein RS is as defined above, AMENDED SHEET :
PCT/US99/13948 Y -C-R® wherein R® is as defined above, 7 -C-OR® where RS is as defined above, or 7 “CNR wherein R® and R® are the same or different RS and are as defined above for R®, and n is as defined above; R’ is OH or SH; with the proviso the R’, R* R* and R* are hydrogen or at least one of R?, R* R*, or R* is fluorine; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
10. A method according to Claim 9 wherein the compound is of the formula OH i i ~~) CH,CH,C—OH °
11. A method according to Claim 9 wherein the compound is 4-(4'-chlorobiphenyl-4-yl)-4-hydroxyimino-butyric acid.
12. A method according to Claim 1 wherein the MMP inhibitor is a compound of the formula Sue xX . wherein : X is oxygen or -C-CH,- NOH R? is -C-CH,CH-COOH or -SO;NHGHCOOH, and Re ® R3 is alkyl, halo, alkoxy, acyl, or aryl. AMENDED SHEET
PCT/US99/13948
13. A method according to Claim 12 wherein the compound is of the formula GEG R3
14. A method according to Claim 12 wherein the compound is (S)-2-(9H- fluorene-2-sulfonylamino)-4-phenyl-butyric acid.
15. A method according to Claim 12 wherein the compound is of the formula ~N a OC SO,NH (s) CQ,H
16. A method according to Claim 1 wherein the MMP inhibitor is a compound of formula I O l_—E—Cor? nv RC © R? wherein: R! is C,-C, alkyl, halo, nitro, (CH,),,-NR‘R’, 7 0 cyano, OR*, CH, CF,, CNR‘R’, and COORY, : R? is hydrogen or C,-C, alkyl, optionally substituted by the following groups: phenyl, substituted phenyl, phenoxy, substituted phenoxy, 1 NR‘R®, ORS, carboxy, carboxamido, H,N-C-HN-, thio, methylthio, indole, imidazole, and phthalimido; R’ is OH, O, C,-C, alkyl, or NHOH, AMENDED SHEET
® PCT/US99/13948 R* is hydrogen, C,-C, alkyl, or C,-C; alkanoyl, R’ is hydrogen or C,-C; alkyl; and Ris hydrogen, C,-C;, alkyl, C,-C, alkanoyl, phenyl, or substituted phenyl, and pharmaceutically acceptable salts and solvates thereof.
17. A method according to Claim 1 wherein the MMP inhibitor is selected from the group consisting of (S)-2-(4’-Bromo-biphenyl-4-sulfonylamino)—3-methyl-butyric acid; (S)-2-(4’-Chloro-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-3-Methyl-2-(4’-nitro-biphenyl-4-sulfonylamino)-butyric acid; (S)-2~(4’-Amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2+(4’-Cyano-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(3’,4’-Dibromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid, sodium salt; (S)-2-(3’-Bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(4’-Bromo-2'-flucro-biphenyl-4-sulfonylamino)-3-methyl- butyric acid, (R)-2-(4’-Bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(# -Bromo-biphenyl-4-sulfonylamino)-propionic acid; (S)-2-(4’-Bromo-biphenyl-4-sulfonylamino)-4-methyl-pentanoic acid; (S)-2-(4’-Methoxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; AMENDED SHEET
PCT/US99/13948 (S)-2-(4’-Fluoro-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; (S)-2-(3"-Fluoro-biphenyl-4-sulfonylamino)-3 -methyl-butyric acid; (S)-3 -Methyl-2-(4’-trifluoromethyl-biphenyl-4-sulfonylamino)- : butyric acid; 2-(4’-Formyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; 4’-(1-Carboxy-2-methyl-propylsulfamoyl)-biphenyl-4-carboxylic acid; 2-(4’-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; 2-(4’-AminomethYl-biphenyl-4-suifonvlamino)-3-methyl-butyric acid; (S)-2-(4’-Bromo-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid; (S)-(4’-1sopropyl-biphenyl-4-sulfony1amino)-3-Phenyl-propionic acid; (S)-2-(4’-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid; and (S)-2-(4’-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert.-butyl ester.
18. A method according to Claim 1 wherein the ACAT inhibitor is a compound of the formula Oo 0 { R,-X- | “a C-Y-R, OR or a pharmaceutically acceptable salt thereof wherein: X and Y are selected from oxygen, sulfur and (CR'R"), wherein n is an integer of from 1 to 4 and R’ and R” are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, cycloalkyl, phenyl optionally substituted or R' and R” together form a spirocycloalkyl or a carbonyl, AMENDED SHEET
C PCT/US99/13948
R is hydrogen, a straight or branched alkyl of from | to 8 carbon atoms or benzyl; Rj and Ry are each independently selected from (a) phenyl or phenoxy each of which is unsubstituted or is substituted with 1 to 5 substituents selected from : ‘phenyl, an alkyl group having from 1 to 6 carbon atoms and which is straight or branched, an alkoxy group having from 1 to 6 carbon atoms and which is straight or branched; . phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched, -(CH2)pNR3R4 wherein p is zero or one, and each of R3 and Ry is selected from hydrogen or a straight or branched alkyl group having 1 to 4 carbon atoms; (®) 1- or 2-naphthyl unsubstituted or substituted with from 1 to 3 substituents selected from phenyl, an alkyl group having from 1 to 6 carbon atoms and which is straight or branched, an alkoxy group having from 1 to 6 carbon atoms and : which is straight or branched; hydroxy, phenoxy, AMENDED SHEET
PCT/US99/13948 : fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched, -(CH,),NR,R, wherein p, R; and R, have the meanings defined above; (c) arylalkyl, (d) a straight or branched alkyl chain having from 1 to 20 carbon atoms and which is saturated or contains from 1 to 3 double bonds; or (e) adamantyl or a cycloalkyl group wherein the cycloalkyl moiety has from 3 to 6 carbon atoms.
19. A method of Claim 18 wherein R, is phenyl.
20. A method of Claim 18 wherein R, is phenyl! disubstituted in the 2,6-positions.
21. A method of Claim 18 wherein R, is phenyl.
22. A method of Claim 18 wherein R, is phenyl disubstituted in the : 2,6-positions.
23. A method of Claim 18 wherein each of R, and R, is phenyl.
24. A method of Claim 23 wherein each phenyl is disubstituted in the. 2,6-positions. AMENDED SHEET
PCT/US99/13948
25. A method of Claim 18 wherein R, is phenyl disubstituted in the 2,6-positions and R, is phenyl trisubstituted in the 2,4,6-positions.
26. A method of Claim 18 wherein R, is 2,6-bis(1-methylethyl)phenyl and R, is 2,6-bis(1-methylethyl)phenyl or 2,4,6-tris(1-methylethyl)phenyl.
27. A method of Claim 18 wherein R, is phenyl or isophenyl disubstituted in the 2,6-positions, wherein R, is phenyl or is phenyl disubstituted in the 2,6-positions, wherein each of R, and R, is phenyl, wherein each phenyl is disubstituted in the 2,6-position, wherein R, is phenyl disubstituted in the 2,6-positions and R, is phenyl trisubstituted in the 2,4,6-positions, wherein R, is 2,6-bis(1-methylethyl)pheny! and R, is 2,6-bis(1-methylethyl)phenyl or 2,4,6-tris(1-methylethyl)phenyl, wherein one of R, and R, is the group T (CH), - C-(CH,).R, : R¢ wherein t is zero or 1 to 4; w is zero or 1 to 4 with the proviso that the sum of t and w is not greater than 5; R; and Rg are each independently selected from hydrogen or alkyl having from 1 to 6 carbon atoms, or when Ry is hydrogen, R, can be selected from the groups defined for Ry; and R, is phenyl or phenyl substituted with from 1 to 3 substituents selected from a straight or branched alkyl group having from 1 to 6 carbon atoms, straight or branched alkoxy group having from 1 to 6 carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, COOalkyl wherein alkyl has from 1 to 4 carbon atoms, or -(CH,),NRsR, wherein P, R, and R, have the meanings defined above. AMENDED SHEET
® PCT/US99/13948
28. A method according to Claim 18 wherein X is oxygen, sulfur or (CR'R"),; Y is oxygen, sulfur or (CR'R”), with the proviso that at least one of X or Y is (CR'R"), wherein n is an integer of from 1 to 4 and R’ and R” are each independently hydrogen, straight or branched alkyl of from 1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, or R’ and R” taken together form a carbonyl or a spirocycloalkyl group of from 3 to 10 carbons; R is hydrogen; R, is phenyl optionally substituted, straight or branched alkyl of from 1 to 10 carbon atoms, cycloalkyl or from 3 to 10 carbon atoms; R, is phenyl optionally substituted, straight or branched alkyl of from 1 to 10 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, phenoxy optionally substituted.
29. A method according to Claim 18 wherein X is oxygen, Y is (CR'R”"), wherein n is an integer of from 1 to 2; R is hydrogen; R, is optionally substituted phenyl, R, is optionally substituted phenyl or phenoxy, straight or branched alkyl of from 1 to 10 carbons, or cycloalkyl of from 3 to 10 carbons; R’' and R” are each independently hydrogen, straight or branched alkyl of from 1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, or R’ and R” taken together form a carbonyl or a ~ spirocycloalkyl. | :
30. A method according to Claim 18 wherein the compound is sulfamic acid[[2,4,6-tris(1-methylethyl)phenyl]acetyl]-2,6-bis(1methylethyl)phenyl ester.
3 1. A method of Claim 18 wherein the compound is selected from the group consisting of Sulfamic acid (phenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, : AMENDED SHEET
( PCT/US99/13948
Sulfamic acid[[2,6-bis(1-methylethyl)phenyl]acetyl}-2,6- bis(1-methylethyl)phenyl ester, Sulfamic acid [[2,4,6-tris(1-methylethyl)phenyljacetyl-2,4,6- tris(1-methylethyl)phenyl ester, Sulfamic acid[[2,6-bis(1-methylethyl)phenyljacetyl]-2,4,6- tris(1-methylethyl)phenyl ester, Sulfamic acid{adamantaneacetyl]-2,6-bis[1-methylethyl)phenyl ester, Sulfamic acid[[2,6-bis(1-methylethyl)phenyl]acetyl]- 2,6-bis(1-methylethyl)pheny! ester-sodium salt, Sulfamic acid[[2,4,6-tris(1-methylethyl)phenyljacetyl]- . 2,6-bis(1-methylethyl)phenyl ester-sodium salt, Sulfamic acid (decanoyl)-2,6-bis-(1-methylethyl)phenyl ester, Sulfamic acid (dodecanoyl)-2,6-bis-(1-methylethyl)phenyl ester, 2,6-Bis(1-methylethyl)-N-[[[2,4,6-tris(] -methylethyl)phenyl]- methyl]sulfonyl]benzeneacetamide, 2,6-Bis(1-methylethyl)-N-[[[2,4,6-tris(1-methylethyl)phenyl]- methyl]sulfonyi]benzeneacetamide-sodium salt, 2,6-Bis(1-methylethyl)phenyl[[[2,4,6-tris(1-methylethyl)phenyl]- methyl]sulfonyl]carbamate, 2,6-Bis(1-methylethyl)phenyl[[[2,4,6-tris(1-methylethyl)phenyl}- methyl]sulfonyl]carbamate-sodium salt, Sulfamic acid (1-oxo-3,3-diphenylpropyl)-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid [2,6-dichlorophenyl(acetyl)]-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid [2,6-dichlorophenyl(acetyl)]-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid trans-[(2-phenylcyclopropyl)carbonyl]-2,6-bis(1- methylethyl)pheny! ester, Sulfamic acid [2,5-dimethoxyphenyl(acetyl)]-2,6-bis(1- methylethyl)phenyl ester, AMENDED SHEET
® PCT/US99/13948
Sulfamic acid [2,4,6-trimethoxyphenyl(acetyl)}-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid [2,4,6-trimethylphenyl(acetyl)]-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid [2-thiophenyl(acetyl)]-2,6-bis(1-methylethyl)phenyl ester, : Sulfamic acid [3-thiophenyl(acetyl)]-2,6-bis(1-methylethyl)pheny! ester, Sulfamic acid [2-methoxyphenyl(acetyl)]-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid (oxophenylacetyl)-2,6-bis(1-methylethy!)phenyl ester, Sulfamic acid [2-trifluoromethylphenyl(acetyl)]-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid (1-oxo-2-phenylpropyl)-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid (cyclopentylphenylacetyl)-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid (cyclohexylacetyl)-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid (diphenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid (triphenylacetyl)-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [(1-phenylcyclopéntyl)carbonyl] -2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl)-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid (1-oxo-2-phenylbutyl)-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid (cyclohexylphenylacetyl)-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid (1-0xo0-2,2-diphenylpropyl)-2,6-bis(1- methylethyl)phenyl ester, AMENDED SHEET
® PCT/US99/13948 Sulfamic acid [(9H-fluoren-9-yl)carbonyl]}-2,6-bis(1- methylethyl)phenyl ester, : Sulfamic acid (1-oxo-3-phenylpropyl)-2,6-bis(1- methylethyl)phenyl ester, Sulfamic acid [1-0x0-3-[2,4,6-tris(1-methylethyl)phenyl]- 2-propenyl}-2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [1-0x0-3-[2,4,6-tris(1-methylethyl)phenyl]propyl]}- 2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [(acetyloxy)[2,4,6-tris(1-methylethyl)phenyl]acetyl]- 2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [hydroxy[2,4,6-tris(1-methylethyl)phenyl]acetyl]- 2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [fluoro[2,4,6-tris(1-methylethyl)phenyljacetyl]- 2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl)-2,6-bis(1- methylethyl)phenyl ester sodium salt, Sulfamic acid {[2,4,6-tris(1-methylethyl)phenoxyJacetyl]- 2,6-bis(1-methylethyl)phenyl ester, Sulfamic acid [[2,6-bis(1-methylethyl)phenoxy]acetyl]-2,6-bis- (1-methylethyl)phenyl ester, and Sulfamic acid [[2,4,6-tris(1-methylethyl)phenyl]acetyl]- 2,6-bis(phenyl)phenyl ester.
32. A method according to Claim 1 wherein the MMP inhibitor is selected 5s from and AMENDED SHEET
PCT/US99/13948 X SO,NH CO,H and the ACT inhibitor is selected from [(2,4,6-triisopropyl-phenyl)-acetyl] - sulfamic acid 2,6-diisopropyl-phenyl ester and N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl- acetamide.
33. A pharmaceutical composition for treating and/or preventing atherosclerotic lesions comprising a therapeutically effective amount of an ACAT inhibitor and a MMP inhibitor.
34. A method according to Claim 1 wherein the MMP inhibitor is selected from We We SSN and 0 or Lenn and the ACAT inhibitor is selected from [(2,4,6-triisopropyl-phenyl)- 18 acetyl]-sulfamic acid 2,6-diisopropyl-phenyI ester and N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl- acetamide are administered.
35. A method according to Claim 1 wherein the ACAT inhibitor is selected from: 4-Hexadecylamino-benzoic acid monosodium salt; 3,5-Dimethyl-1-[5-(1,4,5-triphenyl-2H-imidazol-2-ylsulfanyl}- : pentyl]-1H-pyrazole monosodium salt; AMENDED SHEET
. @ PCT/US99/13948
8-(1,4,5-Triphenyl-2H-imidazol-2-yloxy)-octanoic acid; 9-Bromo-6,11-dihydro-dibenzo[b,eJoxepine-11 -carboxylic acid (2,6-diisopropyl-phenyl)-amide; 5-((3,5-Di-tert-butyl-4-hydroxy-phenylamino)-{ [4-(2,2-dimethyl- propyl)-benzyl]-hexyl-amino}-methylene)-2,2-dimethyl-[ 1,3]dioxane- 4,6-dione; : 3-(2,4-Difluoro-phenyl)-1 -(4-(2,2-dimethyl-propyl)-benzyl}- 1-heptyl-urea; 1-Heptyl-1-[4-(3 -methyl-butyl)-benzyl]-3-(2,4,6-trifluoro-phenyl)- urea; 3-(2,4-Difluoro-phenyl)-1-[5-(4,5-diphenyl-1H-imidazol- 2-ylsulfanyl)-pentyl]-1-heptyl-urea; 1-Butyl-3-{2-[3-(5-ethyl4-phenyl-imidazol-1-yl)-propoxy]- 6-methyl-phenyl}-urea; 1-(2-{2-[4~(2,2-Dimethyl-propyl )-phenyl]-ethyl}-4,6-difluoro- phenyl)-3-heptyl-urea; Octadeca-9,12-dienoic acid (1-phenyl-ethyl)-amide; 31 H-Indol-3-yl)-2-octadec-9-enoylamino-propionic acid ethyl ester; 3-(Dimethyl-nonyl-silanyl)-N-(1-phenyl-2-p-tolyl-ethyl)- propionamide; (R)2-Hexyl-decanoic acid (6-methyl-2,4-bis-methylsulfanyl- pyridin-3-yl)-amide; N-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-ethyl]-4-fluoro- benzenesulfonamide; 2-(2-Ethoxy-ethylsulfanyl)-4,5-diphenyl- | H-imidazole; 4-Cyano-N-[2-(4-cyano-phenyl)-3-methyl-5,5-bis-trifluoromethyi- 4,5-dihydro-3H-imidazol-4-yl]-N-methyl-benzamide; 1-{3-[3-(1-Methyl-1H-imidazol-2-y1)-2-phenethyl-2H-chromen- 6-yloxy]-propyl}-cyclopentanecarboxylic acid ethyl ester: 1-[4-(2-Chioro-phenyl)-2-ethyl-thienof2,3-b]pyridin-5-yl]- 3-(2,4-difluoro-phenyl)-urea; AMENDED SHEET
@® PCT/US99/13948
1-(2-Cyclohexyl-[1,3]dithiolan-2-yimethyl)-3-(2,6-diisopropyl- phenyl)-urea; 1-Cycloheptyl-1-(2,3-dihydro-benzo( 1,4]dioxin-5-ylmethyl)- 3-(2,4,6-trimethyl-phenyl)-urea; 1-{2-[4-(1,2-Dimethoxy-ethoxy)-phenyl]-ethyl }-3-(2,4-dimethoxy- phenyl)-1-heptyl-urea; 2-(4-{2-[3-(2,4-Dimethoxy-phenyl)-1-heptyl-ureido]-ethyl} - phenoxy)-2-methyl-propionic acid; 3-(2,4-Difluoro-phenyl)-1-octyl-1-(2,3,4,5-tetrahydro-
benzo[bJoxepin-5-yl)-urea; N-(2,6-Diisopropyl-phenyl)-2-octadecylsulfanyi-acetamide; 2-Bromo-6,11-dihydro-dibenzo[b,e]oxepine-1 | -carboxylic acid
(2,6-diisopropyl-phenyl)-amide; (#)N-(1,2-Diphenyl-ethyl)-3-(2-heptyloxy-phenyl)-propionamide; 2,2-Dimethyl-dodecanoic acid (7-methoxy-4-oxo-chroman-8-yl)- amide; (Z)1-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-octadec- 9-en-1-one; (2)2,2,5,5-Tetramethyl-[ 1,3 ]dioxane-4-carboxylic acid [2-(2-octadec-9-enoylamino-ethylcarbamoyl)-ethyl]-amide; 1-Benzyl-1-(5-methyl-3-phenyl-benzofuran-2-ylmethyl)- 3-(2,4,6-trifluoro-phenyl)-urea; 5-Chloro-3-o-tolyl-benzofuran-2-carboxylic acid (2,6-diisopropyi- phenyl)-amide; 2-(2,4a-Dimethyl-4a,5-dihydro-naphthalen-1-ylsulfanyl)-N- {2-[(6,6-dimethyl-hepta-2,4-diynyl)-pentyl-amino]-ethyl } -acetamide; (Z2)Octadec-9-enoic acid [2-(1,4-dioxa-8-aza-spiro{4.5]dec-8-yl)- I -phenyl-ethyl]-amide; N-(4-Dihexylamino-6-mercapto-2-methyl-pyrimidin-5-yl)- 4<(phenyl-propyl-amino)-butyramide; (Z)1+6,7-Dimethoxy-3-phenyi-3,4-dihydro- 1 H-isoquinolin-2-yl)- octadec-9-en-1-one; AMENDED SHEET
® PCT/US99/13948
(trans) 1,4-Bis-(4-methoxy-phenyl)-3-(3-phenyl-propyl)-azetidin- 2-one; 1-Butyl-3-{2-dimethylamino-6-{3-(4-phenyl-imidazol-1-yl)- propoxy]-phenyl}-urea; 1-{2-Dimethylamino-6-[3-(4-phenyl-imidazol-1-yl)-propoxy]- - phenyl}-3-pentyl-urea; 1-{2-Dimethylamino-6-[3-(5-methyl-4-phenyl-imidazol-1-yl)- \ propoxy]-phenyl}-3-pentyl-urea; 12-{2-[4-(2,2-Dimethyl-propyl)-phenyl]-ethyl} -4,6-difluoro- ) 10 : phenyl)-3-heptyl-urea; (4S-trans)6~(4,5-Diphenyl- 1 H-imidazol-2-ylsulfanylmethyi)- 4-hydroxy-4-methyl-tetrahydro-pyran-2-one; 2-(3-[1,3]Dioxan-2-yl-propylsulfanyl)-4,5-diphenyl- 1 H-imidazole; Hydroxy-phenyl-acetic acid 3,3,5-trimethyl-cyclohexyl ester; Acetic acid 1-(11-hydroxy-4-methoxy-9-methyl-5-0xo0-5H,7H- 6,12-dioxa-dibenzo[a,d]-cycloocten-3-yl)-3-methyl-butyl ester; 10-Hydroxy-2,42,6a,60,9,10,12a-heptamethyl-4-octadecanoyloxy- 1,2,3,4,4a,5,6, 6a,6b,7,8,8a,9,10, 11,12,122a,12b,13,14b-eicosahydro- picene-2-carboxylic acid; 3-[(2,2,5,5-Tetramethyl-[1,3]dioxane-4-carbonyi)-amino]- propionic acid 2-[3-(2,2-dimethyl-propyl)-3-nonyi-ureido}-cyclohexyl ester; 1-(2,6-Diisopropyl-phenyl)-3-(2-p-tolyl-heptyl)-urea; 1-[4-(2-Chloro-phenyl)-6,8-dimethyl-quinolin-3-y1]-3-(2,4- difluoro-phenyl)-ures; 1-[4-(2-Chloro-phenyl)-1,6,7-trimethyl-2-0x0-1,2-dihydro- quinolin-3-yl}-3-(2,4-difluoro-phenyl)-urea; 1-{4-(2-Chloro-phenyl}-6,7-dimethyl-2-oxo-2H-chromen-3-yl]- : 3-(2,4-difluoro-phenyl)-urea; (S)1-[6-Bromo-5-(2-chloro-phenyl)-1,3-dimethyl-2-0x0- 2,3-dihydro-1H-benzo[e][ 1,4]-diazepin-7-yl}-3-(2-hydroxy- I-hydroxymethyl--methyl-ethyl)-urea; AMENDED SHEET
® PCT/US99/13948 3-(4,5-Diphenyl-1H-imidazol-2-ylsulfanylmethyl)-1 -methyl- piperidine; 2-(5,5-Dimethyl-{1,3]dioxan-2-yl1)-4,5-diphenyl-1H-imidazole; 2,2-Dimethyl-5-[3-(1-methyl- 1 H-imidazol-2-yl)-2-propyl- chroman-6-yloxy]-pentanoic acid ethyl ester; N-(4-Hexadecylamino-benzoy!)-4-methyl-benzenesulfonamide; 2-(4-Chloro-phenyl)-6-cyclohexyl-4-(2-oxo-2-phenyl-ethyl)- 6,7-dihydro-4H-1,4,6,8a-tetraaza-s-indacene-5,8-dione; [2-(3-tert-Butyl-4-hydroxy-naphthalen- 1-yl)- 1-(diethoxy- ) 10 phosphoryl)-vinyl]-phosphonic acid diethyl ester; 5-[1 ~(acetyloxy)-3-methylbutyl}-2’-(hydroxymethyl)-4-methoxy- 4’-methylspiro[benzofuran-2(3H),1 ’-cyclohexa-2’,4’-diene]-3,6’-dione; 5-[1-(acetyloxy)-3-methylbutyl]-4-methoxy-4’-methyl- 3,6-dioxospiro [benzofuran-2(3H), ’~cyclohexa-2’,4’-diene}-2’- carboxaldehyde; (3040.22.01, 240r)-3-hydroxy-22-{(1-oxooctadecyl)oxy]-24-norolean- 12-en-29-oic acid; 1-[5-(4,5-Diphenyl-1H-imidazole-2-sulfinyl)-pentyl]-3,5-dimethyl- 1H-pyrazole; and N-butyl-3-[[(4-decyloxyphenyl)carbonyl]-amino]-4-(methylthio)- benzamide.
36. A method according to Claim 1 wherein the MMP inhibitor is selected from: 4-[2+(2-Carboxymethyl-4-phenyl-butylamino)-3-cyclohexyl propionylamino]jbenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-phenyl-butyrylamino)-3,3-methyl- butyrylamino]-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-phenyl-butyrylamino)-3,3-dimethyl- butyrylamino]-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3- dimethyl-butyrylamino]-benzoic acid methyl ester; AMENDED SHEET od PCT/US99/13948
4-(2-(2-Carboxymethyl-4-methyl-valerylamino)-3,3-dimethyl- butyrylamino]-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-5-methyl-valerylamino)-3,3- dimethyl-butyrylamino}-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-phenyl-butylamino)-2- cyclohexylpropionylamino]benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-methyl-valerylamino)-4-methyl- valerylamino]-benzoic acid methyl ester; : 4-[2-(2-Carboxymethyl-5-phenyl-valerylamino)-3,3-dimethyl- butyrylamino]-benzoic acid methyl ester; 4-{2-(2-Carboxymethyl-4-methyl-pentanoylamino)-3-(1H-indol-3- yl)-propionylamino-benzoic acid methyl ester; 5-Methyl-3-(9-0x0-1,8-diaza-tricyclo[10.6.1.0 13,18]nonadeca- 12(19),13,15,17-tetraen-10-ylcarbamoyl)-hexanoic acid; 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-3,3- methyl-butyrylamino]-benzoic acid methyl ester; 4-[2~(2-Hydroxaminocarbonylmethyl-4-phenyl-butyrylamino)-2- cyclohexylpropionylamino]-benzoic acid methyl ester benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-4-methyl-valerylamino)-4- methyl-valerylamino]-benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-4-phenyl-butylamino)-3- cyclohexylpropionylamino]benzoic acid methyl ester; 4-[2-(2-Methoxyaminocarbonylmethyl-4-phenyl-butylamino)-3- cyclohexylpropionylamino]benzoic acid methyl ester; 4-[2-(2-Hydroxaminocarbonylmethyl-5-phenyl-valerylamino)-3,3- dimethyl-butyrylamino}-benzoic acid methyl ester; 5-Methyl-3-(9-0xo-1,8-diaza-tricyclo[10.6.1.0,13,18]nonadeca- 12(19),13,15,17-tetraen-10-ylcarbamoyl)-1-hexylhydroxamic acid; 4-[2-(2-Hydroxaminocarbonylmethyl-4-methyl-pentanoylamino)- 3-(1H-indol-3-yl)-propionylamino-benzoic acid methyl ester; 3-[2-(4-Methoxy-benzylsulfanyl)-2-methyl-1-phenylcarbamoyl- propylcarbamoyl]-5-methyl-hexanoic acid; : AMENDED SHEET
¢ PCT/US99/13948
3-[2-(4-Methoxy-benzylsulfanyl)-2-methyl- 1-phenylcarbamoyl- : propylcarbamoyl]-5-methyl-hexanoic acid N-hydroxyamide; 4-[2-(2-Hydroxaminocarbonylmethyl-4-methyl-pentanoylamino)- 2-cyclohexyl-acetylamino]-benzoic acid methyl! ester; 2-(Phenyl-2-ethyl)benzoic acid N-hydroxy amide; : 4-[2-(2-Acylhyrdazinomethyl-4-methyl-pentanoylamino)-3-(1 H- indol-3-yl)-propionylamino}-benzoic acid methyl ester; ~ 2-(Propylthio)-pyridine-3-N-~(hydroxy)carboxamide; 4-[2-(2-Carboxymethy!-5-phenyl-pentanoylamino)-2- cyclohexylacetylamino]benzoic acid methyl ester; [4-(N-Hydroxyamino)-2R-isobutyl-3S-((thien-2- ylthio)methyl)succinyl]-L-phenylalanine-N-methylamide; N-Hydroxy-5-phenylpentanamide; 4-[2-(2-Carboxymethyl-5-(3-hydroxyphenyl)-valeroyl)amino)-4- methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-hydroxyphenyl)-4-pentenoyl)amino)- 4-methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)-4-pentenoyl)amino)-4- methyl-valeroyl]aminobenzoic acid methyl ester, trifluoroacetate salt; 2-(Phenyl-2-ethyl)pyridine-3-N-hydroxycarboxamide; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)-valeroyl)amino)-4- methyl-valeroyljaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)acetyl)amino)-4-methyl- valeroylJaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(3-aminophenyl)acetyl)amino)-4-methyl- valeroyl]Jaminobenzoic acid methyl ester; 2-[3-(3-Hydroxy-phenyl)-propyl]-benzohydroxamic acid; 2-(Thiobenzyl)benzoic acid N-hydroxy amide; 1-(3-Phenyl-propyl)-pyrrolidine-2-hydroxamic acid; 4-[2-(2-Carboxymethyl-5-(5-hydroxyvaleroyl)amino)-4-methyl- valeroyl]aminobenzoic acid methyl ester; AMENDED SHEET
® PCT/US99/13948
4-[2-(2-Carboxymethyl-5-(N’-methylureido)valeroyl)amino)-4- methyl-valeroyljaminobenzoic acid methyl ester; 4-[2+(2-Carboxymethyl-5-(triflouroacetamido)valeroyi)amino)-4- methyl-valeroylJaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-2-phenylacetylamino)-4-methyl- valeroyl]aminobenzoic acid methyl ester; 4-[2~(2-Hydroxaminocarbonylmethyl-2-phenylacetylamino)-4- methyl-valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-methyl-pentanoylamino)-2-cyclohexyl- acetylamino]-benzoic acid methyl ester; 2-[3-(3-Amino-phenyl)-propyl}-benzohydroxamic acid; cis-4-Benzyloxy-pyrrolidine-2-carboxylic acid; 4-[2~(2-Carboxymethyl-5-(3-amino-4-(triflouromethyl)phenyl)- valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methy! ester; 4-[2-(2-Carboxymethyl-5-(methanesulfamido)valeroyl)amino)-4- methyl-valeroyl]aminobenzoic acid methyl ester; N-Cbz-L-Tyrosine; N-Boc-L-Tryptophan; : 4-[2-(Carboxy-2-o-tolyl-propionylamino-4-methyl- pentanoylamino]-benzoic acid methyl ester; 4-[2-(Carboxymethyl-hepanoylamino)-4-methyl-pentanoylamino}- benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(4-n-butylphenyl)-valeroyl)amino)-4- methyl-valeroyl]aminobenzoic acid methyl ester; : 25 4-[2-(2-Carboxymethyl-5-(4-n-butylphenyl)-4-pentenoyl)amino)-4- methyl-valeroylJaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-2-(2-thienyl)acetylamino)-4-methyl- valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-(3-aminophenyl)-butyryl)amino)-4- methyl-valeroyl]Jaminobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5~(biphen-4-yl)-valeroyl)amino)-4-methyi- valeroyl]aminobenzoic acid methyl ester; AMENDED SHEET
¢ PCT/US99/13948 cis-4-Benzylsulfanyl-pyrrolidine-2-carboxylic acid; 2-Cyclohexylmethyl sulfonyl-benzoic acid; Pyrrolidine-1-carbothioic acid phenethyl-amide; 3-(2-Methyl-thiazol-4-yI}-N-phenethyl-propionamide; N-Phenyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-4- yl}-propionamide; 3-(3H-Imidazol-4-yl)-N-phenethyl-propionamide; 4-[2-(2-Carboxymethyl-5-(formamido)valeroyl)amino)-4-methyl- valeroylJaminobenzoic acid methyl ester;
2-Cyclohexylmethyl sulfonyl-benzohydroxamic acid; [2-Oxo-3-(3-phenyl-propyl)-tetrahydro-furan-3-yl]-acetic acid; 4-[2-(2-Carboxymethyl-5-(fluoren-2-yl)valeroyl)amino)-4-methyl-
valeroyl]arinobenzoic acid methyl ester; 4-[2-(2-Carboxymethyl-2-(3-thienyl)acetylamino)-4-methyl-
valeroyl]aminobenzoic acid methyl ester; 4-[2-(2-Benzylthio-3-carboxy-propionylamino)-4-
methylpentanoylamino]-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-4-(2-indolyl)butyrylamino)-4-methyi- valeroyl]Jaminobenzoic acid methyl ester;
1-Allyl-3-(2-hydroxyethyl)-2-thiourea;
: 3-(1-Hydroxyimino-propyl)-6-phenyl-hexanoic acid; 2-(3H-Imidazol4-ylmethyl)-N1 N4-diphenethyl-succinamide; oo 3-(2-Hydroxymethyl-3H-imidazol-4-yl)-N-phenethyl- propionamide;
6-Phenyl-3-propionyl-hexanoic acid;
4-{2-([2-Hydroxyamino-2-hydroxyimino-ethyl]-5-phenyl- pentanoylamino)-4-methyl-pentanoylamino } -benzoic acid methyl ester; 4-[2-(2-(2-Phenylcyclopropyl)succinylamino)-4-methyl- valeroyllaminobenzoic acid methyl! ester;
6-Biphenyl-4-yl-[2,2-dimethyl- 1-(pyridin-4-ylcarbamoyl)-
propylcarbamoyl]-hexanoic acid trifluoroacetate salt; AMENDED SHEET
PCT/US99/13948
3-[1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3-methyl- : butylcarbamoyl]-5-methyl-hexanoic acid; 6-Biphenyl-4-yl-3-[1-(5,6-dichloro- | H-benzoimidazol-2-yl)-3- methyl-butylcarbamoyl]-5-methyl-hexanoic acid; 2-Carboxymethyl-heptanoyl-2-(N-methylcarboxamide)piperidine; 4-[242-(2-Phenylcyclopropyl)succinylamino)-4-methyl- valeroyljaminobenzoic acid methyl ester; 2-Carboxymethyl-heptanoyl-3-(N-methylcarboxamide)- hexahydropyridazine;
6-Biphenyl-4-yl-3-[1-[3-(3-hydroxy-ethyl)-phenylcarbamoyl]-2,2-
dimethyl-propylcarbamoyl]-hexanoic acid; 2R-(3-(4-Biphenyl)propyl-N-(2R-hydroxy-3-(2-hydroxyphenyl)-5-
methyl-3S-hexyl)succinamide; 6-Biphenyl-4-yl-3-[1-[3-(2-aminoethyl)-phenylcarbamoyl}-2,2-
dimethyl-propylcarbamoyl]-hexanoic acid; 2R-(3-(4-Biphenyl)propyl)-N-(diphenylmethyl)succinamide; 2R~(3-(4-Biphenyl)propyl)-N-(phenylmethyl)succinamide; 2-(2-Oxo-imidazolidin-4-ylmethyl)-5-phenyl-pentanoic acid;
2-(3-Biphenyl-4-yl-propyl)-N I-[1-(5,6-dichloro-1H-
benzoimidazol-2-yl)-3-methyl-butyl]-N4-hydroxy-succinamide hexanoic acid; 6-Biphenyl-4-yl-[2,2-dimethyl- 1-(pyridin-4-ylcarbamoyl)- propylcarbamoyl]-hexanoic acid, N-hydroxyamide; 2R-(3-(4-Biphenyl)propyl)-N-((1-hydroxy-1- methylethyl)phenylmethyl)succinamide; 6-Biphenyl-4-yl-3-[1-phenylcarbamoyl-2-(4-cyano- benzylsulfanyl)-2-methyl-propylcarbamoyl]-hexanoic acid; 4-{2-[2-Carboxymethyl-5-(4"-hydroxy-biphenyl-4-yl)- pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methyl ester; 1-(N-Methyl-N-phenethylthiocarbomyl)-pyrrolidine-2-carboxylic acid; AMENDED SHEET
® PCT/US99/13948
6-Biphenyl-4-yl-3-({ cyclohexyl-[2-(4-sulfanoyl-phenyl)- ethylcarbamoyl]-methyl}-carbamoyl)-hexanoic acid; 3R(6-(4-Biphenyl)-3-(N-benzylcarbamoyl))-hexanoic acid N-hydroxyamide;
[3-(3-Biphenyl-4-yl-propyl)-2-oxo-pyrrolidin-3-yl]-acetic acid; 2-Benzylsulfonyl-cyclopent-1-ene-carboxylic acid hydroxamide; [2-Oxo-3-(3-phenyl-propyl)-pyrrolidin-3 -yl]-acetic acid; [3-(3-Naphthalen-2-yl-propyl)-2-oxo-pyrralidin-3-yl]-acetic acid; 2-Benzylsulfonyl-cyclohex-1-enecarboxylic acid hydroxy amide;
6-Benzylsulfonyl-cyclohex-1 -enecarboxylic acid hydroxy amide; IR~(3-(4-Biphenyl)propyl)-N-(3-methylpyridine)succinamide; {3-[3-(3-Hydroxy-phenyl)-propyl}-2-oxo-pyrrolidin-3-yl} -acetic acid; 6-Biphenyl-4-yl-{[cyclohexyl-(3-morpholin-4-yl-
propylcarbamoyl)-methyl]-carbamoyl} hexanoic acid; [2-Ox0-3-(3-biphenyl-propyl)-tetrahydro-furan-3-yl]-acetic acid; 4-[2-(2-Thicamidomethyl-5-phenyl-valerylamino)-4-methyl-
valeroylamino]-benzoic acid methyl ester; 4-[2-(2-Amino-2-hydroxyimino-ethyl-5-phenyl-valerylamino)-4-
methyl-valeroylamino]-benzoic acid methyl ester; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfamoyl- phenylcarbamoyl)-propylcarbamoyl}-hexanoic acid, 6-Biphenyl-4-yl-3-(2,2-dimethyl-1-(2-hydroxyethylsulfamoyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid;
: 1-(N-Hydroxy)-3-(2-bibenzyl)urea; 4-(2-{5-[7-(2-Amino-acetylamino)-9H-fluoren-2-y1]-2-
carboxymethyl-pentanoylamino}-4-methyl-pentanoylamino)-benzoic acid methyl ester TFA salt; 3R-(6-(4-Biphenyl)propyl)-N-(3-methylpyridinecarbamoyl)-
hexanoic acid N-hydroxy amide; 6-Biphenyl-4-yl-3-[cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl)-
phenylcarbamoyl)-methylcarbamoyl}-hexanoic acid; AMENDED SHEET
@ PCT/US99/13948
6-Biphenyl-4-yl-3-[cyclohexyl-(4-(2-dimethylamino- ethylsulfamoyl)-phenylcarbamoyl)-methylcarbamoyl]-hexanoic acid, trifluoroacetate salt; 4-(2-{2-Carboxymethyl-5-[4-(1 H-tetrazol-5-y1)-phenyl]- S pentanoylamino } -4-methyl-pentanoylamino)-benzoic acid methyl ester; 4-[2-(2-Carboxymethyl-5-(4-(2-hydroxy-ethyl)-phenyl)- pentanoylamino)-4-methyl-pentanoylamino}-benzoic acid methyl ester; 4-(2-{[5-Hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2-H- pyrrole-3-carbonyl}-amino}-4-methyl-pentanoylamino)benzoic acid methyl ester; 5-Hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2-H-pyrrole-3- carboxylic acid(2-cyclohexyl-1-methylcarbamoyl-ethyl)amide; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4-(3-morpholin-4-yl- sulfamoyl)-phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfanyl- phenylcarbamoyl)-propylcarbamoyl}-hexanoic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfonyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 4-[2-(5-Biphenyl-4-yl-2-carboxymethyl-pentanoylamino)-pent-4- enoylamino]-benzoic acid methyl ester; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4-methylsulfinyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 4-(2-{[5-Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3- carbonyl]-amino } -4-methyl-pentanoylamino)benzoic acid methyl ester; 5-Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3- carboxylic acid(2-cyclohexyl-1-methylcarbamoyl-ethyl)amide; 6-Biphenyl-4-yl-[2,2-dimethyl-1-(pyridin-4-ylcarbamoy!)- propylcarbamoyl]-hexanoic acid; 4-[2-(2-Carboxymethyl-5-(4-cyano-biphenyl-4-yl)- pentanoylamino)-4-methy!-pentanoylamino]-benzoic acid methyl ester; 6-Biphenyl-4-y-3-(R)-(2-hydroxy-1-(S )-phenyl-ethylcarbamoyl)- hexanoic acid; AMENDED SHEET
® PCT/US99/13948
3-(R)~(1-(R)-Benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-yi- hexanoic acid; 6-Biphenyl-4-yl-3-(R)~«(2-hydroxy-1-hydroxymethy!- ethyicarbomyl)-hexanoic acid; 4-[2-(2-Carboxymethyl-5-(4-pyridin-4-yl-phenyl)- pentanoylamino)-4-methyl-pentanoylamino]benzoic acid methyl ester; 6-Biphenyl-4-yl(2-hydroxy-2-methyl- 1-phenylcarbamoyl- propylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl(2-hydroxy-2-methyl- 1-phenylcarbamoyl- propylcarbamoyl)-hexanoic acid; 3-{2-Allylsufamyl-2-methyl-1-[2-(4-sulfamoyl-phenyl)- ethylcarbamoyl]-propylcarbamoyl}-6-biphenyl-4-yl-hexanoic acid, 4-[2-(5-Biphenyl-4yl-2-carboxymethyl-pentanoylamino)-4,5- dihydroxy-pentanoylamino]-benzoic acid methyl ester; 4-(2-{5-[4’-(2-Amino-ethoxy)-biphenyl-4-yl]-2-carboxymethyl- pentanoylamino }-4-methyl-pentanoylamino)-benzoic acid methyl ester; 6-Biphenyl-4-y-3-(R)-(2-hydroxy-1-(S)-phenyl-ethylcarbamoyl)- hexanehydroxamic acid; 3-(R)-(1-(R)-Benzyl-2-hydroxy-ethylcarbamoyl)-6-biphenyl-4-yl- hexanehydroxamic acid; N-[5-(Biphenyl-4-yl)-2-(N-hydroxyformamido)methylpentanoyl]- tert-leucine, N-(pyrid-4-yl)amide; [3-(3-Naphthalen-2-yl-propyl)-2-oxo-tetrahydro-furan-3-yl]-acetic acid; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy-1-hydroxymethyl- ethylcarbomyl)-hexanehydroxamic acid; 4-[2-(2-Carboxymethyl-5-naphthalen-2-yl-pentanoylamino)-4- methyl-pentanoylamino]-benzoic acid methyl ester; 3-2,2-Dimethyl- 1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl}-5- methyl-hexanoicacid; N1-[2,2-Dimethyl-1-(pyridin-4-ylcarbamoy!)-propyl]-N4-hydroxy- 2-isobutyl-succinamide; AMENDED SHEET o PCT/US99/13948
4-{2-[2-Carboxymethyl-5-(2-fluoro-biphenyl-4-yl)- pentanoylamino]-4-methyl-pentanoylamino }-benzoic acid methyl ester; 6-Biphenyl-4-yl-3(R)-(1(S)-hyroxymethyl-2,2-dimethyl- propylcarbamoyl)-hexanoic acid; 4-{2-[5-Biphen-4-yl-2-(1-carboxy-ethylamino}-pentanoylamino]- 4-methyl-pentanoylamino } -benzoic acid methyl ester; 6-Biphenyl-4-yl-3(R)-(1(S)-hyroxymethyl-2,2-dimethyl- propylcarbamoy!)-hexanehydroxamic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl- 1-(4-methylsulfinyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 2-(Biphenyl-4-ylsulfonyl)-cyclohex-1-enecarboxylic acid hydroxyamide; 5-(Biphenyl-4-ylsulfonyl)-cyclohex-1-enecarboxylic acid hydroxyamide; 2-Phenethylsulfanyl-cyclohex-1-enecarboxylic acid hydroxyamide; 6-(4’-cyano-biphenyl-4-yl)-3-[2-hydroxy-1-(4-methylsulfinyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; ’ 1-{1-[1-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl- butylcarbamoyl]-3-methyl-butylcarbamoyl } -pyrrolidine-2-carboxylic acid; 6-Biphenyl-4-yl-3-[2,2-dimethyl-1-(4S-methylsulfinyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 4-[2~(2-Carboxymethyl-5-(4-(2-hydroxy-3,3,3-triflucropropyl)- phenyl)-pentanoylamino)-4-methyl-pentanoylamino}-benzoic acid methyl ester; 2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide; : 1-{1-[1-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl- butylcarbamoyl]-3-methyl-butylcarbamoyl} -pyrrolidine-2-carboxylic acid; trans-2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide; 4-[2-(2-Carboxymethyl-5-(4-(2-methylthiazol-4-yl)phenyl)- valeroyl)amino)-4-methyl-valeroyl]aminobenzoic acid methyl ester; AMENDED SHEET
® PCT/US99/13948 1-{1-[1-(4-Methoxycarbonyl-phenylcarbamoyl)-3-methyl- butylcarbamoyl]-3-methyl-butylthiocarbamoy!}-pyrrolidine-2-carboxylic acid; 3-[(Cyclohexyl-(4-(2-hydroxy-ethylsulfamoyl)-phenylcarbamoyl)- methyl)-carbamoyl]-6-(4-pyridin-4-yl-phenyl)-hexanoic acid trifluoroacetate salt; trans-2-(Biphenyl-4-yl-methylsulfanyl)-cyclohexancarboxylic acid hydroxamide; 6-Biphenyl-4-yl-3-(1-hydroxymethyl-2,2-dimethyl-but-3- enylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(1-hydroxymethyl-2,2-dimethyl-but-3- enylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(R)~(1-hydroxymethyl-2-(S)-(1H-imidazol-4- yl)-ethylcarbamoyl)-hexanoic acid; 3-(R)-(2-(R)-Benzyloxy-1-(S)-hydroxymethyl-propylcarbamoyl)- 6-biphenyl-4-yl-hexanoic acid, 4-[4-Methyl-2-(2-nitromethyl-5-phenyl-pentanoylamino)- pentanoylamino]-benzoic acid methyl ester; 6-Biphenyl-4-yl-3-[3-methyl-1 -(4-(2-hydroxyethylsulfamoyl)- phenylcarbamoyl)-butylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-(1-hydroxymethyl-2-phenyl-ethylcarbamoyl)- hexanoic acid; N11 -Benzyl-2-hydroxy-ethyl)-2-(3-biphenyl-4-yl-propyl)-N4- hydroxy-succinamide; 6-Biphenyl-4-yl-3-(R)-(1-hydroxymethyl-2-(S)-( 1 H-imidazol-4- yl)-ethylcarbamoyl)-hexanehydroxamic acid; N-Hydroxy-2-[2-Oxo-3-(3-phenyl-propyl)-tetrahydro-furan-3-yl}- acetamide; © 4[2-(2-Carboxymethyl-5-(2-hydroxy-biphen—4-yl)- : 30 valeroylamino)-4-methyl-valeroylamino]-benzoic acid methyl ester;
N1.(2-Benzyloxy-1-hydroxymethyl-propyl)-2-(3-biphenyl-4-yl- propyl)-N4-hydroxy-succinamide; AMENDED SHEET
® PCT/US99/13948 trans-2-(4-Phenoxy-benzylsulfanyl)-cyclohexancarboxylic acid hydroxamide; 2-(4-Indol-1 -yl-benzylsulfanyl)-cyclohexancarboxylic acid hydroxamide; 6-Biphenyl-4-yl-3-[2-hydroxy-2-methyl- 1-(4S-methylsulfinyl- phenylcarbamoyl)-propylcarbamoyl]-hexanoic acid; 6-Biphenyl-4-yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro- pyran-3-ylcarbamoyl)-hexanoic acid; 5-Biphenyl-4-yl-2-[(formyl-hydroxy-amino)-methyl]-pentanoic acid{1 -[4-(2-dimethylamino-ethylsulfamoyl)-phenylcarbamoyl] -3-methyl- butyl}-amide; 2-(3-Biphenyl-4-yl-propy!)-N4-hydroxy-N1-(2,4,5-trihydroxy-6- hydroxymethyl-tetrahydro-pyran-3-yl)-succinamide; 6-Biphenyl-4-yl-3-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro- pyran-3-ylcarbamoyl)-hexanoic acid; N-[2,2-Dimethyl-1 S-(pyridin-4-ylcarbamoyl)-propyl]-3R- thiophen-3-yl-succinamic acid; 4-[2S~(2R-(3-Biphenyl-4-yl-pyrrol-1 -yl)-3-carboxy- propionylamido)-4-methyl-pentanoylamino}-benzoic acid methyl ester; 3-(R)-(2-Beizyloxy-phenyl)-1-(S)-hydroxymethyl- ethylcarbamoyl)-6-biphenyl-4-yl-hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy-1 -(S)~(4-hydroxy-benzyl)- ethylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(1-hydroxyimino-ethyl)-hexanoic acid; N-[2-(3-(4-biphenyl)propyl)-5,5-difluoro-4-oxopentanoyl)-L-t- leucine, N’-4-(methylthio)pheny! amide; 6-Biphenyl-4-yl-3-(R)-(2-hydroxy-1~(S)-(4-hydroxy-benzyl)- ethylcarbamoy1)-hexanehydroxamic acid; 4-{2-[2-carboxymethyl-5-(4’-sulfamoyl-biphenyl-4-y1)- pentanoylamino]-4-methyl-pentanoylamino}-benzoic acid methy! ester; 2-(2-Biphenyl-4-yl-ethylsulfanyl)-cyclohexane carboxylic acid hydroxyamide; AMENDED SHEET
® PCT/US99/13948
3-Acetyl-6-biphenyl-4-yl-3-hexanoic acid; N-[5-(Biphen-4-yl)-2-(1-carboxy-2-hydroxybut- 1-yl)pentanoyl}-t- L-leucine, N’-(4-methylthiophenyl)amide; 6-Biphenyl-4-yl-3-(2-Hydroxy-cyclohexylcarbamoyl)-hexanoic acid; 2-(3-Biphenyl-4-yl-propyl)-N4-hydroxy-N1-(2-hydroxy- cyclohexyl)-succinamide; 6-Biphenyl-4-yl-3-(1-hydroxyimino-ethyl)-hexanoic acid hydroxamide; 6-Biphenyl-4-yl-3-(2-Hydroxy-cyclohexylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-y1-3-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl)- * propylcarbamoyl]}-hexanoic acid ethyl ester; 2-(3-Biphenyl-4-yl-pyrrol-1-yl)-3-carboxy-N-(1-hydroxy-3- phenyl-prop-2-yl)-propionamide; N-[5-(Biphen-4-yl)-2-(1-carboxy-2-hydroxyethyl)pentanoyl]-L-t- leucine, N'-(4-methylthiophenyl)amide; 3-(R)-(2-Hydroxy-1-(S)-(1H-imidazol-4-yl)-ethylcarbamoyi)-6-(4- (2-metayl-thiazol-4-yl)-phenyl)-hexanoic acid; : 3-(R)-(2-Hydroxy-1-(S)-(1H-imidazol-4-yl)-ethylcarbamoyl)-6-(4- (2-methyl-thiazol-4-yl)-phenyl)-hexanehydroxamic acid; 5-Biphenyl-4-yl-2-(1-hydroxymethyl-3-methylsulfanyl- propylcarbamoyl)-pentanoic acid; 2-(3-Biphenyl-4-yl-propyl)-N-hydroxy-N’-(1-hydroxymethyl-3- methylsulfanyl-propyl)malonamide; 6-Biphenyl-4-yl-3-(3-hydroxy-piperidine-1-carbony!)-hexanoic acid; 6-Biphenyl-4-yl-3-(3-hydroxy-piperidine- 1 -carbonyl)-hexanoic acid-hydroxyamide; 1-(4-Methoxy-benzenesulfonyl)-piperidine-2-carboxylic acid hydroxamide; } AMENDED SHEET
® PCT/US99/13948 1-[4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxyamide; N-(1-Benzyl-2-methoxy-ethyl)-3-(3-biphenyl-4-yl-pyrrol-1-yl)- succinamic acid; N-(1-Benzyl-2-methoxy-ethyl)-3-(3-biphenyl-4-yl-pyrrol-1-yl})- succinamichydroxamic acid; 6-Biphenyl-4-yl-3(R)-2(S)-hydroxy-(1(S)-hydroxymethyl-2,2- dimethyl-propylcarbamoyl)-hexanoic acid; 3-(1-Benzyl-2-hydroxy-ethylcarbamoyl)-5-methyl-hexanoic acid;
N1.(1-benzyl-2-hydroxy-ethyl)-N4-hydroxy-2-isobutyl- succinamide; 6-Biphenyl-4-yl-3(R)-2(S)-hydroxy-(1(S)-hydroxymethyl-2,2- dimethyl-propylcarbamoyl)-hexanoic hydroxamic acid; 1-[4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylic acid; 6-Biphenyl-4-yl-3-(2-hydroxy-1-hydroxmethyl-propylcarbamoyl)- hexanoic acid, 6-Biphenyl-4-yl-3-(R)-(2-oxo-cyclohexyl-1-(S)-carbamoyl)- hexanoic acid; 6-Biphenyl-4-yl-3-(2-hydroxy-1-hydroxmethyi-propylcarbamoyl)- hexanoichydroxamic acid; 2S-[(1S-Benzyl-2-hydroxyethylcarbamoyl)-3R-biphenyl-4-yl- pyrrol-1-yl-methyl]-pentanoic acid; 3R-(3-Biphenyl-4-yl-pyrrol-1-yl)-N-(2R-hydroxy-cyclohexyl-1R- yl)-succinamic acid; ’ 2-(3-Biphenyl-4-yl-pyrrol-1-yl)-3-carboxamate-N-( 1-hydroxy-3- phenyl-prop-2-yl)-propionamide; - trans-2-(3-Biphenyl-4-yl-propyl)-cyclobexane carboxylic acid; trans-2-(3-Biphenyl-4-yl-propyl)-cyclobexane carboxylic acid hydroxyamide; 6-Biphenyl-4-yl-3-(R)-(1-(S)-hydroxymethyl-2-(3-pyridyl)- ethylcarbamoyl)-hexanoic acid; AMENDED SHEET
¢ PCT/US99/13948 6-Biphenyl-4-yl-2-(S)-hydroxy-3-(R)-(1-hydroxymethyl-2-(S)- (1H-imidazol-4=yl)-ethylcarbamoyl)-hexanoic acid; 1-[4-Biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acid; 1-[4-B iphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide; 1 ~(4-Phenoxy-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide; 6-Biphenyl-4-yl-2S-hydroxy-3R-(1S-hydroxymethyl-3- methylsulfanyl-propylcarbamoyl)-hexanoic acid; 6-Biphenyl-4-yl-3-(R)-(1-(S)-hydroxymethyl-2-(3-pyridy!)- ethylcarbamoyl)-hexanehydroxamic acid; 6-Biphenyl-4-yl-2S-hydroxy-3R~(1 S-hydroxymethyl-3- methylsulfanyl-propylcarbamoyl)-hexanoic hydroxmic acid; 1 -[4-(4-Bromo-phenoxy)-benzenesulfonyl]4-(tert- butoxycarbonyl)-piperazine-2-carboxylic acidhydroxyamide; 1 -[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperazine-2- carboxylic acidhydroxyamide; 3R-(3-Biphenyl-4-yl-pyrrol-1 -yl)-N-[2-hydroxy-1S-(1 H-imidazol- 4-yl-methyl)-ethyl]-succinamic acid trifluoroacetate; 3R~(3-Biphenyl-4-yl-pyrrol-1-y1)-N-[1 S-(methoxy- methylcarbamoyl)-3-methyl-butyl]-succinamic acid; N~(1-Acetyl-3-methyl-butyl)-3~(3-biphenyl4-yl-pyrrol-1-y1)- succinamic acid; 6-Biphenyl-4-yl-3-(R)-(2-0x0-1-tetrahydrofuran-3-(S)- ylcarbamoyl)-hexanoic acid; 3-[2,2-Dimethyl-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-2- hydroxy-5-methyl-hexanoic acid-hydrochloride salt; N4-(2,2-Dimethy}-1-methylcarbamoyl-propyl)-2, N'-dihydroxy-3- isobutyl-succinamide; 6-Biphenyl-4-yl-3-(R)-(2-0x0-azepan-3-(S)-ylcarbamoyl)-hexanoic acid; AMENDED SHEET
, .
® PCT/US99/13948
N-(1-Benzyl-2-hydroxy-ethyl)-3-(4-biphenyl-4-yl-pyrazol-1 -yl)- succinamic acid; N-(8-Ox0-4-0xa-1,7-diaza-tricyclo[9.6.1.0 12,17)octadeca- 11(18),12(17),13,15-tetraen-9R-yl}-3S-(3-phenyl-pyrrol-1 -yl)-suceinamic acid; 4-Acetyl-1-[4-phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid, N-hydroxyamide; 1-(Diphenylphosphinic)-piperidine-2-carboxylic acid hydroxamide; 3R~(3-Biphenyl-4-yl-pyrrol-1-y1)-N-[3S-(2RS-hydroxy-5-methyl)- hexyl}-succinamic acid; N-(1-(5)-Benzyl-2-hydroxy-ethyl)-3-(R)-(2-biphenyl-4-yl- cyclopropylmethyl)-succinamic acid; 6-Biphenyl-4-yl-3-(R)-(2-0x0-1-tetrahydrofiran-3-(S)- ylcarbamoyl)-hexanehydroxamic acid; 1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-4-methyl-piperazine-2- carboxylic acid N-hydroxyamide; 4-(4-Methoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic : acidhydroxyamide; 3-(Diphenylphosphinic)-propanoic acid; 3-(Diphenylphosphinic)-propanoic acid hydroxyamide; 4-[2-(2-Carboxymethyl-5-(4-(3-hydroxy-propyl)-phenyl)- pentanoylamino)-4-methyl-pentanoylamino]-benzoic acid methyl ester; 1-{4-(4-Chlorophenoxy)benzenesulfonyl]-N-hydroxy-4-(N- methylcarbamoyl)piperazine-2-carboxamide; 4-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-thiomorpholine-3- carboxylic acid N-hydroxyamide; 3-(3-Biphenyl-4-yl-pyrrol-1-yl)-N-(2,2-dimethyl-1- methylcarbamoyl-propyl)-suc¢cinamic acid; 1-[4-Phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid, N-hydroxyamide; 4[4-Phenoxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid N-hydroxyamide; AMENDED SHEET
® PCT/US99/13948 3-[2-Biphenyl-4-yl-ethylsulfanyl]-tetrahydro-pyran--4-carboxylic acid N-hydroxyamide; 6-Biphenyl-4-yl-3-(carboxylic acid)-hexanoic acid; 1 -[4-(4-Bromo-phenoxy)-benzenesulfonyl]piperdine-2-amidoxime; 2-(3-Biphenylnitrile-4-yl-pyrrol-1-yl)-3-carboxy-N-(1-hydroxy-3- phenyl-prop-2-yl)-propionamide; {3-[3-(3-Amino-pheny!)-propyl]-2-oxo-tetrahydro-furan-3-yl }- acetic acid; 6-Biphenyl-4-y1-2S-hydroxy-3R-(carboxylic acid)-hexanoic acid; 5-Biphenylvaleric acid; 1-{4-(Methoxy)-benzenesulfonyl]piperdine-2-amidoxime; 1-[4-Phenoxy-benzenesulfonyl] -4-methyl-piperazine-2-carboxylic acid N-hydroxyamide; {3-(3-(3-Methylamino-phenyl)-propyl)-2-oxo-tetrahydro-furan-3- yl}-acetic acid; 6-Biphenyl-4-yl-3-(R)-(2-0x0-azepan-3-(S)-ylcarbamoyl)- hexanehydroxamic acid; 4-(1H-Indole-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide; 1R-[4-Bromo-phenoxy)-benzenesulfonyl)-N-amino-piperidine-2- carboxamide;
© 2.(3-Biphenyl-4-yl-propyl)-3, N-4-dihydroxy-N!-(1(S)- hydroxymethyl-3-methanesulfinyl-propyl)-succinamide; N-(1-Benzyl-2-hydroxy-ethyl)-3-[3-(4’-carbamoyl-biphenyl-4-yl)- pyrrol-1-yl]-succinamic acid; 1-(Methyl-phenylphosphinic)-piperidine-2-(R)-carboxylic acid hydroxamide; 4-(4-(4-Chlorophenoxy)benzenesulfonyl)-N-hydroxy-morpholine- 3R-carboxamide; 2S-[IR~(3-(4-Cyano-biphenyl-4-yl)-pyrrol-1-yl)-N-(2,2-dimethy!- 1S-hydroxymethylpropylcarbamoyl)-methyl)]-pentanoic acid; AMENDED SHEET
® PCT/US99/13948
2(S,R)-{1 S-Benzyl-2-hydroxyethylcarbamoyl-[3R-(4"-cyano- biphenyl-4-yl)-pyrrol-1-yl}-methyl} pentanoic acid; 2S-[3-(Biphenyl-4-yl)-pyrrol-1R-yl-(1S-hydroxymethyl-2,2- dimethyl-propylcarbamoyl)-methyl]-5-hydroxypentanoic acid; 1-(1,3-Dihydro-isoindole-2-sulfonyl)-piperidine-2-carboxylic acid hydroxamide; 3-[3~(4’-Carbamoyl-biphenyl-4-yl]-pyrroi-1 -yD)-N-(1- hydroxymethyl-2,2-dimethyl-propyl)-succinamic acid; 4-Methyl-1 ~(4-(4-chlorophenyl)benzenesulfonyl)-N-hydroxy-2R- piperazinecarboxamide hydrochloride; 1-[4-Chlorophenoxybenzenesulfonyl] -N-hydroxy-2R- piperazinecarboxamide; 2-(3-Phenyl-propylsulfonyl)-cyclohexane carboxylic acid hydroxamide; 1-(Pyrolidine- 1-sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; 1-(Piperidine-1 -sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; : 4-{4-Bromo-phenoxy-benzenesulfonyl]-oxothiomorpholine-3- carboxylic acid-N-hydroxyamide; 1-[4-(4-Methoxy-phenylsulfany ])-benzenesulfonyl]-piperdine-2- carboxylic acid hydroxyamide; 1-[4-(4-Nitrile-phenoxy)-benzenesulfonyl]-4-(tert- butoxycarbonyl)-piperazine-2-carboxylic acid N-hydroxyamide; 2S-[3-(Biphenyl-4-yl)-pyrrol-1R-yl-(1 S-hydroxymethyl-2,2- dimethyl-propylcarbamoyl)-methyl]-pent-4-enoic acid; 6-Ox0-3-(4-phenoxy-benzenesul fonyl)-hexahydro-pyrimidine-4- carboxylic acid hydroxamate; 4-(t-Butoxycabonyl)-1 -(4-(pyridin-2-yl)oxybenzensulfonyl)-N- hydroxy-piperazine-2-carboxamide; 4-[(4-Fluorophenoxy)-benzenesulfonyl]-thiomorpholine-3- carboxylic acid-N-hydroxyamide; AMENDED SHEET :
® PCT/US99/13948
4-[4-(Fluoro-phenoxy)-benzenesulfonyl]-oxothiomorpholine-3- carboxylic acid-N-hydroxyamide; N-(2,2-Dimethyl-1S-hydroxymethyl-propyl)-3R-[3-(4-pyridin-4- yl-phenyl)-pyrrol-1-yl]-succinamic acid, N-(1S-Benzyl-2-hydroxy-ethyl)-3S-(5-biphenyl-4-yl-furan-2-yl)- succinamic acid; 4-(4-Butoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide; 4-(4-Butoxy-benzenesulfonyl)- 1-oxothiomorpholine-3-carboxylic acid hydroxyamide; 1-[4-(4-Fluorophenyl)benzenesulfonyl]-4-(tert-butoxycarboxyl)- 2R-piperazine-2-carboxylic acid hydroxyamide; 1-((4-(4-Chlorophenyl)-piperazine)-1-sulfonyl)-piperidine-2- carboxylic acid hydroxamide; cis-2-Phenethylsulfanyl-cyclohexanecarboxylic acid hydroxyamide; N-(2-Hydroxy-1S-phenyl-ethyl)-3R-[3-(4-pyridin-4-yl-phenyl)- pyrrol-1-yl}-succinamic acid; 1-[4-(4-Fluorophenyl)benzenesulfonyl)-N-hydroxy-2R- piperazinecarboxamide hydrochoride; i 1-(Diphenylphosphinic)-pyrolidine-2-(R)-carboxylic acid- hydroxyamide; N,N-{(Diphenylphosphinic)-(acetic acid-sodium salt)}-hydrazide; N-(1-Benzyl-2-hydroxy-ethyl)-3-(1-biphenyl-4-yl-1H-pyrrol-3-yl)- succinamic acid; trans-2-Phenethylsuifonyl-cyclohexanecarboxylic acid hydroxyamide; 1-{4~(4-Flourophenyl)-piperazine- 1 -sulfony!]-piperidine-2- carboxylic acid hydroxamide; 1-{4~(4-Fluarophenylsulfanyl}-benzenesulfonyl]-piperidine-2- : carboxylic acid hydroxyamide; } 4-{4-(Bromo-phenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo- : thiomorpholine-3-carboxylic acid hydroxyamide; AMENDED SHEET
@ PCT/US99/13948
N-(2,2-Dimethyl-1S-methylcarbamoyl-propyl)-3R-(3-phenyi- pyrrol-1-yl)-succinamic acid; 3R-(3-Biphenyl-4-y1)-N-(2-hydroxy-1S-hydroxymethyl-2-methyl- propyl)-succinamic acid; 1-(Pyrrolidine-1-carbonyl)-pyrrolidine-2(R)-carboxylic acid; 1-(Pyrrolidine-1-carbonyl)-pyrrolidine-2(R)-carboxylic acid hyroxyamide; 1-Phenethylcarbamoyl-pyrrolidine-2(R)-carboxylic acid; R-4-[4-(Bromopbenoxy)-benzenesulfonyl}-2,2-dimethyl-1-oxo- thiomorpholine-3-carboxylic acid hydroxyamide; oo 4-(Ethoxycarbonyl)methyl-1-(4-(4-chlorophenyi)benzenesulfonyl)- N-hydroxy-2R-piperazinecarboxamide hydrochloride; N-(2R-Hydroxy-indan-1R-yl)-3R-[3-(4-pyridin-4-yl-phenyl})- pyrrol-1-yl}-succinamic acid; N-(4,4-Dimethyl-2-oxo-tetrahydro-furan-38-yl)-3R-[3-(4-pyridin- 4-yl-phenyl)-pyrrol-1-yl]-succinamic acid; N-(2,2-Dimethyl-1S-methylcarbamoyl-propyl)-3R-{3-(4-pyridin-4- yl-phenyl-4-yl)-pyrrol-1-yl}-succinamic acid; 1-Phenethylcarbamoyl-pyrrolidine-2-(R)-carboxylic acid hydroxyamide; N-(2,2-Dimethyl-1S-methyl carbamoyl-propyl)-3R-[3-(4-propyl- phenyl)-pyrrol-1-yl]-succinamic acid; 1-(4-Benzyl-piperazine- 1 -sulfonyl)-piperdine-2-carboxylic acid hydroxyamide; 3(S)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2- dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 2(R)4-Methyl- 1-(4-(4-fluorophenyl)benzenesulfonyl)-N-hydroxy- piperazine-J-carboxamide; N-(2,2-Dimethyl-1-methylcarbamoyl-propyl)-3-(S-biphenyl-4-yl- furan-2-yl)-succinamic acid; N-(2,2-Dimethyl-1S-methylcarbamoyl-propyl)-3R-(3-pyridin-4-yl- pyrroi-1-yl)-succinamic acid; AMENDED SHEET
PCT/US99/13948
1-((2-Pyridyl)-4-piperazine- | -sulfonyl)-piperdine-2-carboxylic acid hydroxyamide; 1-[4-(Pyridin-4-ylsulfamyl)-benzenesulfonyl]-piperdine-2- carboxylic acid hydroxyamide;
N-(4-Phenoxy-benzenesulfonyl)-D-tert-leucine; N-(4-Phenoxy-benzenesulfonyl)-D-tert-leucine,N-hydroxyamide; N-(8-0x0-4-0xa-1,7-tricyclo[9.6.1.0,12,17]octadeca-
11(18),12(17),13,15-tetraen-9-y1)-3-[4-(4-pyridyl)-3-phenyl-pyrrol-1-yl)- succinamic acid; ’ | . 3-[3-(4-Pyridyl)phenyl-4-yl-pyrrol-1-yl1]-N-[2,2-dimethyl-1-(4- : pyridyl)carbamoyl-propyl]-succinamic acid; 2,2-Dimethyl-4-[4-(pyridin-2-yloxy)-benzenesulfonyl]-thio- morpholine-3-carboxylic acid hydroxyamide; N-[4-(4-Fluorophenoxyl)benzenesulfonyl)-D-tert-leucine; N-[4-(4-Fluorophenoxyl)benzenesulfonyl)-D-tert-leucine, N-hydroxyamide; 2-[2-(N’-Acetyl-hydrazino)-2-oxo-ethyl]-5-biphenyl-4-yl- pentanoic acid; 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2- dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide hydrochloride; 2-[4-(4-Chloro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl- butyric acid; 2-[4~(4-Chloro-phenoxy)-benzenesulfonylamino)-N-hydroxy-3,3- dimethyl-butyramide; - 3(R)-N-Hydroxy-4-(4-(fur-3-yl)phenoxybenzenesulfonyl)-2,2- dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D- cysteine; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(benzylthio)-D- cysteine, N-hydroxyamide; 2-[4-(Pyridin-2-yl-oxy)-benzenesulfonylamino}-3,3-dimethyl butyric acid; AMENDED SHEET
® : PCT/US99/13948
2-[4~(Pyridin-2-yl-oxy)-benzenesulfonylamino}-N-hydroxy-3,3- dimethyl butyramide; N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D- cysteine; 3-[3-(4’-Carbamoyl-biphenyl-4-yl)-pyrrol-1-yl]-N~(2,2-dimethyl-1- methylcarbamoyl-propyl)-succinamic acid; 3-[3-(4’-Cyano-biphenyl-4-yl)-pyrrol-1-y]-N-(2,2-dimethyl-1- methylcarbamoyl-propyl)-succinamic acid; 2-(2-Biphenyl-4-yl-ethylsulfonyl)-cyclohex-1-ene-carboxylic acid hydroxyamide; 6-(2-Biphenyl-4-yl-ethyl sufonyl)-cyclohex-1-ene-carboxylic acid hydroxyamide; . N-(4-Pyridin-4-yl-oxy-benzenesulfonyl)-3,3-dimethyl-S- (benzylthio)-D-cysteine; 3-[3-4’-Carbamoyl-biphenyl-4-yl)-pyrrol-1-yl]-N-{2,2-dimethyl-1- (pyridin-4-yl-carbamoyl)-propyl]-succinamic acid; N-(4-Phenoxy-benzenesulfonyl)-3 ,3-dimethyl-S-(methylthio)-D- cysteine, N-hydroxyamide; 1-(4-Phenoxy-piperdine-1-sulfonyl)-piperdine-2-carboxylic acid hydroxyamide; 3(R)-4-[4-(4-Bromo)phenoxybenzenesulfonyl]-2,2-dimethyl- tetrahydro-2H-1,4-thiazine-3-carboxylic acid; N-(4-[4-Chloro-phenoxy]-benzenesulfonyl)-3 ,3-dimethyl-S- (methylthio)-D-cysteine; N«4-[4-Chlorophenoxy]-benzenesulfonyl)-3,3-dimethyl-S- (methylthio)-D-cysteine, N-hydroxyamide; N-(4-[4-Chlorophenoxy]-benzenesulfonyl)-3,3-dimethy I-S- (methylsulfoxy)-D-cysteine, N-hydroxyamide; 2(R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3- (pyridin-2-ylsulfanyl)-butyric acid; 2(R)-[4~(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3- (pyridin-3-ylsulfanyl)-butyric acid; AMENDED SHEET
® PCT/US99/13948
2(R)-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3- (pyridin-4-ylsulfanyl)-butyric acid; cis-2-(2-Phenyl-ethanesulfonyl)-cycloheaxanecarboxylic acid hydroxyamide; 3(R)-N-Hydroxy-4-(4-(imidaz-1-yl)phenoxybenzenesulfonyl)-2,2- dimethyl-tetrahydro-2H-1,4-thiazine-3 ~carboxamide; 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2- dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide; 4-[2-(2-Hydroxycabamoylimethyl-5-phenyl-pentanoylamino)-4- methyl-pentanoyl-benzoic acid methyl ester; trans-2-(2-Phenyl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxyamide; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid; 2-[4-(4-Chlorophenyl)-piperazine- 1-sulfonylamino]-3-methyl-3- (pyridin-2-ylmethylsullany!)-butyric acid, 3R-[3-(4’-Cyano-biphenyl-4-yl)pyrrol-1 -yl}-N-[2,2-dimethyl-1S- (pyridin-4-ylcarbamoyl)-propyl]-succinamic acid; 3,3-Dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid, N-hydroxyamide; N-(2,2-dimethyl-1-methylcarbamoyl-propyl)-3-[1-(4- fluorophenyl)-1H-pyrrol-3-yl]-succinamic acid; 2(R)-[4~(4-Bromo-phenoxy)-benzenesulfonylamino}-3-methyl-3- (pyridi-n-2-ylsulfanyl)-butyric acid; 2-(2-Biphenyl-4-yl-ethanesulfonyl)-cyclohexanecarboxylic acid hydroxamate; 2-[4~(4-Chloropheny!)-piperazine- 1-sulfonylamino}-3-methyl-3- (pyridin-2ylmethylsulfanyl)-butyric acid, N-hydroxyamide; 33 -Dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid; 3,3-Dimethyl-2<(4-phenoxy-phenylsulfonylmethyl)-butyric acid, N-hydroxyamide; 3-tert-Butoxycarbonylmethylsulfanyl-2-(4-(4-fluoro- phenoxy)benzenesulfonylamino)-3-methyl-butyric acid; AMENDED SHEET
@® PCT/US99/13948
1-(4-Phenylsulfanyl-piperidine- 1-sulfonyl)-piperidine-2-carboxylic acid hydroxyamide; 1-[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-3 ,3-dimethyl-5-oxo0- piperazine-2-carboxylic acid; N-(4-[4-Fluorophenoxy]-benzenesulfonylamino)-3-methyl-3-(1- benzyl-imidazole-2-yl-sulfanyl)-butyric acid; 2(R)-[4-(4-Fluoro-phenoxy)benzenesulfonylamino]-3-methyl-3- (pyridi-n-2-yl sulfanyl)-butyric acid, hydroxyamide; 3(R)-N-Hydroxy-4-(4-((pyridin-4-yl)methyl)oxybenzenesulfonyl)- 2,2-dimethyl-tetrahydro-2H-1 ,4-thiazine-3-carboxamide; 1-[4-(4-Chloro-phenoxy)-benzenesulfonyl}-4-(1 -methyl-1H- imidazole-4-sulfonyl)-piperazine-2-carboxylic acid hydroxamide; N-(2,2-Dimethyl-1S-methylcarbamoyl-propyl)-3R-[1-(4"- cyanobiphenyl-4-yl)-H-pyrrol-3-yl}-succinamic acid; 3-Carboxymethylsulfanyl-2-(4-(4-fluoro-phenoxy)- benzenesulfonylamino)-3-methyl-butyric acid; 2,2-Dimethyl-1-0x0-4-[4-(pyridin-4yloxy)-benzenesulforyl]-1S 14- thiomorpholine-3-carboxylic acid hydroamide; 1-[4-(Pyridin-2-ylsulfanyl)-piperidine-1-sulfonyl]-piperidine-2- carboxylic acid hydroxyamide; 2(R)-[4-(4-(fur-3-y1)-phenoxy)-benzenesulfonylamino]-3-methyl- 3-(pyridi-n-yl-sulfanyl)-butyric acid; 2,2-Dimethyl-1-0x0-4-[4-(pyridin-4yloxy)-benzenesulfonyl]-1514- thiomorpholine-3-carboxylic acid hydroamide; {2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-2- hydroxycarbamoyl-1,1-dimethyl-ethylsulfanyl}-acetic acid tert-butyl ester; 1-[4-(Pyridin-4-ylsulfanyl)-piperidine-1-suifonyl]-piperidine-2- carboxylic acid hydroxyamide; 2(R)-[4~(4-Bromo-phenoxy)benzenesulfonylamino]-3-methyl-3- (pyridi-n-yl-sulfanyl)-butyric acid, hydroxyamide; trans-2-(2-Biphenyl-4-yl-ethylsulfanyl)-cyclohexanecarboxylic : acid hydroxyamide; AMENDED SHEET
® PCT/US99/13948 N-{1S-(1H-Imidazol-2-yl)-3-methyl-butyl]-3R-[3-(4-pyridin-4-yl- phenyl)-pyrrol-1-yl]-succinamic acid formate; N-Methyl-3-[3-(4-pyridin-4-yi-phenyl)-pyrrol-1-yl}-succinamic acid; N(4)-(2,2-Dimethyl-1S-hydroxymethyl-propyl)-N(1)-hydroxy-3R- [3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl]-succindiamide; {2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-2- hydroxycarbamoyl-1,1-dimethyl-ethylsulfanyl } -acetic acid; 1-[4[(4-Fluoro-phenoxy)-benzenesulfonyl)]-3,3-dimethyl-5-oxo-
10 . piperazine-2-carboxylic acid hydroxyamide; N-(4-[4-Bromophenoxy]-benzenesulfonylamino)-3-methyl-3-(1- benzyl-imidazole-2-yl-sulfanyl)-butyric acid; _ 3R-[3«(4’-Cyanobiphenyl-4-yl)-pyrrol-1-yi]-N-(2,2-dimethyl-1S- hydroxymethyl-propyl)-succinamic acid; 2-(R)-[4-(4-Iodophenoxy)benzenesulfonylamino]-3 -methyl-3- (pyridi-n-2-yl-sulfanyl)-butyric acid; 3R-[3-(4-Cyano-phenyl)-pyrrol-1-y1}-N-(2,2-dimethyl-13- hydroxymethyl-propyl)-succinamic acid; 2(R)- [4-(4-lodo-phenoxy)benzenesulfonylamino]-3-methyl-3- (pyridi-n-yl-sulfonyl)butyric acid, hydroxyamide; 2(R)-[4-(4-Nitrile-phenoxy)benzenesulfonylamino]-3-methyl-3- (pyridi-n-yl-sulfonyl)butyric acid; 2-[4~«(-Fluoro-phenoxy)-benzene sulfonylamino]-3,3-dimethyl- pent-4-enoic acid; 2-{4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5- methyl-isoxazole-3-yimethylsulfanyl)-butyric acid; 2-[4-(4-Bromo-phenoxy)-benzenesulfonylamino]-3-methyl-3-(5- : methyl-isoazole-3-ylmethylsulfanyl)-butyric acid; 2-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-N-hydroxy-3- methyl-3-(5-methyl-isoxazole-3-ylmethylsulfanyl)-butyramide; AMENDED SHEET
PCT/US99/13948
2-[4~(4-Bromo-phenoxy)-benzenesulfonylamino]-N-hydroxy-3- methyl-3-(5-methyl-isoxazole-3-yimethylsulfanyl)-butyramide; 2-[4-(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3- (carbomethoxyethylsulfanyl)-butyric acid; b) 1-[2-(Benzothiazol-2-ylsulfanyl)-piperidine-1-sulfonyl]-piperidine- 2-carboxylic acid hydroxyamide; 3R-[3-(4-Cyano-phenyl)-pyrrol-1-y1]-N-(2,2-dimethyl-1S- methylcarbamoyl-propyl)-succinamic acid, 2-[4-(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3- (hydroxyethylsulfanyl)-butyric acid; [4-Methoxy-benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl- sulfanyl)-butyric acid; N-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3S-yl)-3R-[1-(4’- cyanobiphenyl-4-yl)- 1 H-pyrrol-3-yi]-succinamic acid; 2-[4~(4-Fluorophenoxy)-benzenesulfonylamino]-3-methyl-3- (amidoethylsulfanyl)-butyric acid; [4-Methoxy-benzenesulfonylamino]-3-methyl-3 ~(pyridin-2- ylsulfany!)-butyric acid; 2-{4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-3,3-dimethyl-5- phenyl-pent-4-enoic acid; 5-[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-4,5,6,7-tetrahydro-3H- imidazole[4,5,-c]pyridine-6-carboxylic acid hydroxyamide 2(R)-[4-(4-Methylphenoxy)benzenesulfonylamino]-3-methyl-3- (pyridi-n-yl-sulfonyl)butyric acid; 3(S)-4-(4-((Pyrid-4-yl)oxy)benzenesulfonyl)-2,2-dimethyl- : tetrahydro-2H-1,4-thiazine-3-carboxylic acid; 1-[4-(Pyridin-4-ylsulfanyl)-piperidine-1-sulfanyl]-piperidine-2- carboxylic acid hydroxyamide; N-[1-(1H-imidazol-2-yl)-3-methyl-butyl]-3-[1 -(4’-cyanobiphenyl- 4-yl)-1H-pyrrol-3-yl]-succinamic acid; 3R-{3-[(4-Cyano-phenyl)-acety!]-pyrrol-1 -yl}-N-(2,2-dimethyl- 1S-methylcarbamoyl-propyl)-succinamic acid; AMENDED SHEET
® PCT/US99/13948
1-[4-(4-Methoxy-phenylsulfamyl)-piperidine-1-sulfonyl]- piperidine-2-carboxylic acid hydroxamide; 3R-[3-(4-Cyano-phenyl)-pyrrol-1-yl}-N-(2,2-dimethyl-18- methylcarbamoyl-propyl)-succinamic acid methyl ester; 2(R)-[4-(4-Methylphenoxy)benzenesulfonylamino]-3-methyl-3- (pyridi-n-yl-sulfonyl)butyric acid, hydroxyamide; 1-[4-(4-Methy!-phenylsulfamyl)-piperidine-1-sulfonyl]-piperidine- 2-carboxylic acid hydroxamide; 4-(4-Methoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3- carboxylic acid; 4-4(-Methoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3- carboxylic acid hydroxyamide; 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl- thiomorpholine-3-carboxylic acid; 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl- thiomorpholine-3-carboxylic acid hydroxyamide; 2(R)-[4-(4-bromo-phenoxy)benzenesulfoxylamino]-3-methyl-3- (pyridi-n-yl-sulfuroxide)butyric acid, hydroxyamide; 4-(4-Methoxy-bezensulfonyl)-2,2-dimethy!-1-oxo-thiomorpholine- 3-carboxylic acid hydroxyamide; 2,2-Dimethyl-4-[4-(pyridin-4-yloxy)-benzenesulfonyi]- thiomorpholin-3-ol; : 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethoxy-1-oxo- - thiomorpholine-3-carboxylic acid hydroxyamide; 2-(R)-3-Methyl-3-(pyridin-2-yl-sulfanyl)-{4-(4- triflucromethylphenoxy)benzenesulfonylamino]-butyric acid; 3(R)-4-(4-(Pyridin-4-yl)oxybenzenesulfonyi)-2,2-dimethyl- tetrahydro-2H-1,4-thiazine-3-carboxamide; 2R-3-Methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-[4- (pyridin-4-yl-oxy)-benzenesulfonylamino]-butyric acid; 2R-N-Hydroxy-3-methyl-3-[(5-methyl-isoxazol-3- yDmethylsulfanyl]-[4-(pyridin-4-yl-oxy)-benzenesulfonylamino]- butyramide; AMENDED SHEET
@® PCT/US99/13948
2R-[4-(4-Bromophenoxy)-benzenesulfonylamino}-3-hydroxy-3- methyl-butyric acid; 3(S)-2,2-Dimethyl-4-[4-(pyridin-4-ylsulfanyl)-benzenesulfonyl]- thiomorpholine-3-carboxylic acid hydroxyamide; 2R-3-Methyl-3-[(5-methyl-isoxazol-3-yl)methylsulfanyl]-{4- (pyridin-4-yl-sulfanyl)-benzenesulfonylamino]-butyric acid; 2R-N-Hydroxy-3-methyl-3-[(5-methyl-isoxazol-3- yl)methylsulfanyl}-[4-(pyridin-4-yl-sulfanyl)-benzenesulfonylamino]- butyrarmide; "3 3-Dimethyl-2R-[4-(pyridin-4-ylsulfany)-piperidine-1- sulfonylamino]-butyric acid; 3,3-Dimethyl-N-hydroxy-2R-[4-(pyridin-4-ylsulfanyl)-piperidine- 1-sulfonylamino}-butyramide; 2R-[4-(4-Bromophenoxy)-benzenesulfonylamino]-N-hydroxy-3- methyl-3-[(1 -methyl-imidazol-2-y))methylsulfanyl]-butyramide; 2R-[4-(4-Bromophenoxy)-benzenesulfonylamino]-3 -methyl-3-{(1- methyl-imidazol-2-yl)methylsulfanyl]-butyric acid; N-Hydroxy-2-[(4-methylbenzenesulfonyl)amino]acetamide; 1-{4-(4-Imidazol-1-yl-phenoxy)-piperidine-1 -sulfonyl}-piperidine- 2-carboxylic acid hydroxyamide; 1-[4-(4-Imidazol-1-yl-phenylsulfanyl)-piperidine-1 -sulfonyi]- piperidine-2-carboxylic acid hydroxyamide; 2(R)-[4-(4-Chloro-benzoyl)-cyclohexanesulfonyl]-piperidine-1- carboxylic acid hydroxyamide; 1(R)-[4~(4-Chloro-benzoy!)-piperidine-1-sulfonyl]-piperidine-2- carboxylic acid amide; 1(R)-(4-Pyridin-2-yl-piperazine-1 -sulfonyl)-piperidine-2- carboxylic acid hydroxyamide; 1(R)-[4~(4~Imidazol-1-yl-phenoxy)-piperidine-1 -sulfonyl}- piperidine-2-carboxylic acid; 1(R)-[4-(4-Imidazol-1-yl-phenoxy)-piperidine-1 -sulfonyl]- piperidine-2-carboxylic acid hydroxyamide; AMENDED SHEET N
® PCT/US99/13948
N-Hydroxy-3,3-dimethyl-2R-[4-(morpholine-4- carbonyl)piperidine- 1-sulfonylamino]butyramide; N-Hydroxy-3-methyl-3-(5-methyl-isoxazol-3-yl-methylsulfanyl)- 2R-[4-(pyridin-4-ylsulfanyl)-piperidine-sulfonylamino]-butyramide; 4-(4’-Chloro-biphenyl-4-y1)-2RS-{2-(1,3-dioxo- 1,3-dihydro- isoindol-2-yl)-ethyl]-4-oxo-butyric acid; 4-(4’-Chloro-biphenyl-4-y1)-2R- [2-(1,3-dioxo-1,3-dihydro- isoindol-2-yl)-ethyl]-4-oxo-butyric acid; N-Hydroxy-2R-[4-(4-imidazol-1-yl-phenoxy)-piperidine-1- sulfonylamino]-3,3-dimethyl-butyramide; 2R-[4~(4-Chloro-benzoyl)-piperazine-1 -sulfonylamino]-N- hydroxy-3-methyl-3-methylsulfanyl-butyramide; N-Hydroxy-3-methyl-3-methylsulfanyl-2R-[4-(pyridin-4- yisulfany!)-piperidine- 1-sulfonyl amino]-butyramide; 4-(Pyridin-4-yloxy)benzenesulfonic acid; 4-(Pyridin-4-yloxy)benzenesulfonyl chloride hydrochloride; 3 $)-2,2-Dimethyl-3-thiomorpholine carboxylic acid; 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2- dimethyl-1,1-dioxo-tetrahydro-2H-1 ,4-thiazine-3-carboxamide; 1R-3S-2,2-Dimethyl-1-o0x0-4-[4-(pyridin-4-yloxy)- benzenesulfonyl]-1-thiomorpholine-3-carboxylic acid amide; 15-3S-2,2-Dimethyl- 1 -oxo-4-[4~(pyridin-4-yloxy)- benzenesulfonyl]-1-thiomorpholine-3-carboxylic acid amide; and 4-[4-(1 -Hydroxy-pyridin-4-yloxy)-benzenesulfonyl]-2,2-dimethyl- thiomorpholine-3-carboxylic acid amide.
AMENDED SHEET
PCT/US99/13948 37 Use of an ACAT inhibitor and a MMP inhibitor in the manufacture of a preparation for treating and/or preventing atherosclerotic lesions in a mammal.
38. Use of an ACAT inhibitor and a MMP inhibitor in the manufacture of a preparation for preventing plaque rupture and for promoting lesion regression in a mammal.
39. Use according to Claim 37 wherein the MMP inhibitor is a compound as defined in Claim 3.
40. Use according to Claim 39 wherein the compound is as defined in Claim 4.
41. Use according to Claim 37 wherein the MMP inhibitor is a compound as defined in Claim 5.
42. Use according to Claim 37 wherein the MMP inhibitor is a compound as defined in Claim 6.
43. Use according to Claim 42 wherein the compound is as defined in Claim 7.
44. Use according to Claim 42 wherein the MMP inhibitor is a compound as defined in Claim 8.
45. Use according to Claim 38 wherein the MMP inhibitor is a compound as defined in Claim 9.
46. Use according to Claim 45 wherein the compound is as defined in Claim
10.
47. Use according to Claim 45 wherein the compound is as defined in Claim
11. AMENDED SHEET
PCT/US99/13948
48. Use according to Claim 37 wherein the MMP inhibitor is a compound as defined in Claim 12.
49. Use according to Claim 48 wherein the compound is as defined in Claim
13.
50. Use according to Claim 48 wherein the compound is as defined in Claim
14.
51. Use according to Claim 48 wherein the compound is as defined in Claim
15.
52. Use according to Claim 37 wherein the MMP inhibitor is a compound as defined in Claim 16.
53. Use according to Claim 37 wherein the MMP inhibitor is a compound as defined in Claim 17.
54. Use according to Claim 37 wherein the ACAT inhibitor is a compound as defined in Claim 18. 55 Use of Claim 54 wherein the compound is as defined in Claim 19.
56. Use of Claim 54 wherein the compound is as defined in Claim 20. 57 Use of Claim 54 wherein the compound is as defined in Claim 21. 58 Use of Claim 54 wherein the compound is as defined in Claim 22. 50 Use of Claim 54 wherein the compound is as defined in Claim 23.
60. Use of Claim 59 wherein the compound is as defined in Claim 24. AMENDED SHEET
PCT/US99/13948
61. Use of Claim 54 wherein the compound is as defined in Claim 25. 62 Use of Claim 54 wherein the compound is as defined in Claim 26.
63. Use of Claim 54 wherein the compound is as defined in Claim 27.
64. Use according to Claim 54 wherein the compound is as defined in Claim
28.
65. Use according to Claim 54 wherein the compound is as defined in Claim
29.
66. Use according to Claim 54 wherein the compound is as defined in Claim
30.
67. Use of Claim 54 wherein the compound is as defined in Claim 31.
68. Use according to Claim 37 wherein the MMP inhibitor is a compound as defined in Claim 32.
69. Use according to Claim 37 wherein the MMP inhibitor is a compound as defined in Claim 34.
70. Use according to Claim 37 wherein the ACAT inhibitor is a compound as defined in Claim 35.
71. Use according to Claim 37 wherein the MMP inhibitor is a compound as defined in Claim 36.
72. A substance or composition for use in a method for treating and/or preventing atherosclerotic lesions in a mammal, said substance or composition comprising an ACAT inhibitor and a MMP inhibitor, and said method comprising administering to said mammal an effective amount of said substance or composition. AMENDED SHEET
A PCT/US99/13948
73. A substance or composition for use in a method for preventing plaque rupture and for promoting lesion regression in a mammal, said substance or composition comprising an ACAT inhibitor and a MMP inhibitor, and said method comprising administering to said mammal an effective amount of said substance or composition.
74. A substance or composition for use in a method of treatment according to : Claim 72 wherein the MMP inhibitor is a compound as defined in Claim 3.
75. A substance or composition for use in a method of treatment according to Claim 74 wherein the compound is as defined in Claim 4.
76. A substance or composition for use in a method of treatment according to Claim 72 wherein the MMP inhibitor is a compound as defined in Claim 3.
77. A substance or composition for use in a method of treatment according to Claim 72 wherein the MMP inhibitor is a compound as defined in Claim 6. 78 A substance or composition for use in a method of treatment according to Claim 77 wherein the compound is as defined in Claim 7. 79 A substance or composition for use in a method of treatment according to Claim 77 wherein the MMP inhibitor is a compound as defined in Claim 8.
80. A substance or composition for use in 2 method of treatment according to Claim 73 wherein the MMP inhibitor is a compound as defined in Claim 9.
81. A substance or composition for use in a method of treatment according to Claim 80 wherein the compound is as defined in Claim 10.
82. A substance or composition for use in a method of treatment according to Claim 80 wherein the compound is as defined in Claim 11. AMENDED SHEET
PCT/US99/13948
83. A substance or composition for use in a method of treatment according to Claim 72 wherein the MMP inhibitor is a compound as defined in Claim 12.
84. A substance or composition for use in a method of treatment according to Claim 83 wherein the compound is as defined in Claim 13.
85. A substance or composition for use in a method of treatment according to Claim 83 wherein the compound is as defined in Claim 14.
86. A substance or composition for use in a method of treatment according to Claim 83 wherein the compound is as defined in Claim 15.
87. A substance or composition for use in a method of treatment according to Claim 72 wherein the MMP inhibitor is a compound as defined in Claim 16.
88. A substance or composition for use in a method of treatment according to Claim 72 wherein the MMP inhibitor is a compound as defined in Claim 17. 89 A substance or composition for use in a method of treatment according to Claim 72 wherein the ACAT inhibitor is a compound as defined in Claim
18.
90. A substance or composition for use in a method of treatment of Claim 89 wherein the compound is as defined in Claim 19. 91 A substance or composition for use in a method of treatment of Claim 89 - wherein the compound is as defined in Claim 20. 92 A substance or composition for use in a method of treatment of Claim 89 wherein the compound is as defined in Claim 21.
93. A substance or composition for use in a method of treatment of Claim 89 wherein the compound is as defined in Claim 22. AMENDED SHEET
: PCT/US99/13948
94. A substance or composition for use in a method of treatment of Claim 89 wherein the compound is as defined in Claim 23.
95. A substance or composition for use in a method of treatment of Claim 94 wherein the compound is as defined in Claim 24.
96. A substance or composition for use in a method of treatment of Claim 89 wherein the compound is as defined in Claim 25.
97. A substance or composition for use in a method of treatment of Claim 89 wherein the compound is as defined in Claim 26.
98. A substance or composition for use in a method of treatment of Claim 89 wherein the compound is as defined in Claim 27.
99. A substance or composition for use in a method of treatment according to Claim 89 wherein the compound is as defined in Claim 28. : 100. A substance or composition for use in a method of treatment according to Claim 89 wherein the compound is as defined in Claim 29.
101. A substance or composition for use in a method of treatment according to Claim 89 wherein the compound is as defined in Claim 30.
102. A substance or composition for use in a method of treatment of Claim 89 wherein the compound is as defined in Claim 31.
103. A substance or composition for use in a method of treatment according to Claim 72 wherein the MMP inhibitor is a compound as defined in Claim : 32. AMENDED SHEET
PCT/US99/13948
104. A substance or composition for use in a method of treatment according to Claim 72 wherein the MMP inhibitor is a compound as defined in Claim
34.
105. A substance or composition for use in a method of treatment according to Claim 72 wherein the ACAT inhibitor is a compound as defined in Claim
35.
106. A substance or composition for-use in a method of treatment according to - Claim 72 wherein the MMP inhibitor is a compound as defined in Claim
36. )
107. A method according to Claim 1 or Claim 2, substantially as herein described and illustrated.
108. Use according to Claim 37 or Claim 38, substantially as herein described and illustrated.
109. A substance or composition for use in a method of treatment according to Claim 72 or Claim 73, substantially as herein described and illustrated.
110. A new non-therapeutic method of treatment, new use of an ACAT inhibitor and a MMP inhibitor, or a substance or composition foranewuseina method of treatment, substantially as herein described. AMENDED SHEET
ZA200100294A 1998-07-21 2001-01-10 Coadministration of ACAT and MMP inhibitors for the treatment of atherosclerotic lesions. ZA200100294B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US9363998P 1998-07-21 1998-07-21

Publications (1)

Publication Number Publication Date
ZA200100294B true ZA200100294B (en) 2002-01-10

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Families Citing this family (11)

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CN1414848A (en) * 1999-11-05 2003-04-30 沃尼尔·朗伯公司 Prevention of plaque rupure by ACAT inhibitors
DOP2000000107A (en) 1999-12-01 2002-09-16 Agouron Pharmaceutical Inc COMPOUNDS, COMPOSITIONS AND METHODS TO STIMULATE THE GROWTH AND LENGTH OF NEURONS
EP1237862A1 (en) * 1999-12-17 2002-09-11 Versicor, Inc. Succinate compounds, compositions and methods of use and preparation
AU2001282541B2 (en) * 2000-09-01 2004-06-24 Sankyo Company, Limited Medicinal compositions
GB0100761D0 (en) 2001-01-11 2001-02-21 Biocompatibles Ltd Drug delivery from stents
NZ536116A (en) * 2002-04-03 2007-01-26 Topotarget Uk Ltd Carbamic acid compounds comprising a piperazine linkage as HDAC inhibitors
KR101011373B1 (en) * 2002-07-11 2011-01-28 비큐론 파마슈티컬스 인코포레이티드 N-hydroxyamide derivatives possessing antibacterial activity
WO2011092284A1 (en) * 2010-01-29 2011-08-04 Euroscreen S.A. Novel amino acid derivatives and their use as gpr43 receptor modulators
CN104211695B (en) * 2013-06-04 2017-04-12 中国医学科学院医药生物技术研究所 Use of group of carbamyl phenylsulfonyl compounds
WO2016113713A1 (en) * 2015-01-15 2016-07-21 Biocant - Associação De Transferência De Tecnologia Treatment of hutchinson-gilford progeria syndrome and diseases related to vascular ageing
CN106831697B (en) * 2017-03-15 2019-11-05 深圳市康道生物有限公司 The effective extract component of river hazel and its application in prevention and treatment atherosclerosis

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Publication number Priority date Publication date Assignee Title
US5366987A (en) * 1991-08-22 1994-11-22 Warner-Lambert Company Isoxazolyl-substituted alkyl amide ACAT inhibitors
US5491172A (en) * 1993-05-14 1996-02-13 Warner-Lambert Company N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents
ES2191762T3 (en) * 1995-08-04 2003-09-16 Warner Lambert Co USE OF DERIVATIVES OF SULFAMIC ACID, ACIL SULFONAMIDS OR SULFONIL CARBAMATES FOR THE PREPARATION OF A MEDICINAL PRODUCT TO REDUCE LEVELS OF LIPOPROTEINS.
SK282863B6 (en) * 1996-05-17 2002-12-03 Warner-Lambert Company Biphenylsulfonamide matrix metalloproteinase inhibitors
CA2256716A1 (en) * 1996-09-04 1998-03-12 Warner-Lambert Company Matrix metalloproteinase inhibitors and their therapeutic uses

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JP2002521328A (en) 2002-07-16
HRP20010055A2 (en) 2002-04-30
NO20010291D0 (en) 2001-01-18
CZ2001126A3 (en) 2002-01-16
EA200100153A1 (en) 2001-08-27
YU3501A (en) 2005-06-10
AU4701799A (en) 2000-02-14
NO20010291L (en) 2001-01-18
IL140982A0 (en) 2002-02-10
BR9912296A (en) 2001-04-17
EE200100046A (en) 2002-06-17
WO2000004892A3 (en) 2000-05-18
SK502001A3 (en) 2002-06-04
CA2335062A1 (en) 2000-02-03
CN1310629A (en) 2001-08-29
KR20010083134A (en) 2001-08-31
PL346011A1 (en) 2002-01-14
AP2001002035A0 (en) 2001-03-31
WO2000004892A2 (en) 2000-02-03
TR200100205T2 (en) 2001-05-21
ID30030A (en) 2001-11-01
BG105162A (en) 2001-12-29
IS5809A (en) 2001-01-12
EP1098662A2 (en) 2001-05-16
HUP0102880A2 (en) 2002-06-29
HUP0102880A3 (en) 2002-11-28
OA11584A (en) 2004-07-20

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