Note: Descriptions are shown in the official language in which they were submitted.
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STATIN-MATRIX METALLOPROTEINASE INHIBITOR COMBINATIONS
FIELD OF THE INVENTION
This invention concerns a combination of a statin compound, which are
known to cause a reduction in plasma levels of low-density lipoproteins (LDL)
cholesterol, and an MMP inhibitor, which reduce the breakdown of connective
tissues. The combination is useful for treating vascular disorders and
preventing
heart failure.
BACKGROUND OF THE INVENTION
Several clinical studies have established that lowering certain forms of
cholesterol in a mammal is an effective way to treat and prevent heart
attacks,
sudden death, and angina, both in subjects having higher than normal levels of
circulating cholesterol, as well as those having normal levels of cholesterol.
Lowering LDL, the bad form of cholesterol, is now one of the primary
objectives
of physicians treating patients who have, or who have a high risk of
developing,
cardiovascular diseases such as coronary heart disease, atherosclerosis,
myocardial infarction, stroke, cerebral infarction, and even restenosis
following
balloon angioplasty. Many physicians are now utilizing cholesterol lowering
agents purely as a prophylactic treatment in healthy subjects whose
cholesterol
levels are normal, thereby guarding against development of cardiovascular
diseases.
The most commonly used cholesterol lowering agents are the statins,
which are compounds which inhibit the enzyme 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase, the enzyme responsible for catalyzing the
conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step
in the cholesterol biosynthetic pathway.
Compounds which inhibit the enzymes that mediate the breakdown of
connective tissues are useful for treating heart failure and associated
ventricular
dilatation. Such enzymes are known as native matrix metalloproteinases (MMP),
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which 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 with a number of diseases which result from
breakdown of connective tissues, such as rheumatoid arthritis, osteoarthritis,
osteoporosis, multiple sclerosis, and even tumor metastasis. We have now
discovered that treatment and prevention of vascular diseases can be effected
by
administering a combination of a statin with an MMP inhibitor.
SUMMARY OF THE INVENTION
This invention provides a method of treating and preventing heart failure
and other vascular diseases in a mammal comprising administering an effective
amount of a matrix metalloproteinase inhibitor together with a statin. The
invention also provides a method for treating and preventing ventricular
dilatation
comprising administering an effective amount of a matrix metalloproteinase
inhibitor together with a statin.
The methods can be practiced by administering any statin in combination
with any MMP inhibitor, e.g., any chemical compound that is effective in
inhibiting the biological activity of a matrix metalloproteinase such as
collagenase, stromelysin, gelatinase, or elastase. Numerous compounds are
known
to be matrix metalloproteinase inhibitors, and any of such compounds can be
utilized in the method of this invention.
In a preferred embodiment, the matrix metalloproteinase inhibitor to be
utilized is a substituted bicyclic compound of the formula
R2
A
wherein:
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A is phenyl or - ~ - where Y is CH or N;
R1 is a substituent such as alkyl, aryl, halo, amino, substituted and
disubstituted amino, and alkoxy;
R2 is carboxyalkyl ketone or oxime, or a carboxyalkyl sulfonamide such
as
-S02NHCHCOOH where R3 is alkyl, substituted alkyl, amino, substituted and
R3
disubstituted amino, and aryl. Preferred alkyl and alkoxy groups are C 1-C l0
alkyl
and C 1-C 10 alkoxy, which can be straight chain or branched, and optionally
substituted by halo, amino, nitro, carboxy, hydroxy, aryl, and heteroaryl.
A particularly preferred embodiment is a method of treating and
preventing heart failure and ventricular dilatation by administering a statin
together with a biphenylsulfonamide (compounds of the above formula when A is
phenyl) such as
O
Br ~ ~ ~ ~ S-H-CHCOOH
O
which is also known as CI-1026 and PD 166793.
In another embodiment, CHF and ventricular dilatation is treated or
prevented by administering a statin together with a matrix metalloproteinase
which is a substituted fused tricyclic compound of the formula
R1 ~ ~ ~ ~ R2
W T Z
where R 1 and R2 are as defined above, T is O, CH2, SQ (O)0,1 or 2, C=O, NR3,
or
-NR3C-, and W, W 1, Z, and Z1 are each the same or different and each is CR3,
O
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where R3 is alkyl, halo, alkoxy, aryl, and aryl. A preferred method utilizes
dibenzofurans and fluorenes of the above formula, for instance compounds such
as
R2 and
~O~
where R2 is, for instance,
NOH
-C-CH2-CH-COOH, or -S02NH-CH-COOH.
R3 R3
Especially preferred MMP inhibitors to be utilized are (S)-2-
(dibenzofuran-3-sulfonylamino)-3-methyl-butyric acid and (S)-2-(dibenzofuran-3-
sulfonylamino)-succinic acid.
All of the matrix metalloproteinase inhibitors to be utilized in the method
of this invention are either known or are readily available by common
synthetic
processes.
Typical statins to be employed in combination with the MMP inhibitor
include atorvastatin, simvastatin, pravastatin, cerivastatin, mevastatin,
velostatin,
fluvastatin, lovastatin, dalvastatin, and fluindostatin. The statins can be
employed
as pharmaceutically acceptable salts.
A particularly preferred composition of this invention utilizes a biphenyl-
sulfonamide MMP inhibitor together with a statin selected from atorvastatin
calcium, pravastatin sodium, simvastatin, lovastatin, and cerivastatin. The
most
preferred composition employs atorvastatin calcium together with the MMP
inhibitor 2-(4'-bromobiphenyl-4-sulfonylamino)-3-methylbutyric acid.
Also provided by the invention are methods for treating vascular diseases
such as peripheral vascular disease, coronary heart disease, stroke, and
restenosis.
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DETAILED DESCRIPTION OF THE INVENTION
We have discovered that combining a statin with an MMP inhibitor
provides a surprisingly effective composition for treating and preventing
vascular
diseases. As noted above, the MMP inhibitors and statins are known in the art
and
are readily available. The compounds can be the free acid, a salt form, or the
tetrazolyl or aldehyde analog.
The term "statin", where used in the specification and the appendant
claims, is synonymous with the terms "3-hydroxy-3-methylglutaryl-Coenzyme A
reductase inhibitor" and "HMG-CoA reductase inhibitor." These three terms are
used interchangeably throughout the specification and appendant claims. As the
synonyms suggest, statins are inhibitors of 3-hydroxy-3-methylglutaryl-
Coenzyme A reductase and, as such, are effective in lowering the level of
blood
plasma cholesterol. Statins and pharmaceutically acceptable salts thereof are
particularly useful in lowering low-density lipoprotein cholesterol (LDL-C)
levels
in mammals and particularly in humans.
The HMG-CoA reductase inhibitors suitable for use herein include, but are
not limited to, simvastatin, pravastatin, rivastatin, mevastatin,
fluindostatin,
cerivastatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin,
compactin, or
lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin,
rivastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin,
dalvastatin, dihydrocompactin, compactin, lovastatin, or pharmaceutically
acceptable salts thereof. However, it is to be noted that atorvastatin calcium
is a
particularly preferred statin to be employed in the present combination. See
U.S.
Patent 5,273,995 incorporated herein by reference.
The statins disclosed herein are prepared by methods well-known to those
skilled in the art. Specifically, simvastatin may be prepared according to the
method disclosed in U.S. Patent 4,444,784, which is incorporated herein by
reference. Pravastatin may be prepared according to the method disclosed in
U.S.
Patent 4,346,227, which is incorporated herein by reference. Cerivastatin may
be
prepared according to the method disclosed in U.S. Patent 5,502,199, which is
incorporated herein by reference. Cerivastatin may alternatively be prepared
according to the method disclosed in European Patent Application Publication
No.
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EP617019. Mevastatin may be prepared according to the method disclosed in U.S.
Patent 3,983,140, which is incorporated herein by reference. Velostatin may be
prepared according to the methods disclosed in U.S. Patent 4,448,784 and U.S.
Patent 4,450,171, both of which are incorporated herein by reference.
Fluvastatin
may be prepared according to the method disclosed in U.S. Patent 4,739,073,
which is incorporated herein by reference. Compactin may be prepared according
to the method disclosed in U.S. Patent 4,804,770, which is incorporated herein
by
reference. Lovastatin may be prepared according to the method disclosed in
U.S.
Patent 4,231,938, which is incorporated herein by reference. Dalvastatin maybe
prepared according to the method disclosed in European Patent Application
Publication No. 738510 A2. Fluindostatin may be prepared according to the
method disclosed in European Patent Application Publication No. 363934 A 1.
Dihydrocompactin may be prepared according to the method disclosed in U.S.
Patent 4,450,171, which is incorporated herein by reference.
It will be recognized that certain of the above statins contain either a free
carboxylic acid or a free amine group as part of the chemical structure.
Further,
certain statins within the scope of this invention contain lactone moieties,
which
exist in equilibrium with the free carboxylic acid form. These lactones can be
maintained as carboxylates by preparing pharmaceutically acceptable salts of
the
lactone. Thus, this invention includes pharmaceutically acceptable salts of
those
carboxylic acids or amine groups. The expression "pharmaceutically acceptable
salts" includes both pharmaceutically acceptable acid addition salts and
pharmaceutically acceptable cationic salts. The expression "pharmaceutically
acceptable cationic salts" is intended to define but is not limited to such
salts as
the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal
salts (e.g.,
calcium and magnesium), aluminum salts, ammonium salts, and salts with organic
amines such as benzathine (N,N'-dibenzylethylenediamine), choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine
(N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-
hydroxymethyl-1,3-propanediol) and procaine. The expression "pharmaceutically
acceptable add addition salts" is intended to define but is not limited to
such salts
as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate,
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hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate,
methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
The pharmaceutically acceptable cationic salts of statins containing free
carboxylic acids may be readily prepared by reacting the free acid form of the
statin with an appropriate base, usually one equivalent, in a co-solvent.
Typical
bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium
hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide,
benzathine, choline, diethanolamine, piperazine, and tromethamine. The salt is
isolated by concentration to dryness or by addition of a non-solvent. In many
cases, salts are preferably prepared by mixing a solution of the acid with a
solution of a different salt of the cation (sodium or potassium
ethylhexanoate,
magnesium oleate), employing a solvent (e.g., ethyl acetate) from which the
desired cationic salt precipitates, or can be otherwise isolated by
concentration
and/or addition of a non-solvent.
The pharmaceutically acceptable acid addition salts of statins containing
free amine groups may be readily prepared by reacting the free base form of
the
statin with the appropriate acid. When the salt is of a monobasic acid (e.g.,
the
hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the
hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate),
or the
dihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, the
citrate), at
least one molar equivalent and usually a molar excess of the acid is employed.
However, when such salts as the sulfate, the hemisuccinate, the hydrogen
phosphate, or the phosphate are desired, the appropriate and exact chemical
equivalents of acid will generally be used. The free base and the acid are
usually
combined in a co-solvent from which the desired salt precipitates, or can be
otherwise isolated by concentration and/or addition of a non-solvent.
In addition, the MMP inhibitors and pharmaceutically acceptable acid
addition salts thereof may occur as hydrates or solvates. Further, the statins
of the
instant invention and the pharmaceutically acceptable salts of the statins of
the
instant invention may also occur as hydrates or solvates. Said hydrates and
solvates are also within the scope of the 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
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one matrix metalloproteinase enzyme that is naturally occurring in a mammal.
Such compounds are also referred to as "MMP inhibitors". Numerous matrix
metalloproteinase inhibitors are known, and all are useful in the method of
this
invention. For example, 4-biarylbutyric and 5-biarylpentanoic acid derivatives
are
described in WO 96/15096, 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 incorporated herein and can be employed in
this invention. Especially preferred compounds to be utilized include the
following:
[I,1'-Biphenyl)-4-butanoic acid, 4'-chloro-a-(2-methylpropyl)-y-oxo-;
[l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-(2-methylpropyl)-y-oxo-, (S~-
[I,I'-Biphenyl]-4-butanoic acid, 4'-chloro-a-(2-methylpropyl)-Y-oxo-,
(R)-
[I,1'-Biphenyl]-4-butanoic acid, 4'-chloro-(3-(2-methylpropyl)-y-oxo-, (S~;
[ 1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-(3-(2-methylpropyl)-~y-oxo-, (R)-
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-Y-oxo-;
[ 1, I'-Biphenyl]-4-butanoic acid, 4'-bromo-y-oxo-;
[ I ,1'-Biphenyl]-4-butanoic acid, 4'-fluoro-~y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 2'-fluoro-y-oxo-;
[ 1, I'-Biphenyl]-4-butanoic acid, 2'-chloro-y-oxo-;
[I,I'-Biphenyl]-4-butanoic acid, 2',4'-difluoro-y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 3'-chloro-'y-oxo-;
[l,l'-Biphenyl]-4-butanoic acid, a-(2-methyl-propyl)-y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-bromo-a-(2-methylpropyl)-y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-fluoro-a-(2-methylpropyl)-y-oxo-;
[l,l'-Biphenyl]-4-butanoic acid, 4'-ethyl-a-(2-methylpropyl)-y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 2'-fluoro-a-(2-methylpropyl)-y-oxo-;
[I,1'-Biphenyl]-4-butanoic acid, 2'-chloro-a-(2-methylpropyl)-Y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-methoxy-a-(2-methylpropyl)-'y-oXO-;
[I,1'-Biphenyl]-4-butanoic acid, 2',4'-difluoro-a-(2-methylpropyl)-Y-oxo-;
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[1,1'-Biphenyl]-4-butanoic acid, 4'-methyl-a-(2-methylpropyl)-y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, a-(2-methyl-propyl)-y-oxo-4'-pentyl-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-methylene-y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 2'-chloro-a-methylene-'y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-methyl-Y-oxo-;
[l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-y-oxo-a-pentyl-;
Benzenebutanoic acid, 4-chloro-a-(2-methylpropyl)-y-oxo-;
Benzenebutanoic acid, 4-methyl-a-methylene-y-oxo-;
2-Butenoic acid, 4-(4'-chloro[1,1'-biphenyl]-4-yl)-4-oxo-, (E~-;
2-Butenoic acid, 4-[4-(4-chlorophenyoxy)-phenyl]-4-oxo, (E~-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-hydroxy-a-(2-methylpropyl)-~y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-[i-methylene-~y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-y-hydroxy-a-(2-methylpropyl)-
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-y-hydroxy-a-(2-methylpropyl)-
2(3H)-Furanone, 5-(4'-chloro[ 1, i'-biphenyl]-4-yl)dihydro-3-(2-
methylpropyl)-;
2(3H)-Furanone, 5-(4'-chloro[1,1'-biphenyl]-4-yl)dihydro-3-(2-
methylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 3',4'-dichloro-y-oxo-a-(3-phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 3',5'-dichloro-'y-oxo-a-(3-phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-(acetyloxy)-y-oxo-a-(3-phenylpropyl)-
Benzenepentanoic acid, a-[2-[4-(5-chloro-2-thienyl)phenyl]-2-oxoethyl]-;
2-Furancarboxylic acid, 5-[4-(3-carboxy-1-oxo-6-phenylhexyl)phenyl]-;
Benzenepentanoic acid, a-[2-oxo-2-[4-(3-pyridinyl)phenyl]ethyl]-;
Benzenepentanoic acid, a-[2-oxo-2-[4-[6-(pentyloxy)-3-
pyridinyl]phenyl]ethyl]-;
[ 1,1'-Biphenyl]-4-butanoic acid, y-oxo-4'-(pentylthio)-a-(3-
phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-methoxy-Y-oxo-a-(3-phenylpropyl)-;
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[1,1'-Biphenyl]-4-butanoic acid, 3'-chloro-4'-fluoro-Y-oxo-a-(3-
phenylpropyl)-;
[l,l'-Biphenyl]-4-butanoic acid, 4'-ethoxy-Y-oxo-a-(3-phenylpropyl)-;
Benzenepentanoic acid, a-[2-oxo-2-[4-(3-thienyl)phenyl]ethyl]-;
[1,1'-Biphenyl]-4-butanoic acid, 2',4'-dichloro-y-oxo-a-(3-phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-formyl-Y-oxo-a-(3-phenylpropyl)-;
[l,l'-Biphenyl]-4-butanoic acid, y-oxo-a-(3-phenylpropyl)-3',5'-
bis(trifluoromethyl)-;
Benzenepentanoic acid, a-[2-oxo-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-oxo-a-(3-phenylpropyl)-;
[ 1,1'-Biphenyl]-4-butanoic acid, 4-hydroxy-Y-oxo-a-(3-phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid,'y-oxo-a-(3-phenylpropyl)-4'-propoxy-;
[1,1'-Biphenyl]-4-butanoic acid,'y-oxo-4'-(pentyloxy)-a-(3-phenylpropyl)-
[1,1'-Biphenyl]-4-butanoic acid, y-oxo-4'-(pentyloxy)-a-(3-phenylpropyl)-
[1,1'-Biphenyl]-4-butanoic acid, y-oxo-4'-(pentyloxy)-a-(3-phenylpropyl}-
. (R)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-(hexyloxy)-y-oxo-a-(3-phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-butoxy-'y-oxo-a-(3-phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, y-oxo-4'-(3-phenylpropoxy)-a-(3-
phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-(1-methylethoxy)-y-oxo-a-(3-
phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-(heptyloxy)-y-oxo-a-(3-phenylpropyl}-
(1,1'-Biphenyl]-4-butanoic acid, 4'-(cyclohexyl-methoxy)-y-oxo-a-{3-
phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-(2-methyl-propoxy)-Y-oxo-a-(3-
phenylpropyl)-;
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[1,1'-Biphenyl]-4-butanoic acid, y-oxo-a-(3-phenylpropyl)-4'-(2-
propenyloxy)-;
[l,l'-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-a-(2-phenylethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(2-iodophenyl)ethyl]-Y-
oxo-;
[ 1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(3-iodophenyl)ethyl]-~y-
oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(4-iodophenyl)ethyl]-Y-
oxo-;
[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-a-phenyl-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-y-oxo-a-(phenylmethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-y-oxo- a-(2-phenylethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-y-oxo- a-
[(trimethylsilyl)methyl]-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-brorno-'y-oxo- a-(3-phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, -y-oxo-a-(3-phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-amino-Y-oxo-a-(2-phenylethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, y-oxo-a-(2-phenylethyl)-4'-
[[(phenylmethoxy)carbonyl]amino]-;
[1.1'-Biphenyl]-4-butanoic acid, 4'-[[(1,1-
dimethylethoxy)carbonyl]amino]-y-oxo-a-(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]-a-(2-
phenylethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-((3,3-dimethyl-1-oxobutyl)amino]-Y-
oxo-a-(2-phenylethyl)-;
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[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[2-
(methoxycarbonyl)phenyl]-ethyl]-'y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, a-[2-(2-carboxyphenyl)ethyl]-4'-chloro-
y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[2-
[(diethylamino)carbonylJphenyl]ethyl]-y-oxo-;
[ 1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-
[(diethylamino)carbonyl]phenyl]ethyl]-y-oxo-, (S~-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-
[(diethylamino)carbonyl]phenyl]ethyl]-~y-oxo-, (R)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-
5-[(phenylmethoxy)methyl]-, {1a,2(3,5[i)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-
5-(phenoxymethyl)-, (1a,2[i,5(3)-;
Cyclopentanecarboxylic acid, 2-[(benzoyloxy)- methyl]-S-[(4'-
chloro[l,l'-biphenyl]-4-yl)carbonyl]-, (1a,2~i,5[i)-;
1,2-Benzenedicarboxylic acid, 1-[[2-carboxy-3-[(4'-chloro[1,1'-biphenyl]-
4-yl)carbonyl]cyclopentyl]- methyl]-2-methyl ester,(Ia,2~i,3a)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro[ 1,1'-biphenyl]-4-yl)carbonyl]-
5-[(2-thienylthio)methyl]-, (1a,2~3,5(3)-;
Cyclopentanecarboxylic acid, 2-[(benzoylamino)methyl]-5-[(4'-
chloro[1,1'-biphenyl]-4-yl)carbonyl]-, (1a,2[i,5j3)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro[ 1,1'-biphenyl]-4-yl)carbonyl]-
5-[[(2-methoxyethoxy)methoxy]methyl]-, (1a,2~,5[i)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro[ 1,1'-biphenyl]-4-yl)carbonyl]-
5-[[(phenylmethyl)thio]methyl]-, (1a,2(3,5(3)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-
5-[(phenylthio)methyl]-, (1a,2~3,5[i)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro(l,l'-biphenyl]-4-yl)carbonyl]-
5-[(propylthio)methyl]-, (1a,2~,5~3)-;
Cyclopentanecarboxylic acid, 2-[(2-benzothiazolylthio)methyl]-5-[(4'-
chloro[1,1'-biphenyl]-4-yl)carbonyl]-, (1a,2~,5(3)-;
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Benzoic acid, 2-[[[2-carboxy-3-[(4'-chloro[1,1'-biphenyl]-4-yl)-
carbonyl]cyclopentyl]methyl]thio]-, 1-methyl ester, (1a,2/3,3a)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro[ 1,1'-biphenyl]-4-yl)carbonyl]-
5-[[[(phenylmethoxy)carbonyl]-amino]methyl]-, (1a,2(3,5[i)-;
Benzoic acid, 2-methyl-, [2-carboxy-3-[(4'-chloro[ 1,1'-biphenyl]-4-
yl)carbonyl]cyclopentyl]methyl ester, (1a,2[i,3a)-;
Benzoic acid, 3-methyl-, [2-carboxy-3-[(4'-chloro[1,1'-biphenyl]-4-
yl)carbonyl]cyclopentyl]methyl ester, (1a,2(3,3a)-;
Benzoic acid, 4-methyl-, [2-carboxy-3-[(4'-chloro[ 1,1'-biphenyl]-4-
yl)carbonyl]cyclopentyl]methyl ester, (1a,2~,3a)-;
Benzoic acid, 2-methoxy-, [2-carboxy-3-[(4'-chloro[1,1'-biphenyl]-4-
yl)carbonylJcyclopentyl]methyl ester, (1a,2[i,3a)-;
Benzoic acid, 3-methoxy-, [2-carboxy-3-[{4'-chloro[1,1'-biphenyl]-4-
yl)carbonyl]cyclopentyl]methyl ester, (1a,2[3,3a)-;
Benzoic acid, 4-methoxy-, (2-carboxy-3-[(4'-chloro[ 1,1'-biphenyl]-4-
yl)carbonyl]cyclopentyl]methyl ester, {1a,2[i,3a)-;
Cyclopentanecarboxylic acid, 2-[(2-benzoxazolylthio)methyl]-5-[(4'-
chloro[1,1'-biphenyl]-4-yl)carbonyl]-, {1a,2[3,5[i)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro( 1,1'-biphenyl]-4-yl)carbonyl]-
5-[(1,3-dihydro-4-nitro-1,3-dioxo-2H isoindol-2-yl)methyl]-, (1a,2/3,5[i)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro[ 1,1'-biphenyl]-4-yl)carbonyl]-
5-[(1,3-dihydro-5-nitro-1,3-dioxo-2H isoindol-2-yl)methyl]-, (1a,2[i,5(3)-;
2H-Benz[f]isoindole-2-butanoic acid, a-[2-(4'-ethoxy[1,1'-biphenyl]-4-
yl }-2-oxoethyl]-1,3-dihydro-1,3-dioxo-;
[1,1'-Biphenyl]-4-butanoic acid, a-(acetylamino)-4'-chloro-~y-oxo-;
2H-Isoindole-2-hexanoic acid, a-[2-(4'-chloro[1,1'-biphenyl]-4-yl)-2-
oxoethyl]-1,3-dihydro-1,3-dioxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[3-
(methoxycarbonyl)phenyl]thio]methyl]-r-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[(2,6-(dimethylphenyl)thio]-
methyl]-'y-oxo-;
[l,l'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[4-fluoro-2-
(methoxycarbonyl)phenyl]thio]methyl]-y-oxo-;
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[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[3-
[(dieihylamino)carbonyl]phenyl]thio]methyl]-'y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[2-
[(dimethylamino)carbonyl]phenyl]thio]methyl]-y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[[[3-
[(dimethylamino)carbonyl]phenylJthio]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'-chloro[1,1'-biphenyl]-4-yl)-
carbonyl]-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro[ 1,1'-biphenyl]-4-yl)carbonyl]-
5-j(phenylmethyl)thio]-, (1a,2(3,Sa)-;
Cyclopentanecarboxylic acid, 2-[(4'-chloro[ 1,1'-biphenyl-4-yl)carbonyl]-
5-[(phenylmethyl)thio]-, (1a,2(3,5(3)-;
1-Cyclopentene-1-carboxylic acid, 5-[[4'-(pentyloxy)[1,1'-biphenyl]-4-
yl]carbonyl]-;
1-Cyclopentene-1-carboxylic acid, 5-[[4'-(hexyloxy)[1,1'-biphenyl]-4-
yl)Jcarbonyl]-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-hydroxy-y-oxo-a-
[(phenylthio)methyl]-;
[1,1'-Biphenyl]-4-butanoic acid, a-[2-[2-
[(butylamino)carbonyl J phenyl] ethyl]-4'-chloro-y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, a-[2-(3-carboxyphenyl)ethyl]-4'-chloro-
y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-[(diethylamino)-
carbonyl]phenyl]ethyl]-y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, a-[2-[3
[(butylamino)carbonyl]phenyl]ethyl]-4'-chloro-'y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[4-
[(diethylamino)carbonylJphenyl]ethyl]-y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, a-[2-[4
[(butylamino)carbonyl]phenyl]ethyl]-4'-chloro-'y-oxo-;
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[1,1'-Biphenyl]-4-butanoic acid, a-(2-(4-carboxyphenyl)ethyl]-4'-chloro-
y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-methoxy-Y-oxo-a-(2-phenylethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-hydroxy-~y-oxo-a-(2-phenylethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-ethoxy-y-oxo-a-(2-phenylethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, Y-oxo-a-(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-a-(2-phenylethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, ~y-oxo-a-(2-phenylethyl)-4'-
(phenylmethoxy)-;
[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, a-(2-(3-[(diethylamino)carbonyl]-
phenyl]ethyl]-'y-oxo-4'-(pentyloxy)-;
[1,1'-Biphenyl]-4-butanoic acid, a-[2-(3-[(diethylamino)carbonyl]-
phenyl]ethyl]-'y-oxo-4'-{phenylmethoxy)-;
1,2-Pyrrolidinedicarboxylic acid, 3-[(4'-chloro[1,1'-biphenyl]-4-
yl)carbonyl]-, 1-(phenylmethyl) ester, (2S-traps)-;
1,2-Pyrrolidinedicarboxylic acid, 3-[(4'-chloro[1,1'-biphenyl]-4-
yl)carbonyl]-, 1-(phenylmethyl) ester, (2'R-traps)-;
L-Proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-[[(phenylmethyl)-
amino]carbonyl]-, traps-;
L-Proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-(1-oxo-3-
phenylpropyl)-, traps-;
L-Proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-(phenylacetyl)-,
traps-;
L-Proline, 3-[(4'-chloro[1,1'-biphenyl]-4-yl)carbonyl]-1-(3,3-dimethyl-1-
oxobutyl)-, traps-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-heptyl-'y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-decyl-y-oxo-;
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[ 1,1'-Biphenyl]-4-butanoic acid, 4'-nitro-Y-oxo-a-(2-phenylethyl)-;
[ 1,1'-Biphenyl]-4-butanoic acid, 4'-cyano-y-oxo-a-(2-phenylethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(2-iodophenyl)ethyl]-y-
oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(3-iodophenyl)ethyl]-y-
oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(4-iodophenyl)ethyl]-~y-
oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-(3,5-
dimethoxyphenyl)ethyl]-y-oxo-;
[I,1'-Biphenyl]-4-butanoic acid, 4'-chloro-7-oxo-a-phenyl-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-'y-oxo-a-(phenylmethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-y-oxo-a-(2-phenylethyl)-;
[I,1'-Biphenyl]-4-butanoic acid, 4'-chloro-y-oxo-a-
[(trimethylsilyl)methyl]-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-bromo-y-oxo-a-(3-phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 7-oxo-a-(3-phenylpropyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-amino=y-oxo-a-(2-phenylethyl)-;
[ 1,1'-Biphenyl]-4-butanoic acid, 'y-oxo-a-(2-phenylethyl)-4'-
[[(phenylmethoxy)carbonyl]amino]-;
[1,1'-Biphenyl)-4-butanoic acid, 4'-[[(1,1-
dimethylethoxy)carbonyl]amino]-y-oxo-a-(2-phenylethyl)-;
[l,l'-Biphenyl]-4-butanoic acid, 4'-(acetylamino)-y-oxo-a-(2-
phenylethyl)-;
[ 1,1'-Biphenyl]-4-butanoic acid, y-oxo-4'-[( 1-oxopentyl)amino]-a-(2-
phenylethyl)-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-[(3,3-dimethyl-1-oxobutyl)amino]-y-
oxo-a-(2-phenylethyl)-;
[I,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[2-methoxycarbonyl)-
phenyl]ethyl]-'y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, a-[2-{2-carboxyphenyl)ethyl)-4'-chloro-
'y-oxo-;
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[ 1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[2-
[(diethylaminokarbonyl)phenyl]ethyl]-Y-oxo-;
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-
[(diethylamino)carbonyl)phenyl]ethyl]-y-oxo-, {S~-; and
[1,1'-Biphenyl]-4-butanoic acid, 4'-chloro-a-[2-[3-
((diethylamino)carbonyl)phenyl]ethyl]-Y-oxo-, (R)-.
Fenbufen and compounds related to fenbufen can be utilized. Such
compounds are described in United States Patent Number 3,784,701 and by Child,
et al., 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
R, where R is
O
CCH2CH2COOH (fenbufen), COCH=CHCOOH, S02NH2,
COCH2CHCOOH, COCH2CH2COOH, COCH2CH2S03Na,
CH3
CH(OH)CH2CH2COOH, COCH2CHCOOH, COCH2CH2CONHOH,
OH
C(=NOH)CH2CH2COOH, and COCH2SCH2COOH.
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
0 R1 R2 0
RCS
N N NR4R5
H
R8 O R3
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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:
N-[2,3-bis-Acetylmercaptopropanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-acetylmercapto-3-methoxycarbonylpropanoyl]-L-leucyi-L-
phenylalanine N-methylamide;
N-[2-ZCetylmercapto-4-methoxycarbonylbutanoyl]-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-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.-methoxycarbonylbutanyol]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-mercapto-4-methoxycarbonylpentanoyl ]-L-ieucyl-L-phenylalanine
N-methylamide;
N-[2-mercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-mercapto-4-phthalimidobutanoyl]-L-leucyl-phenyl-alanine
N-methylamide;
N-[2-mercapto-S-phthalimidopentanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
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N-[2-mercapto-6-phthalimidohexanyoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-acetylmercapto-5-methoxycarbonylpentanoyl]-L-leucyl-L-
phenylalanine N-methylamide;
N-[2-acetylmercapto-6-methoxycarbonylhexanyol]-L-leucyl-L-
phenylalanine N-methylamide;
N-[2-acetylmercapto-6-methoxycarbonylhexanyol]-L-valinyl-L-
phenylalanine N-methylamide;
N-j2-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-[(3-{4-
thiazolyl)]alaine N-methylamide;
N-[2-acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-([i-(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;
N-[2-mercapto-6-methoxycarbonylhexanyol]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-mercapto-6-methoxycarbonylhexanyol]-L-leucyl-L-trptophan
N-methylamide;
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N-[2-mercapto-S-phthalimidopentanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-mercapto-S-phthalimidopentanoyl]-L-leucyl-L-tryptophan
N-methylamide;
N-[2-mercapto-S-phthalimidopentanoyl]-L-leucyl-L-[[i-(4-
thiazolyl)alanine N-methylamide;
N-[2-mercapto-S-phthalimidopentanoyl]-L-leucyl-L-[(3-(2-pyridyl)]alanine
N-methylamide;
N-[2-mercapto-S-phthalimidopentanoyl]-L-leucyl-S-methyl-L-glutamic
acid N-methylamide;
N-[2-mercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[N-mercaptoacetyl)-L-leucyI]-L-phenylalanine N-methylamide;
N-[acetomercaptoacyl)-L-leucyl-L-phenylalanine methylamide;
(RS)-2-(acefylthio)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-(acetylthio)-3-phenylpropanoyl-L-leucyl-L-phenylalanine
N-methylamide;
(RS)-2-(acetylthio)-4-phenylbutanoyl-L-Ieucyl-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;
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(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; and
N-[N-(mercaptoacetyl)-L-leucyl]-L-tryptophan methylamide.
Additional matrix metalloproteinase (MMP) inhibitors, which can be
utilized to prevent and treat heart failure and ventricular dilatation,
include the
following:
[4-(N-Hydroxyamino)-2(R)-cyclohexylmethylsuccinyl]-L-(3-
cyclohexylalanine-N-(2-phenylethyl)amide;
[4-N-(Hydroxyamino)-2R-isobutylsuccinyl]-L-[i-cyclohexylalanine-N-(2-
phenylethyl)amide;
[4-(N-hydroxyamino)-2R-phenylpropylsuccinyl]-L-(3-cyclohexylalanine-
N-(2-phenylethyl)amide;
[4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-[i-cyclohexylalanine-
N-[2-(N,N-dimethylamino]ethyl)amide;
[4-(N-Hydroxyamino)-2R-phenylpropylsuccinylJ-L-[i-cyclohexylalanine-
N-[2-(p-sulphonamidophenyl)ethyl)amide;
[4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl)-L-[i-cyc lohexylalanine-
N-(2-(p-sulphonylphenyl)ethyl)amide;
[4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-[i-cyclohexylalanine-
N-[2-(2-pyridyl)ethyl]amide;
[4-(N-Hydroxyamino)-2R-pentylsuccinyl]-L-(3-cyclohexylalanine-N-(2-
phenylethyl)amide;
[4-(N-Hydroxyamino)-2R-isoamylsuccinyl]-L-(3-cyclohexylalanine-N-(2-
phenylethyl)amide;
[4-(N-Hydroxyamino)-2R-phenylbutylsuccinyl]-L-[i-cyclohexylalanine-N-
(2-phenylethyl)amide;
[4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-[i-cyclohexylalanine-
N-[3-(4-morpholinyl)propyl)amide;
[4-(N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-[i-cyclohexylalanine-
N-[(3-alanine]amide;
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[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-ø-cyclohexylalanine amide;
[4-(N-Hydroxyamino)-2R-(3-phenylpropyl)succinyl]-L-ø-
cyclohexylalanine amide;
[4-(N-Hydroxyamino)-2R-(3-phenylbutyl)succinyl]-~,-ø-cyclohexylalanine
amide;
[4-N-(Hydroxyamino)-2R-phenylethylsuccinyl]-L-leucine-N-(2-
phenylethyl)amide;
[4-{N-Hydroxyamino)-2R-phenylpropylsuccinyl]-L-leucine-N-(2-
phenylethyl)amide;
[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-L-tryptophan amide;
[4-(N-Hydroxyamino)-2(R)-isobutylsuccinylJ-L-valine amide;
[3-Phosphono-2R, S-phenylpropyl-1-oxopropyl]-L-ø-cycI ohexylalanine-N-
(2-phenylethyl)amide, dimethylester;
[3-Phosphono-2R-phenylpropyl-1-oxopropyl]-L-ø-cyclohexylalanine-N-
(2-phenylethyl)amide;
[3-Phosphono-2S-phenylpropyl-1-oxopropyl]-L-ø-cyclohexylalanine-ø-
alanine;
[3-Phosphono-2R-phenylpropyl-1-oxopropyl]-L-ø-cyclohexylalanine;
[3-Phosphono-2S-phenylpropyl-1-oxopropyl]-L-ø-cyclohexylalanine-ø-
alanine, methyl ester;
[3-Phosphono-2R,S-phenylpropyl-1-oxopropyl]-L-ø-cyclohexylalanine-N-
[4(3-aminopropyl)morpholine]amide, bromine salt;
[3-Phosphono-2R,S-(4-methylphenyl)propyl-1-oxopropyl]-L-ø-
cyclohexylalanine-N-(2-phenylethyl)amide, diethylester;
[3-Phosphono-2R,S-(4-methylphenyl)propyl-1-oxopropyl]-L-ø-
cyclohexylalanine-N-(2-phenylethyl)-amide;
4-t-Butoxy-2(R)-[3-{2-phenoxyethyl)succinyl]-L-ø-cyclohexylalanine-N-
(2-phenylethyl)amide;
4-Hydroxy-2(R)-[3-(2-phenoxyethyl)succinyl]-L-ø-cyclohexylalanine-N-
(2-phenylethyl)amide;
4-(N-Hydroxyamino-2(R)-[3-{2-phenoxyethyl)succinyl]-L-ø-
cyclohexylalanine-N-(2-phenylethyl)amide;
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{ 4-Hydroxy-2(R)-[3-(4-pyridinium)propyl] succinyl } -L-(3-
cyclohexylalanine-N-(2-phenylethyl)amide;
{ 4-(N-Hydroxyamino)-2(R)-[3-(4-pyridinium)propyl] succinyl } -L-(3-
cyclohexylalanine-N-(2-phenylethyl)amide;
{ 4-(N-Hydroxyamino)-2(R)-[3-(N-methyl-4-pyridinium)propyl] succinyl } -
L-(3-cyclohexylalanine-N-(2-phenylethyl)amide;
{ 4-Hydroxy-2-(R)-[3-(4-methylphenyl)propyl]succinyl }-L-[i-
cyclohexylalanine-N-[(2-morpholine-sulphonylamino)ethyl]amide;
{ 4-(N-Hydroxyamino)-2-(R)-[3-(4-methylphenyl)propyl] succinyl } -L-[3-
cyclohexylalanine-N-[(2-morpholinesulphonylamino)ethyl]amide;
{ 4-(N-Hydroxyamino)-2-(R)-[3-(4-chlorophenyl)propyl] succinyl } -L-[i-
cyclohexylalanine-N-[(2-morpholinesulphonylamino)ethyl]amide;
{ 4-N-Hydroxyamino)-2-(R)-[3-(4-methylphenyl)propyl]succinyl }-L-(3-
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)propyl]succinyl]-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-methylpropyl)succinyl]-L-[S-
methyl)penicillamine]-N-methylamide;
N4-Hydroxy-N 1-( 1-(S )-c arbamoyl-2,2-dimethylpropyl )-2-(R)-4-
(chlorophenylpropyl)succinamide;
N4-Hydroxy-N 1-( 1-(S)-carbamoyl-2,2-dimethylpropyl )-2-(R)-(4-
methylphenylpropyl)succinamide;
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N4-Hydroxy-N 1-( 1-(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4-
methoxyphenylpropyl)succinamide;
N4-Hydroxy-N 1-( 1-(S)-carbamoyl-2,2-dimethylpropyl)-2-(R)-(4-
trifluoromethylphenylpropyl)succinamide;
N4-Hydroxy-N 1-( 1-(S)-carbamoyl-2,2-dimethylpropyl)-2-{R)-(4-
chloromethylphenylpropyl)succinamide;
N-[N-(Mercaptoacetyl)-L-leucyl]-L-phenylalanine 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-(Acetylthio)-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;
N-[N-(Mercaptoacetyl)-L-threonyl]-L-phenylalanine methylamide;
N-[N-(Mercaptoacetyl)-L-leucyl]-L-tryptophan methylamide;
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N [2,3-bis-Acetylmercaptopropanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N [2-Acetylmercapto-3-methoxycarbonylpropanoyl]-L-leucyl-L-
phenylalanine N methylamide;
N-[2-Acetylmercapto-4-methoxycarbonylbutanoyl]-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-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;
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-S-methoxycarbonylpentanoyl]-L-leucyl-L-
phenylalanine N-methylamide;
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N [2-Acetylmercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-
phenylalanine N methylamide;
N (2-Acetylmercapto-6-methoxycarbonylhexanoyl]-L-valinyl-L-
phenylalanine N-methylamide;
N [2-Acetylmercapto-6-methoxycarbonylhexanoyl]-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-S-phthalimidopentanoyl]-L-leucyl-L-[ø-(4-
thiazolyl)]alanine N methylamide;
N [2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-L-[(3-(2-
pyridyl)]alanine N methylamide;
N [2-Acetylmercapto-5-phthalimidopentanoyl]-L-leucyl-5-methyl-L-
glutamic acid 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-leucyl-L-phenylalanine
N methylamide;
N [2-Mercapto-6-methoxycarbonylhexanoyi]-L-leucyl-L-phenylalanine
N-methylamide;
N [2-Mercapto-6-methoxycarbonylhexanoyl]-L-leucyl-L-tryptophan
N methylamide;
N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-[2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-tryptophan
N-methylamide;
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N [2-Mercapto-5-phthalimidopentanoyl]-L-Ieucyl-L-[(3-(4-
thiazolyl)alanine N-methylamide;
N (2-Mercapto-5-phthalimidopentanoyl]-L-leucyl-L-[~i-(2-pyridyl)]alanine
N-methylamide;
N-[2-Mercapto-5-phthalimidopentanoyl]-L-Ieucyl-5-methyl-L-glutamic
acid N methylamide;
N [2-Mercapto-6-phthalimidohexanoyl]-L-leucyl-L-phenylalanine
N-methylamide;
N-Hydroxy-2(R)-[(4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-
methylbutanamide;
N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-3-picolyl)amino]-2-
cyclohexylacetamide;
N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-4-
methylpentanamide;
N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-6-[(N,N-
dimethylglycyl)amino]hexanamide hydrochloride;
N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-
methylbutanamide;
N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(4-picolyl)amino]-2-
cyclohexylacetamide;
N-Hydroxy-2(R)-[(4-methoxybenzenesulfonyl]-(4-picolyl)amino]-2-(2-
tetrahydrofuranyl)acetamide;
N-Hydroxy-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-
methylbutanamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-piperazic
acid N-methyl amide;
[4-{N-Hydroxyamino)-2R-isobutyl-3 S-benzylsuccinyl]-N2-(S )-piperazic
acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methoxyphenylsuccinyl]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methoxybenzylsuccinyl]-N2-(S)-
piperazic acid N-methyl amide;
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[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thiophenylsuccinyl]-N2-
(S)-piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thiobenzylsuccinyl]-N2-
(S)-piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(methylthio-2-thienyl)succinyl]-
N2-(S)-piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylacetate]-N2-(S)-piperazic
acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3 S-methyl-isopropanoate]-N2-(S )-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-tert-butanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thioacetate]-N2-(S )-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-thioisopropanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-(2-pyridyl)]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-(3-pyridyl)]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-(4-pyridyl)]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl thio-tert-butanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methylsuccinyl]-N2-(S)-piperazic
acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2-(S)-piperazic acid
N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methoxyphenylsuccinyl]-NZ-(S)-
piperazic acid N-methyl amide;
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[4-(N-Hydroxyamino)-2R-hexyl-3S-methoxybenzylsuccinyl]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methylthiophenylsuccinyl]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methylthiobenzylsuccinyl]-NZ-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-(methylthio-2-thienyl)succinylJ-N2-
(S)-piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2-(S)-piperazic acid
N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methyl acetate]-N2-(S)-piperazic acid
N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methylisopropanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methyl tert-butanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methylthioacetate]-N2-(S)-piperazic
acid N-methyl amide;
(4-(N-Hydroxyamino)-2R-hexyl-3S-methylthioisopropanoate]-N2'(S)-
piperazic acid N-methyl amide;
(4-(N-Hydroxyamino)-2R-hexyl-3S-methylthio-tert-butanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methyl-(2-pyridyl)]-N2-(S)-piperazic
acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methyl-(3-pyridyl)]-N2-(S)-piperazic
acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-hexyl-3S-methyl-(4-pyridyl)]-NZ-(S)-piperazic
acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylsuccinyl]-N2-(S)-
piperazic acid N-methyl amide;
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[4-(N-Hydroxyamino)-2R-ethylphenyl-3S-benzylsuccinyl]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methoxyphenylsuccinyl]-N2-
(S)-piperazic acid N-methyl amide;
(4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methoxybenzylsuccinyl)-N2-
(S)-piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthiophenylsuccinyl]-N2-
(S)-piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthiobenzylsuccinyl]-N2-
(S)-piperazic acid N-methyl amide;
(4-(N-Hydroxyamino)-2R-ethylphenyl-3S-(methylthio-2-
thienyl)succinyl]-N2-(S)-piperazic acid N-methyl amide;
[4-(N-Hydroxyamino}-2R-ethylphenyl-3S-benzylsuccinyl]-N2-(S)-
piperazic acid N-methyl amide;
[4-{N-Hydroxyamino)-2R-ethylphenyl-3S-methyl acetate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylisopropanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-ethylphen yl-3 S-methyl-tert-butanoate]-N2-(S )-
piperazic acid N-methyl amide;
[4-(N-Hydroxyarnino)-2R-ethylphenyl-3S-methylthioacetate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-ethylphenyl-3S-methylthioisopropanoate]-N2-
(S)-piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-ethylphenyl-3 S-methylthio-tert-butanoate]-N2-
(S)-piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methyisuccinyl]-N2-(S)-piperazic acid
N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methylthiophenylsuccinyl]-N2-(S)-
piperazic acid N-methyl amide;
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[4-{N-Hydroxyamino)-2R-octyl-3S-methylthiobenzylsuccinyl]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methylthio-2-thienyi)succinyl]-N 1-
(S)-piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methyl acetate]-N2-(S)-piperazic acid
N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methylisopropanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methyl tert-butanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methylthioacetate]-N2-(S )-piperazic
acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methylthioisopropanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methylthio-tert-butanoate]-N2-(S)-
piperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methyl-(2-pyridyl)]-N2-(S)-piperazic
acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methyl-(3-pyridyl)]-N2-(S}-piperazic
acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-octyl-3S-methyl-(4-pyridyl)]-N2-(S)-piperazic
acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-4' (S/R)-
benzylpiperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-5' (SIR)-
benzylpiperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyisuccinyl]-N2-(S)-6'(SlR)-
benzylpiperazic acid N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-
[5',6']benzopiperazic acid N-methyl amide;
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N-[1(R)-Carboxy-ethyl]-a-(S)-isobutylglycine-(S)-N2-piperazic acid
methyl amide;
N-[ 1 {R)-Carboxy-ethyl]-a-(S)-hexylglycine-(S)-N2-piperazic acid methyl
amide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-heptylglycine-(S)-N2-piperazic acid methyl
amide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-octylglycine-(S)-N2-piperazic acid methyl
amide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-ethylphenylglycine-(S)-N2-piperazic acid
methyl amide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-propylphenylclycine-{S)-N2-piperazic acid
methyl amide;
N-[ 1 (R)-Carboxy-ethylthiobenzyl]-a-(S)-isobutylglycine-(S)-N2-piperazic
acid methyl amide;
N-[ 1 (R)-Carboxy-ethylthiobenzyl]-a-(S)-hexylglycine-(S )-N2-piperazic
acid methyl amide;
N-[ 1 (R)-Carboxy-ethylthiobenzyl]-a-(S)-ethylphenylglycine-(S)-N2-
piperazic acid methyl amide;
N-[ 1 (R)-Carboxy-ethylthiobenzyl]-a-(S)-propylphenylglycine-(S)-N2-
piperazic acid methyl amide;
N-( 1 (R)-Carboxy-ethyloxybenzyl]-a-(S)-isobutylglycine-(S)-N2-piperazic
acid methyl amide;
N-[ 1 (R)-Carboxy-ethyloxybenzyl]-a-(S)-hexylglycine-(S)-N2-piperazic
acid methyl amide;
N-[1 (R)-Carboxy-ethyloxybenzyl]-a-(S)-ethylphenylglycine-(S)-N2-
piperazic acid methyl amide;
N-[ 1 (R)-Carboxy-ethyloxybenzyl]-a-(S)-propylphenylglycine-(S)-N2-
piperazic acid methyl amide;
N-[ 1 (R)-Carboxy-4-(p-toluenesulfonyl)butyl]-a-(S)-phenethylglycyl-(S)-
N2-piperazic acid methyl amide;
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N-[ 1 (R)-Carboxyethyl]-a-[2-(4-phenylphenoxy)ethyl]-glycyl-(S)-N2-
piperazic acid methyl amide;
2-[2(R)-[2-[ 1,1'-Biphenyl)yl]ethyl]-4-butyl-4(S)-carboxy-1-oxobutyl]-
3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[ 1, I'-Biphenyl)yl]ethyl]-4-methyl-4(S)-carboxy-1-oxobutyl]-
3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[ 1,1'-Biphenyl)yl]propyl]-4-butyl-4(S)-carboxy-1-oxobutyl]-
3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-(4-Propylphenyl)ethyl]-4-butyl-4(S)-carboxy-I-oxobutyl]-3(S)-
methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-(4-Butylphenyl)ethyl]-4-butyl-4(S )-carboxy-1-oxobutyl]-3 (S )-
methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-(4-t-Butylphenyl)ethyl]-4-butyl-4(S)-carboxy-1-oxobutyl]-
3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[4-(4-Fluorophenyl)phenyl]ethyl]-4-butyl-4(S)-carboxy-1-
oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-(2(R)-[2-[4-{4-Fluorophenyl)phenyl]ethyl]-4-methyl-4(S )-carboxy-1-
oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-n-Octyl-4-methyl-4{S)-carboxy-1-oxobutyl]-3(S)-
methylaminocarbonyl-hexahydropyridazine;
2-(2(R)-[2-[(4-Thiazolyl)phenyl]ethyl]-4-butyl-4(S)-carboxy-1-oxobutyl]-
3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-((4-Thiazolyl)phenyl]ethyl]-4-methyl-4.(S)-carboxy-1-
oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[(4-Thiazolyl)phenyl)ethyl]-4-[3-{phenylsulfonyl)propyl-4(S)-
carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[(4-Thiazolyl)phenyl]ethyl]-4-(3-phenylpropyl)-4{S)-carboxy-
1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[(4-Oxazolyl)phenyl]ethyl]-4-butyl-4(S)-carboxy-1-oxobutyl]-
3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[(4-Oxazolyl)phenyl]ethyl]-4-methyl-4(S)-carboxy-1-
oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
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2-[2(R)-[2-[{4-Oxazolyl)phenyl]ethyl]-4-[3-(phenylsulfonyl)propyl-4(S)-
carboxy-1-oxobutyl]-3 (S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[(4-Oxazolyl)phenyl]ethyl]-4-(3-phenylpropyl)-4(S)-carboxy-
1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[4-(Dimethylamino)methylphenyl]ethyl]-4-butyl-4(S)-carboxy-
1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[4-(Dimethylamino)methylphenyl]ethyl]-4-methyl-4(S)-
carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[4-(Dimethylarnino)methylphenyl]ethyl]-4-[3-
(phenylsulfonyl)propyl-4(S )-carboxy-1-oxobutyl]-3 (S )-methylaminocarbonyl-
hexahydropyridazine;
2-[2(R)-[2-[4-(Dimethylamino)methylphenyl]ethyl]-4-(3-phenylpropyl)-
4(S)-carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-(2-[(4-Imidazolyl)phenyl]ethyl]-4-butyl-4(S)-carboxy-1-
oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-(2(R)-[2-[(4-Imidazolyl)phenyl]ethyl]-4-methyl-4(S)-carboxy-1-
oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-((4-Imidazolyl)phenyl]ethyl]-4-[3-(phenylsulfonyl)propyl-4(S)-
carboxy-1-oxobutyl]-3(S )-methylaminocarbonyl-hexahydropyridazine;
2-[2(R)-[2-[(4-Imidazolyl)phenyl]ethyl]-4-[3-(phenylpropyl)-4(S)-
carboxy-1-oxobutyl]-3(S)-methylaminocarbonyl-hexahydropyridazine;
HS(CH2)2_(S-D-Leu)-Phe-NHMe;
HS(S)CHMeCH2_(S-D-Leu)-Phe-NHMe;
HS (S)CH(PhtNBu)CH2_(S-D-Leu)-Phe-NHMe;
HS (S)CH(PhtNEt)CH2-(S-D-Leu)-Phe-NHMe;
HS ( 1,2-Cyclopentyl )(S-D-Leu)-Phe-NHMe
Me-S(NH)2-(CH2_DL-Leu)-Trp-NHBn;
n-Bu-S(NH)2_(CH2-DL-Leu)-Trp-NHBn;
n-Bu-S(NH)2-(CH2-DL-TyrOCH3)-Trp-NHBn;
Me-RS-SO(NH)-(CH2-L-Leu)-Phe-Ala-NH2;
n-Bu-RS-SO(NH)-(CH2-L-Leu)-Phe-Ala-NH2;
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HONH-C-CH2CH(CH2CH(CH3)z)-CO-Nal-Ala-NH2;
O
HO-NH-CO-CHZ-CH-(CH2-CH(CH3)2-CO-Nal-Pro-NH2;
HO-NH-CO-CH(CH3-CH(CH2)-CH(CH3)2)-CO-Nal-Ala-NH2;
HON-COCH2-CH-CO-Pal--Ala-NH2
wherein Pal is 3-pyridylalanine;
HON-COCH2-CH-CO-Nal (CH2S ) Ala-NH2
HO-NH-CO-CH2-CH(CH2CH(CH3)2)-CONaI-(CH2NH)-Ala-NH2;
o ~ o
H
HO~ N
N ~ NH2
H
O
O ~ O
H
H0~ N~ NHEt
N ~ N
H H
0 O
00
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I
HONHC- CH2 CHC-NH- ~ HCH2 S ~ HCONH2
iH2 CH2 CH3
CH
(CH3)2
II
NONH-C- CH2 CHC-NH-CHC-NH CHz CONH2
iH2 CH2 CH3
CH
(CH3)2
'OCH3
OCH3
4-( 1,3-Di hydro-1, 3-dioxo-2H-Benz [f] i soindol-2-yl )-2-(R)-[ [3-methyl-1-
(S)-[[(2-morpholin-4-ylethyl)anuno]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-bent[fJisoindol-2-yl)-2-(R)-[(3-methyl-1-
(S)-[[methylamino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[fJisoindol-2-yl)-2-(R)-([3-methyl-1-
(S)-[[(1H-imidazol-2-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[fJisoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(1H-tetrazol-5-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[fJisoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[([(2-(phenyl)ethyl]amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(pyridin-3-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[fJisoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(2-methyl-2H-tetrazo-5-ylmethyl)amino]carbonyl]butyl]amino]-butanoic
acid;
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4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(4-hydroxy-2-methyl-pyrimidin-5-ylmethyl)amino]carbonyl]butyl]amino]-
butanoic acid;
4-( 1,3-Dihydro-1, 3-dioxo-2H-benz [f j isoindol-2-yl )-2-(R)-[ [3-methyl-1-
(S)-[[[2-(2-pyridin-3-yl)ethyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[fjisoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[1-(IH-tetrazol-5-yl)ethyl]amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[ [3-methyl-1-
(S)-[[(5-amino-4H-[ 1,2,4]-triazol-3-ylmethyl)amino]carbonyl]butyl]amino]-
butanoic acid;
4-( 1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl )-2-(R)-[ [3-methyl-1-
(S}-[[[ 1-(6-oxo-1,6-dihydro-pyridazin-3-yl)ethyl]amino]carbonyl]butyl]amino]-
butanoic acid;
4-{ 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(phenyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz [ f] i soindol-2-yl)-2-(R)-[ [ 3-methyl-1-
(S)-[[(benzyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-bent[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(pyridin-4-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-{R)-[[3-methyl-1-
(S)-[[[2-(1H-imidazol-4-yl)ethyl]amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz [f] i soindol-2-yl )-2-(R)-[ [3-methyl-1-
(S)-[[(pyridin-2-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-bent [f] isoindol-2-yl )-2-(R)- [ [3-methyl-1-
(S)-[[(4-sulfamoyl-phenyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl)-2-(R)-[ [3-methyl- I -
(S)-[[(3-sulfamoyl-phenyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(4-dimethylamino-benzyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl )-2-(R)-[ [ 3-methyl-1-
(S)-[[[ 1-(S)-phenyl-ethyl]amino]carbonyl]butyl]amino]-butanoic acid;
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4-( 1,3-Dihydro-1,3-dioxo-2H-Benz [f j isoindol-2-yl)-2-(R)-( (3-methyl-1-
{S )-[ [( 1,1-dioxo-tetrahydro-thiophen-3-yl)amino] carbonyl ]butyl] amino]-
butanoic
acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-bent[f]isoindol-2-yl)-2-(R)-j[3-methyl-1-
(S)-[[(4-sulfamoyl-benzyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz(f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[[1-(R)-phenyl-ethyl]amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-([3-methyl-1-
(S)-[[(3-fluorobenzyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz [f j isoindol-2-yl)-2-(R)-[ [3-methyl-1-
(S)-[[(furan-2-ylmethyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1, 3-dioxo-2H-Benz [f] isoindol-2-yl )-2-(R)-( [ 3-methyl-1-
(S)-[[( 1-methyl-1H-tetrazol-5-ylmethyl)amino]carbonyl]butyl]amino]-butanoic
acid;
4-( 1,3-Dihydro-1, 3-dioxo-2H-bent [f] isoindol-2-yl )-2-(R)-[ [3-methyl-1-
(S)-[(( 1,2,3,4-tetrahydro-naphthalen-1-yl)amino]carbonyl]butyl]amino]-
butanoic
acid;
4-( 1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl )-2-(R)-[ [ 3-methyl-1-
(S)-[[(2,4-difluoro-benzyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz[f]isoindol-2-yl)-2-(R)-[ [3-methyl-1-
(S)-[[{3-nitrobenzyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(4-nitrobenzyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1, 3-dioxo-2H-Benz [f j isoindol-2-yl )-2-(R)-[ [ 3-methyl-1-
(S)-[[(4-methanesulfonylamino-benzyl)amino]carbonyl]butyl]amino]-butanoic
acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-([(3-methanesulfonylamino-benzyl)amino]carbonyl]butyl]amino]-butanoic
acid;
4-(1,3-Dihydro-1,3-dioxo-2H-Benz[f)isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[((3,4-difluoro-benzyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(3-trifluoromethyl-benzyl)amino]carbonyl]butyl]amino]-butanoic acid;
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4-[2-(S)-[ 1-(R)-Carboxy-3-( 1,3-dioxo-1,3-dihydro-benzo[#]isoindol-2-yl)-
propylamino]-4-methyl-pentanoylamino-methyl)-benzoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
{S)-[[(2-hydroxy-l, l-bis-hydroxymethyl-ethyl)amino]carbonyl]butyl]amino]-
butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(3,5-difluoro-benzyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz[fjisoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[benzylmethyl-amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(2-dimethylaminoethyl)-methyl-amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1, 3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl )-2-(R)-[ [3-methyl-1-
(S)-[[(1-azabicyclo[2.2.2)-oct-3(R)-amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[( 1-azabicyclo[2.2.2]oct-3-(S)-yl)amino]carbonyl]butyl]amino]-butanoic
acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-bent[fJisoindol-2-yl)-2-(R)-[ [3-methyl-1-
(S )-[ [ (3-(R)-4-(S )-5-(R)-6-tetrahydrox-tetrahydra-pyran-2-(R)-yl
methyl)amino]-
carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(N,N'-dimethyl-hydrazino)carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(methylmethoxy)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[ [3-methyl-1-
(S)-[[(dimethyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(2-oxo-tetrahydro-thiophen-3-{R)-yl)anvno]carbonyl]butyl]amino]-butanoic
acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(2-oxo-tetrahydro-thiophen-3-(S)-yl)amino]carbonyl]butyl]amino]-butanoic
acid;
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4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(3-(R)-acetylamino-4-(S)-5-(S)-dihydroxy-6-(R)-hydroxymethyl-tetrahydro-
pyran-2-yl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl)-2-(R)-( [3-methyl-1-
(S)-[[[benzyl(2-hydroxyethyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz [f J i soindol-2-yl )-2-(R)-[ [3-methyl-1-
(S)-[3,4-dihydro-1H-isoquinoline-2-carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz[fJisoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[4-methylpiperazine-1-carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz [fj i soindol-2-yl )-2-(R)-[ [3-methyl-1-
(S)-[1-oxo-[1,4]thiazinane-4-carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[fJisoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[morpholine-4-carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[fJisoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[4-(2-3-dihydroxy-propyl)-piperazine-1-carbonyl]butyl]amino]-butanoic
acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz(f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[3,4,5,6-tetrahydro-H-(2,3]bipyridinyl-1]carbonyl]butyl]amino]-butanoic
acid;
4-( 1, 3-Dihydro-1, 3-dioxo-2H-benz [f j isoindol-2-yl )-2-(R )-[ [3-methyl-1-
(S)-[[( 1-methyl-8-oxo-1,7-diazacyclotridec-9-yl)amino]carbonyl)butyl]amino]-
butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz [f Jisoindol-2-yl )-2-(R)-[ [ 3-methyl-1-
(S)-[[methyl-1-methyl-piperidin-4-yl)amino]carbonyl]butyl]amino]-butanoic
acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[fJisoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[(4-hydroxy-1,1-dioxo-tetrahydro-thiophen-3-yl)amino]carbonyl]butyl]-
amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz [f j isoindol-2-yl )-2-(R)-[ [3-methyl-1-
(S)-(4-ethoxycarbonylmethyl-piperazine-1-carbonyl)butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[[( 1,1-dioxo-tetrahydro-thiophen-3-yl)-methyl-amino]carbonyl]butyl]amino]-
butanoic acid;
4-( 1,3-Dihydro-1, 3-dioxo-2H-Benz [~ i soindol-2-yl)-2-(R)-[ [ 3-methyl-1-
(S)-[2-(R)-(pyridin-3-yl)-pyrrolidinecarbonyl]butyl)amino]-butanoic acid;
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4-( 1,3-Dihydro-1,3-dioxo-2H-Benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- I-
(S)-[2-(S)-(pyridin-3-yl)-pyrrolidinecarbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro- I ,3-dioxo-2H-benz [f] isoindol-2-yl }-2-(R)-[ [3-methyl-1-
(S)-[3-oxo-2-(R)-phenyl-piperazine-I-carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-Benz[f]isoindol-2-yl)-2-(R)-((3-methyl-1-
(S)-[3-oxo-2-(S)-phenyl-piperazine-1-carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1, 3-dioxo-2H-benz(f j isoindol-2-yl )-2-(R)-[ (3-methyl-1-
(S)-[(pyridine-3-carbonyl-hydrazino)carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro- I ,3-dioxo-2H-bent[ f] isoindol-2-yl)-2-(R)-[ [ 3-methyl-1-
(S)-[[(benzenesulfonyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-(1,3-Dihydro-1,3-dioxo-2H-Benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-I-
{S)-[[(3-aminobenzyl)amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-1-
(S)-[([4-(trifluoro-methanesulfonylamino)benzyl]amino]carbonyl]butyl]amino]-
butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl-I-
(S)-[[(2-hydroxy-(R)-bicyclo[4.3.0]nona-3,6( 1 )-diene]amino]carbonyl]butyl]-
amino]-butanoic acid;
4-( 1, 3-Dihydro-1, 3-dioxo-2H-benz [f] isoindol-2-yl)-2-(R}-[ [3-methyl- I -
(S)-[[(2-hydroxy-(S)-bicyclo[4.3.0]nova-3,6( 1 )-diene]amino]carbonyl]butyl]-
amino]-butanoic acid;
4-( 1, 3-Dihydro-1,3-dioxo-2H-benz [ f] isoindol-2-yl )-2-(R)-[ [ 3-methyl- I -
(S)-[[(N-methyl-pyrrolidine)-methyl-amino]carbonyl]butyl]amino]-butanoic acid;
4-( 1,3-Dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-(R)-[[3-methyl- I -
{S)-[(N-ethoxycarbonylmethyl-piperazine)-1-carbonyl]butyl]amino]-butanoic
acid;
2-(R)-[ 1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-bromo-
1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid;
2-(R)-[ I -(S )-(Benzylamino)carbonyl-3-methylbutylamino]-4-(S-propox y-
1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid;
2-(R)-[ 1-(S )-(Benzylamino)carbonyl-3-methylbutylamino]-4-( 5-nitro-1,3-
dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid;
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2-(R)-[ 1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(S-amino-
1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid;
2-(R)-[ 1-(S )-(Benzyl amino)carbonyl-3-methylbutylamino]-4-(5-methyl-
1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid;
2-(R)-[ 1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-methoxy-
1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid;
2-(R)-[ 1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(S-
benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butaroic acid;
2-(R)-[ 1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-phenyl-
1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid;
2-(R)-[ 1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-( 1,3-dioxo-
1,3-dihydro-isoindol-2-yl)-butanoic acid;
2-(R}-[1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-
methanesulfonylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid;
2-(R)-[ 1-(S )-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-
benzenesulfonylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid;
2-(R)-[ 1-(S)-(Benzylamino)carbonyl-3-methylbutylamino]-4-(5-hydroxy-
1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid;
2-(R)-[[3-Methyl-1-(S)-[[(pyridin-3-ylmethyl)amino]carbonyl]-
butyl]amino]-4-( 1,3,5,7-tetraoxo-3,5,6-tetrahydro-1 H-pyrolo[3,4-f]isoindol-2-
yl)butanoic acid;
EtONHCONMe-CHZCH(iBu)-CO-L-Trp-NHEt;
EtCONOH-CH2CH(iBu)-CO-L-Trp-NHEt;
n-PrCONOEt-CH2CH(iBu)-CO-L-Trp-NHEt;
EtNHCONOMe-CH2CH(iBu)-CO-L-Trp-NHEt;
MeNHCONOH-CH2CH(iBu)-CO-L-Trp-NHEt;
EtONHCONMe-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt;
EtCONOH-CHZCH(iBu)-CO-L-Ala(2-naphthyl)-NHEt;
n-PrCONOEt-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt;
EtNHCONOMe-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt;
MeNHCONOH-CH2CH(iBu)-CO-L-Ala(2-naphthyl)-NHEt;
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HONHCONHCH2CH(iBu)-CO-L-TrpNHMe;
HONHCONHCH2CH2CH(iBu)-CO-L-TrpNHMe;
HONHCONHCH(iBu)-CO-L-TrpNHMe;
H2NCON(OH)CH(iBu)-CO-L-TrpNHMe;
N(OH)CH2CH(iBu)-CO-L-TrpNHMe;
H2NCON(OH)CH2CH2CH(iBu)-CO-L-TrpNHMe;
CH3CON(OH)CH(iBu)-CO-L-TrpNHMe;
CH3CON(OH)CH2CH(iBu)-CO-L-TrpNHMe;
CH3CON(OH)CH2CH2CH(iBu)-CO-L-TrpNHMe;
NHOHCOCH2CH(i-Bu)CO-L-Trp-NHMe;
HONHCONHCH2CH(i-Bu)CONHCHCOOH or
R4
ROOCCH2CH(i-Bu)CONHCHCOOH;
R4
N- { D,L-2-(Hydroxyaminocarbonyl)methyl-4-methylpentanoyl } -L-3-(2' -
naphthyl)alanyl-L-alanine, 2-(amino)ethyl amide;
N-{ D,L-2-(Hydroxyaminocarbonyl)methyl-4-methylpentanoyl }-L-3-
amino-2-dimethylbutanoyl-L-alanine, 2-(amino)ethyl amide;
4(S)-[3-Hydroxyaminocarbonyl-2(R)-(2-methylpropyl)propanoyl]amino-
1,2,3,4,5-tetrahydro-3H-2-benzazepin-3-one;
[4-(N-Hydroxyamino)-(2R)-isobutyl-3-methylsuccinyl]-L-phenylglycine-
N-methylamide;
4(S)-[2(R)-[ 1 (R)-Hydroxycarbamoyl-2-morpholinoethylJ-4-
methylvaleryl J amino-1,2,4,5-tetrahydro-3 H-2-benzazepine-3-one;
( 1R,4S)-4.-[(2R)-Hydroxycarbamoylmethyl-4-methylvaleryl]amino-3-oxo-
1,2,4,5-tetrahydro-3H-2-benzazepine-1-carboxylic acid;
3-[2-(N-Methylcarbamoyl)ethylsulfinyl]-5-methylhexanohydroxamic acid;
N-[(2-Thenoylmercapto-3-methyl)-butanoyl]-homocysteine thiolactone;
N-[ 1 {R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine,
N-phenylamide;
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N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-isoleucine,
N-phenylamide;
N-[ 1 (R)-Carboxy-ethylJ-a-(S)-(2-phenyl-ethyl)glycine-(L)-alanine,
N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-phenylalanine,
N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-serine-O-
benzyl ether, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-tryptophan,
N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl)-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(2-phenyl-
ethyl)glycine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-norleucine,
N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-valine,
N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-serine,
N-phenylamide hydrochloride;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-asparagine,
N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl)-a-(S)-(2-phenyl-ethyl)glycine-(L)-threonine,
N-phenylamide hydrochloride;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-lysine,
N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-glutamic acid,
N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-tyrosine,
N-phenylamide hydrochloride;
N-[1 (R)-Carboxy-5-(1,3-dioxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-
ethyl)glycine-(L)-leucine, N-phenylamide;
N-[ 1 (R)-Carboxy-5-( 1-oxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)-
glycine-(S)-leucine, N-phenylamide hydrochloride;
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N-[ 1 (R)-Carboxy-5-( 1-oxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)-
glycine-(S)-arginine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a,-(S)-(2-(3-hydroxyphenyl)-ethyl)glycine-(S)-
leucine, N-phenylamide hydrochloride;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-(4-methylphenyl)-ethyl)glycine-(S )-
leucine, N-phenylamide hydrochloride;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-(2'-thienyl)ethyl)glycine-(L)-leucine,
N-phenylamide;
N-[ 1 {R)-Carboxy-ethyl]-a-(S)-(2-(4-ethylphenyl)ethyl)glycine-(L)-
leucine, N-phenylamide;
N-[ 1 (R)-Carboxy-5-( 1-oxo-isoindolin-2-yl)pentyl]-a-{S)-(2-(4-
propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-(4-chlorophenyl)ethyl)glycine-(L)-
leucine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(2-
cyclohexyl-ethyl)glycine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(cyclohexyl)-
glycine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(cyclohexyl-
methyl)glycine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-[i-
naphthylalanine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-a-
naphthylalanine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-[(L)-glutamic acid,
a,S-bis-N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine,
N-cyclohexylamide;
N-[( 1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(4-
hydroxyphenylethyl)glycine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-phenylglycine,
N-phenyl amide;
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N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-glutamic acid,
Ng-benzylamide, Na-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-ornithine,
N-phenylamide;
N-[ I (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-arginine,
N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(3-
phenylpropyl)glycine, N-phenylamide;
N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-n-
octylglycine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4-
carboxyphenyl)amide;
N-[1(R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4-
trifluoromethylphenyl)amide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L}-leucine, N-(3-
pyridyl)amide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine,
N-(benzothiazol-2-yl)amide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S)-(2-(4-n-propylphenyl)ethyl)glycine-(L)-
leucine, N-phenylamide;
N-[ 1 (R)-Carboxy-ethyl]-a-(S}-(2-4-propylphenyl)ethyl)glycine-(L)-
arginine, N-phenylamide;
N-[ I (R)-Carboxy-ethyl]-a-(S)-(2-(3,4-dimethylphenyl-ethyl)glycine-(L)-
leucine, N-phenylamide;
(2-(((4-( 1, 3-Dihydro-1,3-dioxo-2H-isoindol-2-
yl)butyl)hydroxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine, N-
phenylamide;
(2-(((4-( 1,3-Dihydro-1-oxo-2H-isoindol-2-yl)butyl)hydroxyphosphinyl)-
methyl}-4-phenylbutanoyl)-L-leucine, N-phenylamide;
(2-(((4-( 1,3-Dihydro-1-oxo-2H-isoindol-2-yl)butyl)(2-methyl-1-( 1-
oxopropoxy)propoxy)phosphinyl)methyl)-4-phenylbutanoyl)-L-leucine,
N-phenyiamide;
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(2-((Hydroxylmethyl)phosphinyl)methyl)-4-phenylbutanoyl)-L-leucine,
N-phenylamide;
[[Hydroxyl I (R)-(N-(N-acetyl-L-prolyl-L-alanyl)-amino]-ethyl]-
phosphinyl]-methyl]-4-phenyl-butanoyl-L-leucyl, N-phenylamide;
[Hydroxy-[N-(N-(benzoyl)-L-prolyl)aminobutyl]phosphinyl]methyl]-4.-
phenyl-butanoyl-L-leucine, N-phenylamide;
[Hydroxy-[2-Methylpropyloxycarbonyi-aminobutyl]-phosphinyl]methyl]-
4-phenylbutanoyl-L-leucine, N-phenylamide;
[Hydroxy-[ 1-Methylethylaminocarbonyl-aminobutyl]-phosphinyl]methyl]-
4-phenylbutanoyl-L-leucine, N-phenylamide;
N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucinamide;
N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucine, N-phenylarnide;
N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucine, N-benzylamide;
N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-leucine, N-(2-phenylethyl)amide;
N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-phenylalaninamide;
N-(2-Thiomethyl-4.-phenylbutanoyl)-(L)-phenylalanine N-phenylamide;
N-(2-Thiomethyl-4-phenylbutanoyl)-(L)-phenylalanine N-benzylamide;
N-{2-Thiomethyl-4-phenylbutanoyl)-(L)-phenylalanine-b-alanine;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-1,5-pentanedioic acid 1-(L-leucine,
N-phenylamide)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-1,5-pentanedioic acid 1-(2LS)-t-
butyl)glycine, N-phenylamide)amide;
2(R)-(2-{4-(1-n-Propyl)phenyl)ethyl)-1,5-pentanedioic acid I-(2(S)-t-
butyl)glycine, N-(4-pyridylamide)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-1,5-pentanedioic acid 1-(L-arginine,
N-methylamide)amide;
2(R)-(2-(4-(I-n-Propyl)phenyl)ethyl)-4-methyl-I,5-pentanedioic acid
1-(L-leucine, N-phenylamide)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid
I-(2L)-t-butyl)glycine, N-phenylamide)amide;
2(R)-{2-(4-(1-n-Propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid
I-(2(S)-(4-thiazolylmethyl)glycine, N-phenylamide)amide;
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2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid
1-(2(S)-(3-pyridylmethyl)glycine, N-phenylamide)amide;
2()~-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid
1-{L-leucine, N-(4-pyridyl)amide)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid
1-(2(S)-(2-pyridylmethyl)glycine, N-phenylamide)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid
1-(L-arginine, N-phenylamide)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4.-methyl-1,5-pentanedioic acid
1-(L-phenylalanine, N-4-pyridylamide)amide;
2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-( 1-(4-(N-(2-oxoisoindolinyl))-
butyl))-1,5-pentanedioic acid 1-(L-leucine, N-phenylamide)amide;
2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-( 1-{4-(N-{2-oxoisoindolinyl))-but-
2-enyl))-1,5-pentanedioic acid 1-(L-leucine, N-phenylamide)amide;
2(R)-(2-(4-(4-Fluorophenyi)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid
1-(L-leucine, N-phenylamide)amide;
2{R)-(2-(4-(Phenyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid 1-(L-
leucine, N-phenylamide)amide;
2(R)-(2-(4-(4-Methoxyphenyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic
acid 1-(L-leucine, phenylamide)amide;
2(R)-(2-{4-(4-Methylphenyl)phenyl)ethyl)-4-methyl-1,5-pentanedioic acid
1-(L-leucine, phenylamide)amide;
2(R)-(2-(4-(4-Hydroxy-n-butyl)-phenyl)-ethyl)-4-methylpentanedioic acid
1-{S-leucine, phenylamide)amide;
2(R),4(S)-(2-{4-(3-Hydroxy-n-propyl)phenyl)ethyl)-4-methyl-1,5-
pentanedioic acid I-(L-leucine, N-phenylamide)amide;
2(R)-(2-Phenylethyl)-4-methyl-1,5-pentanedioic acid 1-(L-leucine,
N-phenylamide)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-1,5-pentanedioic acid I-(L-leucine,
N-ethylamide)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-1,5-pentanedioic acid 1-(L-leucine,
N-isopropylamide)amide;
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2(R)-{2-(4-(1-n-Propyl)phenyl)propyl)-1,5-pentanedioic acid 1-(2(S)-tert-
butyl-glycine, N-4-pyridyl)amide)amide;
2(R)-(3-(4-(1-n-Propyl)phenyl)propyl)-1,3-pentanedioic acid 1-(L-leucine,
N-phenylamide)amide;
2(R)-{2-(4-(1-n-Propyl)phenyl)ethyl)-4-hexyl-1,5-pentanedioic acid
1-(L-leucine, N-phenylamide)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-butyl-1,5-pentanedioic acid
1-(L-leucine, N-phenylamide)amide;
2(R)-(2-(4-( I -n-Propyl)phenyl)ethyl)-4.-(3-methylbenzyl)-1,5-pentanedioic
acid 1-(L-leucine, N-phenylamide)amide;
2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-(4-(2-benzimidazolyl)butyl)-1,5-
pentanedioic acid 1-(L-leucine, N-phenylamide)amide;
2(R)-{2-(4-( 1-n-Propyl)phenyl)ethyl)-4-(4-(2-benzthiazolyl)butyl}-1,5-
pentanedioic acid 1-(L-leucine, N-phenylamide)amide;
2(R}-(2-(4-( 1-n-Propyl)phenyl)ethyl )-4-(4-(2-benzoxazolyl)butyl)-1,5-
pentanedioic acid 1-(L-leucine, N-phenylamide)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
I-(L-leucine, N-phenylamide)amide 9-piperidineamide;
2(R)-(2-{4-{1-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
1-{L-leucine, N-methylamide)amide 9-phenylamide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
1-(L-leucine, N-methylamide)amide 9-tert-butylamide;
2(R)-(2-{4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
I-(L-leucine, N-methylamide)amide 9-benzylamide;
2(R)-(2-{4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
1-(L-leucine, N-methylamide)amide 9-morpholineamide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
1-(L-leucine, N-methylamide)amide 9-{1(R)-phenylethyl)amide;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
1-(L-leucine, N-methylamide)amide 9-( 1 (S)-phenylethyl)arnide;
2(R)-(2-{4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
1-(L-leucine, N-methylamide)amide 9-(N-methyl-N-phenyl)amide;
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2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
I-(L-leucine, N-methylamide)amide 9-(N'-methylpiperazine)amide trifluoroacetic
acid salt;
2(R)-(2-(4-(1-n-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
1-(L-leucine, N-methylamide)amide 9-(3-pyridyl)amide;
2(R)-(2-(4-(1-Propyl)phenyl)ethyl)-4-carboxy-1,9-nonanedioic acid
I-(L-leucine, N-methylamide)amide;
2(R)-(2-(4-(1-Propyl)phenyl)ethyl)-1,5-pentanedioic acid 1-((R)-(S-p-
methoxybenzyl)penicillamine, N-phenylamide)amide;
2(R)-(2-(4-(1-Propyl)phenyl)ethyl)-1,5-pentanedioic acid 1-((R)-(S-p-
methoxybenzyl)penicillamine sulfone, N-phenylamide)amide;
2-(2-(4-( I-Propyl)phenyl)ethyl)-4-( 1-(4-(2-phthalimido))butyl)-1,5-
pentandioic acid I-(L-leucine, N-methylamide)amide;
2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-(4-benzoylamino-1-butyl)- I ,5-
pentandioic acid 1-(L-leucine, N-methylamide)amide;
2(R)-(2-(4-{ I-n-Propyl)phenyl)ethyl)-4-(4-pivaloylamino-1-butyl)-1,5-
pentandioic acid I-{L-leucine, N-methylamide)amide;
2{R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-(4-phenylsulfonylamino-1-butyl)-
I,5-pentandioic acid 1-(L-leucine, N-methylamide)amide;
2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-(4-(N'-phenylureido)-1-butyl)-1,5-
pentandioic acid I-(L-leucine, N-methylamide)amide;
2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-(4-phenyloxycarbonylamino- I -
butyl)-1,5-pentandioic acid 1-(L-leucine, N-methylamide)amide;
2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-(4-N'-benzyloxycarbonylamino-L-
prolylamino)-1-butyl)-I,5-pentandioic acid I-(L-leucine, N-methylamide)amide;
2(R)-(2-(4-( 1-n-Propyl)phenyl)ethyl)-4-(4-cyclopentylamino-1-butyl)-1,5-
pentandioic acid 1-(L-leucine, N-methylamide)amide;
2(R)-(2-(4-( I -n-Propyl)phenyl)ethyl)-4-(4-(2-c arboxybenzoylamino)-1-
butyl)-1,5-pentandioic acid 1-{L-leucine, N-methylamide)amide;
2(R)-(2-(4-( 1-n-Propyl )phenyl)ethyl )-4-(4-cyano-1-butyl)- I ,5-pentandioic
acid 1-(L-leucine, N-phenylamide)amide;
N-[1(R)-Carboxyethyl]-a-(S)-(9-amino-n-nonyl)]glycine-(L)-leucine, N-
phenylamide;
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N-[1(R)-Carboxyethyl]-a-(S)-(n-octyl)]glycine-(L)-leucine, N-
phenylamide;
N-[ 1 (R)-Carboxyethyl]-a-(S)-(n-octyl)]glycine-(L)-arginine, N-
phenylamide;
N-[1(R)-Carboxyethyl]-a-(S)-(9-amino-n-nonyl)]glycine-(L)-arginine, N-
phenylamide;
N-[1(R)-Carboxyethyl]-a-(S)-(n-decyl)]glycine-{L)-leucine, N-
phenylamide;
1-(2-(4-Propylphenyl)ethyl)cyclopentane-1,3-dicarboxylic acid 1-(L-
leucine, N-phenylamide)amide;
1-(2-(4-Propylphenyl)ethyl)cyclohexane-1,3-dicarboxylic acid 1-(L-
leucine, N-phenylamide)amide;
N-[ 1 {R)-Carboxyethyl]-a-(S)-2-(4-fluorobiphenyl)-glycyl-(S)-2-(tert-
butyl)glycine, N-phenylamide;
3S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-
dihydrocarbostyril;
3S-[4-(N-Hydroxyamino)-2R-isobutyl-3S-acetylthio-
methylsuccinyl]amino-3,4-dihydrocarbostyril;
3S-[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-1-
methoxy-3,4-dihydrocarbostyril;
3S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxymethyl-
3,4-dihydrocarbostyril;
1-Carboxymethyl-3S-[4-N-hydroxyamino)-2R-isobutyl-3S-
methylsuccinyl]amino-3,4-dihydrocarbostyril;
3S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-1-
methoxyethoxymethyl-3,4-dihydrocarbostyril;
3S-[4-(N-Hydroxyamino)-2R-heptylsuccinyl]amino-1-methoxy-3,4-
dihydrocarbostyril;
7-Chloro-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-
methoxymethyl-3,4-dihydrocarbostyril;
3S-[4-(N-Hydroxyanuno)-2R-isobutylsuccinyl]amino-1-methoxyethyl-
3,4-dihydrocarbostyril;
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3S-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-
6,7-methylenedioxy-3,4-dihydrocarbostyril;
3R-[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-
6,7-methylenedioxy-3,4-dihydrocarbostyril;
2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl) (3-morpholin-4-yl-3-
oxopropyl)amino]-3-methyl-butyramide;
2-(R)-2-[(2-Benzylcarbamoylethyl)(4-methoxy-benzenesulfonyl)amino]-
N-hydroxy-3-methylbutyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) (2-[(pyridin-3-
yImethyl)carbamoyl]ethyl)amino)-3-methylbutyramide;
2-(R)-N-Hydroxy-2-([4-methoxybenzenesulfonyl]-[2-(methylpyridin-3-
ylmethylcarbamoyl)ethyl] amino)-3-methylbutyramide;
4-(3-[ 1-(R)-1-Hydroxycarbamoyl-2-methylpropyl)(4-
methoxybenzenesulfonyl)amino]propionyl)piperazine-1-carboxylic acid, tert-
butyl ester;
2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3-piperazin-1-
ylpropyl)amino)-3-methylbutyramide hydrochloride;
2-(R)-2-[(Benzylcarbamoylethyl)(4-methoxy-benzenesulfonyl)amino]-N-
hydroxy-3-methylbutyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl] [(2-morpholin-4-
ylethylcarbamoyl)methyl]amino]-3-methylbutyramide;
2-(R)-N-Hydroxy-2-{(4-methoxybenzenesulfonyl) ([(pyridin-3-
ylmethyl)carbamoyl]methyl)amino)-3-methylbutyramide;
2-(R)-3,3,3,-Trifluoro-N-hydroxy-2-[(methoxy-benzenesuIfonyl)(3-
morpholin-4-yl-3-oxopropyl)amino]propionamide;
2-(R)-N-Hydroxy-2-((4-phenoxybenzenesulfonyl)[2-methylpyridin-4-
ylmethylcarbamoyl)ether]amino)-3-methylbutyramide;
4-[4-Methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-1-
methylpiperidene-4-carboxylic acid hydroxyamide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)-[3-(4-methylpiperazin-
1-yl)-3- oxopropyl]amino)-3-methylbutyramide;
2-(R)-2-[(2-Carboxyethyl)(4-methoxybenzene-sulfonyl)amino]-N-
hydroxy-3-methylbutyramide;
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[(2-Carboxyethyl)(3,4-dimethoxybenzene-sulfonyl)amino]-N-hydroxy-
acetamide;
2-(R)-2-[(2-Carbamoylethyl)(4-methoxybenzene-sulfonyl)amino]-N-
hydroxy-3-methylbutyramide;
2-(R), 3-(R)-3, N-Dihydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3-
piperidin-1-ylpropyl)amino]-butyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)[3-(methylpyridin-3-
ylmethylcarbamoyl)propyl]amino)-3-methylbutyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) [2
(methylcarboxymethylcarbamoyl)ethyl]amino)-3-methyl-butyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)[( 1-methylpiperidin-4-
ylcarbamoyl)methyl] amino)-3-methylbutyramide;
2-(R)-N-Cyclohexyl-N-hydroxy-2-((4-methoxy-benzenesulfonyl)-[3-(4-
methylpiperazin-1-yl)-3-oxopropyl]amino)-acetamide;
2-(R)-N-Hydroxy-2-[(methoxybenzenesulfonyl)(3-moipholin-4-yl-[3-
oxopropyl)amino]-4-(morpholin-4-yl)butyrarnide;
[4-N-Benzyloxyamino)-2(R)-isobutylsuccinyl]-L-leucyl-L-alanine ethyl
ester;
[4-N-Benzyloxyamino)-2(R)-isobutylsuccinyl]-3(RS)-aminolaurolactam;
Na-[4-(N-Benzyloxyamino)-2(R)-isobutylsuccinyl]-Ne-(N-
benzyloxycarbonylglycyl)-L-lysyl-L-alanine ethyl ester;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine ethyl
ester;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine
isopentylamide;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-valylglycine ethylamide;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine
ethylamide;
Na-[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-Ne-
tert.butoxycarbonyl-L-lysylglycine ethylamide;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-O-methyl-L-
tyrosinylglycine ethyl ester;
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[4-(N-Hydroxyamino)-2(RS )-isobutylsuccinyl]-O-methyl-L-
tyrosinylglycine ethylamide;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucyl-L-alanine ethyl
ester;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylglycine isopentyl
ester;
[4-(N-Hydroxyamino)-2(R)-propylsuccinyl]-L-leucylglycine ethyl ester;
[4-(N-Hydroxyamino)-2(RS)-sec.butylsuccinyl]-L-leucylglycine ethyl
ester;
[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-L-leucyl-L-alanine;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinylJ-L-leucylglycine methyl
ester;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucylsarconsine ethyl
ester;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinylJ-L-leucyl-L-proline ethyl
ester;
[4-(1V-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-L-alanine
isopropyl ester;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-2-
oxopropylamide;
[4-{N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-2-
methoxyethylamide;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-leucine-2,2-
dimethoxyethylamide;
Na-[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-Ne-glycyl-L-lysine
methylamide;
Na-[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-Ne-(4-carboxybenzoyl)-
L-lysl-L-alanine ethyl ester;
Na-[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl]-Ne-(4-carboxybenzoyl)-
L-lysyl-L-alive;
[4-(N-Hydroxyamino)-2(R)-isobutylsuccinyl)-3(RS)-aminooctahydro-2H-
azonin-2-one;
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[4-(N-Hydroxyamino)-3(S)-methyl-2(R)-isobutyl-succinyl]-L-
leucylglycine ethyl ester;
[(3-Aminophthalimido)methyl][(RS)-4-methyl-2-[[(S)3-methyl-1-
(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid;
((RS)-4-Methyl-2-[[(S)-3-methyl-1-(methyl-
carbamoyl)butyl]carbamoyl]pentyl]( 1,8-naphthalenedi-
carboximidomethyl)phosphinic acid;
[(R or S)-4-Methyl-2-[[(R or S)-2-oxo-3-
azacyclotridecyl]carbamoyl]pentyl]( 1.8-
naphthalenedicarboximidomethyl)phosphinic acid;
N-[N-[(R or S)-2[[[[[N-[1-(Benzyloxy)carbonyl]-L-prolyl]-L-
leucyl]amino]methyl]hydroxyphosphinyl]-methyl]-4-methylvaleryl]-L-leucyl]-L-
alanine;
[[1,4-Dihydro-2,4-dioxo-3(2H)-quinazolinyl]-methyl][[(R or S)-4-methyl-
2-([(R or S)-2-oxo-3-azacyclotridecyl]carbamoyl]pentyl]phosphinic acid;
NZ-[(R)-Hydroxycarbamoylmethyl]-4-methylvaleryl]-N 1,3-dimethyl-L-
valinamide;
N2-[2(R or S)-[[[(5-Bromo-2,3-dihydro-6-hydroxy)-1,3-dioxo-1H-
bent[d,e]isoquinol-2-yl)methyl]-[(hydroxy)phosphinyl]methyl]-4-methylvaleryl]-
N 1,3-dimethyl-L-valinamide;
N2-[(R or S)-[[{R)-{Amino)((5-brorno-2,3-dihydro-6-hydroxy-1,3-dioxo-
1H-benz[d,e]isoquinol-2-yl)methyl](hydroxy)phosphinyl]methyl]-4-
methylvaleryl]-N3,1-dimethyl-L-valinamide hydrobromide;
N2-[2{R or S)-[ 1 (S)-(Hydroxycarbamoyl)ethyl-4-methylvaleryl]-N I,3-
dimethylvalinamide;
N2-[2(R)-[ I (R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyi]-4-
methylvaleryl]-N 1,3-dimethyl-L-valinamide;
N2-[2(R)-[ 1 (R or S)-(Hydroxycarbamoyl)-4-(methoxy-carbonyl)butyl]-4-
methylvaleryl]-N 1,3-dimethyl-L-valinamide;
M2-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-4-phenyl-butyl]-4-
methylvaleryl]-N 1,3-dimethyl-L-valinamide;
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N2-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-succinimidoethyl)-4-
methylvaleryl]-N 1,3-dimethyl-L-valinamide;
4-[2(R)-[ 1 (R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4-
methylvaleryl]morpholine;
4-[2(R)-[ 1 (R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4-
methylvaleryl]tetrahydro-1,4-thiazine;
1-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-phthalimidoethyl]-4-
methylvaleryl]-4-piperidinol;
1-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-(1,2-dimethyl-3,5-dioxo-1,2,4-
triazolidin-4-yl)ethyl]-4-methylvaleryl]piperidine;
4-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-(3-methyl-2,5-dioxo-1-
imidazolidinyl)ethyl]-4-methylvaleryl]tetrahydro-1,4-thiazine;
Hexahydro-2-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-
4-methylvaleryI]-N-methyl-3(S)-pyridazinecarboxamide;
1-[2(R)-(R or S)-(Hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-
imidazolidinyl)ethyl]-4-methylvaleryl]-4-piperidinol;
[4-(N-Hydroxyamino)-2(R or S)-heptylsuccinyl]-L-leucyl-L-leucine
ethylamide;
[4-(N-Hydroxyamino)-2(R or S)-nonylsuccinyl]-L-leucyl-L-leucine
ethylamide;
[4-(N-Hydroxyamino)-2(R or S)-heptyl-3(S)-methylsuccinyl]-L-leucyl-L-
leucine ethylamide;
(4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-
(phthalimidomethyl)succinyl]-L-leucyl-L-leucine ethylamide;
[4-(N-Hydroxyamino)-2(RS)-nonylsuccinyl]-L-tert.butylglycine
methylamide;
[4-(N-Hydroxyamino)r2(RS)-heptylsuccinyl]-L-phenylalanine
methylamide;
[4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-
phthalimidomethyl)succinyl]-L-tert.butylglycine methylamide;
[4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-(3-phenylpropyl)-succinyl]-
L-leucyl-L-leucine ethylamide;
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[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-leucine methylamide;
[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-leucine neopentylamide;
[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-alanyl-L-leucine
ethylamide;
[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-(Ne-phthaloyl)-lysyl-L-
leucine ethylamide;
[4-(N-Hydroxyamino)-2(RS)-undecylsuccinyl]-L-leucyl-L-leucine
ethylamide;
[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-phenylalanyl-L-leucine
ethylamide;
[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-nonalyl-L-leucine
ethylamide;
[4-(N-Hydroxyamino)-2(RS )-heptyIsuccinyl]-phenylalanine
tert.butylamide;
[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-tertbutylglycine
methylamide;
[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-neopentylglycine
methylamide;
[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-homophenylalanyl-L-
leucine ethylamide;
[4-(N-Hydroxyamino)-2(RS)-heptylsuccinyl]-L-cyclohexylalanine
methylamide;
[4-(N-Hydroxyamino)-2(RS)-isooctylsuccinyl]-L-phenylalanine
methylamide;
[4-(N-Hydroxyamino)-2(R)-heptylsuccinyl]-L-neonpentylglycine
methylamide;
[4-(N-Hydroxyamino)-2(R)-heptylsuccinyl]-(D or L)-[i,[3-
dimethylphenylalanine methylamide;
[4-(N-Hydroxyamino)-2{R)-heptylsuccinyl]-(D or L)-threo-[i-
methylphenylalanine methylamide;
[4-(N-Hydroxyamino)-2(R)-heptylsuccinyl]-DL-erthro-[i-
methylphenylalanine methylamide;
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[4-(N-Hydroxyamino)-2(R)-heptyl-3(R or S)-[(3-methyl-2,5-dioxo-I-
imidazolidinyl)methyl]succinyl]-L-leucyl-L-leucine ethylamide;
N2-(3-Cyclobutyl-2(R or S)-[(hydroxycarbamoyl)-methyl]-propionyl]-
N 1,3-dimethyl-L-valinamide;
N2-[3-Cyclopropyl-2(R or S)-((hydroxycarbamoyl)-methyl]-propionyl]-
N 1,3-dimethyl-L-valinamide;
N2-[3-Cyclopentyl-2(R or S)-[(hydroxycarbamoyl)-methyl]-propionyl]-
N 1,3-dimethyl-L-valinamide;
N2-(3-Cyclopropyl-2(R)-[1(R or S)-[(hydroxy-carbamoyl)-2-(3,4,4-
trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-N 1,3-dimethyl-L-
valinamide;
N2-(3-Cyclopropyl-2(R)-[1(R or S)-[(hydroxy-carbamoyl)-4-
phenylbutyl)]propionyl]-N 1,3-dimethyl-L-valinamide;
N2-[3-Cyclobutyl-2(R)-[ 1 (R or S)-(hydroxy-carbamoyl)-4-
phenylbutyl]propionyl]-N 1,3-dimethyl-L-valinamide;
N2-[3-Cyclopentyl-2(R)-[ 1 (R or S)-(hydroxycarbamoyl)-4-
phenylbutyl]propionyl]-N 1,3-dimethyl-L-valinamide;
I-[3-Cyclopropyl-2(R)-[I(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-
trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine;
1-(3-Cyclopropyl-2(R)-[ I (R or S)-(hydroxy-carbamoyl)-2-(3,4,4-
trimethyl-2,5-dioxo- I-imidazolidinyl)ethyl]propionyl]-4-piperidinol;
1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-I-imidazolidinyl)ethyl]propionyl]piperidine;
1-[3-Cyclobutyl-2(R)-[ 1 (R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-I-imidazolidinyl)ethyl]propionyl]-4-piperidinol;
1-(3-Cyclopentyl-2(R)-[I(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-
trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol;
I-[3-Cyclopentyl-2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-
trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine;
3-[3-Cyclobutyl-2(R)-[1(R or S)-{hydroxycarbamoyl)-2-(3,4,4-trimethyl-
2,S-dioxo-I-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane;
3-[3-Cyclopropyl-2(R)-[ 1 (R or S)-(hydroxy-carbamoyl)-2-(3,4,4-
trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-
azabicyclo[3.2.2]nonane;
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3-[3-Cyclopentyl-2(R)-[ 1 (R or S)-(hydroxy-carbamoyl)-2-(3,4,4-
trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-
azabicyclo[3.2.2]nonane;
1-(3-Cyclohexyl-2(R)-[1{R or S)-(hydroxycarbamoyl)-2-{3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethylJpropionyl]piperidine;
4-[3-Cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethyl]propionylJtetrahydro-1,4-thiazine;
4-[3-Cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazine S,S-
dioxide;
4-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazine;
3-[3-Cyclopentyl-2(R)-[ 1 (R or S)-(hydroxycarbamoyl}-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-5,5-dimethyl-N-propyl-[4(R)-
thiazolidinecarboxamide;
4-[3-Cyclopentyl-2(R)-[ 1 (R or S)-(hydroxycarbarnoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]morpholine;
3-[3-Cyclopentyl-2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-
trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-N,S,S-trimethyl-4(R)-
thiazolidinecarboxamide;
4-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-phenylpiperazine;
4-[3-Cyclobutyl-2(R)-[ 1 (R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethylJpropionyl]morpholine;
1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethylJpropionyl]pyrrolidine;
8-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-1,4-dioxa-8-azaspiro[4,5]decane;
1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-methoxypiperidine;
1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]octahydroazocine;
1-[3-Cyclobutyl-2(R)-(1(R or S)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4-
dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine;
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1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-
2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]hexahydroazepine;
1-[3-Cyclobutyl-2(R)-[2-(hexahydro-1,3-dioxo-pyrazolo[ 1,2-
a][1,2,4]triazol-2-yl)-1(R or S)-(hydroxycarbamoyl)ethyl]propionyl]piperidine;
1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-
phthalimidoethyl]propionyl]piperidine;
2-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-4-phenylbutyl]nonanoyl]-
hexahydro-N-methyl-3(S)-pyridazinecarboxamide;
N-Cyclohexyl-hexahydro-2-[2(R)-[ 1 (RS)-(hydroxycarbamoyl)-4--
phenylbutyl]nonanoyl]-3(S)-pyridazinecarboxamide;
Hexahydro-2-[2(R)-[ 1 (RS)-(hydroxycarbamoyl)-4.-phenylbutyl]nonanoyl]-
N-(2,2,6,6-tetramethyl-4-piperidinyl)-3(S)-pyridazinecarboxamide;
1-[2(R)-[ 1 (R or S)-Hydroxycarbamoyl)-4-
phenylbutyl]nonanoyl]piperidine;
N2-[2(R)-[ 1 (RS )-(Hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-
imidazolidinyl)ethyl]nonanoyl]-N 1-methyl-L-prolinamide;
1-[2(R)-[1(R or S)-(Hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1--
imidazolidinyl)ethyl]nonanoyl]piperidine;
Hexahydro-2-[2(R)-1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-
dioxo-1-imidazolidinyl)ethyl]nonanoyl]-N-methyl-3(S)-pyridazinecarboxamide;
Hexahydro-2-[2(R or S)-[ 1 (S)-(hydroxycarbamoyl)-3-
phenylpropyl] undecanoyl]-N-methyl-3 (S )-pyridazinecarboxamide;
Hexahydro-2-[2(R or S)-[ 1 (S)-(hydroxycarbamoyl)-3-
phenylpropyl]undecanoyl]-N-methoxy-N-methyl-3(S)-pyridazinecarboxamide;
Hexahydro-2-[2(R or S)-[( 1 (S)-(hydroxycarbamoyl)-3-phenylpropyl]-
undecanoyl]-N-( 1,2,2,6,6-pentamethyl-4-piperidinyl)-3(S)-pyridazine-
carboxamide;
Hexahydro-2-[2(R or S)-[1(S)-(hydroxycarbamoyl)ethyl]undecanoyl]-N-
methyl-3(S)-pyridazinecarboxamide;
Hexahydro-2-[2(R or S)-[1(S)-(hydroxycarbamoyl)-3-
phenylpropyl]nonanoyl]-N-methyl-3(S)-pyridazinecarboxamide;
Hexahydro-2-[2(R or S)-[1(S)-(hydroxycarbamoyl)ethyl]nonanoyl]-N--
methyl-3 (S )-pyridazinecarboxamide;
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1-[2(R or S)-[1(S)-(Hydroxycarbamoyl)ethyl]undecanoyl]piperidine;
1-[2-(R or S)-[1(S)-(hydroxycarbamoyl)-3-
phenylpropyl]undecanoyl]piperidine;
Hexahydro-2-[2(R or S)-[1(S)-(hydroxycarbamoyl)-3-phenylpropyl]-
undecanoyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl )-3 (S )-
pyridazinecarboxamide;
Hexahydro-2-[2(R or S)-[l(S)-(hydroxycarbamoyl)ethyl]undecanoyl]-N-
(2,2,6,6-tetramethyl-4-piperidinyl)-3(S)-pyridazinecarboxamide;
1-[2(R or S)-[1(S)~~(hydroxycarbamoyl)-4-phenylbutyl]undecanoyl]-
piperidine;
4-[2(R or S)-[1(S}-(hydroxycarbamoyl)-4-phenylbutyl]undecanoyl]-
morpholine;
1-(Benzyloxycarbonyl)-hexahydro-2-[2(R)-[(R or S)-(hydroxycarbamoyl)-
4-phenylbutyl] nonanoyl]-N-(a(S)-methylbenzyl)-3 (S)-pyri dazinecarboxamide;
N-[(2R}-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5(carboxy)pentanoyl]-L
phenylalanine N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-
(phenylmethoxy)hexanoyl]-L-phenylalanine N-methylamide; N-[(2R)-2-[2'-
(Hydroxyamino)-2'-(oxo)ethyl]-6(propylamino)-6-(oxo)hexanoyl]-L-
phenylalanine N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-(6RS)-6-
(hydroxy)heptanoyl]-L-phenylalanine N-methylamide;
(2S)-N-2-[(2'R)-2'-[2"-(Hydroxyamino}-2"-(oxo)ethyl]-6'-
(hydroxy}hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
(2S )-N-2-[(2' R)-2' -[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6' -
(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
N-[(2'R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(4'-
oxobutylamino)hexanoyl]-L-phenylalanine N-methylamide;
2(S)-N-2-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-(oxo)-6'-
(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
N-[{2R)-2-[( 1' S)-1'-{Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6-
(phenylmethoxy)hexanoyl]-L-phenylalanine N-methylamide;
N-[(2R)-2-[( 1'S)-1'-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(oxo)-
6-(propylamino)hexanoyl]-L-phenylalanine N-methylamide;
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(2S )-N-2 [(2' R)-[( 1 "R)-1 "-( 1,3-Dihydro-1,3-dioxo-2H-i soindol-2-
yl)methyl-2"-(hydroxyamino)-2"-(oxo~thyl]-6'-
(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2' -(oxo)ethyl]-6-(oxo)-6-
(propylamino)hexanoyl]-L-phenylalanine N-2-phenylethylamide;
(2S )-N-2-[(2' R)-2'-[( 1 "S )-1 "-(Methyl)-2"-(hydroxyamino)-2"-
(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-
phenylethylamide;
(2S)-N-2-[(2'R)-2'-[(1"S)-1"-(Methyl)-2"- (hyroxyamino)-2"-(oxo)ethyl]-
6'-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-
phenylethylamide;
(2S)-N-2-[(2' R)-2'-[( 1 "S)-1 "-(Methyl)-2"-(hydroxyamino)-2"-
(oxo)ethyl]-6'-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid
N-2-(4'-sulfamoyl)phenylethylamide;
(2S)-N-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo~thyl]-6'-
(phenylmethoxy)hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4'-sulfamoyl)-
phenylethylamide;
N-[2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6'-(phenyl-
methoxy)hexanoyl]-L-(3,5-dimethyl)phenylalanine N-2-(4'-
sulfamoyl)phenylethylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-
methoxy)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-
sulfamoyl)phenylethylamide;
(2S)-N-2'-[(2'R)-2'-[2"-.(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-
methyl)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)-
phenylethylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[( 1-
oxo)butylamino]hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4'-sulfamoyl)-
phenylethylamide;
(2S)-N-2-[(2'R)-2'-[( 1 "S)-1 "-(Methyl)-2"-(hydroxyamino)-2"-
(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-
methylamide;
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(2S)-N-2-[(2' R)-2'-[( I "S)- I "-(2-Methylpropyl)-2"-(hydroxyamino)-2"-
(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-
methylamide; N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenoxy)-
hexanoyl]-L-phenylalanine N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-(phenoxy)heptanoyl]-L-
phenylalanine N-methylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-
(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-
phenylethylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-
(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)-
phenylethylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5-
(phenylmethoxy)pentanoyl]-L-phenylalanine N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-
(phenylmethoxy)heptanoyl]-L-phenylalanine N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenyloxy)hexanoyl]-L-
phenylalanine N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-[(phenyloxy)heptanoyl]-
L-phenylalanine N-methylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(2-
phenethylamino)-6'-(oxo)hexanoyl]amino-3,3-dimethylbutanoic acid N-
methylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-
methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-
chlorophenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(3-
methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
(2S)-N-2'-[(2'R)-2'-(carboxymethyl)-6'-(3-
methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methyiamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5-(carboxy)pentanoyl]-L-
phenylalanine N-methylamide;
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N-[(2R)-2-[2'-(Hydroxyamino)-2' -(oxo)ethyl]-6-
(phenylmethoxy)hexanoyl]-L-phenylalanine N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6- (propylamino)-6-
(oxo)hexanoyl]-L-phenylalanine N-methylamide;
N-[(2R)-2-(2'-(Hydroxyamino)-2'-(oxo)ethyl]-(6RS)-6-
(hydroxy)heptanoyl]-L-phenylalanine N-methylamide;
(2S}-N-2-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-
(hydroxy)hexanoyl]amino-3,3-dimethylbutaroic acid N-methylanude;
(2S)-N-2-[(2'R)-2'-[2"-(Hydroxyamino}-2"-(oxo)ethyl]-6'-
(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylarnide;
N-[(2'R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-{4'-
oxobutylamino)hexanoyl]-L-phenylalanine N-methylamide;
2(S)-N-2-[(2' R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-(oxo)-6'-
(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
N-[(2R)-2-[(1'S)-1'-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6-
{phenylmethoxy)hexanoyl]-L-phenylalanine N-methylamide;
N-[(2R)-2-[(1'S)-1'-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl]-6-(oxo)-6-
(propylamino)hexanoyl]-L-phenylalanine N-methylamide;
(2S)-N-2[(2'R)-[( 1"R)-1 "-{ 1,3-dihydro-1,3-dioxo-2H-isoindol-2-
yl)methyl-2"-(hydroxyamino)-2"-(oxo)ethyl)-6'-
(phenylmethoxy)hexanoyl]amino-3,3-dirnethylbutanoic acid N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(oxo)-6-
(propylamino)hexanoyl]-L-phenylalanine N-2-phenylethylamide;
(2S )-N-2-[(2' R)-2'- [ ( 1 "S )-1 "-(Methyl )-2"-(hydroxyamino)-2"-
(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-
phenylethylamide;
(2S)-N-2-[(2'R)-2'-[( 1"S)-1"-(Methyl)-2"-(hydroxyamino)-2"-
(oxo)ethyl]-6'-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid
N-2-phenylethylamide;
(2S)-N-2-[(2'R)-2'-[( 1 "S)-1 "-(Methyl)-2"-(hydroxyamino)-2"-
(oxo)ethyl]-b'-(oxo)-6'-(propylamino)hexanoyl]amino-3,3-dimethylbutanoic acid
N-2-(4'-sulfamoyl)phenylethylamide;
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(2S)-N-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-
(phenylmethoxy)hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4'-sulfamoyl)-
phenylethylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5'-
(phenylmethoxy)hexanoyl]-L-(3,5-dimethyl)phenylalanine N-2-(4'-
sulfamoyl)phenylethylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-
methoxy)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-
sulfamoyl)phenylethylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-
methyl)phenoxy]hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)-
phenylethylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[( 1-
oxo)butylamino]hexanoyl]amino-3-cyclohexylpropionic acid N-2-(4'-sulfamoyl)-
phenylethylamide;
(2S )-N-2-[ (2' R)-2' -[( 1 "S )-1 "-(Methyl)-2"-( hydroxyamino)-2"-
(oxo)ethyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-
methylamide;
(2S)-N-2-[(2'R)-2'-[( 1 "S)-1 "-(2- Methylpropyl)-2"-(hydroxyamino)-2"-
(oxo~thyl]-6-(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-
methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenoxy)hexanoyl]-L-
phenylalanine N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-(phenoxy)heptanoyl]-L-
phenylalanine N-methylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino}-2"-(oxo)ethyl]-6'-
(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-
phenylethylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-
(phenylmethoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)-
phenylethylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-5-
(phenylmethoxy)pentanoyl]-L-phenylalanine N-methylamide;
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N-[(2R)-2-[2'-(Hydroxyamino)-2' -(oxo)ethyl)-7-(phe-
nylmethoxy)heptanoyl]-L-phenylalanine N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-6-(phenyloxy)hexanoyl]-L-
phenylelanine N-methylamide;
N-[(2R)-2-[2'-(Hydroxyamino)-2'-(oxo)ethyl]-7-[(phenyloxy)heptanoyl]-
L-phenylalanine N-methylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(2-
phenethylamino)-6'-(oxo)hexanoyl]amino-3,3-dimethylbutanoic acid N-
methylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-
methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
(2S)-N-2'-[(2'R)-2'-[2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(4-
chlorophenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
(2S)-N-2'-[(2'R)-2'-(2"-(Hydroxyamino)-2"-(oxo)ethyl]-6'-[(3-
methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
(2S)-N-2'-[(2'R)-2'-(Carboxymethyl)-6'-(3-
methylphenoxy)hexanoyl]amino-3,3-dimethylbutanoic acid N-methylamide;
(3R, lOS)-5-Methyl-3-(9-oxo-1,8-diazatricyclo[ 10.6.1.0]nonadeca-
12( 19),13( 18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid;
(3R,lOS)-N Hydroxy-5-methyl-3-(9-oxo-1,8-
diazatricyclo[ 10.6.1.0]nonadeca-12( 19),13( 18),14,16-tetraen-10-
ylcarbamoyl)hexanamide;
(3R,11S)-N Hydroxy-5-methyl-3-( 10-oxo-1,9-diazatricyclo[ 11.6.1.0]eicosa-
13(20),14( 19),15,17-tetraen-11-ylcarbamoyl)hexanamide;
(3R,9S)-5-Methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0] octadeca-
11 ( 18),12( 17),13,15-tetraen-9-ylcarbamoyl)hexanoic acid;
(3R,9S)-N Hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0]octadeca-
11 ( 18),12( 17),13,15-tetraen-9-ylcarbamoyl)hexanamide;
( l OS)-[4-Methyl-2-(9-oxo-1,8-diazatricyclo[ 10.6.1.0]nonadeca-
12( 19),13( 18),14,16-tetraen-10-ylcarbamoyl)pentyl]-(quinolin-2-
ylthiomethyl)phosphinic acid;
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(3R,lOS)-N Hydroxy-5-methyl-2-methoxycarbonyl-3- (9-oxo-1,8-
diazatricyclo[ 10.6.1.0]nonadeca-12( 19),13( I 8),14,16-tetraen-10-
ylcarbamoyl)hexanamide;
N (4-Methyl-2-carboxymethylpentanoyl)-L-leucine-N'-(4-
methoxycarbonylphenyl)carboxamide;
N-(4-Methyl-2-(N"-hydroxycarbamoyl)methylpentanoyl)-L-leucine-N'-(4-
methoxycarbonylphenyl)carboxamide;
N (4-Methyl-2-(N"-hydroxycarbamoyl)methylpentanoyl)-L-leucine-N'-(4-
carboxyphenyl)carboxamide;
N (4-Methyl-2-(N"-hydroxycarbamoyl)methylpentanoyl)-L-tryptophan-
N'-(4-carboxyphenyl)carboxamide;
N (4-Methyl-2-(N"-hydroxycarbamoyl)methylpentanoyl)-L-
cyclohexylglycine-N'-(4-methoxycarbonylphenyl)carboxamide;
N-(4-Methyl-2-(N"-hydroxycarbamoyl)methylpentanoyl)-L-t-leucine-N'-
(4-methoxycarbonylphenyl)carboxamide;
(3R,1 OS)-6-Biphenyl-4-yl)-3-(9-oxo-1,8-diazatricyclo[ 10.6.1.0]onadeca-
12(19),13(18),14,16-tetraen-10-ylcarbamoyI)hexanoic acid;
(3R, lOS)-3-(9-Oxo-1,8-diazatricyclo[ 10.6.1.0]nonadeca-
12( 19),13( 18),14,16-tetraen-10-ylcarbamoyl)-5-(thiophen-2-y1)pentanoic acid;
(3R, l OS)-3-Cyclopentyl-3-(9-oxo-1,8-diazatricyclo[ 10.6.1.0]nonadeca-
12( 19),13( 18),14,16-tetraen-10-ylcarbamoyl)propionic acid;
(3R, l OS)-4-Cyclopentyl-3-(9-oxo-1,8-diazatricyclo[ 10.6.1.0]nonadeca-
12( 19),13( 18),14,16-tetraen-10-ylcarbamoyl)butanoic acid;
(3R, lOS)-4-Cyclopropyl-3-(9-oxo-1,8-diazatricyclo[ 10.6.1.0]nonadeca-
12( 19),13( 18),14,16-tetraen-10-ylcarbamoyl)butanoic acid;
(3R, lOS)-5-Methyl-3-(9-oxo-1,8-diazatricyclo[ 10.6.1.0]nonadeca-
12( 19),13( 18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid;
(3R, IOS)-N Hydroxy-5-methyl-3-(9-oxo-1,8-
diazatricyclo[ 10.6.1.0)nonadeca-12( 19),13( 18),14,16-tetraen-10-
ylcarbamoyl)hexanamide;
(3R,11S)-N Hydroxy-5-methyl-3-(10-oxo-1,9-
diazatricyclo[ 11.6.1.0]eicosa-13 (20),14( 19),15,17-tetraen-11-
ylcarbamoyl)hexanamide;
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(3R,9S)-N 5-Methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0]octadeca-
11 ( 18),12( 17),13,15-tetraen-9-ylcarbamoyl)hexanoic acid;
(3R,9S)-N-Hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0]octadeca-
11 ( 18),12( 17),13, I S-tetraen-9-ylcarbamoyl)hexanamide;
(IOS)-2-Mercaptomethyl-4-methyl-N (9-oxo-1,8-
diazatricyclo[ 10.6.1.0]nonadeca-12( 19),13( 18),14,16-tetraen-10-
ylcarbamoyl)pentanamide;
(lOS)-2-Acetylthiomethyl ~4-methyl-N-(9-oxo-1,8-
diazatricyclo[ 10.6. I .0]nonadeca-12( 19),13( 18),14,16-tetraen-10-
ylcarbamoyl)pentanamide;
(3R,1 OS)-2-(Methanesulfonamidomethyl )-5-methyl-3-(9-oxo-1, 8-
diazatricyclo[ 10.6.1.0]nonadeca-12( 19),13( 18),14,16-tetraen-10-
ylcarbamoyl)hexanoic acid;
(3R,1 OS)-2-(3-Ethylureidomethyl)-5-methyl-3-(9-oxo-1,8-
diazatricyclo[ 10.6.1.0]nonadeca-12{ 19),13( 18),14,16-tetraen-10-
ylcarbamoyl)hexanoic acid;
(3R,9S)-N-Hydroxy-2-hydroxy-5-methyl-3-(8-oxo-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12( 17),14,16-tetraen-9-
ylcarbarnoyl)hexanamide or its (2S,3R,9S) stereoisomer;
(3R,IOS)-N Hydroxy-5-methyl-2-methoxycarbonyl-3-(9-oxo-1,8-
diazatricyclo[ 10.6.1.0]nonadeca-12( 19),13( I 8),14,16-tetraen-10-
ylcarbamoyl)-
hexanamide;
(3R,9S)-5-Methyl-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca-
1 I ( 18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid;
(3R,9S)-3-Cyclobutylmethyl-N-(8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)succinamic
acid;
(3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca-
11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)-5-phenoxy-pentanoic acid;
(3R,9S)-5-(4-Chlorophenoxy)-3-(8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)pentanoic
acid;
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(3R,9S )-5-(4-Chlorophenoxy)-3-(8-axo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18), I2,14,16-tetraen-9-
ylcarbamoyl)pentanoic
acid ethyl ester;
(3R,9S)-3-(8-Oxo-1,7-diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-
tetraen-9-ylcarbamoyl)pentanoic acid ethyl ester;
(3R,9S)-6-(4-Hydroxy-phenyl)-3-(8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)hexanoic
acid;
(3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca-
11 ( 18), I2,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoic acid;
(3R,9S)-6-[4-(3-Hydroxy-propoxy)-phenyl]-3-(8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18 ),12,14,16-tetraen-9-
ylcarbamoyl)hexanoic
acid;
(3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca-
11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)-5-(4-phenoxy-phenyl)pentanoic acid;
(3R,9S )-6-[4-(2-Hydroxy-ethox y)-phenyl]-3-(8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)hexanoic
acid;
(3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca-
11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)-6-[4-(2-pyrrolidin-1-yl-
ethoxyphenyl]hexanoic acid;
(3R,9S)-6-(4-Methoxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-
octadeca-11 ( 18), I2,14,16-tetraen-9-ylcarbamoyl)hexanoic acid;
(3R,9S)-6-[4-(2-Methoxy-ethoxy)-phenyl]-3-(8-oxo-4-ox a-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)hexanoic
acid;
(3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca-
11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)-5-phenyl-pentanoic acid;
(3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca-
11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)-6-phenyl-hexanoic acid;
(3R,9S)-6-(3-H ydroxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-
octadeca-11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid;
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(3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca-
11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)-6-[4-(3-piperidin-1-yl-
propoxy)phenyl]hexanoic acid;
(3R,9S )-6-[4-(3-Dimethylamino-propoxy)-phenyl]-3-(8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)hexanoic
acid;
(3R,9S)-6-[4-(2-Dimethylamino-ethoxy)-phenyl]-3-(8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)hexanoic
acid;
(3R,9S)-6-(4-Cyano-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-
octadeca-11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid;
(3R,9S)-6-Naphthalen-2-yl-3-(8-oxo-4-ox a-1,7-diazatricyclo[9.6.1.0]-
octadeca-11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid;
(3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.O]octadeca-
11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)-6-(4-pyrrol-1-yl)hexanoic acid;
(3R,9S)-6-(4-Hydroxy-3-methyl-phenyl)-3-(8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)hexanoic
acid;
(3R,9S)-6-(4-Benzylox y-phenyl)-3-( 8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)hexanoic
acid;
(3R,9S)-6-(4-(4-Aminobutoxy-phenyl)]-3-(8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)hexanoic
acid;
(3R,9S)-S-(4-Methoxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-
octadeca-11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)pentanoic acid;
(3R,9S)-6-(4-Amino-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]-
octadeca-11 ( 18),12,14,16-tetraen-9-ylcarbamoyl)hexanoic acid;
(3R,9S)-3-(8-Oxo-4-oxa-1,7-diazatricyclo[9.6.1.0]octadeca-
11 { 18),12,14,16-tetraen-9-ylcarbamoyl)-6-[4-(pyridin-4-
ylmethoxy)phenyl]hexanoic acid;
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(3R,9S )-6-(4-Acetylamino-phenyl)-3-(8-oxo-4-oxa-1,7-
diazatricyclo[9.6.1.0]octadeca-11 ( 18),12,14,16-tetraen-9-
ylcarbamoyl)hexanoic
acid;
Na-[[3-(N-Hydroxycarbamoyl)-4-methylthio-2-propoxymethyl]butylyl]-
N,O-dimethyltyrosine amide;
Na-[[3-(N-Hydroxycarbamoyl)-4-isopropylthio-2-
propoxymethyl]butylyl]-N,O-dimethyltyrosine amide;
Na-[[3-(N-Hydroxycarbamoyl)-2-propylthio]butylyl]-N,O-
dimethyltyrosine amide;
N-[N-( 1-Phosphono-3-phenylpropyl )-(S )-leucyl ]-(S )-phenyl al anine-N-
methylamide;
N-[N-( 1-Phosphono-3-(4-bromo-1,8-naphthalene-dicarboximido)propyl)-
(S)-leucyl]-(S)-phenylalanine methylamide;
N-[N-( 1-Phosphono-3-(benzyloxycarbonylamino)propyl)-(S)-leucyl]-(S)-
phenylalanine methylamide;
N-[N-( 1-Phosphono-3-(2-hydroxyphenyl)propyl)-(S)-leucyl]-(S)-
phenylalanine methylamide;
N-[N-( 1-Phosphono-3-{methylmercapto )propyl )-(S )-leucyl ]-(S )-
phenylalanine-N-methylamide;
N-[N-( 1-Phosphono-3-(methylsulphinyl)propyl)-(S)-leucyl]-(S)-
phenylalanine-N-methylamide;
N-[N-( 1-Phosphono-3-(methylsulphonyl)propyl)-(S)-leucyl]-(S)-
phenylalanine-N-methylamide;
N-[N-( 1-Phosphono-3-( 1,8-naphthalenedicarboximido)propyl}-(S)-leucyl]-
(S)-tryptophan-N-methylamide;
N-[N-( 1-Phosphono-3-( 1,8-naphthalenedicarboximido)propyl)-(S)-leucyl]-
(S)-lysine-N-methylamide;
N-[N-( 1-Phosphono-3-{ 1,8-naphthalenedicarboximido)propyl)-(S)-leucyl]-
(-)-aminoazacyclotridecan-2-one;
N-[N-(1-Phosphono-3-( 1,8-naphthalenedicarboximido)propyl)-(S)-leucyl]-
(S)-lysine-N-(aminoethyl)amide;
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N-[N-( I -Phosphono-3-( I ,8-naphthalenedicarboxinudo)propyl )-(S )-leucyl ]-
{S)-Lysine-N-(ethylpyrrolidine)amide;
N-[N-( 1-Phosphono-3-( 1,8-naphthalenedicarboximido)propyl)-(S)-leucyl]-
(S)-lysine-N-(ethyl-N-methylpiperazine)amide;
N-[N-( 1-Phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5]decyl)]propyl)-(S)-
leucyl]-(S)-phenylalanine-N-methylamide; and
N-[N-( 1-Phosphono-3-[8-(7,9-dioxo-8-azaspiro[4,5Jdecyl)]propyl)-(S)-
leucyl]-(S)-lysine-N-methylamide.
As noted above, numerous inhibitors of matrix metalloproteinases are
known. A large number of inhibitors are characterized as hydroxamic acid-based
and/or carboxylic acid-based compounds. Typical of such compounds are those
described in the following references, all of which are incorporated herein by
reference, since all of the disclosed compounds can be used in the method of
this
invention.
US 4599361 (Searle)
EP-A-2321081 (ICI)
EP-A-02368?2 (Roche)
EP-A-0274453 (Bellon)
WO 90/05716 (British Biotechnology)
WO 90/05719 (British Biotechnology)
WO 91/02716 (British Biotechnology)
WO 92/09563 (Glycomed)
US 5183900 (Glycomed)
US 5270326 (Glycomed)
WO 92/17460 (Smith-Kline Beecham)
EP-A-0489577 (Celltech)
EP-A-0489579 (Celltech)
EP-A-0497192 (Roche)
US 5256657 (Sterling Winthrop)
WO 92/13831 (British Biotechnology)
WO 92/22523 {Research Corporation Technologies)
WO 93/09090 (Yamanouchi)
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WO 93/09097 (Sankyo)
WO 93/20047 (British Biotechnology)
WO 93/24449 ~ (Celltech)
WO 93/244 (Celltech)
EP-A-0574758 (Roche)
WO 94/02447 (British Biotechnology)
WO 94/02446 (British Biotechnology)
WO 97/27174 (Shionogi)
An especially preferred group of compounds to be employed in the present
method are those described in WO 95/35275 and WO 95/35276, both of which are
incorporated herein by reference. Typical compounds from within these groups
to
be employed include:
N-Hydroxy-2-[ [(2-(4-methoxy-phenoxy)-ethyl-(toluene-4-sulfonyl)-
amino]-acetamide;
N-Hydroxy-2-[(4-phenoxy-ethyl)-toluene-4-sulfonyl) amino]-acetamide;
N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-nonyl-amino]-acetamide;
2-[-Decyl-(toluene-4-sulfonyl)-amino]-N-hydroxy-acetamide;
2-Benzyl-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide;
N-Hydroxy-2-[(2-methoxy-benzyl)-(octane-1-sulfonyl)-amino]-acetamide;
2-[(2-Ethoxy-benzyl)-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide;
N-Hydroxy-2-[(naphthalen-2-yl-methyl)-(octane-1-sulfonyl)-amino]-
acetamide;
2-[(4-Chloro-benzyl)-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide,
and salts, solvates, or hydrates thereof.
Another class of matrix metalloproteinase inhibitors are aryl sulfonamides
of the formula
1
Ar-S-N C-C-NHOH
O CH2R R2
where Ar is carbocyclic or heterocyclic aryl, and R, Rl, and R2 include
hydrogen,
alkyl, aryl, heteroaryl, amino, substituted and disubstituted amino. These
compounds are disclosed in European Patent Number 0606046, incorporated
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herein by reference. Specific compounds to be employed in the present method
include:
N-Hydroxy-2-[[4-methoxybenzenesulfonyl](isobutyl) amino]acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl](cyclo-hexylmethyl)aminoJ-
acetamide;
N-Hydroxy-2-[ [4-methoxybenzenesulfonylJ (cyclo-
hexyl)amino]acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonylJ(phenethyl) aminoJacetamide;
N-H ydroxy-2-[ [4-methoxybenzenesulfonyl] (3-
methylbutyl)amino] acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl](sec-butyl)amino]acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl](tert-butyl)amino]acetamide;
N-Hydroxy-2-[ [4-methoxybenzenesulfonyl] (4-
fluorobenzyl)amino]acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl](4-
chlorobenzyl)amino]acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl] (isopropyl)-amino]acetamide;
N-Hydroxy-2-[ [4-methoxybenzenesulfonylJ (4-
methylbenzyl)amino]acetamide;
4-N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-
amino]-1-[dimethylaminoacetyl]-piperidine hydrochloride;
4-N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-
amino]-1-[3-picolylJ-piperidine dihydrochloride;
4-N-Hydroxy-carbamoyl]-4.-[[4-methoxybenzene-sulfonyl(benzyl)-
amino]-1-[carbomethoxymethyl]-piperidine hydrochloride;
4-N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-
amino]-1-piperidine trifluoroacetate;
4-N-Hydroxy-carbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-
amino]-1-[t-butoxycarbonyl]-piperidine;
4-N-Hydroxycarbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-amino]-
1-[methylsulfonyl]-piperidine;
N-Hydroxycarbamoyl]-4-[[4-methoxybenzene-sulfonyl(benzyl)-amino]-1-
[4-picoly]-piperidine hydrochloride;
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N-Hydroxycarbamoyl]-4-[(4-methoxybenzene-sulfonyl(benzyl)amino]-1-
[morpholinocarbonyl]-piperidine hydrochloride;
N-(t-Butyloxy)-2-[(4-methoxybenzenesulfonyl (benzyl)amino]-2-[2-(4-
morpholino)ethyl]acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonylJ(isobutyl)- amino-2-(2-(4-
morpholino)ethyI] acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-picoly)- amino-2-(2-(4-
morpholino)ethyl]acetamide dihydro-chloride;
N-Hydroxy-2-[(4-methoxybenzenesulfonyl] (3-picolyl)amino]-2-[2-(4-
morpholino)ethyl]acetamide dihydrochloride;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl](2-methyl-thiazol-4-
ylmethyl)amino]-2-[2-(4-morpholino) ethyl]acetamide dihydrochloride;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl] benzyl)amino]-2-[2-(4-
thiomorpholino]ethyl] acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl] (benzyl)amino]-2-[2-(4-
methylthiazol-4-ylmethyl] acetamide;
N-Hydroxy-2-([4-methoxybenzenesulfonyl (benzyl)amino]-2-[(6-
chloropiperonyl]acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl (benzyl)amino]-2-[(1-
pyrazolyl)methyl]acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl (3-picolyi)amino]-2-[3-
picolyl]acetamide;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl(benzyl)-amino]-2-[( 1-methyl-
4-imidazolyl)methyl]acetamide hydrochloride;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl(isobutyl) amino]-2-[(1-methyl-
4-imidazoiyl)methyl]acetamide hydrochloride;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl](3-picolyl) amino]-2-[(1-
methyl-4-imidazolyl) methyl]acetamide hydrochloride;
N-Hydroxy-2-[[4-methoxybenzenesulfonyl(2-picolyl) amino]-2-[(1-
methyl-4-imidazolyl)methyl]-acetamide hydrochloride; and
N-Hydroxy-2-[[4-methoxybenzenesulfonyl] (2-methylthiazol-4-
ylmethyl)amino-2-[(1-methyl-4-imidazolyl)methyl]acetamide hydrochloride.
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Another group of small peptide matrix metalloproteinase inhibitors are
described in United States Patent Numbers 5,270,326, 5,530,161, 5,525,629, and
5,304,604 (incorporated herein by reference). The compounds are hydroxamic
acids, for example compounds of the formula
R2 O R3 R4
R 1 S On-A-CH-CH-C-NH-CH-C-N-RS
CONHOH O
where R1, R2, R3, R4, and RS can be alkyl, A includes a hydrocarbon chain, and
n is 0 to 2. Typical compounds to be employed in the instant method include
the
following:
N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-D-tryptophan
methylamide;
N-(2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-N-methyl-L-
tryptophan methylamide;
N-[2-Isobutyl-3-(N-hydroxycarbonylamido)-propanoyl]-L-3-(2-naphthyl)-
alanine methylamide;
N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L-tryptophan 2-
hydroxyethylamide;
N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L-tryptophan
amylamide;
N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L-tryptophan
piperidinamide;
N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl-L-tryptophan
dodecylamide;
N-[2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L-tryptophan(S)-
methylbenzylamide;
N-[L-2-Isobutyl-3-(N'-hydroxycarbonylamido)-propanoyl]-L-
tryptophan(6-phenylmethoxycarbonyl-amino-hexyl-1 )amide;
2S-Hydroxy-3R-[ 1 S-(3-methoxy-2,2-dimethyl-propylcarbamoyl)-2,2-
dimethyl-propylcarbamoyl]-5-methyl-hexanohydroxamic acid;
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2S-Hydroxy-3R-[ 1 S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-
6-(4-chloro)phenyl-hexanohydroxamic acid;
2S-Hydroxy-3R-[ 1 S-(methylcarbamoyl)-2,2-dimethyl-propyl-
carbamoyl]octanohydroxamic acid;
2S-Hydroxy-3R-[ 1 S-(pyridin-2-ylmethylcarbamoyl)-2,2-dimethyl-propyl-
carbamoyl]-5-methyl-hexanohydroxamic acid;
2S-Hydroxy-3R-[ 1 S-(pyridin-3-ylmethylcarbamoyl)-2,2-dimethyl-propyl-
carbamoyl]-5-methyl-hexanohydroxamic acid;
2S-Hydroxy-3R-[ 1 S-(pyridin-4-ylmethylcarbamoyl)-2,2-dimethyl-propyl-
carbamoyl]-5-methyl-hexanohydroxamic acid;
2S-Hydroxy-3R-( 1 S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-
4-methoxy-butanohydroxamic acid;
2S-Hydroxy-3R-[ 1 S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-
4-benzyloxy-butanohydroxamic acid;
2S-Hydroxy-3R-[ 1 S-(methylcarbamoyl)-2,2-dimethyl-propylcarbamoyl]-
4-benzylthio-butanohydroxamic acid;
2S-Hydroxy-3R-[ 1 S-(methylcarbamoyl)-2,2-dimethyl-buten-3-
ylcarbamoyl]-5-methyl-hexanohydroxamic acid;
2S-Hydroxy-3R-[ 1 S-(tert-butylcarbamoyl)-2,2-dimethyl-propyl-
carbamoyl]-5-methyl-hexanohydroxamic acid;
2S-Hydroxy-3R-[ 1 S-(N,N-dimethyl-carbamoyl)-2,2-dimethyl-propyl-
carbamoyl]-S-methyl-hexanohydroxamic acid;
2S-Hydroxy-3R-[ 1S-(3-hydroxy-2,2-dimethyl-propylcarbamoyl)-2,2-
dimethyl-propylcarbanoyl]-5-methyl-hexanohydroxamic acid;
2S-Hydroxy-3R-[1S-(methylcarbamoyl)-2,2-dimethyl-propylcarbarnoyl]-
6-phenyl-hexanohydroxamic acid;
2S-Hydroxy-3R-[ 1 S-(methylcarbamoyl)-2,2-dimethyl-butylcarbamoyl]-5-
methyl-hexanohydroxamic acid;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-
hydroxyethyl)-amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalaninyl-proline;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-
hydroxyethyl )-N-methyl amide;
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[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalaninyl-D-prolinol;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalaninyl-L-prolinol;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(5-N-
methyl-pentylcarboxamide)amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-
ethylthioethyl)amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-
methoxyethyl)amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-N-
acetylethyl)amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(3-(2-
pyrrolidone)propyl)amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(3-(2-
pyrrolidone)propyl)amide sodium salt;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-{2-
acetoxyethyl)amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-
N-(3-(2-pyrrolidone)propyl)amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-
N-methyl-N-(2-hydroxyethyl)amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-
N-(2-hydroxyethyl)amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalaninyl-
D-prolinol;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-
N-{3-(2-pyrrolidone)propyl)amide sodium salt;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-
N-(3-(2-pyrrolidone)propyl )amide;
[4-{N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-
N-(3-(2-pyrrolidone)propyl)amide or a salt thereof;
NZ-[4-(N-Hydroxyamino)-3S-{4-hydroxyphenylthiomethyl)-2R-
~isobutylsuccinyl]-N6-tert-butyloxycarbonyl-L-lysine-N 1-methylamide;
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NZ-[4-(N-Hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-
isobutylsuccinyl]-N6-tert-butyloxycarbonyl-N6-(4-hydroxyphenylthiomethyl)-L-
lysine-N 1-methylamide;
NZ-[4-(N-Hydroxyamino)-3S-(2-thienylthiomethyl)-2R-isobutylsuccinyl]-
N6-tent-butyloxycarbonyl-L-lysine-N 1-methylamide;
N2-[4-(N-Hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-
isobutylsuccinyl]-O-tert-butyl-L-threonine-N I -methylamide;
N2-[4-(N-Hydroxyamino)-3S-(4-hydroxyphenylthiomethyl)-2R-
isobutylsuccinyl]-L-glutamine-N I,NS-dimethylamide;
N2-[4-(N-Hydroxyamino)-3S-(4-hydroxyphenylsulphonylmethyl)-2R-
isobutylsuccinyl]-N6-acetyl-L-lysine-N I-methylamide;
3R-(3-Methoxycarbonyl-1 S-methylcarbamoyl-propylcarbamoyl)-5-
methyl-2S-2-propenyl-hexanohydroxamic acid;
3R-( 1 S-Methylcarbamoyl-2-thien-2-yl-ethylcarbamoyl)-5-methyl-2S-2-
propenyl-hexanohydroxamic acid;
3R-(3-Methyl-1 S-methylcarbamoyl-butylcarbamoyl)-5-methyl-2S-2-
propenyl-hexanohydroxamic acid;
2S-[ 1 S-Methylcarbamoyl-2-oxadiazol-5-yl-ethylcarbamoyl)-5-methyl-2S-
2-propenyl-hexanohydroxamic acid;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxylic
acid)phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxy-N-
methylamide)phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxy-beta-
alanine)phenyl alanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-
oxymethylcarboxyglycine)phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-oxymethylcarboxy-N-
benzylamide)phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-cyano)phenylalanine-N-
methylamide;
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[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-
acetamido)phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-(4-
oxymethylcarboxamide)-henylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethylsuccinyl]-L-(4-
N-acetylamino)-henylalanine-N-methyl amide;
[4-(N-Hydroxyamino)-2R-isobutyi-3S-(2-thienylthiomethylsuccinyI]-L-(4-
N-methylsuccinylamide)phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-aminophenylthiomethyl)-
succinyl]-L-(4-N-(methylsuccinylamide)phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-
aminophenylthiomethylsuccinyl]-L-(4-N-(4-(4-oxobutanoic
acid)aminophenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3 S-(4-hydroxyphenylthiomethyl)-
succinyl]-L-(4-N-methylsuccinylamido)phenylalanine-N-rnethylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-hydroxyphenylthiomethyl)-
succinyl]-L-(4-N-(4-(4-oxobutanoic acid)aminophenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)-succinyl]-L-
(4-oxymethylcarboxymethyl)phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)-succinyl]-L-
(4-N-(oxymethylcarboxylic acid)phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)-succinyl]-L-
4-oxymethylcarboxyglycyl methyl ester)-phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)-succinyl]-L-
4-oxymethylcarboxyglycine)phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl-succinyl]-L-4-
(oxymethylcarboxyglycyl methyl ester)-phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methyl)-succinyl]-L-4-
(oxymethylcarboxyglycine)-phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-4-oxymethylnitrile)-
phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-3-( 1-(2-
methyloxycarbonyI)-ethyl)-4-methoxyphenylalanine-N-methylamide;
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[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-3-(hydroxymethyl)-4-
methoxyphenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-3-methyl-4-
methoxyphenylalanine-N-methylamide;
2-[Benzyl-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide;
N-Hydroxy-2-[(2-methoxy-benzyl)-(octane-1-sulfonyl)-amino]-acetamide;
2-[(2-Ethoxy-benzyl)-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide;
N-Hydroxy-2-[(naphthalen-2-yl-methyl)-(octane-1-sulfonyl)-amino]-
acetamide;
2-[(4-Chloro-benzyl)-(octane-1-sulfonyl)-amino]-N-hydroxy-acetamide;
N2-[3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl]-L-leucine-
N 1-methylamide;
N2-[3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl)]-5-methyl-L-
glutamic acid-N1-methylamide;
N2-[3S-Hydroxy-4-(N-hydroxyamino)-2R-isobutylsuccinyl)]-L-
phenylalanine-N 1-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(thienylthiomethyl)succinyl]-L-
phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-phenylthiomethyl)succinyl]-L-
phenylalanine-N-methylamide;
2S-(4-Methoxyphenylsulfanylmethyl)-3R-(2-phenyl-1 S-methylcarbamoyl-
ethylcarbamoyl)-S-methyl-hexanohydroxamic acid;
2S-(3-Chlorophenylsulfanylmethyl)-3R-(2-phenyl-1 S-methylcarbamoyl-
ethylcarbamoyl)-S-methyl-hexanohydroxamic acid;
2S-(Phenylsulfanylmethyl)-3R-(2-phenyl-1 S-(pyrid-3-
ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(3-Methylphenylsulfanylmethyl)-3R-(2-phenyl-1 S-methylcarbamoyl-
ethylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(Thien-2-ylsulfanylmethyl)-3R-(2-(4-carboxymethoxyphenyi)-1 S-
methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(Thien-2-ylsulfanylmethyl)-3R-(2-phenyl-1 S-(pyrid-3
ylmethylcarbamoyl)-ethylcarbamoyl)-S-methyl-hexanohydroxamic acid;
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2S-(4-Hydroxyphenylsulfanylmethyl)-3R-(2-phenyl-1 S-(pyrid-3-
ylmethylcarbamoyl)-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(Thien-2-ylsulfanylmethyl)-3R-(2-naph-2-yl-1 S-methylcarbamoyl-
ethyicarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(4-Hydroxyphen ylsulfanylmethyl)-3R-(2R-hydroxy-1 S-
methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(4-Hydroxyphenylsulfanylmethyl)-3R-(5-acetamido-1 S-
methylcarbamoyl-pentylcarbamoyl)-5-methyl-hexanohydrexamic acid;
2S-(4-Hydroxyphenylsulfanylmethyl)-3R-(3-[ 1,1-
dimethylethoxycarbonyl]-1 S-methylcarbamoyl-propylcarbamoyl)-5-methyl-
hexanohydroxamic acid;
2S-(Thien-2-ylsulfonylmethyl)-3R-(2-phenyl-1S-methylcarbamoyl-
ethylcarbamoyl)-5-methyl-hexanohydroxamic acid;
3S-(2-(4-Acetamido-phenyl]-1 S-methylcarbamoyl-ethylcarbamoyl)-5-
methyl-hexanohydroxamic acid;
2S-(4-Phthalimido-butyl)-3R-(3-methyl-1 S-
ethoxycarbonylmethylcarbamoyl-butylcarbamoyl)-5-methyl-hexanohydroxamic
acid;
3R-(2-[4-Methoxy-phenyl]-1 S-methylcarbamoyl-ethylcarbamoyl)-2S,5-
dimethyl-hexanohydroxamic acid;
3R-(2-Phenyl-1 S-[2-oxo-pyrolid-1-yl]-propylcarbamoyl-ethylcarbamoyl)-
5-methyl-hexanohydroxamic acid;
3R-(2-[4-Methoxy-phenyl]-1 S-methylcarbamoyl-ethylcarbamoyl)-5-
methyl-hexanohydroxamic acid;
3R-(2-Phenyl-1S-[pyrid-3-ylmethylcarbamoyl]-ethylcarbamoyl)-5-methyl-
hexanohydroxamic acid;
3R-(2,2-Dimethyl-1S-methylcarbamoyl-propylcarbamoyl)-5-methyl-
hexanohydroxamic acid;
Isobutylmalonoyl-L-alanine-furfurylamide hydroxamate;
2-Isobutyl-3-carbonyl-3'-(4-acetylaniline)propionic acid;
N-Benzyloxycarbonyl-a,-phosphonoglycyl-L-alanine furfurylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(phenyithiomethyl)succinyl]-L-
phenylalanine-N-methylamide;
SU~'f ITUTE SHEET (RULE 26~
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[4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-methoxyphenylthiomethyl)-
succinyl]-L-phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-hydroxyphenylthiomethyl)-
succinyl]-L-phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(2,4-dimethylphenylthiomethyl)-
succinyl]-L-phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(3-bromophenylthiomethyl)-
succinyl]-L-phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(3-chlorophenylthiomethyl)-
succinyI]-L-phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(3-methylphenylthiomethyl)-
succinyl]-L-phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-(4-(N-acetyl}-amino-
phenylthiomethyl)succinyl]-L-phenylalanine-N-methylamide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-phenylsulphinylmethylsuccinyl]-L-
phenylalanine-N-methylamide;
3R-(3-Methoxycarbonyl-1S-methylcarbamoyl-propylcarbamoyl)-5-
methyl-2S-phenylsulfanylmethyl- hexanohydroxamic acid;
3R-(3-Methoxycarbonyl-1 S-methylcarbamoyl-propylcarbamoyl)-5-
methyl-2S-(thien-2-ylsulfanylmethyl)-hexanohydroxamic acid;
2S-(4-Methoxy-phenylsulfanylmethyl)-3R-(3-methoxycarbonyl-1 S-
methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(4-Amino-phenylsulfanylmethyl)-3R-(3-methoxycarbonyl-1 S-
methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(Ethylsulfanylmethyl)-3R-(3-methoxycarbonyl-1 S-methylcarbamoyl-
propylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(Acetylsulfanylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-
propylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-{Benzylsulfanylmethyl)-3R-(3-methoxycarbonyl-1S-methylcarbamoyl-
propylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(tert-Butylsulfanylmethyl)-3R-(3-methoxycarbonyl-1S-
methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid;
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2S-Thiomethyl-3R-(3-methoxycarbonyl-1 S-methylcarbamoyl-
propylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(4-Hydroxy-phenylsulfanylmethyl)-3R-(2-tert-butoxycarbonyl-1 S-
methylcarbamoyl-ethylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(4-Hydroxy-phenylsulphinylmethyl)-3R-(3-methoxycarbonyl-1S-
methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid;
2S-(4-Hydroxy-phenylsulphonylmethyl)-3R-(3-methoxycarbonyl-1 S-
methylcarbamoyl-propylcarbamoyl)-5-methyl-hexanohydroxamic acid;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[ 1-(2-
aminoethyl)-pyrrolidine]amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[ 1-(3-
aminopropyl)-2(RS)-methylpiperidine]amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[2-(2-
aminoethyl)-1-methylpyrrole]amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(3-
aminomethylpyridine)amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(2-
aminornethylpyridine)amide;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N-(4-
aminomethylpyridine)amide;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N-( 1-(3-
aminopropyl)-imidazole)amide;
[4-(N-Hydroxyamino)-2(RS)-isobutylsuccinyl]-L-phenylalanine-N-(2-
aminomethylbenzimdazole)amide;
[4-(N-Hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-L-phenylalanine-
N-[4-(2-aminoethyl)-morpholino]amide;
[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[4-(2-
aminoetliyl)-morpholine] amide;
[4-(N-Hydroxyamino)-2(R,S)-isobutylsuccinyl]-L-phenylalanine-N-[2-(2-
aminoethyl)-pyridine]amide;
[4-(N-Hydroxyamino)-2(R,S)-isobutylsuccinyl]-L-phenylalanine-N-[4-(2-
aminopropyl)-morpholine]amide;
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[4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-(3-
aminomethylpyridine)amide hydrochloride; and
(4-(N-Hydroxyamino)-2R-isobutylsuccinyl]-L-phenylalanine-N-[4-(2-
aminoethyl)-morpholine]amide hydrochloride.
In a preferred embodiment, tricyclic butyric acid derivatives which are
inhibitors of matrix metalloprotienases are employed to treat or prevent heart
failure and ventricular dilatation according to this invention. A preferred
group of
tricyclic butyric acid derivatives are defined by the formula:
W1 Z1 R1
R3 / ( ~ \
\
W Y~Z R2
R4
O X
wherein one of Rl or R2 is -C-CH-(CH)a-C-R5:
R Ra
wherein X is O,
N-OR6 wherein R6 is hydrogen,
-(CH2)n-aryl wherein n is zero or an integer of 1 to 5,
alkyl, or
-(CHZ)n-cycloalkyl wherein n is as defined above, or
N-N-R6 wherein R6 and R6a are each
R6a the same or different and each is as defined above for R6;
R and Ra are each the same or different and each is hydrogen,
-(CH2)n-aryl wherein n is as defined above,
-(CH2)n-heteroaryl wherein n is as defined above,
-(CH2)p-R~-{CH2)q-aryl wherein R~ is O or S and p or q is each
zero or an integer of 1 to S and the sum of p + q equals an integer of 5,
-(CH2)p-R~-(CHZ)q-heteroaryl
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wherein p, q, and R~ are as defined above,
alkyl,
-(CH2)n-cycloalkyl wherein n is as defined above, or
-(CH2)r-NH2 wherein r is an integer of 1 to 9;
a is zero or an integer of 1 to 3;
RS is OH,
OR6 wherein R6 is as defined above.
NR6 wherein R6 and R6a are each
R6a the same or different and are as defined above for R6, or
NH-OR6 wherein R6 is as defined above;
R3 and R4 are each the same or different and each is hydrogen,
alkyl,
N02,
halogen,
OR6 wherein R6 is as defined above,
CN,
C02R6 wherein R6 is as defined above,
S03R6 wherein R6 is as defined above,
CHO,
O
-C-R wherein R is as defined above,
O
-C-N-R6 wherein R6 and R6a are each
R6a the same or different and are as defined
above
for R6, or
-(CH2)n-N-R6 wherein R6 and R6a are
R6a each the same or different and are as defined
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above for R6;
W, W l, Z, and Zl are each the same or different and each is CR3 wherein
R3 is as defined above, or
N providing only one of W or W 1 is
N and/or only one of Z or Zl is N; and
Y is - i - wherein R is as defined above,
R
-O-,
-S-(O)m- wherein m is zero or an integer of 1 or 2,
-CH2-,
-C-,
O
-C- wherein R6 is as defined above,
N-OR6
-CH- wherein R6 is as defined above,
OR6
-C- wherein R6 and R6a are the same or
h
N- i -R6 different and are as defined above for R6,
R6a
-C-N- wherein R6 is as defined above,
O R6
-N-C-
R60 wherein R6 is as defined above,
-C-O-,
O
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-O-C-,
O
-CH2-O-,
-O-CH2-,
-CH2-S(O)m- wherein m is as defined above,
-S(O)m-CHZ- wherein m is as defined above,
-CH2-N- wherein R6 is as defined above,
R6
-N-CH2_ wherein R6 is as defined above,
R6
-CH=N-, or
-N=CH-;
with the proviso that when X is O, and RS is not NH-OR6, at least one of
R or Ra is not hydrogen; and corresponding isomers thereof; or a
pharmaceutically acceptable salt thereof.
Typical compounds from this class include:
4-Dibenzofuran-2-yl-4-hydroxyimino-butyric acid; 2-(2-Dibenzofuran-2-
yl-2-hydroxyimino-ethyl)-4-methyl-pentanoic acid;
2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-phenyl-pentanoic acid;
4-Dibenzofuran-2-yl-4-hydroxyimino-2-phenethyl-butyric acid;
5-(4-Chloro-phenyl)-2-(2-dibenzofuran-2-yl-2-hydroxyimino-ethyl)-
pentanoic acid;
2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-(4-fluoro-phenyl)-
pentanoic acid;
2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-(4-methoxy-phenyl)-
pentanoic acid;
2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-p-tolyl-pentanoic acid;
3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-5-methyl-hexanoic acid;
3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-phenyl-hexanoic acid;
3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-5-phenyl-pentanoic acid;
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6-(4-Chloro-phenyl)-3-(dibenzofuran-2-yl-hydroxyimino-methyl)-
hexanoic acid;
3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-fluoro-phenyl)-
hexanoic acid;
3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-methoxyphenyl)-
hexanoic acid; and
3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-p-tolyl-hexanoic acid; and
corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
Tricyclic butyric acids having an a-amino substituent are defined by the
formula:
~ R~
wherein X is O, NOR9, S, OH, SH, or ; N N ~
R7a
R~ and Rya independently are
hydrogen,
CI-C2p alkyl or substituted Cl-C2p alkyl,
(CHZ)0-6-~'Yh
(CH2)0-6-heteroaryl, or
(CH2)0-6-cYcloalkyl;
R 1 and R2 independently are
hydrogen,
C 1 _C2p alkyl or substituted C 1 _C2p alkyl,
halo,
N02,
CN,
CHO,
CORE,
COOR6,
S03R6,
OR6,
CONR4R5,
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_9p_
(CH2)p-6-ai'Yl~
(CH2)p-6-heteroaryl, or
(CH2)p_6-cycloalkyl;
R6 is hydrogen,
C1-C2p alkyl or substituted C1-C2p alkyl;
aryl is phenyl or substituted phenyl;
R3 is hydroxy,
O-C 1-C2p alkyl or substituted O-C 1-C2p alkyl,
O-(CH2)1-3 ai'Yl, or
NHOR6;
R4 and RS independently are hydrogen,
Cl-C2p alkyl or substituted C1-C2p alkyl,
(CH2)p-(-ar'Yl~
(CH2)p_6-heteroaryl; or one of R4and RS is hydrogen and the other is:
CORg,
CSRg,
CONRgR9,
CSNRgR9,
COORg,
COSRg,
COCHRg;
NR 1 R2,
CON-CONRgR9,
R1
CON-COORg,
Rl
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CON-COSRg, or
R1
CON-S02NRgRg;
R1
CON-S03Rg;
R1
Y is -N-,
R1
-O-,
-S(O)p~ 1 or 2~
_CH2_,
O
-C-,
NORg
-CH_,
ORg
-C-,
p
N-N-RgR9
-C-N-,
O Rg
-N-C-,
R80
-C-O,
O
-CHZ-O-,
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-O-CH2-,
-CH2S(O)p~ 1 or 2~
-S(O)p, 1 or 2-CH2-,
-CH2-N-,
Rg
-N-CH2-,
Rg
-CH=N, or
-N=CH-;
Rg and Rg independently are
hydrogen
Cl-C2p alkyl or substituted C1-C2p alkyl,
(CH2)p-6-~Yl
(CH2)p_6-heteroaryl, or
(CH2)p_6-cYcloalkyl;
W, W l, Z, and Zl independently are CRl or N;
and the pharmaceutically acceptable salts, isomers, stereoisomers, and
solvates
thereof.
Specific examples of compounds to be employed in the present method
include:
(S )-4-Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric
acid;
(R)-4-Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric
acid;
(S)-2-Amino-4-dibenzofuran-2-yl-4-oxo-butyric acid
(S)-2-Acetylamino-4-dibenzofuran-2-yl-4-oxo-butyric;
(S}-4-Dibenzofuran-2-yl-2-[3-(2,6-diisopropyl-phenyl)-ureido]-4-oxo-
butyric acid;
(S)-2-Benzoylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid
(S)-4-Dibenzofuran-2-yl-4-oxo-2-phenylacetylamino-butyric acid;
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(S)-4-Dibenzofuran-2-yl-4-oxo-2-(3-phenyl-propionylamino)-butyric acid;
(S)-4-Dibenzofuran-2-yl-4-oxo-2-(7-phenyl-heptanoylamino)-butyric acid;
(S)-2-[(Biphenyl-4-carbonyl)-amino]-4-dibenzofuran-2-yl-4-oxo-butyric
acid;
(S)-4-Dibenzofuran-2-yl-4-oxo-2-(dodecanoylamino)-butyric acid;
(S}-4-Dibenzofuran-2-yl-4-oxo-2-(dodecanoyl-amino)-butyric acid;
(S)-4-Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric
acid;
(R)-4-Dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric
acid;
(S)-2-Amino-4-dibenzofuran-2-yl-4-oxo-butyric acid;
(S)-2-Acetylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid;
(S)-4-Dibenzofuran-2-yl-2-[3-(2,6-diisopropyl-phenyl)-ureido]-4-oxo-
butyric acid;
(S)-2-Benzoylamino-4-dibenzofuran-2-yl-4-oxo-butyric acid;
(S}-4-Dibenzofuran-2-yl-4-oxo-2-phenylacetylamino-butyric acid;
(S)-4-Dibenzofuran-2-yl-4-oxo-2-(3-phenyl-propionylarnino)-butyric acid;
(S)-4-Dibenzofuran-2-yl-4-oxo-2-(7-phenyl-heptanoylamino)-butyric acid;
(S)-2-[(Biphenyl-4-carbonyl)-amino]-4-dibenzofuran-2-yl-4-oxo-butyric
acid;
(S)-4-Dibenzofuran-2-yl-4-oxo-2-(octanoylamino)-butyric acid; and
(S}-4-Dibenzofuran-2-yl-4-oxo-2-(dodecanoylamino)-butyric acid.
Tricyclic sulfonamide matrix metalloproteinase inhibitors include
compounds of the formula
O
I I
R ~ I i-o
R4 M
wherein M is a natural (L) alpha amino acid derivative having the structure
COR
N H
H
R
X is O, S, S(O)n, CH2, CO, or NH;
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R is a side chain of a natural alpha amino acid;
R I is C I-CS alkoxy, hydroxy, or -NHORS;
R2 and R4 are independently hydrogen, -CI_CS alkyl, -NO2, halogen, -ORS, -CN,
-C02R5, -S03R5,-CHO, -CORS, -CONRSR6, -(CH2)nNR5R6, -CF3, or -
NHCORS;
each RS and R6 are independently hydrogen or C 1 _CS alkyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, ester, amides, and
prodrugs
thereof.
Specific compounds from this class to be employed include:
(L)-2-(Dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-propionic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid;
(Dibenzofuran-2-sulfonylamino)-acetic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-succinic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-tritylsulfanyl-propionic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-mercapto-propionic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid
hydroxyamide;
(L)-2-(Dibenzofuran-2-sulfonylamino)-4-methyl-pentanoic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-propionic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-butyric acid;
(Dibenzofuran-2-sulfonylamino)-acetic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-succinic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-tritylsulfanyl-propionic acid;
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-mercapto-propionic acid; and
(L)-2-(Dibenzofuran-2-sulfonylamino)-3-methyl-pentanoic acid
hydroxyamide.
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Additional tricyclic sulfonamides are defined by the formula:
/o
R2 \ I \ S\Q
i ~J~~
X 4
R
wherein Q is an un-natural amino acid;
X is O, S, S(O)n, CH2, CO, or NH;
RZ and R4 are independently hydrogen, Cl-CS alkyl, -N02, halogen, -ORS, -CN,
-C02R5, -S03R5, -CHO, -CORS, -CONRSR6, -(CH2)nNRSR6, -CF3, or
-NHCORS;
each RS and R6 are independently hydrogen or Cl_CS alkyl; and
n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides, and
prodrugs
thereof.
Specific examples of such compounds include:
(S)-2-(Dibenzofuran-2-sulfonylamino)-4-phenyl-butyric acid;
2 (S)-3-[(Dibenzofuran-2-sulfonylamino)-methyl]-5-methyl-hexanoic acid;
(S)-2-(Dibenzofuran-2-sulfonylamino)-4-phenyl-butyric acid; and
2 (S)-3-[(Dibenzofuran-2-sulfonylamino)-methyl]-5-methyl-hexanoic acid.
Another general class of matrix metalloproteinase inhibitors, which are
useful to combine with statins to treat and prevent heart failure and
ventricular
dilatation, are biphenyl butyric acid derivatives, including compounds of the
formula:
R2
C C C C-R5
R ~ R3a R4a
R1
wherein R and R 1 are the same or different and are
hydrogen,
alkyl,
halogen,
vitro,
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cyano,
trifluoromethyl,
-OR6 wherein R6 is hydrogen,
alkyl,
aryl,
arylalkyl,
heteroaryl, or
cycloalkyl,
-N-R6 wherein R6 and R6a are the same or
R6a
different and are as defined above for R6,
O
-O-C-R6 wherein R6 is as defined above,
O
-NH-C-R6 wherein R6 is as defined above,
O
-S-C-R6 wherein R6 is as defined above,
-SR6 wherein R6 is as defined above,
O
-C-R6 wherein R6 is as defined above,
-CHZ-OR6 wherein R6 is as defined above,
-CH2-N-R6 wherein R6 and R6a are the same or
R6a
different and are as defined above for R6,
O
-C-N-R6 wherein R6 and R6a are the same or
R6a
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different and are as defined above for R6,
O
-S-R6 wherein R6 is as defined above,
O
cycloalkyl, or
heteroaryl, with the proviso that R and R 1 are not both hydrogen;
R2 is -OR6 wherein R6 is as defined above, or
-N-R6 wherein R6 and R6a are the same or
ba
different and are as defined above for R6;
R3, R3a, R4, and R4a are the same or different and are
hydrogen,
fluorine,
alkyl,
-(CH2)n-aryl wherein n is an integer from 1 to 6,
-(CH2)n-heteroaryl wherein n is as defined above,
-(CH2)n-cycloalkyl wherein n is as defined above,
-(CH2)p-X-(CH2)q-aryl wherein X is O, S, SO, S02, 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,
-(CHZ)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above,
or
-(CHZ)n-R7 wherein R7 is
N-phthalimido,
N-2,3-naphthyimido,
-OR6 wherein R6 is as defined above,
-N-R6 wherein R6 and R6a are the same or
R6a
different and are as defined above for R6,
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-SR6 where R6 is as defined above,
O
-S-R6 wherein R6 is as defined above,
O
-S-R6 wherein R6 is as defined above,
O
O
-O-C-R6 wherein R6 is as defined above,
O
-N-C-R6 wherein R6 and R6a are the same
R6a
or different and are as defined above for R6,
O
-S-C-R6 wherein Rb is as defined above,
O
-C-R6 wherein R6 is as defined above,
O
-C-OR6 wherein R6 is as defined above, or
O
-C-N-R6 wherein R6 and R6a are the same
R6a
or different and are as defined above for R6, and
n is as defined above;
RS is OH or SH; with the proviso that R3, R3a, R4, and R4a are hydrogen or at
least one of R3, R3a, R4, or R4a is fluorine; and corresponding isomers
thereof; or
a pharmaceutically acceptable salt thereof.
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Typical compounds from this class that are routinely utilized in
combination with a statin to treat and prevent heart failure include:
4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
4-(4'-Bromo-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
4-(4'-Chloro-biphenyl-4-yl)-4-(dimethylhydrazono)- butyric acid;
4-(4'-Fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxy-butyric acid;
4-(4'-Bromo-2'-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yi)-3-fluoro-4-oxo-butyric acid;
4-(2',4'-Dichloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
4-(2',4'-Difluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(3-
phenylpropyl)-butyric acid;
(~).-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(2-
phenylethyl)-butyric acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(3-
phthalimidopropyl)-butyric acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-
(phenylthiomethyl)-butyric acid;
4-(4'-Chloro-2'-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
4-Hydroxyimino-4-(4'-trifluoromethyl-biphenyl-4-yl)-butyric acid;
4-(4'-Chloro-biphenyl-4-yl)-4-methoxyimino-butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yl )-2-fluoro-2-[2-( 1, 3-dioxo-1, 3-dihydro-
isoindol-2-yl)-ethyl]-4-hydroxyirnino-butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-( 1 H-indol-3-
yl)methyl-butyric acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-rnethyl-
butyric acid;
(~)-2-[2-(4'-Chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-2-fluoro-6-
phenyl-hexanoic acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-2-fluoro-2-[2-( 1,3-dioxo-1,3-dihydro-
benzo[F]isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid;
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(~)-2-[2-(4'-Chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-6-( 1,3-dioxo-
1,3-dihydro-isoindol-2-yl)-2-fluoro-hexanoic acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-[2-(phenyl-
ethylcarbamoyl)-ethyl]-butyric acid;
4-(4'-Chloro-biphenyl-4-yl)-3,3-difluoro-4-hydroxyimino-butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yl)-3,3-dimethyl-2-fluoro-4-hydroxyimino-
butyric acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-2,2-dimethyl-3-fluoro-4-hydroxyimino-
butyric acid;
4-(4'-Chloro-biphenyl-4-yl)-2,2-difluoro-4-hydroxyimino-butyric acid;
and
4-(4'-Chloro-biphenyl-4-yl)-2,2,3,3-tetrafluoro-4-hydroxyimino-butyric
acid.
A compound selected from the group consisting of:
4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
4-(4'-Bromo-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
4-(4'-Chloro-biphenyl-4-yl)-4-(dimethylhydrazono)- butyric acid;
4-(4'-Fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxy-butyric acid;
4-(4'-Bromo-2'-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yl)-3-fluoro-4-oxo-butyric acid;
4-(2',4'-Dichloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
4-(2',4'-Difluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(3-
phenylpropyl)-butyric acid;
(~)-4-(4' -Chloro-biphenyl-4-yl )-4-hydroxyimino-2-fluoro-2-(2-
phenylethyl)-butyric acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-(3-
phthalimidopropyl)-butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-
(phenylthiomethyl)-butyric acid;
4-(4'-Chloro-2'-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid;
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4-Hydroxyimino-4-(4'-trifluoromethyl-biphenyl-4-yl)-butyric acid;
4-(4'-Chloro-biphenyl-4-yl)-4-methoxyimino-butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yl)-2-fluoro-2-[2-( 1,3-dioxo-1,3-dihydro-
isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-( 1 H-indol-3-
yl)methyl-butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-methyl-
butyric acid;
(~)-2-[2-(4'-Chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-2-fluoro-6-
phenyl-hexanoic acid;
(~)-4.-(4'-Chloro-biphenyl-4-yl)-2-fluoro-2-[2-( 1,3-dioxo-1,3-dihydro-
benzo[F]isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid;
(~)-2-[2-(4' -Chloro-biphenyl-4-yl)-2-hydroxyiminoethyl]-6-( 1, 3-dioxo-
1,3-dihydro-isoindol-2-yl)-2-fluoro-hexanoic acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-4-hydroxyimino-2-fluoro-2-[2-(phenyl-
ethylcarbamoyl)-ethyl)-butyric acid;
4-(4'-Chloro-biphenyl-4-yl)-3,3-difluoro-4-hydroxyimino-butyric acid;
(~)-4-(4'-Chloro-biphenyl-4-yl)-3,3-dimethyl-2-fluoro-4-hydroxyimino-
butyric acid;
(t)-4-(4'-Chloro-biphenyl-4-yl)-2,2-dimethyl-3-fluoro-4-hydroxyimino-
butyric acid;
4-(4'-Chloro-biphenyl-4-yl)-2,2-difluoro-4-hydroxyimino-butyric acid;
and
4-(4'-Chioro-biphenyl-4-yl)-2,2,3,3-tetrafluoro-4-hydroxyimino-butyric
acid.
Biphenyl sulfonamides are also particularly good in the present method.
Such compounds include those of the formula:
_ _ 0
R1 / \ / OI
IS-NH-CH-COR3
R2
wherein:
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R 1 is C 1 _C6 alkyl, halo, nitro, NR4R5, cyano, OR4, and COOR4;
R2 is C 1 _C6 alkyl, optionally substituted by phenyl, substituted phenyl,
NR4R5,
OR6,
NH
carboxy, carboxamido, H2N-C-NH-, thio, methylthio, indole, imidazole,
phthalimido, phenyl, and substituted phenyl;
R3 is OH, OCl-C6 alkyl, or NHOH;
R4 is hydrogen, Cl-C6 alkyl, or CI-C6 alkanoyl;
RS is hydrogen or Cl-C6 alkyl; and
R6 is hydrogen, CI-C6 alkyl, Cl-C6 alkanoyl, phenyl, or substituted phenyl.
Specific compounds which can be employed include a compound of the
above formula wherein Rl is at the 4' position.
Another class of matrix metalloproteinase inhibitors useful in the present
method are the heterocyclic substituted phenyl butyric acid derivatives, for
example those defined by the formula:
- O
Ar-Y~N \ / Z
~ R
R1 R2 R3
Ar is selected from phenyl,
phenyl substituted with
alkyl,
N02,
halogen,
ORS wherein RS is hydrogen or alkyl,
CN,
C02R5 wherein RS is as defined above,
S03R5 wherein RS is as defined above,
CHO,
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CORS wherein RS is as defined above,
CONHRS wherein RS is as defined above, or
NHCORS wherein RS is as defined above,
2-naphthyl, or
heteroaryl;
R1 is selected from hydrogen,
methyl,
ethyl,
N02,
halogen,
ORS wherein RS is as defined above,
CN,
COZRS wherein RS is as defined above,
S03R5 wherein RS is as defined above,
CHO, or
CORS wherein RS is as defined above;
R2 and R3 are the same or different and independently selected from hydrogen,
alkyl,
-(CHZ)v-aryl wherein v is an integer from 1 to 5,
-(CH2)v-heteroaryl wherein v is as defined above,
-(CH2)v-cycloalkyl wherein v is as defined above,
-(CH2)p-X-(CH2)q-aryl wherein X is O or S and p and q is
each zero or an integer of 1 to 5, and the sum of p +
q is not greater than an integer of 5,
-(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as
defined above,
-(CH2)tNR6R6a, wherein t is zero or an integer of from
1 to 9 and R6 and R6a are each the same or different
and are as defined above for R5,
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-(CH2)vSRS, wherein v and RS are as
defined above,
-(CH2)vC02R5, wherein v and RS are as defined above, or
-(CH2)vCONR6R6a, wherein R6 and R6a are the same or
different and are as defined above for RS and v is as
defined above;
R3 is additionally -(CH2)rR~ wherein r is an integer from 1 to 5 and R~ is 1,3-
dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo-
benzo[fjisoindol-2-yl;
Y is CH or N;
/OH
Zis C~ 10,
R
wherein R1~ is as defined above for R2 and R3, and is independently the
same or different from R2 and R3 provided that
/OH
when Z is C~R10 , then R4 must be OH,
C=O,
C=NORS wherein RS is as defined above, or
C=N-NR6R6a wherein R6 and R6a are the same or different and are as
defined above for R5;
W is -CHRS wherein RS is as defined above;
n is zero or an integer of 1;
R4 is OH,
NR6R6a wherein Rb and R6a are the same or different and are as defined
above for R5, when R4 is NR6R6a then Z must be C=O or
NHOR9 wherein R9 is hydrogen, alkyl, or benzyl;
and corresponding isomers thereof; or a pharmaceutically acceptable salt
thereof.
Especially preferred MMP inhibitors have the formula
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- O
Ar-Y\ N ~ , ~~Z
(W)n ~R4
R1 R2 R3
Ar is selected from phenyl,
phenyl substituted with
alkyl,
N02,
halogen,
ORS wherein RS is hydrogen or alkyl,
CN,
C02R5 wherein RS is as defined above,
S03R5 wherein RS is as defined above,
CHO,
CORS wherein RS is as defined above,
CONHRS wherein RS is as defined above, or
NHCORS wherein RS is as defined above,
2-naphthyl, or
heteroaryl;
R 1 is selected from hydrogen,
methyl,
ethyl,
N02,
halogen,
ORS wherein RS is as defined above,
CN,
C02R5 wherein RS is as defined above,
S03R5 wherein RS is as defined above,
CHO, or
CORS wherein RS is as defined above;
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R2 and R3 are the same or different and independently selected from hydrogen,
alkyl,
-(CH2)v-aryl wherein v is an integer from 1 to 5,
-(CH2)v-heteroaryl wherein v is as defined above,
-(CH2)v-cycloalkyl wherein v is as defined above,
-(CH2)p-X-(CH2)q-aryl wherein X is O or S and p and q is
each zero or an integer of 1 to 5, and the sum of p +
q is not greater than an integer of 5,
-(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as
defined above,
-(CH2)tNR6R6a, wherein t is zero or an integer of from
1 to 9 and R6 and R6a are each the same or different
and are as defined above for R5,
-(CH2)vSRS, wherein v and RS are as
defined above,
-(CHZ)vC02R5, wherein v and RS are as defined above, or
-(CH2)vCONR6R6a, wherein R6 and R6a are the same or
different and are as defined above for RS and v is as
defined above;
R3 is additionally -(CH2)rR~ wherein r is an integer from 1 to 5 and R~ is
1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo-
benzo[f]isoindol-2-yl;
YisCHorN;
/OH
Z is C ~R10
wherein R 1 ~ is as defined above for R2 and R3, and is independently the
same or different from R2 and R3 provided that
/OH
when Z is C ~R10 , then R4 must be OH,
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C=O,
C=NORS wherein RS is as defined above, or
C=N-NR6R6a wherein R6 and R6a are the same or different and are as
defined above for R5;
W is -CHRS wherein RS is as defined above;
n is zero or an integer of i ;
R4 is OH,
NR6R6a wherein R6 and R6a are the same or different and are as defined
above for R5, when R4 is NR6R6a then Z must be C=O or
NHOR9 wherein R9 is hydrogen, alkyl, or benzyl;
and corresponding isomers thereof; or a pharmaceutically acceptable salt
thereof.
Preferred compounds to be employed include:
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassium salt;
N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide;
E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric
acid;
4-Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid;
(t)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl)-pentanoic acid;
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassium salt;
N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide;
E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric
acid;
4-Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid; and
(~)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid.
A compound which is 4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-
butyric acid.
Similar compounds which are sulfonamide derivatives have the formula:
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O
4
_ I I R
Ar- ( CH2 ) m - ~ ~ ~ (
Ra O R2 R3
R1
wherein:
,Ar is selected from phenyl;
phenyl substituted with alkyl, -N02, halogen, -ORS, -CN, -C02R5, -S03R5, -
CHO, -CORS, -CONHRS, -NHRS, or -NHCORS;
heteroaryl; or
2-naphthyl;
R1 is hydrogen, methyl, -N02, -Cl, -NH2, -NHC02CH3, -OH, or -C02H;
R2 and R3 are the same or different and are independently selected from
hydrogen, alkyl, -(CH2)v-aryl, -(CH2)v-heteroaryl, -(CH2)v-cycloalkyl, -
(CH2)p-X-(CHZ)q-aryl, -(CH2)p-X-(CH2)q-heteroaryl, -(CH2)tNR6R6a,
(CH2)vR~, -(CHZ)vC02R5, -(CH2)vCONRbR6a, or -(CH2)vSRS;
m is zero or 1;
Y is CH or N; provided that when m = 1, Y does not = N;
z is zero or l;
W is -CHRB;
n is zero or l;
R4 is -OH, -NR6R6a, or -NHOR9;
RS is hydrogen or alkyl;
v is 1 to 5;
XisOorS;
p and q are independently 1 to 5, provided that p+q is not greater than 5;
t is 1 to 9;
R6 and R6a are each the same or different and are hydrogen or alkyl;
R~ is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3-dihydro-1,3-dioxo-
benzo[fJisoindol-2-yl;
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Rg is hydrogen or alkyl; and
Rg is hydrogen, alkyl, or benzyl; or
a pharmaceutically acceptable salt thereof.
Specific sulfonamide derivatives to be employed in the present method
include:
[4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetic acid;
N-Hydroxy-2-[4-(4-phenyl-piperidin-1-yl}-benzenesulfonylamino]-
acetamide;
3-[4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;
(R)-4-Methyl-2-[4-{4-phenyl-piperidin-1-yl }-benzenesulfonylamino]-
pentanoic acid;
(S)-4-Methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
pentanoic acid;
(S)-3-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
propionic acid;
(R)-3-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
propionic acid;
(S)-3-( 1H-Indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl)-
benzenesulfonylamino]-propionic acid;
(~)-5-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
pentanoic acid;
[4-(4-Phenyl-piperazin-1-yl)-benzene-sulfonylamino]-acetic acid;
{ Isobutyl-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonyl]amino } -acetic
acid;
(S )-4-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
butyric acid;
(R)-2-[4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-3-
tritylsulfanyl-propionic acid, sodium salt;
(R)-3-( 1 H-Indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl)-
benzenesulfonylamino]-propionic acid, disodium salt, monohydrate;
(S)-2-{4-[-4-(4-Hydroxy-phenyl)-piperazin-1-yl]-benzenesulfonylamino }-
3-phenyl-propionic acid;
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(S)-2-{ 4-[-4-(4-Chloro-phenyl)-piperazin-1-yl]-benzenesulfonylamino } -3-
phenyl-propionic acid, hydrochloride;
(R)-3-Mercapto-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
propionic acid, trifluoracetic acid salt;
(S)-2-[4-(4-Benzyl-piperidin-1-yl)-benzenesulfonylamino]-3-phenyl-
propionic acid;
(S)-3-(4-Benzyloxy-phenyl)-2-[4-{4-phenyl-piperidin-1-yl)-
benzenesulfonylamino]-propionic acid;
(S)-3-(4-Hydroxy-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-
benzenesulfonylamino]-propionic acid;
(S )-3-Phenyl-2-[4-(4-phenyl-piperazin-1-yl )-benzenesulfonylamino]-
propionic acid;
(S)-2-{ 4-[-4-(3-Methoxy-phenyl)-piperazin-1-yl]-benzenesulfonylamino } -
3-phenyl-propionic acid;
(S)-2-{ 4-[-4-(3-Hydroxy-phenyl)-piperazin-1-yl]-benzenesulfonylamino }-
3-phenyl-propionic acid hydrobromide;
(S)-2- { 4-[-4-(4-Methoxy-phenyl )-piperazin-1-yl]-benzenesulfonylamino } -
3-phenyl-propionic acid;
(R)-4-Methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
pentanoic acid;
(S)-4-Methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
pentanoic acid;
(S)-3-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
propionic acid;
(R)-3-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
propionic acid;
(S )-3-( 1 H-Indol-3-yl )-2-[4-(4-phenyl-piperidin-1-yl )-
benzenesulfonylamino]-propionic acid;
[4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetic acid;
N-Hydroxy-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
acetamide;
3-[4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-propionic acid;
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(R)-4-Methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
pentanoic acid;
(S )-4-Methyl-2-[4-(4-phenyl-piperidin-1-yl )-benzenesulfonylamino]-
pentanoic acid;
(S)-3-Phenyl-2-[4-(4-phenyl-piperidin-I-yl)-benzenesulfonylamino]-
propionic acid;
(R)-3-Phenyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
propionic acid;
(S )-3-( 1 H-Indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl )-
benzenesulfonylamino]-propionic acid;
(~)-5-Phenyl-2-[4-(4-phenyl-piperidin-I-yl)-benzenesulfonylamino]-
pentanoic acid;
[4-(4-Phenyl-piperazin-I-yl)-benzene-sulfonylamino]-acetic acid;
{ Isobutyl-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonyl] amino }-acetic
acid;
(S)-4-Phenyl-2-[4-(4-phenyl-piperidin-I-yl)-benzenesulfonylamino]-
butyric acid;
(R)-2-[4-(4-Phenyl-piperidin-1-yl)-benzenesulfonylamino]-3-
tritylsulfanyl-propionic acid, sodium salt;
(R)-3-( 1 H-Indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl )-
benzenesulfonylamino]-propionic acid, disodium salt, monohydrate;
(S )-2- { 4-[-4-(4-Hydroxy-phenyl)-piperazin-1-yl ]-benzenesulfonylamino } -
3-phenyl-propionic acid;
(S)-2-{ 4-[-4-(4-Chloro-phenyl)-piperazin-1-yl]-benzenesulfonylamino } -3-
phenyl-propionic acid, hydrochloride;
(R)-3-Mercapto-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
propionic acid, trifluoracetic acid salt;
(S)-2-[4-(4-Benzyl-piperidin-1-yl)-benzenesulfonylamino]-3-phenyl-
propionic acid;
(S)-3-(4-Benzyloxy-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-
benzenesulfonylamino]-propionic acid;
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(S)-3-(4-Hydroxy-phenyl )-2-[4-(4-phenyl-piperidin-1-yl)-
benzenesulfonylamino]-propionic acid;
(S)-3-Phenyl-2-[4-(4-phenyl-piperazin-1-yl)-benzenesulfonylaminoJ-
propionic acid;
(S )-2- { 4-[-4-(3-Methoxy-phenyl )-piperazin-1-yl ]-benzenesulfonylamino } -
3-phenyl-propionic acid;
(S )-2- { 4-[-4-( 3-Hydroxy-phenyl)-piperazin-1-yi ]-benzenesulfonylamino } -
3-phenyl-propionic acid hydrobromide;
(S)-2- { 4-[-4-(4-Methoxy-phenyl)-piperazin-1-yl]-benzenesulfonylamino } -
3-phenyl-propionic acid;
(R)-4-Methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
pentanoic acid;
(S)-4-Methyl-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
pentanoic acid;
(S)-3-Phenyl-2-[4-{4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-
propionic acid;
(R)-3-Phenyl-2-[4-(4-phenyl-piperidin-1-yl )-benzenesulfonylamino]-
propionic acid; and
(S)-3-( 1 H-Indol-3-yl)-2-[4-(4-phenyl-piperidin-1-yl)-
benzenesulfonylamino]-propionic acid.
Additional specific compounds which can be used include:
2-(Dibenzofuran-2-sulfonylamino)-3-(4-fluoro-phenyl)-propionic acid;
2-(Dibenzofuran-2-sulfonylamino)-3-phenyl-propionic acid;
3-(4-tert-Butoxy-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionic
acid;
{Dibenzofuran-2-sulfonylamino)-phenyl-acetic acid;
3-tert-Butoxy-2-{dibenzofuran-2-sulfonylamino)-propionic acid;
2-(Dibenzofuran-2-sulfonylamino)-3-(1H-imidazol-4-yl)-propionic acid;
2-(Dibenzofuran-2-sulfonylamino)-3-hydroxy-propionic acid;
3-Benzyloxy-2-(dibenzofuran-2-sulfonylamino)-propionic acid;
6-Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-hexanoic
acid;
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5-Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-pentanoic
acid;
(Dibenzofuran-2-sulfonylamino}-(4-methoxy-phenyl)-acetic acid;
3-Chloro-2-(dibenzofuran-2-sulfonylamino)-propionic acid;
3-(4-Benzyloxy-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionic
acid;
2-(Dibenzofuran-2-sulfonylamino)-5-p-tolyl-sulfanylamino-pentanoic
acid;
2-(Dibenzofuran-2-sulfonylamino)-4-mercapto-butyric acid;
3-(4-Bromo-phenyl)-2-(dibenzofuran-2-sulfonyl-amino}-propionic acid;
2-(Dibenzofuran-2-sulfonylamino)-butyric acid;
1-(Dibenzofuran-2-sulfonylamino)-cyclopropane-carboxylic acid;
3-(4-Chloro-phenyl)-2-(dibenzofuran-2-sulfonyl-amino)-propionic acid;
2-(Dibenzofuran-2-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-fluoro-
benzenesulfonylamino)-hexanoic-acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-methoxy-
benzenesulfonylamino)-hexanoic acid;
6-(4-Bromo-benzenesulfonylamino)-2-(4'-bromo-biphenyl-4-
sulfonylamino)-hexanoic-acid;
6-(2-Acetylamino-thiazole-5-sulfonylamino)-2-(4'-bromo-biphenyl-4-
sulfonylamino)-hexanoic-acid;
6-(4-Acetylamino-benzenesulfonylamino)-2-(4'-bromo-biphenyl-4-
sulfonylamino)-hexanoic-acid;
6-Benzenesulfonylamino-2-(4'-bromo-biphenyl-4-sulfonylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(pentane-1-sulfonylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(naphthalene-2-
sulfonylamino)-hexanoic-acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(naphthalene-1-
sulfonylamino)-hexanoic-acid;
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2-(4'-Bromo-biphenyl-4.-sulfonylamino)-6-(2-phenyl-
ethenesulfonylamino)-hexanoic-acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-phenyl-acetylamino-hexanoic
acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-chloro-phenoxy)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino}-6-[2-(4-chloro-phenoxy)-2-
methyl-propionylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino}-6-[2-(pyridin-4-ylsulfanyl)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(2,4-dichloro-phenoxy)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-thiophen-2-yl-acetylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(3-phenyl-acryloylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(7-phenyl-heptanoylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(2-trifluoromethyl-phenyl)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-phenoxy-butyrylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-phenyl-sulfanyl-
acetylamino)-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-phenoxy-acetylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(3, 4-dimethoxy-phenyl)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-tent-butyl-phenoxy)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(3, 4-dimethoxy-phenyl)-
propionylamino]-hexanoic acid;
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2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-cyclopent-1-enyl-
acetylamino)-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-methoxy-phenoxy)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(naphthalen-1-yloxy)-
acetylamino]-hexanoic acid;
2-(4' -Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-nitro-phenoxy)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[4-(4-chloro-3-methyl-
phenoxy)-butyrylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-methoxy-phenyl)-
propionylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino)-
hexanoic acid;
6-(2-Benzo[ 1,3]dioxol-S-yl-acetylamino)-2-(4'-bromo-biphenyl-4-
sulfonylamino)-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-2-yl-acetylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-tert-butyl-phenoxy)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl)-
propionylamino]-hexanoic acid;
2-(4' -B romo-biphenyl-4-sulfonylamino)-6-(2-cyclopent-1-enyl-
acetylamino)-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-methoxy-phenoxy)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(naphthalen-1-yloxy)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-nitro-phenoxy)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino}-6-[4-(4-chloro-3-methyl-
phenoxy)-butyrylamino]-hexanoic acid;
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2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-methoxy-phenyl)-
propionylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino)-
hexanoic acid;
6-(2-Benzo[ 1,3]dioxol-5-yl-acetylamino)-2-(4'-bromo-biphenyl-4-
sulfonylamino)-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-2-yl-acetylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-(4-nitro-phenyl)-
butyrylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-tent-butyl-phenoxy)-
acetylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl)-
propionylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-cyclopent- I -enyl-
acetylamino)-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[2-(4-methoxy-phenoxy)-
acetylamino)-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-phenyl-butyrylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[4-(4-chloro-3-methyl-
phenoxy)-butyrylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-chloro-phenyl)-
propionylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-[3-(4-methoxy-phenyl)-
propionylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino)-
hexanoic acid;
6-(2-Benzo[ 1,3]dioxol-5-yl-acetylamino)-2-(4'-bromo-biphenyl-4-
sulfonylamino)-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2-naphthalen-1-yl-
acetylamino)-hexanoic acid;
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2-(4'-Bromo-biphenyl-4-sulfonylamino)-b-[3-(4-chloro-phenoxy)-
propionylamino]-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(6-phenyl-hexanoylamino)-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(4-thiophen-2-yl-
butyrylamino)-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(2,4,b-triisopropyl-
benzoylamino)-hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-isobutoxycarbonylamino-
hexanoic acid;
2-(4'-Bromo-biphenyl-4-sulfonylamino)-6-(9H-fluoren-9-
ylmethoxycarbonylamino)-hexanoic acid;
6-(Adamantan-1-yloxycarbonyl amino)-2-(4' -bromo-biphenyl-4-
sulfonylamino)-hexanoic acid; and
6-Allyloxycarbonylamino-2-(4'-bromo-biphenyl-4-sulfonylamino)-
hexanoic acid.
Numerous succinamide MMP inhibitors are known and can be utilized in
the method of this invention. Typical succinamides include:
2S,N1-Dihydroxy-3R-isobutyl-N4-{ 1S-[2-(2-methoxy-
ethoxymethoxy)ethylcarbamoyl]-2,2-dimethyl-propyl }-succinamide;
2S-Allyl-N1-hydroxy-3R-isobutyl-N4-{ 1S-[2-(2-methoxy-
ethoxymethoxy)ethylcarbamoyl]-2-phenyl-ethyl }-succinamide;
2S-Allyl-N1-hydroxy-3R-isobutyl-N4-{ 1S-[2-(2-methoxy-
ethoxymethoxy)ethylcarbamoyl]-2,2-dimethyl-propyl }-succinamide;
2S-Allyl-N 1-hydroxy-3R-isobutyl-N4-( 1 S- { 2-[2-(2-methoxy-ethoxy)-
ethoxyJ-ethylcarbamoyl)-2,2-dimethyl-propyl } -succinamide;
2S-Allyl-N4-{ 1S-[2,2-di-(methoxymethyl)-propylcarbamoyl}-2,2-
dimethyl-propyl]-N 1-hydroxy-3R-isobutyl-succinamide;
2S-Allyl-N4-{ 1S-[2,2-di-(methoxymethyl)-butylcarbamoyl]-2,2-dimethyl-
propyl } -N 1-hydroxy-3R-isobutyl-succinamide;
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N4'Hydroxy-2R-isobutyl-N1-{ 1S-[2-(2-methoxy-ethoxy}-
ethylcarbamoyl]-2,2-dimethyl-propyl }-3S-(thiophen-2-yl-sulfanylmethyl)-
succinamide;
N4-Hydroxy-2R-i sobutyl-N 1-( 1 S- { 2-[2-(2-methoxy-ethoxy)-ethoxy]-
ethylcarbamoyl }-2,2-dimethyl-propyl)-3S-(thiophen-2-yl-sulfanylmethyl)-
succinamide;
N1-{ 1S-[2,2-Di-(methoxymethyl)-propylcarbamoyl]-2,2-dimethyl-
propyl }-N4-hydroxy-3R-isobutyl-3S-(thiophen-2-yl-sulfanylmethyl)-
succinamide;
N4-Hydroxy-2R-isobutyl-N1-{ 1S-[2-(2-methoxy-ethoxy)-
ethylcarbamoyl]-2,2-dimethyl-propyl }-3S-propyl-succinamide;
N4-( 1 S-Cyclobutylcarbamoyl-2,2-dimethyl-propyl )-2S,N 1-dihydroxy-3 R-
isobutyl-succinamide;
N4-( 1 S-Cyclopropylcarbamoyl-2, 2-dimethyl-propyl )-2S,N 1-dihydroxy-
3R-isobutyl-succinamide;
N4-( 1 S-Cyclopentylcarbamoyl-2,2-dimethyl-propyl)-2S,N 1-dihydroxy-
3R-isobutyl-succinamide;
N4-( 1 S-Cyclohexylcarbamoyl-2,2-dimethyl-propyl)-2S,N 1-dihydroxy-3R-
isobutyl-succinamide;
N4-( 1 S-Cycloheptylcarbamoyl-2,2-dimethyl-propyl)-2S,N 1-dihydroxy-
3R-isobutyl-succinamide;
N4-( 1 S-Cyclopropylcarbamoyl-2-mercapto-2-methyl-propyl)-2S,N 1-
dihydroxy-3R-isobutyl-succinamide;
N4-( 1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-2S,N 1-dihydroxy-
3R-(3-phenyl-propenyl)-succinamide;
N4-( 1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-2S,N 1-dihydroxy-
3R-(3-phenyl-propyl)-succinamide;
N4-[2,2-Dimethyl-1 S-(2-phenyl-cyclopropylcarbamoyl)-propyl]-2S,N 1-
dihydroxy-3R-isobutyl-succinamide;
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2S-Allyl-N4-( 1-cyclopropylcarbamoyl-2,2-dimethyl-propyl)-N 1-hydroxy-
3R-isobutyl-succinamide;
2S-Allyl-N4-( 1 S-cyclopropylcarbamoyl-2-mercapto-2-methyl-propyl)-N 1-
hydroxy-3R-isobutyl-succinamide;
N4-( 1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-N 1-hydroxy-3R-
isobutyl-2S-(thiophen-2-ylsulfanylmethyl)-succinamide;
N4-( 1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-N 1-hydroxy-2S-(4-
hydroxy-phenylsulfanylmethyl)-3R-isobutyl-succinamide; and
N4-( 1 S-Cyclopropylcarbamoyl-2,2-dimethyl-propyl)-2S-( 1,3-dioxo-1,3-
dihydro-isoindol-2-ylmethyl)-N 1-hydroxy-3R-isobutyl-succinamide.
Another especially preferred group of MMP inhibitors to be utilized in
combination with a statin according to the method of this invention are the
sulfonated amino acid derivatives described in WO 97/27174, incorporated
herein
by reference. Those compounds have the general structure
R11
R15 R14 R13 SO N_
coY
R12
where R11 is substituted or unsubstituted lower alkyl, substituted or
unsubstituted
aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted
heteroaryl, or substituted or unsubstituted heteroaryl alkyl;
R 12 is hydrogen, or a group as defined for R 11;
R 13 is a single bond, substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
R 14 is a single bond, -(CH2) 1 or 2-~ -CH=CH-, -C-_-C-, -CO-, -CONH-, -N=N-,
NH, N-alkyl, -NHCONH-, -NHCO-, -O-, -S-, -S02NH-, -S02NH-N=CH-,
or tetrazoldiyl;
R15 is substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, or
substituted or unsubstituted non-aromatic heterocyclic group; and
Y is NHOH or OH.
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Especially preferred compounds to be employed in the method of this
invention have the above formula wherein R13 is phenylene or substituted
phenylene. Typical of such compounds that can be employed have the formula
R11
N N -
R1~-N~ ~ SO N' _COOH
N ~ ~ 2i
R12
where R1~1 and R12 are as defined above, and R1~ is substituted or
unsubstituted
aryl or substituted or unsubstituted heteroaryl.
Especially preferred are compounds of the formula
R11
R18 SO NH' _COOH
2
wherein R 11 and R 18 are as follows:
R11 R18
S ~N
CH2
H - -
N
CH2
CH2
CF3CH2 - -
N ~ ~ CH2
HOOC CH2 - -
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R11 R18
H - -
N
CH2 F ~ / ~ /
(CH3)2CH -
H3C ~ /
(CH~)2CH -
CH2 F ~ / ~ /
(CH3)2CH -
/ O ~ /
H - -
N
HO ~ / O
/ CH2-
- -
CH2
N I N
/ ' CH2 \ O ~ /
CH2 ~ / N=N ~ /
~~3 ~ 2~ -
Br ~ / ~2 H ~ /
i
C C
S
~-~ CH2 HS ~ ~ C=C
S
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R11 R18
(C'~i3 ) 2q~ _ N N
~ I N~N ~ I
Especially preferred are the MMP inhibitors currently in clinical
development, for example batimastat (2).
MMP compounds in clinical development include batimastat (2) for the
treatment of malignant pleural effusion, and marimastat (1) for the treatment
of
pancreatic cancer. Galardin (3) is for the treatment of corneal ulcers, and a
specific MMP-1 inhibitor is RO 31-9790 (4).
Compounds in Clinical Development
o ~ o
HOHNOC N~ HOHNOC N
NHMe ~ NHMe
OH O ~ S j O
S
(1)
\ O ~ O
HOHNOC N~ HOHNOC N
NHMe
w
O
NH
(3) ~ / (4)
All that is required to practice the present invention is to administer to a
mammal suffering from a vascular disorder, including heart failure or
ventricular
dilatation, or at risk of developing any such vascular disorder, an effective
amount
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of a matrix metalloprotainase inhibitor in combination with an effective
amount of
a statin. Compounds which can inhibit the actions of matrix metalloproteinase
enzymes can be identified utilizing routine in vitro and in vivo assays.
Several
compounds from within the foregoing classes have been evaluated in such
standard assays and determined to be potent matrix metalloproteinase
inhibitors.
The assays measure the amount by which a test compound reduces the hydrolysis
of a thiopeptolide substrate caused by a matrix metalloproteinase enzyme. Such
assays are described in detail by Ye, et al., in Biochemistry, Vol. 31, No 45,
1992,
(11231-11235), which is incorporated herein by reference.
Thiopeptolide substrates show virtually no decomposition or hydrolysis in
the absence of a matrix metalloproteinase enzyme. A typical thiopeptolide
substrate commonly utilized for assays is Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-
OEt. A 100 uL assay mixture will contain 50 mM of 2-morpholinoethane sulfonic
acid monohydrate (MES, pH 6.0) 10 mM CaCl2, 100 pM thiopeptolide substrate,
and 1 mM 5,5'-dithio-bis-(2-nitro-benzoic acid) (DTNB). The thiopeptolide
substrate concentration is varied from 10 to 800 uM to obtain Km and Kcat
values. The change in absorbance at 405 nm is monitored on a Thermo Max
microplate reader (moleucular Devices, Menlo Park, CA) at room temperature
(22°C). The calculation of the amount of hydrolysis of the
thiopeptolide substrate
is based on E412 = 13600 m-1 cm-1 for the DTNB-derived product 3-carboxy-4-
nitrothiophenoxide. Assays are carried out with and without matrix
metalloproteinase inhibitor compounds, and the amount of hydrolysis is
compared
for a determination of inhibitory activity of the test compounds.
Several representative compounds have been evaluated for their ability to
inhibit various matrix metalloproteinase enzymes. Table I below presents
inhibitory activity for compounds from various classes. In the table, MMP-1
refers
to interstitial collagenase; MMP-2 refers to Gelatinase A; MMP-3 refers to
stromelysin; MMP-7 refers to matrilysin; and MMP-9 refers to Gelatinase B.
Test
compounds were evaluated at various concentrations in order to determine their
respective IC50 values, the micromolar concentration of compound required to
cause a 50% inhibition of the hydrolytic activity of the respective enzyme.
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N
O O
M
_ _ O_v
O O O N O ~ ~ O N O O O
C O O N O O O O O O O O
N
h v~
S O ~ O ~ M ~ ~O N o0 N
O O O O O O O O O O
M M
M p
O O O O O
O
N N
U :-
E
,
a ~ ~ o
~
Q ,
H w
a
,
~ ~C ~ ~O.y C
~I
O r d ~ T ~ V ~ 7
_ ~ V U ~ ~ p
O U C
N ~ ~ 7, G.j,O ~
i~ .~ N _
'fl
~
N y C .= . t0 C .a
.E a
> >, , a,>.
p
' L w T iv
a . a
a o s a 0. a ~ a
~1~. C
G
T . ~ ~ '~F.
_N_ L N j, ~ >,= C ~'G
.
S C C '
:n ~ ~ ~ .aa
~
a ..
X v OD d' v d'T C N
O T v G .' a
X
N ~ c s
V ~ T ~ V C
L ~ '
~ ~ ~ ~
'r
U ~ ~ ~ , a o c .' a ,
z ~y
~,
~
. ._e
W ' I~
~
7 ~ ~ v i
c E C'~ ~ s s '
~ ert~. _ N e
~?N ~ a" O
E G C G fn ~ ~'~ M O 7,O v ~ ~ 'G
~ c3 p X , X .
C ~ .a., x ~ ,
to s LlC7 io 'oN p O O ,
0. ~ _ ~ ~ z
oa ~ a a V . a x ~ z ~
_
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~O O O~~O~~'--O~N It
G7 C C O O C C C C C C
I00 M hN M_ ~et~ ~O 00 V1
IO, O ~0~4MO,L~~~ N
'o o c c c o c o o c o
b 0.
N
M
U
O 'n
O
U ~ c ;v
... a, W .E :n .d;g R .fl
d w U U
t C ~ R V e3
E-~ tit ~ V O
N ..~'.~ ",~,L1 ~
C ~
N t ~ GL ~ ~ TJ U
E N ~ ~ ' cace ~ v r
c~ C i~ ~ ~ T V V i C3
~, t O ~ N .w.~ O t~ 3
C 7, ~ C ~ t ~ ~ C ~ .D
w ~, '~~,0. N ?, T
C M t0M M t,~ ed~ C
N O c O O C
C .N C O C C .E ~ ~ G.
.E '
C ~ N ~ ~ K X ~ T O
C i y.i>>, O O W C
G n G C ~-~- E t
7, i 'O'D '
~ ~ >,w w ~, ~! T
7 7 ~ t '."~
t ~ W C
!~~ ~~i . !~ ~
a _ ~ t
i~T >'>, T T 7
o. ~ C ~ C C ~ V' ~ C '~
~ t N ~ N N
o. ~ a n. c a a
N ~ C o ~'o oC too. n.o ~?
E ~;C E .D~ .OO N
U ~ .GO' T .EO ' C
~r ~, O O O L
i o x, t a as o ~ o a
v--c O
~' _ ~ ~ ~ ~ U CA V ~
N ~ N ~'N M N N ~ ~ ~ 'V'N
C
i=.C'~ .=.~'~.~ i~ v ~ ~t~ i.
O L ~ ~r ~r
~ v +~ ~n
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M
r N ~ b M ~ h M N
r~~~00~r0~M~00
~MO~oO~~tf~oo~0
O O O O~ ~ O M O O O
b
U
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The pharmaceutical combinations and methods of this invention are all
adapted to therapeutic use as agents in the prevention and treatment of
atherosclerosis, angina pectoris, and a condition characterized by the
presence of
both hypertension and hyperlipidemia in mammals, particularly humans. Further,
S since these diseases and conditions are closely related to the development
of
cardiac disease and adverse cardiac conditions, these combinations and
methods,
by virtue of their action as antiatherosclerotics, antianginals,
antihypertensives,
and antihyperlipidemics, are useful in the management of cardiac risk in
subjects
at risk of developing adverse cardiac conditions and in subjects at risk of
suffering
adverse cardiac events and heart failure such as CHF and ventricular
dilatation.
The utility of the compositions of the present invention as medical agents
in the treatment of vascular disorders such as atherosclerosis and CHF in
mammals (e.g., humans) is demonstrated by the activity of the compounds of
this
invention in conventional assays and in a clinical protocol such as that
described
below. The following examples are illustrative only, and are not intended to
limit
the invention in any way.
EXAMPLE 1
The following animal assay established the ability of an MMP inhibitor
together with a statin to treat vascular disorders.
Four groups of male New Zealand White rabbits were fed a chow diet
(Ralston Purina) combining 2% cholesterol, 3% peanut oil, 3% coconut oil diet
for
1 week prior to administering test compounds, and throughout the test. Water
was
available ad libitum. One group of 10 animals served as untreated controls.
Ten
milligrams per kilograms of PD 166793 (CI-1026) was administered daily to one
group of 10 animals for 8 weeks. Five milligrams per kilogram atorvastatin
calcium was administered daily to a group of 10 animals for 8 weeks. The
combination of both agents was administered at the same doses to a group of
10 animals for 8 weeks. At necropsy, blood was collected for plasma
cholesterol
measurements, aortic arch was removed for morphologic, morphometric and
biochemical analysis. The gross surface extent of atherosclerosis within the
aortic
arch, lesion cross-sectional area and monocyte-macrophage content were
measured as indices of antiatherosclerotic activity.
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Biochemical Methods. Plasma total cholesterol and triglyceride levels were
measured enzymatically throughout the study on an Abbott VP Series II
Bichromatic Analyzer (Chicago, IL), using the Boehringer-Mannheim total
cholesterol reagent (Indianapolis, IN) and the Abbott triglyceride reagent
(Chicago, IL). The lipid measurements were made monthly or biweekly
throughout the study on plasma samples collected 24 hours post-meal.
The aortic arch was assayed for its cholesteryl ester (CE), free cholesterol,
and
total phospholipid content. The lipids were extracted in chloroform:methanol
(2:1 v/v) and 300-500 p.L of an internal standard, ie, 200 mg/mL of a solution
of
4-hydroxy-cholesterol in ethyl acetate:acetone (2:1 v/v), was added to the
extracts
of the aortic samples. After extraction, the organic phase was dried under
nitrogen
and redissolved in isooctane/tetrahydrofuran (97:3 v/v). The lipid content and
composition of the aortic arch were measured using an HPLC method.
Cytochemical Methods. For histologic evaluation of the aortic arch lesions
and for quantification of aortic arch cross-sectional lesion area, a 1 cm
segment of
the ascending aorta distal to the aortic valves was fixed in 10% neutral
buffered
formalin for 24 hours. The vessels were dehydrated, cleared in xylene, and
infiltrated with molten paraffin (<60EC) using a Tissue Tek VIP autoprocessor
(Miles Scientific, Elkhart, Indiana). The tissue segments were embedded in
paraffin and sectioned at 5 um with a Reichert-Jung microtome (Baxter, McGraw
Park, Illinois). In order to obtain a thorough representation of the
histologic
appearance of the aortic arch lesions, 3 ribbons of 20 sections each were cut.
Each
ribbon of sections was spaced approximately 100 um apart. Three pairs of
sections, ie, 1 pair from each ribbon, were affixed to cleaned
3-aminopropyltriethoxy-silane coated glass slides and stored until stained.
The
general histologic character was evaluated in Verhoeff's elastica stained
sections.
Morphometric Methods. Gross extent of atherosclerosis within the aortic
arch was measured. The area of the aortic arch distal to the 1 cm segment
taken
for histologic evaluation to the first intercostal ostia was removed from the
animal, opened longitudinally, and images of the surface of the vessel were
collected using a digital camera. The lesions were identified as raised,
opaque
areas, and their area was determined using the Image Pro Plus image analysis
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software. The area of the entire aortic arch was also determined. The
percentage
of aortic arch covered by atherosclerotic lesions was calculated.
The cross-sectional area and macrophage content of lesions located distal
to the aortic valve ring were also measured. Sections of the aortic arch, a
site of
hypercholesterolemia-induced lesions, stained using the Verhoeff's elastica
procedure were used for quantification of lesion cross-sectional area. The
internal
elastic lamina (IEL) was identified as a blue-black ring and images of that
region
were collected using a digital camera. The area within the IEL was quantified
using the Image Pro Plus image analysis software. The area of the lumen of the
aortic arch was also quantified in a similar fashion. Lesion area was defined
as the
difference between the area circumscribed by the internal elastic lamina and
the
lumen area. Contiguous sections stained for monocyte-macrophages using
antibodies specific for rabbit macrophages were used for quantification of
macrophage area. The red- or brown-stained regions within the aortic arch
lesions
were identified, and images were collected using a digital camera. Since the
macrophages were darker than the surrounding lesion area, a histogram of grey
levels was used to identify an inflection point in the image grey level
intensities
which arbitrarily delineated the grey levels associated with macrophages.
After
delineation of the macrophages, their area was quantified using the Image Pro
Plus image analysis software.
The data thus generated established that MMP inhibitor-statin
combinations are surprisingly useful for treating vascular disorders.
EXAMPLE 2
Effect of MMP Inhibitor and a Statin, Alone and in Combination,
on the Treatment of Atherosclerosis
This study is a prospective randomized evaluation of the effect of a
combination of an MMP inhibitor or a pharmaceutically acceptable salt thereof
and a statin on the progression/regression of coronary and carotid artery
disease
The study is used to show that a combination of an MMP inhibitor, e.g., 2-(4'-
bromophenyl-4-sulfonylamino)-3-methyl-butyric acid, or a pharmaceutically
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acceptable acid addition salt, and a statin, e.g. atorvastatin calcium, is
effective in
slowing or arresting the progression or causing regression of existing
coronary
artery disease (CAD) as evidenced by changes in coronary angiography or
carotid
ultrasound, in subjects with established disease.
This study is an angiographic documentation of coronary artery disease
carried out as a double-blind, placebo-controlled trial of a minimum of about
500 subjects and preferably of about 780 to about 1200 subjects. It is
especially
preferred to study about 1200 subjects in this study. Subjects are admitted
into the
study after satisfying certain entry criteria set forth below.
Entry criteria: Subjects accepted for entry into this trial must satisfy
certain criteria. Thus, the subject must be an adult, either male or female,
aged
18 to 80 years of age in whom coronary angiography is clinically indicated.
Subjects will have angiographic presence of a significant focal lesion such as
30%
to 50% on subsequent evaluation by quantitative coronary angiography {QCA) in
a minimum of one segment (non-PTCA, non-bypassed, or non-MI vessel) that is
judged not likely to require intervention over the next 3 years. It is
required that
the segments undergoing analysis have not been interfered with. Since
percutaneous transluminal cardiac angioplasty (PTCA) interferes with segments
by the insertion of a balloon catheter, non-PTCA segments are required for
analysis. It is also required that the segments to be analyzed have not
suffered a
thrombotic event, such as a myocardial infarct (MI). Thus, the requirement for
non-MI vessels. Segments that will be analyzed include: left main, proximal,
mid
and distal left anterior descending, first and second diagonal branch,
proximal and
distal left circumflex, first or largest space obtuse marginal, proximal, mid
and
distal right coronary artery. Subjects will have an ejection fraction of
greater than
30% determined by catheterization or radionuclide ventriculography or ECHO
cardiogram at the time of the qualifying angiogram or within the previous
3 months of the acceptance of the qualifying angiogram provided no intervening
event such as a thrombotic event or procedure such as PTCA has occurred.
Generally, due to the number of patients and the physical limitations of
any one facility, the study is carried out at multiple sites. At entry into
the study,
subjects undergo quantitative coronary angiography as well as B-mode carotid
artery ultrasonography and assessment of carotid arterial compliance at
designated
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testing centers. This establishes baselines for each subject. Once admitted
into the
test, subjects are randomized to receive the MMP inhibitor (200 mg) and
placebo
or a statin (dose is dependent upon the particular statin used; however,
generally
80 mg will be used at first) and placebo or MMP inhibitor (200 mg) and a
statin
(80 mg). It will be recognized by a skilled person that the free base form or
other
salt forms of MMP inhibitors or the free base form or other salt forms of the
statin
may be used in this invention. Calculation of the dosage amount for these
other
forms of the statin and MMP inhibitor is easily accomplished by performing a
simple ratio relative to the molecular weights of the species involved. The
amount
of MMP inhibitor may be varied as required. Generally, a subject will start
out
taking 200 mg, and the amount will be titrated down to as little as 50 mg as
determined by the clinical physician. The amount of the statin will similarly
be
titrated down from 80 mg if it is determined by the physician to be in the
best
interests of the subject. The subjects are monitored for a 1- to 3-year
period,
generally 3 years being preferred. B-mode carotid ultrasound assessment of
carotid artery atherosclerosis and compliance are perfdrmed at regular
intervals
throughout the study.
Generally, 6-month intervals are suitable. Typically this assessment is
performed using B-mode ultrasound equipment. However, a person skilled in the
art may use other methods of performing this assessment. Coronary angiography
is performed at the conclusion of the 1- to 3-year treatment period. The
baseline
and posttreatment angiograms and the intervening carotid artery B-mode
ultrasonograms are evaluated for new lesions or progression of existing
atherosclerotic lesions. Arterial compliance measurements are assessed for
changes from baseline and over the 6-month evaluation periods.
The primary objective of this study is to show that the combination of
MMP inhibitor or a pharmaceutically acceptable acid addition salt and a statin
reduces the progression of atherosclerotic lesions as measured by quantitative
coronary angiography (QCA) in subjects with clinical coronary artery disease.
QCA measures the opening in the lumen of the arteries measured.
The primary endpoint of the study is the change in the average mean
segment diameter of the coronary artery tree. Thus, the diameter of an
arterial
segment is measured at various portions along the length of that segment. The
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average diameter of that segment is then determined. After the average segment
diameter of many segments has been determined, the average of all segment
averages is determined to arrive at the average mean segment diameter. The
mean
segment diameter of subjects taking a statin and MMP inhibitor or a
pharmaceutically acceptable acid addition salt will decline more slowly, will
be
halted completely, or there will be an increase in the mean segment diameter.
These results represent slowed progression of atherosclerosis, no change in
the
progression of atherosclerosis, and regression of atherosclerosis,
respectively.
The secondary objective of this study is that the combination of MMP
inhibitor or a pharmaceutically acceptable acid addition salt and a statin
reduces
the rate of progression of atherosclerosis in the carotid arteries as measured
by the
slope of the maximum intimal-medial thickness measurements averaged over
12 separate wall segments (Mean Max) as a function of time, more than does the
MMP inhibitor or a pharmaceutically acceptable acid addition salt or a statin
alone. The intimal-medial thickness of subjects taking a statin and an MMP
inhibitor or a pharmaceutically acceptable salt thereof will increase more
slowly,
will cease to increase, or will decrease. These results represent slowed
progression
of atherosclerosis, halted progression of atherosclerosis, and regression of
atherosclerosis, respectively. Further, these results may be used to
facilitate
dosage determinations.
The utility of the compounds of the present invention as medical agents in
the treatment of angina pectoris in mammals (e.g., humans) is demonstrated by
the
activity of the compounds of this invention in conventional assays and the
clinical
protocol described below.
EXAMPLE 3
Effect of MMP Inhibitor and a Statin, Alone and in Combination, on the
Treatment of Angina
This study is a double-blind, parallel-arm, randomized study to show the
effectiveness of MMP inhibitor or a pharmaceutically acceptable acid addition
salt
thereof and a statin given in combination in the treatment of symptomatic
angina.
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Entry criteria: Subjects are males or females between 18 and 80 years of
age with a history of typical chest pain associated with one of the following
objective evidences of cardiac ischemia: ( 1 ) stress test segment elevation
of about
one millimeter or more from the ECG; (2) positive treadmill stress test; (3)
new
wall motion abnormality on ultrasound; or (4) coronary angiogram with a
significant qualifying stenosis. Generally a stenosis of about 30% to 50% is
considered to be significant.
Each subject is evaluated for about 10 to 32 weeks. At least 10 weeks are
generally required to complete the study. Sufficient subjects are used in this
screen to ensure that about 200 to 800 subjects and preferably about 400
subjects
are evaluated to complete the study. Subjects are screened for compliance with
the
entry criteria, set forth below, during a 4-week run-in phase. After the
screening
criteria are met, subjects are washed out from their current anti-anginal
medication
and stabilized on a long acting nitrate such as nitroglycerine, isosorbide-5-
mononitrate or isosorbide dinitrate. The tenor "washed out", when used in
connection with this screen, means the withdrawal of current anti-anginal
medication so that substantially all of said medication is eliminated from the
body
of the subject. A period of 8 weeks is preferably allowed for both the washout
period and for the establishment of the subject on stable doses of said
nitrate.
Subjects having one or two attacks of angina per week while on stable doses of
long acting nitrate are generally permitted to skip the washout phase. After
subjects are stabilized on nitrates, the subjects enter the randomization
phase
provided the subjects continue to have either one or two angina attacks per
week.
In the randomization phase, the subjects are randomly placed into one of the
four
arms of the study set forth below. After completing the washout phase,
subjects in
compliance with the entry criteria undergo 24-hour ambulatory
electrocardiogram
(ECG) such as Holter monitoring, exercise stress testing such as a treadmill,
and
evaluation of myocardial perfusion using photon emission tomography (PET)
scanning to establish a baseline for each subject. When conducting a stress
test,
the speed of the treadmill and the gradient of the treadmill can be controlled
by a
technician. The speed of the treadmill and the angle of the gradient are
generally
increased during the test. The time intervals between each speed and gradient
increase is generally determined using a modified Bruce Protocol.
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After the baseline investigations have been completed, subjects are
initiated on one of the following four arms of the study: ( 1 ) placebo; (2) a
statin
(about 2.5 mg to about 160 mg); {3) MMP inhibitor (about 25 mg to about
200 mg); or (4) a combination of the above doses of MMP inhibitor and a statin
together. The subjects are then monitored for 2 to 24 weeks. It will be
recognized
by a skilled person that the free base form or other salt forms of MMP
inhibitor or
the free base form or other salt forms of the statin may be used in this
invention.
Calculation of the dosage amount for these other forms of the statin and MMP
inhibitor is easily accomplished by performing a simple ratio relative to the
molecular weights of the species involved.
After the monitoring period has ended, subjects will undergo the following
investigations: ( 1 ) 24-hour ambulatory ECG, such as Holter monitoring;
(2) exercise stress testing (e.g., treadmill using said modified Bruce
Protocol); and
(3) evaluation of myocardial perfusion using PET scanning. Patients keep a
diary
of painful ischemic events and nitroglycerine consumption. It is generally
desirable to have an accurate record of the number of anginal attacks suffered
by
the patient during the duration of the test. Since a patient generally takes
nitroglycerin to ease the pain of an anginal attack, the number of times that
the
patient administers nitroglycerine provides a reasonably accurate record of
the
number of anginal attacks.
To demonstrate the effectiveness and dosage of the drug combination of
this invention, the person conducting the test will evaluate the subject using
the
tests described. Successful treatment will yield fewer instances of ischemic
events
as detected by ECG, will allow the subject to exercise longer or at a higher
intensity level on the treadmill or to exercise without pain on the treadmill,
or will
yield better perfusion or fewer perfusion defects on PET.
The utility of the compounds of the present invention as medical agents in
the treatment of hypertension and hyperlipidemia in mammals (e.g., humans)
suffering from a combination of hypertension and hyperlipidemia is
demonstrated
by the activity of the compounds of this invention in conventional assays and
the
clinical protocol described below.
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EXAMPLE 4
Effects of MMP Inhibitor and a Statin, Alone and in Combination, on the
Treatment of Subjects Having Both Hypertension and Hyperlipidemia
This study is a double-blind, parallel-arm, randomized study to show the
effectiveness of an MMP inhibitor or a pharmaceutically acceptable acid
addition
salt thereof and a statin given in combination in controlling both
hypertension and
hyperlipidemia in subjects who have mild, moderate, or severe hypertension and
hyperlipidemia.
Each subject is evaluated for IO to 20 weeks and preferably for 14 weeks.
Sufficient subjects are used in this screen to ensure that about 400 to 800
subjects
are evaluated to complete the study.
Entry criteria: Subjects are male or female adults between 18 and 80 years
of age having both hyperlipidemia and hypertension. The presence of
hyperlipidemia is evidenced by evaluation of the LDL cholesterol level of the
IS subject relative to certain positive risk factors. If the subject has no
coronary heart
disease (CHD) and has less than two positive risk factors, then the subject is
considered to have hyperlipidemia, which requires drug therapy if the LDL of
the
subject is >_190 mg/dL. If the subject has no CHD and has two or more positive
risk factors, then the subject is considered to have hyperlipidemia, which
requires
drug therapy if the LDL of the subject is >_160 mg/dL. If the subject has CHD,
then the subject is considered to have hyperlipidemia if the LDL of the
subject is
>_ 130 mg/dL.
Positive risk factors include: ( 1 ) male over 45, (2) female over 55 wherein
said female is not undergoing hormone replacement therapy (HRT), (3) family
history of premature cardiovascular disease, (4) the subject is a current
smoker,
(S) the subject has diabetes, (6) an HDL of less than 45 mg/dL, and (7) the
subject
has hypertension. An HDL of >60 mg/dL is considered a negative risk factor and
will offset one of the above mentioned positive risk factors.
The presence of hypertension is evidenced by a sitting diastolic blood
pressure (BP) of >90 mmHg or sitting systolic BP of >140 mmHg. All blood
pressures are generally determined as the average of three measurements taken
5 minutes apart.
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Subjects are screened for compliance with the entry criteria set forth
above. After all screening criteria are met, subjects are washed out from
their
current antihypertensive and lipid lowering medication and are placed on the
NCEP ATP II Step 1 diet. The NCEP ATP II (adult treatment panel, 2nd revision)
Step 1 diet sets forth the amount of saturated and unsaturated fat which can
be
consumed as a proportion of the total caloric intake. The term "washed out",
where used in connection with this screen, means the withdrawal of current
antihypertensive and lipid lowering medication so that substantially all of
said
medication is eliminated from the body of the subject. Newly diagnosed
subjects
generally remain untreated until the test begins. These subjects are also
placed on
the NCEP Step 1 diet. After the 4-week washout and diet stabilization period,
subjects undergo the following baseline investigations: {1) blood pressure and
(2) fasting lipid screen. The fasting lipid screen determines baseline lipid
levels in
the fasting state of a subject. Generally, the subject abstains from food for
12 hours, at which time lipid levels are measured.
After the baseline investigations are performed, subjects are started on one
of the following: ( 1 ) a fixed dose of MMP inhibitor, generally about 25 to
200 mg;
(2) a fixed dose of a statin, generally about 2.5 mg to about 160 mg; or (3) a
combination of the above doses of MMP inhibitor and a statin together. It will
be
recognized by a skilled person that the free base form or other salt forms of
MMP
inhibitor or the free base form or other salt forms of the statin may be used
in this
invention. Calculation of the dosage amount for these other forms of the
statin and
MMP inhibitor is easily accomplished by performing a simple ratio relative to
the
molecular weights of the species involved. Subjects remain on these doses for
a
minimum of 6 weeks, and generally for no more than 8 weeks. The subjects
return
to the testing center at the conclusion of the 6 to 8 weeks so that the
baseline
evaluations can be repeated. The blood pressure of the subject at the
conclusion of
the study is compared with the blood pressure of the subject upon entry. The
lipid
screen measures the total cholesterol, LDL-cholesterol, HDL-cholesterol,
triglycerides, apoB, very low-density lipoprotein (VLDL) and other components
of the lipid profile of the subject. Improvements in the values obtained after
treatment relative to pretreatment values indicate the utility of the drug
combination.
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The utility of the compounds of the present invention as medical agents in
the management of cardiac risk in mammals (e.g., humans) at risk for an
adverse
cardiac event is demonstrated by the activity of the compounds of this
invention in
conventional assays and the clinical protocol described below.
EXAMPLE 5
Effects of an MMP Inhibitor and a Statin, Alone and in Combination,
on Subjects at Risk of Future Cardiovascular Events
This study is a double-blind, parallel-arm, randomized study to
demonstrate the effectiveness of carboxyalkylether or a pharmaceutically
acceptable acid addition salt and a statin given in combination in reducing
the
overall calculated risk of future events in subjects who are at risk for
having future
cardiovascular events. This risk is calculated by using the Framingham Risk
Equation. A subject is considered to be at risk of having a future
cardiovascular
event if that subject is more than one standard deviation above the mean as
calculated by the Framingham Risk Equation. The study is used to evaluate the
efficacy of a fixed combination of carboxylalkylether or a pharmaceutically
acceptable acid addition salt and a statin in controlling cardiovascular risk
by
controlling both hypertension and hyperlipidemia in patients who have both
mild
to moderate hypertension and hyperlipidemia.
Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks.
Sufficient subjects are recruited to ensure that about 400 to 800 subjects are
evaluated to complete the study.
Entry criteria: Subjects included in the study are male or female adult
subjects between 18 and 80 years of age with a baseline 5-year risk, which
risk is
above the median for said subject's age and sex, as defined by the Framingham
Heart Study, which is an ongoing prospective study of adult men and women
showing that certain risk factors can be used to predict the development of
coronary heart disease. The age, sex, systolic and diastolic blood pressure,
smoking habit, presence or absence of carbohydrate intolerance, presence or
absence of left ventricular hypertrophy, serum cholesterol, and HDL of more
than
one standard deviation above the norm for the Framingham Population are all
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evaluated in determining whether a patient is at risk for adverse cardiac
event. The
values for the risk factors are inserted into the Framingham Risk Equation and
calculated to determine whether a subject is at risk for a future
cardiovascular
event.
Subjects are screened for compliance with the entry criteria set forth
above. After all screening criteria are met, patients are washed out from
their
current antihypertensive and lipid lowering medication and any other
medication
which will impact the results of the screen. The patients are then placed on
the
NCEP ATP II Step 1 diet, as described above. Newly diagnosed subjects
generally
remain untreated until the test begins. These subjects are also placed on the
NCEP
ATP II Step 1 diet. After the 4-week washout and diet stabilization period,
subjects undergo the following baseline investigations: (1) blood pressure;
(2) fasting; (3) lipid screen; (4) glucose tolerance test; (5) ECG; and (6)
cardiac
ultrasound. These tests are carned out using standard procedures well-known to
persons skilled in the art. The ECG and the cardiac ultrasound are generally
used
to measure the presence or absence of left ventricular hypertrophy.
After the baseline investigations are performed, patients will be started on
one of the following: ( 1 ) a fixed dose of MMP inhibitor (about 25 to 200
mg);
(2) a fixed dose of a statin (about 2.5 mg to about 160 mg); or (3) the
combination
of the above doses of MMP inhibitor and a statin. Patients are kept on these
doses
and are asked to return in 6 to 8 weeks so that the baseline evaluations can
be
repeated. At this time, the new values are entered into the Framingham Risk
Equation to determine whether the subject has a lower, greater, or no change
in
the risk of future cardiovascular event.
The above assays demonstrating the effectiveness of an MMP inhibitor or
pharmaceutically acceptable acid addition salts thereof and a statin such as
atorvastatin or pharmaceutically acceptable salts thereof in the treatment of
angina
pectoris, atherosclerosis, hypertension and hyperlipidemia together, and the
management of cardiac risk, also provide a means whereby the activities of the
compounds of this invention can be compared between themselves and with the
activities of other known compounds. The results of these comparisons are
useful
for determining dosage levels in mammals, including humans, for the treatment
of
such diseases.
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The following dosage amounts and other dosage amounts set forth
elsewhere in this specification and in the appendant claims are for an average
human subject having a weight of about 65 kg to about 70 g. The skilled
practitioner will readily be able to determine the dosage amount required for
a
subject whose weight falls outside the 65 to 70 kg range, based upon the
medical
history of the subject and the presence of diseases, e.g., diabetes, in the
subject.
All doses set forth herein, and in the appendant claims, are daily doses.
In general, in accordance with this invention, the MMP inhibitor is
generally administered in a dosage of about 25 mg to about 500 mg. Preferably,
MMP inhibitor is administered in a dosage of about 5 mg to about 100 mg. It
will
be recognized by a skilled person that the free base form or other salt forms
of
MMP inhibitor may be used in this invention. Calculation of the dosage amount
for these other forms of or the free base form or other salt forms of MMP
inhibitor
is easily accomplished by performing a simple ratio relative to the molecular
weights of the species involved.
In general, in accordance with this invention, the above statins are
administered in the following dosage amounts:
Simvastatin, generally about 2.5 mg to about 160 mg and preferably about
10 mg to about 40 mg;
Pravastatin, generally about 2.5 mg to about 160 mg and preferably about
10 mg to about 40 mg;
Cerivastatin, generally about 25 p.g to about 5 mg and preferably about
1 mg to about 3.2 mg;
Fluvastatin, generally about 2.5 mg to about 160 mg and preferably about
20 mg to about 80 mg;
Lovastatin, generally about 2.5 mg to about 160 mg and preferably about
10 mg to about 80 mg; and
Atorvastatin, generally about 2.5 mg to about 160 mg and preferably about
10 mg to about 80 mg.
It will be recognized by a skilled person that the free base form or other
salt forms of the above statins may be used in this invention. Calculation of
the
dosage amount for these other forms of or the free base form or other salt
forms
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said statins is easily accomplished by performing a simple ratio relative to
the
molecular weights of the species involved.
The compounds of the present invention are generally administered in the
form of a pharmaceutical composition comprising at least one of the compounds
of this invention together with a pharmaceutically acceptable carrier or
diluent.
Thus, the MMP inhibitors and the statins can be. administered either
individually
or together in any conventional oral, parenteral, or transdermal dosage form.
For oral administration, a pharmaceutical composition can take the form of
solutions, suspensions, tablets, pills, capsules, powders, and the like.
Tablets
containing various excipients such as sodium citrate, calcium carbonate, and
calcium phosphate are employed along with various disintegrants such as starch
and preferably potato or tapioca starch and certain complex silicates,
together with
binding agents such as polyvinylpyrrolidone, sucrose, gelatin, and acacia.
Additionally, lubricating agents such as magnesium stearate, sodium lauryl
sulfate, and talc are often very useful for tableting purposes. Solid
compositions of
a similar type are also employed as fillers in soft- and hard-filled gelatin
capsules;
preferred materials in this connection also include lactose or milk sugar, as
well as
high molecular weight polyethylene glycols. When aqueous suspensions and/or
elixirs are desired for oral administration, the compounds of this invention
can be
combined with various sweetening agents, flavoring agents, coloring agents,
emulsifying agents, and/or suspending agents, as well as such diluents as
water,
ethanol, propylene glycol, glycerin, and various like combinations thereof.
The combinations of this invention may also be administered in a
controlled release formulation such as a slow release or a fast release
formulation.
Such controlled release formulations of the combination of this invention may
be
prepared using methods well-known to those skilled in the art. The method of
administration will be determined by the attendant physician or other person
skilled in the art after an evaluation of the subject's condition and
requirements.
The generally preferred formulation of atorvastatin calcium is Lipitor~ as
described in U.S. Patent 5,686,104 incorporated herein by reference.
For purposes of parenteral administration. solutions in sesame or peanut
oil or in aqueous propylene glycol can be employed, as well as sterile aqueous
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solutions of the corresponding water-soluble salts. Such aqueous solutions may
be
suitably buffered, if necessary, and the liquid diluent first rendered
isotonic with
sufficient saline or glucose. These aqueous solutions are especially suitable
for
intravenous, intramuscular, subcutaneous, and intraperitoneal injection
purposes.
In this connection, the sterile aqueous media employed are all readily
obtainable
by standard techniques well-known to those skilled in the art.
Methods of preparing various pharmaceutical compositions with a certain
amount of active ingredient are known, or will be apparent in light of this
disclosure, to those skilled in this art. For examples, see Remington's
Pharmaceutical Sciences, Mack Publishing Company, Easter, Pennsylvania., 15th
Edition (1975).
Pharmaceutical compositions according to the invention may contain 0.1 %
to 95% of the compound{s) of this invention, preferably 1% to 70%. In any
event,
the composition or formulation to be administered will contain a quantity of a
compounds) according to the invention in an amount effective to prevent or
treat
the condition or disease of the subject being treated, namely a vascular
disorder,
including CHF.
Since the present invention relates to the treatment of diseases and
conditions with a combination of active ingredients which may be administered
separately, the invention also relates to combining separate pharmaceutical
compositions in kit form. The kit includes two separate pharmaceutical
compositions: an MMP inhibitor or a pharmaceutically acceptable acid addition
salt thereof, and a statin or a pharmaceutically acceptable salt thereof. The
kit
includes container means for containing the separate compositions such as a
divided bottle or a divided foil packet; however, the separate compositions
may
also be contained within a single, undivided container. Typically, the kit
includes
directions for the administration of the separate components. The kit form is
particularly advantageous when the separate components are preferably
administered in different dosage forms (e.g., oral and parenteral), are
administered
at different dosage intervals, or when titration of the individual components
of the
combination is desired by the prescribing physician.
It should be understood that the invention is not limited to the particular
embodiments described herein, but that various changes and modifications may
be
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made without departing from the spirit and scope of this novel concept as
defined
by the following claims.
