Sulfonylamino acid derivatives

Details Sulfonylamino acid derivatives Sulfonylamino acid derivatives

1996-07-29

2001-01-23

Gerstl, Robert (Department: 1620)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S542000, C514S562000, C560S012000, C560S013000, C562S430000

Reexamination Certificate

active

06177466

ABSTRACT:

SUMMARY
This invention is related to sulfonylamino acid derivatives and matrix metalloproteinase inhibitors containing sulfonylamino acid derivatives as active ingredient. More particularly, this invention is related to:
(i) matrix metalloproteinase inhibitors containing sulfonylamino acid derivatives of the formula (Ia):
wherein all the symbols are the same meaning as hereinafter defined. and non-toxic salts thereof as active ingredient,
(ii) novel sulfonylamino acid derivatives of the formula (Ib):
wherein all the symbols are the same meaning as hereinafter defined, and non-toxic salts thereof, and
(iii) process for the preparation of the compounds of the formula (Ib).
BACKGROUND
The matrix metalloproteinases (MMPs) are neutral metalloproteinases and zinc (Zn
2+
) is essential in the active site for their activation. They degrade collagen, laminin, proteoglycans, fibronectin, elastin, gelatin etc. under physiological conditions and therefore, are effective on growth and tissue remodeling of articulation tissue, bone tissue, connective tissue. At least 10 classes of MMPs which differ in primary structure are identified. As common characters of each enzymes, MMPs
(1) have Zn
2+
in the active site and the activity depends on calcium (Ca
2
+),
(2) are secreted as an inactive proenzyme and activated outside of cells,
(3) have high homology on amino acid sequence,
(4) have degradable ability on various extracellular matrix components in vivo,
(5) are regulated by tissue inhibitors of metalloproteinases (TIMP) which are specific to MMPs.
MMP inhibitors are useful for prevention and/or treatment of various diseases induced by overexpression and excess activation of MMP. Such diseases are, for example, rheumatoid, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, metastasis of, invasion of or growth of tumor cells, autoimmune diseases (Crohn's disease, Sjogren's syndrome etc.), diseases caused by vascular emigration or infiltration of leukocytes, arterialization.
RELATED ARTS
Some compounds possessing inhibitory activity against MMP are known. A sequence in the vicinity of cleavage site of collagen (Gly-Ile-Ala-Gly or Gly-Leu-Ala-Gly) has high affinity for collagenase.
A lot of research and development of substrate analogous MMP inhibitors, which are chemically modified so as to have zinc affinity groups on a cleaving site of substrate, are carried out energetically [Inhibitors of matrix metalloproteinases (MMP's), Nigel R A Beeley, Phillip R J Ansell, Andrew J P Docherty et. al., Curr. Opin. Ther. Patents., 4, 7-16 (1994), Current Drugs Ltd ISSN 0962-2594]. However, these substrate-analogues inhibitors might have various problems. Therefor, it is desired a non-peptide inhibitor and some compounds are reported.
For example, in the specification of EP 606046, aryl-sulfonamide derivatives of the formula (X):
wherein (a) Ar
X
is carbocyclic or heterocyclic aryl; R
X
is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl etc.; R
1X
is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl etc.; R
2X
is hydrogen, lower alkyl; or (b) R
X
and R
1X
together with the chain to which they are attached form 1, 2, 3, 4-tetrahydro-isoquinoline, piperidine etc.; Ar
X
and R
2X
are the same meaning as (a); or (c) R
1X
and R
2X
together with the carbon to which they are attached form C3-7 cycloalkane, oxa-cyclohexane, thia-cyclohexane etc. which is unsubstituted or substituted by lower alkyl; and Ar
X
and R
2X
are the same meaning as (a); are disclosed to have inhibitory activity against matrix metalloproteinase.
Phenylsulfonylamino acid derivatives of the formula (Y):
wherein R
1Y
is hydrogen, R
2Y
is hydrogen;
R
1Y
is 4-methoxy, R
2Y
is hydrogen;
R
1Y
is 4-fluoro, R
2Y
is hydrogen;
R
1Y
is 4-nitro, R
2Y
is hydrogen;
R
1Y
is 3-nitro, R
2Y
is hydrogen;
R
1Y
is 2-nitro, R
2Y
is hydrogen;
R
1Y
is 4-formyl, R
2Y
is hydrogen;
R
1Y
is hydrogen, R
2Y
is (S)-phenyl;
R
1Y
is hydrogen, R
2Y
is (R)-phenyl;
R
1Y
is 4-methyl, R
2Y
is (S)-phenyl;
R
1Y
is 4-methyl, R
2Y
is (R)-phenyl;
R
1Y
is 4-methoxy, R
2Y
is (S)-phenyl;
R
1Y
is 4-methoxy, R
2Y
is (R)-phenyl;
R
1Y
is 4-fluoro, R
2Y
is (S)-phenyl;
R
1Y
is 4-fluoro, R
2Y
is (R)-phenyl;
R
1Y
is 4-nitro, R
2Y
is (S)-phenyl; or
R
1Y
is 4-nitro, R
2Y
is (R)-phenyl;
are disclosed to have inhibitory activity against aldose reductase [Biochemical Pharmacology, 40, 2219-2226 (1990)].
In the specification of EP347168, p-substituted phenyl ester of pivalic acid derivatives of the formula (Z):
wherein Y
Z
is sulfonyl (—SO
2
—) or carbonyl (—CO—); R
1Z
and R
2Z
, same or different, is hydrogen, C1-16 alkyl which may be substituted by carboxy (—COOH); R
3Z
is hydrogen, hydroxy, C1-6 alkyl, halogen, C1-4 alkoxy or C2-5 acyloxy; m
Z
is 1-4; are disclosed to have inhibitory activity against elastase.
The following compounds are disclosed to possess antimicrobial activity [J. Serb. Chem. Soc. 56(6), 311-318 (1991)].
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]glycine,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-alanine,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-&bgr;-alanine,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-valine,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-valine,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-leucine,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-leucine,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-serine,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-phenylalanine,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-tyrosine,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-alanine methyl ester,
N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-valine methyl ester,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-valine methyl ester,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-leucine methyl ester,
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-serine methyl ester, and
N-[[4-(2, 4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-tyrosine methyl ester.
The following compounds are disclosed to possess antifilarial activity [Indian J. Chem. 30B, 182-187 (1991)].
N-[[4-(3-Nitrobenzoylamino)phenyl]sulfonyl]-L-aspartic acid,
N-[[3-(3-Nitrobenzoylamino)phenyl]sulfonyl]-L-aspartic acid,
N-[[4-(3-Aminobenzoylamino)phenyl]sulfonyl]-L-aspartic acid and
N-[[3-(3-Aminobenzoylamino)phenyl]sulfonyl]-L-aspartic acid.
The following compounds are disclosed to possess antineoplastic activity [Indian J. Chem. 28B, 843-847 (1989)].
N-[[4-(Benzoylamino)phenyl]sulfonyl]-L-glutamic acid,
N-[[4-(4-Chlorobenzoylamino)phenyl]sulfonyl]-L-glutamic acid and
N-[[4-(4-Nitrobenzoylamino)phenyl]sulfonyl]-L-glutamic acid.
PURPOSE OF INVENTION
Energetic investigations have been carried out in order to make a matrix metalloproteinase inhibitor, the present inventors have found that a series of sulfonylamino acid derivatives of the formula (Ia) have inhibitory activity against matrix metalloproteinase and have accomplished the present invention.
Sulfonylamino acid derivatives of the formula (Ia) of the present invention are not known as matrix metalloproteinase inhibitors at all. And sulfonylamino acid derivatives of the formula (Ib) of the present invention are novel compounds that are not known at all.
Moreover, the compounds of the present invention possess, especially, a selective inhibitory activity against gelatinases classified in matrix metalloproteinases.
DISCLOSURE OF THE INVENTION
The present in

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