Highly water-soluble metalloproteinase inhibitors

Details Highly water-soluble metalloproteinase inhibitors Highly water-soluble metalloproteinase inhibitors

2000-01-27

2001-09-04

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S016000, C560S034000, C560S039000, C560S041000, C562S426000, C562S430000, C562S434000, C562S437000, C562S439000, C562S448000, C562S564000, C562S015000, C562S106000, C562S106000

Reexamination Certificate

active

06284914

ABSTRACT:

SPECIFICATION
1. Field of Industrial Application
The invention relates to new highly water-soluble compounds, which inhibit matrix metalloproteinases (MMPs) derived from vertebrates and/or tumor necrosis factor-&agr; (TNF-&agr;) converting enzyme, preparation intermediates thereof and a process for the preparation thereof.
2. Background Art
MMPs which belong to endo proteinases containing zink are involved in the decomposition of an extra-cellular matrix in a connective tissue. Up to now, it is known that there exist ten-odd MMPs, and the expression of these enzymes are strictly controlled in healthy volunteers. However, an abnormal aggravation of MMPs is observed in cases such as chronic rheumatoid arthritis, osteoarthritis, periodental disease, corneal ulcer, various kinds of bullosis (epidermolisis bullosa hereditaria, epidermolisis bullosa acquisita, porphylia cutanea tarda, bullos penphigoid, pemphigus vulgaris), intractable skin ulcer (bedsore, skin ulcer in radiotherapy, skin ulcer in diabetes mellitus, skin ulcer in arteriosclerotic obliteration), wound (external injury or burn), osteoporosis, cancer metasis and the like, and these are considered to participate in the destruction of the extra-cellular matrix. [D. Brown et al.,
Current Eye Research
, 12, 571(1993)/Y. Okada et al.,
Virchows Archiv. B, Cell Pathol
., 59, 305(1990)/W. G. Stetler-Stevenson,
Cancer Metastasis Reviews
, 9,289(1990)/H. Birkedal-Hansen et al.,
Critical Reviews in Oral Biology and Medicine
, 4(2),197(1993)] On the contrary, TNF-&agr; is produced as a membrane-bound type precursor of molecular weight 26K, and in case of the excess of an extra-cellular release is considered the occurrence of diseases such as sepsis, chronic rheumatoid arthritis or the like. Recently, it was reported that the enzyme (TNF-&agr; converting enzyme) inducing the release of TNF&agr; was a metalloproteinase whose activity was controlled by a MMPs inhibitor. [A. J. H. Gearing et al.,
Journal of Leukocyte Biology
, 57, 774(1995), K. M. Mohler et al.,
Nature
, 370, 218(1994), G. M. NcGeehan et al.,
Nature
, 370, 558(1994)].
Accordingly, in the above diseases, inhibiting the action of these enzymes becomes an effective method of therapy. However, as the compounds having MMPs inhibitory activities are known the compounds divided into four families which are phosphonic acid derivatives, hydroxamic acid derivatives, derivatives having mercapto group and derivatives having carboxyl group. Especially, on the hydroxamic acid derivatives are proposed compounds having various skeletons (see U.S. Pat. No. 4,599,361, EP, 575844 A2, U.S. Pat. No. 5,412,145, WO, 92/13831, U.S. Pat. No. 5,183,900, WO, 94/02447, EP, 606046 A1 and GB 2268933 A), and many of these compounds have highly inhibitory activities for various kinds of MMPs. However, each of these compounds is poor in its water-solubility and their administration methods are limited. For example, in case of applying these compounds as injections (aqueous solution), medicaments of high concentration cannot be prepared. Furthermore, in case of administering injections into joint, if there is a particle not less than 50 &mgr;m, the occurrence of a synovial inflammation is known, therefore, it becomes a necessary condition for a compound to be completely dissolved state. In the known compounds, such an administration is impossible, and it is a present situation that they are not effectively utilized as therapeutic agents.
DISCLOSURE OF THE INVENTION
The inventors gave attention to the hydroxamic acid derivatives having highly inhibitory activities, and as the result of making an extensive studies to enhance the availability, we accomplished the invention by finding out new hydroxamic acid derivatives whose water-solubility was dramatically increased compared with that of the above compounds' group.
Accordingly, the invention provides compounds of general formula (I)
(wherein R
1
is a hydrogen atom, or a hydroxyl, aryl(C
1
-C
6
)alkylene or —A—SOn—B group (A is a (C
1
-C
6
) alkylene group; B is a (C
1
-C
6
) alkyl, (C
1
-C
6
) acyl, aryl or heterocyclyl groups; n is 0, 1 or 2), R
2
is a hydrogen atom, or a (C
1
-C
6
) alkyl, (C
1
-C
6
) alkyloxy or (C
1
-C
6
) alkylthio groups, R
3
and R
4
are identical or different, representing a hydrogen atom, or a (C
1
-C
6
) alkyl, aryl or aryl(C
1
-C
6
)alkylene groups, R
5
is a Y—C″ or C″ group (Y is a (C
1
-C
6
) alkylene group, an oxygen atom, an imino or (C
1
-C
6
) alkyleneimino groups, C″ is a sulfonic acid, phosphonic acid, amidino, (C
1
-C
6
) acyl, acylimidoyl, diphosphonomethine or dicarboxymethine groups), and R
6
is a hydrogen atom, or a nonsubstituted or substituted benzyl, trialkylsilyl, tert-butyldiphenylsilyl, tetrahydropyranyl or tert-butyl groups) or stereoisomers thereof, and pharmaceutically acceptable salts thereof and solvates thereof, and metalloproteinase inhibitors which comprise one or more compounds selected from those compounds as effective ingredients and inhibit matrix metalloproteinases (MMPs) and/or TNF-&agr; converting enzyme. Further, the invention provides preparation intermediates to obtain the compounds of the above formula (I) and process for the preparation.
In the following, the invention will be explained in detail.
In the compounds represented by the general formula (I) according to the invention are included compounds described below.
The sulfonic acid group indicates —SO
3
H, and the sulfuric acid group is —OSO
3
H. The phosphonic acid group indicates —PO
3
H
2
, and phosphate is —OPO
3
H
2
. The amidino group indicates —C(═NH)NH
2
, and the guanido group does —NH—C(═NH)NH
2
. The aminomethylene group indicates —CH
2
NH
2
and the guanidomethylene group —CH
2
—NH—C(═NH)NH
2
. The acetamidomethylene group indicates —CH
2
NH—COCH
3
, the acetimidoyliminomethylene group —CH
2
—NH—C(═NH)CH
3
, the propionimidoyliminomethylene group —CH
2
—NH—C(═NH)CH
2
CH
3
, the benzimidoyliminomethylene group —CH
2
—NH—C(═NH)C
6
H
5
, the diphosphonomethine group —CH[PO(OH)
2
]
2
and the dicarboxymethine group —CH(CO
2
H)
2
, respectively.
The (C
1
-C
6
) alkyl group indicates an alkyl group of straight chain or branched chain containing 1-6 carbon atoms, including methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl and hexyl groups, etc. The (C
1
-C
6
) alkylene group indicates —(CH
2
)
n
—(n=1-6). The imino group indicates —NH—.
The (C
1
-C
6
) alkyleneimino group indicates —(CH
2
)
n
—NH—(n=1-6), which is preferably (C
1
-C
3
) alkyleneimino group and more preferably —CH
2
—NH—.
The (C
1
-C
6
) acyl group indicates a alkylacyl group of straight chain or branched chain containing 1-6 carbon atoms, including formyl, acetyl, n-propanoyl and n-butanoyl groups, etc.
The acylimidoyl group indicates —C(═NH)—[(C
1
-C
6
)alkyl] or —C(═NH)-(aryl).
The heterocyclyl group indicates a cyclic skeleton saturated or unsaturated, having at least one of hetero atoms such as sulfur, oxygen or nitrogen atoms, etc. Illustrative of the preferable heterocyclyl group are, for example, thienyl, thiazolyl, imidazolyl or pyridyl groups, etc.
The aryl group indicates aromatic rings such as phenyl, naphthyl or anthracenyl groups, etc., which can be substitued.
The substituents on the aryl group include (C
1
-C
6
) alkyl, (C
1
-C
6
) acyl, hydroxyl, amino and carboxyl groups, a halogen atom, etc., and in case having two or more substituents, can be a combination of these.
The halogen atom indicates fluorine, chlorine, bromine or iodine atoms.
Additionally, as the salts of compounds of the general formula (I) are included inorganic salts consisting of alkaline metals such as sodium and potassium, etc., alkaline earth metals such as magnesium and calcium, etc., or mineral acids such as hydrochloric acid and hydrobromic acid, etc., and ammonia consisting of organic salts, morpholine, piperidine, dimethylamine, diethylamine, acetic acid, citric acid, oxalic acid, etc. Further, the solvate is, for e

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