Cyclic N-substituted alpha-imino carboxylic acids for...

Details Cyclic N-substituted alpha-imino carboxylic acids for... Cyclic N-substituted alpha-imino carboxylic acids for...

2003-02-26

2004-04-06

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S309000, C546S118000, C546S142000

Reexamination Certificate

active

06716853

ABSTRACT:

SUMMARY OF THE INVENTION
The invention relates to the use of cyclic N-substituted alpha-imino carboxylic acids of the formula I for selective inhibition of collagenase (MMP 13). The compounds of the formula I can therefore be employed for treating degenerative joint disorders.
BACKGROUND OF THE INVENTION
In disorders such as osteoarthritis and rheumatism there is destruction of the joint caused in particular by the proteolytic degradation of collagen by collagenases. Collagenases belong to the superfamily of metalloproteinases (MP) or matrix metallproteinases (MMP). The MMPs form a group of Zn-dependent enzymes which are involved in biological degradation of the extracellular matrix (D. Yip et al in Investigational New Drugs 17 (1999), 387-399 and Michaelides et al in Current Pharmaceutical Design 5 (1999) 787-819). These MMPs are able in particular to degrade fibrillary and non-fibrillary collagen, and proteoglycans, both of which represent important matrix constituents. MMPs are involved in processes of wound healing, of tumor invasion, of metastasis migration and in angiogenesis, multiple sclerosis, heart failure and atherosclerosis (Michaelides p. 788; see above). In particular, they play an important part in degradation of the joint matrix in arthrosis and arthritis, whether osteoarthrosis, osteoarthritis or rheumatoid arthritis.
A selected subgroup within the MMPs is formed, for example, by collagenases. Only collagenases are able to degrade native collagen which exercises an important supporting function in the matrix. This subgroup consists of interstitial collagenase MMP-1, of neutrophil collagenase MMP-8, and of MMP-13 which was identified only later. It was virtually impossible to detect MMP-13 in the body of healthy adult individuals; it is expressed only during the course of diseases, e.g. in cancer cells or ulcers. MMP-13 has also been detected in the joint matrix of arthrotic people and mammals, especially in clinically advanced arthrosis, while it does not occur in the joint tissue of healthy adults. Inhibition of MMP-13 by appropriate inhibitors is therefore particularly suitable for controlling said diseases.
A large number of different inhibitors of MMPs and of collagenases are known (EP 0 606 046; WO94/28889; WO 96/27583). It is also known that cyclic and heterocyclic N-substituted alpha-imino hydroxamic and carboxylic acids are inhibitors of metalloproteinases (EP 0 861 236).
After initial clinical studies on humans, it has now emerged that inhibitors of MMPs can cause side effects. The side effects which are mainly mentioned are musculoskeletal pain or arthralgias. It is, therefore, expected from the prior art that selective inhibitors will be able to reduce these side effects mentioned (Yip, page 387, see above).
A disadvantage of known inhibitors of MMPs is, therefore, frequently the lack of specificity of the inhibition for only one class of MMPs. Thus, most MMP inhibitors inhibit a plurality of MMPs simultaneously, because the MMPs have a catalytic domain of similar structure. Accordingly, the inhibitors act in an unwanted manner on many enzymes, even those with a vital function (Massova I, et al., The FASEB Journal (1998) 12, 1075-1095).
The application WO 97/18194 (EP 0 861 236) has already described cyclic and heterocyclic N-substituted alpha-imino hydroxamic and alpha-imino carboxylic acids which have a strong inhibitory effect on MMP-3 and MMP-8. The compounds disclosed by the description in the examples in WO 97/18194 also show a strong inhibitory effect on MMP-13.
In the effort to find effective compounds for the treatment of connective tissue disorders, it has now been found that the compounds employed according to the present invention are strong inhibitors of matrix metalloproteinase 13, while the compounds employed according to the invention are essentially ineffective for MMPs 3 and 8. These compounds employed according to the invention are thus more suitable in a much more targeted manner for the selective treatment of said diseases than the compounds disclosed and described in the examples in WO 97/18194, which inhibit other MMPs besides MMP-13. It is therefore to be expected that these selective inhibitors will show a considerable decrease in side effects on treatment of said disorders.
DETAILED DESCRIPTION OF THE INVENTION
The invention therefore relates compounds of the formula I
and/or all stereoisomeric forms of the compound of the formula I and/or mixtures of these forms in any ratio, and/or a physiologically tolerated salt of the compound of the formula I, wherein
R1 is —(C
1
-C
10
)-alkyl in which alkyl is linear or branched,
—(C
2
-C
10
)-alkenyl in which alkenyl is linear or branched,
—(C
2
-C
10
)-alkynyl in which alkynyl is linear or branched,
—(C
1
-C
4
)-alkylphenyl,
—(C
1
-C
4
)-alkyl-(C
3
-C
7
)-cycloalkyl,
—(C
3
-C
7
)-cycloalkyl, or
—CH
2
CF
3
; and
R2, R3, R4 and R5 are each, independently of one another, hydrogen, or —(C
1
-C
4
)-alkyl.
A preferred embodiment of the invention provides for compounds of formula I wherein
and wherein R1, R2, R3, R4 and R5 are as defined above.
Another preferred embodiment of the invention provides for compounds of formula I wherein
and wherein R1, R2, R4 and R5 are as defined above.
Yet another preferred embodiment of the invention provides for compounds of formula I wherein
and wherein
R1 is —(C
2
-C
6
)-alkyl in which alkyl is linear or branched, —CH
2
-phenyl, or —CH
2
-cyclopropyl; and
R2, R3, R4 and R5 are each, independently of one another, hydrogen or methyl.
Another preferred embodiment of the invention provides for compounds of formula I
wherein
R1 is —(C
1
-C
10
)-alkyl in which alkyl is linear or branched,
—(C
2
-C
10
)-alkenyl in which alkenyl is linear or branched,
—(C
2
-C
10
)-alkynyl in which alkynyl is linear or branched,
—(C
1
-C
4
)-alkylphenyl,
—(C
1
-C
4
)-alkyl-(C
3
-C
7
)-cycloalkyl,
—(C
3
-C
7
)-cycloalkyl, or
—CH
2
CF
3
, and
R2, R4 and R5 are each, independently of one another, hydrogen, or —(C
1
-C
4
)-alkyl.
The invention further relates to compounds of the formula II
wherein
R1 is —(C
2
-C
6
)-alkyl in which alkyl is linear or branched, —CH
2
-phenyl, or —CH
2
-cyclopropyl; and
R2 is hydrogen or methyl.
A further aspect of the invention relates to compounds of the formula III
wherein
R1 is —(C
2
-C
6
)-alkyl in which alkyl is linear or branched, —CH
2
-phenyl, or —CH
2
-cyclopropyl; and
R2 is hydrogen or methyl.
The invention also provides for pharmaceutical compositions comprising compounds of formula I and a pharmaceutically acceptable carrier.
The invention also provides for methods of preventing and treating disorders, the progression of which involves an enhanced activity of matrix metalloproteinase 13, by administering to a patient in need thereof, a pharmaceutically effective amount of a compound of formula I.
The invention further provides for methods of preventing and treating a degenerative joint disorder such as osteoarthroses, spondyloses, chondrolysis after joint trauma or prolonged joint immobilization after meniscus or patellar injuries or ligament tears, or connective tissue disorders such as collagenoses, periodontal disorders, wound healing disturbances, or chronic disorders of the locomotor system such as inflammatory, immunologically or metabolism-related acute or chronic arthritides, arthropathies, myalgias or disturbances of bone metabolism or an ulceration, atherosclerosis or stenosis, or inflammatory disorders, cancer, tumor metastasis, cachexia, anorexia or septic shock.
The term “(C
1
-C
10
)-alkyl” means hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 10 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, 2,3-dimethylbutyl, neohexyl, heptyl, octanyl, nonanyl, and decanyl.
The term “(C
2
-C
10
)-alkenyl” means hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 10 carbon atoms and, depending on the chain length, 1, 2 or 3 double bonds.
The term “(C
2
-C
10
)-alkynyl” means

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