3-aryl-succinamido-hydroxamic acids, methods for producing...

Details 3-aryl-succinamido-hydroxamic acids, methods for producing... 3-aryl-succinamido-hydroxamic acids, methods for producing...

2000-07-06

2003-06-10

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S228200, C514S237800, C514S252010, C514S374000, C514S378000, C514S616000, C544S088000, C544S098000, C544S168000, C546S309000, C548S237000, C548S215000, C548S240000, C562S623000

Reexamination Certificate

active

06576628

ABSTRACT:

The present application concerns inhibitors of matrix metalloproteases. In particular it concerns 3-aryl-succinamido-hydroxamic acids.
In healthy tissue there is an equilibrium between synthesis and degradation of the extracellular matrix. The extracellular matrix is mainly degraded by proteases of the matrix metalloprotease (MMP) family. Examples of members of this family are collagenases, stromelysins and gelatinases. In healthy tissue this degradation is regulated by inhibition with TIMPs (tissue inhibitor of metalloproteases). This equilibrium between matrix metalloproteases and TIMPs is disturbed in various diseases such as rheumatoid and osteoarthritis, multiple sclerosis, metastasis and invasion of tumours, cornea ulcer, meningitis, cardiovascular diseases such as restenosis and arteriosclerosis as well as diseases of bones and gums. Many examples show that an inhibition of these enzymes can have a positive influence on the clinical picture of these diseases (Beckett et al., 1996).
The two gelatinases A (MMP-2) and B (MMP-9) appear to be the most important MMPs for metastasis and invasion. A selective inhibition of these two enzymes would be desirable. The furthest developed substance at present in this area, Marimastat, which is in clinical phase III is active but exhibits major side-effects such as muscle pain. In its present form Marimastat is a broad-range MMP inhibitor and consequently MMPs like MMP1 which are absolutely essential for tissue metabolism are also inhibited. It is generally assumed that the side-effects are due to the non-specificity.
It has now surprisingly been found that the new 3-aryl-succinamido-propionohydroxamic acids have a more favourable pharmacological profile than Marimastat. These substances differ inter alia from Marimastat by an aryl substitution at position 3 of the succinyl residue. The specificity with respect to gelatinases is considerably improved in the new compounds or rather is now present for the first time. I.e. it is possible to avoid inhibition of MMP1 and other important enzymes.
The present application concerns substances of the general formula I
In order to achieve an optimal inhibition of the gelatinases, the residues R and R1 of the compounds of the general formula I should have certain hydrophobicities. A suitable parameter for this is clogP which can be determined with the aid of “PCModels clogp3” from Daylight Chemical Information Systems Inc. (1993). The coefficients are based on Hansch, C. & Leo, A.: Substituent Constants for Correlation Analysis in Chemistry and Biology. Wiley Interscience New York (1979), whereas the algorithm is based on the following citation: Chou, J. & Jurs, P., J. Chem. Inf. Comput. Sci. 19, 172 (1979). The fragments are entered as complete molecules for the calculation i.e. not as a radical or ion. In order to get informative values the clogP values for R are determined together with the neighbouring phenyl ring (Ph-R fragments). The clogP values for the residue R1 are determined together with the neighbouring carbonyl and amino group as (CHO)(NH
2
)CHR1 (aminocarbonyl-R1 fragments).
Examples for Ph-R
Examples for aminocarbonyl-R1:
The clogP values for R in the form of Ph-R fragments in the compounds of the present invention are 2.0 to 6.0, preferably 2.5 to 5.0, particularly preferably 3.0 to 4.5.
The clogP values for R1 in the form of aminocarbonyl-R1 fragments in the compounds of the present invention are between −1.5 and 2.0, preferably between −1.2 and 1.5, particularly preferably between −1.0 and 1.2.
The present application therefore concerns substances of the general formula I
in which
R as a Ph-R fragment has a clogP value between 2.0 and 6.0, preferably between 2.5 and 5.0 and particularly preferably between 3.0 and 4.5,
R1 as an aminocarbonyl-R1 fragment has a clogP value between −1.5 and 2.0, preferably between −1.2 and 1.5 and particularly preferably between −1.0 and 1.2 and
R5 denotes hydrogen or a C
1
-C
8
alkyl residue
R6 denotes hydrogen, an optionally substituted C
1
-C
8
alkyl or an optionally substituted monocyclic or bicyclic cycloalkyl, aryl, heteroaryl, aralkyl or alkylheteroaryl residue, or
R5 and R6 together with the N atom denote a saturated or unsaturated 5-membered or 6-membered ring which contains at most one additional heteroatom,
pharmacologically compatible salts, esters and derivatives thereof which are metabolized in vivo into compounds of the general formula I as well as the use of these compounds for the production of pharmaceutical preparations.
Alternatively the subject matter of the present application can be represented as compounds of the general formula I:
in which
R denotes an optionally substituted C
1
-C
8
alkyl, or an optionally substituted monocyclic or bicyclic cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, or aralkyl residue,
R1 denotes an optionally substituted C
1
-C
8
alkyl or an optionally substituted monocyclic or bicyclic cycloalkyl, aryl, heteroaryl, aralkyl or alkylheteroaryl residue,
R5 denotes hydrogen or a C
1
-C
8
alkyl residue
R6 denotes hydrogen, an optionally substituted C
1
-C
8
alkyl or an optionally substituted monocyclic or bicyclic cycloalkyl, aryl, heteroaryl, aralkyl or alkylheteroaryl residue, or
R5 and R6 together with the N atom denote a saturated or unsaturated 5-membered or 6-membered ring which contains at most one additional heteroatom,
pharmacologically compatible salts, esters and derivatives thereof which are metabolized in vivo into compounds of the general formula I as well as the use of these compounds for the production of pharmaceutical preparations.
The residues listed under R, R1 and R6 can, independently of one another, be optionally substituted once, twice or three times by halogen, hydroxy, thio, alkyl, C
3
-C
8
cycloalkyl, C
4
-C
8
cycloalkenyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, chloroalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, nitro, carboxyl, carboxamido, alkoxycarbonyl, alkoxycarbonylalkyl, perfluoroalkyl or amino or aminocarbonyl optionally substituted once or twice by lower alkyl, nitrile, oxo or acyl.
In this connection a halogen, hydroxy, oxo, thio, alkoxy, &ohgr;-hydroxyalkoxy, &ohgr;-chloroalkoxy, alkylthio, amino, aminocarbonyl, carboxyl and acyl group are preferred. Methyl, halogen and hydroxyl are particularly preferred.
If they are substituted a single substitution is preferred.
If not stated otherwise cycloalkyl denotes a saturated mono or polyunsaturated carbocycle or heterocycle containing 3 to 8 structural atoms, preferably 5-7 structural atoms which can optionally be interrupted once or several times by heteroatoms such as nitrogen, oxygen or sulphur and in particular denotes a cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydrofuryl or tetrahydropyranyl residue.
The alkyl residue in aralkyl and heteroalkyl in R, R1 and R6 denotes independently of one another C
1
or C
2
alkyl.
Acyl in the residues R, R1 and R6 denotes above all the acetyl group.
If not stated otherwise in the residues R, R1 and R6 alkyl alone or in combination e.g. with alkoxy, alkylthio, arylsulfonyl, alkylsulfonyl, alkylamino-carbonyl, arylaminocarbonyl, alkylamino, alkoxycarbonyl, aryloxycarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, denotes a straight-chained or branched, saturated or unsaturated residue with 1-3 carbon atoms such as methyl, ethyl, propyl, isopropyl, allyl or propinyl.
C
1
-C
8
alkyl in the residues R, R1, R5 and R6 denotes independently of one another a straight-chained, branched, saturated or unsaturated residue containing 1 to 8 carbon atoms which can be interrupted by 1 or 2 heteroatoms such as O, N or S, where no interruption or an interruption by oxygen is preferred and in the case of an interruption by oxygen C
1
-C
7
alkoxy is particularly preferred. Examples of C
1
-C
8
alkyl residues are methyl, ethyl, propyl, pentyl, octyl, allyl, propargyl, 2,4-pentadienyl, isopropyl, sec.butyl, tert.butyl, 3-methyl-butyl, 2-hydroxy-hexy

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