Prodrug derivatives of enzyme inhibitors having hydroxyl groups,

Details Prodrug derivatives of enzyme inhibitors having hydroxyl groups, Prodrug derivatives of enzyme inhibitors having hydroxyl groups,

1995-09-12

1998-09-08

Tsang, Cecilia J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 18, 514 19, 530323, 530330, 530331, A61K 3800, C07K 500

Patent

active

058045597

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/00561 filed Feb. 25, 1994.


FIELD OF THE INVENTION

The present invention relates to prodrugs with the aid of which the water-solubility and pharmaco kinetic parameters of enzyme inhibitors can be improved.


DESCRIPTION OF THE PRIOR ART

It is known that a wide diversity of compounds having a hydroxyl group (--OH) are beneficial active compounds for treatment of or combating various clinical syndromes or states. It is also known that such compounds corresponding to the prior art sometimes have a certain intrinsic disadvantage, in particular problems with bioavailability after administration and problems with the stability or the pharmaceutical formulation. Such a reduced bio-availability can sometimes be attributed to poor solubility in water and also to metabolism losses during and after conventional administration. The poor water-solubility of many products corresponding to the prior art also makes it difficult or impossible to prepare formulations which are suitable for intravenous or intramuscular injections or ophthalmic uses.
A promising approach to solving these problems lay in esterification of the hydroxyl function of active compounds in order to obtain pharmacologically improved prodrug forms.
Some types of esters have already been described as prodrugs of hydroxyl-containing active compounds (Hans Bundgaard, Design of Prodrugs, Elsevier Science Publishers B. V., Amsterdam, 1985).
These ester prodrugs are dependent on enzymatic hydrolysis (esterases) in order to obtain usable conversion rates of prodrugs into active compounds. This approach accordingly has several disadvantages: individuals. This can lead to nonuniform and unpredictable levels of active compound. on the acid and also on the hydroxyl-containing part of the ester (Bundgaard, loc. cit.). Some esters, for example esters of sterically demanding hydroxyl-containing active compounds, are very poor substrates for esterases.


SUMMARY OF THE INVENTION

It is the aim of this invention to provide ester prodrugs of hydroxyl-containing medicaments in which the above-mentioned disadvantages do not occur.


DESCRIPTION OF THE PREFERRED EMBODIMENTS

It has now been found that certain prodrugs of enzyme inhibitors do not have the abovementioned disadvantages. The invention accordingly relates to compounds of the formula I in which radicals which occur several times and are defined in the same way can be independent of one another inhibitor, a is 1, 2 or 3 and R.sup.5 is a radical of the formula III, IV or V ##STR2## R.sup.5 is preferably a radical of the formula III or IV, and R.sup.5 is particularly preferably a radical of the formula III, NR.sup.20, -C.sub.7)-cycloalkyl, --CH.sub.2 --(CH.sub.2).sub.n --NR.sup.21 R.sup.24, --CH.sub.2 --C(O)--R.sup.28 CH.sub.2 CONH(C.sub.1 -C.sub.6)-alkyl, which can be substituted by up to 5 OH groups, COO(C.sub.1 -C.sub.6)-alkyl or --CH.sub.2 --P(O)((C.sub.1 -C.sub.4)-alkyl).sub.2, preferably H, (C.sub.1 -C.sub.4)-alkyl, or --CH.sub.2 --C(O)--R.sup.28 or --CH.sub.2 --P(O)Me.sub.2, particularly preferably H or (C.sub.1 -C.sub.4)-alkyl, H or (C.sub.1 -C.sub.4)-alkyl, preferably H or methyl, (C.sub.1 -C.sub.4)-alkyloxycarbonyl, preferably H or (C.sub.1 -C.sub.4)-alkyl, (C.sub.2 -C.sub.18)-alkenyl, (C.sub.2 -C.sub.18)-alkynyl or (C.sub.6 -C.sub.14)-aryl, each of which can be mono-, di- or trisubstituted by (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryloxy, (C.sub.3 -C.sub.14)-cycloalkyl, hydroxyl, (C.sub.1 -C.sub.4)-alkoxy, --C(O)--R.sup.28, P(O)((C.sub.1 -C.sub.4)-alkyl).sub.2, NH.sub.2 or halogen and are linked with NR.sup.21 directly or optionally via CO, or an .alpha.-amino acid linked via the carbonyl group, or R.sup.24 is ((C.sub.1 -C.sub.4)-alkyl)-N( (C.sub.1 -C.sub.4)-alkyl)-(C.sub.1 -C.sub.4)-alkyl-NH--((C.sub.1 -C.sub.4)-alkyl), or R.sup.24 forms a heterocyclic radical with R.sup.21, and substituted by phenyl, NH.sub.2 or (C.sub.3 -C.sub.7)-cycloalkyl and is linked with NR.sup.21 directly or optionally via CO, a naturally occurring .alpha.-amino acid linked via t

REFERENCES:
Bolis et al. J. Med. Chem. 30(10) pp. 1729-1737 (1987).
Bundgaard Design of Prodrugs CH. 1 (1985) pp. 1-24.
Silverman, The Organic Chemistry of Drug Design and Drug Action (Academic Press, Inc. 1992) pp. 352-401.
Aggarwal et al., J. Med. Chem. vol. 33 (1990) 1505-1510.

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