Tight-binding inhibitors of leukotriene A.sub.4 hydrolase

Details Tight-binding inhibitors of leukotriene A.sub.4 hydrolase Tight-binding inhibitors of leukotriene A.sub.4 hydrolase

1993-06-17

1995-10-03

Dees, Jose G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514539, 514561, 514563, 514541, 514620, 514649, 514653, 514654, A61K 3124

Patent

active

054552710

ABSTRACT:
Inhibitors of leukotriene A.sub.4 hydrolase are disclosed, corresponding to Formula I, below: ##STR1## wherein the depicted --NH.sub.2 group is in the (S) configuration; --W is --CH.sub.2 SH, --CH.sub.2 NH.sub.2 or C(.dbd.Z)--Y, wherein .dbd.Z is .dbd.O, or --H and --OH; and --Y is selected from the group consisting of (a) phenyl, (b) trifluoromethylphenyl, (c) carboxyphenyl, (d) benzyl, (e) C.sub.1 -C.sub.6 alkylenecarboxyl, (f) C.sub.1 -C.sub.6 alkyl, (g) C.sub.2 -C.sub.6 alkenyl, (h) C.sub.1 -C.sub.6 alkylenephenyl and (i) --C(.dbd.O)--X--R.sup.1 wherein X is O or NH and, R.sup.1 is selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkylenecarboxyl, and benzyl; R.sup.2 is hydrogen, benzyloxy or 2-naphthylmethyloxy, and a pharmaceutically acceptable acid addition salt thereof. Inhibitors wherein --W is --CH.sub.2 SH, --CH.sub.2 NH.sub.2 or C(.dbd.Z)--Y wherein .dbd.Z is .dbd.O and --Y is --C(.dbd.O)--X--R.sup.1 are particularly preferred, as are those compounds wherein .dbd.Z is .dbd. O and --Y is selected from the group consisting of (a) phenyl, (b) trifluoromethylphenyl, (c) carboxyphenyl, (d) benzyl, (e) C.sub.1 -C.sub.6 alkylenecarboxyl, (f) C.sub.1 -C.sub.6 alkyl, (g) C.sub.2 -C.sub.6 alkenyl, (h) C.sub.1 -C.sub.6 alkylenephenyl. An inhibitor where --W is --CH.sub.2 SH, --CH.sub.2 NH.sub.2 or C(.dbd.Z)--Y wherein .dbd.Z is .dbd.O and --Y is --C(.dbd.O)--X--R.sup.1 is particularly preferred, as are those inhibitor compounds where .dbd.Z is .dbd.O and --Y is (a)--(h).

REFERENCES:
patent: 4704464 (1987-11-01), Brunner et al.
patent: 4743585 (1988-05-01), Hudspeth et al.
Medline 91083646 Dec. 14, 1990.
Ocain et al., J. Med. Chem., 35(3):451-456 (1992).
Yuan et al., Bioorg. Med. Chem. Lett., 1(10):551-556 (1991).
Goka et al., J. of Medicinal Chemistry, 34(8):2547-2557 (1991).
Bioorg. Med. Chem. Lett 1(10), pp. 551-556 Yuan et al.; Oct., 1991.
J. Med. Chem. 35(3) pp. 451-456 Ocain et al.; Feb. 7, 1992.
Journal of Medicinal Chemistry 1991, vol. 34 No. 8 pp. 2547-2557, Goka et al.; Oct. 1991.

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