4H-3,1-benzoxazin-4-ones and related compounds and use as enzyme inhibitors

A compound of the formula:

• ##STR31## or a pharmaceutically acceptable ester or salt thereof, wherein:
• R.sup.1 is hydrogen or lower alkyl;
• R.sup.2 and R.sup.3 are each independently hydrogen, halo, lower alkyl, hydroxy, lower alkoxy, lower thioalkyl, --NO.sub.2, --N(R').sub.2, --NR'COR', --NHCON(R').sub.2 or --NHCOOR', with the proviso that at least one of R.sup.1, R.sup.2 and R.sup.3 is not hydrogen when X is NHR or NR'COR";
• X is a radical chosen from the group consisting of:
• ##STR32## in which:
• R is lower alkenyl, lower alkynyl, a saturated hydrocarbon ring of 3 to 6 carbon atoms, either unsubstituted, or substituted with 1 to 5 substituents selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, amino, halo, nitro, lower alkyl amino, or lower dialkylamino;
• or a phenyl ring attached to an alkyl chain of one to six carbon atoms, wherein the phenyl ring is either unsubstituted, or substituted with one to three substituents selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, amino, halo, nitro, lower akyl amino, or lower dialkylamino;
• each R' is independently hydrogen or lower alkyl, or lower alkenyl or lower alkynyl where the unsaturated bond is at least one carbon removed from the O or N atom;
• each R" is independently R, lower alkoxy, NHR' or AOR';
• and
• A is an amino acid residue, or a peptide of 2 to 3 amino acid residues.

A compound of the formula:

• ##STR33## or a pharmaceutically acceptable ester or salt thereof, wherein:
• R.sup.1 is lower alkyl;
• R.sup.2 and R.sup.3 are each independently hydrogen, halo, lower alkyl, hydroxy, lower alkoxy, lower thioalkyl, --NO.sub.2, --N(R').sub.2, --NR'COR', --NHCON(R').sub.2 or --NHCOOR';
• and
• X is a radical chosen from the group consisting of:
• ##STR34## in which:
• R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, lower alkenyl, lower alkynyl, a saturated hydrocarbon ring of 3 to 6 carbon atoms, either unsubstituted, or substituted with 1 to 5 substituents selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, amino, halo, nitro, lower alkyl amino, or lower dialkylamino;
• or a phenyl ring attached to an alkyl chain of one to six carbon atoms, wherein the phenyl ring is either unsubstituted, or substituted with one to three substituents selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, amino, halo, nitro, lower alkyl amino, or lower dialkylamino;
• each R' is independently hydrogen or lower alkyl, or lower alkenyl or lower alkynyl where the unsaturated bond is at least one carbon removed from the O or N atom;
• each R" is independently R, lower alkoxy, NHR' or AOR';
• and
• A is an amino acid residue, or a peptide of 2 to 3 amino acid residues.

A compound of the formula:

• ##STR35## or a pharmaceutically acceptable ester or salt thereof, wherein:
• R.sup.1 is lower alkyl;
• R.sup.2 and R.sup.3 are each independently hydrogen, halo, lower alkyl, hydroxy, lower alkoxy, lower thioalkyl, --NO.sub.2, --N(R').sub.2, --NR'COR', --NHCON(R').sub.2 or --NHCOOR';
• X is NHR in which R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl;
• and
• each R' is independently hydrogen or lower alkyl, or lower alkenyl or lower alkynyl where the unsaturated bond is at least one carbon removed from the O or N atom.

A compound of the formula:

• ##STR36## or a pharmaceutically acceptable ester or salt thereof, wherein:
• R.sup.1 is lower alkyl;
• R.sup.2 is halo, lower alkyl, hydroxy, lower alkoxy, lower thioalkyl, --NO.sub.2, --N(R').sub.2, --NR'COR', --NHCON(R').sub.2 or --NHCOOR';
• R.sup.3 is hydrogen;
• X is a radical chosen from the group consisting of:
• ##STR37## in which:
• R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, lower alkenyl, lower alkynyl, optionally substituted lower cycloalkyl, optionally substituted phenyl lower alkyl;
• each R' is independently hydrogen or lower alkyl, or lower alkenyl or lower alkynyl where the unsaturated bond is at least one carbon removed from the O or N atom;
• each R" is independently R, lower alkoxy, NHR' or AOR';
• and
• A is an amino acid residue, or a peptide of 2 to 3 amino acid residues.

A compound of the formula:

• ##STR38## or a pharmaceutically acceptable ester or salt thereof, wherein:
• R.sup.1 is hydrogen or lower alkyl;
• R.sup.2 is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower thioalkyl, --NO.sub.2, --N(R').sub.2, --NR'COR', --NHCON(R').sub.2 or --NHCOOR',
• with the proviso that at least one of R.sup.1 and R.sup.2 is not hydrogen;
• R.sup.3 is hydrogen;
• and
• X is a radical chosen from the group consisting of:
• ##STR39## in which:
• R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, lower alkenyl, lower alkynyl, a saturated hydrocarbon ring of 3 to 6 carbon atoms, either unsubstituted, or substituted with 1 to 5 substituents selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, amino, halo, nitro, lower alkyl amino, or lower dialkylamino;
• or a phenyl ring attached to an alkyl chain of one to six carbon atoms, wherein the phenyl ring is either unsubstituted, or substituted with one to three substituents selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, amino, halo, nitro, lower alkyl amino, or lower dialkylamino;
• each R.sup.1 is independently hydrogen or lower alkyl, or lower alkenyl or lower alkynyl where the unsaturated bond is at least one carbon removed from the O or N atom;
• each R" is independently R, lower alkoxy, NHR' or AOR';
• and
• A is an amino acid residue, or a peptide of 2 to 3 amino acid residues.

A method for treating inflammation comprising the step of administering a therapeutically effective amount of a compound of the formula:

• ##STR40## or a pharmaceutically acceptable ester or salt thereof, wherein:
• R.sup.1 is hydrogen or lower alkyl;
• R.sup.2 and R.sup.3 are each independently hydrogen, halo, lower alkyl, hydroxy, lower alkoxy, lower thioalkyl, --NO.sub.2, --N(R').sub.2, --NR'COR', --NHCON(R').sub.2 or --NHCOOR',
• with the proviso that at least one R.sup.1, R.sup.2 and R.sup.3 is not hydrogen when X is NHR or NR'COR";
• and
• X is a radical chosen from the group consisting of:
• ##STR41## in which:
• R is lower alkyl, lower alkenyl, lower alkynyl, a saturated hydrocarbon ring of 3 to 6 carbon atoms, either unsubstituted, or substituted with 1 to 5 substituents selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, amino, halo, nitro, lower alkyl amino, or lower dialkylamino;
• or a phenyl ring attached to an alkyl chain of one to six carbon atoms, wherein the phenyl ring is either unsubstituted, or substituted with one to three substituents selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, amino, halo, nitro, lower alkyl amino, or lower dialkylamino;
• each R' is independently hydrogen or lower alkyl, or lower alkenyl or lower alkynyl where the unsaturated bond is at least one carbon removed from the O or N atom;
• each R" is independently R, lower alkoxy, NHR' or AOR';
• and
• A is an amino acid residue, or a peptide of 2 to 3 amino acid residues.

A method for inhibiting serine proteases comprising the step of administering a therapeutically effective amount of a compound of the formula:

• ##STR42## or a pharmaceutically acceptable ester or salt thereof, wherein:
• R.sup.1 is hydrogen or lower alkyl;
• R.sup.2 and R.sup.3 are each independently hydrogen, halo, lower alkyl, hydroxy, lower alkoxy, lower thioalkyl, --NO.sub.2, --N(R').sub.2, --NR'COR', --NHCON(R').sub.2 or --NHCOOR',
• with the proviso that at least one of R.sup.1, R.sup.2 and R.sup.3 is not hydrogen when X is NHR or NR'COR";
• and
• X is a radical chosen from the group consisting of:
• ##STR43## in which:
• R is lower alkyl, lower alkenyl, lower alkynyl, a saturated hydrocarbon ring of 3 to 6 carbon atoms, either unsubstituted, or substituted with 1 to 5 substituents selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, amino, halo, nitro, lower alkyl amino, or lower dialkylamino;
• or a phenyl ring attached to an alkyl chain of one to six carbon atoms, wherein the phenyl ring is either unsubstituted, or substituted with one to three substituents selected independently from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, amino, halo, nitro, lower alkyl amino, or lower dialkylamino;
• each R' is independently hydrogen or lower alkyl, or lower alkenyl or lower alkynyl where the unsaturated bond is at least one carbon removed from the O or N atom;
• each R" is independently R, lower alkoxy, NHR' or AOR';
• and
• A is an amino acid residue, or a peptide of 2 to 3 amino acid residues.