Vanilloid fatty hydroxamates as therapeutic anti-inflammatory pharmaceuticals
View Patent ↗Three unique subtypes of N-hydroxyamides and N-hydroxycarbamates containing both the vanilloid moiety (4-hydroxy-3-methoxybenzyl) and a lipophilic aliphatic moiety. Also disclosed are direct syntheses of these vanilloid fatty hydroxamates. The compounds possess inhibitory activity against the enzymes fatty acid amide hydrolase (FAAH) and matrix metallo-proteinase 9 (MMP-9). In addition, these substances bind to the calcium channel protein TRPV1 and inhibit vesicant-induced inflammation in skin and cornea. The compounds have utility in treating topical or systemic inflammatory processes in the skin and/or eye.
1. A vanilloid fatty N-hydroxy amide or vanilloid fatty N-hydroxy carbamate compound represented by Formula (V):
wherein when (1) X is N(OH) and Y is C(═O)O, or (2) X is N(OH) and Y is C(═O), R is a lipophilic moiety selected from the group consisting of unsubstituted linear alkyl, branched alkyl, optionally branched cycloalkyl, linear alkenyl, branched alkenyl, optionally branched cycloalkenyl, linear alkynyl, branched alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; and
when (3) X is C(═O) and Y is N(OH), R is a lipophilic moiety selected from the group consisting of unsubstituted linear alkyl, branched alkyl, optionally branched cycloalkyl, linear alkenyl, branched alkenyl, and optionally branched cycloalkenyl;
or the compounds of Formula (V) are prodrugs or pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , selected from the group consisting of alkyl-N-hydroxy-N-4-hydroxy-3-methoxybenzylcarbamates.
3. The compound of claim 1 , selected from the group consisting of N-hydroxy-N-4-hydroxy-3-methoxybenzylcarboxamides.
4. The compound of claim 1 , selected from the group consisting of N-hydroxy-N-alkyl-(4-hydroxy-3-methoxyphenyl)acetamides.
5. The compound of claim 4 which is a prodrug or a pharmaceutically acceptable salt.
6. A method for preparing a compound according to claim 2 , comprising the step of reacting a benzylic hydroxylamine with a chloroformate in the presence of magnesium oxide to direct acylation onto the nitrogen atom of the hydroxylamine and thereby yield an alkyl-N-hydroxy-N-benzylcarbamate of formula
7. A method for preparing a compound according to claim 3 , comprising the step of reacting a benzylic hydroxylamine with an acylated 2-mercaptothiazoline to direct acylation onto the nitrogen atom of the hydroxylamine and thereby yield an N-hydroxy-N-benzyl-carboxamide of formula
8. A method for preparing a compound according to claim 4 , comprising the steps of:
(a) condensing an aliphatic aldehyde with O-benzylhydroxylamine to form an oxime,
(b) reducing the oxime to an O-benzylhydroxylamine,
(c) condensing the O-benzylhydroxyamine with homovanillic acid (4-hydroxy-3-methoxyphenylacetic acid) to form an amide, and
(d) subjecting the amide to hydrogenolysis to cleave the O-benzyl group and thereby yield the N-hydroxy-N-alkyl(4-hydroxy-3-methoxyphenyl)acetamide of formula
9. The compound of claim 1 , wherein said pharmaceutically acceptable salt is selected from the group consisting of acetate, benzoate, methanesulfonate, benzenesulfonate, and hydrochloride salts.
10. The compound of claim 1 , wherein said prodrug is selected from the group consisting of O-acylated and O-carbamoylated derivatives of the hydroxamic acid moiety.
11. The compound of claim 5 , wherein said pharmaceutically acceptable salt is selected from the group consisting of acetate, benzoate, methanesulfonate, benzenesulfonate, and hydrochloride salts.
12. The compound of claim 5 , wherein said prodrug is selected from the group consisting of O-acylated and O-carbamoylated derivatives of the hydroxamic acid moiety.