Hydroxamates as modulators of arachidonic acid metabolic pathways

Claim 2

A compound of the formula: and salts thereof; wherein R 2 is H, lower alkyl, formyl or C 2 -C 10 alkanoyl; R and R 1 are each independently hydrogen, lower cycloalkyl, fused cycloalkyl or lower alkyl-substituted fused cycloalkyl, lower alkyl, phenyl, naphthyl or a nitrogen, oxygen, or sulfur heterocyclic ring or heterocyclic-lower alkyl; Z, Z 1 and Z 2 are each a chemical bond, or an alkylene chain or a mono- or di-substituted alkylene chain containing up to 6 carbon atoms in the principal chain and up to a total of about 10 carbon atoms, a lower cycloalkyl, a nitrogen, oxygen, or sulfur heterocyclic ring or heterocyclic-lower alkyl, or a mono- or di-substituted lower cycloalkyl or heterocyclic lower alkyl, and the substituents are hydrogen, lower alkyl, aryl, lower aralkyl, lower alkoxy, hydroxy, lower aralkoxy, aryloxy, carboxy, lower carbalkoxy, carbaryloxy, lower carbaralkoxy, amino, lower alkyl amino, amino loweralkyl, di-loweralkylamino or cyano; X and Y are each independently O, S, CR 3 R 4 or a chemical bond; R 3 and R 4 are each independently H or lower alkyl; Ar is phenyl or naphthyl or a nitrogen, oxygen, or sulfur heterocyclic; each R 5 is hydrogen, aryl, lower alkanoyl, formyl, nitro, cyano, amino, lower aminoalkyl, lower alkylamino, lower aralkylamino, halo, trihaloalkyl carbamoyl or aroyl; n is an integer from 0-2; and n 1 is an integer from 1-2.

Claim 3

The compound according to Claim 1 wherein Ar is phenyl, naphthyl or pyridyl.

Claim 4

The compound according to Claim 1 wherein n l is 1.

Claim 5

The compound according to Claims 1-3 wherein R and R 1 are independently hydrogen, loweralkyl, phenyl, naphthyl or quinolyl.

Claim 6

The compound according to Claims 1-4 wherein R 2 is hydrogen or lower alkyl.

Claim 7

A compound according to Claims 1-5 wherein R 5 is hydrogen, halo or benzoyl.

Claim 8

The compound according to Claim 1 having the formula: and salts thereof wherein Ar is phenyl or naphthyl; Y is 0 or CR 3 R 4 ; X is 0 or C R 3 R 4 ; Z and Z 1 are independently a chemical bond or an alkylene chain having up to 6 carbon atoms in the principal chain and up to a total of 10 carbon atoms; Z 2 is a chemical bond or an alkylene chain or a mono-substituted alkylene chain containing up to 6 carbon atoms in the principal chain and up to a total of 10 carbon atoms and the substituents are hydrogen. lower alkyl, aryl, lower aralkyl, hydroxy, lower alkoxy, lower aralkoxy, aryloxy, carboxy, lower carbalkoxy, carbaryloxy, lower carbaralkoxy, lower carbalkoxy lower alkoxy, amino, lower alkylamino, diloweralkylamino or cyano; R and R 1 are each independently hydrogen, lower alkyl, lower cycloalkyl, phenyl, naphthyl or quinolyl; R 2 , R 3 and R 4 are each hydrogen or lower alkyl; each R S is hydrogen, aryl, lower alkanoyl, formyl, nitro, cyano, amino, lower aminoalkyl, lower alkylamino, lower aralkylamino, halo, trihaloalkyl, carbamoyl or aroyl; and n is an integer from 0-2.

Claim 9

The compound according to Claim 1 having the formula: and salts thereof; wherein R and R 1 are each independently hydrogen, lower alkyl, phenyl, naphthyl or a nitrogen, oxygen or sulfur heterocyclic ring; Z and Z 1 are independently a chemical bond or an alkylene chain having up to 6 carbon atoms in the principal chain and up to a total of 10 carbon atoms; Z 2 is a chemical bond or an alkylene chain or a mono-substituted alkylene chain containing up to 6 carbon atoms in the principal chain and up to a total of 10 carbon atoms and the substituents are hydrogen, lower alkyl, aryl, lower aralkyl, hydroxy, lower alkoxy, lower aralkoxy, aryloxy, carboxy, lower carbalkoxy, carbaryloxy, lower carbaralkoxy, lower carbalkoxy lower alkoxy, amino, lower alkylamino, diloweralkylamino or cyano; X and Y are each independently 0, S, or C R 3 R 4 ; R 3 and R 4 are each independently hydrogen or lower alkyl; n is 0, 1 or 2; and each R 5 is hydrogen, aryl, lower alkanoyl, formyl, nitro, cyano, amino, lower aminoalkyl, lower alkylamino, lower dialkylamino, halo, trihaloalkyl, carbamoyl or aroyl.

Claim 10

The compound according to Claims 1-8 wherein Y is 0 or CR 3 R 4 .

Claim 11

The compound according to Claims 1-9 wherein R and R 1 are each independently H, lower alkyl, phenyl, naphthyl or quinolyl.

Claim 12

The compound according to Claim 1 having the formula: and salts thereof; wherein n is 0 or 1; R and R 1 are each independently hydrogen, lower alkyl, phenyl, naphthyl or a nitrogen, oxygen or sulfur heterocyclic ring; Z and Z l are independently a chemical bond or an alkylene chain having up to 6 carbon atoms in the principal chain and up to a total of 10 carbon atoms; Z 2 is a chemical bond or an alkylene chain or a mono-substituted alkylene chain containing up to 6 carbon atoms in the principal chain and up to a total of 10 carbon atoms and the substituents are hydrogen, lower alkyl, aryl, lower aralkyl, hydroxy, lower alkoxy, lower aralkoxy, aryloxy, carboxy, lower carbalkoxy, carbaryloxy, lower carbaralkoxy, lower carbalkoxy lower alkoxy, amino, lower alkylamino, diloweralkylamino or cyano; X is independently 0, S, or CR 3 R 4 ; R 3 is independently hydrogen or lower alkyl; n is 0, 1 or 2; and each R 5 is hydrogen, aryl, lower alkanoyl, formyl, nitro, cyano, amino, lower aminoalkyl, lower alkylamino, lower dialkylamino, halo, trihaloalkyl, carbamoyl or aroyl.

Claim 13

The compound according to Claims 1-11 wherein X is 0 or CR 3 R 4 .

Claim 14

The compound according to Claims 1-12 wherein n is 0 or 1.

Claim 15

The compound according to Claim 1 having the formula: and salts thereof; wherein R and R 1 are each independently hydrogen, lower alkyl, phenyl, naphthyl or a nitrogen, oxygen or sulfur heterocyclic ring; Z and Z 1 are independently a chemical bond or an alkylene chain having up to 6 carbon atoms in the principal chain and up to a total of 10 carbon atoms; Z 2 is a chemical bond or an alkylene chain or a mono-substituted alkylene chain containing up to 6 carbon atoms in the principal chain and up to a total of 10 carbon atoms and the substituents are hydrogen, lower alkyl, aryl, lower aralkyl, hydroxy, lower alkoxy, lower aralkoxy, aryloxy, carboxy, lower carbalkoxy, carbaryloxy, lower carbaralkoxy, lower carbalkoxy lower alkoxy, amino, lower alkylamino, diloweralkylamino or cyano; R 3 is independently hydrogen or lower alkyl; and each R5 is hydrogen, aryl, lower alkanoyl, formyl, nitro, cyano, amino, lower aminoalkyl, lower alkylamino, lower dialkylamino, halo, trihaloalkyl, carbamoyl or aroyl.

Claim 16

The compound according to Claims 1-14 wherein Z and Z 1 are each a chemical bond or an alkylene chain containing up to 3 carbon atoms in the normal chain.

Claim 17

The compound according to Claims 1-15 wherein Z 2 is an alkylene chain containing up to 5 carbon atoms in the normal chain.

Claim 18

The compound according to Claims 1-16 wherein R and R l are mono- or di-substituted with halo, hydroxy, lower alkyl, lower alkoxy, amino, cyano, lower alkyl, amino, lower aralkyl, aryloxy, lower aralkoxy, nitro or trihalomethyl.

Claim 19

The compound according to Claim 1 which is α-(4-benzyloxyphenyl)-N-benzyl- acetohydroxamate; α-methyl- α-(4-(2-methylpropyl)phenyl)-N-benzyl acetohydroxamate; α-methyl-α-(2-(6-methoxynaphthyl)-N-benzyl acetohydroxamate; α-(4-benzyloxyphenyl)-N-phenethyl acetohydroxamate; α-(4- (2-methylpropyl) phenyl- α-methyl-N- (2-phenethyl) - acetohydroxamate; α-(4-benzyloxyphenyl)-N-(3-phenylpropyl)acetohydroxamate; α-(4-benzyloxyphenyl)-N-methyl acetohydroxamate; α-(4-hydroxyphenyl)-N-(α-methylbenzyl)acetohydroxamate; α-(4-(2-methylpropyl)phenyl)-α-methyl-N-(α-methylbenzyl)acetohydroxamate; α-phenethyl-N-phenethyl acetohydroxamate; α-(4-benzyloxyphenyl)-N-(α-methylbenzyl)acetohydroxamate; α-(4-benzyloxyphenyl)-N-(1-benzylpropyl)acetohydroxamate; α-(3-(2-quinolinylmethoxy)phenyl)-N-(2-phenethyl)-acetohydroxamate; α-(5-benzyloxy-2-pyridyl)-N-benzyl-acetohydroxamate; α-(4-phenoxyphenyl)-N-pentyl-acetohydroxamate; α-(4-benzyloxyphenyl)-N-(5-pentanoic acid)-acetohydroxamate; α-(4-benzyloxybenzyl)-N-(2-phenethyl)acetohydroxamate; α-(4-benzyloxy-3-chlorophenyl)-N-(2-phenethyl)-acetohydroxamate; α-(4-benzyloxy-3-chlorophenyl)-N-(1-carbethoxy-2-phenethyl)acetohydroxamate; α-(3-benzyloxyphenyl)-N-(1-methyl-2-phenethyl)-acetohydroxamate; α-(2-pyridyl)-N-phenethyl acetohydroxamate; c(-(4-benzyloxyphenyl)-N-(2-pyridylmethyl)acetohydroxamate; α-(4-benzyloxyphenyl)-N-phenethyl-0-acetyl acetohydroxamate; N-hydroxy-N-phenethyl-4-benzyloxy-benzamide; N-Hydroxy-N-methyl-3-((quinolin-2-yl)methoxy)phenyl acetamide; N-Hydroxy-N-methyl-5-phenylvaleramide; N-Hydroxy-N-methyl-4-((quinolin-2-yl)methoxy)phenyl acetamide; N-Hydroxy-N-methyl-4-(4-methoxyphenyl)butyramide; N-Hydroxy-N-(2-phenethyl)-2-(3-benzyloxyphenyl) propionamide; N-(3-carboxypropyl)-N-hydroxy-4-phenylbutyramide; N-(2-phenethyl)-N-hydroxy-5-phenylvaleramide; N-Hydroxy-N-(2-methyl-2-(4-methoxyphenyl)ethyl-4-hydroxy-phenylacetamide; N-Hydroxy-N-(2-phenethyl)-2-(3-benzoylphenyl) propionamide; N-Hydroxy-N-(4-chlorophenethyl)-4-benzyloxyphenyl- acetamide; N-(3-carboxypropyl)-N-hydroxy-4-phenylbutyramide; N-Benzyl-N-hydroxy-4-phenylbutyramide; N-Hydroxy-N-[2-methyl-2-(4-benzyloxyphenyl)ethyl]-4-benzyloxyphenylacetamide; N-Hydroxy-N-(1-benzylpropyl)-4-phenylbutyramide; N -Hydroxy-N-(3-phenylpropyl)-3-phepylpropionamide; N-Hydroxy-N-(2-phenethyl)-3-phenoxypropionamide; N-Hydroxy-N-(2-phenethyl)-4-(4-methoxyphenyl)-butyramide; N-Hydroxy-N-propyl-2-(4-benzyloxyphenyl)acetamide; N-Hydroxy-N-methyl-2-(3-chloro-4-benzyloxy)phenyl)-acetamide; N-Hydroxy-N-(2-phenethyl)-4-methoxyphenylacetamide; or N-(t-Butyl)-N-hydroxy-4-benzylphenylacetamide.

Claim 20

A therapeutic composition comprising a compound according to any of Claims 1-18 and a pharmaceutical carrier therefor.