Substituted amino acids as neutral sphingomyelinase inhibitors

A method for treating a disease or condition in which inhibition of neutral sphingomylenase is indicated comprising administering to the individual in need thereof an effective amount of the compound of Formula 1:

• wherein;
• R1 is the side chain of an amino acid, wherein said amino acid is selected from the group consisting of natural α-amino acids of L configuration, natural α-amino acids of D-configuration, α-aminoadipic acid, 4-aminobutanoic acid, 6-aminohexanoic acid, α-aminosubenic acid, 5-arninopentanoic acid, p-aminophenylalanine, α-aminopimetic acid, γ-carboxyglutamic acid, p-carboxyphenylalanine, carnitine, citrulline, α,β-diaminopropionic acid, α,γ-diaminobutyric acid, homocitrulline, homoserine, and statine, where if said side chain contains a protectable group, that group may be protected with a member of the group consisting of succinyl, glutaryl, 3,3-dimethylgiutaryl, C1-5alkyl, C1-5alkoxycarbonyl, acetyl, N-(9-fluorenylmethoxycarbonyl), trifluoroacetyl, omega-carboxyC1-5alkytcarbonyl, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, phenylsulfonyl, ureido, t-butyl, cinnamoyl, trityl, 4-methyltrityl, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, tosyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, phenylureido, and substituted phenylureido (where the phenyl substituents are phenoxy, halo, C1-5alkoxycarbonyl);
• R2 and R3
• are taken together to form a six-membered aromatic ring which is fused to the depicted ring, or,
• are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromnethyl, nitro, amino, phenyl, phenoxy, phenylC1-5alkyl, phenyl C1-5alkoxy,
• substituted phenyl (where the substituents are selected from C1-5alky), C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenylC1-5alkyl (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenylC1-5alkoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino), and
• substituted amino (where the substituents are selected from one or more members of the group consisting of C1-5alkyl, halosubstitutedC1-5alkyl, C1-5alknyl, C1-5alkenyl, phenyl, phenylC1-5alkyl, C1-5alkylcarbonyl, halo substituted C1-5alkylcarbonyl, carboxyC1-5alkyl, C1-5alkoxyC1-5alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C1-5alkylsulfonyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, phenylC1-5alkylsulfonyl substituted phenylcarbonyl, substituted phenylC1-5alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC1-5alkylsulfonyl, substituted phenyl, and substituted phenylC1-5alkyl[where the aromatic phenyl, phenylC1-5alkyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, and phenylC1-5alkylsulfonyl substitutents are independently selected from one to five members of the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino]):
• R4 and R5
• are taken together to form a six-membered aromatic ring which is fused to the depicted ring, or,
• are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC1-5alkyl, phenyl C1-5alkoxy,
• substituted phenyl (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, rfluoromethyl, nitro, nitrile, and amino),
• substituted phenylC1-5alkyl (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenylC1-5alkoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino), and
• substituted amino (where the substituents are selected from one or more members of the group consisting of C1-5alkyl, halosubstitutedC1-5alkyl, C1-5alknyl, C1-5alkenyl, phenyl, phenylC1-5alkyl, C1-5alkylcarbonyl, halo substituted C1-5alkylcarbonyl, carboxyC1-5alkyl, C1-5alkoxyC1-5alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C1-5alkylsulfonyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, phenylC1-5alkylsulfonyl substituted phenylcarbonyl, substituted phenylC1-5alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC1-5alkylsulfonyl, substituted phenyl, and substituted phenylC1-5alkyl [where the aromatic phenyl, phenylC1-5alkyl, phenylcarbonyl, phenyC1-5alkylcarbonyl, phenylsulfonyl, and phenylC1-5alkylsulfonyl substitutents are independently selected from one to five members of the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino]);
• W is selected from the group consisting of —CH═CH—,
• Q is selected from the group consisting of —CH═CH—,
• X is selected from the group consisting of carbonyl, C1-5alkyl, C1-5alkenyl, C1-5alkenylcarbonyl, C2-5alkynyl, C2-5alkynylcarbonyl and (CH2)m—C(O)— where m is 2-5,
• Y is selected from the group consisting of carbonyl, C1-5alkyl, C1-5alkenyl, C1-5alkenylcarbonyl, C2-5alkynyl, C2-5alkynylcarbonyl and (CH2)m—C(O)— where m is 2-5;
• Z is selected from the group consisting of hydroxy, C1-5 alkoxy, phenoxy, phenylC1-5alkoxy, amino, C1-5alkylamino, diC1-5alkylamino, phenylamino, phenylC1-5alkylamino, piperidin-1-yl
• substituted piperidin-1-yl (where the substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, halo, aminocarbonyl, C1-5alkoxycarbonyl, and oxo;
• substituted phenylC1-5alkylamnino (where the aromatic substitutents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, phenylC1-5alkenyloxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenoxy (where the aromatic substitutents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenylC1-5alkoxy (where the aromatic substitutents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluorornethyl, nitro, nitrile, and amino),
• —OCH2CH2(OCH2CH2)sOCH2CH2O—, —NHCH2CH2(OCH2CH2)sOCH2CH2NH—, —NH(CH2)pO(CH2)qO(CH2)pNH—, —NH(CH2)qNCH3(CH2)sNH—, —NH(CH2)sNH—, and (NH(CH2)s)3N,
• where s, p, and q are independently selected from 1-7
• or a pharmaceutically acceptable salt thereof.

A neutral sphingomyelinase inhibiting compound of formula II

• wherein:
• R1 is the side chain of an amino acid Cl, where if said side chain contains a protectable group, that group may be protected with a member of the group consisting of succinyl, glutaryl, 3,3-dimethylglutaryl, C1-5alkyl, C1-5alkoxycarbonyl, acetyl, N-(9-fluorenylmethoxycarbonyl), trifluoroacetyl, omega-carboxyC1-5alkylcarbonyl, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, phenylsulfonyl, ureido, t-butyl, cinnamoyl, trityl, 4-methyltrityl, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, tosyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, phenylureido, and substituted phenylureido (where the phenyl substituents are phenoxy, halo, C1-5alkoxycarbonyl);
• R2 and R3
• are taken together to form a six-membered aromatic ring which is fused to the depicted ring, or
• are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC1-5alkyl, phenyl C1-5alkoxy,
• substituted phenyl (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenoxy (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenylC1-5alkyl (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenylC1-5alkoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino), and
• substituted amino (where the substituents are selected from one or more members of the group consisting of C1-5alkyl, halosubstitutedC1-5alkyl, C1-5alknyl, C1-5alkenyl, phenyl, phenylC1-5alkyl, C1-5alkylcarbonyl, halo substituted C1-5alkylcarbonyl, carboxyC1-5alkyl, C1-5alkoxyC1-5alkyl, cinnamoyl, naphthylcar-bonyl, furylcarbonyl, pyridylcarbonyl, C1-5alkylsulfonyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, phenylC1-5alkylsulfonyl substituted phenylcarbonyl, substituted phenylC1-5alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC1-5alkylsulfonyl, substituted phenyl, and substituted phenylC1-5alkyl[where the aromatic phenyl, phenylC1-5alkyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, and phenylC1-5alkylsulfonyl substitutents are independently selected from one to five members of the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino]);
• R4 and R5
• are taken together to form a six-membered aromatic ring which is fused to the depicted ring, or
• are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC1-5alkyl, phenyl C1-5alkoxy,
• substituted phenyl (where the substituents are selected from C1-5alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenylC1-5alkyl (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenylC1-5alkoxy (where the substituents are selected from C1-5 alkyl, C1-5 alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino), and
• substituted amino (where the substituents are selected from one or more members of the group consisting of C1-5alkyl, halosubstitutedC1-5alkyl, C1-5alknyl, C1-5alkenyl, phenyl, phenylC1-5alkyl, C1-5alkylcarbonyl, halo substituted C1-5alkylcarbonyl, carboxyC1-5alkyl, C1-5alkoxyC1-5alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C1-5alkylsulfonyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, phenylC1-5alkylsulfonyl substituted phenylcarbonyl, substituted phenylC1-5alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC1-5alkylsulfonyl, substituted phenyl, and substituted phenylC1-5alkyl [where the aromatic phenyl, phenylC1-5alkyl, phenylcarbonyl, phenylC1-5alkylcarbonyl, phenylsulfonyl, and phenylC1-5alkylsulfonyl substitutents are independently selected from one to five members of the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino]);
• W is selected from the group consisting of —CH═CH—;
• Q is selected from the group consisting of —CH═CH—;
• X is selected from the group consisting of C2-5alkynyl, and C2-5alkynylcarbony;
• Y is selected from the group consisting of C2-5alkynyl, and C2-5alkynylcarbonyl;
• Z is selected from the group consisting of hydroxy, C1-5 alkoxy, phenoxy, phenylC1-5alkoxy, amino, C1-5alkylamino, diC1-5alkylamino, phenylamino, phenylC1-5alkylamino, piperidin-1-yl
• substituted piperidin-1-yl (where the substituents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, halo, aminocarbonyl, C1-5alkoxycarbonyl, and oxo;
• substituted phenylC1-5alkylamino (where the aromatic substitutents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, phenylC1-5alkenyloxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenoxy (where the aromatic substitutents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino),
• substituted phenylC1-5alkoxy (where the aromatic substitutents are selected from the group consisting of C1-5alkyl, C1-5alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino),
• —OCH2CH2(OCH2CH2)sOCH2CH2O—, —NHCH2CH2(OCH2CH2)sOCH2CH2NH—, —NH(CH2)pO(CH2)qO(CH2)pNH, —NH(CH2)qNCH3(CH2)sNH—, —NH(CH2)sNH—, and (NH(CH2)s)3N,
• where s, p, and q are independently selected from 1-7
• or a pharmaceutically acceptable salt thereof.