A new process for preparing novel N-(acyloxy-alkoxy) carbonyl derivatives useful as bioreversible prodrug moieties for primary and secondary amine functions in drugs

Claim 2

A compound of the formula: wherein X is phenyl substituted with one or more of the substituents selected from the group consisting of nitro, halo, cyano, C 1-6 alkylsulfonyl, C 1-6 alkylsulfenyl, trihalomethyl, trihalomethylthio, trihalomethylsulfonyl and trihalomethylsulfenyl or a radical selected from the group consisting of C 1-5 polyhaloalkyl and C 2-12 alkylsulfonylalkyl; R 1 and R 2 can be the same or different and are - selected from the group consisting of hydrogen, C 1-6 alkyl, substituted C 1-5 alkoxycarbonyl alkyl, aryl and aralkyl; and R 3 is selected from the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, aryl, C 7-10 aralkyl, C 3-8 cycloalkyl, C 3-10 cycloalkenyl, C 2-20 carboxyalkyl, carbox y C 5-20 cycloalkyl, C2-20 haloalkyl, C 1-5 alkoxycarbonyl C 2-10 alkyl, C 2-20 alkylsulfoxide, C 2-20 carbamyl substituted alkyl, C 2-20 carbamyl substituted aralkyl, and saturated or unsaturated mono- or polyheterocyclics having from 1 to 3 rings having one or more heteroatoms.

Claim 3

The compound of Claim 1 wherein X is halophenyl, nitrophenyl or polyhaloalkyl; R l and R 2 are hydrogen, alkyl or substituted C 1-5 alkoxycarbonylalkyl and R 3 is alkyl, aryl, mono- or polyheterocyclic or alkoxycarbonylalkyl.

Claim 4

The compound of Claim 2 wherein X is nitrophenyl; R 1 and R 2 are hydrogen or methyl and R 3 is methyl, nicotinyl, hexanoyl, pivaloyl or palmitoyl.

Claim 5

A process for preparing a compound of the formula: wherein RR'N is any drug, pharmaceutical or medicament having a primary or secondary amine function; R 1 and R 2 can be the same or different and are selected from the group consisting of hydrogen, C 1-6 alkyl, substituted C 1-5 alkoxycarbonylalkyl, aryl and aralkyl; and R 3 is selected from the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, aryl, C 7-10 aralkyl, C 3-8 cycloalkyl, C 3-10 cycloalkenyl, C 2-20 carboxyalkyl, carboxy C 5-20 cycloalkyl, C2-20 haloalkyl, C 1-5 alkoxycarbonyl C 2-10 alkyl, C 2-20 alkylsulfoxide, C 2-20 carbamyl substituted alkyl, C 2-20 carbamyl substituted aralkyl, and saturated or unsaturated mono- or polyheterocyclics having from 1 to 3 rings having at least one heteroatom, which comprise reacting a drug, pharmaceutical or medicament of the formula RR'NH wherein RR'N is as described above with a compound of the formula: wherein X is phenyl substituted with at least one substituent selected from the group consisting of nitro, halo, cyano, Cl-6 alkylsulfonyl, C l - 6 alkylsulfenyl, trihalomethyl, trihalomethylthio, trihalomethylsulfonyl and trihalomethylsulfenyl or a radical selected from the group consisting of trifluoroethyl, trichloroethyl and C 2-12 alkylsulfonylalkyl; and R 1 , R 2 and R 3 are as previously defined in the presence of a polar aprotic solvent and optionally a catalyst at a temperature ranging from 0° to 100°C.

Claim 6

A process for preparing a compound of the formula: wherein RR'N is any drug, pharmaceutical or medicament having a primary or secondary amine function; R 1 and R 2 can be the same or different and are selected from the group consisting of hydrogen, C 1-6 alkyl, substituted C 1-5 alkoxycarbonylalkyl, aryl and aralkyl; and R 3 is selected from the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, aryl, C 7-10 aralkyl, C 3-8 cycloalkyl, C 3-10 cycloalkenyl, C 2-20 carboxyalkyl, carboxy C 5-20 cycloalkyl, C2-20 haloalkyl, C 1-5 alkoxycarbonyl C 2-10 alkyl, C 2-20 alkylsulfoxide, C 2-20 carbamyl substituted alkyl, C 2-20 carbamyl substituted aralkyl, and saturated or unsaturated mono- or polyheterocyclics having from 1 to 3 rings having at least one heteroatom, which comprise reacting a drug, pharmaceutical or medicament of the formula RR'NH wherein RR'N is as described above with a compound of the formula: wherein X is phenyl substituted with at least one substituent selected from the group consisting of nitro, halo, cyano, Cl-6 alkylsulfonyl, C l - 6 alkylsulfenyl, trihalomethyl, trihalomethylthio, trihalomethylsulfonyl and trihalomethylsulfenyl or a radical selected from the group consisting of trifluoroethyl, trichloroethyl and C 2-12 alkylsulfonylalkyl; and R 1 , R 2 and R 3 are as previously defined in the presence of a polar aprotic solvent and optionally a catalyst at a temperature ranging from 0° to 100°C.

Claim 7

The process of Claim 4 wherein the polar aprotic solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, hexamethylphosphorictriamide, and 1,3-dimethyl-2-imidazolidinone and the catalyst is selected from the group consisting of 1-hydroxybenzotriazole, imidazole, pyrazole and 1,2,4-triazole at a temperature ranging from 25° to 60°C.

Claim 8

The process of Claim 4 further comprising conducting the reaction in presence of a catalyst.

Claim 9

The process of Claim 6 wherein the catalyst is 1-hydroxybenzotriazole.

Claim 10

The process of Claim 4 for preparing N-[1'-acetoxyethoxycarbonyl isopropylamino]-3-(1-naphthyloxy)-2-propanol, 4-[2-hydroxy-3-[N-(1'-acetoxyethoxycarbonyl)isopropylamino)propoxy]benzeneacetamide, 3-[3-acetoxymethoxycarbonyl-t-butylamino-2-hydroxypropoxyl-4-morpholino-1,2,5-thiadiazole, 1-[N-(l'-acetoxyethoxycarbonyl)isopropylamino-3-(p-cyclopropylmethoxyethyl)phenoxy]-2-propanol, N-(acetoxyethoxycarbonyl)-3-(3',4'-dihydroxyphenyl)-2-methylalanine, 4-[2-hydroxy-3-[N-(1'-acetoxyethoxycarbonyl)isopropylamino]propoxy]indole, N-(acetoxymethoxycarbonyl)-3-(3',4'-dihydroxyphenyl)-2-methylalanine, N-(pivaloxyethoxycarbonyl)-3-(3',4'-dihydroxyphenyl)-2-methylalanine, N-(pivaloxymethoxy- carbonyl)-3-(3',4'-dihydroxyphenyl)-2-methylalanine, N-(palmitoyloxymethoxycarbonyl)-3-(3',4'-dihydroxyphenyl)-2-methylalanine or N-(pyridine-3'-carboxy- methoxycarbonyl)-3,4-dimethoxyphenethylamine.

Claim 11

A process for preparing a compound of the formula: wherein X is phenyl substituted with one or more of the substituents selected from the group consisting of nitro, halo, cyano, C 1-6 alkylsulfonyl, C 1-6 alkylsulfenyl, trihalomethyl, trihalomethylthio, trihalomethylsulfonyl and trihalomethylsulfenyl or a radical selected from the group consisting of trifluoroethyl, trichloroethyl and C 2-12 alkylsulfonylalkyl; R, and R 2 can be the same or different and are selected from the group consisting of hydrogen, C 1-6 alkyl, substituted C 1-5 alkoxycarbonylalkyl, aryl and aralkyl; and R 3 is selected from the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, aryl, C 7-10 aralkyl, C 3-8 cycloalkyl, C 3-10 cycloalkenyl, C2-20 carboxyalkyl, carboxy C 5-20 cycloalkyl, C 2-20 haloalkyl, C 1-5 alkoxycarbonyl C 2-10 alkyl, C 2-20 alkylsulfoxide, C 2-20 carbamyl substituted alkyl, C 2-20 carbamyl substituted aralkyl, and saturated or unsaturated mono- or polyheterocyclics having from 1 to 3 rings, which comprises reacting a compound of the formula: wherein X is as previously defined with a compound of the formula: wherein Y is halo or an amine conjugate, Z is halo and R 1 and R 2 are as previously defined in the presence of a nonprotic solvent and base at a temperature ranging from -78° to 100°C resulting in a compound of the formula: wherein R 1 , R 2' X and Z are as previously defined, displacing the Z moiety with an acyl group by treating with a reagent of the formula: wherein R 3 is as previously defined and M is selected from the group consisting of alkali and alkaline earth metal ion or a mono or polyvalent metal in the presence of an inert solvent at ambient or room temperature to the boiling point (reflux) of the inert solvent.

Claim 12

A process for preparing a compound of the formula: wherein X is phenyl substituted with one or more of the substituents selected from the group consisting of nitro, halo, cyano, C 1-6 alkylsulfonyl, C 1-6 alkylsulfenyl, trihalomethyl, trihalomethylthio, trihalomethylsulfonyl and trihalomethylsulfenyl or a radical selected from the group consisting of trifluoroethyl, trichloroethyl and C 2-12 alkylsulfonylalkyl; R, and R 2 can be the same or different and are selected from the group consisting of hydrogen, C 1-6 alkyl, substituted C 1-5 alkoxycarbonylalkyl, aryl and aralkyl; and R 3 is selected from the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, aryl, C 7-10 aralkyl, C 3-8 cycloalkyl, C 3-10 cycloalkenyl, C2-20 carboxyalkyl, carboxy C 5-20 cycloalkyl, C 2-20 haloalkyl, C 1-5 alkoxycarbonyl C 2-10 alkyl, C 2-20 alkylsulfoxide, C 2-20 carbamyl substituted alkyl, C 2-20 carbamyl substituted aralkyl, and saturated or unsaturated mono- or polyheterocyclics having from 1 to 3 rings, which comprises reacting a compound of the formula: wherein X is as previously defined with a compound of the formula: wherein Y is halo or an amine conjugate, Z is halo and R 1 and R 2 are as previously defined in the presence of a nonprotic solvent and base at a temperature ranging from -78° to 100°C resulting in a compound of the formula: wherein R 1 , R 2' X and Z are as previously defined, displacing the Z moiety with an acyl group by treating with a reagent of the formula: wherein R 3 is as previously defined and M is selected from the group consisting of alkali and alkaline earth metal ion or a mono or polyvalent metal in the presence of an inert solvent at ambient or room temperature to the boiling point (reflux) of the inert solvent.

Claim 13

A process according to Claim 9 wherein the nonprotic solvent is selected from the group consisting of chloroform, dichloromethane, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate and acetonitrile; base is selected from the group consisting of pyridine, triethylamine, l,8-bis(dimethylamino)naphthalene and 4-dimethylaminopyridine; metal ion is selected from the group consisting of sodium, potassium, magnesium, calcium, silver, mercury and zinc; the reaction being conducted in an inert solvent selected from the group consisting of chloroform, dioxane, ethanol, water, dimethylformamide, hexamethylphosphoramide, acetonitrile, benzene, toluene, xylene and organic acid at temperatures ranging from room temperature to 150°C.