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US 6,387,389 B1Granted
Sustained-release derivatives of hydroxylated analogs of substituted 1-[2[bis(aryl)methoxy]ethyl]-piperazines and -homopiperazines and their use
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsRichard B. Rothman, Kenner C. Rice, David Lewis, Dorota Matecka, John R. Glowa
Life of this patent
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Abstract
The present invention provides sustained-release derivatives of hydroxylated analogs of substituted 1-[2[bis(aryl)methoxy]ethyl]-piperazines and -homopiperazines, pharmaceutical compositions comprising the same, and a method of using such sustained-release derivatives to bind the dopamine transporter to achieve a desired effect, such as antagonism of dopamine reuptake inhibitors, such as cocaine, or dopamine releasers or norepinephrine and/or serotonin reuptake inhibitors, such as methamphetamine.
Claims34
A compound selected from the group consisting of:
- 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-[3-phenyl-3-hydroxypropyl]piperazine,
- 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-[3-phenyl-2-hydroxypropyl]piperazine,
- 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-[3-(2-hydroxy-phenyl)-propyl]piperazine,
- 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-[3-(3-hydroxy-phenyl)-propyl]piperazine, and
- 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-[3-(4-hydroxy-phenyl)-propyl]piperazine,
- in which said hydroxy substituent is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
3 more elements
A compound of formula 1:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- wherein at least one of R3 and R4 is hydroxyl and the other is hydrogen or hydroxyl,
- wherein at least one hydroxyl at R3 or R4 is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl,
- and the stereochemistry of R3 and R4 is R, S or RS.
1 more element
A compound of formula 14:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- R3 is 2-, 3-, or 4-hydroxyl,
- Ar can comprise from 1 to 4 atoms selected from the group consisting of O, N and S,
- b—c is a single, double (cis or trans) or triple bond, and
- wherein at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
2 more elements
A compound of formula 5:
- or formula 6:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- wherein at least one of R3 and R4 is a hydroxyl and the other is hydrogen or hydroxyl,
- Ar contains from 1 to 4 atoms selected from the group consisting of O, N and S,
- wherein at least one hydroxyl at R3 or R4 is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl,
- and the stereochemistry of R3 and R4 is R, S or RS.
3 more elements
A compound of formula 7:
- or formula 8:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- Ar contains from 1 to 4 atoms selected from the group consisting of O, N and S,
- R3 is hydroxyl at any one or more of positions 1-7 of Ar of formula 7 and at any one or more of positions 1-8 of Ar of formula 8, and
- wherein at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
2 more elements
A compound of formula 9:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- R3 is hydrogen or hydroxyl, the stereochemistry of which is R, S or RS,
- Ar contains from 1 to 4 atoms selected from the group consisting of O, N and S,
- R4 is hydroxyl at any one or more of positions 1-8 of Ar, and
- wherein at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
2 more elements
A compound of formula 10:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- R3 is hydrogen or C1-7 alkyl,
- R4 is hydroxyl,
- R5 is hydrogen, C1-7 alkyl, aryl or aryl alkyl,
- wherein the stereochemistry of R3, R4 and R5 is R, S, or RS, and
- wherein at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
3 more elements
A compound of formula 11:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- R3 is hydrogen,
- R4 is hydroxyl,
- R5 is hydrogen, C1-7 alkyl, aryl or aryl alkyl,
- n is (CH2), (CH2)2 or (CH2)3 and can be substituted with R5,
- wherein the stereochemistry of R3, R4 and R5 is R, S, or RS, and
- wherein at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
4 more elements
A compound of formula 12:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- R3 is hydroxyl,
- n is (CH2), (CH2)2 or (CH2)3,
- wherein the stereochemistry of R3 is R, S or RS, and
- wherein at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
2 more elements
A compound of formula 13:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- each of R3-R6 is hydrogen, hydroxyl, C1-7 alkyl, cycloalkyl, cycloalkyl alkyl, halo, halo C1-7 alkyl, C1-7 alkoxy, hydroxy C1-7 alkyl, C2-7 alkenyl, and C2-7 lower alkynyl,
- each of R7 and R8 is hydrogen or hydroxyl,
- wherein the stereochemistry of R3-R8 is R, S, or RS, and
- wherein at least one of R1, R2, R7 and R8 is hydroxyl and at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
2 more elements
A compound of formula 15:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- R3 is hydroxyl at any one or more of positions 2-5,
- Ar can contain 1-3 atoms selected from the group consisting of O, N and S,
- b—c is a single, double (cis or trans) or triple bond, and
- wherein at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
2 more elements
A compound of the formula:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- R3 is hydrogen or hydroxyl, the stereochemistry of which is R, S or RS,
- R4 is hydroxyl at any one or more of positions 1-7 of Ar, and
- wherein at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
1 more element
A compound of the formula:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- R3 is hydrogen or hydroxyl, the stereochemistry of which is R, S or RS,
- R4 is hydroxyl at any one or more of positions 1-7 of Ar, and
- wherein at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
1 more element
A compound of the formula:
- wherein each of R1 and R2 is one or more of the substituents selected from the group consisting of hydrogen, hydroxyl, a C1-7 alkyl, a cycloalkyl, a cycloalkyl alkyl, a C1-7 alkoxy, halo, a halo C1-7 alkyl, a hydroxy C1-7 alkyl, an amino, a C1-7 alkyl mono amino, a C1-7 alkyl di amino, a C1-7 alkanoyl, a C2-7 alkenyl, and a C2-7 alkynyl,
- R3 is hydrogen or hydroxyl, the stereochemistry of which is R, S or RS,
- R4 is hydroxyl at any one or more of positions 1-7 of Ar, and
- wherein at least one hydroxyl is esterified with an alkanoic acid comprising a C6-20 alkyl, a C6-20 aryl alkyl or a C6-20 cycloalkyl alkyl.
1 more element
Dependencies are inferred from the claim text.