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US 5,051,448 AGranted
GABA esters and GABA analog esters
AssigneeThe McLean Hospital Corporation
InventorVictor E. Shashoua
Life of this patent
Estimating the term…
Abstract
Ester derivatives of gamma-aminobutyric acid (GABA) and GABA analogues which cross the blood-brain barrier are disclosed, as well as methods of synthesizing and using the compounds. The ester derivatives have the formula: ##STR1## where A is a radical compound having at least one esterifiable OH group; n varies from one to the total number of esterifiable OH group contained in A; and R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are hydrogen or a substituent.
Claims73
A compound of the formula:
- ##STR16## wherein:
- R.sub.1, R.sub.2, and R.sub.3 are the same or different and are selected from:
- (a) hydrogen;
- (b) lower alkyl groups having one to four carbon atoms;
- (c) substituted lower alkyl group shaving one to four carbon atoms;
- (d) lower alkenyl groups having one to four carbon atoms;
- (e) substituted lower alkenyl groups having one to four carbon atoms;
- (f) lower alkynyl groups having one to four carbon atoms;
- (g) substituted lower alkynyl groups having one to four carbon atoms;
- (h) aryl groups;
- (i) substituted aryl groups;
- (i) substituted aryl groups;
- (j) hydroxyl groups or hydroxy groups protected with lower acyl or aroyl groups;
- (k) lower acyl groups;
- (l) oxo groups, in which case hydrogen is not present on the carbon atom;
- (m) amino groups;
- (n) substituted amino groups;
- (o) R.sub.1 and R.sub.3 together forming a carbocyclic ring;
- (p) R.sub.2 and R.sub.3 together forming a carbocyclic ring;
- R.sub.4 is hydrogen or acyl;
- n can vary from 1 to the total number of esterifiable OH groups contained in A;
- or pharmaceutically acceptable acid addition salts thereof,
- said ester having a Brain Penetration Index greater than 2%.
20 more elements
A pharmaceutical composition useful for promoting the brain uptake of a GABA- or GABA analogue-containing compound, comprising:
- ##STR18## wherein:
- R.sub.1, R.sub.2, and R.sub.3 are the same or different and are selected from:
- (a) hydrogen;
- (b) lower alkyl groups having one to four carbon atoms;
- (c) substituted lower alkyl groups having one to four carbon atoms;
- (d) lower alkenyl groups having one to four carbon atoms;
- (e) substituted lower alkenyl groups having one to four carbon atoms;
- (f) lower alkynyl groups having one to four carbon atoms;
- (g) substituted lower alkynyl groups having one to four carbon atoms;
- (h) aryl groups;
- (i) substituted aryl groups;
- (j) hydroxy groups or hydroxy groups protected with lower acyl or aroyl groups;
- (i) lower acyl groups;
- (l) oxo groups, in which case hydrogen is not present on the carbon atoms;
- (m) amino groups;
- (n) substituted amino groups;
- (o) R.sub.1 and R.sub.3 together forming a carbocyclic ring;
- (p) R.sub.2 and R.sub.3 together forming a carbocyclic ring;
- R.sub.4 is hydrogen or acyl;
- A represents the radical of a compound having at least one esterifiable OH group, selected from the group consisting of saturated Aliphatic alcohols having more than one OH substituent, unsaturated aliphatic alcohols, cyclic alcohols having 5 to 14 carbon ring atoms, aromatic alcohols, carbohydrates, alcohols containing at least one non-cyclic heteroatom and glyceryl esters of fatty acids;
- with the proviso that said alcohols are other than glycerol and are capable of crossing the blood-brain barrier of an animal;
- n can vary from 1 to the total number of esterifiable OH groups contained in A;
- or pharmaceutically acceptable acid addition salts thereof;
- said ester having a Brain Penetration Index greater than 2%;
- and
- a pharmaceutically acceptable excipient.
23 more elements
A method of promoting the uptake of GABA by the brain, comprising administration to a patient in need of said uptake at least one compound of the formula:
- ##STR19## R.sub.1, R.sub.2, and R.sub.3 are the same or different and are selected from:
- (a) hydrogen;
- (b) lower alkyl groups having one to four carbon atoms;
- (c) substituted lower alkyl groups having one to four carbon atoms;
- (d) lower alkenyl groups having one to four carbon atoms;
- (e) substituted lower alkenyl groups having one to four carbon atoms;
- (f) lower alkynyl groups having one to four carbon atoms;
- (g) substituted lower alkynyl groups having one to four carbon atoms;
- (h) aryl groups;
- (i) substituted aryl groups;
- (j) hydroxy groups or hydroxy groups protected with lower acyl or aroyl groups;
- (k) lower acyl groups;
- (l) oxo groups, in which case hydrogen is not present on the carbon atom;
- (m) amino groups;
- (n) substituted amino groups;
- (o) R.sub.1 and R.sub.3 together forming a carbocyclic ring;
- (p) R.sub.2 and R.sub.3 together forming a carbocyclic ring;
- R.sub.4 is hydrogen or acyl;
- A represents the radical of a compound having at least one esterifiable OH group, selected from the group consisting or saturated Aliphatic alcohols having more than one OH substituent, unsaturated aliphatic alcohols, cyclic alcohols having 5 to 14 carbon ring atoms, aromatic alcohols, carbohydrates, alcohols containing at least one non-cyclic heteroatom and glyceryl esters of fatty acids;
- with the proviso that said alcohols are other than glycerol and are capable of crossing the blood-brain barrier of an animal;
- n can vary from 1 to the total number of esterifiable OH groups contained in A;
- or pharmaceutically acceptable acid addition salts thereof,
- said ester having a Brain Penetration Index greater than 2%,
- in an amount sufficient to promote the crossing of the blood-brain barrier of said patient by said compound.
21 more elements
A compound of the formula:
- ##STR20## wherein:
- R.sub.1, R.sub.2, and R.sub.3 are the same or different and are selected from:
- (a) hydrogen;
- (b) lower alkyl groups having one to four carbon atoms;
- (c) substituted lower alkyl groups having one to four carbon atoms;
- (d) lower alkenyl groups having one to four carbon atoms;
- (e) substituted lower alkenyl groups having one to four carbon atoms;
- (f) lower alkynyl groups having one to four carbon atoms;
- (g) substituted lower alkynyl groups having one to four carbon atoms;
- (h) aryl groups;
- (i) substituted aryl groups;
- (j) hydroxy groups or hydroxy groups protected with lower acyl or aroyl groups;
- (k) lower acyl groups;
- (l) oxo groups, in which case hydrogen is not present on the carbon atom;
- (m) amino groups;
- (n) substituted amino groups;
- (o) R.sub.1 and R.sub.3 together forming a carbocyclic ring;
- (p) R.sub.2 and R.sub.3 together forming a carbocyclic ring;
- R.sub.4 is hydrogen or acyl;
- A represents a glyceryl ester of a fatty acid capable of crossing the blood-brain barrier of an animal;
- n can vary from 1 to the total number of esterifiable OH groups contained in A;
- or pharmaceutically acceptable acid addition salts thereof,
- said ester having a Brain Penetration Index greater than 2%.
20 more elements
A pharmaceutical composition useful for promoting the brain uptake of a GABA- or GABA analogue-containing compound, comprising:
- ##STR21## wherein:
- R.sub.1, R.sub.2, and R.sub.3 are the same or different and are selected from:
- (a) hydrogen;
- (b) lower alkyl groups having one to four carbon atoms;
- (c) substituted lower alkyl groups having one to four carbon atoms;
- (d) lower alkenyl groups having one to four carbon atoms;
- (e) substituted lower alkenyl groups having one to four carbon atoms;
- (f) lower alkynyl groups having one to four carbon atoms;
- (g) substituted lower alkynyl groups having one to four carbon atoms;
- (h) aryl groups;
- (i) substituted aryl groups;
- (j) hydroxy groups or hydroxy groups protected with lower acyl or aroyl groups;
- (k) lower acyl groups;
- (l) oxo groups, in which case hydrogen is not present on the carbon atom;
- (m) amino groups;
- (n) substituted amino groups;
- (o) R.sub.1 and R.sub.3 together forming a carbocyclic ring;
- (p) R.sub.2 and R.sub.3 together forming a carbocyclic ring;
- R.sub.4 is hydrogen or acyl;
- A represents a glyceryl ester of a fatty acid capable of crossing the blood-brain barrier of an animal;
- n can vary from 1 to the total number of esterifiable OH groups contained in A;
- or pharmaceutically acceptable acid addition salts thereof,
- said ester having a Brain Penetration Index greater than 2%;
- and
- a pharmaceutically acceptable excipient.
22 more elements
A method of promoting the uptake of GABA by the brain, comprising administration to a patient in need of said uptake at least one compound of the formula:
- ##STR22## wherein:
- R.sub.1, R.sub.2, and R.sub.3 are the same or different and are selected from:
- (a) hydrogen;
- (b) lower alkyl groups having one to four carbon atoms;
- (c) substituted lower alkyl groups having one to four carbon atoms;
- (d) lower alkenyl groups having one to four carbon atoms;
- (e) substituted lower alkenyl groups having one to four carbon atoms;
- (f) lower alkynyl groups having one to four carbon atoms;
- (g) substituted lower alkynyl groups having one to four carbon atoms;
- (h) aryl groups;
- (i) substituted aryl groups;
- (j) hydroxy groups or hydroxy groups protected with lower acyl or aroyl groups;
- (k) lower acyl groups;
- (l) oxo groups, in which case hydrogen is not present on the carbon atom;
- (m) amino groups;
- (n) substituted amino groups;
- (o) R.sub.1 and R.sub.3 together forming a carbocyclic ring;
- (p) R.sub.2 and R.sub.3 together forming a carbocyclic ring;
- R.sub.4 is hydrogen or acyl;
- A represents a glyceryl ester of a fatty acid capable of crossing the blood-brain barrier of an animal;
- n can vary from 1 to the total number of esterifiable OH groups contained in A;
- or pharmaceutically acceptable acid addition salts thereof,
- said ester having a Brain Penetration Index greater than 2%,
- in an amount sufficient to promote the crossing of the blood-brain barrier of said patient by said compound.
21 more elements
Dependencies are inferred from the claim text.