EP0133795A1
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Gaba esters and gaba analogue esters
Assignee: McLean Hospital
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Filing: 1984-08-01
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Granted: —
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Expires: 2004-08-01
Abstract
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: where A is a radical compound having at least one esterifiable OH group; n varies from one to the total number of esterifiable OH groups contained in A; and R 1 , R 2 , R 3 and R 4 are hydrogen or a substituent.
Inventors
- 👤 Victor E. Shashoua
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-01 23:40
CPC Classifications
C; C07; C07H; C07H13/00; C07H13/02; C07H13/04; A; A61; A61K; A61K31/00; A61K31/21; A61K31/215; A61K31/22; C07D; C07D317/00; C07D317/08; C07D317/10; C07D317/14; C07D317/18; C07D317/24; C07J; C07J41/00; C07J41/0033; C07J41/0055
Claims Analysis
Total Claims: 76
Claim 1
Independent Claim
258 words
A compound of the formula: wherein: R 1 , R 2 , and R 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; (1) oxo groups, in which case hydrogen is not present on the carbon atom; (m) amino groups; (n) substituted amino groups; (o) R 1 and R 3 together forming a carbocyclic ring; ( p ) R 2 and R 3 together forming a carbocyclic ring; R 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 carbohydrates, saturated aliphatic alcohols having more than one OH substituent, unsaturated aliphatic alcohols, cyclic alcohols, aromatic alcohols, alcohols containing at least one heteroatom and glyceryl esters of fatty acids, and being 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 about 2%.
Claim 2
Dependent Claim
258 words
A compound of the formula: wherein: R 1 , R 2 , and R 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; (1) oxo groups, in which case hydrogen is not present on the carbon atom; (m) amino groups; (n) substituted amino groups; (o) R 1 and R 3 together forming a carbocyclic ring; ( p ) R 2 and R 3 together forming a carbocyclic ring; R 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 carbohydrates, saturated aliphatic alcohols having more than one OH substituent, unsaturated aliphatic alcohols, cyclic alcohols, aromatic alcohols, alcohols containing at least one heteroatom and glyceryl esters of fatty acids, and being 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 about 2%.
Claim 3
Dependent Claim
14 words
The compound of Claim 1, having a Brain Penetration Index greater than about 3%.
Claim 4
Dependent Claim
14 words
The compound of Claim 2 having a brain penetration index greater than about 25%.
Claim 5
Dependent Claim
14 words
The compound of Claim 1, having an n-octanol/water partition coefficient greater than about 1.
Claim 6
Dependent Claim
14 words
The compound of Claim 4 having an n-octanol/water partition coefficient greater than about 2.
Claim 7
Dependent Claim
14 words
The compound of Claim 5, having a n-octanol/water partition coefficient greater than about 6.
Claim 8
Dependent Claim
23 words
The compound of Claim 1, wherein A represents a radical of a carbohydrate having a carbon chain of 3 to 20 carbon atoms.
Claim 9
Dependent Claim
15 words
The compound of Claim 7 wherein the carbon chain contains 3 to 7 carbon atoms.
Claim 10
Dependent Claim
199 words
The compound of Claim 7, wherein the carbohydrate has the general formula: wherein (1) p is 1 to 18, (2) R 6 , R 7 and R 8 may be the same or different and represent: (a) H; (b) OH, except that R 7 and R 8 cannot be OH; (c) branched or unbranched amino of the formula (CH 2 ) n NH 2' wherein n is 1 to 15; (d) branched or unbranched hydrazino of the formula (CH 2 ) n NHNH 2 , wherein n is as defined above; (e) haloalkyl of the formula (CH 2 ) n CX m H (3-m) , wherein n is as defined above and m is 1 to 3; (f) alkyl of 1 to 15 carbon atoms; (g) alkenyl of 1 to 15 carbon atoms; (h) alkynyl of 1 to 15 carbon atoms; or ( i ) (CH 2 ) n OPO 3 H 2 , wherein n is as defined above; and in addition (3) R 7 and R a may be the same or different and represent haloalkyl of the formula (CX m H 3-m) wherein m and X are as defined above; and (4) R 6 represents acetyl.
Claim 11
Dependent Claim
48 words
The compound of Claim 5 wherein the carbohydrate is selected from the group consisting of D-glucose; D-glyceraldehyde; D-erythrose; D-threose; D-ribose; D-arabinose; D-xylose; D-allose; D-mannose; D-gulose; D-idose; D-galactose; D-talose; dihydroxyacetone; D-erythrulose; D-ribulose; D-xylulose; D-psikose; D-fructose; D-sorbose; their 0-acetyl derivatives; their 0-methyl derivatives; their deoxy-D-derivatives; their amino-D-derivatives; and their acid-D-derivatives.
Claim 12
Dependent Claim
34 words
The compound of Claim 1, wherein A represents the radical of a branched or unbranched saturated aliphatic alcohol having more than one OH substituent and a carbon chain of 2 to 40 carbon atoms.
Claim 13
Dependent Claim
24 words
The compound of Claim 1, wherein A represents the radical of a branched or unbranched aliphatic alcohol, having at least one point of unsaturation.
Claim 14
Dependent Claim
15 words
The compound of Claim 12, wherein the carbon chain contains 3 to 40 carbon atoms.
Claim 15
Dependent Claim
15 words
The compound of Claim 13, wherein the carbon chain contains 4 to 30 carbon atoms.
Claim 16
Dependent Claim
15 words
The compound of Claim 14, wherein the carbon chain contains 8 to 20 carbon atoms.
Claim 17
Dependent Claim
11 words
The compound of Claim 12, wherein the alcohol is an alkenyl.
Claim 18
Dependent Claim
11 words
The compound of Claim 13, wherein the alcohol is an alkynyl.
Claim 19
Dependent Claim
190 words
The compound of Claim 5, wherein the alcohol has the formula: wherein: (1) q is 1 to 38; (2) R 9 , R 10 , R 11 , R 12 , R13 and R 14 may be the same or different, and represent: (a) H, with the proviso that at least one is different from H; (b) OH, except that R 13 and R 14 cannot be OH; (c) branched or unbranched amine of the formula (CH 2 ) n NH 2 , wherein n is 1 to 15; (d) branched or unbranched alkyl of 1 to 15 carbon atoms; (e) branched or unbranched hydrazino of the formula (CH 2 ) n NH-NH 2 , wherein n is as defined above; (f) branched or unbranched haloalkyl of the formula (CH 2 ) n CX m H (3-m) , wherein X represents F, Cl, Br, or I, n is as defined above, and m is 1 to 3; (g) branched or unbranched alkenyl of 1 to 15 carbon atoms; (h) branched or unbranched alkynyl of 1 to 15 carbon atoms; (i) acetyl; (j) their O-acetyl derivatives; and (k) their 0-methyl derivatives.
Claim 20
Dependent Claim
31 words
The compound of Claim 18, wherein the alcohol has one or more carbon rings, and R 10 and R 12 may be a cyclic structure containing one or more carbon rings.
Claim 21
Dependent Claim
19 words
The compound of Claim 19, wherein one or more of the carbon rings in the cyclic alcohol are aromatic.
Claim 22
Dependent Claim
12 words
The compound of Claim 20, wherein the aromatic alcohol is a polyalcohol.
Claim 23
Dependent Claim
28 words
The compound of Claim 1, wherein A represents a radical of a branched or unbranched, saturated or unsaturated cyclic alcohol, having a maximum of 18 ring carbon atoms.
Claim 24
Dependent Claim
12 words
The compound of Claim 22 having 5 to 14 carbon ring atoms.
Claim 25
Dependent Claim
12 words
The compound of Claim 22 having 6 to 10, carbon ring atoms.
Claim 26
Dependent Claim
47 words
The compound of Claim 22, wherein the cyclic alcohol is selected from the group consisting of cyclopentanol; cyclohexanol, cycloheptanol; cyclo- octanol; cyclodecanol; cyclododecanol; cyclotetra- decanol; cyclohexadecanol; cycloocatadecanol; inositol; their derivatives having multiple hydroxyl substituents; their 0-acetyl derivatives; their 0-methyl derivatives; their amine derivatives; and their halogenated derivatives.
Claim 27
Dependent Claim
16 words
The compound of Claim 22, wherein the cyclic alcohol may contain one or more aromatic rings.
Claim 28
Dependent Claim
27 words
The compound of Claim 1, wherein A represents the radical of a branched or unbranched alcohol with 2 to 40 carbon atoms having one or more heteroatoms.
Claim 29
Dependent Claim
22 words
The compound of Claim 27, wherein A contains from 1 to 3 atoms of oxygen, nitrogen or sulfur, or a combination thereof.
Claim 30
Dependent Claim
28 words
The compound of Claim 28, wherein A is selected from the group of alkyl, alkenyl and alkynyl alcohols having a carbon chain of 2 to 60 carbon atoms.
Claim 31
Dependent Claim
19 words
The compound of Claim 28, wherein the alcohol is a cyclic alcohol of 5 to 18 carbon ring atoms.
Claim 32
Dependent Claim
12 words
The compound of Claim 30 having 6 to 10 carbon ring atoms.
Claim 33
Dependent Claim
14 words
The compound of Claim 27, wherein the alcohol has one or more aromatic rings.
Claim 34
Dependent Claim
27 words
The compound of Claim 27, wherein the hetero alcohol is selected from the group consisting of ethanolamine, choline, serine, O-aminoacylglycerol, their alkyl derivatives, and their 0-acyl derivatives.
Claim 35
Dependent Claim
36 words
The compound of Claim 1, wherein A represents the radical of a glycerol esterified with up to two radicals of carboxylic acids having C 2 -C 60 carbon atoms, which may be the same or different.
Claim 36
Dependent Claim
22 words
The compound of Claim 34, wherein the carboxylic acids, are branched or unbranched aliphatic acids having 6 to 40 chain carbon atoms.
Claim 37
Dependent Claim
12 words
The compound of Claim 35 having 10 to 30 chain carbon atoms.
Claim 38
Dependent Claim
16 words
.The compound of Claim 35 wherein the carboxylic acids have an even number of carbon atoms.
Claim 39
Dependent Claim
16 words
The compound of Claim 34, wherein the carboxylic acids contain at least one point of unsaturation.
Claim 40
Dependent Claim
24 words
The compound of Claim 38, wherein the carboxylic acids are derived from an alkenyl or alkynyl radical having more than one point of unsaturation.
Claim 41
Dependent Claim
21 words
The compound of Claim 34, wherein the glycerol radical is esterified by one fatty acid and one GABA or GABA analogue
Claim 42
Dependent Claim
22 words
The compound of Claim 40, wherein the glycerol radical is esterified by one fatty acid and two GABAs or two GABA analogues.
Claim 43
Dependent Claim
21 words
The compound of Claim 40, wherein the glycerol radical is esterified by two fatty acids and one GABA or GABA analogue.
Claim 44
Dependent Claim
49 words
The compound of Claim 35, wherein the carboxylic acids are selected from a group consisting of lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, cerebronic acid, cardiolypin, their 0-acetyl derivatives, their 0-methyl derivatives, and their amino derivatives.
Claim 45
Dependent Claim
28 words
The compound of Claim 1, wherein A is the radical derived from a compound selected from the group consisting of inositol, cholesterol, dexamethasone, dilinolenoyl glycerol, and linolenoyl glycerol.
Claim 46
Dependent Claim
35 words
A pharmaceutical composition useful for promoting the brain uptake of a GABA- or GABA analogue-containing compound, comprising: an effective amount of the compound of Claim 1, or a combination thereof; and a pharmaceutically acceptable excipient.
Claim 47
Dependent Claim
17 words
The composition of Claim 45, wherein the excipient is suitable for the oral administration of the compound.
Claim 48
Dependent Claim
18 words
The composition of Claim 46, wherein said composition is in the form of dragees, tablets., syrups and ampules.
Claim 49
Dependent Claim
9 words
The composition of Claim 47, in unitary dosage form.
Claim 50
Dependent Claim
17 words
The composition of Claim 45, wherein the excipient is suitable for the rectal administration of the compound.
Claim 51
Dependent Claim
15 words
The composition of Claim 49, wherein said composition is in the form of a suppository.
Claim 52
Dependent Claim
9 words
The composition of Claim 50, in unitary dosage form.
Claim 53
Dependent Claim
20 words
The composition of Claim 45, wherein the excipient is suitable for the subcutaneous, intramuscular or intravenous administration of the composition.
Claim 54
Dependent Claim
9 words
The composition of Claim 52, in unitary dosage form.
Claim 55
Dependent Claim
17 words
The composition of Claim 45, wherein the excipient is suitable for the topical application of the compound.
Claim 56
Dependent Claim
18 words
The composition of Claim 54, wherein the composition is in the form of a pomade or a gel.
Claim 57
Dependent Claim
9 words
The composition of Claim 55, in unitary dosage form.
Claim 58
Dependent Claim
44 words
A method of promoting the uptake of GABA by the brain, comprising administering to a patient in need of said uptake the compound of Claim 1 in an amount sufficient to promote the crossing of the blood-brain barrier of said patient by said compound.
Claim 59
Dependent Claim
36 words
A method of treating a condition associated with abnormal GABA levels in the brain comprising administering to a patient susceptible to said condition an effective amount of the compound of Claim 1, or a combination thereof.
Claim 60
Dependent Claim
26 words
The method of Claim 58, wherein the condition is selected from the group consisting of epilepsy, Huntington's disease, manic depression, general depression, schizophrenia and neuropsychiatric disorders.
Claim 61
Dependent Claim
30 words
A method of regulating general locomotor activity comprising administering to a patient susceptible to abnormal locomotor activity, an effective amount of one or more of the compounds of Claim 1.
Claim 62
Dependent Claim
32 words
A method of preventing or treating a condition associated with seizures comprising administering to a patient susceptible to seizures, an effective amount of the compound of Claim 1, or a combination thereof.
Claim 63
Dependent Claim
88 words
A process of preparing the compound of Claim 1, comprising: (a) reacting GABA or GABA analogue with 2-t(t-butoxycarbonyl)oximinol-2-phenylacetonitrile to obtain t-butoxycarbonyl-GABA or t-butoxycarbonyl-GABA analogue; (b) dehydrating the t-butoxycarbonyl-GABA or t-butoxycarbonyl-GABA analogue in the presence of a dehydrating agent to obtain t-butoxycarbonyl-GABA anhydride or t-butoxycarbonyl-GABA analogue anhydride; (c) esterifying the t-butoxycarbonyl GABA anhydride or t-butoxycarbonyl-GABA analogue anhydride with a compound of the formula: to obtain a t-butoxycarbonyl-GABA-A or t-butoxycarbonyl-GABA analogue-A ester; and (d) deamidifying the t-butoxycarbonyl-GABA or t-butoxycarbonyl-GABA analogue ester to obtain the deamidified GABA-A or GABA analogue-A ester.
Claim 64
Dependent Claim
14 words
The process of Claim 62, wherein the dehydrating agent of step (b), is dicyclohexylcarbodiimide.
Claim 65
Dependent Claim
20 words
The process of Claim 62 wherein the deamidi- fication step (d) is carried out in the presence of trifluoroacetic acid.
Claim 66
Dependent Claim
164 words
A process for preparing the compound of Claim 34, comprising: (a) protecting two of the OH groups contained in the glyceryl compound by forming a glyceryl acetonide of the formula: (b) esterifying the free OH group by reacting the glyceryl acetonide with an anhydride of the formula: wherein R is a radical of a carboxylic acid as defined above, in a dry organic solvent, in the presence of 4-dimethylaminopyridine, and whereby a monoester of the glyceryl acetonide is obtained; (c) freeing the two previously protected OH groups by reacting the monoester of the diglyceryl acetonide with an acid to obtain a diglyceryl-R monoester; (d) esterifying a t-butoxycarbonyl GABA anhydride or t-butoxycarbonyl GABA analogue anhydride with the diglyceryl-R monoester in a molar ratio of about 2:1 or greater, and in the presence of 4-dimethylaminopyridine in benzene, thereby obtaining a di-t-butoxycarbonyl-GABA-R-glyceryl ester or di-t-butoxycarbonyl-GABA-analogue-R-glyceryl ester; and (e) deamidifying the di-t-butoxycarbonyl-GABA-R-glyceryl ester or di-t-butoxycarbonyl-GABA . analogue-R-glyceryl ester,- thereby obtaining the deamidified diGABA-R-glyceryl ester or di-GABA analogue-R-glyceryl ester.
Claim 67
Dependent Claim
14 words
The process of Claim 65, where the acid of step (c) is trifluoroacetic acid.
Claim 68
Dependent Claim
74 words
The process of Claim 65, wherein step (e) is replaced by the following steps: (a) converting the thus obtained glyceryl ester to the corresponding glyceryl ester-trifluoroacetate salt in the presence of trifluoroacetic acid in an atmosphere of N 2 gas; and (b) extracting the di-GABA or di-GABA analogue, R glyceryl triester-trifluoroacetate salt with a mixture of aqueous NaHCO 3 and an organic solvent, and whereby the free di-GABA or di-GABA analogue-R-glyceryl triester is obtained.
Claim 69
Dependent Claim
65 words
The process of Claim 65, wherein the molar ratio of the t-butoxycarbonyl GABA or GABA analogue anhydride and the diglyceryl-R monoester in step (d) is less than 1:1; and further comprising, after step (d), the following additional step: (e) esterifying the t-butoxycarbonyl GABA or GABA analogue-R-monoglyceryl ester with a compound selected from: or whereby a t-butoxycarbonyl GABA or GABA analogue, diR glyceryl ester is obtained.
Claim 70
Dependent Claim
127 words
The process of Claim 63, wherein the anhydride of step (b) is N-carbobenzoxy-GABA or GABA analogue anhydride and the product obtained thereof is an N-carbobenzoxy-GABA or -GABA analogue ester of the glyceryl acetonide; and further comprising the following steps thereafter; . (c) hydrogenating the thus obtained N-carbobenzoxy-GABA or GABA analogue ester of the glyceryl acetonide with hydrogen gas in the presence of Pd-C to obtain the diglyceryl ester of N-carbobenzoxy-GABA or -GABA analogue; (d) reacting the thus obtained diglyceryl ester of N-carbobenzoxy-GABA or -GABA analogue with trifluoroacetic acid to obtain the trifluoroacetate salt of the diglyceryl ester of GABA or -GABA analogue; and (e) forming an HCl addition salt of the diglyceryl ester of GABA or GABA analogue by reacting the product of step (d) with HCl.
Claim 71
Dependent Claim
21 words
The compound of Claim 1 wherein R 2 , R 3 and R 4 are hydrogen, and R 1 is vinyl.
Claim 72
Dependent Claim
9 words
The compound of Claim 70 wherein A is glucosyl.
Claim 73
Dependent Claim
9 words
The compound of Claim 70 wherein A is cholesteryl.
Claim 74
Dependent Claim
10 words
The compound of Claim 1 which is gamma-vinyl GABA-di-linolenoyl-glyceryl triester.
Claim 75
Dependent Claim
10 words
The compound of Claim 1 which is di-(gamma-vinyl GABA)-linolenoyl-glyceryl triester.
Claim 76
Dependent Claim
13 words
The compound of Claim 1 wherein A represents the radical of dihydroxy acetone.
References Cited (Backward Citations)
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