US2003225161A1PendingUtilityA1
GABA and L-glutamic acid analogs for antiseizure treatment
Priority: Nov 27, 1990Filed: Apr 28, 2003Published: Dec 4, 2003
Est. expiryNov 27, 2010(expired)· nominal 20-yr term from priority
Inventors:Richard B. SilvermanRyszard AndruszkiewiczPo-Wai YuenDenis Martin SobierayLloyd Charles FranklinMark Alan Schwindt
C07C 247/12G11B 20/1426G11B 27/3027C07C 229/28C07C 2601/14C07C 309/73C07C 229/08A61K 31/197C07C 229/24C07C 69/675C07D 263/22C07C 69/34C07D 263/26C07C 229/34
54
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
A compound of the formula wherein R 1 is a straight or branched alkyl group having from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R 2 is hydrogen or methyl; and R 3 is hydrogen, methyl or carboxyl; which is useful in the treatment of seizure disorders. Processes are disclosed for the preparation of the compound. Intermediates prepared during the synthesis of the compound are also disclosed.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound selected from the following formula
wherein R 1 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R 2 is hydrogen or methyl; and R 3 is hydrogen, methyl, or carboxyl; individual enantiomers thereof; and pharmaceutically acceptable salts thereof; with the proviso that when each of R 2 and R 3 is hydrogen, R 1 is other than methyl.
2 . A compound of claim 1 wherein R 1 is a straight or branched alkyl having from 1 to 6 carbon atoms.
3 . A compound of claim 2 wherein the alkyl group has 4 carbon atoms.
4 . A compound of claim 3 which is 4-amino-3-(2-methylpropyl)butanoic acid.
5 . A compound of claim 3 which is S-(+)-4-amino-3-(2-methylpropyl)butanoic acid.
6 . A compound of claim 3 which is R(−)-4-amino-3-(2-methylpropyl)butanoic acid.
7 . A method of treating a patient having seizure disorders which comprises administering to said patient an effective amount of a compound of the formula
wherein R 11 is a straight or branched alkyl group having from 1 to 6 carbon atoms, phenyl, or cycloalkyl group having from 3 to 6 carbon atoms; R 12 is hydrogen or methyl; and R 13 is hydrogen, methyl, or carboxyl; individual enantiomers thereof; and pharmaceutically acceptable salts thereof.
8 . The method of claim 7 wherein R 11 is a straight or branched alkyl group having from 1 to 6 carbon atoms.
9 . The method of claim 8 wherein the alkyl group has 4 carbon atoms.
10 . The method of claim 9 wherein the compound is 4-amino-3-(2-methylpropyl)butanoic acid.
11 . The method of claim 9 wherein the compound is S-(+)-4-amino-3-(2-methylpropyl)butanoic acid.
12 . The method of claim 9 wherein the compound is R-(−)-4-amino-3-(2-methylpropyl)butanoic acid.
13 . The method of claim 7 wherein the seizure disorder is the result of epilepsy, acerebral ischemic condition, Parkinson's disease, Huntington's disease, or a spastic condition.
14 . The method of claim 13 wherein the seizure disorder is the result of epilepsy.
15 . The method of claim 13 wherein the seizure disorder is the result of a spastic condition.
16 . A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable carrier.
17 . The composition of claim 16 wherein the compound is one wherein R 1 is a straight or branched alkyl group having from 1 to 6 carbon atoms.
18 . The composition of claim 17 wherein the compound is 4-amino-3-(2-methylpropyl)butanoic acid.
19 . The composition of claim 17 wherein the compound is S-(+)-4-amino-3-(2-methylpropyl)butanoic acid.
20 . The composition of claim 17 wherein the compound is R-(−)-4-amino-3-(2-methylpropyl)butanoic acid.
21 . A process for preparing a chiral compound of Formula I which comprises converting an acid of the formula HOC(=0)CH(R 1 ) (R 2 ) to the corresponding acid chloride of the formula ClC(=0)CH(R 1 ) (R 2 ) which was added to a solution of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone and n-butyllithium at −78° C. under argon to give an oxazolidinone derivative of the formula
which was treated with benzyl α-bromoacetate to give the ester
which was treated with hydrogen peroxide and lithium oxide followed by treatment with sodium metabisulfite to give compounds of the formula
which is treated with borane dimethyl sulfide complex to give the alcohol
which is converted to the corresponding tosylate (Formula A wherein P is Tso) which is further converted to the azide (Formula A wherein P is N 3 ) and the azide is reduced to the amine of the formula
wherein R 1 and R 2 have the meanings defined in claim 1 , Ph is phenyl, Me is methyl, and Bn is benzyl.
22 . A compound which is
4-methyl-5-phenyl-2-oxazolidinone, 4-methyl-(2-methylpropyl)-2-dioxo-5-phenyl-3-oxazolidine butanoic acid, phenylmethyl ester, 4-methyl-pentanoyl chloride, 4-methyl-3-(4-methyl-1-oxopentyl)-5-phenyl-2-oxazolidinone, 2-(2-methylpropyl)-butanedioic acid, 4-(phenylmethyl) ester, 3-(azidomethyl)-5-methyl-hexanoic acid, phenylmethyl ester, 3-(hydroxymethyl)-5-methyl-hexanoic acid, phenylmethyl ester, 5-methyl-3-[[[(4-methylphenyl)sulfonyl]oxy]-methyl]-hexanoic acid, phenylmethyl ester, 3-(azidomethyl)-5-methyl-hexanoic acid, 2-(2-methylpropyl)-1,4-butanedioic acid, 4-(1,1-dimethylethyl) ester, 3-(azidomethyl)-5-methyl-, 1,1-dimethylethyl ester, 3-(hydroxymethyl)-5-methyl-hexanoic acid, 1,1-dimethyl ester, 5-methyl-3-[[[(4-methyl(phenyl)sulfonyl]oxy]-methyl-hexanoic acid, 1,1-dimethylethyl ester, or 4-methyl-(2-methylpropyl)-2-dioxo-5-phenyl-3-oxazolidinebutanoic acid, 1,1-dimethylethyl ester.
23 . A compound which is
(S)-3-(azidomethyl)-5-methyl-hexanoic acid.
24 . A compound which is
(S)-3-(azidomethyl)-5-methyl-hexanoic acid, 1,1-dimethylethyl ester.
25 . A compound which is
(S)-5-methyl-3-[[[(4-methyl(phenyl)sulfonyl]-oxy]methyl-hexanoic acid, 1,1-dimethylethyl ester, (S)-3-(hydroxymethyl)-5-methyl-, 1,1-di-methylethyl ester, (S)-2-(2-methylpropyl)-1,4-butanedioic acid, 4-(1,1-dimethylethyl) ester, or (S)-4-methyl-(2-methylpropyl)-2-dioxo-5-phenyl-3-oxazolidinebutanoic acid, 1,1-dimethylethyl ester.
26 . A process for preparing a chiral compound of the formula
wherein R 1 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R 2 is hydrogen or methyl; and R 3 is hydrogen, methyl, or carboxyl, which comprises hydrolyzing an azide of the formula
to an intermediate azide of the formula
and the intermediate azide is reduced to the amine of the formula
wherein, R 1 and R 2 have the meanings defined in claim 1 , Ph is phenyl, Me is methyl, and Bn is benzyl.
27 . A process as defined in claim 26 wherein the azide is hydrolysed by treatment with sodium hydroxide.
28 . A process as defined in claim 26 further comprising the step of extraction of intermediate azide into an aqueous base.
29 . A process as defined in claim 28 further comprising the step of acidifying the aqueous extract.
30 . A process as defined in claim 26 wherein the intermediate azide is reduced under near neutral conditions to give the amino acid.
31 . The amino acid obtained by the process defined in claim 26 .
32 . A process for preparing a chiral compound of the formula
wherein R 1 is a straight or branched alkyl of from 1 to 6 carbon atoms; R 2 is hydrogen or methyl; and R 3 is hydrogen, methyl, or carboxyl, which comprises hydrolyzing an azide of the formula
to an intermediate azide of the formula
and the intermediate azide is reduced to the amine of the formula
wherein R 1 and R 2 have the meanings defined in claim 1 , Ph is phenyl, and Me is methyl.
33 . A process as defined in claim 32 wherein the azide is hydrolysed by treatment with sodium hydroxide.
34 . A process as defined in claim 32 further comprising the step of extraction of intermediate azide into an aqueous base.
35 . A process as defined in claim 34 further comprising the step of acidifying the aqueous extract.
36 . A process as defined in claim 32 wherein the intermediate azide is reduced under near neutral conditions to give the amino acid.
37 . The amino acid obtained by the process defined in claim 32.Join the waitlist — get patent alerts
Track US2003225161A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.