Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Recombinant or stably-transformed bacterium encoding one or...
Patent
1982-04-09
1984-03-06
Reamer, James H.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Recombinant or stably-transformed bacterium encoding one or...
424324, 424319, 424320, 424330, 562561, 562456, 562440, 564510, 564367, 564372, 564305, 564215, 564220, 564182, 564183, 564184, A61K 3113, C07C 8722
Patent
active
044354258
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to novel fluorinated diaminobutane compounds of the following general formula: ##STR2## wherein: R.sub. represents hydrogen, C.sub.1 -C.sub.6 alkyl, or phenyl-(C.sub.1 -C.sub.4 alkyl); -C.sub.4 alkyl), or R.sub.4, where R.sub.4 is as defined below; R.sub.4, where R.sub.4 is as defined below; phenylcarbonyl, phenyl-(C.sub.1 -C.sub.4 alkyl)carbonyl, or an aminocarboxylic acid residue derived by removal of an hydroxy group from the carboxy moiety of an L-aminocarboxylic acid; and gamma-aminobutyric acid transaminase (GABA-T). The invention also provides pharmaceutical compositions comprising said compounds, methods of medical treatment using said compounds, and processes for preparing said compounds.
BACKGROUND OF THE INVENTION
The biotransformation of gamma-aminobutyric acid (GABA) to succinic acid semialdehyde, which is catalyzed by the enzyme GABA-transaminase (GABA-T), is the primary reaction responsible for the catabolism of GABA, an inhibitory neurotransmitter of the central nervous system. It is known that low levels of endogenous GABA are associated with seizures disorders (such as those produced by epilepsy, alcohol withdrawal, or barbiturate withdrawal), with disorders involving involuntary movement (such as Huntington's chorea, the extrapyrimidal effect of drugs, for example tardive dyskinesia) and certain psychoses (such as schizophrenia and mania/depression). Blockade of the transformation of GABA to succinic acid semialdehyde, such as by irreversible inhibition of GABA-T, can elevate GABA levels in the central nervous system (CNS) and, thus provides a means for treating those disorders of the central nervous system associated with low GABA levels.
Certain compounds are known to be irreversible inhibitors of GABA-T and thereby elevate brain levels of GABA, for example fluorinated methyl gamma-aminobutyric acid and certain derivatives thereof (see U.K. Patent Specification No. 2005264A). Further, it is disclosed in U.K. Patent Specification No. 2058052A that fluorinated methyl aminopropionic acids and certain derivatives thereof are also irreversible inhibitors of GABA-T.
SUMMARY OF THE INVENTION
The compounds of the invention are represented by the following general Formula I: ##STR3## wherein: R.sub.1 represents hydrogen, C.sub.1 -C.sub.6 alkyl or phenyl-C.sub.1 -C.sub.4 alkyl; -C.sub.4 alkyl or R.sub.4, where R.sub.4 is as defined below; R.sub.4, where R.sub.4 is as defined below; phenylcarbonyl, phenyl-(C.sub.1 -C.sub.4 alkyl)carbonyl, or an aminocarboxylic acid residue derived by removal of an hydroxy group from the carboxy moiety of an L-aminocarboxylic acid; and
Pharmaceutically acceptable salts of the compounds of Formula I and individual optical isomers of the compounds of Formula I are also included within the scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION
In the above general Formula 1, R.sub.1 and R.sub.2 can be the same or different and can represent hydrogen, C.sub.1 -C.sub.6, especially C.sub.1 -C.sub.4, alkyl, phenyl-C.sub.1 -C.sub.4 alkyl, preferably benzyl or phenethyl, or, in the case of R.sub.2 only, C.sub.2 -C.sub.5 alkylcarbonyl, phenylcarbonyl, phenyl-(C.sub.1 -C.sub.4 alkyl)carbonyl, or an aminocarboxylic acid residue derived by removal of an hydroxy group from the carboxy moiety of an L-aminocarboxylic acid. It is prefered that both R.sub.1 and R.sub.2 represent hydrogen.
In the above general Formula I, R.sub.3 represents hydrogen, or, when R.sub.2 represents hydrogen, alkyl or phenalkyl, C.sub.2 -C.sub.5 alkylcarbonyl, phenylcarbonyl, phenyl (C.sub.1 -C.sub.4 alkyl)carbonyl, or an aminocarboxylic acid residue derived by removal of an hydroxy group from the carboxy moiety of an L-aminocarboxylic acid. Preferably, R.sub.3 represents C.sub.2 -C.sub.5 alkylcarbonyl and, especially, hydrogen.
When R.sub.4 is an aminocarboxylic acid residue, it can be for example, of the formula --COCH(R.sub.9)NH.sub.2 or --CO(CH.sub.2).sub.n CH(NH.sub.2)CO.sub.2 H wherein R.sub.9 is hydrogen, C.sub.1 -C.sub.4 alkyl, aminopr
REFERENCES:
patent: 2931804 (1960-05-01), Spivack
patent: 3975443 (1976-08-01), Harper et al.
patent: 4134918 (1979-01-01), Bey
patent: 4286983 (1981-09-01), Gilse et al.
Bey et al., Tit. Lett, #52, pp. 5225-6228.
Seiler et al., "Enzyme Activated Irreversible Inhibitors", pp. 55-70 (1978).
Bey Philippe
Gerhart Fritz
Jung Michel
Schirlin Daniel
Sjoerdsma Albert
McDonald Raymond A.
Merrell Toraude et Compagnie
Reamer James H.
Stein William J.
Street Gary D.
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