&agr;-amino acid phenyl ester derivatives

Details &agr;-amino acid phenyl ester derivatives &agr;-amino acid phenyl ester derivatives

2001-01-18

2002-09-17

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C558S390000, C560S038000, C560S039000, C560S169000, C560S172000

Reexamination Certificate

active

06451854

ABSTRACT:

The invention relates to &agr;-amino acid phenyl ester derivatives, to pharmaceutical compositions containing the same, as well as to the use of these &agr;-amino acid phenyl ester derivatives as hypnotics for the induction and maintenance of general anaesthesia.
It has been reported (G. Brancaccio and A. Larizza, II Farmaco 1964, 19, 986-1002) that &agr;-amino acid phenyl ester derivatives, wherein the amino group is either dialkylated or is part of an heterocyclic system (GB 1,102,011: Richardson-Merrell S.p.A.), possess local anaesthetic activity, with piperazinyl derivatives proving the most active. In GB 1,160,468 (May & Baker Ltd.) an &agr;-amino acid phenyl ester wherein the amino group is part of a morpholinyl ring, i.e. 2,6-dimethoxyphenyl 2-morpholinopropionate, is disclosed as an intravenous general anaesthetic having a short duration of activity with rapid, smooth recovery. The hypnotic properties of this compound are attained at rather high dose levels and consequently there exists a need for new water soluble intravenous general anaesthetics with improved potency.
The present invention provides &agr;-amino acid phenyl ester derivatives having the general formula I
wherein
R
1
is (C
1-3
)alkyloxy;
R
2
is (C
1-3
)alkyl, (C
1-3
)alkyloxy or (C
2-3
)alkenyl;
R
3
is hydrogen, (C
1-3
)alkyl, (C
1-3
)alkyloxy or (C
2-3
)alkenyl;
R
4
is (C
1-6
)alkyl;
R
5
and R
6
are independently (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
2-6
)alkynyl or aralkyl, each of which may be optionally substituted with (C
1-3
)alkyloxy, (C
1-3
)alkyloxycarbonyl, cyano or NR
7
R
8
;
R
7
and R
8
are independently (C
1-6
)alkyl;
or a pharmaceutically acceptable salt thereof, with the exclusion of 2,6-dimethoxyphenyl 2-(diethylamino)propionate and 2,6-dimethoxyphenyl 2-(diethylamino)butyrate.
Since 2,6-dimethoxyphenyl 2-(diethylamino)propionate and 2,6-dimethoxyphenyl 2-(diethylamino)butyrate have been described as local anaesthetics by G. Brancaccio and A Larizza (vide supra), no protection is sought for these compounds per se.
The &agr;-amino acid phenyl ester derivatives of formula I, having a dialkylated amino group, were surprisingly found to be potent intravenous hypnotics with quick onset, and a short duration of action with rapid, smooth recovery.
The term (C
1-6
)alkyl, as used in the definition of formula I, means a branched or unbranched alkyl group having 1-6 carbon atoms, like hexyl, pentyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl. The term (C
1-3
)alkyl means an alkyl group having 1-3 carbon atoms, like n-propyl, isopropyl, ethyl and methyl. In the term (C
1-3
)alkyloxy as used in formula I, (C
1-3
)alkyl has the meaning as previously given, preferably methyl. The term (C
2-6
)alkenyl means a branched or unbranched alkenyl group having 2-6 carbon atoms, like for example hexenyl, pentenyl, butenyl, 1,3-butadienyl, 1-methyl-propen-2-yl, propen-2-yl(allyl), propen-1-yl or ethenyl(vinyl). Alkenyl groups having at least 3 carbon atoms may be in the E- or Z-form, or a mixture thereof. The term (C
2-3
)alkenyl means an alkenyl group having 2 or 3 carbon atoms, like propen-2-yl, propen-1-yl or ethenyl(vinyl).
The term (C
2-6
)alkynyl means a branched or unbranched alkynyl group having 2-6 carbon atoms, like hexynyl, pentynyl, butynyl, propyn-2-yl or ethynyl. The term aralkyl means an aryl(C
1-3
)alkyl group, wherein alkyl means a bivalent carbon radical having 1-3 carbon atoms, such as methylene, ethan-1,2diyl, propan-1,3-diyl, ethylidene or propylidene, and wherein aryl means a C
6-12
aromatic group and includes one or two C
6
-aromatic rings, like for example phenyl, naphthyl or biphenyl.
Preferred &agr;-amino acid phenyl ester derivatives of the invention correspond to compounds having formula I wherein R
1
and R
2
are methoxy; and R
4
is (C
2-3
)alkyl, like ethyl, propyl or isopropyl, and wherein R
3
, R
5
and R
6
have the previously given meanings. Further preferred are compounds of formula I wherein R
1
and R
2
are methoxy, R
3
is hydrogen or (C
1-3
)alkyl, R
4
is (C
2-3
)alkyl and wherein R
5
and R
6
are independently (C
1-6
)alkyl or aralkyl, each of which may be optionally substituted with (C
1-3
)alkyloxy. More preferred are the compounds wherein R
1
and R
2
are methoxy, R
3
is hydrogen or methyl, R
4
is (C
2-3
)alkyl, and R
5
and R
6
are independently methoxyethyl or ethoxyethyl. Especially preferred &agr;-amino acid phenyl ester derivatives of the invention correspond to formula I wherein R
1
and R
2
are methoxy; R
3
is hydrogen or methyl; R
4
is ethyl; and R
5
and R
6
are methoxyethyl.
The compounds of formula I and their salts contain at least one centre of chirality, i.e. at the &agr;-carbon atom, and exist therefore as stereoisomers, including enantiomers and, when appropriate, diastereomers. The present invention includes the aforementioned stereoisomers within its scope and each of the individual R and S enantiomers of the compounds of formula I and their salts, substantially free, i.e. associated with less than 5%, preferably less than 2%, in particular less than 1% of the other enantiomer, and mixtures of such enantiomers in any proportions including the racemic mixtures containing substantially equal amounts or the two enantiomers.
Preferred are the &agr;-amino acid phenyl ester derivatives of formula I wherein the configuration at the &agr;-carbon atom is that of the R-enantiomer. Particular preferred compounds according to the invention, which have found to be useful as hypnotics for intravenous anaesthesia, are:
R-2-[N-bis(2-methoxyethyl)amino]butyric acid 2,6-dimethoxy-4-methylphenyl ester;
R-2-[N-bis(2-methoxyethyl)amino]butyric acid, 2,6-dimethoxyphenyl ester; and pharmaceutically acceptable salts thereof.
&ggr;-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter within the central nervous system and it is probable that compounds potentiating the effects of GABA at GABA
A
receptors will induce anaesthesia (S. A. Zimmerman, M. V. Jones and N. L. Harrison, J. Pharmacol. Exp. Therap. 1994, 270, 987-991; N. P. Franks and W. R. Lieb, Nature 1994, 367, 607-614). Indeed there is compelling evidence that many hypnotics exert their biological activity via modulation of GABA
A
receptors, including steroids, barbiturates, benzodiazepines and propofol (D. L. Tanelian, P. Kosek, I. Mody and M. B. Maclver, Anesthesiology 1993, 78, 757-776). The compounds of the present invention have been shown to allosterically modulate GABA
A
receptors by inhibiting the specific binding of the radioligand [
35
S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes. The in vitro results presented in Table 1 demonstrate modulation of GABAergic function by the compounds of the present invention and suggest this mechanism mediates or enhances their hypnotic activity.
In addition to their general anaesthetic activity, the compounds of the invention can be used as sedative and analgesic drugs and in the treatment of GABA related diseases, such as anxiety (e.g. panic attack), stress, sleep disorders, post natal depression, and premenstrual tension, and in the alleviation of seizure.
The invention also relates to pharmaceutical compositions comprising an &agr;-amino acid phenyl ester derivative having the general formula I or a pharmaceutically acceptable salt thereof.
The compounds of the invention may be prepared by condensation of an appropriately R
1
,R
2
,R
3
-substituted phenol, wherein R
1
, R
2
and R
3
have the previously given meanings, with an acid halogenide according to the formula Hal
1
-CHR
4
—CO-Hal
2
, wherein R
4
has the meaning as previously defined and Hal
1
and Hal
2
are independently iodo, bromo or chloro, preferably bromo, after which the resulting intermediate ester derivative of formula II
is reacted with an amine according to the formula R
5
R
6
NH, wherein R
5
and R
6
have the meanings as previously defined, optionally followed by conversion into a pharmaceutically acceptable salt.
The acid halogenide according to the formula Hal
1
-CHR
4
—CO-Hal
2
may be prepar

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