Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-12-11
2004-08-03
Kim, Vickie (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S215000, C564S217000, C564S218000
Reexamination Certificate
active
06770784
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of amides of &ggr;-hydroxybutyric acid, herein referred to as GHB, in the treatment of drug addiction, such as heroine, cocaine and, in particular, in the treatment of alcoholism, and more particularly in reducing chronic alcoholics desire for and habit of consuming alcoholic drinks and in the treatment of abstinence syndrome.
TECHNICAL PROBLEM
The salts of 4-hydroxybutyric acid, e.g. the sodium salt, proved to be effective both in the treatment of the syndrome of abstinence from alcohol and in reducing the desire for and addiction to alcohol in alcoholic patients and disclosed in EP-A-344,704 and in the treatment of drug addiction, as reported in WO 93/00083. One of the advantages of said salts is that they do not cause the inconveniences of Disulfiram (Antabuse®), a drug having several untoward effects, such as for example the symptoms known as the “acetaldehyde syndrome”, which may also result in fatality.
The sodium salt of GHB is absorbed very quickly by the gastroenteric apparatus with a maximum concentration peak already at about 35-40 min after administration. However, it presents a half-life time of about 20-25 min, its elimination from the body being rather quick [EP-A-635,265].
In view of the foregoing, to secure a satisfactory pharmacological cover in patients having a craving for alcohol, especially in the early time of treatment, GHB sodium salt has to be administered several times a day, in particular at least 4 times a day.
Therefore, the need for new drugs, active in the treatment of alcoholism, capable of improving the pharmacokinetic aspects of sodium &ggr;-hydroxybutyrate, is deeply felt.
PRIOR ART
U.S. Pat. No. 4,195,096 discloses N-chlorobenzyl-, N-fluorobenzyl- and N-alkyl amides of &ggr;-hydroxybutyric acid as fungicides for plants.
U.S. Pat. No. 3,940,258 describes the use, as aquatic herbicides, of N-phenylalkylamides and in particular the N-benzylamides of GBH, optionally substituted on the phenyl group with methyl or halo groups, useful also as thickeners for lubricants and paints.
N-alkylenebenzoxazinoamides of GHB showing anti-MAO activity are known [J. Heterocyclic Chem., 1983, 20(1), 139-144].
GHB acid amides useful as inflammation and/or allergy inhibitors are N-alkylenebenzenamides of GHB substituted on the benzene ring with alkylene, alkenyl, and alkyleneoxy residues containing hydroxyl groups (Chemical Abstracts, Vol. 112, 1990: CA 112: 55263z relating to JP 01,121,255 [89,121,255]) and an N-alkylenecycloalkylamide of GHB acid described in Chemical Abstracts, Vol. 118, CA 118: 1011592-Eur. J. Med. Chem., 1992, 27(6), 595-610.
U.S. Pat. No. 2,773,062 and U.S. Pat. No. 2,849,455 describe N-&agr;-ethyl-piperonyl ethers of N-benzyl, N-furfuryl, and N-tetrahydrofurfuryl amides of GHB showing insecticidal activity.
Up to the present time no biological activity has been described for the 0-acyl derivatives of GHB amides, such as for example the benzoyl esters of GHB N-benzylamides, useful as components of thermosensitive coating materials [Chemical Abstracts, Calif. 116: 140229; data base abstract referred to JP 3,240,588].
A pharmacological activity has been attributed to imidazoquinolinone-etherified GCIB amides, erg. they are blood-platelet-antiaggregating agents, antiinflammatory agents and/or antithrombotics [Drug Des. Discovery, 1955, 12(3), 249-258].
Chemical Abstract: CA 122:105695 referred to U.S. Pat. No. 957,491 describes the carbostyriloxytocin receptor antagonist activity and the use of GHB carbostyril N-benzylamides as vasodilators and antihypertensives.
Chemical Abstract, Vol. 110, 1989, CA 110: 135655c, referred to EP-A-257,378, describes the antiviral activity of halo-phenyl ethers of a nucleosidic alkylene-pyrimidine amide of GHB.
The body growth stimulation properties of phenoxyamides, e.g. of N-benzylamide of a chlorophenyl ether of GHB, and their use as animal feed additives, have also.
The body growth stimulation properties of phenoxyamides, e.g. of N-benzylamide of a chlorophenyl ether of GHB, and their use as animal feed additives, have also been described [Chemical Abstract, Vol. 104, 1986, p. 607, CA 104:186147x-DD 161,247].
SUMMARY
The applicant has now unexpectedly found that the amides of &ggr;-hydroxybutyric (GHB) acid show a neuropharmacological activity qualitatively comparable to or exceeding that of GHB. If compared to GHB they cause excitatory effects at lower doses and/or of longer duration. Therefore, said amides are useful in the treatment of drug addictions, such as heroin, cocaine and, in particular, in the treatment of alcoholism, and more particularly in reducing chronic alcoholics desire for and habit of consuming alcoholic drinks and in the treatment of abstinence syndrome.
The present invention relates to the use of amides of formula (I)
where R
1
is a mono- or polycyclic aromatic group, containing one or more carbocyclic or heterocyclic aromatic rings or mixtures thereof, having 5 to 7 atoms in the ring, said rings being optionally substituted with one or more groups selected from C
1
-C
8
alkyl, C
1
-C
8
alkoxyl, one or more aminic monoalkylaminic, dialkyl aminic groups and halogen, where said C
1
-C
8
alkyl and alkoxyl groups may contain or be substituted with one or more double or triple bonds, or with one or more halogen groups and said mono or dialkyl aminic group typically having from 1 to 8 carbon atoms;
R
2
is selected from H; a linear or branched alkyl, typically having 1 to 6 carbon atoms; a linear or branched alkyl substituted with one or more double or triple bonds, or with one or more aromatic groups, typically having 1 to 6 carbon atoms;
Q is selected from H and a linear or branched alkyl having 1 to 6 carbon atoms; n is an integer from 1 to 4;
T
1
and T
2
, individually, are selected from H and a linear or branched alkyl having 1 to 6 carbon atoms.
The aforesaid amides are erg. useful in the treatment of alcoholism, and more in particular in reducing the voluntary consumption of ethyl alcohol in alcoholic patients and in the treatment of the abstinence syndrome.
The aforesaid amides are also useful in the treatment of the crises of abstinence from habit-forming drugs, such as heroin, morphine, cocaine, and psychoactive drugs, which are originated from the same biochemical mechanisms as those responsible for the crises of abstinence from alcohol.
To the best of the applicant's knowledge, pharmaceutical compositions containing a therapeutically effective dose of at least an amide of formula (I), in which R
1
, Q, T
1
, T
2
and n are as defined above, and R
2
is selected from the group consisting of H; a linear or branched alkyl, typically having 1 to 6 carbon atoms; a linear or branched alkyl substituted with one or more double or triple bonds or with one or more aromatic groups, typically having 1 to 6 carbon atoms; in combination with one or more pharmaceutically acceptable excipients and/or diluents, have not been described up to the present time.
To the best of the applicant's knowledge, the following amides, the pharmaceutical compositions containing same, and the preparation procedure thereof, have not been described up to the present time and, therefore, constitute further features of the present invention:
a) amides of formula (I), in which R
1
, Q, T
1
, T
2
and n are as defined above for formula (I), and R
2
is selected from the group consisting of a linear or branched alkyl, typically C
1
-C
6
; a linear or branched alkyl, typically C
1
-C
6
, substituted with one or more double or triple bonds or with one or more aromatic groups;
b) amides of formula (I), in which R
1
, is an aromatic heterocycle, Q, T
1
, T
2
and n are as defined above for formula (I), and R
2
is as defined above for formula (I), provided it is different from an aromatic group, and more particularly R
2
is H;
c) amides of formula (I), in which Q is a C
1
-C
6
alkyl, and R
1
, R
2
, T
1
, T
2
and n are as defined above for formula (I).
The present invention also r
Cacciaglia Roberto
Guano Lorenza
Loche Antonella
Perlini Vincenzo
Hedman & Costigan ,P.C.
Kim Vickie
Laboratorio Farmaceutico C.T. S.r.l.
LandOfFree
Use of &ggr;-hydroxybutyric acid amides in the treatment of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of &ggr;-hydroxybutyric acid amides in the treatment of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of &ggr;-hydroxybutyric acid amides in the treatment of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3288900