Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-03-10
2001-04-24
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S214020, C514S221000, C514S248000, C514S299000, C514S327000, C514S397000, C514S403000
Reexamination Certificate
active
06221878
ABSTRACT:
This invention relates to a new medical use for certain chemical compounds and pharmaceutical compositions containing them. In particular it relates to the use in the treatment of depression of compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at receptors known in the art as 5-HT
3
, 5-HT‘M’ or 5-HT ‘M′-like’ receptors. Such receptors have been described for example by Fozard et al., Eur. J. Pharmacol., 1979, 59, 195-210; Ireland, Straughan and Tyers, Br. J. Pharmacol., 1982, 75, 16P; Humphrey, Neuropharm., 1984, 23, 1503-1570; Richardson et al., Nature, 1985, 316, 126-131; and Bradley et al., Neuropharm., 1986, 25, 563-576. Receptors of this type are now designated as 5-HT
3
receptors.
5-HT receptors of this type are located, for example, on the terminals of afferent sensory neurones, in the isolated guinea-pig ileum preparation and are also present in the central nervous system. Compounds which act as antagonists of 5-HT at 5-HT
3
receptors may be identified using standard tests, for example, in vitro by measuring their inhibition of the depolarising effect of 5-HT on the rat or rabbit isolated vagus nerve, or the tachycardia produced by 5-HT in the rabbit isolated heart or the contraction produced by 5-HT in the guinea-pig isolated ileum, or in vivo by measuring their effect on the Von Bezold-Jarisch reflex (induced by 5-HT) as described, for example, in the above-mentioned references.
A variety of compounds which act as antagonists of 5-HT at 5-HT
3
receptors have been described in the art. These compounds are generally azabicyclo derivatives and/or benzoic acid derivatives, or imidazole derivatives. The azabicyclo derivatives include compounds containing a bridged piperidyl group, such as a tropyl, pseudotropyl, homotropyl or quinoclidinyl group, and they preferably contain a carbocyclic or heterocyclic aromatic group linked, for example as an ester or amide, to the azabicyclic ring. The aromatic group may be for example an optionally substituted phenyl, indolyl, benzofuranyl, benzothienyl, benzisoxazolyl, indazolyl or pyrimidinyl group.
The benzoic acid derivatives which act as antagonists of 5-HT at 5-HT
3
receptors include benzoates and benzamides, for example esters or amides formed with an azabicyclic group as defined above, or formed with a piperidyl group.
Such compounds have been disclosed inter alia in published UK Patent Applications Nos. 2100259, 2125398, 2131420, 2132189, 2145416, 2152049, 2153821 and 2169292, published European Patent Applications Nos. 111608, 116255, 158265, 191562, 200444, 210840, 214772, 219193, 221702, 226267, 227215, 230718, 235878 and 242973, and published Australian Patent Application No. 87/67121. The compounds disclosed in published European Patent Application Nos. 13138, 67615, and 94742 have also been described as antagonists of 5-HT at 5-HT
3
receptors in published European Application Nos. 215545 and 220011. In addition 4-amino-N-1-azabicyclo[2.2.2]oct-3-yl-5-chloro-2-methoxy benzamide (also known as zacopride), described in European Patent Specification No. 99789, has also now been shown to be an antagonist of 5-HT at 5-HT
3
receptors.
The compounds disclosed in these specifications have been described as being of use in a variety of conditions, including migraine.
We have now found that compounds which act as 5-HT antagonists at 5-HT
3
receptors may be used in the treatment of depression.
1,2,3,9-Tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-4H-carbazol-4-one and its salts and solvates, which are disclosed in published UK Patent Application No. 2153821A are however excluded from the present invention. It will be appreciated that general references hereinafter to “compounds which act as antagonists of 5-HT at 5-HT
3
receptors” and to those compounds “disclosed in published UK Patent Application No. 2153821A” exclude 1,2,3,9-tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-4H-carbazol-4-one and its salts and solvates.
Accordingly the invention provides a method of treatment of a subject, in particular a human subject, suffering from depression which comprises administering to the subject an effective amount of a compound which acts as an antagonist of 5-HT at 5-HT
3
receptors, or a physiologically acceptable salt or solvate thereof.
References in this specification to treatment include prophylactic treatment as well as the acute alleviation of symptoms.
Preferred 5-HT
3
receptor antagonists for use in the present invention are azabicyclo derivatives (e.g. containing a bridged piperidyl group such as tropyl, pseudotropyl, homotropyl or quinoclidinyl group) and benzoic acid derivatives (e.g. benzoates and benzamides). Further preferred 5-HT
3
receptor antagonists for use in the present invention are 3-(imidazol-1-yl)methyltetrahydrocarbazolones and 3-(imidazol-4-yl)-(indol-3-yl)-1-propanones.
Particular mention may be made of the compounds which act as antagonists of 5-HT at 5-HT
3
receptors disclosed in published UK Patent Specification Nos. 2100259, 2125398, 2131420, 2132189, 2145416, 2152049, 2153821 and 2169292, published European Patent Specification Nos. 13138, 67615, 94742, 99789, 111608, 116255, 158265, 191562, 200444, 210840, 214772, 219193, 221702, 226267, 227215, 230718, 235878 and 242973, and published Australian Patent Application No. 87/67121.
Preferred compounds for use according to the invention are those compounds which act as antagonists of 5-HT at 5-HT
3
receptors described in published UK Patent Specification Nos. 2100259, 2132189, 2125398, 2152049 and 2153821, published European Patent Specification Nos. 13138, 94742, 99789, 116255, 200444, 221702, 226267, 235878 and 242973 and published Australian Patent Application No. 87/67121.
Particularly preferred compounds for use according to the present invention are those described in published UK Patent Specification Nos. 2100259 and 2125398 and published European Patent Specification Nos. 94742, 200444 and 242973. A further particularly preferred compound for use according to the invention is zacopride.
A preferred group of compounds of ruse according to the invention, described in UK Specification No. 2125398, may be represented by the general formula (I):
wherein R
1
and R
2
independently represent hydrogen, halogen, C
1-4
alkyl, C
1-4
alkoxy, hydroxy, amino, C
1-4
alkylamino, di(C
1-4
)alkylamino, mercapto or C
1-4
alkylthio;
R
3
represents hydrogen, C
1-4
alkyl, C
3-5
alkenyl, aryl or aralkyl;
R
4
represents hydrogen, C
1-7
alkyl, C
3-5
alkenyl, or aralkyl;
n is 2 or 3;
the free valence is attached to either fused ring, and the azabicyclic ring is in either the exo or endo configuration; and acid addition salts and quaternary ammonium salts thereof.
In the compounds of formula (I) R
1
and R
2
may, for example, independently represent hydrogen, halogen or C
1-4
alkyl, R
3
may be, for example, hydrogen or C
1-4
alkyl and R
4
may be, for example, hydrogen, C
1-7
alkyl or aralkyl, the carbonyl group is preferably attached to the 3-position of the indole ring, and the azabicyclic ring is preferably in the endo configuration.
Another preferred group of compounds for use according to the invention, described in UK Specification No. 2100259, may be represented by the general formula (II):
wherein R
5
represents C
1-4
alkyl, C
1-4
alkoxy, or halogen; and
R
6
and R
7
independently represent hydrogen, C
1-4
alkyl, C
1-4
alkoxy or halogen provided that R
6
is hydrogen when R
7
is hydrogen;
and pharmaceutically acceptable salts thereof. A preferred class of compounds of formula (II) are those in which R
5
and R
7
are the same and each represents methyl, methoxy or chlorine, and R
6
represents hydrogen.
A further preferred group of compounds for use according to the invention, described in European Specification No. 94742, may be represented by the general formula (III):
wherein R
8
represents a C
1-6
alkoxy or amino N-substituted by one or two groups selected from C
1-6
alkyl or C
3-8
cycloalkyl or optionally N-substituted by C
4-5
polymethylene;
one of R
9
, R
1
Bacon & Thomas PLLC
Glaxo Group Limited
Spivack Phyllis G.
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