Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-03-27
2004-07-06
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S276700
Reexamination Certificate
active
06759421
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new indoline compounds having 5-HT
2c
antagonist properties, to a process for their preparation and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
5-HT
2c
receptors exert inhibitory control over dopaminergic and noradrenergic transmission (Neuropharmacology, 1997, 36, 609, J. Psychopharmacol. 2000, 14 (2), 114-138). 5-HT
2c
antagonists are accordingly considered to be useful in the treatment of numerous pathologies of the central nervous system (CNS). There may be mentioned, without this list being entirely exhaustive, disorders such as anxiety (Br. J. Pharmacol., 1996, 117, 427), depression (Pharmacol. Biochem. Behav., 1988, 29, 819-820), impulsive disorders (Biol. Psych., 1993, 33, 3-14), sexual dysfunctions (J. Pharmacol., 1997, 11, 72), Parkinson's disease (Drug News Perspect., 1999, 12, 477), migraine (Life Sci., 1994, 54, 641-644), cognitive disorders (Neurosci. Biobehav. Rev., 1999, 23, 1111-1125), sleep disorders (Neuropharmacology, 1994, 33, (3/4), 467-471), schizophrenia (Neurosci. Lett., 1996, 181, 65) and appetite disorders such as bulimia and anorexia (British J. Pharmacol., 1998, 123, 1707-1715).
The present invention relates to new indoline compounds which differ from the compounds of the Applications WO 9529177 and WO 9748699 not only in the absence of a pyridyloxy substituent on the 3-pyridylaminocarbonyl group of the indoline but also, especially, in the presence of a benzo group fused to the indoline group.
Surprisingly, those structural changes provide the compounds of the invention with pharmacological activities that are clearly superior to those of the compounds of the Applications WO 9529177 and WO 9748699. The compounds of the invention have been found, especially, to be very active by the oral route.
Use of the benzoindoline radical in the compounds of the invention has accordingly made possible a remarkable improvement in the pharmacological properties.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
R
1
and R
2
together form a benzo ring optionally substituted by a halogen atom or by an alkyl, alkoxy, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino or trifluoromethyl group, and R
3
represents a hydrogen atom, or
R
1
represents a hydrogen atom, and R
2
and R
3
together form a benzo ring optionally substituted by a halogen atom or by an alkyl, alkoxy, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino or trifluoromethyl group,
to their enantiomers and diastereoisomers, and to addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that:
the term “alkyl” denotes a linear or branched hydrocarbon chain containing from 1 to 6 carbon atoms,
the term “alkoxy” denotes a linear or branched alkyl-oxy group containing from 1 to 6 carbon atoms.
Among the pharmaceutically acceptable acids there may be mentioned hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid etc.
Among the pharmaceutically acceptable bases there may be mentioned sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are those wherein R
1
and R
2
together form a benzo ring which is unsubstituted or substituted by a group selected from methoxy and cyano, and R
3
represents a hydrogen atom.
Among the preferred compounds of the invention there may be mentioned, more especially, N-(3-pyridyl)-1,2-dihydro-3H-benzo[e]indole-3-carboxamide, 7-methoxy-N-(3-pyridyl)-1,2-dihydro-3H-benzo[e]indole-3-carboxamide, 6-cyano-N-(3-pyridyl)-1,2-dihydro-3H-benzo[e]indole-3-carboxamide and N-(3-pyridyl)-2,3-dihydro-1H-benzo[f]-indole-1-carboxamide.
The present invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material a benzoindole of formula (II)
wherein R
1
, R
2
and R
3
are as defined for formula (I),
which is condensed, under the action of heat, with a compound of formula (III):
wherein Y represents a group —N═C═O or —C(O)—N
3
, to yield the compound of formula (I),
which may be purified, if necessary, according to a conventional purification technique,
which is separated, if desired, into its isomers (diastereoisomers and enantiomers) by a conventional separation technique,
which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that the indoline of formula (II) is prepared according to known procedures, for example starting from the corresponding nitronaphthylacetonitrile compound.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal or transdermal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels etc.
The useful dosage varies according to the age and weight of the patient, the nature and severity of the disorder, and also the administration route, which may be oral, nasal, rectal or parenteral. The unit dose generally ranges from 0.05 to 500 mg per 24 hours for treatment in 1 to 3 administrations.
The examples that follows illustrate, but do not limit, the invention.
The structures of the compounds described have been determined by conventional spectroscopic and spectrometric techniques.
The starting materials used are known products or are prepared according to known procedures.
Preparation 1:
Step A: (2-Nitro-1-naphthyl)acetonitrile
Prepare a solution of 53.5 g (0.477 mol) of potassium tert.-butanolate in 400 ml of dimethylformamide. Cool the resulting solution to −10° C. and add thereto, over the course of about 1 hour, a solution of 40 g of 4-chlorophenoxyacetonitrile (0.24 mol) and 37 g of 2-nitronaphthalene (0.213 mol) in 200 ml of dimethylformamide. After 2 hours at −5° C., pour the mixture into 4 liters of water containing 1 liter of concentrated hydrochloric acid and extract the aqueous phase with 3×500 ml of dichloromethane. Wash the organic phase with 300 ml of water, dry it over magnesium sulphate, filter and then evaporate off the solvent.
65 g of product are obtained.
Recrystallise that 65 g from a mixture of cyclohexane/ethyl acetate: 50/50.
Step B: 3H-Benzofelindole
At ambient temperature and under 4 bars of hydrogen, hydrogenate 33 g of (2-nitro-1-naphthyl)acetonitrile (0.155 mol) dissolved in 630 ml of ethanol containing 10% water and 6.3 ml of pure acetic acid, using 19 g of 10% palladium-on-carbon. After absorption has ceased, filter off the catalyst, concentrate the solvent in vacuo and then take up the residue in 250 ml of dichloromethane; wash the organic phase with 100 ml of 0.1N potassium hydroxide solution and then dry the organic phase over magnesium sulphate, filter and concentrate.
The residue is purified by chromatography over silica, the eluant being cyclohexane/ethyl acetate: 80/20.
Step C: 2,3-Dihydro-1H-benzo[e]indole
10 g (0.06 mol) of the compound prepared in the previous step are dissolved in 50 ml of tetrahydrofuran. To the resulting solution, at 0° C., add 120 ml of borane/THF complex as a 1M solution in tetrahydrofuran, and then 120 ml of trifluoroacetic acid. After 30 minutes, add, at 0° C., 6 ml of water, stir for 15 minutes and then concentrate the mixture to dryness. The residue is taken up in 200 ml of dichloromethane and washed with 200 ml of IN sodium hydroxide solution. The organic
Gobert Alain
Lavielle Gilbert
Millan Mark
Muller Olivier
Les Laboratoires Servier
Morris Patricia L.
The Firm of Hueschen and Sage
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