Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-13
2001-11-27
Rotman, Alan L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S305000, C514S411000, C546S125000, C546S133000, C548S450000
Reexamination Certificate
active
06323216
ABSTRACT:
The subject of the present invention novel basic derivatives of benz[e]isoindol-1-ones and pyrrolo[3,4-c]quinolin-1-ones which can be represented by the general formula (I) indicated below:
and in which
X is CH or N,
r is H, Cl or OR
1
in which R
1
is H or an alkyl group having from 1 to 3 carbon atoms,
Het is the 3-endotropyl group (that is, the 8-methyl-8-azadicyclo[3.2.1]oct-3-yl group) or the 3-quinuclidyl group (that is, the 1-azadicyclo[2.2.2]oct-3-yl group).
The compounds of the present invention have been found to be potent and selective antagonists of the 5-HT
3
serotoninergic receptor and can therefore advantageously be used in the treatment of various diseases in man, for example, as anti-emetics, particularly for vomiting associated with antitumoral chemotherapy, and in various pathological conditions of the central nervous system such as, for example, anxiety, depression, schizophrenia, psychosis, Alzheimer's disease and senile dementia, and also as antitussives. Since serotonin is also known to be involved in the regulation of the peristalsis of the gastrointestinal tract, the compounds of the invention can also advantageously be used as prokinetic agents in various pathological conditions connected with hypomotility of the gastrointestinal tract such as, for example, non-ulcerous dyspepsia, reflux oesophagitis and in irritable bowel syndrome.
In addition to the compounds currently used in treatment as anti-emetics, such as Granisetron and Ondasetron, many publications and patents describe novel compounds with 5-HT
3
antagonistic activity. Thus, for example, U.S. Pat. No. 5,200,413 describes N-azadicyclo-indol-1-carboxyamides with 5-HT-anatagonistic activity; U.S. Pat. No. 5,260,303 describes azacyclo-imidazopyridines with 5-HT
3
-antagonistic activity, U.S. Pat. No. 5,280,028 describes benzimidazole derivatives active as 5-HT
3
-antagonists and 5-HT
4
-antagonists, U.S. Pat. No. 5,399,562 describes indolone derivatives substituted with groups such as endotropyl and quinuclidyl groups. Recently, tropyl-azaindole derivatives with mixed 5-HT
3
- and sigma-oppioid-antagonist activity having antitussive activity (WO 04742-A-1995), 1-heteroaryl-4-alkyl-4-aminopiperidine derivatives which easily overcome the blood-brain barrier [EP-647639-A (1995)], tetrahydrobenzimidazole derivatives with mixed anti-5-HT
3
and H
3
histamine activity [WO 9509168-A(1995)] and imidazol-4-yl-piperidine derivatives with mixed anti-5-HT
3
and -5-HT
4
activity (EP-646583-A(1995)] have also been described. All of this research shows that there is a great therapeutic need to find novel, ever more potent, selective and better tolerated drugs with 5-HT
3
-antagonistic activity. In accordance with this need, the object of the present invention is to provide novel drug treatments having potent and selective 5-HT
3
-antagonistic activity for the treatment of all pathological conditions, both central and peripheral, which are due to poor operation of the 5-HT
3
serotoninergic receptor system. Pharmaceutical forms of the compounds of the invention can be prepared by conventional techniques, for example, as tablets, capsules, suspensions, solutions, suppositories or patches, and may be administered orally, parenterally, rectally or transdermally, or as other forms suitable for achieving the therapeutic effect such as, for example, solid preparations for oral use with protracted action which permit controlled release of the active substance over time.
The active ingredient is normally administered to the patient with a reference dose variable from 0.001 to 1 mg/kg of body weight per dose. For parenteral administration, the use of a water-soluble salt of the compounds of the invention, such as the hydrochloride or another non-toxic and pharmaceutically acceptable salt, is preferable. As inactive ingredients, substances commonly used in pharmaceutical technology such as excipients, binders, flavourings, disaggregants, colourings, humectants, etc. may be used.
The method of preparing the derivatives of the invention consists of a series of reactions which comprise:
a) reacting esters of formula (IV)
prepared as described by Mayer et al (Berichte 1922, 55, 1835-1861), in which X and R have the meanings given above and R′ may be methyl or ethyl, with N-bromosuccinimide in the presence of benzoyl peroxide, in an organic solvent such as, for example, carbon tetrachloride, at a temperature between ambient temperature and the reflux temperature of the solvent, for a period of between 1 and 8 h, to give the corresponding 2-bromomethyl derivatives of formula III (see Synthesis scheme 1, step 1);
b) reacting the bromo derivatives of formula III
with a stoichiometric quantity of a heterocyclic amine of formula (II)
NH
2
-Het (II)
in which Het is the 3-endotropyl group, that is, the 8-methyl-8-azadicyclo[3.2.1]oct-3-yl group, in the presence of an inert tertiary base which functions as a proton acceptor, or with an excess of the amine (II), at the reflux temperature of an anhydrous solvent, preferably toluene, for a period of between 1 and 24 h, to give the corresponding amide derivatives of formula (I) in accordance with Synthesis scheme 1, step 2. The compounds of formula (I) in which R is OH are prepared by hot acid hydrolysis of the corresponding ethereal derivatives.
Synthesis Scheme 1
Step 1
Step 2
in which Het is the 3-endotropyl (8-CH
3
-8-azadicyclo[3.2.1]oct-3-yl) group
The method for the preparation of the derivatives of the invention in which Het is the 3-quinuclidyl group (that is, the 1-azadicyclo[2.2.2]oct-3-yl group) consists of a series of reactions illustrated by Synthesis scheme 2, comprising: protecting the tertiary endocyclic nitrogen of the 3-aminoquinuclidine by alkylation with allyl bromide, reacting the non-isolated quaternized intermediate (VI) with the appropriate bromine derivative of formula (III) indicated in Scheme 1, to give the quaternary ammoniacal salt of the cyclized compound (V) which, in turn, is not isolated, and deprotecting hot with n-dipropylamine in dimethyl formamide in the presence of a catalytic quantity of Pd(PPh
3
)
2
Cl
2
to give amide derivatives of formula (I) according to Synthesis scheme 2, step 3, in which Het is the 3-quinuclidyl group and X and R have the meanings given above.
Synthesis scheme 2
Step 1
Step 2
Step 3
in which Het is the 3-quinuclidyl group (that is, the 1-azadicyclo[2.2.2.]oct-3-yl group).
REFERENCES:
patent: 5200413 (1993-04-01), King et al.
patent: 5260303 (1993-11-01), Becker et al.
patent: 5280028 (1994-01-01), Flynn et al.
patent: 5399562 (1995-03-01), Becker et al.
patent: 0485962A (1992-05-01), None
patent: 0646583A (1995-04-01), None
patent: 0647639A (1995-04-01), None
patent: WO 91/17161A (1991-11-01), None
patent: WO 92/12149A (1992-07-01), None
patent: WO 95/04742 (1995-02-01), None
patent: WO 95/09168 (1995-04-01), None
patent: WO95/32209A (1995-11-01), None
1. “Untersuchungen und Ringschlusse in der Reihe der Methyl-naphthaline” by F. Mayer et al., Berichte 1922, 55, pp. 1835-1861.
2. “Short Communications” by Nelson et al., Biochem. Pharmacol. 1989, 38, pp. 1693-1695.
3. The B-adrenergic transduction system in kidneys from youn and senescent rats by Vanscheeuwijck et al., Eur. J. Pharmacol., 1990, 188, pp. 129-137.
4. [3H]Ketanserin (R41 468), a Selective 3H-Ligand for Serotonin Receptor Binding Sites, by Leysen et al., Mol. Pharmacol. 1982, 21, pp. 301-314.
5. “[3H]8-Hydroxy-2-(Di-n-Propylamino) Tetralin Bindfing to Pre-and Postsynaptic 5-Hydroxytryptamine Sites in Variours Regionso f the Rat Brain” by Hall et al. , J. Neurochem. 1985, 44 pp. 1685-1696.. “Near-offset multiple suppression” by Eduard Filpo, The Leading Edge, Jan. 1999, pp. 40-44 “Deep-water multiple suppression in the near-offset range” Eduardo Filpoilva et al., WEG, 69thAnnual Meeting, Tulsa, OK, USA Oct.
6. “Vagal Sensory Receptors and their Reflex Effects” by Paintal, Physio. Rev.
Anzini Maurizio
Cappelli Andrea
Makovec Francesco
Rovati Lucio Claudio
Vomero Salvatore
Rotman Alan L.
Rotta Research Laboratorium S.p.A
Sughrue Mion Zinn Macpeak & Seas, PLLC
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