US20020042426A1 - Novel basic derivatives of benz[e] isoindol-1-ones and pyrrolo[3,4-c] quinolin-1ones with 5-HT3-antagonistic activity, their preparation and their therapeutic use - Google Patents
Novel basic derivatives of benz[e] isoindol-1-ones and pyrrolo[3,4-c] quinolin-1ones with 5-HT3-antagonistic activity, their preparation and their therapeutic use Download PDFInfo
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- US20020042426A1 US20020042426A1 US09/967,972 US96797201A US2002042426A1 US 20020042426 A1 US20020042426 A1 US 20020042426A1 US 96797201 A US96797201 A US 96797201A US 2002042426 A1 US2002042426 A1 US 2002042426A1
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- HVWOXWSKLYNGFI-UHFFFAOYSA-N C=CC[N+]12CCC(CC1)C(N)C2.[Br-] Chemical compound C=CC[N+]12CCC(CC1)C(N)C2.[Br-] HVWOXWSKLYNGFI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Definitions
- X is CH or N
- R is H, Cl or OR 1 in which R 1 is H or an alkyl group having
- 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.
- 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.
- 5,399,562 describes indolone derivatives substituted with groups such as endotropyl and quinuclidyl groups.
- 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.
- 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.
- compositions 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.
- a water-soluble salt of the compounds of the invention such as the hydrochloride or another non-toxic and pharmaceutically acceptable salt, is preferable.
- inactive ingredients substances commonly used in pharmaceutical technology such as excipients, binders, flavorings, disaggregants, colorings, humectants, etc. may be used.
- the method of preparing the derivatives of the invention consists of a series of reactions which comprise:
- Het is the 3-endotropyl group, that is, the 8-methyl-8-azadicyclo[3.2.1.]oct-3-yl group
- 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, nor a period of between 1 and 24 h, to give the corresponding amide derivatives of forms a (I) in accordance with Synthesis scheme 1, step 2.
- R is OH are prepared by hot acid hydrolysis of the corresponding ethereal dervazives.
- Het is the 3-quinuclidyl group (that is, the 1- azadicyclo[2.2.2.]oct-3-yl group).
- Example 1 The method described in Example 1 was followed with the use of 3-methyl-4-quinoline ethyl carboxylate instead of the 2- methyl-1-naphthalene methyl carboxylate. After reaction with N-bromosuccinimide and in the presence of benzoyl peroxide, the corresponding 3-bromomethyl-4-quinoline ethyl carboxylate, a dense yellow-orange oil, was obtained and was reacted with an excess of endo-3-aminotropane in toluene under reflux for 8 h. Upon completion the oily residue obtained was rendered friable and crystallized from an n-hexane-ethyl acetate mixture. Overall yield 38%. Melting point 153-154° C.
- This compound was synthesized by following the method used for the synthesis of Compound 1 , with the use of 8.7 g (35 mmoles) of 2-chloro-3-methyl-4-quinoline ethyl carboxylate instead of the 2-methyl-1-naphthalene methyl carboxylate and in accordance with the stoichiometry described above. 7.2 g of Compound 3 was obtained (yield 60%). Recrystallization from n-hexane-ethyl acetate gave a pure product which melted at 169-171° C.
- This compound was synthesized by following the method used for the synthesis of Compound 1, with the use of 2.6 g (9.5 mmoles) of 2-propoxy-3-methyl-4-quinoline ethyl carboxylate instead of the 2-methyl-2-naphthalene methyl carboxylate and in accordance with the stoichiometry described above. 1.5 g of Compound 4 was obtained (yield 43%). After crystallization from n-hexane-ethyl acetate, a pure compound in the form of colorless needles which melted at 170-171° C. was obtained.
- the (R) enantiomer of Compound 6 was prepared by following the method described above for Compound 6, with the use of (R)-3-aminoquinuclidine dihydrochloride instead of (R,S)-3- aminoquinuclidine dihydrochloride. Yield 35%. Melting point 155-157° C.
- [3H]-BRL43694 (Granisetron) was used as a marked ligand for the investigation of the 5-HT 3 receptors
- [3H]- paroxetine was used for the investigation of the serotonin uptake site
- [3H]-ketanserine was used for the investigation of the 5-HT 2 receptors
- [3H]-8-OH DPAT was used for the investigation of the 5HT-1A receptors.
- Rat prefrontal cortex was used to produce a pellet having a final concentration of 8 mg of tisssue/sample.
- Specific activity of the tracer 80.9 Ci/mmole; incubation time: 20 min; incubation temperature: 37° C.
- Specific binding: 90% of the total; Kd 0.5 ⁇ 10 ⁇ 9 M.
- Compound 10 that is, the analogous 3-hexotropyl derivative of the corresponding 3-endotrophyl (Compound 1), described herein purely for comparative purposes, was almost 2 orders of logarithmic magnitude less active than Compound 1; similarly, Compound 11 which is also given for comparative purposes, that is endo-2-[-methyl-8-azadicyclo[3.2.1]oct-3-yl]-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one, which has a “linear” polycyclic fusion and which is the pyrrolo-quinolne analogue of compound 2 was approximately 60 times less active than the latter, in which the polycyclic fusion takes place on the “e” face and is hence angular.
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Abstract
Description
-
- and in which
- X is CH or N,
- R is H, Cl or OR1 in which R1 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-HT3 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-HT3 antagonistic activity. Thus, for example, U.S. Pat. No. 5200413 describes N-azadicyclo-indol-1-carboxyamides with 5-HT-antagonistic activity; U.S. Pat. No. 5,260,303 describes azacyclo-imidazopyridines with 5-HT3-antagonistic activity, U.S. Pat. No. 5,280,028 describes benzimidazole derivatives active as 5-HT3-antagonists and 5-HT4-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-HT3- 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-HT3 and H3 histamine activity [WO 9509168-A(1995)] and imidazol-4-yl-piperidine derivatives with mixed anti-5-HT3 and -5-HT4 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-E3-antagonistic activity. In accordance with this need, the object of the present invention is to provide novel drug treatments having potent and selective 5-HT3-antagonistic activity for the treatment of all pathological conditions, both central and peripheral, which are due to poor operation of the 5-HT3 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, flavorings, disaggregants, colorings, humectants, etc. may be used.
- The method of preparing the derivatives of the invention consists of a series of reactions which comprise:
-
- 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);
-
- with a stoichiometric quantity of a heterocyclic amine of formula (II)
- NH2-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, nor a period of between 1 and 24 h, to give the corresponding amide derivatives of forms a (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 dervazives.
- Synthesis scheme 1
-
- 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 ally bromide, reacting the non-isolated Quaternizea 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(PPh3)2Cl2 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.
- in which Het is the 3-quinuclidyl group (that is, the 1- azadicyclo[2.2.2.]oct-3-yl group).
- The following examples are given below to illustrate the invention further.
- A mixture constituted by 10 g (51 mmoles) of 2-methyl-1-naphthalene methyl carboxylate, 9.9 g (55.6 mmoles) of N—bromosuccinimide, and 1.5 g (6.2 mmoles) of benzoyl peroxide in 300 ml of CCl4 was heated under reflux for 2 h. The solvent was evaporated, the residue was taken up with the minimum quantity of CCl4, the succinimide was filtered out, and the filtrate was evaporated under reduced pressure to give 15 g of yellowish oil which was used as such for the subsequent reaction (NMR indicated that this oil was constituted by 85-95% of 2-bromomethyl-1-naphthalene methyl carboxylate). A mixture of 15 g of this oil with 25.9 g (185 mmoles) of endo-3-aminotropane in 500 ml of toluene was heated under reflux for 8 h with azeotropic removal of the methanol evolved in the course of the reaction. The solvent was evaporated under reduced pressure, the residue was taken up with CHCl3, washed with water and then with a saturated NaCl solution, dehydrated and evaporated under reduced pressure. The oily residue, treated with hexane-ethyl acetate, was rendered friable by resting. It was recrystallized from ethyl acetate, to give 8.5 g. Yield 54.5%. Melting point 174-175° C. H NMR (CDCl3): 1.54-1.61 (m, 4H), 2.15-2.19 (m, 2H), 2.25-2.60 (m, 5H), 3,28 (m, 2H), 4.41 (s, 2H), 4.64 (m, 1H), 7.47-7.67 (m, 3H), 7.90 (d, J=7.6, 1H), 7.97 (d, J=8.3, 1H), 9.24 (d, J=8.4, 1H).
- The method described in Example 1 was followed with the use of 3-methyl-4-quinoline ethyl carboxylate instead of the 2- methyl-1-naphthalene methyl carboxylate. After reaction with N-bromosuccinimide and in the presence of benzoyl peroxide, the corresponding 3-bromomethyl-4-quinoline ethyl carboxylate, a dense yellow-orange oil, was obtained and was reacted with an excess of endo-3-aminotropane in toluene under reflux for 8 h. Upon completion the oily residue obtained was rendered friable and crystallized from an n-hexane-ethyl acetate mixture. Overall yield 38%. Melting point 153-154° C.1H NMR (CDCl3):1.50-1.65 (m, 4H), 2.14-2.21 (m, 5H), 2.42-2.59 (m, 2H), 3,28 (m, 2H), 4.46 (s, 2H), 4.61 (m, 1H), 7.61-7.79 (m, 2H), 8.15 (d, J=8.4, 1H), 9.05 (m, 2H), MS: m/z 307 (M+, 22).
- This compound was synthesized by following the method used for the synthesis of Compound1, with the use of 8.7 g (35 mmoles) of 2-chloro-3-methyl-4-quinoline ethyl carboxylate instead of the 2-methyl-1-naphthalene methyl carboxylate and in accordance with the stoichiometry described above. 7.2 g of Compound 3 was obtained (yield 60%). Recrystallization from n-hexane-ethyl acetate gave a pure product which melted at 169-171° C. 1H NMR (CDCl3) : 1.47-1.66 (m, 4H) , 2.16-2.23 (m, 5H), 2.45-2.60 (m, 2H), 3.29 (m, 2H), 4.41 (s, 2H), 4.67 (m, 1H), 7.64-7.83 (m, 2H), 8.09 (d, J=8.3, 1H), 9.04 (d, J=8.6, 1H) , MS: m/z 341 (M+, 16).
- This compound was synthesized by following the method used for the synthesis of Compound 1, with the use of 2.6 g (9.5 mmoles) of 2-propoxy-3-methyl-4-quinoline ethyl carboxylate instead of the 2-methyl-2-naphthalene methyl carboxylate and in accordance with the stoichiometry described above. 1.5 g of Compound 4 was obtained (yield 43%). After crystallization from n-hexane-ethyl acetate, a pure compound in the form of colorless needles which melted at 170-171° C. was obtained.1H NMR (CDCl3):1.08 (t, J=7.4, 3H), 1.48-1.67 (m, 4H), 1.80-1.98 (m, 2H), 2.19-2.23 (m, 5H), 2.43-2,58 (m, 2H), 3.28 (m, 2H), 4.33 (s, 2H), 4.50-4.73 (m, 3H), 7.48 (t, J=7.4, 1H), 7.65 (t, J=8.1, 1H), 7.90 (d, J=8.3, 1H) , 8.93 (d, J=9.0, 1H).
- 8 g (24.9 mmoles) of Compound3 was dissolved in 1 liter of 1 HCl and heated to 80° C for 4 h with stirring. The reaction mixture was then cooled to 0° C., brought to pH 9 with 5N NaOH and extracted with chloroform. The organic extracts were dehydrated with anhydrous sodium sulphate, filtered and evaporated at reduced pressure to give 7 g of Compound 5 (yield 88%). Crystallization from ethyl acetate, gave a pure compound which melted at 245-246° C. 1H NMR (CDCl3): 1.46-1.61 (m, 4H), 2.16-2.23 (m, 5H), 2.43-2.58 (m, 2H), 3.27 (m, 2H), 4.35 (s, 2H), 4.61 (m, 1H), 7.28-7.36 (m, 2H), 7.55 (m, 1H), 8.84 (d, j=8.2, 1H), 10.63 (br s, 1H), MS: m/z 323 (M+, 28).
- A suspension of 11.2 g (56 mmoles) of 3-aminoquinuclidine dihydrochloride, 22 g (207 mmoles) of anhydrous Na2CO3, and 300 ml of ethanol was heated under reflux in an inert atmosphere with vigorous stirring for 1 h and was then cooled to ambient temperature and supplemented with 4.8 ml (55 mmoles) of allyl bromide. The mixture was allowed to react with stirring at ambient temperature for 20 min. and then heated under reflux for 1 h and finally supplemented with 14.6 g (50 mmoles) of 2-bromomethyl-1-naphthalene methyl carboxylate (prepared as described in the synthesis method of Example 1) dissolved in the minimum quantity of ethanol. The resulting mixture was heated under reflux for 12 h. The solvent was evaporated under reduced pressure and the residue was taken up with 500 ml of dimethyl formamide. The solid which had not dissolved was filtered out and the filtrate was supplemented with 40 ml (292 mmoles) of dipropylamine and 0.5 g (0.71 mmoles) of Pd(PPh3)2Cl2. The resulting mixture was heated to 100° C. for about 30 minutes in an inert nitrogen atmosphere and then poured into water and ice and extracted with CHCl2. The extracts were washed thoroughly with water, dehydrated over sodium sulphate and evaporated at reduced pressure. The semi-solid residue which was obtained was solidified as a result of repeated washings with ethyl ether. 5.1 g of pure, solid, microcrystalline Compound 6 was thus obtained. Yield 34%. Melting point 138-141° C. 1H NMR (CDCl3): 1.59-1.96 (m, 4H), 2.20 (m, 1H), 2.89-3.18 (m, 5H), 3.41 (m,1H), 4.48 (t, J=8.3, 1H), 4.64 (m, 2H), 7.49-7.68 (m, 3H), 7.90 (d, J=8.1, 1H) , 7.98 (d, J=8.4, 1H), 9.20 (d, J=8.3, 1H)
- The (S) enantiomer of Compound 6 was prepared by following the method described above for Compound 6, with the use of
- (S)-3-aminoquinuclidine dihydrochloride instead of (R,S)-3-aminoquinuclidine dihydrochloride. Yield 32%. Melting point 152-154° C.
- The (R) enantiomer of Compound 6 was prepared by following the method described above for Compound 6, with the use of (R)-3-aminoquinuclidine dihydrochloride instead of (R,S)-3- aminoquinuclidine dihydrochloride. Yield 35%. Melting point 155-157° C.
- The method described for the preparation of Compound6 was followed, with the use of 3-bromomethyl-4-quinoline ethyl carboxylate instead of 2-bromomethyl-1-naphthalene methyl carboxylate. Upon completion, the oily residue obtained was rendered friable with n-hexane to give an amorphous solid without a definite melting point. Calculated analysis for C18H19N3O:C, 73.69; H, 6.53; N, 14.32. Found: C, 73.98, H, 6.66, N. 13.99.
- Some derivatives of formula (I) produced in accordance with the invention are given in Table 1 below with some identifying chemical and physical characteristics, without thereby in any way limiting the spirit and subject of the invention.
TABLE 1 Compounds of formula (I) Compounds X Het R Formula Melting point Crystallization solvents 1 CH 3-endo-tropyl(1) H C20H22N2O 174-175° C. ethyl acetate 2 N 3-endo-tropyl H C19H21N3O 153-154° C. n-hexane-ethyl acetate 3 N 3-endo-tropyl Cl C19H20ClN3O 169-171° C. n-hexane-ethyl acetate 4 N 3-endo-tropyl OC3H7 C22H27N3O2 170-171° C. n-hexane-ethyl acetate 5 N 3-endo-tropyl OH C19H21N3O2 245-246° C. ethyl acetate 6(R, S) CH 3-quinuclidyl(2) H C19H20N2O 153-154° C. n-hexane-ethyl ether 7(S) CH 3-quinuclidyl H C19H20N2O 152-154° C. n-hexane-ethyl ether 8(R) CH 3-quinuclidyl H C19H20N2O 155-157° C. n-hexane-ethyl ether 9 N 3-quinuclidyl H C18H19N3O amorphous — - In order to evaluate the affinity of the compounds of the invention for the various subtypes of serotoninergic receptors, [3H]-BRL43694 (Granisetron) was used as a marked ligand for the investigation of the 5-HT3 receptors, [3H]- paroxetine was used for the investigation of the serotonin uptake site, [3H]-ketanserine was used for the investigation of the 5-HT2 receptors and [3H]-8-OH DPAT was used for the investigation of the 5HT-1A receptors.
- a) Affinity for the 5-HT3 receptors
- The method of Nelson et al. (Biochem. Pharmacol. 1989, 38, 1693-95) was followed with slight modifications. Rat cortex and hippocampus were used to produce a pellet having a final concentration of 20 mg of tissue/sample. Specific activity of the tracer: 81 Ci/mmole; incubation time: 30 min; incubation temperature: 25° C. Specific binding: 70% of the total; Kd=0.6×10−9M.
- b) Affinity for the serotonin uptake site
- The method of Plenge et al (Eur. J. Pharmacol., 1990, 189, 129-134) was followed with slight modifications. The entire rat brain was used to produce a pellet having a final concentration of 2 mg of tissue/sample. Specific activity of the tracer: 29.7 Ci/mmole; incubation time: 60 min.; incubation temperature: 25° C. Specific binding: 75% of the total; Kd=0.09×10−9M.
- c) Affinity for the 5-HT2 receptors
- The method of Leysen et al (Mol. Pharmacol. 1982, 21, 301-314) was followed with slight modifications. Rat prefrontal cortex was used to produce a pellet having a final concentration of 8 mg of tisssue/sample. Specific activity of the tracer: 80.9 Ci/mmole; incubation time: 20 min; incubation temperature: 37° C. Specific binding: 90% of the total; Kd=0.5×10−9M.
- d) Affinity for the 5-HT1A receptors
- The method of Hall et al (J. Neurochem. 1985, 44, 1685-1696) was followed with slight modifications. Rat hippocampus was used to produce a pellet having a final concentration of 4 mg of tissue/sample. Specific activity of the tracer: 137 Ci/mmole; incubation time 10 min; incubation temperature: 37° C. Specific binding: 80% of the total; Kd=2.3×10−9M.
- It can be seen from the data given in Table 2 that many of the compounds of the invention are potent antagonists of the 5-HT3 subtype receptor. For example Compound 7 has a sub-nanomolar affinity for the 5-HT3 receptor and was the most active of all of the compounds tested. The compounds of the invention were also shown to possess a high selectivity for this receptor since they were very slightly active or inactive at the other receptor subtypes tested. It is also interesting to note that even small structural variations of the compounds of the invention cause a significant loss of affinity for the 5HT3 receptor. Thus, for example, Compound 10, that is, the analogous 3-hexotropyl derivative of the corresponding 3-endotrophyl (Compound 1), described herein purely for comparative purposes, was almost 2 orders of logarithmic magnitude less active than Compound 1; similarly, Compound 11 which is also given for comparative purposes, that is endo-2-[-methyl-8-azadicyclo[3.2.1]oct-3-yl]-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one, which has a “linear” polycyclic fusion and which is the pyrrolo-quinolne analogue of compound 2 was approximately 60 times less active than the latter, in which the polycyclic fusion takes place on the “e” face and is hence angular.
- The potent 5-HT3-antagonistic activity performed by the compounds of the invention in vitro was confirmed in vivo in the rat in the bradycardial reflex test according to Bezold-Jarisch (Paintal, Physio. Rev. 1973, 53, 159). Serotonin injected i.v. induced a bradycardial effect in the rat. Products 1-9 of the invention, injected in doses of 0.1 mg/kg i.v. 5 minutes before the administration i.v. of 0.03 mg/kg of serotonin completely blocked the bradycardial effect induced thereby. It should be noted that the same compounds injected alone, even in doses 10 times higher, did not induce any variation in cardiac frequency in the rat, thus behaving as pure antagonists.
TABLE 2 Affinity of some compounds of the invention for binding to various serotonin receptor subtypes (Ki(nM) ± SE) 5-HT3 Subtype 5-HT Uptake 5-HT2A Subtype 5-HT1A Subtype Compound ([3H]-BRL43694) ([3H]-paroxetin) ([3H]-ketanserine) ([3H]-8OH-DPAT) 1 1.0 ± 0.2 632 ± 51 21110 ± 2300 30619 ± 6460 2 1.3 ± 0.2 503 ± 86 IN (10−6M) IN (10−6M) 3 2.6 ± 0.4 175 ± 30 IN (10−6M) IN (10−6M) 4 0.7 ± 0.2 108 ± 15 IN (10−6M) IN (10−6M) 5 0.9 ± 0.06 485 ± 37 IN (10−6M) IN (10−6M) 6 0.7 ± 0.08 95.8 ± 9.6 26477 ± 8700 IN (10−6M) 7 0.3 ± 0.09 — — — 8 1.8 ± 0.5 — — — 9 1.6 ± 0.6 123.7 ± 22 IN (10−6M) IN (10−6M) 10* 85.5 ± 16 — — — 11** 87 ± 37 — — — serotonin 118 ± 34 738 ± 117 — 7.3 1.3 quipazinc 1.8 ± 0.3 31.3 ± 2.9 1808 ± 476 3649 ± 799 Granisetron 0.6 ± 0.06 — — — 6-NO2-quipazine — 0.12 ± 0.01 — — 8-OH-DPAT — — — 1.18 ± 0.13
Claims (15)
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US09/967,972 US6413978B1 (en) | 1998-10-13 | 2001-10-02 | Basic derivatives of benz[e] isoindol-1-ones and pyrrolo[3,4-c] quinolin-1-ones with 5-HT3-antagonistic activity, their preparation and their therapeutic use |
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ITT098A0871 | 1998-10-13 | ||
IT1998TO000871A IT1303123B1 (en) | 1998-10-13 | 1998-10-13 | BASIC DERIVATIVES OF BENZ (E) ISOINDOL-1-ONI AND PIRROLE (3,4-C) CHINOLIN-1-ONI WITH ACTIVITY 5HT3 ANTAGONIST, THEIR PREPARATION AND |
US09/417,098 US6323216B1 (en) | 1998-10-13 | 1999-10-13 | Basic derivatives of benz[E]isoindol-1-ones and pyrrolo[3,4-c]quinolin-1-ones with 5-HT3-antagonistic activity, their preparation and their therapeutic use |
US09/967,972 US6413978B1 (en) | 1998-10-13 | 2001-10-02 | Basic derivatives of benz[e] isoindol-1-ones and pyrrolo[3,4-c] quinolin-1-ones with 5-HT3-antagonistic activity, their preparation and their therapeutic use |
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US09/967,972 Expired - Fee Related US6413978B1 (en) | 1998-10-13 | 2001-10-02 | Basic derivatives of benz[e] isoindol-1-ones and pyrrolo[3,4-c] quinolin-1-ones with 5-HT3-antagonistic activity, their preparation and their therapeutic use |
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US20090118326A1 (en) * | 2007-11-02 | 2009-05-07 | Faming Jiang | Nicotinic Acetylcholine Receptor Modulators |
US20110172264A1 (en) * | 2010-01-11 | 2011-07-14 | Zaveri Nurulain T | Nicotinic acetylcholine receptor modulators |
WO2020097389A1 (en) * | 2018-11-09 | 2020-05-14 | Vivace Therapeutics, Inc. | Bicyclic compounds |
US11420935B2 (en) | 2019-04-16 | 2022-08-23 | Vivace Therapeutics, Inc. | Bicyclic compounds |
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CA2420235A1 (en) * | 2000-08-21 | 2002-02-28 | Georgetown University | 2-3-disubstituted quinuclidines as modulators of monoamine transporters and therapeutic and diagnostic methods based thereon |
EP1620435A1 (en) * | 2003-04-21 | 2006-02-01 | Pfizer Inc. | IMADAZOPYRIDINE COMPOUNDS HAVING 5-HT sb 4 /sb RECEPTOR AGONISTIC ACTIVITY AND 5-HT sb 3 /sb RECEPTOR ANTAGONISTIC ACTIVITY |
SE0400970D0 (en) | 2004-04-14 | 2004-04-14 | Astrazeneca Ab | Nicotinic acetylcholine receptor ligands |
CA2728096C (en) * | 2008-07-29 | 2017-01-03 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | Substituted 2h-pyrrolo[3,4-c]quinoline compound with serotoninergic activity, processes to prepare and pharmaceutical compositions comprising the compound |
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US5200413A (en) | 1987-01-05 | 1993-04-06 | Beecham Group P.L.C. | Indolyl carboxamides useful treating migraine, cluster headache, trigeminal neuralgia or emesis |
GB9009542D0 (en) * | 1990-04-27 | 1990-06-20 | Beecham Group Plc | Novel compounds |
US5189041A (en) * | 1990-11-16 | 1993-02-23 | Syntex (U.S.A.) Inc. | Tricyclic 5-ht3 receptor antagonists |
AU1161292A (en) * | 1991-01-09 | 1992-08-17 | Smithkline Beecham Plc | Azabicydic and azatricydic derivatives, process and intermediates for their preparation and pharmaceutical compositions containing them |
US5260303A (en) | 1991-03-07 | 1993-11-09 | G. D. Searle & Co. | Imidazopyridines as serotonergic 5-HT3 antagonists |
US5280028A (en) | 1992-06-24 | 1994-01-18 | G. D. Searle & Co. | Benzimidazole compounds |
IT1265057B1 (en) | 1993-08-05 | 1996-10-28 | Dompe Spa | TROPIL 7-AZAINDOLIL-3-CARBOXYAMIDE |
WO1995009168A1 (en) | 1993-09-30 | 1995-04-06 | Tokyo Tanabe Company Limited | Indoline compound and 5-ht3 receptor antagonist containing the same as active ingredient |
FR2710915B1 (en) | 1993-10-04 | 1995-11-24 | Synthelabo | Piperidine derivatives, their preparation and their therapeutic use. |
EP0647639A1 (en) | 1993-10-11 | 1995-04-12 | Sanofi | Heteroarylpiperidines, process for their preparation and pharmaceutical compositions containing them |
US5399562A (en) | 1994-02-04 | 1995-03-21 | G. D. Searle & Co. | Indolones useful as serotonergic agents |
GB9410441D0 (en) * | 1994-05-25 | 1994-07-13 | Erba Carlo Spa | Azabicycloakyl derivatives of imidazo (1,5-a) indol-3-one and process for their preparation |
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US20090118326A1 (en) * | 2007-11-02 | 2009-05-07 | Faming Jiang | Nicotinic Acetylcholine Receptor Modulators |
US8697722B2 (en) | 2007-11-02 | 2014-04-15 | Sri International | Nicotinic acetylcholine receptor modulators |
US20110172264A1 (en) * | 2010-01-11 | 2011-07-14 | Zaveri Nurulain T | Nicotinic acetylcholine receptor modulators |
US9062042B2 (en) | 2010-01-11 | 2015-06-23 | Astraea Therapeutics, Llc | Nicotinic acetylcholine receptor modulators |
WO2020097389A1 (en) * | 2018-11-09 | 2020-05-14 | Vivace Therapeutics, Inc. | Bicyclic compounds |
CN113302175A (en) * | 2018-11-09 | 2021-08-24 | 维瓦斯治疗公司 | Bicyclic compounds |
US11866431B2 (en) | 2018-11-09 | 2024-01-09 | Vivace Therapeutics, Inc. | Bicyclic compounds |
US11420935B2 (en) | 2019-04-16 | 2022-08-23 | Vivace Therapeutics, Inc. | Bicyclic compounds |
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US6323216B1 (en) | 2001-11-27 |
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AU5359799A (en) | 2000-04-20 |
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