EP0566609A1 - Derives azabicydiques et azatricydiques, leurs procedes et intermediaires de preparation et compositions pharmaceutiques les contenant - Google Patents

Derives azabicydiques et azatricydiques, leurs procedes et intermediaires de preparation et compositions pharmaceutiques les contenant

Info

Publication number
EP0566609A1
EP0566609A1 EP19920902098 EP92902098A EP0566609A1 EP 0566609 A1 EP0566609 A1 EP 0566609A1 EP 19920902098 EP19920902098 EP 19920902098 EP 92902098 A EP92902098 A EP 92902098A EP 0566609 A1 EP0566609 A1 EP 0566609A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
alkyl
compound according
formula
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19920902098
Other languages
German (de)
English (en)
Inventor
Francis David Smithkline Beecham Pharma. King
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB919100370A external-priority patent/GB9100370D0/en
Priority claimed from GB919100580A external-priority patent/GB9100580D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0566609A1 publication Critical patent/EP0566609A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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

  • This invention relates to novel compounds having useful pharmacological properties, to a process for their
  • EP-A-337547 (Merck Sharp and Dohme Limited), EP-A-329932
  • Patents 4920219 and 4920227 disclose classes of compounds which have a saturated azabicyclic moiety, such as tropanyl, granatyl or quinuclidinyl, and are 5-HT 3 receptor antagonists.
  • X is a phenyl group or a monocyclic 5 or 6 membered
  • heteroaryl group either of which group is optionally fused to a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic ring;
  • A is a linking moiety
  • R is hydrogen or methyl
  • X may be unsubstituted or substituted, usually by one or more substituents selected from halogen, C 1 - 6 alkoxy, C 1-6 alkylthic, C 1- 6 alkyl, hydroxy, amino, C 1-6 alkylamino, C 1 -7 alkanoylamino, or two substituents on X (when fused), may be linked to form a saturated or unsaturated optionally
  • Heteroatoms for heteroaryl and heterocyclic groups are selected from oxygen, nitrogen and sulphur.
  • Halo includes bromo, chloro and fluoro.
  • X may be joined to A by an aromatic carbon atom, or (when X is fused), by a carbocyclic ring carbon atom, or by a heterocyclic ring carbon or nitrogen atom. When X is fused, and A is attached at an aromatic carbon atom, it is
  • Suitable examples of X are as described in the
  • Suitable examples of A include CONH (amide), COO (ester), NHCONH (ureide), CONHCONH (extended ureide), or a group of structure (j):
  • the present invention provides a compound of formula (IA), or a pharmaceutically acceptable salt thereof:
  • Y is NH or O (or is joined to R 10 as defined below);
  • X 1 is a group of formula (a), (b), (c), (d), (e), (f), (g)
  • R a to R e and R g to R h are selected from hydrogen, halogen or hydroxy
  • R 1 is hydrogen and R 2 is hydrogen or C 1 -4 alkyl
  • R 1 and R 2 together are a bond
  • R 3 to R 7 are independently hydrogen or C 1 -6 alkyl
  • R 4 together with R 2 may be C 2-7 polymethylene or C 2 - 6
  • R 8 and R 9 are independently selected from hydrogen or
  • R 11 is hydrogen, halo, C 1-6 alkoxy or C 1-6 alkyl
  • R 10 and R 1 1 are joined to form -OCH (R 15 R 16 )-E- wherein E is
  • R 12 is
  • R 13 is halo, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio
  • R 14 is hydrogen or C 1-6 alkyl
  • CO-Y- is in the 1-position and either R 15 is in the
  • R 15 is in the 4-position and is hydrogen, halogen, CF 3 , C 1- 6 alkyl , C 1-7 acyl , C 1- 7 acylamino , phenyl optionally substituted by one or two C 1-6 alkyl, C 1-6 alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally substituted by one or two C 1-6 alkyl or C 3-8 cycloalkyl groups or by C 4-5 polymethylene or by phenyl, C 1-6 alkylsulphonyl, C 1-6 alkylsulphinyl , C 1- 6 alkoxy, C 1 -6 alkylthio, hydroxy or nitro; or
  • CO-Y- is in the 3-position and either R 15 is in the
  • R 15 is in the 4-position and is hydrogen or C 1-6 alkoxy;
  • L is CH or N
  • moieties in alkyl or alkyl containing groups in Z or in R 1 to R 15 include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl, preferably methyl.
  • Cycloalkyl moieties include C 3 , C 4 , C 5 , C 6 , C 7 and C 8 cycloalkyl.
  • Halo moieties include fluoro, chloro, bromo and iodo.
  • R 2 and R 4 or R 8 and R 9 when joined include C 2 , C 3 , C 4 , C 5 or C 6 polymethylene, preferably C 2 , C 3 , C 4 or C 5 Polymethylene .
  • R a to R e and R g to R h are preferably selected from hydrogen, fluoro, chloro and hydroxy, most preferably hydrogen.
  • R b may be 5-, 6- or 7-chloro or fluoro.
  • R 1 and R 3 is preferably hydrogen and one or both of R 2 and R 4 (most preferably both) are alkyl groups, such as methyl, or are joined to form C 2-7 polymethylene; or when one of R 2 and R 4 is hydrogen, the other is preferably ethyl or n- or iso- propyl.
  • R 5 is preferably hydrogen or a methyl or ethyl group.
  • R 7 is preferably methyl.
  • R 8 and R 9 are preferably both methyl groups.
  • R 10 is C 1-6 alkoxy or is joined to Y
  • R 12 is preferably amino and R 13 is preferably chloro or bromo, most preferably chloro.
  • R 10 is preferably methoxy when C 1-6 alkoxy.
  • R 11 and R 13 are preferably chloro or methyl and R 10 is preferably hydrogen.
  • R 14 is preferably hydrogen or methyl.
  • R 15 when in the 4-position, include the following: hydrogen, chloro, bromo, methyl, ethyl, amino, methylamino, dimethylamino, phenyl, C 1 _ 4 alkanoylamino such as formylamino, acetylamino, propionylamino, n- and
  • aminosulphonyl optionally substituted by one or two methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl or phenyl groups; nitro, n- and iso-propoxy, methylthio, ethylthio, n- and iso-propylthio, hydroxy, methylsulphonyl and ethylsulphonyl or when R 15 is in the 3-position suitable examples, include the following groups, hydrogen, methyl, ethyl, n- or iso-propyl, methoxy, and ethoxy.
  • R 15 when in the 1-position include hydrogen, methyl, ethyl, n- or iso- propyl, or when R 15 is in the 4-position, suitable examples include the following: hydrogen, methoxy and ethoxy.
  • Preferred R 15 groups, in any of the positions specified above, include hydrogen, methyl and methoxy.
  • CO-Y- is preferably in the 1-position.
  • Y is preferably NH.
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with
  • Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R x -T wherein R x is C 1-6 alkyl, phenyl-C 1-6 alkyl or C 5 -7 cycloalkyl, and T is a radical corresponding to an anion of an acid.
  • R ⁇ include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl.
  • Suitable examples of T include halide such as chloride, bromide and iodide.
  • Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.
  • the compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable
  • X-CO-Y- in compounds of formula (I) may adopt an ⁇ or ⁇ or configuration with respect to Z.
  • the compounds of formula (I) are prepared by linking
  • azabicyclic side chain intermediates may be prepared from the corresponding ketones of formula (II) and (III):
  • the ketones of the formula (II) may be prepared according to the method described by G. H. Dewar, R.T. Parfitt, L. Sheh; Eur. J. Med. Chem., 1985, 20 , 228, and the ketone of formula (III) may be prepared according to the method described in the Description 2 hereinafter.
  • the compounds of the present invention are 5-HT 3 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of pain, emesis, CNS disorders and gastrointestinal disorders. Pain includes migraine, cluster headache, trigeminal neuralgia and visceral pain; emesis, includes, in particular, that of preventing vomiting and nausea associated with cancer therapy, post-operative emesis, and nausea associated with migraine.
  • cancer therapy examples include that using cytotoxic agents, such as platinum complexes including cisplatin, and also doxorubicin and cyclophosphamide, particularly cisplatin; and also radiation treatment.
  • CNS disorders include anxiety, psychosis, cognitive disorders such as senile dementia and age associated memory impairment (AAMI), and drug dependence.
  • Gastrointestinal disorders include irritable bowel syndrome and diarrohea.
  • 5-HT 3 receptor antagonists may also be of potential use in the treatment of obesity, arrhythmia, and/or disorders associated with myocardial instability.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions are prepared by admixture and are usually adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories .
  • Orally administrable compositions are preferred, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional
  • excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art, for example with an enteric coating.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,
  • emulsifying agents for example lecithin, sorbitan
  • non-aqueous vehicles which may include edible oils, for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
  • the oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by
  • a surfactant or wetting agent is included in the composition to facilitate uniform
  • the invention further provides a method of treatment or prophylaxis of pain, emesis, CNS disorders and/or
  • gastrointestinal disorders in mammals such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.5 to 500mg, of the compound of the invention.
  • Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of pain, emesis, CNS disorders and/or
  • the oxime (1.97g, 0.012mol) was dissolved in amyl alcohol (80ml) and heated to reflux under N 2 .
  • Sodium metal (6.5g, 0.28mol) was added portionwise over a 20 minute period and heating was continued for a further 1.5h.
  • the solution was allowed to cool slightly and water (20ml) was added
  • Compounds are given intravenously and the concentration required to reduce the 5-HT-evoked response to 50% of the control response (ED 50 ) is then determined.

Abstract

Composés correspondant à la formule (I): X-A-Z, et leur sel acceptable pharmaceutiquement dans laquelle Z présente la structure (a) ou (b), dans laquelle X représente un groupe phényle ou un groupe hétéroaryle monocyclique à 5 ou 6 éléments, l'un ou l'autre de ces groupes étant éventuellement fusionné avec un noyau hétérocyclique ou carbocyclique saturé ou insaturé et comportant entre 5 et 7 éléments; A représente une fraction de liaison; et R représente hydrogène ou méthyle. Lesdits composés présentent une activité antagoniste au récepteur de 5-HT3.
EP19920902098 1991-01-09 1992-01-09 Derives azabicydiques et azatricydiques, leurs procedes et intermediaires de preparation et compositions pharmaceutiques les contenant Withdrawn EP0566609A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9100370 1991-01-09
GB919100370A GB9100370D0 (en) 1991-01-09 1991-01-09 Pharmaceuticals
GB9100580 1991-01-10
GB919100580A GB9100580D0 (en) 1991-01-10 1991-01-10 Pharmaceuticals

Publications (1)

Publication Number Publication Date
EP0566609A1 true EP0566609A1 (fr) 1993-10-27

Family

ID=26298233

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19920902098 Withdrawn EP0566609A1 (fr) 1991-01-09 1992-01-09 Derives azabicydiques et azatricydiques, leurs procedes et intermediaires de preparation et compositions pharmaceutiques les contenant

Country Status (4)

Country Link
EP (1) EP0566609A1 (fr)
JP (1) JPH06506443A (fr)
AU (1) AU1161292A (fr)
WO (1) WO1992012149A1 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9214184D0 (en) * 1992-07-03 1992-08-12 Smithkline Beecham Plc Pharmaceuticals
JP3235913B2 (ja) * 1993-07-30 2001-12-04 エーザイ株式会社 アミノ安息香酸誘導体
GB9721139D0 (en) * 1997-10-07 1997-12-03 Glaxo Group Ltd Medicaments
IT1303123B1 (it) 1998-10-13 2000-10-30 Rotta Research Lab Derivati basici di benz(e)isoindol-1-oni e pirrolo(3,4-c)chinolin-1-oni ad attivita' 5ht3 antagonista, loro preparazione ed
TW200306189A (en) 2002-03-21 2003-11-16 Merz Pharma Gmbh & Co Kgaa Azabicyclic, azatricyclic and azaspirocyclic derivatives of aminocyclohexane NMDA, 5HT3, and neuronal nicotinic receptor antagonists
KR101129933B1 (ko) 2002-09-25 2012-03-23 메모리 파마슈티칼스 코포레이션 인다졸, 벤조티아졸 및 벤조이소티아졸 및 그의 제조 및용도
US6984652B2 (en) 2003-09-05 2006-01-10 Warner-Lambert Company Llc Gyrase inhibitors
PL1697378T3 (pl) 2003-12-22 2008-04-30 Memory Pharm Corp Indole, 1h-indazole, 1,2-benzoizoksazole i 1,2-benzoizotiazole oraz ich wytwarzanie i zastosowania
JP4995075B2 (ja) 2004-03-25 2012-08-08 メモリー・ファーマシューティカルズ・コーポレイション インダゾール、ベンゾチアゾール、ベンゾイソチアゾール、ベンズイソキサゾール、ならびにそれらの調製および使用
US7488737B2 (en) 2004-04-22 2009-02-10 Memory Pharmaceutical Corporation Indoles, 1H-indazoles, 1,2-benzisoxazoles, 1,2-benzoisothiazoles, and preparation and uses thereof
AU2005243147A1 (en) 2004-05-07 2005-11-24 Memory Pharmaceuticals Corporation 1H-indazoles, benzothiazoles, 1,2-benzoisoxazoles, 1,2-benzoisothiazoles, and chromones and preparation and uses thereof
EP1758891A2 (fr) 2004-06-15 2007-03-07 Pfizer Japan Inc. Derives de benzimidazolone d'acide carboxylique
US7737163B2 (en) 2004-06-15 2010-06-15 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
DE602005019094D1 (de) 2004-12-22 2010-03-11 Memory Pharmaceutical Corp Nikotinische alpha-7-rezeptorliganden gegen erkrankungen des zns
BRPI0607456A2 (pt) 2005-02-22 2009-09-08 Pfizer derivados de oxindol como agonistas do receptor 5ht4
US8106066B2 (en) 2005-09-23 2012-01-31 Memory Pharmaceuticals Corporation Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof
KR101106517B1 (ko) 2006-10-11 2012-01-20 닛뽕소다 가부시키가이샤 피페리딘-4-온 유도체의 제조 방법
WO2022175402A1 (fr) 2021-02-18 2022-08-25 Aprea Therapeutics Ab Dérivés de quinuclidine-3-one

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL59004A0 (en) * 1978-12-30 1980-03-31 Beecham Group Ltd Substituted benzamides their preparation and pharmaceutical compositions containing them

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9212149A1 *

Also Published As

Publication number Publication date
AU1161292A (en) 1992-08-17
WO1992012149A1 (fr) 1992-07-23
JPH06506443A (ja) 1994-07-21

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