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EP0509005A1 - Antagonistes de recepteurs muscariniques a base de diphenylsulphoximine - Google Patents

Antagonistes de recepteurs muscariniques a base de diphenylsulphoximine

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Publication number
EP0509005A1
EP0509005A1 EP91901475A EP91901475A EP0509005A1 EP 0509005 A1 EP0509005 A1 EP 0509005A1 EP 91901475 A EP91901475 A EP 91901475A EP 91901475 A EP91901475 A EP 91901475A EP 0509005 A1 EP0509005 A1 EP 0509005A1
Authority
EP
European Patent Office
Prior art keywords
formula
alkyl
compound
group
het
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Withdrawn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
EP91901475A
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German (de)
English (en)
Inventor
David Alker
John Edward Glyn Kemp
Peter Edward Cross
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.)
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Pfizer Inc
Original Assignee
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Pfizer Inc
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Application filed by Pfizer Corp Belgium, Pfizer Ltd Great Britain, Pfizer Corp SRL, Pfizer Inc filed Critical Pfizer Corp Belgium
Publication of EP0509005A1 publication Critical patent/EP0509005A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C07C381/10—Compounds containing sulfur atoms doubly-bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms

Definitions

  • This invention relates to diphenylsulphoximine derivatives.
  • GB-A-1,168,700 discloses certain N-substituted
  • aminoalkyl-S,S-diphenylsulphoximine derivatives which exhibit specific broncholytic-antispasmodic activity in mammals and which are useful in treating conditions generally associated with bronchial diseases.
  • the compounds of the present invention are useful for the curative or prophylactic treatment of disease states where the gastrointestinal and bladder selective reduction of
  • acetylcholine-mediated smooth muscle contraction would be of benefit such as in the treatment of motility disorders of the gut, in particular as in irritable bowel syndrome, and in the treatment of urinary incontinence, emesis or diverticular disease.
  • Irritable bowel syndrome is a motility disorder characterised by altered bowel habit (i.e. constipation and/or diarrhoea), distension and abdominal pain.
  • the muscarinic receptor i.e. constipation and/or diarrhoea
  • antagonists of the present invention reduce the motility of the gut thus having an antispasmodic effect on the bowel without producing, or significantly reducing, bronchial or cardiac effects.
  • the present invention provides compounds of the formula: -
  • R and R 1 are each independently H or C 1 -C 4 alkyl
  • X is a group of the formula:-
  • R 2 is H or C 1 -C 4 alkyl and R 3 is C 1 -C 4 alkyl, or R 2 and R 3 taken together represent -(CH 2 ) r - wherein r is an integer of from 2 to 5;
  • R 4 is C 1 -C 4 alkyl
  • X 1 is a direct link, 0 or S;
  • R 5 is a group of the formula:-
  • R 6 and R 7 are each independently H, halo, C 1 -C 4 alkyl,
  • R 6 and R 7 taken together represent a group of the formula -X 2 -(CH 2 ) t -X 3 - wherein X 2 and X 3 are each independently 0 or CH 2 and t is an integer of from 1 to 3;
  • R 8 and R 9 are each independently H or C 1 -C 4 alkyl, or R 8 is hydrogen and R 9 is -SO 2 (C 1 -C 4 alkyl), -CONR 10 R 11 ,
  • R 10 and R 11 are each independently hydrogen or C 1 -C 4 alkyl
  • Het is thienyl, pyridinyl or pyrazinyl
  • n 1, 2 or 3;
  • n 0, 1 or 2;
  • p is 0 or 1; and s is 0, 1 or 2:
  • halo means F, Cl, Br or I and C 3 andC 4 alkyl and alkoxy groups may be straight or branched chain.
  • R and R 1 are both H.
  • R 2 is H or methyl and R 3 is methyl;
  • R 4 is methyl.
  • R 1 is a direct link.
  • R 5 is a group of the formula:-
  • R 5 is (C 1 -C 4 alkoxy)phenyl, hydroxyphenyl or a group of the formula:-
  • t 1 or 2.
  • R 5 is 3- or 4-methoxy ⁇ henyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl or 1,4-benzodioxan-6-yl.
  • n 2
  • n is 0 or 1.
  • X contains a pyrrolidinyl or piperidinyl group, preferably X is either N-substituted-3-piperidinyl or
  • N-substituted-2-pyrrolidinylmethyl where the N-substituent is a group -(CH 2 ) m -X 1 -R 5 as previously defined.
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts formed from acids which form non-toxic salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, mandelate, benzoate, salicylate,
  • the compounds of the formula (I) contain at least one asymmetric centre and will therefore exist as a pair of
  • enantiomers or as diastereoisomeric pairs of enantiomers may be separated by physical methods, for example by fractional
  • the invention includes both the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof.
  • a particularly preferred individual compound provided by the present invention is (3R)-N-[1-(4-methoxyphenethyl)piperidin-3- yl]diphenylsulphoximine or a pharmaceutically acceptable salt thereof.
  • R,R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p and X 1 are as previously defined for the formula (I) and Y is a suitable leaving group, e.g. halo (preferably chloro or bromo), methanesulphonyloxy, trifluoromethanesulphonyloxy or p-toluenesulphonyloxy.
  • halo preferably chloro or bromo
  • a diphenylsulphoximine derivative of the formula (II) is deprotonated with approximately one equivalent of a suitable strong base, e.g. sodium hydride, n-butyllithium or lithium diisopropylamide, and then reacted in situ with an alkylating agent of the formula (III) or (IV), as required, in a suitable inert organic solvent, e.g. xylene or toluene.
  • a suitable strong base e.g. sodium hydride, n-butyllithium or lithium diisopropylamide
  • an alkylating agent of the formula (III) or (IV) as required
  • a suitable inert organic solvent e.g. xylene or toluene.
  • the reaction is preferably carried out by adding the strong base to a solution of compound (II) at about room temperature and under an inert atmosphere (e.g.
  • diphenylsulphoximine derivative (II) in situ to provide the necessary anion it is also possible to react the alkylating agent directly with a suitable salt of a compound of the formula (II), e.g. the lithium, sodium, potassium or calcium salt.
  • a suitable salt of a compound of the formula (II) e.g. the lithium, sodium, potassium or calcium salt.
  • R 5 , m, X 1 and Y are as previously defined for a compound of the formula (IV), in this process may provide a mixture of products of the formula (I) wherein X is a group of the formula:-
  • R, R 1 , R 5 , X 1 and m are as previously defined for the formula (I). Indeed in certain circumstances the rearrangement product may be the exclusive product of the reaction.
  • This aziridinium ion is open to two routes of nucleophilic attack by the anion derived from a diphenylsulphoximine derivative (II) in the alkylation reaction, thus accounting for the product mixture observed (Scheme 2).
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p and X 1 are as previously defined for the formula (I) and Y is a suitable leaving group, e.g. halo (preferably chloro, bromo or iodo), methanesulphonyloxy, trifluoromethanesulphonyloxy or p-toluenesulphonyloxy.
  • halo preferably chloro, bromo or iodo
  • a compound of the formula (VIII) or (IX), as appropriate, is reacted with a compound of the formula (X) in the presence of a suitable acid acceptor, e.g. sodium or potassium carbonate, and, where Y 1 is chloro or bromo, optionally in the presence of sodium or potassium iodide to accelerate the rate of the reaction.
  • a suitable acid acceptor e.g. sodium or potassium carbonate
  • Y 1 is chloro or bromo
  • the reaction is carried out in a suitable organic solvent, e.g. acetonitrile, at from room temperature to, and preferably at, the reflux temperature of the mixture.
  • the product of the formula (I) is then isolated and purified by conventional techniques.
  • a suitable organic solvent e.g. 1,4-dioxane.
  • the rate may be accelerated by elevating the reaction temperature and/or by the addition of a suitable acidic or basic catalyst, e.g. benzyltrimethylammonium hydroxide.
  • the product of the formula (XI) or (XII) may be isolated and purified by conventional techniques.
  • R, R 1 , X 1 , m and p are as defined for the formula (I) and R 5 is as defined for the formula (I) with the exception that when
  • R 6 nor R 7 can be -CONR 10 R 11 , -(CH 2 ) s NHCO( C 1 -C 4 alkyl),
  • R 10 , R 11 and s are as defined for the formula (I), may be prepared by reduction of a compound of the formula:-
  • R, R 1 R 5 , X 1 , m and p are as previously defined in this method, using a suitable strong reducing agent, e.g. aluminium hydride, and in a suitable inert organic solvent, e.g.
  • the reaction is typically carried out by generating aluminium hydride in situ by treating an. ice-cooled suspension of lithium aluminium hydride in tetrahydrofuran with concentrated sulphuric acid.
  • Compound (XIII) is then added and the resulting mixture is stirred at from 0°C to the reflux temperature of the mixture, preferably at about room temperature.
  • the product of the formula (I) is isolated and purified by conventional techniques.
  • R 5 is a substituted phenyl group
  • R 5 is a substituted phenyl group
  • R 5 is a substituted phenyl group
  • a C 1 -C 4 alkoxy, preferably methoxy, substituent on the phenyl group may be converted to hydroxy by treatment with hydrogen bromide.
  • aqueous hydrobromic acid is used at from room temperature to, and preferably at, the reflux temperature of the mixture.
  • This dealkylation can also be achieved by treatment with either a C 1 -C 4 alkanethiol in the presence of a strong base, e.g. sodium hydride, or directly with a suitable C 1 -C 4 alkanethiolate salt, e.g. the sodium salt, and in a suitable organic solvent.
  • a strong base e.g. sodium hydride
  • a suitable C 1 -C 4 alkanethiolate salt e.g. the sodium salt
  • Butanethiol is the preferred thiol.
  • a -CONR 10 R 11 substituent on the phenyl group, wherein R 10 and R 11 are as previously defined for the formula (I) may be reduced to -CH 2 NR 10 R 11 with a suitable reducing agent, e.g. diborane.
  • the reaction is typically carried out in a suitable organic solvent, e.g. tetrahydrofuran, at from room temperature to the reflux temperature of the mixture.
  • a suitable organic solvent e.g. tetrahydrofuran
  • a hydroxy substituent on the phenyl group may be converted to -OCO(C 1 -C 4 alkyl) by acylation using either a C 1 -C 4 alkanoyl chloride or bromide, or a C 1 -C 4 alkanoic anhydride.
  • the presence of an acid acceptor is preferable, e.g. sodium bicarbonate or pyridine.
  • the reaction is typically carried out in a suitable organic solvent at from 0°C to room temperature and heating is not usually necessary.
  • reaction may be carried out in pyridine, the pyridine acting as both the solvent and the acid acceptor.
  • reaction may be carried out in the presence of an excess of the acid anhydride and in the absence of additional solvent or an acid acceptor.
  • a -(CH 2 ) s NH 2 substituent on the phenyl group, wherein s is 0, 1 or 2 may be converted to -(CH 2 ) s NHCO(C 1 -C 4 alkyl) by acylation with a C 1 -C 4 alkanoyl chloride or bromide or a C 1 -C 4 alkanoic anhydride.
  • the reaction may be carried out similarly to method 5(c) above.
  • a -(CH 2 ) s NH 2 substituent on the phenyl group, wherein s is 0, 1 or 2, may be converted to -(CH 2 ) s NHSO 2 (C 1 -C 4 alkyl) by reaction with either a C 1 -C 4 alkanesulphonyl chloride or bromide, or a C 1 -C 4 alkanesulphonic anhydride and in a suitable organic solvent.
  • an acid acceptor such as pyridine, sodium bicarbonate or sodium or potassium carbonate, is preferable.
  • a -(CH 2 ) s NH radical substituent on the phenyl group may be converted to -(CH 2 ) s NHSO 2 NH 2 by reaction with sulphamide.
  • the reaction is typically carried out at the reflux temperature in a suitable organic solvent, e.g. 1,4-dioxane.
  • a hydroxy substituent on the phenyl group may be converted to C 1 -C 4 alkoxy, firstly by reaction with a suitable strong base, such as sodium hydride, and then by reaction with a C 1 -C 4 alkyl bromide or iodide.
  • the reaction is preferably carried out at about room temperature in a suitable solvent, e.g. N,N-dimethylformamide.
  • a suitable solvent e.g. N,N-dimethylformamide.
  • a -(CH 2 ) s NH, substituent on the phenyl group, wherein s is 0, 1 or 2 may be converted to-(CH 2 ) s NHCONH(C 1 -C 4 alkyl) by reaction with a C 1 -C 4 alkyl isocyanate.
  • the reaction is typically carried out at about room temperature in a suitable organic solvent, e.g. dichloromethane.
  • a -(CH 2 ) s NHCO(C 1 -C 4 alkyl) substituent on the phenyl group, wherein s is 0, 1 or 2 may be hydrolysed to
  • a -CH 2 OH substituent on the phenyl group may be converted to -CH 2 NR 8 R 9 , wherein R 8 and R 9 are each
  • reaction firstly with a suitable halogenating agent, e.g. thionyl chloride, and secondly with ammonia or the required amine R 8 R 9 NH.
  • a suitable halogenating agent e.g. thionyl chloride
  • ammonia or the required amine R 8 R 9 NH is typically carried out with heating, preferably under reflux, and optionally in a suitable organic solvent, e.g. dichloromethane.
  • the reaction with ammonia or the amine is typically carried out in a suitable organic solvent, e.g. ethanol, at from room temperature to the reflux temperature of the solvent: most conveniently a bomb is used as the reaction vessel.
  • the intermediates used in the preparation of the compounds of the formula (I) provided by the invention may be prepared by the following methods, as illustrated in the following Preparations section:- 1)
  • the diphenylsulphoximine derivatives of the formula (II) may be prepared by the routes, or similar routes, to those disclosed in the literature references
  • an aminoalcohol of the formula (XIV) or (XV) is alkylated with a compound of the formula (X) in the presence of a suitable acid acceptor, e.g. sodium or potassium carbonate, and in a suitable organic solvent, e.g. acetonitrile.
  • a suitable acid acceptor e.g. sodium or potassium carbonate
  • a suitable organic solvent e.g. acetonitrile.
  • the reaction is preferably heated under reflux and, when Y 1 is chloro or bromo, the reaction is optionally carried out in the presence of sodium or potassium iodide, in order to accelerate the rate of reaction.
  • the secondary amine of the formula (XVI) may be methylated to provide the tertiary amine (XVII), wherein R 4 is methyl, using conventional procedures.
  • the methylation may be carried out by reacting (XVI) with either an aqueous solution of formaldehyde in formic acid under reflux conditions, or by reacting (XVI) with a solution of formaldehyde in methanol in the presence of sodium cyanoborohydride.
  • the alcohol of the formula (XVII) may be converted to a compound of the formula (III) by conventional techniques, e.g. when Y represents chloro or bromo, by reaction with thionyl chloride or bromide respectively; most preferably, when Y is chloro, a compound (III) is formed by reaction with
  • the intermediates of the formula (XIV), (XV), (XVI) and (XVII) used in the preparation of compounds of the formula (III) may be advantageously used in this process with a protected hydroxy group.
  • Suitable protecting groups for this purpose may include those listed in "Protective Groups in Organic Synthesis", Theodora W. Greene (John Wiley & Sons) . Triphenylmethyl is the preferred protecting group.
  • a protected compound (XVII) may then be deprotected by a conventional procedure prior to conversion to compound (III), e.g. when the hydroxy group is protected with triphenylmethyl the protecting group may be removed by refluxing in aqueous acetic acid.
  • R 5 , m, n, p, X 1 and Y are as previously defined for the formula (I) and Y 1 is as previously defined for the formula (X).
  • a compound of the formula (XIX) may be converted to a compound (IV) by conventional procedures.
  • Y is preferably chloro and such compounds are prepared by reaction of compound (XIX) with either methanesulphonyl chloride or thionyl chloride, the reaction being carried out in a suitable organic solvent, e.g.
  • Compound (II) is alkylated with either a compound (XX) or (XXI), as appropriate, by a similar method to that disclosed in method (1) for the preparation of compounds of the formula (I) above, where an alkylating agent of the formula (III) or (IV) is used instead.
  • the resulting product, (XXII) or (XXIII), may be deprotected under conventional conditions, e.g. when Z is p-toluenesulphonyl using sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al ® ) in toluene, to provide a compound of the formula (VIII) or (IX), respectively. 5)
  • R, R 1 , R 5 , X 1 , m and p are as defined for the formula (I) and Y 3 and Y 4 , which may be the same or different, are suitable leaving groups, e.g. halo (preferably chloro or bromo). Most preferably Y 3 and Y 4 are both bromo.
  • a compound of the formula (XXVI) may be prepared from an amine of the formula (XXV) either by acylation with an acid chloride of the formula (XXIV, Cl) in a suitable solvent, e.g. toluene, and in the presence of a suitable acid acceptor, e.g. pyridine or triethylamine, or by reacting with a carboxylic acid of the formula (XXIV, OH) under conventional peptide coupling conditions.
  • a suitable solvent e.g. toluene
  • a suitable acid acceptor e.g. pyridine or triethylamine
  • An amide (XXVI) may be cyclised to a lactam (XXVII) under standard conditions, for example where Y 3 and Y 4 are both bromo by stirring the amide (XXVI) with Amberlite ® IRA-400 (Cl) ion exchange resin, dichloromethane and aqueous sodium hydroxide solution at about room temperature.
  • a lactam (XXVII) may be then reacted with an anion formed from a diphenylsulphoximine derivative (II) to provide a compound (XIII) using a similar alkylation method to that described in method (1) for the preparation of compounds of the formula (I) above.
  • the starting materials of the formulae (XXIV) and (XXV) are either known compounds which may be commercially available or are prepared by conventional procedures in accordance with literature precedents.
  • Pharmaceutically acceptable acid addition salts are readily prepared by mixing solutions containing equimolar amounts of the free base and the desired acid. The salt generally precipitates from solution and is collected by filtration, or is recovered by evaporation of the solvent.
  • the selectivity of the compounds as muscarinic receptor antagonists can be measured as follows.
  • Dose-response curves to either acetylcholine (ileum) or carbachol (trachea, bladder and right atrium) are determined using a 1-5 minute contact time for each dose of agonist until the maximum response is achieved.
  • the organ bath is drained and refilled with physiological salt solution containing the lowest dose of the test compound.
  • the test compound is allowed to equilibrate with the tissue for 20 minutes and the agonist dose-response curve is repeated until the maximum response is obtained.
  • the organ bath is drained and refilled with
  • physiological salt solution containing the second concentration of test compound and the above procedure is repeated.
  • concentrations of the test compound are evaluated on each tissue.
  • the concentration of the test compound which causes a doubling of the agonist concentration required to produce the original response is determined (pA 2 value - Arunlakshana and Schild, Brit. J. Pharmacol., 1959, 14, 48-58).
  • tissue selectivity for muscarinic receptor antagonists is determined.
  • Activity against agonist induced gut or bladder contractility in comparison with changes in heart rate is determined in the anaesthetised dog. Oral activity is assessed in the conscious dog determining compound effects on, for example, heart rate, pupil diameter and gut motility.
  • the dose to cause a doubling of pupil size is determined as well as the dose to inhibit by 50% the salivation and tremor responses to intravenous oxotremorine.
  • oral dosages of the compounds will generally be in the range of from 3.5 to 350 mg daily for an average adult patient (70 kg).
  • individual tablets or capsules will typically contain from 1 to 250 mg of active compound in a suitable pharmaceutically acceptable vehicle or carrier for administration singly or in multiple doses, once or several times a day.
  • Dosages for intravenous administration will typically be within the range 0.35 to 35 mg per single dose as required.
  • the compounds of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected
  • parenterally for example, intravenously, intramuscularly or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the invention provides a
  • composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also includes a compound of the formula (I) or a pharmaceutically acceptable salt or composition thereof, for use as a medicament, particularly for use in the treatment of irritable bowel syndrome.
  • the invention further includes the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or
  • composition thereof for the manufacture of a medicament for the treatment of diseases associated with motility disorders of the gut such as irritable bowel syndrome, and for the treatment of emesis, diverticular disease and urinary incontinence.
  • the invention yet further provides a method of treating a human being to cure or prevent either a disease associated with a motility disorder of the gut, such as irritable bowel syndrome, or emesis, diverticular disease or urinary incontinence, which comprises treating said human being with an effective amount of a compound of the formula (I), or with, as appropriate, a motility disorder of the gut, such as irritable bowel syndrome, or emesis, diverticular disease or urinary incontinence, which comprises treating said human being with an effective amount of a compound of the formula (I), or with, as appropriate, a motility disorder of the gut, such as irritable bowel syndrome, or emesis, diverticular disease or urinary incontinence, which comprises treating said human being with an effective amount of a compound of the formula (I), or with, as appropriate, a motility disorder of the gut, such as irritable bowel syndrome, or emesis, diverticular disease or urinary incontinence, which comprises treating said human being with an
  • the invention also includes any novel intermediates disclosed herein, such as those of the formulae (VIII), (IX) and (XIII).
  • Examples were each prepared by a similar method to that described for Examples 1A and 1B by reacting diphenylsulphoximine with sodium hydride in refluxing xylene and then treating the mixture with the appropriate alkylating agent, followed by work-upand separation of the required product.
  • the starting material used in the preparation of Examples 4A and 4B was obtained as described in Preparation 4 as the
  • hydrochloride salt This was converted to the corresponding free base for use in the reaction by basifying with 2M aqueous sodium hydroxide solution, extracting the aqueous mixture with diethyl ether, drying the organic extract over sodium sulphate followed by concentration thereof in vacuo to provide the required material.
  • Example 8 was prepared by a similar method to that used in Example 8 using 1-chloro-2(S)-(N-[4-methoxyphenethyl]-N-methyl)aminopropane (see Preparation 21) instead of 1-chloro-2-(N-[4-methoxyphenethyl]- N-methyl)amino-2-methylpropane as the starting material.
  • the title compound was obtained as an oil. Found: C,70.45; H,7.4; N,6.5; C 25 H 30 N 2 O 2 S.0.25 H 2 O requires: C.70.3; H.7.2; N,6.6%.
  • dichloromethane (5 ml) was added dropwise over 5 minutes to a stirred solution of (2S)-[1-(3-methoxyphenethyl)]pyrrolidine- methanol (2.35 g) (see Preparation 9) and triethylamine (1.01 g) in dichloromethane (25 ml). The mixture was stirred at room temperature for 1.5 hours, diluted with ethyl acetate, washed twice with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated in vacuo.
  • Methanesulphonyl chloride (0.78 ml) was added to a solution of 2-[N-(4-roethoxyphenethyl)-N-methyl]amino-2-methylpropan-1-ol (2.37 g) (see Preparation 19) and triethylamine (1.01 g) in dichloromethane (40 ml) and the mixture was stirred at room temperature for 2 hours then evaporated in vacuo.
  • Triphenylmethyl chloride (5.6 g) and (2S)-aminopropan-1-ol (1.5 g) were mixed to a paste and heated at 140°C for 25 minutes.
  • the resulting hot syrup was poured into dichloromethane and the solution evaporated in vacuo.
  • the residue was purified by chromatography on silica gel performing a gradient elution using 0-4% methanol/dichloromethane plus 0.1% 0.880 aqueous ammonia as the eluant. The appropriate fractions were combined and evaporated in vacuo to give the title compound (5.13 g), m.p. 176°C. Found: C,83.2; H,7.2; N,4.4; C 22 H 23 NO requires: C,83.3; H.7.3; N,4.4%.

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Abstract

On décrit des composés de la formule (I), où R et R1 sont H ou C1-C4 alkyle; et X et un groupe de formule (II) où (III), soit R2 est H ou C1-C4 alkyle et R3 est C1-C4 alkyle, soit R2 et R3 représente -(CH2)r- où r est de 2 à 5; R4 est C1-C4 alkyle; X1 est une liaison directe, O ou S; R5 est phényle mono ou disubstitué, où les substituants sont H, halo, C1-C4 alkyle, C1-C4 alkoxy, -(CH2)sOH, -(CH2)sNR8R9, -CONR10R11, -SO2NH2 ou OCO(C1-C4 alkyle), ou des substituants adjacents peuvent former un anneau fusionné; ou R5 est thiényle, pyridinyle or pyrazinyle; R8 et R9 sont H ou C1-C4 alkyle, ou R8 est hydrogène et R9 est -SO2(C1-C4 alkyle), -CONR10R11, -CO(C1-C4 alkyle) ou -SO2NH2; R10 et R11 sont hydrogène ou C1-C4 alkyle; m est 1, 2 ou 3; n est 0, 1 ou 2; p est 0 ou 1; et s est 0, 1 ou 2, (sous certaines conditions); lesdits composés sont des antagonistes de récepteurs muscariniques sélectifs du tractus gastrointestinal et de la vessie utiles par exemple dans le traitement du syndrome du côlon irritable.
EP91901475A 1990-01-06 1990-12-11 Antagonistes de recepteurs muscariniques a base de diphenylsulphoximine Withdrawn EP0509005A1 (fr)

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GB909000303A GB9000303D0 (en) 1990-01-06 1990-01-06 Therapeutic agents
GB9000303 1990-01-06

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JP (1) JPH05503094A (fr)
CA (1) CA2072127A1 (fr)
FI (1) FI922763A0 (fr)
GB (1) GB9000303D0 (fr)
IE (1) IE910018A1 (fr)
PT (1) PT96418A (fr)
WO (1) WO1991010648A1 (fr)

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GB1168700A (en) * 1966-12-22 1969-10-29 Warner Lambert Pharmaceutical N-Substituted Aminoalkyl-S, S-Diphenyl-Sulfoximines and Process for Their Production.
DE1568734C3 (de) * 1966-12-22 1974-03-28 Goedecke Ag, 1000 Berlin N-Dialkyl-aminoalkyl-S-diphenylsulfoximine und ihre Salze sowie Verfahren zu ihrer Herstellung
DE2539220A1 (de) * 1975-09-03 1977-03-17 Heumann Ludwig & Co Gmbh Substituierte sulfoximide, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
DE2920958C2 (de) * 1979-05-23 1981-06-11 Ludwig Heumann & Co GmbH, 8500 Nürnberg Verfahren zur Herstellung von S,S-Diarylsulfoximidderivaten
CA1102803A (fr) * 1980-02-04 1981-06-09 Manfred Haake Traduction non-disponible

Non-Patent Citations (1)

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Title
See references of WO9110648A1 *

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WO1991010648A1 (fr) 1991-07-25
IE910018A1 (en) 1991-07-17
PT96418A (pt) 1991-10-15
CA2072127A1 (fr) 1991-07-07
FI922763A0 (fi) 1992-06-15
GB9000303D0 (en) 1990-03-07

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