EP0684947A1 - Amide compounds with pharmacological activity - Google Patents

Amide compounds with pharmacological activity

Info

Publication number
EP0684947A1
EP0684947A1 EP94906959A EP94906959A EP0684947A1 EP 0684947 A1 EP0684947 A1 EP 0684947A1 EP 94906959 A EP94906959 A EP 94906959A EP 94906959 A EP94906959 A EP 94906959A EP 0684947 A1 EP0684947 A1 EP 0684947A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
halo
alkoxy
amino
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Withdrawn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
EP94906959A
Other languages
German (de)
French (fr)
Inventor
Francis David King
Laramy Marie Gaster
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
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0684947A1 publication Critical patent/EP0684947A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Amide compounds wi th pharmacol ogical activity Amide compounds wi th pharmacol ogical activity.
  • This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
  • EP-A-501322 (Glaxo Group Limited), WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040, WO 93/18036, PCT/EP93/03054, PCT/GB93/01895, PCT/GB93/02028, PCT/EP93/02808, PCT/EP93/02775, PCT/EP93/02809, PCT/GB93/02130, PCT/EP93/003054, PCT/GB94/000172 (SmithKline Beecham pic) describe compounds having 5-HT4 receptor antagonist activity.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • X is a monocyclic or polycyclic aromatic group, such as a group of formula (a), (b), (c), (d), (e), (f) or (g):
  • L is N or CR S wherein R s is hydrogen, C ⁇ .(. alkoxy, halogen, C1.4 alkyl or cyano;
  • W is CH or N; Xl-(CH2) X -X2 forms a 5-7 membered ring wherein X ⁇ is O or S; X2 is O, S, -CH2 " ' NR or NRCO wherein R is hydrogen or C ⁇ _g alkyl; and x is 1, 2 or 3; one of X3 and X4 is N and the other is C; and X5 is N or CR 1 wherein R 1 is hydrogen, C ⁇ .Q alkoxy, halo, C . alkyl or cyano;
  • Rj a is hydrogen, C io alkyl, C2-6 alkenyl, aralkyl, C2-6 alkanoyl or C2-6 alkanoyl C1.3 alkyl;
  • R3 a is hydrogen, halo, Cj. ⁇ alkyl, amino, nitro or C ⁇ . alkoxy;
  • R4 a is hydrogen, halo, C ⁇ . ⁇ alkyl or C . alkoxy;
  • R ⁇ is C ⁇ . ⁇ alkoxy;
  • R2 ⁇ is hydrogen, chloro or fluoro
  • R3° is hydrogen,Ci_6 alkyl, amino optionally substituted by a C ⁇ . alkyl group, halo, hydroxy or Cj.g alkoxy
  • R4 D is hydrogen, halo, Cj.6 alkyl, Cj.g alkoxy, nitro, amino or C ⁇ _6 alkylthio
  • R ⁇ is hydrogen, halo, C ⁇ . alkyl, C ⁇ . alkoxy or amino
  • R ⁇ is hydrogen, C . alkoxy, halo or C g alkyl
  • Rjd is hydrogen, amino, halo, C ⁇ . alkyl, hydroxy or C ⁇ . alkoxy
  • R2 ⁇ is hydrogen, halo, C ⁇ .
  • alkyl C ⁇ . ⁇ alkoxy, nitro, amino or Cj.6 alkylthio
  • R3 ⁇ is hydrogen, halo, C ⁇ . alkyl, C . alkoxy or amino
  • R4 ⁇ and R ⁇ d are independently hydrogen or C ⁇ . alkyl
  • Rl e is hydrogen, halogen, CF3, C . alkyl, C g alkoxy, ⁇ . alkylthio, C ⁇ _6 alkylsulphonyl, C ⁇ . alkylsulphinyl, C1.7 acyl, cyano, C ⁇ . alkoxycarbonyl, C ⁇ . ⁇ acylamino, hydroxy, nitro or amino, aminocarbonyl, or aminosulphonyl, optionally N-substituted by one or two groups selected from C ⁇ .
  • R z and R] to R4f are independently hydrogen or C ⁇ . alkyl; and/or joined to form C3.6 polymethylene;
  • R a f is hydrogen, halo, C ⁇ 6 alkyl, amino, nitro or C ⁇ _6 alkyl;
  • R[ is hydrogen, halo, C ⁇ . alkyl or C g alkoxy;
  • Xg is O, S, SO, SO2, CH2, CH, N or NR wherein R is hydrogen or C g alkyl; A is a saturated or unsaturated polymethylene chain of 2 - 4 carbon atoms; R ⁇ g and R2S are hydrogen or C ⁇ . alkyl; R3I ⁇ is hydrogen, halo, Ci-g alkyl, amino, nitro or Cj.g alkoxy; R4.? is hydrogen, halo, Cj.g alkyl or C ⁇ . alkoxy; Z is of sub-formula (h), (j) or (k):
  • R5 is hydrogen, C ⁇ _i2 alkyl, aralkyl or R5 is (CH2) z -R ⁇ o wherein z is 2 or 3 and R ⁇ Q is selected from cyano, hydroxyl, Cj.g alkoxy, phenoxy, C(O)C ⁇ 6 alkyl, COC6H5, -CONR 11 R 1 2, NR 1 1 CORi2, SO2NRnR!2 or NRHSO2R12 wherein Rn and
  • Rl2 are hydrogen or C ⁇ g alkyl; or R5 is straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon, C2.7 alkoxycarbonyl, or secondary or tertiary hydroxy substituted Cj_6 alkyl; ; and Rg, R7 and Rg are independently hydrogen or ⁇ . alkyl; and R9 is hydrogen or CJ. ⁇ Q alkyl; having 5-HT4 receptor antagonist activity.
  • alkyl or alkyl containing groups include C , C2, C3, C4, C5, C ⁇ ,
  • C ⁇ _4 alkyl groups include methyl, ethyl, n- and iso-p ⁇ opyl, n-, iso-, sec- and tert-butyl.
  • Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl optionally substituted by one of more alkyl groups of up to 4 carbon atoms.
  • Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C ⁇ . alkyl and C . alkoxy.
  • Values for monocyclic heteroaryl include pyridyl, pyrimidyl, pyrazinyl, pyrryl, imidazolyl, thienyl, furanyl, oxazole or thiazole (all possible isomers).
  • Bicyclic heteroaryl include benzofuranyl, benzothiophenyl, indolyl and indazolyl, quinolyl and is ⁇ quinolyl (all possible isomers).
  • Values for 3 to 8 membered heterocyclyl include cyclic polymethylene interrupted by one or two of N, O or S, linked through C or N, for example N-linked piperidinyl or pyrrolidinyl.
  • Halo includes fluoro, chloro, bromo and iodo, preferably chloro.
  • L in formula (a) is favourably C-H, C-CH3, C-Cl or C-OCH3.
  • Q in formula (a) is favourably NR ⁇ a .
  • Rj a is preferably hydrogen or a methyl or ethyl group.
  • Rj D is preferably methoxy.
  • R3 D is preferably amino.
  • R4J 0 is preferably halo.
  • R5" is preferably hydrogen.
  • a substituent when halo is selected from fluoro, chloro, bromo and iodo.
  • Suitable examples of the X ⁇ -(CH2) X -X2 moiety include O-(CH2)2"O, O-(CH2)3- O, O-CH2-O, O-(CH2)2-NR, O-(CH2)2-S or O-CH 2 -CONR, wherein any of the methylene linkages are optionally mono- or di- substituted by C ⁇ . alkyl groups, such as methyl.
  • X ⁇ -(CH2)2" 2 is 0-(CH2>2-0.
  • X ⁇ -(CH2)2-X2 is O-(CH2)2-CH2- R ⁇ d is preferably hydrogen or amino.
  • R2 ⁇ is preferably hydrogen or halo.
  • R3 ⁇ is preferably hydrogen or halo.
  • R ⁇ ⁇ and R5 ⁇ are often hydrogen. When R or is C ⁇ . ⁇ alkyl, it is often methyl.
  • R ⁇ Q is preferably CF3 or an ethyl group.
  • X5 is preferably N, C-H or C-OCH3;
  • R3 e is preferably hydrogen.
  • R4 e is preferably hydrogen or halo, such as iodo.
  • X6-X7 is preferably NR z -CO, however, such as NH-CO or NEt-CO.
  • R a f is preferably hydrogen.
  • R jj f is preferably hydrogen or halo, such as iodo.
  • Other examples of A are as described in the aforementioned patent publications.
  • RjS and R2£ are often hydrogen or R ⁇ S and R ⁇ o are gem-dimethyl, r is often 1.
  • R36 is preferably hydrogen.
  • R4E is preferably hydrogen or halo, such as fluoro.
  • n 1 is preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n* is preferably 1 when the azacycle is attached at a carbon atom, such as the 4-position when q is 2.
  • v ⁇ - is preferably such that the number of carbon atoms between the ester or amide linkage is from 2 to 4 carbon atoms.
  • n 3 is preferably 2, 3 or 4.
  • Rg and R9 are preferably both alkyl, especially one of Rg and R9 is C4 or larger alkyl.
  • Specific values of Z of particular interest are as follows:
  • the invention also provides novel compounds within formula (I) with side chains (i), (ii), (iii), (iv), (v), (vi) or (vii).
  • the piperidine ring in (i), (ii) or (iii) may be replaced by pyrrolidinyl or azetidinyl, and/or the N-substituent in (i) or (ii) may be replaced by C3 or larger alkyl or optionally substituted benzyl.
  • N-substituent in formula (i) or (ii) may be replaced by (CH2) n R ⁇ as defined in formula (I) of EPA 501322 and in relation to die specific examples of EP-A-501322, or it may be replaced by a substituent as as defined in formula (I) and in relation to the specific examples of in PCT/EP93/03054 (SmithKline Beecham pic).
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, cc-keto glutaric, ⁇ -glycerophosphoric, and glucose- 1 -phosphoric acids.
  • conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids
  • pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, cc-keto glutaric, ⁇ -glycerophosphoric, and glucose- 1 -phosphoric acids.
  • 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 g alkyl, phenyl-C g alkyl or C5.7 cycloalkyl, and T is a radical corresponding to an anion of an acid.
  • R x include methyl, ethyl and n- and is ⁇ -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 solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to. It will also be realised that the (CH2) n 2 moiety in compounds of formula (I) wherein Z is (j), may adopt an ⁇ or ⁇ or configuration with respect to the fused azabicyclic moiety.
  • the compounds of formula (I) may be prepared by conventional methods for forming an amide bond.
  • the invention comprises a process for preparing a compound of formula (I) which process comprises reacting an amine of formula (II) :
  • a reactive derivative of an acid (III) may be for example an acid chloride, acid anhydride or a reactive ester.
  • a group X' may comprise a nucleus corresponding to the group X having substituents convertible to those required in the final product. Examples of such conversions in the aromatic substituents include chlorination of hydrogen to chloro, reduction of nitro to amino, dehalogenation such as debromination, and/or elaboration of a 2,3-dihydroxy-benzoic acid with ethylene dibromide to form the benzodioxan.
  • Suitable examples of conversions in the Z containing moiety include conventional modifications of the N-substituent by substitution and/or deprotection or, in the case of a 2-, 3- or 4- substituted piperidyl desired end compound, reduction of an appropriate pyridyl derivative. Any elaboration of X and/or Z is, however, usually carried out prior to ester or amide coupling.
  • Compounds of formula (II) may be prepared from carboxylic acids of formula X'COOH, for example via an acyl azide (Curtius reaction). Acids X'COOH are themselves well known in the art, for example where X is (a) or (b) such acids are described in GB2125398.
  • Acids of formula (III) may be prepared according to conventional methods, for example from a corresponding ketone.
  • Azabicyclic side chain (CH2) n 2-COOH intermediates when Z is (j) in formula (I) are known compounds or may be prepared from the ketones of formula (IV):
  • the compounds of the present invention are 5-HT4 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.
  • IBS irritable bowel syndrome
  • these compounds block the ability of 5-HT to stimulate gut motility via activation of enteric neurones. In animal models of IBS, this can be conveniently measured as a reduction of the rate of defaecation.
  • IBS irritable bowel syndrome
  • urinary incontinence which is often associated with IBS.
  • IBS urinary incontinence
  • others may also be of potential use in other gastrointestinal disorders, such as those associated with upper gut motility, and as antiemetics.
  • they are of potential use in the treatment of the nausea and gastric symptoms of gastro-oesophageal reflux disease and dyspepsia.
  • Antiemetic activity is determined in known animal models of cytotoxic-agent radiation induced emesis.
  • Migraine sufferers often undergo situations of anxiety and emotional stress that precede the appearance of headache (Sachs, 1985, Migraine, Pan Books, London). It has also been observed that during and within 48 hours of a migraine attack, cyclic AMP levels are considerably increased in die cerebrospinal fluid (Welch et al., 1976, Headache 16, 160-167). It is believed that a migraine, including the prodomal phase and the associated increased levels of cyclic AMP are related to stimulation of 5-HT4 receptors, and hence that administration of a 5-HT4 antagonist is of potential benefit in relieving a migraine attack.
  • Other CNS disorders of interest include schizophrenia, Parkinson's disease and Huntingdon's chorea.
  • 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 enteral such as oral, nasal or rectal, or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositories, injectable and infusable solutions or suspensions.
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • enteral such as oral, nasal or rectal, or parenteral administration
  • oral liquid preparations powders, granules, lozenges, reconstitutable powders, nasal sprays, s
  • 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, polyvinylpo.ypyrrolidone and starch derivatives such as sodium starch glycollate.
  • 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 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, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; 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.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • 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 quantities of fillers. Such operations are, of course, conventional in the art.
  • 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 exposure of ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • the invention further provides a method of treatment or prophylaxis of irritable bowel syndrome, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine 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 lOOOmg 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 irritable bowel syndrome, gastro-oesophageal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine.
  • a preferred compound corresponds to any example, but wherein there is an amino substituent in the 4-position and a chloro substituent in the 5-position of the benzoic acid nucleus depicted in formula (I).
  • 6-Chloro-2H-3,4-dihydrobenzopyran-8-carboxylic acid (1.84g, 8.7mmol) was dissolved in a mixture of trifluoroacetic acid (50ml) and trifluoracetic anhydride (10ml) and the resulting solution cooled to 0°C.
  • Sodium azide (0.79g,12mmol) was added portionwise and the reaction mixture stirred at room temperature under argon for 48 hours. The solvent was removed in vacua and the residue partitioned between water and chloroform.
  • 4-Piperidone monohydrate hydrochloride (lO.OOg, 0.065mol) was dissolved in acetone (100ml) and treated with 1-bromobutane (7.00ml, 0.065mol) and potassium carbonate (18.00g, 0.130mol). The mixture was then heated to reflux with stirring. After
  • reaction mixture solidified, at this point, more DMF (50 ml) was added. The reaction mixture was then stirred overnight, and was then evaporated under reduced pressure, and the residue partitioned between 5N HCl and
  • guinea-pigs Male guinea-pigs, weighing 250-400g are used. Longitudinal muscle-myenteric plexus preparations, approximately 3cm long, are obtained from the distal colon region. These are suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% CO2 in O2 and maintained at 37°C. In all experiments, the Krebs solution also contains methiothepin 10" ⁇ M and granisetron lO' vl to block effects at 5- HTi, 5-HT2 and 5-HT3 receptors.
  • a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40-70% maximum(10- ⁇ M approx).
  • the tissue is then alternately dosed every 15min with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant, dimethylphenylpiperazinium (DMPP).
  • DMPP dimethylphenylpiperazinium
  • increasing concentrations of a putative 5-HT4 receptor antagonist are then added to the bathing solution.
  • the effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, PIC50 values are determined, being defined as the -log concentration of antagonist which reduces the contraction by 50%.
  • a compound which reduces the response to 5-HT but not to DMPP is believed to act as a 5-HT4 receptor antagonist.
  • the compound of Example 1 had a PIC50 value of >6.

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Abstract

Compounds of formula X-NH-CO-Z and pharmaceutically acceptable salts thereof, and the use of a compound of said formula or a pharmaceutically salt thereof, wherein X is a monocyclic or polycyclic aromatic group, Z is of sub-formula (h), (j), or (k), wherein n1 is 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 2, 3, 4 or 5; q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2; R¿5? is hydrogen, C1-12 alkyl, aralkyl or R5 is (CH2)z-R10 wherein z is 2 or 3 and R10 is selected from cyano, hydroxyl, C1-6 alkoxy, phenoxy, C(O)C1-6 alkyl, COC6H5, -CONR11R12, NR11COR12, SO2NR11R12 or NR11SO2R12 wherein R11 and R12 are hydrogen or C1-6 alkyl; or R5 is straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon, C2-7 alkoxycarbonyl, or secondary or tertiary hydroxy substituted C1-6 alkyl; and R6, R7 and R8 are independently hydrogen or C1-6 alkyl; and R9 is hydrogen or C1-10 alkyl; and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

Description

Amide compounds wi th pharmacol ogical activity.
This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
European Journal of Pharmacology 146 (1988), 187-188, and Naunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non classical 5-hydroxytryptamine receptor, now designated the 5-HT4 receptor, and that ICS 205-930, which is also a 5-HT3 receptor antagonist, acts as an antagonist at this receptor. WO 91/16045 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrhythmias and stroke.
EP-A-501322 (Glaxo Group Limited), WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040, WO 93/18036, PCT/EP93/03054, PCT/GB93/01895, PCT/GB93/02028, PCT/EP93/02808, PCT/EP93/02775, PCT/EP93/02809, PCT/GB93/02130, PCT/EP93/003054, PCT/GB94/000172 (SmithKline Beecham pic) describe compounds having 5-HT4 receptor antagonist activity.
It has now been discovered that certain novel compounds also have 5-HT4 receptor antagonist properties.
Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
X-NH-CO-Z (I)
wherein X is a monocyclic or polycyclic aromatic group, such as a group of formula (a), (b), (c), (d), (e), (f) or (g):
wherein
L is N or CRS wherein Rs is hydrogen, C\.(. alkoxy, halogen, C1.4 alkyl or cyano;
QisNRιa,CH2,OorS;
W is CH or N; Xl-(CH2)X-X2 forms a 5-7 membered ring wherein X\ is O or S; X2 is O, S, -CH2"' NR or NRCO wherein R is hydrogen or C ι_g alkyl; and x is 1, 2 or 3; one of X3 and X4 is N and the other is C; and X5 is N or CR1 wherein R1 is hydrogen, C\.Q alkoxy, halo, C . alkyl or cyano;
Rja is hydrogen, C io alkyl, C2-6 alkenyl, aralkyl, C2-6 alkanoyl or C2-6 alkanoyl C1.3 alkyl; R3a is hydrogen, halo, Cj.^ alkyl, amino, nitro or C\. alkoxy; R4a is hydrogen, halo, C\.^ alkyl or C . alkoxy; R^ is C\.β alkoxy; and
R2^ is hydrogen, chloro or fluoro;
R3° is hydrogen,Ci_6 alkyl, amino optionally substituted by a Cγ. alkyl group, halo, hydroxy or Cj.g alkoxy; R4D is hydrogen, halo, Cj.6 alkyl, Cj.g alkoxy, nitro, amino or Cι_6 alkylthio; and R^ is hydrogen, halo, C\. alkyl, C\. alkoxy or amino; Rς is hydrogen, C . alkoxy, halo or C g alkyl; Rjd is hydrogen, amino, halo, C\. alkyl, hydroxy or C\. alkoxy; R2^ is hydrogen, halo, C\. alkyl, C\.β alkoxy, nitro, amino or Cj.6 alkylthio; R3^ is hydrogen, halo, C\. alkyl, C . alkoxy or amino; R4^ and Rζd are independently hydrogen or C\. alkyl;
Rle is hydrogen, halogen, CF3, C . alkyl, C g alkoxy, \. alkylthio, Cι_6 alkylsulphonyl, C\. alkylsulphinyl, C1.7 acyl, cyano, C\. alkoxycarbonyl, C\.η acylamino, hydroxy, nitro or amino, aminocarbonyl, or aminosulphonyl, optionally N-substituted by one or two groups selected from C\. alkyl, C3.8 cycloalkyl, and C3.8 cycloalkyl C1.4 alkyl or disubstituted by C4 or C5 polymethylene; phenyl or phenyl Cμ4 alkyl group optionally substituted in the phenyl ring by one or two of halogen, C\. alkoxy or Cj.g alkyl groups; R3e is hydrogen, halo, Cμ alkyl, amino, nitro or C\. alkyl; R4e is hydrogen, halo, C^.g alkyl or Cj.g alkoxy; X6- 7 s NRz-CO or CRιfR2f-CR3fR4f where
Rz and R] to R4f are independently hydrogen or C\. alkyl; and/or joined to form C3.6 polymethylene; Raf is hydrogen, halo, Cμ6 alkyl, amino, nitro or Cι_6 alkyl; R[ is hydrogen, halo, C\. alkyl or C g alkoxy;
Xg is O, S, SO, SO2, CH2, CH, N or NR wherein R is hydrogen or C g alkyl; A is a saturated or unsaturated polymethylene chain of 2 - 4 carbon atoms; R^g and R2S are hydrogen or C\. alkyl; R3IΪ is hydrogen, halo, Ci-g alkyl, amino, nitro or Cj.g alkoxy; R4.? is hydrogen, halo, Cj.g alkyl or C\. alkoxy; Z is of sub-formula (h), (j) or (k):
( )
(j)
(k)
wherein n1 is 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 2, 3, 4 or 5; q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2;
R5 is hydrogen, Cι_i2 alkyl, aralkyl or R5 is (CH2)z-Rιo wherein z is 2 or 3 and R^Q is selected from cyano, hydroxyl, Cj.g alkoxy, phenoxy, C(O)Cμ6 alkyl, COC6H5, -CONR11R12, NR1 1CORi2, SO2NRnR!2 or NRHSO2R12 wherein Rn and
Rl2 are hydrogen or Cμg alkyl; or R5 is straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon, C2.7 alkoxycarbonyl, or secondary or tertiary hydroxy substituted Cj_6 alkyl; ; and Rg, R7 and Rg are independently hydrogen or \. alkyl; and R9 is hydrogen or CJ.^Q alkyl; having 5-HT4 receptor antagonist activity. Examples of alkyl or alkyl containing groups include C , C2, C3, C4, C5, Cβ,
C7, Cg, C ^ Cιo> i 1 or C12 branched, straight chained or cyclic alkyl, as appropriate. Cι_4 alkyl groups include methyl, ethyl, n- and iso-pτopyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl optionally substituted by one of more alkyl groups of up to 4 carbon atoms.
Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C\. alkyl and C . alkoxy. Values for monocyclic heteroaryl include pyridyl, pyrimidyl, pyrazinyl, pyrryl, imidazolyl, thienyl, furanyl, oxazole or thiazole (all possible isomers). Bicyclic heteroaryl include benzofuranyl, benzothiophenyl, indolyl and indazolyl, quinolyl and isøquinolyl (all possible isomers).
Values for 3 to 8 membered heterocyclyl, include cyclic polymethylene interrupted by one or two of N, O or S, linked through C or N, for example N-linked piperidinyl or pyrrolidinyl.
Halo includes fluoro, chloro, bromo and iodo, preferably chloro.
L in formula (a) is favourably C-H, C-CH3, C-Cl or C-OCH3.
Q in formula (a) is favourably NRιa. Rja is preferably hydrogen or a methyl or ethyl group.
RjD is preferably methoxy. R3D is preferably amino. R4J0 is preferably halo. R5" is preferably hydrogen. A substituent when halo is selected from fluoro, chloro, bromo and iodo. R4a when halo is preferably iodo.
Suitable examples of the Xι-(CH2)X-X2 moiety include O-(CH2)2"O, O-(CH2)3- O, O-CH2-O, O-(CH2)2-NR, O-(CH2)2-S or O-CH2-CONR, wherein any of the methylene linkages are optionally mono- or di- substituted by C\. alkyl groups, such as methyl. Preferably Xι-(CH2)2" 2 is 0-(CH2>2-0.
Further suitable examples of Xι-(CH2)X-X2 include O-(CH2)2"CH2, O-(CH2)3-CH2, O-CH2-CH2, or corresponding values wherein X\ = i ~ H2, wherein any of the methylene linkages are optionally mono- or di-substituted by Cι_6 alkyl groups, such as methyl. Preferably such Xι-(CH2)2-X2 is O-(CH2)2-CH2- R^d is preferably hydrogen or amino.
R2^ is preferably hydrogen or halo. R3^ is preferably hydrogen or halo.
R<\ and R5^ are often hydrogen. When R or is C\.β alkyl, it is often methyl. R\Q is preferably CF3 or an ethyl group.
X5 is preferably N, C-H or C-OCH3; R3e is preferably hydrogen. R4e is preferably hydrogen or halo, such as iodo. Suitable examples of X6-X7 when CRιfR2f-CR3fR4f include CH2-CH2 and CH=CH. X6-X7 is preferably NRz-CO, however, such as NH-CO or NEt-CO. Raf is preferably hydrogen. Rjjf is preferably hydrogen or halo, such as iodo. Values for A include -CH2-(CH2)r-CH2- wherein r is 0, 1 or 2; -CH2-CH=CH-;
-C(CH3)=CH- or when XS is CH or N, A may be -(CH2)2-CH= or -CH=CH-CH=. Other examples of A are as described in the aforementioned patent publications.
RjS and R2£ are often hydrogen or R\S and R~o are gem-dimethyl, r is often 1. R36 is preferably hydrogen.
R4E is preferably hydrogen or halo, such as fluoro.
Other suitable values of X are as described in PCT/GB93/020208, PCT/EP93/02808, PCT/EP93/02775, PCT/EP93/02809, PCT/GB93/02130, PCT/GB94/00172 (all in the name of SmithKline Beecham pic). When Z is of sub-formula (h), n1 is preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n* is preferably 1 when the azacycle is attached at a carbon atom, such as the 4-position when q is 2.
When Z is of sub-formula (j), v~- is preferably such that the number of carbon atoms between the ester or amide linkage is from 2 to 4 carbon atoms. Suitable values for p and m include p = m = 1; p = 0, = 1, p = 1, m = 2, p = 2, m = l.
When Z is of sub-formula (k), n3 is preferably 2, 3 or 4.
Rg and R9 are preferably both alkyl, especially one of Rg and R9 is C4 or larger alkyl. Specific values of Z of particular interest are as follows:
n
NMe Bu (iv)
The invention also provides novel compounds within formula (I) with side chains (i), (ii), (iii), (iv), (v), (vi) or (vii). In a further aspect, the piperidine ring in (i), (ii) or (iii) may be replaced by pyrrolidinyl or azetidinyl, and/or the N-substituent in (i) or (ii) may be replaced by C3 or larger alkyl or optionally substituted benzyl.
In an alternative aspect, the N-substituent in formula (i) or (ii) may be replaced by (CH2)nR^ as defined in formula (I) of EPA 501322 and in relation to die specific examples of EP-A-501322, or it may be replaced by a substituent as as defined in formula (I) and in relation to the specific examples of in PCT/EP93/03054 (SmithKline Beecham pic).
The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, cc-keto glutaric, α-glycerophosphoric, and glucose- 1 -phosphoric acids.
Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds Rx-T wherein Rx is C g alkyl, phenyl-C g alkyl or C5.7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of Rx include methyl, ethyl and n- and isø-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 solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to. It will also be realised that the (CH2)n2 moiety in compounds of formula (I) wherein Z is (j), may adopt an α or β or configuration with respect to the fused azabicyclic moiety.
The compounds of formula (I) may be prepared by conventional methods for forming an amide bond.
Thus in a further aspect the invention comprises a process for preparing a compound of formula (I) which process comprises reacting an amine of formula (II) :
X'NH2 (II)
(wherein X' represents X as hereinbefore defined or a group convertible thereto) with an acid of formula (III) :
HOOCZ' (III)
(wherein Z' represents Z as hereinbefore defined or a group convertible thereto) or a reactive derivative thereof.
The reaction of a compound (II) with a compound (HI) may be carried out using conditions well known in the art for formation of an amide bond. A reactive derivative of an acid (III) may be for example an acid chloride, acid anhydride or a reactive ester. A group X' may comprise a nucleus corresponding to the group X having substituents convertible to those required in the final product. Examples of such conversions in the aromatic substituents include chlorination of hydrogen to chloro, reduction of nitro to amino, dehalogenation such as debromination, and/or elaboration of a 2,3-dihydroxy-benzoic acid with ethylene dibromide to form the benzodioxan.
Suitable examples of conversions in the Z containing moiety include conventional modifications of the N-substituent by substitution and/or deprotection or, in the case of a 2-, 3- or 4- substituted piperidyl desired end compound, reduction of an appropriate pyridyl derivative. Any elaboration of X and/or Z is, however, usually carried out prior to ester or amide coupling.
Compounds of formula (II) may be prepared from carboxylic acids of formula X'COOH, for example via an acyl azide (Curtius reaction). Acids X'COOH are themselves well known in the art, for example where X is (a) or (b) such acids are described in GB2125398.
Acids of formula (III) may be prepared according to conventional methods, for example from a corresponding ketone. Azabicyclic side chain (CH2)n2-COOH intermediates when Z is (j) in formula (I), are known compounds or may be prepared from the ketones of formula (IV):
(IV)
according to conventional metiiods.
The compounds of the present invention are 5-HT4 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.
They are of potential interest in the treatment of irritable bowel syndrome (IBS), in particular the diarrhoea aspects of IBS, i.e., these compounds block the ability of 5-HT to stimulate gut motility via activation of enteric neurones. In animal models of IBS, this can be conveniently measured as a reduction of the rate of defaecation. They are also of potential use in the treatment of urinary incontinence which is often associated with IBS. They may also be of potential use in other gastrointestinal disorders, such as those associated with upper gut motility, and as antiemetics. In particular, they are of potential use in the treatment of the nausea and gastric symptoms of gastro-oesophageal reflux disease and dyspepsia. Antiemetic activity is determined in known animal models of cytotoxic-agent radiation induced emesis.
Specific cardiac 5-HT4 receptor antagonists which prevent atrial fibrillation and other atrial arrhythmias associated with 5-HT, would also be expected to reduce occurrence of stroke (see A.J. Kaumann 1990, Naumyn-Schmiedeberg's Arch. Pharmacol. 342, 619-622, for appropriate animal test method). Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al
1988, Mol Pharmacol., 34, 880-887). Activity can be demonstrated in standard animal models, the social interaction test and the X-maze test.
Migraine sufferers often undergo situations of anxiety and emotional stress that precede the appearance of headache (Sachs, 1985, Migraine, Pan Books, London). It has also been observed that during and within 48 hours of a migraine attack, cyclic AMP levels are considerably increased in die cerebrospinal fluid (Welch et al., 1976, Headache 16, 160-167). It is believed that a migraine, including the prodomal phase and the associated increased levels of cyclic AMP are related to stimulation of 5-HT4 receptors, and hence that administration of a 5-HT4 antagonist is of potential benefit in relieving a migraine attack. Other CNS disorders of interest include schizophrenia, Parkinson's disease and Huntingdon's chorea.
The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Such compositions are prepared by admixture and are usually adapted for enteral such as oral, nasal or rectal, or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositories, injectable and infusable solutions or suspensions. 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, polyvinylpo.ypyrrolidone and starch derivatives such as sodium starch glycollate. 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 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, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; 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 quantities of fillers. Such operations are, of course, conventional in the art. For parenteral administration, 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. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, 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 exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
The invention further provides a method of treatment or prophylaxis of irritable bowel syndrome, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine 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.
An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal. However, a unit dose for a 70kg adult will normally contain 0.05 to lOOOmg 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.
No adverse toxicological effects are indicated within the aforementioned dosage ranges.
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 irritable bowel syndrome, gastro-oesophageal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine. The following Examples illustrates the preparation of compounds of formula (I), and the following Descriptions relate to the preparation of intermediates. A preferred compound corresponds to any example, but wherein there is an amino substituent in the 4-position and a chloro substituent in the 5-position of the benzoic acid nucleus depicted in formula (I).
Description 1 a) 2H-3,4-Dihydrobenzopyran-8-carboxyIic acid
Following the procedure outlined in EP-A-307172 Example 15, 2H-3,4- dihydrobenzopyran (0.85g) was converted to the title compound (0.77g) *H NMR 200MHz (CDCI3) 5 : 9.60 (brs,lH), 8.00 (d,lH), 7.3 (d,lH), 7.00 (t,lH), 4.45 (t,2H), 2.89 (t,2H), 2.25-2.00 (m,2H) b) 6-Chloro-2H-3,4-dihydrobenzopyran-8-carboxylic acid
A solution of 2H-3,4-dihydrobenzopyran-8-carboxylic acid (150mg) in glacial acetic acid (10ml) was treated with a solution of 1.3 equivalents of chlorine (80mg) in glacial acetic acid (2.8ml) dropwise with ice cooling. After stirring overnight at ambient temperature the solvent was evaporated under reduced pressure and the residue triturated with diethyl ether to give the title compound (64mg). iH NMR 200MHz (CDCI3) δ : 10.78 (bs,lH), 7.95 (s,lH), 7.25 (s,lH), 4.45 (t,2H), 2.88 (t,2H), 2.25-2.0 (m,2H) c) N-(6-Chloro -2H-3,4-dihydrobenzopyran-8-yI) trifluoroacetamide
6-Chloro-2H-3,4-dihydrobenzopyran-8-carboxylic acid (1.84g, 8.7mmol) was dissolved in a mixture of trifluoroacetic acid (50ml) and trifluoracetic anhydride (10ml) and the resulting solution cooled to 0°C. Sodium azide (0.79g,12mmol) was added portionwise and the reaction mixture stirred at room temperature under argon for 48 hours. The solvent was removed in vacua and the residue partitioned between water and chloroform. The organic layer was washed with saturated aqueous potassium carbonate solution, dried (Na2SO4) and concentrated in vacua to give a brown solid that was purified by column chromatography using ethyl acetate as eluant. The title compound was isolated as a white solid (D3) (1.19g). !H NMR 250MHz (CDCI3) δ : 8.45 (s, 1H), 8.15 (d,lH), 6.90 (d,lH), 4.30 (t,2H), 2.75 (t,2H), 2.10-2.00 (m,2H) d) 8-Amino-6-chloro-2H-3,4-dihydrobenzopyran
A mixture of N-(6-Chloro-2H-3,4-dihydrobenzopyran-8-yl)trifluoroacetamide (1.18g,4.48mmol) and 10% aqueous sodium hydroxide in methanol (20ml) was heated under reflux for 72 hours. After cooling, the solvent was removed in vacua to leave a gum. This was partitioned between water and chloroform and the organic layer separated and dried over Na2SO4- The solvent was removed to give a brown gum that was purified by column chromatography on silica using dichloromethane as eluant to give the title compound as an orange gum (D4)(0.63g) 1H NMR 250MHz (CDCI3) δ : 6.55 (d,lH), 6.45 (d,lH), 3.8 (brs.2H), 4.20 (t,2H), 2.70 (t,2H), 2.05-1.90 (m,2H)
Description 2 a) l-Butyl-4-piperidone
4-Piperidone monohydrate hydrochloride (lO.OOg, 0.065mol) was dissolved in acetone (100ml) and treated with 1-bromobutane (7.00ml, 0.065mol) and potassium carbonate (18.00g, 0.130mol). The mixture was then heated to reflux with stirring. After
20h, the reaction mixture was allowed to cool, and was then filtered through kieselguhr, and the filtrate evaporated under reduced pressure to give an orange solid, which was purified by silica-gel chromatography (CHCI3 as eluant) to give the title compound as a pale yellow oil (7.00g, 70%)
1H NMR (250 MHz, CDCI3) δ : 2.75 (t, 4H), 2.45 (m, 6H), 1.60-1.25 (m, 4H), 0.95 (t,
3H). b) l-Butyl-4-ethoxycarbonylmethylenepiperidine
To a solution of triethylphosphonoacetate (23.3ml, 0.117mol) in dry DMF
(40ml) at 0°C, potassium tert-butoxide (10. lg, 0.090mol) was added with stirring, followed by a solution of l-butyl-4-piperidone (6.98g, 0.05mol) in dry DMF (40ml) .
During the latter stages of the addition, the reaction mixture solidified, at this point, more DMF (50 ml) was added. The reaction mixture was then stirred overnight, and was then evaporated under reduced pressure, and the residue partitioned between 5N HCl and
EtOAc. The aqueous layer was extracted with EtOAc (2X), The aqueous layer was then treated with solid K2CO3 until pH9 was reached, before being extracted with EtOAc (3X).
The combined organic layers were then dried (Na2SO4), and evaporated under reduced pressure to give an orange oil, which was purified by silica-gel chromatography
(petrol/10% EtOAc in petrol) to give the title compound as a pale yellow oil (6.70g,
66%).
*H NMR (200MHz, CDCI3) δ : 5.65 (s, 1H), 4.12 (q, 2H), 2.98 (t, 2H), 2.52 (q, 4H), 2.32 (t, 4H), 1.52-1.30 (m, 7H), 0.93 (t, 3H). c) l-Butyl-4-ethoxycarbonylmethylpiperidine l-Butyl-4-ethoxycarbonylmethylenepiperidine (6.7g, 29.8mmol) was dissolved in
EtOH (100ml) and hydrogenated at atmospheric pressure in the presence of 10% PdC (lg) for 2 hours. The reaction mixture was then filtered through kieselguhr, and the filtrate evaporated under reduced pressure and dried in vacua to give the tide compound as a clear colourless oil (5.84g, 86%). H NMR (200MHz, CDCI3) δ : 4.12 (q, 2H), 2.90 (d, 2H), 2.35-2.20 (m, 4H), 2.00-1.60
(m, 5H), 1.50-1.20 (m, 9H), 0.92 (t, 3H). d) l-Butyl-4-carboxymethylpiperidine l-Butyl-4-ethoxycarbonylrnethylpiperidine (5.84g, 25.7mmol) was dissolved in ethanol (100ml) and treated with 10% NaOH aq. (32ml). The reaction mixture was then heated to reflux with stirring. After 2h, the reaction mixture was allowed to cool, was evaporated under reduced pressure (to remove EtOH), and the residue was acidified carefully with 5M HCl. This aqueous mixture was then evaporated under reduced pressure to give a sticky white solid which was dried in vacua at 65°C. The solid obtained was then triturated with methanol, the inorganic solids were then filtered off and the filtrate evaporated under reduced pressure to give the title compound as a viscous oil (5.07 g, 99%).
*H NMR (250MHz, CDC13) δ : 6.16 (brs, 1H), 2.95 (d, 2H), 2.40 (t, 2H), 2.10 (m, 4H), 1.65 (m, 3H), 1.45 (m, 2H), 1.35-1.15 (m, 4H), 0.90 (t, 3H).
Example
N-(6-Chloro-2H-3,4-dihydrobenzopyran-8-yl(l-butyl-4-piperidinyl) methyl- carboxamide (El)
A solution of l-butyl-4-carboxymethylpiperidine (0.342g ,1.72mmol) in a mixture of dry dimethylformamide (10ml) and and dry tetrahydrofuran (3ml) was cooled in an ice bath. Triethylamine (0.22ml, 1.55mmol)was added, followed by ethyl chloroformate (0.18ml,1.96mmol) and the reaction mixture was stirred at room temperature for 1 hour.
A solution of 8-amino-6-chloro-2H-3,4-dihydrobenzopyran (0.30g, 1.64mmol) in tetrahydrofuran (4ml) was added and the reaction mixture was heated under reflux for a further 48 hours. After cooling, the solvent was removed in vacua and the residue purified by column chromatography on silica gel using chloroform 95%, methanol 5% as eluant The title compound was isolated as a colourless oil (El)(0.1 lg, 19%) which was converted to the oxalate salt, mp 78-80°C. *H NMR 250MHz (CDCI3) free base δ : 8.20 (d,lH), 7.75 (s,lH), 6.75 (d,lH), 4.25 (t,2H), 3.55-3.40 (m,2H), 2.95-2.85 (m,2H), 2.80-2.60 (m,4H), 1.95-1.80 (m,2H), 2.25-1.80 (m,9H), 1.45-1.30 (m,2H), 0.95 (t,3H) 5-HT4 RECEPTOR ANTAGONIST ACTIVITY 1) Guinea pig colon
Male guinea-pigs, weighing 250-400g are used. Longitudinal muscle-myenteric plexus preparations, approximately 3cm long, are obtained from the distal colon region. These are suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% CO2 in O2 and maintained at 37°C. In all experiments, the Krebs solution also contains methiothepin 10"^M and granisetron lO' vl to block effects at 5- HTi, 5-HT2 and 5-HT3 receptors. After construction of a simple concentration-response curve widi 5-HT, using 30s contact times and a 15min dosing cycle, a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40-70% maximum(10-^M approx). The tissue is then alternately dosed every 15min with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant, dimethylphenylpiperazinium (DMPP). After obtaining consistent responses to both 5-HT and DMPP, increasing concentrations of a putative 5-HT4 receptor antagonist are then added to the bathing solution. The effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, PIC50 values are determined, being defined as the -log concentration of antagonist which reduces the contraction by 50%. A compound which reduces the response to 5-HT but not to DMPP is believed to act as a 5-HT4 receptor antagonist.
The compound of Example 1 had a PIC50 value of >6.

Claims

Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
X-NH-CO-Z (I) wherein
X is a monocyclic or polycyclic aromatic group, such as a group of formula (a), (b), (c), (d), (e), (f) or (g):
wherein
L is N or CRs wherein Rs is hydrogen, C1-6 alkoxy, halogen, C1-4 alkyl or cyano;
Q is NR1 a, CH2, O or S;
W is CH or N;
X1-(CH2)x-X2 forms a 5-7 membered ring wherein X1 is O or S; X2 is O, S, -CH2-, NR or NRCO wherein R is hydrogen or C1-6 alkyl; and
x is 1, 2 or 3;
one of X3 and X4 is N and the other is C; and
X5 is N or CR wherein R is hydrogen, C1-6 alkoxy, halo, C1-6 alkyl or cyano;
R1 a is hydrogen, C1-10 alkyl, C2-6 alkenyl, aralkyl, C2-6 alkanoyl or C2-6 alkanoyl C1-3 alkyl;
R3 a is hydrogen, halo, C1-6 alkyl, amino, nitro or C1-6 alkoxy;
R4 a is hydrogen, halo, C1-6 alkyl or C1-6 alkoxy;
R1 b is C1-6 alkoxy; and
R2 b is hydrogen, chloro or fluoro;
R3 b is hydrogen,C1-6 alkyl, amino optionally substituted by a C1-6 alkyl group, halo, hydroxy or C1-6 alkoxy;
R4 b is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy, nitro, amino or C1-6 alkylthio; and R5 b is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy or amino;
Rc is hydrogen, C1-6 alkoxy, halo or C1-6 alkyl;
R1 d is hydrogen, amino, halo, C1-6 alkyl, hydroxy or C1-6 alkoxy;
R2 d is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy, nitro, amino or C1-6 alkylthio;
R3 d is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy or amino;
R4 d and R5 d are independently hydrogen or C1-6 alkyl;
R1 e is hydrogen, halogen, CF3, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6
alkylsulphonyl, C1-6 alkylsulphinyl, C1-7 acyl, cyano, C1-6 alkoxycarbonyl, C1-7 acylamino, hydroxy, nitro or amino, aminocarbonyl, or aminosulphonyl, optionally N-substituted by one or two groups selected from C1-6 alkyl, C3-8 cycloalkyl, and C3-8 cycloalkyl C1-4 alkyl or disubstituted by C4 or C5 polymethylene; phenyl or phenyl C1-4 alkyl group optionally substituted in the phenyl ring by one or two of halogen, C1-6 alkoxy or C1-6 alkyl groups;
R3 e is hydrogen, halo, C1-6 alkyl, amino, nitro or C1-6 alkyl;
R4 e is hydrogen, halo, C1-6 alkyl or C1-6 alkoxy;
X6-X7 is NRz-CO or CR1 fR2 f-CR3 fR4 f where
Rz and R1 f to R4 f are independently hydrogen or C1-6 alkyl; and/or
R1 f/R2 f and R3 f/R4 f together are a bond and/or R1 f/R2 f/R3 f/R4 f are joined to form C3-6 polymethylene;
Ra f is hydrogen, halo, C1-6 alkyl, amino, nitro or C1-6 alkyl;
Rb f is hydrogen, halo, C1-6 alkyl or C1-6 alkoxy;
Xg is O, S, SO, SO2, CH2, CH, N or NR wherein R is hydrogen or C1-6 alkyl;
A is a saturated or unsaturated polymethylene chain of 2 - 4 carbon atoms;
R1 g and R2 g are hydrogen or C1-6 alkyl;
R3 g is hydrogen, halo, C1-6 alkyl, amino, nitro or C1-6 alkoxy;
R4 g is hydrogen, halo, C1-6 alkyl or C1-6 alkoxy;
Z is of sub-formula (h), (j) or (k):
wherein
n1 is 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 2, 3, 4 or 5;
q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2; R5 is hydrogen, C1-12 alkyl, aralkyl or R5 is (CH2)z-R10 wherein z is 2 or 3 and R10 is selected from cyano, hydroxyl, C1-6 alkoxy, phenoxy, C(O)C1-6 alkyl, COC6H5, -CONR11R12, NR11COR12 , SO2NR11R12 or NR1 1SO2R12 wherein R1 1 and R12 are hydrogen or C1-6 alkyl; or R5 is straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon,
C2-7 alkoxycarbonyl, or secondary or tertiary hydroxy substituted C1-6 alkyl; ; and
R6, R7 and R8 are independently hydrogen or C1-6 alkyl; and
R9 is hydrogen or C1-10 alkyl;
having 5-HT4 receptor antagonist activity.
2. A compound according to claim 1 wherein:
L in formula (a) is C-H, C-CH3, C-Cl or C-OCH3;
Q in formula (a) is NR1 a;
R1 a is hydrogen or a methyl or ethyl group. R1 b is methoxy;
R3 b is amino;
R4 b is halo;
R5 b is hydrogen; X1-(CH2)x-X2 is O-(CH2)2-O, O-(CH2)3-O, O-CH2-O, O-(CH2)2-NR, O-(CH2)2-S, O-CH2-CONR, O-(CH2)2-CH2, O-(CH2)3-CH2, or O-CH2-CH2, wherein any of the methylene linkages are optionally mono- or di- substituted by C1-6 alkyl groups;
R1 d is hydrogen or amino;
R2 d is hydrogen or halo;
R3 d is hydrogen or halo.
R1 e is CF3 or an ethyl group;
X5 is N, C-H or C-OCH3;
R3 e is hydrogen;
R4 e is hydrogen or halo, such as iodo.
X6-X7 when CR1 fR2 f- CR3 fR4f is CH2-CH2, CH=CH; NH-CO or NEt-CO;
Raf is hydrogen; Rb f is hydrogen or halo.
A is -CH2-(CH2)r-CH2- wherein r is 0, 1 or 2; -CH2-CH=CH-; -C(CH3)=CH- or when Xg is CH or N, A may be -(CH2)2-CH= or -CH=CH-CH=;
R1 g and R2 g are hydrogen or R1 g and R2 g are gem-dimethyl;
r is 1;
R3 g is hydrogen;
R4 g is hydrogen or halo.
3. A compound according to any one of claims 1 to 8 wherein Z is a group
(h) in which n1 is 1 and the azacycle is attached at a 4-position carbon atom when q is 2, and Z is 4-piperidinylmethyl and 4-pyrrolidinylmethyl, N-substituted by Ra as defined in claim 1. 4. A compound according to claim 3 wherein Z is N-substituted
4-piperidinylmethyl.
5. A compound according to claim 5 wherein the N-substituent is C2 or greater alkyl, or optionally substituted benzyl.
6. N-(6-Chloro-2H-3,4-dihydrobenzopyran-8-yl(1-butyl-4-piperidinyl) methylcarboxamide, or a salt thereof.
7. A process for preparing a compound of formula (I) which process comprises reacting an amine of formula (II) :
X'NH2 (II)
(wherein X' represents X as hereinbefore defined or a group convertible thereto) with an acid of formula (III) :
HOOCZ' (III)
(wherein Z' represents Z as hereinbefore defined or a group convertible thereto) or a reactive derivative thereof.
8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier.
9. A compound according to claim 1 for use as an active therapeutic substance.
10. The use of a compound according to claim 1 in the manufacture of a medicament for use as a 5-HT4 receptor antagonist.
11. The use according to claim 10 for use as a 5-HT4 receptor antagonist in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.
EP94906959A 1993-02-19 1994-02-18 Amide compounds with pharmacological activity Withdrawn EP0684947A1 (en)

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GB9303340 1993-02-19
GB939303340A GB9303340D0 (en) 1993-02-19 1993-02-19 Pharmaceuticals
PCT/GB1994/000336 WO1994019344A1 (en) 1993-02-19 1994-02-18 Amide compounds with pharmacological activity

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US5852014A (en) * 1992-03-12 1998-12-22 Smithkline Beecham P.L.C. Condensed indole derivatives as 5HT4 -receptor antagonists
US5998409A (en) * 1992-03-12 1999-12-07 Smithkline Beecham Plc Condensed indole derivatives as 5HT4 -receptor antagonists
JPH08502283A (en) * 1992-10-16 1996-03-12 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー 5-HT 4) Fused ring system N-alkylpiperidinyl-4-methylcarboxylic acid ester / amide for receptor antagonist
EP2069332B1 (en) 2006-08-15 2011-03-02 Actelion Pharmaceuticals Ltd. Azetidine compounds as orexin receptor antagonists

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AP401A (en) * 1992-03-12 1995-08-29 Smithkline Beecham Plc Condensed indole derivatives as 5H4-receptor antagonists.

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AU6040994A (en) 1994-09-14

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