Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
  • A61P9/06—Antiarrhythmics
• • 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

• This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
• 5-HT3 receptor antagonists have been disclosed as of potential use in the treatment of certain aspects of irritable bowel syndrome (see
• EP-A- 189002 (Sandoz Limited) and EP-A-201165 (Beecham Group p.l.c)).
• 5-HT3 receptor interactions which are of potential use in the treatment of IBS are those associated either with the visceral pain and abnormal perception of sensation aspects of this disease, or they are related to the ability of some 5- ⁇ T3 receptor antagonists to cause constipation in volunteers.
• 5-HT3 receptor antagonists have been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motility [see EP-A-226266 (Glaxo Group Ltd.) and EP-A- 189002 (Sandoz Limited)]. 5-HT3 receptor antagonists are also well known antiemetics, such as ondansetron, granisetron and tropisetron (see Drugs of the Future 1989, 14 (9) p.875 - F.D. King and G.J. Sanger).
• 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) describes indole derivatives having 5-HT4 antagonist activity.
• EP-A-289170 and EP-A-254584 (Beecham Group p.l.c.) describes inter alia indolizine derivatives with a bridged piperidyl moiety having 5-HT3 receptor antagonist activity.
• the compounds of the present invention also have a potential use in the treatment of CNS disorders such as anxiety and/or migraine, in the treatment of upper gut motility disorders and as antiemetics.
• 'treatment' includes prophylaxis as appropriate.
• the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof
• Rx is hydrogen, halogen, CF3, C ⁇ _g alkyl, C ⁇ _g alkoxy, C ⁇ _g alkylthio, C ⁇ _g alkylsulphonyl, C ⁇ _g alkylsulphinyl, C ⁇ _7 acyl, cyano, C ⁇ _g alkoxycarbonyl, C ⁇ .7 acylamino, hydroxy, nitro or amino, aminocarbonyl, or aminosulphonyl, optionally N-substituted by one or two groups selected from C ⁇ _g alkyl, C3.3 cycloalkyl, and C3-8 cycloalkyl C ⁇ .4 alkyl or disubstituted by C4 or C5 polymethylene; phenyl or phenyl C ⁇ .4 alkyl group optionally substituted in the phenyl ring by one or two of halogen, C ⁇ .g alkoxy or C ⁇ .g alkyl groups; one of x and X2 is N and the other is
• X3 is N or CR wherein R is hydrogen, C ⁇ .g alkoxy, halo, C ⁇ .g alkyl or cyano; R a is hydrogen, halo, C ⁇ .g alkyl, amino, nitro or C ⁇ .g alkyl; Rb is hydrogen, halo, C ⁇ .g alkyl or C ⁇ .g alkoxy;
• Z is of sub-formula (a), (b) or (c):
• R5 is hydrogen, C ⁇ . ⁇ 2 alkyl, aralkyl or R5 is (CH2 10 wherein r is 2 or 3 and R ⁇ o is selected from cyano, hydroxyl, C ⁇ .g alkoxy, phenoxy, C(0)C ⁇ _g alkyl, COCgH 5 , -CONR ⁇ R ⁇ 2, NR ⁇ COR 12 , S ⁇ 2NR ⁇ R ⁇ 2 or N ⁇ S02R ⁇ 2 wherein xx and R ⁇ 2 are hydrogen or C ⁇ .g alkyl; and
• Rg, R7 and Rs are independently hydrogen or C ⁇ .g alkyl; and R9 is hydrogen or C ⁇ _ ⁇ o alkyl; or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere; having 5-HT4 receptor antagonist activity.
• alkyl or alkyl containing groups include C ⁇ > C2, C3, C4, C5, Cg, C7, Cg, Cg f C ⁇ o, Cx or C ⁇ 2 branched, straight chained or cychc alkyl, as appropriate.
• C ⁇ .4 alkyl groups include methyl, ethyl n- and iso-propyl, n-, iso-, sec- and teri-butyl.
• Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C ⁇ .g alkyl and C ⁇ .g alkoxy.
• Halo includes fluoro, chloro, bromo and iodo.
• a suitable bioisostere for the amide or ester linkage containing Y in formula (I), is of formula (d):
• H, J and I independently represent oxygen, sulphur, nitrogen or carbon, provided that at least one of H, J and I is other than carbon; U represents nitrogen or carbon.
• Suitable examples of (d) are as described for X, Y and Z in EP-A-328200 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety.
• Rx is preferably CF3 or an ethyl group.
• X3 is preferably N, C-H or C-OCH3;
• R a is preferably hydrogen.
• b is preferably hydrogen or halo, such as iodo.
• Y is preferably O or NH.
• n ⁇ 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.
• R5 include C3 or larger alkyl or optionally substituted benzyl and those values described for (CH2) ⁇ in formula (I), in relation to (la), preferred classes therein and the specific examples of EP-A-501322.
• Z is of sub-formula (b)
• n 2 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.
• s and Rg are preferably both alkyl, especially one of Rg and R9 is C4 or larger alkyl.
• the invention also provides novel compounds within formula (I) with side chains (i), (ii), (i ⁇ ), (iv), (v), (vi) or (vii).
• the piperidine ring in (i), (ii) or (i ⁇ ) 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) and in relation to the specific examples of EP-A-501322.
• 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, ⁇ -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, ⁇ -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 quatemised by compounds R ⁇ -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.
• Rx is C ⁇ .g alkyl, phenyl-C ⁇ _g alkyl or C5.7 cycloalkyl
• T is a radical corresponding to an anion of an acid.
• Rx include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl.
• Suitable examples of T include halide such as chloride, bromide and iodide.
• Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.
• the compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.
• Azabicyclic side chain intermediates are known compounds or may be prepared from the ketones of formula (II):
• 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. 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.
• platelet-derived 5-HT induces atrial arrhythmias which encourage atrial fibrillation and atrial disorders are associated with symptomatic cerebral and sytemic embolism.
• Cerebral embolism is the most common cause of ischaemic stroke and the heart the most common source of embolic material. Of particular concern is the frequency of embolism associated with atrial fibrillation.
• Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity may 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 the 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.
• 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. Sublingual or transdermal administration is also envisaged. Orally administrable compositions are preferred, since they are more convenient for general use. Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.
• Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
• Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch 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 h drogenated 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 h drogenated edible fats, emulsifying agents, for example lecithin,
• 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 of irritable bowel syndrome, gastro-oesophagal reflux disease, 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.
• the method comprises treatment of IBS or atrial arrhythmias and stroke.
• a unit dose for a 70 kg adult will normally contain 0.05 to 1000 mg for example 0.5 to 500 mg, of the compound of the invention.
• Unit doses maybe 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 50 mg/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-oesophagal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine, in particular IBS or atrial arrhythmias and stroke.
• the invention also provides the use of a compound of formula (I) in the manufacture of a medicament for use as a 5-HT4 receptor antagonist in the treatment of irritable bowel syndrome, gastro-oesophagal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine, in particular, IBS or atrial arrhythmias and stroke.
• the imidazolide was dissolved in dry THF (20 ml) and the resulting solution added dropwise to the solution of the lithium alkoxide at 0°C.
• the reaction mixture was allowed to warm to room temperature and was stirred for 3 hours.
• the solvent was removed in ⁇ acuo and the residue was partitioned between EtOAc and H2O.
• the EtOAc layer was separated, washed several times with H2O, dried and concentrated to give a pale yellow gum.
• the title compound was prepared from 3-trifluoromethyl- imidazo(l,5-a)pyridine-l-carboxylic acid and l-(2-hydroxyethyl)piperidine by the method described for Example 1.
• the product was isolated as the hydrochloride salt, mp 213-14°C.
• the title compound was prepared from 3-ethyhndohzinecarboxy-ic acid and l-(2-hydroxyethyl)piperidine by the method described for Example 1.
• the product was isolated as the hydrochloride salt, mp 198-9°C.
• 3-EthylindoHzine-l-carboxamide oxime was dissolved in dry THF (8 ml) and treated with ground 4A° molecular sieves (lg). The mixture was stirred at room temperature for ⁇ &., sodium hydride (80% disp in mineral oil) (0.049g, 1.62 mmol) was then added and the mixture heated to reflux. After Sh, ethyl 4-piperidinobutyrate in dry THF (3 ml) was added. Reflux was then continued for a further 1.5h. The reaction mixture was then allowed to cool and was filtered. The filter pad was then washed with THF ( ⁇ 15 ml), and the filtrate was evaporated under reduced pressure to give a brown oil.
• the title compound was prepared from 3-ethyhndoHzinecarboxylic acid (F.D. King et al, J. Med. Chem., 1990, 33, 1924) and l-butyl-4- hydroxymethylpiperidine using the method described in Example 1.
• the product was converted to its hydrochloride salt mp 198-200°C (acetone).
• 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 10 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' ⁇ M to block effects at 5-HT ⁇ , 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 l ⁇ min with this concentration of 5-HT and then with an approximately
• DMPP dimethylphenylpiperazinium
• 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 compounds of the Examples had a PIC50 value of of 8 or below, E8 having particularly good activity.
• Rat oesophageal tunica muscularis mucosae is set up according to Baxter et al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991).
• the inner smooth muscle tube of the muscularis mucosae is isolated and mounted for isometric tension recording in oxygenated (95% 02/5% CO2) Tyrodes solution at 37°C. All experiments are performed in pargyline pre- treated preparations (lOOmM for 15 min followed by washout) and in the presence of cocaine (30mM). Relaxant responses to 5-HT are obtained after pre-contracting the oesophagus tissue with carbachol (3mM).

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• 1992
  • 1992-10-15 JP JP5507530A patent/JPH07500588A/ja active Pending
  • 1992-10-15 WO PCT/GB1992/001886 patent/WO1993008187A1/en not_active Application Discontinuation
  • 1992-10-15 EP EP92921182A patent/EP0609278A1/en not_active Withdrawn
  • 1992-10-15 AU AU27526/92A patent/AU2752692A/en not_active Abandoned
  • 1992-10-22 MX MX9206073A patent/MX9206073A/es unknown
  • 1992-10-22 PT PT100994A patent/PT100994A/pt not_active Application Discontinuation

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