CA2146928A1 - Imidazopyridine derivatives as 5-ht4 receptor antagonists - Google Patents
Imidazopyridine derivatives as 5-ht4 receptor antagonistsInfo
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- CA2146928A1 CA2146928A1 CA002146928A CA2146928A CA2146928A1 CA 2146928 A1 CA2146928 A1 CA 2146928A1 CA 002146928 A CA002146928 A CA 002146928A CA 2146928 A CA2146928 A CA 2146928A CA 2146928 A1 CA2146928 A1 CA 2146928A1
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- formula
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
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- 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
Abstract
Compounds of formula (1), and pharmaceutically acceptable salts thereof, and the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or halo; Y is O or NH; Z is of sub-formula (i), (ii), (iii), (iv) or (v), or wherein the piperidine ring in (i) or (ii) is replaced by pyrrolidinyl and/or the N-sub-stituent in (i) or (ii) is replaced by R3 wherein R3 is hydrogen or C1-12alkyl, aralkyl or R3 is (CH2)r-R10 wherein r is 2 or 3 and R10 is selected from cyano, hydroxyl, C1-6 alkoxy, phenoxy, C(O)C1-6alkyl, COC6H5, -CONR11R12, NR11COR12, SO2NR11R12 or NR11SO2R12 wherein R11 and R12 are hydrogen or C1-6 alkyl; or a compound of formula (1) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere; having 5-HT4 receptor antagonist activity.
Description
2 1~ ~ 9 2 ~ PCI/EP93/0280~
Im~dazopyr~dtne der~vat~ves as 5-HT4 receptor antagonists This invention relates to novel compounds having pharmacological activity, to 5 a process for their preparation and to their use as pharm~q~e~ tic~l~
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 10 r~ceptor.
WO 91/16045 (SmithEUine and French Laboratories r.imi~f~d) describes the use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrhythmias and slroke.
EP-A-501322 (Glaxo Group Limited) describes indole derivatives having 15 5-HT4 antagonist activity.
WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and PCT/GB93/00506 (SmithKline Beecham plc) describe compounds having 5-HT4 receptor antagonist activity.
EP-A-504~79 (G.D. Searle & Co.) describes 5-HT3 receptor antagonists with 20 inter alia, an imidazopyridine nucleus.
A class of novel, structurally distinct compounds has now been discovered, which compounds are imidazopyridinyl derivatives with an azacyclic, fused azabicyclic or aminoaL~yl moiety. These compounds have 5-HT4 receptor antagonist activity.
When used herein, 'treatment' includes prophylaxis as appropriate.
Accordingly, ~he present invention provides a compound of formula (I3, or a pharmaceutically acceptable salt thereof:
CO Y-Z
(I) WO 94/08998 ~?,1 4692~ PCI/EP93/02808 wherein Rl is hydrogen or Cl 6 alkyl;
R2 is hydrogen or halo;
YisOorNH;
S Z is of sub-formula (i), (ii), (iii), (iv) or (v):
n ~N Bu (i) /~ N /\~0 (ii) ~N~J (iii) ~N~
~ ' (iv) f~
~ N ~ (v) 10 or wherein the piperidine ring in (i) or (ii) is replaced by pyrrolidinyl and/or the N-substituent in (i) or (ii) is replaced by R3 wherein R3 is hydrogen or Cl-12 alkyl, aralkyl or R3 is (CH2)r-Rlo wherein r is 2 or 3 and Rlo is selected from cyano, hydroxyl, Cl 6 alkoxy, phenoxy, C(O)Cl 6 aLkyl, COC6Hs, -CONRl lR12~ lCR12. S2NRl lR12 or NRl lS02R12 wherein R l l and R12 are hydrogen or C 1-6 alkyl;
or a compound of forrnula (I) wherein tne CO-Y linkage is replaced by a heterocyclic bioisostere;
having S-HT4 receptor antagonist activity.
WO 94/08998 2 1 ~ PCI~/E~93/02808 Examples of alkyl or alkyl cont~inin.~ groups include Cl, C2, C3, C4, Cc, C6, C7, C8, Cg, C 10. C 11 or C 12 branched, straight chaine~l or cy~ lic alkyl, as appropriate. C 1-4 alkyl groups include methyl, etnyl n- and iso-propyl, n-, iso-, sec-and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, 5 cyclohexyl, cycloheptyl and cyclooctyl.
,~ Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, Cl 6 alkyl and Cl 6 aLkoxy.
Halo includes fluoro, chloro, bromo and iodo.
A suitable bioisostere for the amide or ester linkage containing Y in formula 10 (I), is of formula:
H J
~ U--wherein 15 the dotted circle represents one or two double bonds in any position in the 5-membered ring; 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 20 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety.
R1 is preferably hydrogen.
R2 is preferably hydrogen.
Y is preferably O or NH.
The N-substituent in formula (i) or (ii) may be replaced by optionally 25 substituted benzyl or by (CH2)nR4, 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 phar~n~ceu~ lly acceptable organic acids such 30 as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ol-keto glutaric, o~-glycerophosphoric, and glucose-l-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 1-6 alkyl, phenyl-C 1-6 alkyl or Cs 7 cycloalkyl, and T is a 35 radical corresponding to an anion of an acid. Suitable examples of Rx includemethyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examF)les of T include halide such as chloride, bromide and iodidc.
WO94/08998 ~ 469~8 PCr/EP93/02808 Examples of pharmaceutically acceptable salts also include internal salls as N-oxides.
The compounds of the forrnula (1), their pharnl~ceutic~ily accepta~ie salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically 5 acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.
Azabicyclic values of Z may exl'st in a and ~ forms.
The compounds of formula (I) may be prepared by conventional coupling of the moiety with Z. Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A and EP-A-36269 (Beecham Group p.l.c.). When CO-Y is replaced by a heterocyclic bioisostere, suitable methods are described in EP-A-328200 (Merck Sharp & Dohme Limited). Reference is also made to EP-A-501322 (Glaxo Group r~imilecl)~
Imidazopyridine intermediates may be prepared as described in EP-A-504679.
Aza(bi)cyclic side chain intermediates are known compounds or may be prepared according to the methods described in the aformentioned patent publications (SmithKline Beecham p.l.c.).
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 gastrointestin~l 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. ~ m~nn 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 Pharrnacol., 34, 880-887). Activity can be demonstrated in standard animal models, the social interaction test and the X-maze test.
WO 94/08998 2 ~ ~ 6 9 ~ ~ PCI /EP93/02808 Migraine sufferers often undergo situations of anxiety and emotional stress that precede the appearance of headache (Sachs, lg8S, ~igrair.e, Par, Bcokc1, London). It has also been observed that during an~ in 48 hOUlS of a înigraine attack, cyclic ~MP levels are considerably increased in the cerebrospinal fluid (Welch S 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 adminictration 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 a~lminictration, 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 ~dminictrable compositions are preferred, since they are more convenient for general use.
Tablets and capsules for oral ~minictration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, ~iluent.c, 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, m~nnitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, m~gnesium 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 prol yl p-hydroxybenzoate or sorbic acid, and if WO 94/08998 21~ 6 9 ~ - 6 - PCI /EP93/02808 desired conventional flavouring or colouring agents.
Oral liquid preparations are usually in the fcrm of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or ~e presented as a ary 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 ~mini~tration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, dependingon the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and f1lter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local ~n~sthPtic, 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 com~osition to facilitate uniform distribution of the compound of the invention.
The invention furLher provides a method of treatment or prophylaxis of irritable bowel syndrome, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine in m~mm~lc, such as humans, which comprises the a~ministration 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 Pffic~cies of the compounds of the invention, the nature and severity of the disorder being treated and the wcight of the m~mm~l However, a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.5 to 500mg, of thecompound of the invention. Unit doses may be administered once or more than oncea 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.
WO 94/08998 7 ~ ~ 6 9 2 8 PCI~/EP93/0280 The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapel:tic su~stance, in particul~r f~r use in the treatment of irritable bowel syndrome, gastlo-oesophageal r~ilux disease,dyspepsia, atrial a~rhythmias and stroke, anxiety and/or migraine.
The following Examples illustrates the preparation of compounds of formula (I), and the following Description relate to the preparation of an intermediate.v It will be appreciated that any compound prepared wherein Y is O may be provided as the corresponding compound wherein Y is NH or vice versa.
Description a) 2-Amino-5-chloronicotinic acid To a solution of 2-aminonicotinic acid (g) in acetic acid (SOml) was added a solution of chlorine (2.8 lg) in acetic acid (44ml). The reaction mixture was stirred at lS room temperature for 4 days. The solvent was concentrated under reduced pressure and the solid filtered and dried to afford the title compound (4.7g) lH NMR (250MHz) d6-DMSO
o 8.48 (d, lH), 8.29 (d, lH) b) 6-Chloroimidazo[1,2-a]pyridine-8-carboxylic acid 2-Amino-5-chloronicotinic acid (2g) and chloroacetaldehyde (1.83ml) were suspended in ethanol (50ml) and the resulting slurry heated to reflux overnight. The mixture was cooled to room temperature and the solvent concentrated under reduced pressure. The residue was suspended in acetone, filtered and dried to leave 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (Dl) (1.72g) as an off-white solid.
lH NMR (250MHz) d6DMSO
o: 9.58(d, lH), 8.45-8.52(m, 2H), 8.19(d, lH) F.Y~mples Example 1 [Rl = H, R2 = Cl, Y = NH, Z = (i)]
( l-Buty1-4-piperidinylmethyl) 6-chloroimidazo~ 1,2-a]pvridyl-8-carboxamide (E 1) A suspension of 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (Dl) (250mg) in acetonitrile (lOml) was treated with l,1'-carbonyldiimidazole (330mg)and the resulting mixture heated gently for 2h. The solution was cooled to room temperature and the solvent concentrated in ~7acuo. To the residue dissolved in N,N'-dimethylformamide ( lOml) was added a solution of l -butyl-4-aminomethylpiperidine (230mg) in N,N'-dime~hylformamide ( lOml). The resul~ing mixture was stirred at room tem~erature and the solid filtered to afford the title g~-WO 94/08998 PCr/EP93/02808 compound (260mg).
lH NMR (250MHz) CD30D
o: 8.67 (d, lH), 7.77-7.84 (m, 2H), 7.52 (d, lH), 3.31-3.48 (m, 4H), 2.74-;~.97 (m, 4H), 1.83-1.99 (m, 3H), 1.40-1.64 (m, 4H), 1.15-1.44 (m, 2H), 0.83 (t, 3H) Example 2 [Rl = H, R2 = Cl, Y = NH, Z = (iii)]
2-eq-Quinolizidin-2-ylmethy! 6-chloroim~ 7~ 2-a]pyridyl-8-carboxamide (E2) `' Following the procedure outlined in Example 1, eq-2-aminomethyl quinolizidine (200mg) gave the title compound as a white solid (260mg).
lH NMR 250MHz (CD30D) o: 8.83 (d, lH), 7.95-8.01 (m, 2H), 7.71 (d, lH), 3.37-3.55 (m,4H), 2.89-3.16 (m, 3H), 1.33-2.19 (m, 1 lH).
E~;ample3[Rl =H,R2=Cl,Y=O,Z=(i)]
(1-Buty1-4-piperidinylmethyl) 6-chloroimidazo~1,2-a]pyridyl-8-carboxylate (E3) A suspension of 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (Dl) (250m~) in acetonitrile (lOml) was treated with l,l'-carbonyldiimidazole (330mg)and the resulting mixture heated gently for 2h. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in 20 N,N'-dimethylformamide (lOml) and a solution of 1-butyl-4-hydroxymethylpiperidine (230mg) in N,N'-dimethylformamide (lOml) added. The solution was stirred at roomtemperature overnight. The solvent was concentrated in vacuo and the residue panitioned between chloroform and aq.K2C03. The organic phase was dried (Na2S04), filtered and concentrated under reduced pressure. The residue was 25 chromatooraphed on silica to afford the title compound (130mg).
1H NMR 250MHz (CDC13) o: 8.36 (d, lH), 7.87 (d, lH), 7.78 (d, lH), 7.63 (d, lH), 4.39 (d, 2H), 3.01 (bd, 2H), 2.34 (dt, 2H), 1.96 (t, 3H), 1.82 (bd, 2H), 1.41-1.59 (m, 4H), 1.27-1.39 (m, 2H), 0.91 (t, 3H).
WO 94/08998 21~ 6 9 2 ~ PCI/EP93/02808 g 1) Guinea pi~ colon Male guinea-pigs, weighing 250-400g are used. Longltl~(lin~l muscle-myenteric plexus preparations, approximately 3cm long, are obtained from the distal 5 colon region. These are suspended under a 0.5g load in isolated tissue baths cont~ining Krebs solution bubbled with 5% CO2 in 2 and maintained at 37C. In all experiments~ the Krebs solution also contains methiothepin 10-7M and granisetron10-6M to block effects at S-HTl, 5-HT2 and 5-HT3 receptors.
After construction of a simple concentration-response curve with 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(10~9M
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 nicotinereceptor 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, pICso 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 1 and 3 had a pIC50 value of >8, E1 being preferred.
2) Rat oesophagus 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 37C. All experiments are performed in pargyline pre-treated preparations (10011M for 15 min followed by washout) and in the presence of cocaine (30~1M). Relaxant responses to 5-HT are obtained after pre-contracting the oesophagus tissue with carbachol (3~
Im~dazopyr~dtne der~vat~ves as 5-HT4 receptor antagonists This invention relates to novel compounds having pharmacological activity, to 5 a process for their preparation and to their use as pharm~q~e~ tic~l~
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 10 r~ceptor.
WO 91/16045 (SmithEUine and French Laboratories r.imi~f~d) describes the use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrhythmias and slroke.
EP-A-501322 (Glaxo Group Limited) describes indole derivatives having 15 5-HT4 antagonist activity.
WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and PCT/GB93/00506 (SmithKline Beecham plc) describe compounds having 5-HT4 receptor antagonist activity.
EP-A-504~79 (G.D. Searle & Co.) describes 5-HT3 receptor antagonists with 20 inter alia, an imidazopyridine nucleus.
A class of novel, structurally distinct compounds has now been discovered, which compounds are imidazopyridinyl derivatives with an azacyclic, fused azabicyclic or aminoaL~yl moiety. These compounds have 5-HT4 receptor antagonist activity.
When used herein, 'treatment' includes prophylaxis as appropriate.
Accordingly, ~he present invention provides a compound of formula (I3, or a pharmaceutically acceptable salt thereof:
CO Y-Z
(I) WO 94/08998 ~?,1 4692~ PCI/EP93/02808 wherein Rl is hydrogen or Cl 6 alkyl;
R2 is hydrogen or halo;
YisOorNH;
S Z is of sub-formula (i), (ii), (iii), (iv) or (v):
n ~N Bu (i) /~ N /\~0 (ii) ~N~J (iii) ~N~
~ ' (iv) f~
~ N ~ (v) 10 or wherein the piperidine ring in (i) or (ii) is replaced by pyrrolidinyl and/or the N-substituent in (i) or (ii) is replaced by R3 wherein R3 is hydrogen or Cl-12 alkyl, aralkyl or R3 is (CH2)r-Rlo wherein r is 2 or 3 and Rlo is selected from cyano, hydroxyl, Cl 6 alkoxy, phenoxy, C(O)Cl 6 aLkyl, COC6Hs, -CONRl lR12~ lCR12. S2NRl lR12 or NRl lS02R12 wherein R l l and R12 are hydrogen or C 1-6 alkyl;
or a compound of forrnula (I) wherein tne CO-Y linkage is replaced by a heterocyclic bioisostere;
having S-HT4 receptor antagonist activity.
WO 94/08998 2 1 ~ PCI~/E~93/02808 Examples of alkyl or alkyl cont~inin.~ groups include Cl, C2, C3, C4, Cc, C6, C7, C8, Cg, C 10. C 11 or C 12 branched, straight chaine~l or cy~ lic alkyl, as appropriate. C 1-4 alkyl groups include methyl, etnyl n- and iso-propyl, n-, iso-, sec-and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, 5 cyclohexyl, cycloheptyl and cyclooctyl.
,~ Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, Cl 6 alkyl and Cl 6 aLkoxy.
Halo includes fluoro, chloro, bromo and iodo.
A suitable bioisostere for the amide or ester linkage containing Y in formula 10 (I), is of formula:
H J
~ U--wherein 15 the dotted circle represents one or two double bonds in any position in the 5-membered ring; 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 20 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety.
R1 is preferably hydrogen.
R2 is preferably hydrogen.
Y is preferably O or NH.
The N-substituent in formula (i) or (ii) may be replaced by optionally 25 substituted benzyl or by (CH2)nR4, 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 phar~n~ceu~ lly acceptable organic acids such 30 as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ol-keto glutaric, o~-glycerophosphoric, and glucose-l-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 1-6 alkyl, phenyl-C 1-6 alkyl or Cs 7 cycloalkyl, and T is a 35 radical corresponding to an anion of an acid. Suitable examples of Rx includemethyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examF)les of T include halide such as chloride, bromide and iodidc.
WO94/08998 ~ 469~8 PCr/EP93/02808 Examples of pharmaceutically acceptable salts also include internal salls as N-oxides.
The compounds of the forrnula (1), their pharnl~ceutic~ily accepta~ie salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically 5 acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.
Azabicyclic values of Z may exl'st in a and ~ forms.
The compounds of formula (I) may be prepared by conventional coupling of the moiety with Z. Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A and EP-A-36269 (Beecham Group p.l.c.). When CO-Y is replaced by a heterocyclic bioisostere, suitable methods are described in EP-A-328200 (Merck Sharp & Dohme Limited). Reference is also made to EP-A-501322 (Glaxo Group r~imilecl)~
Imidazopyridine intermediates may be prepared as described in EP-A-504679.
Aza(bi)cyclic side chain intermediates are known compounds or may be prepared according to the methods described in the aformentioned patent publications (SmithKline Beecham p.l.c.).
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 gastrointestin~l 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. ~ m~nn 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 Pharrnacol., 34, 880-887). Activity can be demonstrated in standard animal models, the social interaction test and the X-maze test.
WO 94/08998 2 ~ ~ 6 9 ~ ~ PCI /EP93/02808 Migraine sufferers often undergo situations of anxiety and emotional stress that precede the appearance of headache (Sachs, lg8S, ~igrair.e, Par, Bcokc1, London). It has also been observed that during an~ in 48 hOUlS of a înigraine attack, cyclic ~MP levels are considerably increased in the cerebrospinal fluid (Welch S 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 adminictration 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 a~lminictration, 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 ~dminictrable compositions are preferred, since they are more convenient for general use.
Tablets and capsules for oral ~minictration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, ~iluent.c, 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, m~nnitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, m~gnesium 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 prol yl p-hydroxybenzoate or sorbic acid, and if WO 94/08998 21~ 6 9 ~ - 6 - PCI /EP93/02808 desired conventional flavouring or colouring agents.
Oral liquid preparations are usually in the fcrm of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or ~e presented as a ary 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 ~mini~tration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, dependingon the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and f1lter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local ~n~sthPtic, 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 com~osition to facilitate uniform distribution of the compound of the invention.
The invention furLher provides a method of treatment or prophylaxis of irritable bowel syndrome, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine in m~mm~lc, such as humans, which comprises the a~ministration 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 Pffic~cies of the compounds of the invention, the nature and severity of the disorder being treated and the wcight of the m~mm~l However, a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.5 to 500mg, of thecompound of the invention. Unit doses may be administered once or more than oncea 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.
WO 94/08998 7 ~ ~ 6 9 2 8 PCI~/EP93/0280 The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapel:tic su~stance, in particul~r f~r use in the treatment of irritable bowel syndrome, gastlo-oesophageal r~ilux disease,dyspepsia, atrial a~rhythmias and stroke, anxiety and/or migraine.
The following Examples illustrates the preparation of compounds of formula (I), and the following Description relate to the preparation of an intermediate.v It will be appreciated that any compound prepared wherein Y is O may be provided as the corresponding compound wherein Y is NH or vice versa.
Description a) 2-Amino-5-chloronicotinic acid To a solution of 2-aminonicotinic acid (g) in acetic acid (SOml) was added a solution of chlorine (2.8 lg) in acetic acid (44ml). The reaction mixture was stirred at lS room temperature for 4 days. The solvent was concentrated under reduced pressure and the solid filtered and dried to afford the title compound (4.7g) lH NMR (250MHz) d6-DMSO
o 8.48 (d, lH), 8.29 (d, lH) b) 6-Chloroimidazo[1,2-a]pyridine-8-carboxylic acid 2-Amino-5-chloronicotinic acid (2g) and chloroacetaldehyde (1.83ml) were suspended in ethanol (50ml) and the resulting slurry heated to reflux overnight. The mixture was cooled to room temperature and the solvent concentrated under reduced pressure. The residue was suspended in acetone, filtered and dried to leave 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (Dl) (1.72g) as an off-white solid.
lH NMR (250MHz) d6DMSO
o: 9.58(d, lH), 8.45-8.52(m, 2H), 8.19(d, lH) F.Y~mples Example 1 [Rl = H, R2 = Cl, Y = NH, Z = (i)]
( l-Buty1-4-piperidinylmethyl) 6-chloroimidazo~ 1,2-a]pvridyl-8-carboxamide (E 1) A suspension of 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (Dl) (250mg) in acetonitrile (lOml) was treated with l,1'-carbonyldiimidazole (330mg)and the resulting mixture heated gently for 2h. The solution was cooled to room temperature and the solvent concentrated in ~7acuo. To the residue dissolved in N,N'-dimethylformamide ( lOml) was added a solution of l -butyl-4-aminomethylpiperidine (230mg) in N,N'-dime~hylformamide ( lOml). The resul~ing mixture was stirred at room tem~erature and the solid filtered to afford the title g~-WO 94/08998 PCr/EP93/02808 compound (260mg).
lH NMR (250MHz) CD30D
o: 8.67 (d, lH), 7.77-7.84 (m, 2H), 7.52 (d, lH), 3.31-3.48 (m, 4H), 2.74-;~.97 (m, 4H), 1.83-1.99 (m, 3H), 1.40-1.64 (m, 4H), 1.15-1.44 (m, 2H), 0.83 (t, 3H) Example 2 [Rl = H, R2 = Cl, Y = NH, Z = (iii)]
2-eq-Quinolizidin-2-ylmethy! 6-chloroim~ 7~ 2-a]pyridyl-8-carboxamide (E2) `' Following the procedure outlined in Example 1, eq-2-aminomethyl quinolizidine (200mg) gave the title compound as a white solid (260mg).
lH NMR 250MHz (CD30D) o: 8.83 (d, lH), 7.95-8.01 (m, 2H), 7.71 (d, lH), 3.37-3.55 (m,4H), 2.89-3.16 (m, 3H), 1.33-2.19 (m, 1 lH).
E~;ample3[Rl =H,R2=Cl,Y=O,Z=(i)]
(1-Buty1-4-piperidinylmethyl) 6-chloroimidazo~1,2-a]pyridyl-8-carboxylate (E3) A suspension of 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (Dl) (250m~) in acetonitrile (lOml) was treated with l,l'-carbonyldiimidazole (330mg)and the resulting mixture heated gently for 2h. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in 20 N,N'-dimethylformamide (lOml) and a solution of 1-butyl-4-hydroxymethylpiperidine (230mg) in N,N'-dimethylformamide (lOml) added. The solution was stirred at roomtemperature overnight. The solvent was concentrated in vacuo and the residue panitioned between chloroform and aq.K2C03. The organic phase was dried (Na2S04), filtered and concentrated under reduced pressure. The residue was 25 chromatooraphed on silica to afford the title compound (130mg).
1H NMR 250MHz (CDC13) o: 8.36 (d, lH), 7.87 (d, lH), 7.78 (d, lH), 7.63 (d, lH), 4.39 (d, 2H), 3.01 (bd, 2H), 2.34 (dt, 2H), 1.96 (t, 3H), 1.82 (bd, 2H), 1.41-1.59 (m, 4H), 1.27-1.39 (m, 2H), 0.91 (t, 3H).
WO 94/08998 21~ 6 9 2 ~ PCI/EP93/02808 g 1) Guinea pi~ colon Male guinea-pigs, weighing 250-400g are used. Longltl~(lin~l muscle-myenteric plexus preparations, approximately 3cm long, are obtained from the distal 5 colon region. These are suspended under a 0.5g load in isolated tissue baths cont~ining Krebs solution bubbled with 5% CO2 in 2 and maintained at 37C. In all experiments~ the Krebs solution also contains methiothepin 10-7M and granisetron10-6M to block effects at S-HTl, 5-HT2 and 5-HT3 receptors.
After construction of a simple concentration-response curve with 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(10~9M
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 nicotinereceptor 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, pICso 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 1 and 3 had a pIC50 value of >8, E1 being preferred.
2) Rat oesophagus 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 37C. All experiments are performed in pargyline pre-treated preparations (10011M for 15 min followed by washout) and in the presence of cocaine (30~1M). Relaxant responses to 5-HT are obtained after pre-contracting the oesophagus tissue with carbachol (3~
Claims (14)
1. Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
(I) wherein R1 is hydrogen or C1-6 alkyl;
R2 is hydrogen or halo;
Y is O or NH;
Z is of sub-formula (i), (ii), (iii), (iv) or (v):
(i) (ii) (iii) (iv) (v) or wherein the piperidine ring in (i) or (ii) is replaced by pyrrolidinyl and/or the N-substituent in (i) or (ii) is replaced by R3 wherein R3 is hydrogen or C1-12 alkyl, aralkyl or R3 is (CH2)r-R10 wherein r 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 a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere;
having 5-HT4 receptor antagonist activity.
(I) wherein R1 is hydrogen or C1-6 alkyl;
R2 is hydrogen or halo;
Y is O or NH;
Z is of sub-formula (i), (ii), (iii), (iv) or (v):
(i) (ii) (iii) (iv) (v) or wherein the piperidine ring in (i) or (ii) is replaced by pyrrolidinyl and/or the N-substituent in (i) or (ii) is replaced by R3 wherein R3 is hydrogen or C1-12 alkyl, aralkyl or R3 is (CH2)r-R10 wherein r 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 a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere;
having 5-HT4 receptor antagonist activity.
2. A compound according to claim 1 wherein R1 is hydrogen.
3. A compound according to claim 1 or 2 wherein R2 is hydrogen or chloro.
4. A compound according to claim 1, 2, or 3 wherein Y is O or NH.
5. A compound according to claim 1 wherein The N-substituent in sub-formula (i) or (ii) is be replaced by optionally substituted benzyl or by (CH2)nR4, as defined in formula (I) and in relation to the specific examples of EP-A-501322.
6. (1-Butyl-4-piperidinylmethyl) 6-chloroimidazo[1,2-a]pyridyl-8-carboxamide.
7. 2-eq-Quinolizidin-2-ylmethyl 6-chloroimidazo[1,2-a]pyridyl-8-carboxamide
8. (1-Butyl-4-piperidinylmethyl) 6-chloroimidazo[1,2-a]pyridyl-8-carboxylate
9. A compound substantially as hereinbefore described with reference to any one of the Examples.
10. A process for preparing the ester or amide compounds (where Y is O or NH) according to claim 1, which comprises reacting an appropriate acid derivative with an appropriate alcohol or amine.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier.
12. A compound according to claim 1 for use as an active therapeutic substance.
13. The use of a compound according to claim 1 in the manufacture of a medicament for use as a 5-HT4 receptor antagonist.
14. The use according to claim 13 for use as a 5-HT4 receptor antagonist in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929221468A GB9221468D0 (en) | 1992-10-13 | 1992-10-13 | Pharmaceuticals |
| GB9221468.3 | 1992-10-13 |
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|---|---|
| CA2146928A1 true CA2146928A1 (en) | 1994-04-28 |
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ID=10723359
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002146928A Abandoned CA2146928A1 (en) | 1992-10-13 | 1993-10-12 | Imidazopyridine derivatives as 5-ht4 receptor antagonists |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0664808A1 (en) |
| JP (1) | JPH08502274A (en) |
| CN (1) | CN1092775A (en) |
| AU (1) | AU5177093A (en) |
| CA (1) | CA2146928A1 (en) |
| GB (1) | GB9221468D0 (en) |
| MX (1) | MX9306310A (en) |
| WO (1) | WO1994008998A1 (en) |
| ZA (1) | ZA937505B (en) |
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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 |
| WO1994008965A1 (en) * | 1992-10-16 | 1994-04-28 | Smithkline Beecham Plc | N-alkylpiperidinyl-4-methyl carboxylic esters/amides of condensed ring systems as 5-ht4 receptor antagonists |
| EP0977558B1 (en) * | 1996-02-15 | 2003-10-01 | Janssen Pharmaceutica N.V. | Use of 5ht4 receptor antagonists for overcoming gastrointestinal effects of serotonin reuptake inhibitors |
| FR2797630B1 (en) * | 1999-08-20 | 2005-04-29 | Univ Caen Basse Normandie | PYRROLO [1,2-a] QUINOXALINE ETHER DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION |
| US6624162B2 (en) | 2001-10-22 | 2003-09-23 | Pfizer Inc. | Imidazopyridine compounds as 5-HT4 receptor modulators |
| DE60206952T2 (en) * | 2001-10-22 | 2006-06-22 | Pfizer Inc. | Imidazopyridine compounds as 5-HT4 receptor modulators |
| MXPA03000145A (en) | 2002-01-07 | 2003-07-15 | Pfizer | Oxo or oxy-pyridine compounds as 5-ht4 receptor modulators. |
| GB0211230D0 (en) | 2002-05-16 | 2002-06-26 | Medinnova Sf | Treatment of heart failure |
| DOP2003000703A (en) * | 2002-09-20 | 2004-03-31 | Pfizer | IMIDAZOPIRADINE COMPOUNDS AS 5-HT4 RECEIVER AGONISTS |
| AU2003259482A1 (en) | 2002-09-20 | 2004-04-08 | Pfizer Japan Inc. | N-substituted piperidinyl-imidazopyridine compounds as 5-ht4 receptor modulators |
| MXPA05011270A (en) * | 2003-04-21 | 2006-01-24 | Pfizer | Imadazopyridine compounds having 5-ht4. |
| WO2005123718A2 (en) | 2004-06-15 | 2005-12-29 | Pfizer Japan Inc. | Benzimidazolone carboxylic acid derivatives |
| US7737163B2 (en) | 2004-06-15 | 2010-06-15 | Pfizer Inc. | Benzimidazolone carboxylic acid derivatives |
| CN104725376A (en) * | 2015-03-31 | 2015-06-24 | 山东友帮生化科技有限公司 | Synthetic method of 6-chlorine-8-carboxyl imidazo [1,2-a] pyridine |
| CN104761551A (en) * | 2015-03-31 | 2015-07-08 | 山东友帮生化科技有限公司 | Method for synthesizing 6-iodo-8-carboxylimidazo(1,2-a)pyridine |
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| GB9103862D0 (en) * | 1991-02-25 | 1991-04-10 | Glaxo Group Ltd | Chemical compounds |
| US5260303A (en) * | 1991-03-07 | 1993-11-09 | G. D. Searle & Co. | Imidazopyridines as serotonergic 5-HT3 antagonists |
-
1992
- 1992-10-13 GB GB929221468A patent/GB9221468D0/en active Pending
-
1993
- 1993-10-11 MX MX9306310A patent/MX9306310A/en unknown
- 1993-10-11 ZA ZA937505A patent/ZA937505B/en unknown
- 1993-10-12 JP JP6509615A patent/JPH08502274A/en active Pending
- 1993-10-12 CA CA002146928A patent/CA2146928A1/en not_active Abandoned
- 1993-10-12 WO PCT/EP1993/002808 patent/WO1994008998A1/en not_active Application Discontinuation
- 1993-10-12 EP EP93922942A patent/EP0664808A1/en not_active Withdrawn
- 1993-10-12 CN CN93114853A patent/CN1092775A/en active Pending
- 1993-10-12 AU AU51770/93A patent/AU5177093A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
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| WO1994008998A1 (en) | 1994-04-28 |
| AU5177093A (en) | 1994-05-09 |
| CN1092775A (en) | 1994-09-28 |
| JPH08502274A (en) | 1996-03-12 |
| GB9221468D0 (en) | 1992-11-25 |
| MX9306310A (en) | 1994-04-29 |
| ZA937505B (en) | 1994-07-22 |
| EP0664808A1 (en) | 1995-08-02 |
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