WO1994008998A1

WO1994008998A1 - Imidazopyridine derivatives as 5-ht4 receptor antagonists

Info

Publication number: WO1994008998A1
Application number: PCT/EP1993/002808
Authority: WO
Inventors: Francis David King; Laramie Mary Gaster
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 1992-10-13
Filing date: 1993-10-12
Publication date: 1994-04-28
Anticipated expiration: 1995-04-13
Also published as: EP0664808A1; CA2146928A1; AU5177093A; GB9221468D0; JPH08502274A; MX9306310A; ZA937505B; CN1092775A

Abstract

Compounds of formula (I), and pharmaceutically acceptable salts thereof, and the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or C1-6alkyl; 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-substituent 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, C1-6alkoxy, phenoxy, C(O)C1-6alkyl, COC6H5, -CONR11R12, NR11COR12, SO2NR11R12 or NR11SO2R12 wherein R11 and R12 are hydrogen or C1-6alkyl; or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere; having 5-HT4 receptor antagonist activity.

Description

Imidazopyridi ne derivatives as 5-HT4 receptor antagoni sts

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) describes indole derivatives having 5-HT4 antagonist activity.

WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and

PCT/GB93/00506 (SmithKline Beecham pic) describe compounds having 5-HT₄ receptor antagonist activity.

EP-A-504679 (G.D. Searle & Co.) describes 5-HT3 receptor antagonists with 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 aminoalkyl moiety. These compounds have 5-HT₄ receptor antagonist activity.

When used herein, 'treatment' includes prophylaxis as appropriate.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

R₁ is hydrogen or C_1-6 alkyl;

R₂ is hydrogen or halo;

Y s 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-substituent in (i) or (ii) is replaced by R₃ wherein

R₃ is hydrogen or C_{1- 12} alkyl, aralkyl or R₃ is (CH₂)_r-R₁₀ wherein r is 2 or 3 and

R ₁₀ is selected from cyano, hydroxyl, C_{1 -6} alkoxy, phenoxy, C(O)C_1-6 alkyl, COC₆H₅, -CONR_{1 1}R₁₂, NR_{1 1}COR₁₂, SO₂NR_{1 1}R₁₂ or NR _{1 1}SO₂R₁₂ wherein R_{1 1} and R₁₂ hydrogen or C_1-6 alkyl;

or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere;

having 5-HT₄ receptor antagonist activity. Examples of alkyl or alkyl containing groups include C₁, C₂, C₃, C₄, C₅, C₆,

C₇, C₈, C₉, C ₁₀, C_{1 1} or C_{1 2} branched, straight chained or cyclic alkyl, as appropriate. C_1-4 alkyl groups include methyl, ethyl n- and iso-propyl, n-, iso-, sec- and tert-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_1-6 alkyl and C_1-6 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:

wherein

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 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety.

Rj 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 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 pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-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 R_x-T wherein R_x is C_1-6 alkyl, phenyl-C_1-6 alkyl or C_5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R_x 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 values of Z may exist in α and β forms.

The compounds of formula (I) may be prepared by conventional coupling of the moiety with Z. Suitable methods are as described in GB 2125398 A (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 Limited).

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 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 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.

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, 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 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 1000mg for example 0.5 to 500mg, of the compound of the invention. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.

No adverse toxicological effects are indicated within the aforementioned dosace ranees. 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, gastio-oesophageal reilux disease, dyspepsia, atrial arrhythmias 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.

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-chIoronicotinic acid

To a solution of 2-aminonicotinic acid (g) in acetic acid (50ml) was added a solution of chlorine (2.8 lg) in acetic acid (44ml). The reaction mixture was stirred at 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)

1H NMR (250MHz) d₆-DMSO

δ 8.48 (d, 1H), 8.29 (d, 1H)

b) 6-Chloroimidazo[1,2-a]pyridine-8-carboxyIic 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[l,2-a]pyridine-8-carboxylic acid (D1) (1.72g) as an off-white solid. ¹ H NMR (250MHz) d₆DMSO

δ: 9.58(d, 1H), 8.45-8.52(m, 2H), 8.19(d, 1H)

Examples

Example 1 [R] = H, R₂ = Cl, Y = NH, Z = (i)]

(1-Butyl-4-piperidinylmethyl) 6-chloroimidazo[1,2-a]pyridyl-8-carboxamide (El)

A suspension of 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (D1) (250mg) in acetonitrile (10ml) was treated with 1,1'-carbonyldiimidazole (330mg) and the resulting mixture heated gently for 2h. The solution was cooled to room temperature and the solvent concentrated in vacuo. To the residue dissolved in N,N'-dimethylformamide (10ml) was added a solution of 1-butyl-4-aminomethylpiperidine (230mg) in N_.N'-dimethylformamide (10ml). The resulting mixture was stirred at room temperature and the solid filtered to afford the title compound (260mg).

1 H NMR (250MHz) CD₃OD

δ: 8.67 (d, 1H), 7.77-7.84 (m, 2H), 7.52 (d, 1H), 3.31-3.48 (m, 4H), 2.74-2.97 (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 [R₁ = H, R₂ = Cl, Y = NH, Z = (iii)]

2-eq-Quinolizidin-2-yImethyl 6-chloroimidazo[1,2-a]pyridyl-8-carboxamide (E2)

Following the procedure outlined in Example 1, eg-2-aminomethyl quinolizidine (200mg) gave the title compound as a white solid (260mg).

1 H NMR 250MHz (CD₃OD)

δ: 8.83 (d, 1H), 7.95-8.01 (m, 2H), 7.71 (d, 1H), 3.37-3.55 (m,4H), 2.89-3.16 (m, 3H), 1.33-2.19 (m, 11H).

Example 3 [R ₁ = H, R₂ = CI, Y = O, Z = (i)]

(1-Butyl-4-piperidinylmethyl) 6-chloroimidazo[1,2-a]pyridyl-8-carboxylate (E3) A suspension of 6-chloroimidazo[l,2-a]pyridine-8-carboxylic acid (D1) (250mg) in acetonitrile (10ml) was treated with 1,1'-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 N,N'-dimethylformamide (10ml) and a solution of l-butyl-4-hydroxymethylpiperidine (230mg) in N,N'-dimethylformamide (10ml) added. The solution was stirred at room temperature overnight. The solvent was concentrated in vacuo and the residue partitioned between chloroform and aq.K₂CO₃]. The organic phase was dried (Na2Sθ4), filtered and concentrated under reduced pressure. The residue was chromatographed on silica to afford the title compound (130mg).

1 H NMR 250MHz (CDCI₃)

δ: 8.36 (d, 1H), 7.87 (d, 1H), 7.78 (d, 1H), 7.63 (d, 1H), 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).

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^-7M and granisetron 10^-6M to block effects at 5-HT₁, 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 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 compounds of the Examples 1 and 3 had a pK.50 value of >8, El 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% 0^5% CO₂) Tyrodes solution at 37°C. All experiments are performed in pargyline pre-treated preparations (100μM for 15 min followed by washout) and in the presence of cocaine (30μM). Relaxant responses to 5-HT are obtained after pre-contracting the oesophagus tissue with carbachol (3μM).

Claims

1. Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein

R₁ is hydrogen or C _1-6 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-substituent in (i) or (ii) is replaced by R₃ wherein

R₁₀ is selected from cyano, hydroxyl, C_1-6 alkoxy, phenoxy, C(O)C_1-6 alkyl, COC₆H₅, -CONR_{1 1}R₁₂, NR_{1 1}COR₁₂, SO₂NR_{1 1}R₁₂ or NR_{1 1}SO₂R₁₂ wherein R _{1 1} and R₁₂ are hydrogen or C_1-6 alkyl;

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-eg-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.