AU666357B2 - Indole or benzimidazole derivatives - Google Patents

Description

r a-IiI OPI DATE 05/10/93 APPLN. ID 35718/93 I lli l| II ill li I lI| AOJP DATE 09/12/93 PCT NUMBER PCT/GB93/00395 I llllllii 1111 IillllliIIIIIIIIillii AU9335718 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 93/18027 C07D 401/12, 455/02 Al A61K 31/46 (43) International Publication Date: 16 September 1993 (16.09.93) (21) International Application Number: PCT/GB93/00395 (74) Agent: JONES, Pauline; SmithKline Beecham, Corporate Patents, Great Burgh, Yew Tree Bottom Road, Epsom, (22) International Filing Date: 25 February 1993 (25.02.93) Surrey KT18 5XQ (GB).

Priority data: (81) Designated States: AU, CA, JP, KR, NZ, US, European 9204565.7 3 March 1992 (03.03.92) GB patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).

(71) Applicant (for all designated States except US): SMITH- KLINE BEECHAM PLC [GB/GB]; New Horizons Published Court, Brentford, Middlesex TW8 9EP With international search report.

(72) Inventors; and Inventors/Applicants (for US only) KING, Francis, David [GB/GB]; GASTER, Laramie, Mary [GB/GB]; WY- MAN, Paul, Adrian [GB/GB]; SmithKline Beecham Pharmaceuticals, Coldharbour Road, The Pinnacles, 6 Harlow, Essex CM19 5AD (GB).

(54) Title: NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS USEFUL AS PHARMACEUTICALS R CO-Y-Z Ra

(I)

(57) Abstract Compounds of formula and pharmaceutically acceptable salts thereof and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

ic 1 SWO 93/18027 PCT/GB93/00395 NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS USEFUL AS PHARMACEUTICALS 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-HT 4 receptor, and that ICS 205-930, which is also a 5-HT 3 receptor antagonist, acts as an antagonist at this receptor.

WO 91/16045 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT 4 receptor antagonists in the treatment of atrial arrhythmias and stroke.

EP-A-501322 (Glaxo Group Limited) describes indole derivatives having 4 antagonist activity.

EP-A-309423 (Istituto de Angeli S.p.A) and EP-A-247266 (Beecham Group describe 5-HT 3 receptor antagonists derived from a benzimidazolone or indoline nucleus.

A class of novel, structurally distinct compounds has now been discovered, which compounds include benzimidazolone derivatives. These compounds have 5-HT 4 receptor antagonist activity.

Accordingly, the present invention provides a compound of formula or a pharmaceutically acceptable salt thereof: Rb CO-Y-Z VA Ra wherein:

X

1

-X

2 is NRz-CO or CR 4 where Rz an 4 are independently hydrogen or C 1 -6 alkyl; and/or -2wherein: X 1

-X

2 is NRz-CO or CR 1

IR

2

-CR

3

R

4 where Rz and R 1 to R 4 are independently hydrogen or C 1 6 alkyl; or

R

1 with R 3 togvLher are a bond; or R I/R 2 /R3/R 4 are joined to form C 3 6 polymethylene; Ra is hydrogen, halo, C 1 6 alkyl, amino, nitro or Cl..6 ailkyl; Rb is hydrogen, halo, C 1 6 alkyl or C 1 6 alkoxy; Y is 0Oor Nil; and Z is of sub-formula or

(CH

2 )q

-(CH

2 )rR

N

R

(a)

(CH

2

R

7

CH

2 (b)

-(CH

2 )n 3 -N~ 4 4 t(c) C;wherein n 1 is1, 2, 3or 4;n 2 is0, 1, 2, 3or4; n 3 is2, 3, 4or q qisO0, 1, 2or3; pisO0, 1 or 2; misO, 1 or 2; 0R 5 is hydrogen, C 1 12 alkyl, aralkyl, (CH 2 )z-Ri1o wherein z is 2 or 3 and R 10 is selected from cyano, hydroxyl, C 1 6 alkoxy, phenoxy, C(O)C 1 6 alkyl,

COC

6

H

5 CONRI IR 12

NR

1 1 C0R 12 S0 2 NRl 1

R

12 and NR 1 1 S0 2 Rl 2 wherein R 1 1 and R 12 are hydrogen Or C 1 alkyl;

R

6

R

7 and R 8 are independently hydrogen or C 1 6 alkyl; and

R

9 is hydrogen or C 1 10 alkyl; having 5-HT 4 receptor antagonist activity.

Examples of alkyt or alkyl containing groups include C1, 02, 03, 04, 05, 06, 07, 08, 09, C10, C1 or Ci 2 branched, straight chained or cyclic alkyl, as 7 WO 93/18027 PCT/GB93/00395 appropriate. C1-4 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 form is of formula

H-J

(d) wherein the dotted circle represents o or two double bonds in any position in the membered ring; H, J an independently represent oxygen, sulphur, nitrogen or carbon, provided at at least one of H, J and I is other than carbon; U represents nitr en or carbon.

Suita examples of are as described for X, Y and Z in EP-A-328200 .lrck Sharp Dohme Ltd.), such as an oxadiazole moiety.

Suitable examples of X 1

-X

2 when CR 1

R

2

-CR

3

R

4 include CH 2

-CH

2 and CH=CH. X 1

-X

2 is preferably NRz-CO, however, such as NH-CO or NEt-CO.

Ra is preferably hydrogen.

Rb is preferably hydrogen or halo, such as iodo.

Y is preferably O or NH.

J

1 WO 93/18027 PCT/GB93/00395 -4- When Z is of sub-formula n 1 is preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n 1 is preferably 1 when the azacycle is attached at a carbon atom, such as the 4-position when q is 2.

When Z is of sub-formula n 2 is preferably such that the number of carbon atoms between the ester or amide linkage is from 2 to 4 carbon atoms.

Suitable values for p and m include p m 1; p 0, m 1, p 1, m 2, p=2, m 1.

When Z is of sub-formula n 3 is preferably 2, 3 or 4.

R

8 and R 9 are preferably both alkyl, especially one of R 8 and R 9 is C 4 or larger alkyl.

Specific values of Z of particular interest are as follows: (i) N B N (iii) I NMe"Bu (iv) (v) K(vi) IIL. WO 93/18027 PCT/GB93/00395 N (vii) The invention also provides novel compounds within formula with side chains (iii), (vi) or (vii). In a further aspect, the piperidine ring in (ii) or (iii) may be replaced by pyrrolidinyl or azetidinyl, and/or the N-substituent in or (ii) may be replaced by C 3 or larger alkyl or optionally substituted benzyl.

In an alternative aspect, the N-substituent in formula or (ii) may be replaced by (CH2)nR 4 as defined in EP-A-501322 in respect of formula (I) and the specific examples therein.

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, a-keto glutaric, a-glycerophosphoric, and glucose-1-phosphoric acids.

Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula such as the compounds quatemised by compounds Rx-T wherein Rx is C 1 -6 alkyl, phenyl-C -6 alkyl or C5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of Rx include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide.

I

Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.

The compounds of the formula 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 or a salt thereof is herein referred to.

i WO 93/18027 PCT/GB93/00395 It will also be realised that the (CH2)n2 moiety in compounds of formula (I) wherein Z is may adopt an a or p or configuration with respect to the fused azabicyclic moiety.

The compounds of formula may be prepared by conventional coupling of the X 1

/X

2 moiety with Z. Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A and EP-A-36269 (Beecham Group EP-A-429984 (Nisshin Flour Milling Co.) and EP-A-328200 (Merck Sharp Dohme Limited). Reference is also made to EP-A-501322 (Glaxo Group Limited).

Aza(bi)cyclic side chain intermediates are known compounds or may be prepared according to the methods described in PCT/GB92/01519 and /01612 (SmithKline Beecham The compounds of the present invention are 5-HT 4 receptor antagonists and it is thus believed may generally )e 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, 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-HT 4 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).

WO 93/18027 PCT/GB93/00395 -7- It is believed that 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-HT 4 receptors, and hence that administration of a 5-HT 4 antagonist is of potential benefit in relieving a migraine attack.

The invention also provides a pharmaceutical composition comprising a compound of formula 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, injectabl, 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, p-? i ~IXljll WO 93/18027 PCr/GB93/00395 -8and 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 S WO 93/18027 PCT/GB93/00395 -9compound 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 th(i 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 of irritable bowe! 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 or a pharmaceutically acceptable salt thereof. In particular, the method comprises treatment of IBS or atrial arrhythmias and stroke.

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 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 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 50 mg/kg/day, more usually 0.0002 to 25 mg/kg/day.

No adverse toxicological effects are indicated within the aforementioned dosage ranges.

The invention also provides a compound of formula or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use as a 5-HT 4 receptor antagonist in the treatment of the disorders hereinbefore described.

-i I I

I

WO 93/18027 PCT/GB93/00395 The invention also provides the use of a compound of formula in the manufature of a medicament for use as a 5-HT 4 receptor antagonist in the treatment of the disorders hereinbefore described.

The following Examples illustrate the preparation of compounds of formula the following Descriptions illustrate the preparation of intermediates. It will be appreciated that any cr.,pound example wherein X is O may be prepared as the corresponding compound wherein Y is NH and vice versa.

examples X1/X 2 El H E2 H E3 H E4 H

H

E6 H

NH-CO

NEt-CO

CH

2

CH

2

CH=CH

NH-CO

NMe-CO WO 93/18027 PTG9/09 PCr/GB93/00395 11 Examples (cont.)

X

1 1-X 2 E7 E8 E9 Ell El12 E13 El14 E1 6 E17 E18 Ncpm-CO NEt-CO N Prn-CO NPri-CO

NH-CO

N Et-CO N H-CIO Ncpm-CO N Prn-CO

CHCH

3

CH

2

CH(CH

3 2

CH

2

CHR

2 pCHR 4 p cpm cyclopropylunethyl Rpand Rpare joined to form 04 polymethylene WO 93/18027 PCT/GB93/00395 -12- Example 1 (1-Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3H-benzimidazole-1carboxylate (El) A solution of (1-butyl-4-piperidyl)methyl 2-aminophenylcarbamate (Dlb), (2.90g, 0.0095 mole) in dichloromethane (50ml) with triethylamine was added to a stirred solution of trichloromethyl chloroformate (1.88g, 1.15ml, 0.0095 mole) in dichloromethane (50ml) at 500C under nitrogen.

After 1 h the solution was allowed to warm to room temperature and left for a further 1h. The solution was treated with dilute HCI acid (50ml) and the white solid produced was filtered off. The solid was suspended in 10% Na 2

CO

3 (aqueous) solution (50ml) and extracted with dichloromethane (3x100ml).

The organic extracts were combined, dried (Na 2 SO4) and concentrated in vacuo to afford the title compound (El) as an off white solid (2.20g, 70%) mp 130-1320C.

1 H NMR 250MHz (CDC 3 5:9.85 (br s, 1H), 7.92 (dd, 1H), 7.13-7.34 (m, 3H), 4.45 2H), 3.05-3.20 2H), 2.40-2.55 2H), 1.90-2.20 1.35-1.70 6H), 1.02 3H).

MS (El) MH+ 332.

Example 2 (1-Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-ethylbenzimidazole-1carboxylate hydrochloride (E2) To a stirred solution of (1-butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3Hbenzimidazole-1-carboxylate (El, 0.5g, 0.0015 mole) in dry DMF under nitrogen at room temperature was added, portionwise, sodium hydride as an 80% dispersion in mineral oil (45mg, 0.0015 mole). After hydrogen evolution had subsided (90min), the solution was treated with ethyl iodide (0.235g, 0.12ml. 0.0015 mole) and left to stir overnight. The resulting solution was basified via addition of 10% aqueous Na 2

CO

3 solution (30 ml) and extracted into ethyl acetate (3x50ml). The organic extracts were combined WO 93/18027 PCT/GB93/00395 -13and dried (Na 2

SO

4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting initially with chloroform followed by chloroform/ethanol (95:5) to afford the free base of the title compound. This was converted to the hydrochloride salt, which was recrystallised from isopropyl alcohol/acetone to afford the title compound (E2) as a white crystalline solid (0.43g, 80%) mp 190-1920C.

HCI Salt:- 1H NMR 250MHz (CD30D) 8: 7.94 (dd, 1H), 7.20-7.40 3H), 4.45 2H), 4.01 2H), 3.65-3.77 2H), 3.00-3.23 4H), 2.13-2.30 (m, 2H), 1.70-1.90 4H), 1.40-1.60 3H), 1.37 3H), 1.08 3H).

Example 3 2-Piperidylethyl 2,3-dihydroindole-l-carboxylate hydrochloride (E3) 2,3-Dihydroindole-l-carbonyl chloride (0.75g, 4.13 mmole) was dissolved with i stirring in dichloromethane (20ml) and triethylamine (0.632ml, 4.54.mmole) was added, followed by 2-piperidineethanol (0.547 ml, 4.13 mmole). The mixture was then stirred at room temp. After 72h, the reaction mixture was washed with water, the organic layer was then dried (Na 2

SO

4 and evaporated under reduced pressure to give a pink oil. The oil was purified by silica gel chromatography using pentane:EtOAc (3:1 to 5:4) as eluant to give a colourless oil (0.355g, 33%) which was converted to its hydrochloride salt (E3) mp 175-1760C.

HCI Salt:- 1 H NMR (250MHz) (DMSO) 8: 7.72 (br s,1H), 7.20(dd,2H), S6.98(t,1H), 4.53(s,2H), 4.08(t,2H), 3.35-3.52(m,4H), 2.90-3.05(m,4H), 1.60- 1.95(m,5H), 1.48(m,1H).

1h, Pk WO 93/18027 PCT/GB93/OO395 Example 4 2-Piperidylethyl Indole-1 -carboxylate (E4) -Pipenidylethyl 2,3-dihydroindole-1 -carboxiate hydrochloride (E3) (0.1 00g, 0.337mole) was dissolved in chloroform (l0mI) with stirring. DDQ (0.084g, 0.37Ommole) was then added and the mixture was heated to reflux. After 6h, the reaction mixture was allowed to cool. The reaction mixture was then diluted with CHCI 3 and washed with saturated potassium carbonate solution.

The aqueous layer was then extracted with chloroform, and the combined organic layers Were dried (Na 2 SO4) and evaporated to give a yellow solid, which was purified by silica gel chromatography, using petrol:EtOAc as eluant to give the title compound (E4) as a pale yellow oil (0.036g 41%) which was converted to its hydrochloride salt mp 185-1 8600.

Free base:- 1 H NMR (250MHz)(CDC1 3 8.22(d,1 7.52-7.68(m,2H), 7.20-7.41 6.62(d,1 4.54(t,2H), 2.80(t,2H), 2.50(t,4H), 1.52- 1 .68(m,4H), 1 .45(m,2H).

Examples 5 -12 Using analogous methods to those described for the preparation of Examples :ind 2 the following compounds were prepared: 2'-r'i peridylethyl.2,3-dihydro-2-oxo-3H-benzimidazole-1 -carboxyiate hydrochloride mp 1 72-30C Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-methylbenzi mldazole-1 carboxylate hydrochloride (E6) mp 184-1 8700

IL.

WO093/18027 PCr/GB93/00395 (1 -Butyl-4-piperldyl)methyl 2,3-dihydro-2-oxo-3-cyclopropyl methylbenz mid azole-1 -carboxylate hydrochloride (E7) mp 183-50C 2-Pi perid yl ethyl 2,3-d ihydro-2-o xo-3-ethyl benzim id azolIe-1 -carboxvl ate hydrochloride (E8) mp 176-1780C (1 -Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-propylbenzmidazole-1 carboxylate hydrochloride (E9) mp 190-1 9200 (1 -Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-isopropylbenzimidazole- 1 -carboxylate hydrochloride (El 0) mp 155-1570C 1-Azabicyclo[4.4.O]decan-4-ylmethyl 2,3-dihydro-2-oxo-3Hbenzimidazole-1-carboxylate hydrochloride (El 1) 206-2080C 1 -Azablcyclo[4.4.O]decan-4-yl methyl 2,3-dihydro-2-oxo-3ethyl benzimidazole-1 -carboxylate hydrochloride (El12) mp 180-1830C i.

WO093/18027 PCr/GB93/00395 -16- Example 13 (I -Butyl-4-piperidyl)methyl 2,3-dhydro-2-oxo-3H-benzmdazole-1 carboxamide hydrochloride (E13) A mixture of N-(1-butyl-4-pipendyl)methyl-N-(2-aminophenyl)urea (D2b, 0.01 5mole) and triethylamine (2.5m1) in dichloromethane (1 Q0mI) was added to a solution of diphosgene (2.93g, 1 .8m1, 0.01 5mole) in dichioromethane under nitrogen. After addition was complete (1 hour) the solution was treated with 5M HCI (1 O0ml). The precipitate was filtered off and dried to afford the title compound (El 3) as a white solid mp 240-2430C.

Examples 14 and The follo wing compounds were prepared by an analogous procedure to that described for Example 2.

1. (1 -Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3cyclopropylmethylbenzimidazole-1 -carboxamide hydrochloride (El 14) mp 175-177 0

C

(1 -ButyI-4-iniperidyI)methyI 2,3-dihydro-2-oxo-3-propylbenzimidazole-1 carboxamide hydrochloride mp1 35-136 0

C

Examplesl16 -18 The following compounds w.prepared by an analogous procedure to that described for Example 3.

(1 -Butyl-4-piperdyl)meth-,r ,3-dihydro-3-methylindole-l -carboxylate hydrochloride (El 6) mp 173-1750C WO 93/18027 17- PC/GB93/00395 17 2-Piperidylethyl 2,3-dihydro-3,3-dimethylindole-1-carboxylate hydrochloride (E17) 174-1760C (1-Butyl-4-piperidyl)methyl 1,2,3,4-tetrahydrocarbazole-9-carboxylate oxalate (E18).

mp 187-189 0

C

Preparation of N-(1-nbutyl-4-piperidyl)methylamine A stirred solution of isonipecotamide (70g, 0.55 mole) and 1-bromobutane (58.8 ml, 0.55 mole) in ethanol (700 ml) was treated with anhydrous potassium carbonate (152g, 1.10 mole) and heated under reflux for 3h. The mixture was allowed to cool, then filtered and the filtrate concentrated under vacuum. The residual oil was dissolved in chloroform (400 ml) and washed with water (1 x 300 ml), then dried (Na 2

SO

4 and concentrated under vacuum to leave a yellow oil (77.5g). This oil was mixed thoroughly with phosphorus pentoxide (75g) and the mixture heated at 160-1800C under nitrogen for Ir with gentle stirring. The reaction mixture was allowed to cool, then treated j 25 with water (500 ml). When the solid mass had dissolved, the solution was basified by addition of solid K 2

CO

3 and extracted with ethyl acetate (2x400 ml). The combined extracts were dried (Na 2 SO4) and concentrated in vacuo to leave a brown oil (78g). This was dissolved in dry ether (400 ml) and added dropwise over 30 minutes to a stirred suspension of lithium aluminium i 30 hydride (25g, 0.66 mole) in ether (200ml) at 00C under nitrogen. When ~addition was complete, the mixture was allowed to warm upto room temperature and stir for 18h. It was re-cooled to 00C and treated cautiously with water (25ml), 10% NaOH solution (25 ml) and water again (75ml). The mixture was filtered through kieselguhr and the filtrate concentrated in vacuo to leave a brown oil, which was distilled under vacuum to afford the title compound as a colourless oil (66g, 71%) bp 96-990C at 3 mm Hg.

'H NMR (CDCI 3 WO 93/18027 18 PCT/GB93/00395 2.90-3.02(m,2H), 2.58(d,2H), 2.25-2.38(m,2H), 1.65-2.00(m,4H), 1.08- 1.58(m,9H), 0.92(t,3H).

Preparation of (1-nbutyl-4-piperidinyl)methanol A mixture of ethyl isonipecotate (102g, 0.65 mole) and 1-bromobutane (72 ml, 0.67 mole) in ethanol (1.2L) was treated with anhydrous potassium carbonate (180g, 1.3 mole) and heated under reflux for 2h. The mixture was allowed to cool and then filtered through kieselguhr. The filtrate was concentrated in vacuo to leave a yellow oil, which was dissolved in ether (300 ml) and added dropwise over 20 minutes to a stirred suspension of lithium aluminium hydride 1.3 mole) in either (500 ml) at 0oC under nitrogen. The mixture was stirred at room temperature for 18h, then cooled to 0oC and treated with water (50 ml), 10% NaOH solution (50ml) and water (150ml). The mixture was filtered through keiselguhr and the filtrate concentrated under vacuum to leave a pale yellow oil, which was distilled to afford the title compound as a colourless oil (88.5g, 80%) bp 102-1080C at 0.1 mm Hg.

1H NMR (CDCI 3 3.48(d,2H), 2.88-3.03(m,2H), 2.25-2.38(m,2H), 2.10(br s, 1H), 1.66- 2.00(m,4H), 1.17-1.60(m,7H), 0.90(t,3H) i i i WO 93/18027 PCT/GB93/00395 19- Descriptions Description 1 (Intermediate for Examples 1 and 2) a) (1-Butyl-4-piperidyl)methyl 2-nitrophenylcarbamate A stirred suspension of 2-nitrophenylisocyanate (3.60g, 0.22mole) in dry toluene (50ml) at room temperature under nitrogen was treated with (1-butyl- 4-piperidyl)methanol (2.00g, 0.0118mole). The mixture was heated under reflux for 4h with stirring. The resulting solution was concentrated in vacuo to afford the crude title compound as an orange/brown oil (3.40g. 1 H NMR (CDC13) 5:9.85 1H), 8.57 (dd, 1H), 8.23 (dd, 1H), 7.60-7.70 (m, 1H), 7.10-7.18 4.08 2H), 2.94-3.06 2H), 2.30-2.40 2H), 1.86-2.04 2H), 1.65-1.84 3H), 1.30-1.60 6H), 0.93 3H).

b) (1-Butyl-4-piperidyl)methyl 2-aminophenylcarbamate A solution of (1-butyl-4-piperidyl)methyl 2-nitrophenylcarbamate (3.00g, 0.009 mole) in ethanol (100ml) was hydrogenated at atmospheric pressure over Pd/C catalyst. The catalyst was removed and the resulting solution concentrated in vacuo to afford the title compound as pale yellow solid (2.40g, quantitative).

1 HNMR 250MHz (CDC3) 5:7.20-7.35 1H), 6.95-7.10 1H), 6.60-6.90 3H), 4.03 2H), 3.75 (br s, 2H), 2.93-3.10(m, 2H); 2.30-2.45 2H), 1.90-2.10 2H), 1.17-1.83 9H), 0.90 3H).

Description 2 (intermediate for Example 13) a) N-(1-Butyl-4-piperidyl)methyl-N'-(2-nitrophenyl)urea A solution of 2-nitrophenylisocyanate (3.00g, 0.183mole) in dichloromethane (50ml) was treated with a solution of (1-butyl-4-piperidyl)methylamine (3.11g, 0.183mole) in dichloromethane (50ml) and the mixture stirred at room temperature for 16 hours then heated under reflux for 1 hour. The solvent was removed in vacuo and the residue purified by column chromatography on st WO 93/18027 PC'/GB93/00395 silica gel using CHCI3/ MeOH as eluant. The product was isolated as a yellow solid.

1 H NMR (CDC13) 9,80 (br s, 1 8.65 1 8.15 1 7.55 1 H), 7.02 1 5.60 (br s, 1 3.20 2H), 2.92 (br d, 2H), 2.20-2.35 2H), 1.20-1.97 11H), 0.90(t, 3H) b) N-(1-Butyl-4-piperidyl)methyl-N'-(2-aminophenyl)urea A solution of N-(1-butyl-4-piperidyl)methyl-N'-(2-nitrophenyl)urea (5.4g, 0.0163mole) in ethanol (200ml) was hydrogenated over 10% Pd/C at room temperature and pressure. After 2 hours the catalyst was removed by filtration through keiselguhr and the filtrate concentrated in vacuo to give a white solid.

1 H NMR (CDCI3) 8 6.98-7.17 2H), 6.92 1H), 6.67-6.78 2H), 5.25 (br t, 1 3.95 (br s, 2H), 3.05 2H), 2.87 (brd, 2H), 2.2-2.35 2H), 1.15- 1.95 11H), 0.90 3H).

4 RECEPTOR ANTAGONIST ACTIVITY 1) Guinea pig colon Male guinea-pigs, weighing 250-400g are used. Longitudinal musclemyenteric 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% CO 2 in 0 2 and maintained at 37 0 C. In all experiments, the Krebs solution also contains Smethiothepin 10- 7 M and granisetron 10-6M to block effects at 5-HT 1 5-HT 2 and 5-HT 3 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% 9 M approx). The tissue is then alternately dosed every with this concentration of 5-HT and then with an approximately equi-effective T If- WO 93/18027 -21 PCT/GB93/00395 concentration of the nicotine receptor stimulant, dimethylphenylpiperazinium (DMPP). After obtaining consistent responses to both 5-HT and DMPP, increasing concentrations of a putative 5-HT 4 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, plC50 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-HT 4 receptor antagonist.

Compounds were generally active in the range of concentrations of the order of plC50 6.5 or more, E2, E6 and E7 showing particularly good activity.

2) Rat oesophagus Rat oesophageal tunica muscularis mucosae is set up according to Baxter et.

a. 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 370C. All experiments are performed in pargyline pretreated preparations (100pM for 15 min followed by washout) and in the presence of cocaine (30p.M). Relaxant responses to 5-HT are obtained after pre-contracting the oesophagus tissue with carbachol (3p.M).

I I

*I

21a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

0 e H 0 0 0 0 i 000400 oo 951116,pAopcr\dab,35718.spe,21

Claims (25)

1. A compound of formula or a pharmaceutically acceptable salt thereof Rb /CO-Y-Z SN\ R a wherein: X 1 -X 2 is NRz-.CO or CR 1 R 2 -CR 3 R 4 where Rz and Rl to R 4 are independently hydrogen or C 1 6 alkyl; or R 1 with R 3 together are a bond; or R /2R/4are joined to form C 3 6 polymethylene; I'll"Ra is hydrogen, halo, C 1 6 alkyl, amino, nitro or Cl. 6 alkyl; Rb is hydrogen, halo, C 1 6 alkyl or Cl- 6 alkoxy; Y is 0orNH; and Z is of sub-formula or (CHH). R (a) CH 2 -(CH 2 2N (b) 1? -(CH 2 -N~R (c) wherein nl is 1, 2, 3or 4; n 2 is0, 1,2, 3or 4; n 3 is 2,3, 4or q isO0, 1, 2or 3; pis 1or2; misO, 1or 2; R 5 is hydrogen, Cl- 12 alkyl, aralkyl, (CH 2 )z-R1o wherein z is 2 or 3 and R 10 is selected from cyano, hydroxyl, Cl. 6 alkoxy, phenoxy, C(O)Cl 1 6 alkyl, R COC 6 1H 5 CONRl 1 R 12 NR 1 1 C0R 12 S0 2 NRl lR 12 and NRI. lS0 2 Rl 2 wherein R1 1 and R 12 are hydrogen or C 1- alkyl; R 6 R 7 and R 8 are independently hydrogen or Cl-6 alkyl; and ft- -23- R 9 is hydrogen or C 1 1 0 alkyl; having 5-HT 4 recentor antagonist activity.

2. A compound according to claim 1 wherein Ra is hydrogen.

3. A compound according to claim 1 or 2 wherein Rb is hydrogen or halo.

4. A compound according to claim 1, 2, or 3 wherein Xl-X 2 is CH 2 -CH 2 or CH=CH. whri A compound according to claim 1, 2, 3 or 4 wherein X 1 I-X 2 is NRz-CO weenz is as defined in claim 1.

6. A compound according to any one of claims 1 to 5 wherein Y is Nil

7. A compound according to any one of claims i to 6 wherein Z is of sub-formula and (CH2)nl is attached at a carbon atom of the azacycle.

8. A compound according to claim 7 wherein Z is N-substituted 4-piperidylmethyl.

9. A compound according to claim 8 wherein the N-substituent is C 2 1 2 alkyl, or optionally substituted benzyl.

10. (1 -Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3H-benzimidazole- 1- carboxylate.

11. (1-B utyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-ethylbenzimidazole- 1- carbroxylate. 4 4t12. 2-Piperidylethyl 2,3-dihydroindole-1-carboxylate.

13. 2-Piperidylethyl indole-l1-carboxylate.

14. 2-Piperidylethyl 2,3-dihydro-2-oxo-31i-benzimidazole-1-carboxylate. Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-methylbenzimidazole- 1- carboxylate.

16. (1 -Butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-cyclopropylmethyl- benzimidazole-l1-carboxylate.

17. 2-Piperidylethyl 2,3-dihydro-2-oxo-3-ethylbenzimidazole-l1-carboxylate. 'AT 0~ 24

18. (1-B utyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-propylbenzimidazole- 1- c,-.rboxylate.

19. (1 -Butyl-4-pipe-ridyl)methyl 2,3-c.*,hydro-2-oxo-3-isopropylbenzimidazole- 1- carboxylate. 1 -Azabicyclo[4.4.0]decan-4-ylmethyl 2,3-dihydro-2-oxo-3H-benzimidazole- 1 -carboxylate.

21. 1 -Azabicyclo[4.4.0]decan-4-ylmethyl 2,3-dihydro-2-oxo-3- ethylbenzimidazole- 1 -carboxylate.

22. (1-B utyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3H-benzimidazole- 1- carboxamide.

23. (1 -B utyl-4-piperidyi)methyl 2,3-dihydro-2-oxo-3- cyclopropylmethylbenzimidazole- 1 -carboxamide.

24. (1-B utyi-4-piperidyl)methyl 2,3-dihydro-2-oxo-3-propylbenzimidazole- 1- carboxamide.

25. (1 -Butyl-4-piperidyl)methyl 2,3-dihydro-3-methylindole-l1-carhoxylate.

26. 2-Piperidylethyl 2,3-dihydro-3,3-dimethylindole-l1-carboxylate.

27. (1 -Butyl-4-piperidyl)methyl 1 ,2,3,4-tetrahydrocarbazole-9-carboxylate.

28. A pharmaceutically acceptable salt of a compound according to any one of claims 10 to 27.

3029. A process for preparing an ester or amide compound according to claim 6, which comprises reacting an appropriate X 1 -X 2 containing acid derivative with an appropriate alcohol or amine wherein X 1 -X 2 is defined in claim 1. 30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, and a pharmaceutically acceptable carrier. a i i 25 31. A method for the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders which comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 28 to a subject in need thereof. 32. A method according to claim 31, for use in the treatment of irritable bowel syndrome. 33. A method according to claim 31, for use in the treatment of emesis; the nausea and gastric symptoms of gastro-oesophagal reflux disease and dyspepsia; atrial arrhythmias and stroke; anxiety; migraine. 34. Compounds of formula having 5-HT 4 receptor antagonist activity or processes for their preparation, substantially as hereinbefore described with reference to the Examples. DATED this 17th day of November, 1995 SmithKline Beecham plc By Its Patent Attorneys DAVIES COLLISON CAVE o w of ft if Ii 951116,p:\oper\dab,35718.spe,25 L i INTERNATIONAL SEARCH REPORT International Application No PCT/GB 93/00395 0 1. CLASSFCATION OF SUBJECT MATTER (if several classification symnbols apply, Indicate a1l) 6 According to intemnationsal Patent ClassiIication (IPC) or to both National Classification and IPC Int.C1. 5 C07D401/12; C07D455/02; A61K31/46 IT. FVEWS SEARCHED Minimum Documentation Saarchedl Classification System Classification Symbols Int.Cl. 5 C07D Documentation Search~ed other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searchedl A EP,A,0 309 423 (ISTITUTO DE ANGELI) 1,10-15 29 March 1989 cited in the application see claims A EP,A,0 247 266 (BEECHAM) 1,10-15 2 December 1987 cited in the application see page 31 page 54; claims *Special catolgories of cited d omn"s *:10 IT* later document published after the international fling date opriority date and rot in conflict with the apication but 'A0 documsent deffinng the goaal state of the art which is no sited to unrtand the principle or theory usieiizthe considered to be of patcular relevance neto 'r earlier document but published on or after the Interuatonal nr document of partcular relevance; the claimed In-etios filing date cannot be considered novel or cannot be considered to 'V document which may throw doubts on priority claim(s) or Involve an inventive step which is cited to establish the publication date of another 'Y document of particular relevance; the claimed Invention citation or other special reason (as specified) nnot be considered to involve an inventive step when the O0' document referring to an oral disclosure use, exhibition or document is combined with one or more other such docu- other mens ments. such combination being obvious to a person skilled 'P1 document published prior to the International filing date but I h r Lote than the priority date claimed W document member of the same patent fatmly IV. CERTIFICATION Date of the Actual Compltion of the international Smrch Date of Mailing of this International Search Report -22 JUNE 1993 1 3 0. 06, 3 International Searching Authority Signature of Authorized Officer EUROPEAN PATENT OFFICE FRANCOIS J .0. !u PCTISjEWU0 (amn sami (Jimy Ifto ft ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. GB 9300395 SA 71217 This a&oe= lists the patent family members relating to the patent documents cited in the abovementioned internional search report. The numbers wre as contained in the European Patent Office EDP file on The European Patent Office.i in no way liable For them particulars which ame merely given for the purpose of information. 22/06/93 Patent document Publication Patent family Publication cited in search report date members) date j EP-A-0309423 29-03-89 AU-A- JP-A- SU-A- 2237888 1106882 1676451 23-03-89 24-04-89 07-09-91 EP-A-0247266 02-12-87 AU-B- 635024 11-03-93 AU-A- 5514790 08-11-90 AU-A- 6712187 09-07-87 OE-A- 3687980 15-04-93 JP-A- 62252764 04-11-87 'W For more details about this annex see Official Journal of the European Patent Office, No. 12132