CA2131381A1 - Nitrogen containing heterocyclic compounds useful as pharmaceuticals - Google Patents
Nitrogen containing heterocyclic compounds useful as pharmaceuticalsInfo
- Publication number
- CA2131381A1 CA2131381A1 CA002131381A CA2131381A CA2131381A1 CA 2131381 A1 CA2131381 A1 CA 2131381A1 CA 002131381 A CA002131381 A CA 002131381A CA 2131381 A CA2131381 A CA 2131381A CA 2131381 A1 CA2131381 A1 CA 2131381A1
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- alkyl
- compound according
- hydrogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preventing Corrosion Or Incrustation Of Metals (AREA)
Abstract
Compounds of formula (I) and pharmaceutically acceptable salts thereof and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders.
Description
~W O 93/18027 ' ~ 3 ~ 1 PCT/GBg3~00395 This invention rebtes to novel compounds having pharmacological activity, to a process for ~heir preparation and to their use as pharmaceuticals.
European Joumal of Phamlacology 146 (1988),187-188, and Naunyn-Schmiedeberg's Arch. Pharmacoî. (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 ~HT3 receptor antagonist, acts as an 10 antagonist at this receptor.
WO 91/16045 (SmithKline and French Laboratories Limited) describes lhe use of cardiac 5-HT4 receptor antagonists in the treatment ot atrial arrhythmias and stroke.
EP-A-5013æ (Gbxo Group Limited) describes indole derivatives having ~HT4 antagonist activity.
EP-A-309423 (Istituto de Angeli S.p.A) and EP-A-247266 (Beecham Group 20 p.l.a~) describe 5-HT3 rec~ptor antagonists derived from a benzimidæolone or indoline nwleus.
A class of novsl, structurally distinct compounds has now been discovered, which compounds include benzimidæolone derivatives. These compounds 25 have ~HT4 receptor antagonist activity.
Accordingly, the present invention provides a compound of forrnula (I), or a pharmaceutically acceptable salt thereof:
Rb CO Y-Z
~ N, Ra (I) wherein:
X1-X2 is NRz-CO or CR1 R2-CR3R4 where Rz and R1 to R4 are independenlly hydrogen or C1-6 alkyl; and/or ~r~r~ .,~ . ~,~..~..-s ~
wos3/l8027 ~i " 13 ~ i 2 - PCI`/GB93/003 R1/R2 and R3/R4 together are a bond and/or R1/R2/R3/R4 are joined to form C3-6 pOlymethylene;
Ra is hydrogen, halo, C1 6 alkyl, amino, nitro or C1 6 alkyl;
Rb is hydrogen, halo, C1 6 alkyl or C1 6 alkoxy;
5 YisOorNH;
Z is of su~formula (a), (b) or (c):
(C~2)~
-(CH2)n~_ I R6 N R
(a) (CH~ R/
(b) -(CH2) 3 --N~R8 (c) wherein n1 is1,2,30r4;n2isO,1,2,30r4;n3is2,3,40r~;
qisO, 1,20r3;pisO, 1 or2;misO, 1 or2;
Rs is hydrogen, C1 -12 alkyl, aralkyl or Rs is (CH2)z-R1 o wherein z is 2 or 3 and R10 is selected from cyano, hydroxyl, C1-6 alkoxy, phenoxy, C(O)C1 -6 alkyl, COC6Hs, -CONR1 1 R12, NR11 COR1 2~ S02NR1 1 R12 or NR1 1 S02R1 2 wherein R11 and R12 are hydrogen or C1 -6 alkyl;
and R6, R7 and R(8 are independently hydrogen or C1 6 alkyl; and Rg is hydrogen or C1 10 alkyl;
or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere;
having ~HT4 receptor antagonist activity.
Examples of alkyl or alkyl containing groups include C1 . C2, C3, C4, Cs, C6, C7, Cg, Cg, C1 0, C1 1 or C1 2 branched, straight chained or cyclic alkyl, as ~vo 93/18027 ~ ~ ~ 1 3 ~ ~ PCI`/GB93/0039 appropriate. C1 4 alkyl groups include methyl, ethyl, n and is~propyl, r~, iso, sec and t~ butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ~ycloheptyl and cyclooctyl.
5 Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C1-6 alkyl and C1 6 alkoxy.
Halo includes fluoro, chlsro, bromo and iodo.
10 A suitable bioiscstere for the amide or ester linkage containing Y in formula (I), is of formula (d):
H t llju 1~ (d) 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 20 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 Ud.), such as an oxadiazole moiety.
Suitable examples of X1 -X~ when CR1 R2-CR3R4 include Cl 12-CH2 and CH=CH. X1-X2 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.
3$1 WO 93/18027 PCI /GB93/003~
When Z is of sub-formula (a), n1 is preterably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n1 is preterably 1 when the azacycle is attached at a carbon atom, such as the 4-position when q is 2.
5 When Z is of su~tormula (b), n2 is preferably such that the number of carbon atoms between the ester or amide linkage is from 2 to 4 carbon atoms.
Suitable values tor p and m include p = m = 1; p z 0, m = 1, p = 1, m = 2, p=2,m=1.
~0 When Z is ot sub formula (c), n3 is preferably 2, 3 or 4.
R8 and Rg are preferably both alkyl, especially one of R8 and Rg is C4 or larger alkyl.
Specific values of Z of particular interest are as follows:
~/--\ n ~N Bu (j) /\CN /\(~ (ii) ~` N~ (iii) ~NNb Bu (iv) \~N~J (v) ~N/\I
~ (vi) 3 ~ 1 ~vo 93/l8027 pcr/GB93/oo3ss ~ f~
/~N~J (vii) The invention a~so provides novel compounds within formula (I) ~th side chains (i), (ii), (iii), (iv), (v), (vi) or (vii). In a further aspect, the piperidine ring in (i), (ii) or lii) may be replaced by pyrrolidinyl or azetidinyl, and/or the 5 N-substituent in (i) or (ii) may be replaced by C3 or larger alkyl or optionally substituted benzyl.
în an altemative aspect, the N-substituent in formula (i) or (ii) may be - r~pbced by (CH2)nR4 as defined in EP-A-501322 in respect ot formula (I) 10 and lhe specitic examples therein.
The pharmaceutically acceptable salts of the compounds ot the formula (l) include acid addition sal~s with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric æids and pharmaceutically 15 acoep~e organic acids such as acetic, ta~taric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric, a~lycerophosphoric, and ~lucose-1-phosphoric acids.
Examples of pharmaceutically acceptable salts include quaternary derivatives 20 of the compounds of formula (I) such as the compounds quatemised by compounds RX-T wherein Rx is C1-6 alkyl, phenyl-C1 6 alkyl or Cs 7 cycloalkyl, and T is a radical corresponding to an anion of an acid; Suitable examples Of Rx include methyl, ethyl and ~ and is~propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide 25 and iodide.
Examples of pharmaceutically acceptable salts also include intemal salts SUch as N-oxides.
30 The compounds of the formula (I), their pharmaceutically acceptable salts, (indudin~ quatemary derivatives and N-oxides) may also form pharmaceuticall~ acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.
WO 93/18027 PCI`/GB93/003,~.
n will also be realised that the (CH2)n2 moiety in compounds of formula (I) wherein Z is (b), may adopt an a or ~ or configuration with respect to the ~used azabicyclic moiety.
5 The compounds of formub (I) may be prepared by conventional coupling of the X~/X2 mdety with Z. Suitable methods are as descnbed in GB 2125398A
(Sandoz Limited), GB 1593146A and EP-A-36269 (Beecham Group p.l.c.), EP-A~29984 (Nisshin Fbur Milling Co.) and EP-A-328200 (Merck Sharp &
Dohme Limited). Reference is also made to EP-A-501322 (Glaxo Group 10 Limited).
Aza(bikyclic side chain intermediates are known compounds or may be prepared according to the methods described in PCT/GB92/01519 and /01612 (SmithKline Beecham p.l.c.).
The compounds of the present invention are ~HT4 receptor antagonists and ;t is thus believed may generally be used in the trsatment or prophylaxis of ~astrointestinal disorders, c~diovascular disorders and CNS disorders.
20 They are of potential interest in the treatment ot irntable bowel syndrome ~IBS), in particular the diarrhoea aspects ot IBS, i.e., these compounds block 1he ability of 5-HT to stimulate gut motility via activation ot enteric neurones.
In animal mode~ of IBS, this can be conveniently measured as a reduction of the rate of detaecation. They are also ot potential use in the treatment of 25 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 u$e in the treatment of the nausea and gastric sym; ~ms 30 of gastro-oesophageal reflux disease and dyspepsia. Antiemetic activity is determined in known animal models of cytotoxic-agenVradiation induced emesis.
Specific cardiac ~HT4 receptor antagonists which prevent atrial fibrillation 35 and other atnal arrhythmias associated with ~HT, would also be expected to redwe occurrence of stroke (see A.J. Kaumann 1990, Naumyn-Schmiedeberg's Arch. Pharmacol. 342j 619-622, tor appropriate animal test method).
3 8 i ~vo 93/18027 7 PCI`/GB93/00395 It is believed that platelet-derived ~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 hean the most common source of embolic material. Of particular concem is the trequency of embolism associatcd with atrial fibrillation.
Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 10 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 ot headache (Sachs, 1985, Migraine, Pan 15 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 ~tal., 1976, Headache 16, 160-167). It is believed that a migraine, including the prodomal phase and the associated ;ncreased levels of cydic AMP are related to stimulation of ~HT4 receptors, and hence 20 that administration ot a 5-HT4 antagonist is of potential benefit in relieving a migraine attack.
The invention also provides a pharmaceutical composition compnsing a compound of forrnula (I), or a pharmaceutically acceptable salt thereof, and a 25 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 suchmay be in the form of tablets, capsules, oral liquid preparations, powders, 30 granules, lozenges, reconstitutable powders, nasal sprays, suppositories, injectable and infusable solutions or suspensions. Sublingual or transdermal administration is also envisaged Orally administrable compositions are preferred, since they are more convenient for general use 35 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, ~r~ sr ~.~
wo 93/18027 ~ ~ 3 ~ 8 - PCI/GB93/003,!~,$
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 celluhse, mannitol, lactose and other similar 5 agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and sta ch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.
Suitable pharmaceutically acceptable wetting agents include sodium lauryl 10 sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, synups, 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 a-~ditives such as su~spending agents, for example sorbitol, syrup, methyl 15 cellulose, gelatin, hydroxyethylcellubse, carboxymsthylcellulose, aluminium stearate gel or hydrogenated edibb fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionatsd coconut oil, oily esters such as esters of glycerine, propybne glycol, or ethyl alcohol;
20 preservatives, for example methyl or propyl ~hydroxybenzoate or sorbic acid, and if desired conventional tlavouring or colouring agents.
Oral liquid pr~parations are usually in the form of aqueous or oily suspensions, solutions, emulsions, synups, or elixirs or are presented as a dry 25 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), prsservatives, and flavouring or colouring agents.
30 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 tillers. Such operations are, of course, conventional in the art.
35 For parenteral administration, fluid unit dose forms are prepared containing a compound ot 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 3 8 l '`Y~ 93/18027 PCI/GB93/00395 compound in a vehicle and 1ilter 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 5 into 1he 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 10 the sterile vehicle. Advantageously, a su factant or wetting agent is included in lhe composition to facilitate uniform distribution of the compound ot the invention.
The invention further provides a method of treatment of irritable bowel 15 syndrome, gastro-oesophagal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine in mammals, such as humans, which compnses the administration of an effective amount of a compound of the formula (I) or a phal maceutically acceptable salt thereof. In particular, the method comprises treatment of IBS or at~ial arrhythmias and stroke.
An amount effective to treat the disorders hereinbefore described depends on the relative e~lcacies 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 25 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 ~r 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50 mglkg/day, more usually 0.0002 to 25 mg/kglday.
30 No adverse toxico!ogical effects are indicated within the aforemen~ioned dosage ranges.
The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in 35 particular for use as a 5-HT4 receptor antagonist in the treatment of the disorders hereinbefore described.
WO 93/18027 i~ 3 81 1 o PCI~/GB93/003g~
The invention also provides the use of a compound of formula (I) in the manu~acture of a medicament ~or use as a ~HT4 receptor antagonist in the treatment ot the disorders hereinbefore described.
5 ~he folbwing Examples illustrate the preparation ot compounds of formula (I);
the folbwin~ Descriptions i~lustrate the preparation of interrnediates. It will be appreciated that any compound example wherein X is O may be prepared as lhe conespondin~ compound wherein Y is NH and wce versa.
Examples Ra Rb X1/X2 Y Z
E1 H H NH-CO () (i) E2 H H NEt-CO O (i) E3 H H CH2CH2 0 (iii) E4 H H CH=CH O (iii) E5 H H NH-CO O (iii) E6 H H NMe-CO O (i) 38~
PCr/GBs3/003ss Vo 93/18027 - 1 1 -Examples (cont.) Ra Rb X1/X2 Y Z
E7 H H Ncpm-C0 0 (i) E8 H H NEt-C0 0 (iii) E9 H H NPrn-C0 0 (i) E10 H H NPri-C0 0 (i) E11 H H NH-C0 0 (~i) E12 H H NEt-C0 0 (vi) E13 H H NH C0 NH (i) E14 H H Ncpm-C0 NH (i) E15 H H NPrn-C0 NH (i) E16 H H CHCH3CH~ 0 (i) E17 H H CH(CH3)2CH2 ~i) E18 H H CHR2pcHP~4p 0 (i) 35 cpm - cyclopropylmethyl R2p and R4p are joined to ~orm C4 polyme~hylene WO93/18027 ~ 1381 pcr/GBs3/oo3~
Example 1 (1-Butyl4-plperld~l)methyl 2,3 dlhydro-2-oxo~3H~benzlmldazole-1-S ca-boxylate (E1) ~ -A solution of (1 -butyl-4piperidyl)methyl 2-aminophenylcarbamate (D1 b), (2.909, O.OO9S mole) in dichbromethane (SOml) with triethylamine (1.5ml) was added to a stirred solution of t ichbromethyl chlorotormate (1.889, 10 1.15ml, O.OO9S mole) in dichloromethsne (SOml) at 50C under nitrogen.
Atter 1 h the solution was albwed to warm to room temperature and lett for a turlher 1 h. The solution was treated with dilute HCI aad (SOml) and the white solid produced was filtered off. The solid was suspended in 10% Na2C03 (aqueous) solution (50ml) and extracted with dichloromethane (3x100ml).
15 The organic ex~racts were combined, dried (Na2S04) and concentrated in vacuo to afford the title compound (E1) as an off white solid (2.209, 70%) mp 130-132C.
1H NMR 250MHz (CDCI3) ~: 9.85 (br s,1 H), 7.92 (dd,1 H), 7.13-7.34 (m, 20 3H), 4.45 (d, 2H), 3.05-3.20 (m, 2H), 2.40-2.55 (m, 2H), 1.90-2.20 (m, SH), 1,35-1.70 (m, 6H),1.02 (t, 3H).
MS (El) MH+ 332.
Example 2 (1-Butyl~p~peridyl)methyl 2,3-dlhydro-2-oxo-3-ethylbenzimidazole-1 carboxylate hydrochloride (F2) To a stirred solution of (1-butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3H-benzimidazole-1~arboxy1ate (F1, 0.59, 0.001~ mole) in dry DMF (15ml) under nt ogen at room temperature was added, portionwise, sodium hydride as an 80% dispersion in mineral oil (45mg, 0.0015 mole). After hydrogen 35 evolution had subsided (9Omin), the solution was treated with ethyl iodide (0.2359, 0.12ml. 0.0015 mole) and left to stir overnight. The resulting solutionwas basified via addition of 10% aqueous Na2C03 solution (30 ml) and e~nracted into ethyl acetate (3x50ml). The organic extracts were combined 3 8 1vo 93/l8027 PCI`/GB93/00395 and dried (Na2S04) and concentrated in vaCvo. The residue was chromatographed on silica gel eluting initially with chloroform folbwed by chlorotorm/ethanol (95:5) to afford the tree base ot the titb compound. This was convened to the hydrochbride salt, which was recrystallised trom 5 isopropyl alcohoUacetone (1 :1) to afford the title compound (E2) as a white c ystallin~ solid (0.439, 80Yo) mp 190-192C.
HCI Salt:- 1 H NMR 250MHz (CD30D) ~: 7.94 (dd,1 H), 7.20-7.40 (m, 3H), 4.45 (d, 2H), 4.01 (q, 2H), 3.6~3.77 (m, 2H), 3.00-3.23 (m, 4H), 2.13-2.30 (m, 10 2H),1.70-1.90 (m, 4H), 1.40-1.60 (m, 3H),1.37 (t, 3H), 1.08 (t, 3H).
Example 3 15 2~ r~dy~ethyl 2,3-dihydroindole-1-carboxylate hydrochlorlde (E3)
European Joumal of Phamlacology 146 (1988),187-188, and Naunyn-Schmiedeberg's Arch. Pharmacoî. (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 ~HT3 receptor antagonist, acts as an 10 antagonist at this receptor.
WO 91/16045 (SmithKline and French Laboratories Limited) describes lhe use of cardiac 5-HT4 receptor antagonists in the treatment ot atrial arrhythmias and stroke.
EP-A-5013æ (Gbxo Group Limited) describes indole derivatives having ~HT4 antagonist activity.
EP-A-309423 (Istituto de Angeli S.p.A) and EP-A-247266 (Beecham Group 20 p.l.a~) describe 5-HT3 rec~ptor antagonists derived from a benzimidæolone or indoline nwleus.
A class of novsl, structurally distinct compounds has now been discovered, which compounds include benzimidæolone derivatives. These compounds 25 have ~HT4 receptor antagonist activity.
Accordingly, the present invention provides a compound of forrnula (I), or a pharmaceutically acceptable salt thereof:
Rb CO Y-Z
~ N, Ra (I) wherein:
X1-X2 is NRz-CO or CR1 R2-CR3R4 where Rz and R1 to R4 are independenlly hydrogen or C1-6 alkyl; and/or ~r~r~ .,~ . ~,~..~..-s ~
wos3/l8027 ~i " 13 ~ i 2 - PCI`/GB93/003 R1/R2 and R3/R4 together are a bond and/or R1/R2/R3/R4 are joined to form C3-6 pOlymethylene;
Ra is hydrogen, halo, C1 6 alkyl, amino, nitro or C1 6 alkyl;
Rb is hydrogen, halo, C1 6 alkyl or C1 6 alkoxy;
5 YisOorNH;
Z is of su~formula (a), (b) or (c):
(C~2)~
-(CH2)n~_ I R6 N R
(a) (CH~ R/
(b) -(CH2) 3 --N~R8 (c) wherein n1 is1,2,30r4;n2isO,1,2,30r4;n3is2,3,40r~;
qisO, 1,20r3;pisO, 1 or2;misO, 1 or2;
Rs is hydrogen, C1 -12 alkyl, aralkyl or Rs is (CH2)z-R1 o wherein z is 2 or 3 and R10 is selected from cyano, hydroxyl, C1-6 alkoxy, phenoxy, C(O)C1 -6 alkyl, COC6Hs, -CONR1 1 R12, NR11 COR1 2~ S02NR1 1 R12 or NR1 1 S02R1 2 wherein R11 and R12 are hydrogen or C1 -6 alkyl;
and R6, R7 and R(8 are independently hydrogen or C1 6 alkyl; and Rg is hydrogen or C1 10 alkyl;
or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere;
having ~HT4 receptor antagonist activity.
Examples of alkyl or alkyl containing groups include C1 . C2, C3, C4, Cs, C6, C7, Cg, Cg, C1 0, C1 1 or C1 2 branched, straight chained or cyclic alkyl, as ~vo 93/18027 ~ ~ ~ 1 3 ~ ~ PCI`/GB93/0039 appropriate. C1 4 alkyl groups include methyl, ethyl, n and is~propyl, r~, iso, sec and t~ butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ~ycloheptyl and cyclooctyl.
5 Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C1-6 alkyl and C1 6 alkoxy.
Halo includes fluoro, chlsro, bromo and iodo.
10 A suitable bioiscstere for the amide or ester linkage containing Y in formula (I), is of formula (d):
H t llju 1~ (d) 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 20 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 Ud.), such as an oxadiazole moiety.
Suitable examples of X1 -X~ when CR1 R2-CR3R4 include Cl 12-CH2 and CH=CH. X1-X2 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.
3$1 WO 93/18027 PCI /GB93/003~
When Z is of sub-formula (a), n1 is preterably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n1 is preterably 1 when the azacycle is attached at a carbon atom, such as the 4-position when q is 2.
5 When Z is of su~tormula (b), n2 is preferably such that the number of carbon atoms between the ester or amide linkage is from 2 to 4 carbon atoms.
Suitable values tor p and m include p = m = 1; p z 0, m = 1, p = 1, m = 2, p=2,m=1.
~0 When Z is ot sub formula (c), n3 is preferably 2, 3 or 4.
R8 and Rg are preferably both alkyl, especially one of R8 and Rg is C4 or larger alkyl.
Specific values of Z of particular interest are as follows:
~/--\ n ~N Bu (j) /\CN /\(~ (ii) ~` N~ (iii) ~NNb Bu (iv) \~N~J (v) ~N/\I
~ (vi) 3 ~ 1 ~vo 93/l8027 pcr/GB93/oo3ss ~ f~
/~N~J (vii) The invention a~so provides novel compounds within formula (I) ~th side chains (i), (ii), (iii), (iv), (v), (vi) or (vii). In a further aspect, the piperidine ring in (i), (ii) or lii) may be replaced by pyrrolidinyl or azetidinyl, and/or the 5 N-substituent in (i) or (ii) may be replaced by C3 or larger alkyl or optionally substituted benzyl.
în an altemative aspect, the N-substituent in formula (i) or (ii) may be - r~pbced by (CH2)nR4 as defined in EP-A-501322 in respect ot formula (I) 10 and lhe specitic examples therein.
The pharmaceutically acceptable salts of the compounds ot the formula (l) include acid addition sal~s with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric æids and pharmaceutically 15 acoep~e organic acids such as acetic, ta~taric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric, a~lycerophosphoric, and ~lucose-1-phosphoric acids.
Examples of pharmaceutically acceptable salts include quaternary derivatives 20 of the compounds of formula (I) such as the compounds quatemised by compounds RX-T wherein Rx is C1-6 alkyl, phenyl-C1 6 alkyl or Cs 7 cycloalkyl, and T is a radical corresponding to an anion of an acid; Suitable examples Of Rx include methyl, ethyl and ~ and is~propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide 25 and iodide.
Examples of pharmaceutically acceptable salts also include intemal salts SUch as N-oxides.
30 The compounds of the formula (I), their pharmaceutically acceptable salts, (indudin~ quatemary derivatives and N-oxides) may also form pharmaceuticall~ acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.
WO 93/18027 PCI`/GB93/003,~.
n will also be realised that the (CH2)n2 moiety in compounds of formula (I) wherein Z is (b), may adopt an a or ~ or configuration with respect to the ~used azabicyclic moiety.
5 The compounds of formub (I) may be prepared by conventional coupling of the X~/X2 mdety with Z. Suitable methods are as descnbed in GB 2125398A
(Sandoz Limited), GB 1593146A and EP-A-36269 (Beecham Group p.l.c.), EP-A~29984 (Nisshin Fbur Milling Co.) and EP-A-328200 (Merck Sharp &
Dohme Limited). Reference is also made to EP-A-501322 (Glaxo Group 10 Limited).
Aza(bikyclic side chain intermediates are known compounds or may be prepared according to the methods described in PCT/GB92/01519 and /01612 (SmithKline Beecham p.l.c.).
The compounds of the present invention are ~HT4 receptor antagonists and ;t is thus believed may generally be used in the trsatment or prophylaxis of ~astrointestinal disorders, c~diovascular disorders and CNS disorders.
20 They are of potential interest in the treatment ot irntable bowel syndrome ~IBS), in particular the diarrhoea aspects ot IBS, i.e., these compounds block 1he ability of 5-HT to stimulate gut motility via activation ot enteric neurones.
In animal mode~ of IBS, this can be conveniently measured as a reduction of the rate of detaecation. They are also ot potential use in the treatment of 25 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 u$e in the treatment of the nausea and gastric sym; ~ms 30 of gastro-oesophageal reflux disease and dyspepsia. Antiemetic activity is determined in known animal models of cytotoxic-agenVradiation induced emesis.
Specific cardiac ~HT4 receptor antagonists which prevent atrial fibrillation 35 and other atnal arrhythmias associated with ~HT, would also be expected to redwe occurrence of stroke (see A.J. Kaumann 1990, Naumyn-Schmiedeberg's Arch. Pharmacol. 342j 619-622, tor appropriate animal test method).
3 8 i ~vo 93/18027 7 PCI`/GB93/00395 It is believed that platelet-derived ~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 hean the most common source of embolic material. Of particular concem is the trequency of embolism associatcd with atrial fibrillation.
Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 10 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 ot headache (Sachs, 1985, Migraine, Pan 15 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 ~tal., 1976, Headache 16, 160-167). It is believed that a migraine, including the prodomal phase and the associated ;ncreased levels of cydic AMP are related to stimulation of ~HT4 receptors, and hence 20 that administration ot a 5-HT4 antagonist is of potential benefit in relieving a migraine attack.
The invention also provides a pharmaceutical composition compnsing a compound of forrnula (I), or a pharmaceutically acceptable salt thereof, and a 25 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 suchmay be in the form of tablets, capsules, oral liquid preparations, powders, 30 granules, lozenges, reconstitutable powders, nasal sprays, suppositories, injectable and infusable solutions or suspensions. Sublingual or transdermal administration is also envisaged Orally administrable compositions are preferred, since they are more convenient for general use 35 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, ~r~ sr ~.~
wo 93/18027 ~ ~ 3 ~ 8 - PCI/GB93/003,!~,$
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 celluhse, mannitol, lactose and other similar 5 agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and sta ch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.
Suitable pharmaceutically acceptable wetting agents include sodium lauryl 10 sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, synups, 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 a-~ditives such as su~spending agents, for example sorbitol, syrup, methyl 15 cellulose, gelatin, hydroxyethylcellubse, carboxymsthylcellulose, aluminium stearate gel or hydrogenated edibb fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionatsd coconut oil, oily esters such as esters of glycerine, propybne glycol, or ethyl alcohol;
20 preservatives, for example methyl or propyl ~hydroxybenzoate or sorbic acid, and if desired conventional tlavouring or colouring agents.
Oral liquid pr~parations are usually in the form of aqueous or oily suspensions, solutions, emulsions, synups, or elixirs or are presented as a dry 25 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), prsservatives, and flavouring or colouring agents.
30 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 tillers. Such operations are, of course, conventional in the art.
35 For parenteral administration, fluid unit dose forms are prepared containing a compound ot 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 3 8 l '`Y~ 93/18027 PCI/GB93/00395 compound in a vehicle and 1ilter 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 5 into 1he 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 10 the sterile vehicle. Advantageously, a su factant or wetting agent is included in lhe composition to facilitate uniform distribution of the compound ot the invention.
The invention further provides a method of treatment of irritable bowel 15 syndrome, gastro-oesophagal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine in mammals, such as humans, which compnses the administration of an effective amount of a compound of the formula (I) or a phal maceutically acceptable salt thereof. In particular, the method comprises treatment of IBS or at~ial arrhythmias and stroke.
An amount effective to treat the disorders hereinbefore described depends on the relative e~lcacies 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 25 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 ~r 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50 mglkg/day, more usually 0.0002 to 25 mg/kglday.
30 No adverse toxico!ogical effects are indicated within the aforemen~ioned dosage ranges.
The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in 35 particular for use as a 5-HT4 receptor antagonist in the treatment of the disorders hereinbefore described.
WO 93/18027 i~ 3 81 1 o PCI~/GB93/003g~
The invention also provides the use of a compound of formula (I) in the manu~acture of a medicament ~or use as a ~HT4 receptor antagonist in the treatment ot the disorders hereinbefore described.
5 ~he folbwing Examples illustrate the preparation ot compounds of formula (I);
the folbwin~ Descriptions i~lustrate the preparation of interrnediates. It will be appreciated that any compound example wherein X is O may be prepared as lhe conespondin~ compound wherein Y is NH and wce versa.
Examples Ra Rb X1/X2 Y Z
E1 H H NH-CO () (i) E2 H H NEt-CO O (i) E3 H H CH2CH2 0 (iii) E4 H H CH=CH O (iii) E5 H H NH-CO O (iii) E6 H H NMe-CO O (i) 38~
PCr/GBs3/003ss Vo 93/18027 - 1 1 -Examples (cont.) Ra Rb X1/X2 Y Z
E7 H H Ncpm-C0 0 (i) E8 H H NEt-C0 0 (iii) E9 H H NPrn-C0 0 (i) E10 H H NPri-C0 0 (i) E11 H H NH-C0 0 (~i) E12 H H NEt-C0 0 (vi) E13 H H NH C0 NH (i) E14 H H Ncpm-C0 NH (i) E15 H H NPrn-C0 NH (i) E16 H H CHCH3CH~ 0 (i) E17 H H CH(CH3)2CH2 ~i) E18 H H CHR2pcHP~4p 0 (i) 35 cpm - cyclopropylmethyl R2p and R4p are joined to ~orm C4 polyme~hylene WO93/18027 ~ 1381 pcr/GBs3/oo3~
Example 1 (1-Butyl4-plperld~l)methyl 2,3 dlhydro-2-oxo~3H~benzlmldazole-1-S ca-boxylate (E1) ~ -A solution of (1 -butyl-4piperidyl)methyl 2-aminophenylcarbamate (D1 b), (2.909, O.OO9S mole) in dichbromethane (SOml) with triethylamine (1.5ml) was added to a stirred solution of t ichbromethyl chlorotormate (1.889, 10 1.15ml, O.OO9S mole) in dichloromethsne (SOml) at 50C under nitrogen.
Atter 1 h the solution was albwed to warm to room temperature and lett for a turlher 1 h. The solution was treated with dilute HCI aad (SOml) and the white solid produced was filtered off. The solid was suspended in 10% Na2C03 (aqueous) solution (50ml) and extracted with dichloromethane (3x100ml).
15 The organic ex~racts were combined, dried (Na2S04) and concentrated in vacuo to afford the title compound (E1) as an off white solid (2.209, 70%) mp 130-132C.
1H NMR 250MHz (CDCI3) ~: 9.85 (br s,1 H), 7.92 (dd,1 H), 7.13-7.34 (m, 20 3H), 4.45 (d, 2H), 3.05-3.20 (m, 2H), 2.40-2.55 (m, 2H), 1.90-2.20 (m, SH), 1,35-1.70 (m, 6H),1.02 (t, 3H).
MS (El) MH+ 332.
Example 2 (1-Butyl~p~peridyl)methyl 2,3-dlhydro-2-oxo-3-ethylbenzimidazole-1 carboxylate hydrochloride (F2) To a stirred solution of (1-butyl-4-piperidyl)methyl 2,3-dihydro-2-oxo-3H-benzimidazole-1~arboxy1ate (F1, 0.59, 0.001~ mole) in dry DMF (15ml) under nt ogen at room temperature was added, portionwise, sodium hydride as an 80% dispersion in mineral oil (45mg, 0.0015 mole). After hydrogen 35 evolution had subsided (9Omin), the solution was treated with ethyl iodide (0.2359, 0.12ml. 0.0015 mole) and left to stir overnight. The resulting solutionwas basified via addition of 10% aqueous Na2C03 solution (30 ml) and e~nracted into ethyl acetate (3x50ml). The organic extracts were combined 3 8 1vo 93/l8027 PCI`/GB93/00395 and dried (Na2S04) and concentrated in vaCvo. The residue was chromatographed on silica gel eluting initially with chloroform folbwed by chlorotorm/ethanol (95:5) to afford the tree base ot the titb compound. This was convened to the hydrochbride salt, which was recrystallised trom 5 isopropyl alcohoUacetone (1 :1) to afford the title compound (E2) as a white c ystallin~ solid (0.439, 80Yo) mp 190-192C.
HCI Salt:- 1 H NMR 250MHz (CD30D) ~: 7.94 (dd,1 H), 7.20-7.40 (m, 3H), 4.45 (d, 2H), 4.01 (q, 2H), 3.6~3.77 (m, 2H), 3.00-3.23 (m, 4H), 2.13-2.30 (m, 10 2H),1.70-1.90 (m, 4H), 1.40-1.60 (m, 3H),1.37 (t, 3H), 1.08 (t, 3H).
Example 3 15 2~ r~dy~ethyl 2,3-dihydroindole-1-carboxylate hydrochlorlde (E3)
2,~Dihydroindole-1-carbonyl chloride (0.759, 4.13 mmole) was dissolved with stirrin~ in dichbromethane (20ml) and triethylamine (0.632ml, 4.54 mmole) was added, tolbwed by 2-pip~ndineethanol (0.547 ml, 4.13 mmole). The 20 mixture was then stinred at room temp. Atter 72h, the reaction mixture was washed with water, the or~ank byer was then dried (Na2S04) and evaporated under reduced pressure to give a pink oil. The oil was purified by silica ~el chromatography using pentane:EtOAc (3:1 to 5:4) as sluant to give a coburless oil (0.355g, 33%), which was converted to its hydrochloride salt 25 (E3) mp 175-176C.
HCI Sa~t:- 1 H NMR (250MHz) (DMSO) ~: 7.72 (br s,1 H), 7.20(dd,2H), 6.98(t,1 H), 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,1 H).
WO 93/18027 ~13 13 ~ ~ PCI/GB93/003,Q~.
Example 4 2-Plperldylethyl Indol~1-carboxylate (E4) 5 2-Piperidylethyl2,3-dihydroindole-1 carboxlatehydrochloride(E3)(0.100g, 0.337mole) was dissolved in chloroform (10ml) with stirring. DD~ (0.0849, 0.370mmole) was 1hen added and the mixture was heated to reflux. After 6h, the reaction mixture was albwed to cool. The reaction mixture was then diluted with CHCI3 and washed with saturated potassium carbonate solution.
10 The aqueous layerwas then extracted with chloroform, and the combined organic byers ~ere dried (Na2S04) and evaporated to give a yelbw solid, which was purified by silica gel chromatography, using petrol:EtOAc (4:1) as eluant to give th~ title compound (E4) as a pale yellow oil (0.0369 41%), which was converted to its hydrochloride salt mp 18~186C.
Free base:- 1 H NMR (250MHz) (CDCI3) ~: 8.22(d,1 H), 7.52-7.68(m,2H), 7.20-7.41 (m,2H), 6.62(d,1 H), 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 1 and 2 the following compounds were prepared: -2-Piperidylethyl 2,3-dihydro-2-oxo-3H-benzimidazol~1-carboxylate hydrochlonde (E5) mp 172-3C
(1- Butyl~piperidyl)methyl 2,3-dihydro-2-oxo-3-methylbenzimidazole-1-carboxylate hydrochloride (E6) mp 1 84-187C
HCI Sa~t:- 1 H NMR (250MHz) (DMSO) ~: 7.72 (br s,1 H), 7.20(dd,2H), 6.98(t,1 H), 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,1 H).
WO 93/18027 ~13 13 ~ ~ PCI/GB93/003,Q~.
Example 4 2-Plperldylethyl Indol~1-carboxylate (E4) 5 2-Piperidylethyl2,3-dihydroindole-1 carboxlatehydrochloride(E3)(0.100g, 0.337mole) was dissolved in chloroform (10ml) with stirring. DD~ (0.0849, 0.370mmole) was 1hen added and the mixture was heated to reflux. After 6h, the reaction mixture was albwed to cool. The reaction mixture was then diluted with CHCI3 and washed with saturated potassium carbonate solution.
10 The aqueous layerwas then extracted with chloroform, and the combined organic byers ~ere dried (Na2S04) and evaporated to give a yelbw solid, which was purified by silica gel chromatography, using petrol:EtOAc (4:1) as eluant to give th~ title compound (E4) as a pale yellow oil (0.0369 41%), which was converted to its hydrochloride salt mp 18~186C.
Free base:- 1 H NMR (250MHz) (CDCI3) ~: 8.22(d,1 H), 7.52-7.68(m,2H), 7.20-7.41 (m,2H), 6.62(d,1 H), 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 1 and 2 the following compounds were prepared: -2-Piperidylethyl 2,3-dihydro-2-oxo-3H-benzimidazol~1-carboxylate hydrochlonde (E5) mp 172-3C
(1- Butyl~piperidyl)methyl 2,3-dihydro-2-oxo-3-methylbenzimidazole-1-carboxylate hydrochloride (E6) mp 1 84-187C
3~
~i~l381 ~vo 93/18027 PCI/GB93/00395 (1-8utyl~p~perldyl)methyl 2,3 d1hydro-2-oxo-3 cyclopropylmethyl-benzlmldazol~1-carboxylate hydrochloride (E7) mp 1 83-5C
2-Pipertdylethyl 2,3-dihydro-2-oxo~ethylbenzimidazol~1-carboxylate hydrochloride (E8) mp 176-178C
(l-Buty~plperidyl)methyl 2,3-dlhydro-2-oxo-3-propylbenzlmidazole-1-carboxylate hydrochloride (E9) mp 190-1 92C
(1-Butyl-4plperidyl)methyl 2,3-dihydro-2-oxo~-isopropylbenzimidazole-1-carboxylate hydrochloride (E10) mp 15~157C
1-Azabicydo~4.4.0]decan~ylmethyl 2,3-dihydro-2-oxo-3H-benzlmidazole-1-carboxylate hydrochloride (E11 ) 1-Azablcyclol4.4.0]decan~ylmethyl 2,3 dihydro-2-oxo-~ethylbenzlmidazole-1~carboxylate hydrochloride (E12) mp 180-183C
WO 93/18027 1 ~ 1 J ~i l PCI/GB93/003 Example 13 (1-Butyl~piporldyl)mothyl 2,34ihydro-2 oxo-3H-bonzlmldazolo-l-car~oxamide hydrochlorido (E13) A mixture ot N-(1-butyl4-piperidyl)methy~N~-(2-aminophenyl)urea (D2b, 4.59, 0.015mole) and lriethybmine (2.5ml) in dichloromethane (100ml) was added lo a solution of diphosgene ~2.939, 1 .8ml, 0.015mole) in dichloromethane (50ml) under nitrogen. A1ter addition was complete (1 hour) the solution was 10 treated with 5M HCI (100ml). The precipitate was tiltered off and dri~d to afford the 1Ule compound (E13) as a white solid mp 240 243C.
Examples 14 and 15 The folbwin~ compounds were prepared by an analogous procedure to that described for Example 2.
(1-Butyi~piperidyl)methyl 2,3 dihydro-2 oxo-3-20 cyciopropylmethylbenzimidazole-1-carboxamlde hydrochloride (E14) mp 175-177C
(1-Butyl~piperidyl)methyl 2,3~dihydro-2-oxo-3-propylbenzimidazole-1-25 carboxamide hydrochloride (E15) mp1 35-1 36C
30 Examples 16 -18 The following compounds were prepared by an analogous procedure to that described for Example 3.
35 (~-Butyl~plpefldyl)methyl 2,3~dlhydro-3-methylindole-1-carboxylate hydrochlonde (E16) mp 173-175C
1'~13'~
~vo 93/18027 - 17 - PCI`/GB93/0039S
2 Piper~dylethyl 2,3-dihydro 3,3-d~methylindole-1-carboxylate hydrochloride (E17) (1-BInyl~piperidyl)methyl 1,2,3,4 tetrahydrocarbazole~9-carboxylate oxalate (E18).
mp 187-189C
Prep~ration of N~ nbutyl~piperidyl)methylamine A stined solution ot isonipecotamide (709, 0.55 mole) and 1-bromobutane (58.8 ml, 0.55 mole) in ethanol (700 ml) was treated with anhydrous potassium carbonate (1529, 1.10 mole) and heated under reflux for 3h. The mixture was allowed to cool, ~hen filtered and the filtrate concentrated under 20 vacuum. The residual oil was dissolved in chlorotorrn (400 ml) and washed with water (1 x 300 ml), then dried (Na2SO4) and concentrated under vacuum to leave a yellow oil (77.59). This oil was mixed thoroughly with phosphorus pentoxide (759) and the mixture heated at 160-1 80C under nitrogen for 2.5h with gentle stirring. The reaction mixture was allowed to cool, then treated 25 with water (500 ml). When the solid mass had dissolved, the solution was basified by addition of solid K2CO3 and extracted with ethyl acetate (2x400 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a brown oil (789). This was dissolved in dry ether (400 ml) and aWed dropwise over 30 minutes to a stirred suspension of lithium aluminium 30 hydnde (25g, 0.66 mole) in ether (200ml) at 0C under nitrogen. When addition was complete, the mixture was allowed to warm upto room temperature and stir for 1 8h. It was re cooled to 0C 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 3~ to leave a~brown oil, which was distilled under vacuum to afford the title compound as a colourless oil (669, 71 %) bp 96-99C at 3 mm Hg.
'H NMR (CDCI3) WO 93/18027 ~ ~ 3 :L 3 g 1 - 18 - PCI`/GB93/003~5 ~: 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-nbuty~piperldinyl)methanol A mixture o~ ethy~ isonipecotate (102~, 0.65 mole) and 1-bromobutane (72 ml, 0.67 mole) in ethanol (1.2L) was treated with anhydrous potassium carbonate 10 (1809, 1.3 mole) and heated under reflux tor 2h. The mixture was allowed to cool and then filtered through kiesebuhr. The filtrate was concentrated in vactlo to bave a yellow oil, which was dissolved in ether (300 ml) and added dropwise over 20 minutes ~o a stirred suspension of lithium aluminium hydride (509, 1.3 mole) in either (500 ml) at 0C under nitrogen. The mixture was 15 stirred at room temperature for 18h, then cooled to 0C and treated with water (50 ml),10% NaOH solution (50ml) and water (150ml). The mbnure was ~iltered through keisebuhr and the filtrate concentrated under vacuum to bave a pale yelbw oil, which was distilled to afford the title compcund as a coburless dl (88.5~., 80Yo) bp 102-108C at 0.1 mm Hg.
1 H NMR (CDCI3) ~: 3.48~d,2H), 2.88-3.03(m,2H), 2.25-2.38(m,2H), 2.10(br s,1 H),1.66-2.00(m,4H), 1.17-1.60(m,7H), 0.90(t,3H) :`
'"O 93/18027 1 9 PCI /GB93/00395 Descrlptions Description 1 (Intermediate for Examples 1 and 2) 5 a) (1-eutyl~plperldyl)melhyl 2-nUrophenylcarbamate A stined suspension of 2-nitrophenylisocyanate (3.60g, 0.22mole) in dry toluene (50ml) at room temperature under nitrogen was treated with (1-butyl-
~i~l381 ~vo 93/18027 PCI/GB93/00395 (1-8utyl~p~perldyl)methyl 2,3 d1hydro-2-oxo-3 cyclopropylmethyl-benzlmldazol~1-carboxylate hydrochloride (E7) mp 1 83-5C
2-Pipertdylethyl 2,3-dihydro-2-oxo~ethylbenzimidazol~1-carboxylate hydrochloride (E8) mp 176-178C
(l-Buty~plperidyl)methyl 2,3-dlhydro-2-oxo-3-propylbenzlmidazole-1-carboxylate hydrochloride (E9) mp 190-1 92C
(1-Butyl-4plperidyl)methyl 2,3-dihydro-2-oxo~-isopropylbenzimidazole-1-carboxylate hydrochloride (E10) mp 15~157C
1-Azabicydo~4.4.0]decan~ylmethyl 2,3-dihydro-2-oxo-3H-benzlmidazole-1-carboxylate hydrochloride (E11 ) 1-Azablcyclol4.4.0]decan~ylmethyl 2,3 dihydro-2-oxo-~ethylbenzlmidazole-1~carboxylate hydrochloride (E12) mp 180-183C
WO 93/18027 1 ~ 1 J ~i l PCI/GB93/003 Example 13 (1-Butyl~piporldyl)mothyl 2,34ihydro-2 oxo-3H-bonzlmldazolo-l-car~oxamide hydrochlorido (E13) A mixture ot N-(1-butyl4-piperidyl)methy~N~-(2-aminophenyl)urea (D2b, 4.59, 0.015mole) and lriethybmine (2.5ml) in dichloromethane (100ml) was added lo a solution of diphosgene ~2.939, 1 .8ml, 0.015mole) in dichloromethane (50ml) under nitrogen. A1ter addition was complete (1 hour) the solution was 10 treated with 5M HCI (100ml). The precipitate was tiltered off and dri~d to afford the 1Ule compound (E13) as a white solid mp 240 243C.
Examples 14 and 15 The folbwin~ compounds were prepared by an analogous procedure to that described for Example 2.
(1-Butyi~piperidyl)methyl 2,3 dihydro-2 oxo-3-20 cyciopropylmethylbenzimidazole-1-carboxamlde hydrochloride (E14) mp 175-177C
(1-Butyl~piperidyl)methyl 2,3~dihydro-2-oxo-3-propylbenzimidazole-1-25 carboxamide hydrochloride (E15) mp1 35-1 36C
30 Examples 16 -18 The following compounds were prepared by an analogous procedure to that described for Example 3.
35 (~-Butyl~plpefldyl)methyl 2,3~dlhydro-3-methylindole-1-carboxylate hydrochlonde (E16) mp 173-175C
1'~13'~
~vo 93/18027 - 17 - PCI`/GB93/0039S
2 Piper~dylethyl 2,3-dihydro 3,3-d~methylindole-1-carboxylate hydrochloride (E17) (1-BInyl~piperidyl)methyl 1,2,3,4 tetrahydrocarbazole~9-carboxylate oxalate (E18).
mp 187-189C
Prep~ration of N~ nbutyl~piperidyl)methylamine A stined solution ot isonipecotamide (709, 0.55 mole) and 1-bromobutane (58.8 ml, 0.55 mole) in ethanol (700 ml) was treated with anhydrous potassium carbonate (1529, 1.10 mole) and heated under reflux for 3h. The mixture was allowed to cool, ~hen filtered and the filtrate concentrated under 20 vacuum. The residual oil was dissolved in chlorotorrn (400 ml) and washed with water (1 x 300 ml), then dried (Na2SO4) and concentrated under vacuum to leave a yellow oil (77.59). This oil was mixed thoroughly with phosphorus pentoxide (759) and the mixture heated at 160-1 80C under nitrogen for 2.5h with gentle stirring. The reaction mixture was allowed to cool, then treated 25 with water (500 ml). When the solid mass had dissolved, the solution was basified by addition of solid K2CO3 and extracted with ethyl acetate (2x400 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a brown oil (789). This was dissolved in dry ether (400 ml) and aWed dropwise over 30 minutes to a stirred suspension of lithium aluminium 30 hydnde (25g, 0.66 mole) in ether (200ml) at 0C under nitrogen. When addition was complete, the mixture was allowed to warm upto room temperature and stir for 1 8h. It was re cooled to 0C 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 3~ to leave a~brown oil, which was distilled under vacuum to afford the title compound as a colourless oil (669, 71 %) bp 96-99C at 3 mm Hg.
'H NMR (CDCI3) WO 93/18027 ~ ~ 3 :L 3 g 1 - 18 - PCI`/GB93/003~5 ~: 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-nbuty~piperldinyl)methanol A mixture o~ ethy~ isonipecotate (102~, 0.65 mole) and 1-bromobutane (72 ml, 0.67 mole) in ethanol (1.2L) was treated with anhydrous potassium carbonate 10 (1809, 1.3 mole) and heated under reflux tor 2h. The mixture was allowed to cool and then filtered through kiesebuhr. The filtrate was concentrated in vactlo to bave a yellow oil, which was dissolved in ether (300 ml) and added dropwise over 20 minutes ~o a stirred suspension of lithium aluminium hydride (509, 1.3 mole) in either (500 ml) at 0C under nitrogen. The mixture was 15 stirred at room temperature for 18h, then cooled to 0C and treated with water (50 ml),10% NaOH solution (50ml) and water (150ml). The mbnure was ~iltered through keisebuhr and the filtrate concentrated under vacuum to bave a pale yelbw oil, which was distilled to afford the title compcund as a coburless dl (88.5~., 80Yo) bp 102-108C at 0.1 mm Hg.
1 H NMR (CDCI3) ~: 3.48~d,2H), 2.88-3.03(m,2H), 2.25-2.38(m,2H), 2.10(br s,1 H),1.66-2.00(m,4H), 1.17-1.60(m,7H), 0.90(t,3H) :`
'"O 93/18027 1 9 PCI /GB93/00395 Descrlptions Description 1 (Intermediate for Examples 1 and 2) 5 a) (1-eutyl~plperldyl)melhyl 2-nUrophenylcarbamate A stined 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 10 reflux tor 4h with stirring. The resulting solution was concentrated in vaaJo to afford the crude title compound as an orangelbrown oil (3.40g. 50/O).
1 H NMR (CDCI3) ~: 9.85 (s,1 H), 8.57 (dd,1 H), 8.23 (dd,1 H), 7.60-7.70 (m, 1H), 7.10-7.18 (m,1H), 4.08 (d, 2H), 2.94-3.06 (m, 2H), 2.30-2.40 (m, 2H), 15 1.86-2.04 ~m, 2H),1.6~1.84 (m, 3H),1.30-1.60 (m, 6H), 0.93 (t, 3H).
b) (1~Butyl~piperidyl)methyl 2~minophenylcarbamate A solution of (1-butyl-4~iperidyl)methyl 2-nitrophenylcarbamate (3.00g, 0.009 20 mole) in ethanol (100ml) was hydrogenated at atmospheric pressure over 10% Pd/C cata~yst. The catalyst was removed and the resulting solution concentrated in YaaJo to afford the title compound as pale yellow solid (2.40g, quantnative).
25 1 H NMR 250MHz (CDC13) ~: 7.20-7.35 (m,1 H), 6.95-7.10 (m,1 H), 6.60-6.90 (m, 3H), 4.03 (d, 2H), 3.75 (br s, 2H), 2.93-3.10(m, 2H); 2.30-2.4 (m, 2H), 1.90-2.10 (m, 2H),1.17-1.83 (m, 9H~, 0.90 (t, 3tl).
30 Descrtption 2 (intermediate for Example 13) a) N (1-Butyl~piperidyl)methyl-N'-(2-nitrophenyl)urea A solution of 2-nitrophenylisocyanate (3.009, 0.183mole) in dichloromethane 35 (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 tor 16 hours then heated under reflux for 1 hour. The solvent was removed in vacvo and the residue purified by column chromatography on ~13~38~
O 93/18027 PCl'/GB93/00 silica gel using CHCI3/ MeOH (9:1 ) as eluant. The product was isolated as a yellow solid.
1H NMR (CDC13) ~: 9.80 (brs, 1H), 8.65 (d, 1H), 8.15 (d, 1H), 7.55 (t, 1H),
1 H NMR (CDCI3) ~: 9.85 (s,1 H), 8.57 (dd,1 H), 8.23 (dd,1 H), 7.60-7.70 (m, 1H), 7.10-7.18 (m,1H), 4.08 (d, 2H), 2.94-3.06 (m, 2H), 2.30-2.40 (m, 2H), 15 1.86-2.04 ~m, 2H),1.6~1.84 (m, 3H),1.30-1.60 (m, 6H), 0.93 (t, 3H).
b) (1~Butyl~piperidyl)methyl 2~minophenylcarbamate A solution of (1-butyl-4~iperidyl)methyl 2-nitrophenylcarbamate (3.00g, 0.009 20 mole) in ethanol (100ml) was hydrogenated at atmospheric pressure over 10% Pd/C cata~yst. The catalyst was removed and the resulting solution concentrated in YaaJo to afford the title compound as pale yellow solid (2.40g, quantnative).
25 1 H NMR 250MHz (CDC13) ~: 7.20-7.35 (m,1 H), 6.95-7.10 (m,1 H), 6.60-6.90 (m, 3H), 4.03 (d, 2H), 3.75 (br s, 2H), 2.93-3.10(m, 2H); 2.30-2.4 (m, 2H), 1.90-2.10 (m, 2H),1.17-1.83 (m, 9H~, 0.90 (t, 3tl).
30 Descrtption 2 (intermediate for Example 13) a) N (1-Butyl~piperidyl)methyl-N'-(2-nitrophenyl)urea A solution of 2-nitrophenylisocyanate (3.009, 0.183mole) in dichloromethane 35 (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 tor 16 hours then heated under reflux for 1 hour. The solvent was removed in vacvo and the residue purified by column chromatography on ~13~38~
O 93/18027 PCl'/GB93/00 silica gel using CHCI3/ MeOH (9:1 ) as eluant. The product was isolated as a yellow solid.
1H NMR (CDC13) ~: 9.80 (brs, 1H), 8.65 (d, 1H), 8.15 (d, 1H), 7.55 (t, 1H),
5 7.02 (t, 1 H), 5.60 (br s, 1 H), 3.20 ( t, 2H), 2.92 (br d, 2H), 2.20-2.35 (m, 2H), 1.20-1.97 (m, 11 H), 0.90(t, 3H) b) N~ Butyl~plperidyl)methyl-N'-(2~aminophenyl)urea 10 A solution of N-(1-buty~4piperidy1)methyl-N'-(2-nitrophenyl)urea (5.49, 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 keisebuhr and the filtrate concentrated in vacvo to give a white solid.
15 1H NMR (CDCI3) ~: 6.98-7.17 (m, 2H), 6.92 (s, 1H), 6.67-6.78 (m, 2H), 5.25 (brt, 1 H), 3.95 (br s, 2H), 3.05 (t, 2H), 2.87 (br d, 2H), 2.2-2.35 (m, 2H), 1.15-1.95 (m, 11 H), 0.90 (t, 3H).
5-HT4 RECEPTOR ANTAGONIST AC~IVITY
1) Guinea pig colon Male guinea-pigs, weighing 250-4009 are used. Longitudinaî muscle-myenteric plexus preparations, approximately 3cm long, are obtained from the distaî coîon région. These are suspended under a 0.59 Ioad in isolated tissue baths containing Krebs solution bubbled with 5% C02 in 2 and 30 maintained at 37C. In all experiments, the Krebs solution also contains methiothepin 1 o-7M and granisetron 1 o-6M to block effects at 5-HT1, 5-HT2 and ~HT3 receptors.
After construction of a simple concentration-response curve with 5-HT, using 35 30s contact times and a 1 Smin 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 1 5min with this concentration of 5-HT and then with an approximately equi-effective ~i~i3~
~vog3/l8027 - 21 - pcr/GB93/oo39s concentration of the nicotine receptor stimulant, dimethylphenylpip~razinium (DMPP). After obtaining consistent responses to both S-HT and DMPP, increasing concentrations of a putative ~HT4 receptor antagonist are then added to the bathing solution. The effects of this compound are then 5 determined as a percentage reduction of the contractions evoked by ~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 S-HT4 receptor antagonist.
Compounds were generally active in the range of concentrations of the order ot 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 al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991). The inner smooth muscle tube ot the muscularis mucosae is isolated and mounted for isometric tension recording in oxygenated (95% 2/5% C2) 20 Tyrodes solution at 37C. -All experiments are performed in pargyline pre-treated preparations (1 OO~M for 15 min followed by washout) and in the presence of cocaine (30~M). Relaxant responses to S-HT are obtained after pre-contracting the oesophagus tissue with carbachol (3~1M).
15 1H NMR (CDCI3) ~: 6.98-7.17 (m, 2H), 6.92 (s, 1H), 6.67-6.78 (m, 2H), 5.25 (brt, 1 H), 3.95 (br s, 2H), 3.05 (t, 2H), 2.87 (br d, 2H), 2.2-2.35 (m, 2H), 1.15-1.95 (m, 11 H), 0.90 (t, 3H).
5-HT4 RECEPTOR ANTAGONIST AC~IVITY
1) Guinea pig colon Male guinea-pigs, weighing 250-4009 are used. Longitudinaî muscle-myenteric plexus preparations, approximately 3cm long, are obtained from the distaî coîon région. These are suspended under a 0.59 Ioad in isolated tissue baths containing Krebs solution bubbled with 5% C02 in 2 and 30 maintained at 37C. In all experiments, the Krebs solution also contains methiothepin 1 o-7M and granisetron 1 o-6M to block effects at 5-HT1, 5-HT2 and ~HT3 receptors.
After construction of a simple concentration-response curve with 5-HT, using 35 30s contact times and a 1 Smin 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 1 5min with this concentration of 5-HT and then with an approximately equi-effective ~i~i3~
~vog3/l8027 - 21 - pcr/GB93/oo39s concentration of the nicotine receptor stimulant, dimethylphenylpip~razinium (DMPP). After obtaining consistent responses to both S-HT and DMPP, increasing concentrations of a putative ~HT4 receptor antagonist are then added to the bathing solution. The effects of this compound are then 5 determined as a percentage reduction of the contractions evoked by ~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 S-HT4 receptor antagonist.
Compounds were generally active in the range of concentrations of the order ot 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 al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991). The inner smooth muscle tube ot the muscularis mucosae is isolated and mounted for isometric tension recording in oxygenated (95% 2/5% C2) 20 Tyrodes solution at 37C. -All experiments are performed in pargyline pre-treated preparations (1 OO~M for 15 min followed by washout) and in the presence of cocaine (30~M). Relaxant responses to S-HT are obtained after pre-contracting the oesophagus tissue with carbachol (3~1M).
Claims (15)
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof (I) wherein:
X1-X2 is NRz-CO or CR1R2-CR3R4 where Rz and R1 to R4 are independently hydrogen or C1-6 alkyl; and/or R1/R2 and R3/R4 together are a bond and/or R1/R2/R3/R4 are joined to form C3-6 polymethylene;
Ra is hydrogen, halo, C1-6 alkyl, amino, nitro or C1-6 alkyl;
Rb is hydrogen, halo, C1-6 alkyl or C1-6 alkoxy;
Y is O or NH;
Z is of sub-formula (a), (b) or (c):
(a) (b) (c) wherein n1 is 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 2, 3, 4 or 5;
q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2;
R5 is hydrogen, C1-12 alkyl, aralkyl or R5 is (CH2)z-R10 wherein z is 2 or 3 and R10 is selected from cyano, hydroxyl, C1-6 alkoxy, phenoxy, C(O)C1-6 alkyl, COC6H5, -CONR11R12, NR11COR12, SO2NR11R12 or NR11SO2R12 wherein R11 and R12 are hydrogen or C1-6 alkyl;
and R6, R7 and R8 are independently hydrogen or C1-6 alkyl; and R9 is hydrogen or C1-10 alkyl;
or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere;
having 5-HT4 receptor antagonist activity.
X1-X2 is NRz-CO or CR1R2-CR3R4 where Rz and R1 to R4 are independently hydrogen or C1-6 alkyl; and/or R1/R2 and R3/R4 together are a bond and/or R1/R2/R3/R4 are joined to form C3-6 polymethylene;
Ra is hydrogen, halo, C1-6 alkyl, amino, nitro or C1-6 alkyl;
Rb is hydrogen, halo, C1-6 alkyl or C1-6 alkoxy;
Y is O or NH;
Z is of sub-formula (a), (b) or (c):
(a) (b) (c) wherein n1 is 1, 2, 3 or 4; n2 is 0, 1, 2, 3 or 4; n3 is 2, 3, 4 or 5;
q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2;
R5 is hydrogen, C1-12 alkyl, aralkyl or R5 is (CH2)z-R10 wherein z is 2 or 3 and R10 is selected from cyano, hydroxyl, C1-6 alkoxy, phenoxy, C(O)C1-6 alkyl, COC6H5, -CONR11R12, NR11COR12, SO2NR11R12 or NR11SO2R12 wherein R11 and R12 are hydrogen or C1-6 alkyl;
and R6, R7 and R8 are independently hydrogen or C1-6 alkyl; and R9 is hydrogen or C1-10 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 Ra is hydrogen.
3. A compound according to claim 1 or 2 wherein Rb is preferably hydrogen or halo.
4. A compound according to claim 1, 2, or 3 wherein X1-X2 is CH2-CH2 or CH=CH.
5. A compound according to claim 1, 2, 3 or 4 wherein X1-X2 is NRz-CO.
6. A compound according to any one of claims 1 to 5 wherein Y is O or NH.
7. A compound according to any one of claims 1 to 6 wherein Z is of sub-formula (a) and (CH2)n1 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 C2 or greater alkyl, or optionally substituted benzyl.
10. A compound according to claim 1 selected from the compounds E1 to E18 inclusive, as described herein, including pharmaceutically acceptable salts thereof.
11. A process for preparing the ester or amide compounds according to claim 6, which comprises reacting an appropriate X1-X2 containing acid derivative with an appropriate alcohol or amine.
12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, and a pharmaceutically acceptable carrier.
13. A compound according to claim 1 for use as an active therapeutic substance.
14. The use of a compound according to claim 1 in the manufacture of a medicament for use as a 5-HT4 receptor antagonist.
15. The use according to claim 14 for use as a 5-HT4 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 |
|---|---|---|---|
| GB9204565.7 | 1992-03-03 | ||
| GB929204565A GB9204565D0 (en) | 1992-03-03 | 1992-03-03 | Pharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2131381A1 true CA2131381A1 (en) | 1993-09-16 |
Family
ID=10711400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002131381A Abandoned CA2131381A1 (en) | 1992-03-03 | 1993-02-25 | Nitrogen containing heterocyclic compounds useful as pharmaceuticals |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0629198A1 (en) |
| JP (1) | JPH07504428A (en) |
| KR (1) | KR950700285A (en) |
| AU (1) | AU666357B2 (en) |
| CA (1) | CA2131381A1 (en) |
| GB (1) | GB9204565D0 (en) |
| MX (1) | MX9301157A (en) |
| NZ (1) | NZ249217A (en) |
| TW (1) | TW279857B (en) |
| WO (1) | WO1993018027A1 (en) |
| ZA (1) | ZA931430B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5852014A (en) * | 1992-03-12 | 1998-12-22 | Smithkline Beecham P.L.C. | Condensed indole derivatives as 5HT4 -receptor antagonists |
| US5998409A (en) * | 1992-03-12 | 1999-12-07 | Smithkline Beecham Plc | Condensed indole derivatives as 5HT4 -receptor antagonists |
| JPH08502283A (en) * | 1992-10-16 | 1996-03-12 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | 5-HT 4) Fused ring system N-alkylpiperidinyl-4-methylcarboxylic acid ester / amide for receptor antagonist |
| GB9310582D0 (en) * | 1993-05-22 | 1993-07-07 | Smithkline Beecham Plc | Pharmaceuticals |
| IT1275903B1 (en) * | 1995-03-14 | 1997-10-24 | Boehringer Ingelheim Italia | ESTERS AND AMIDES OF 1,4-PIPERIDINE DISPLACED |
| HUP0101511A3 (en) | 1998-04-28 | 2002-12-28 | Dainippon Pharmaceutical Co | 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine derivatives, process for producing the same, medicinal compositions containing the same and intermediates of these compounds |
| AP2184A (en) | 2003-09-03 | 2010-12-02 | Pfizer | Benzimidazolone compounds having 5-HT4 receptor agonistic activity. |
| US7737163B2 (en) | 2004-06-15 | 2010-06-15 | Pfizer Inc. | Benzimidazolone carboxylic acid derivatives |
| AP2418A (en) * | 2004-06-15 | 2012-06-04 | Pfizer | Benzimidazolone carboxylic acid derivatives. |
| EP1758891A2 (en) | 2004-06-15 | 2007-03-07 | Pfizer Japan Inc. | Benzimidazolone carboxylic acid derivatives |
| JP2008509088A (en) * | 2004-09-02 | 2008-03-27 | ファイザー株式会社 | Benzimidazolonecarboxylic acid derivatives |
| AU2006217534B8 (en) | 2005-02-22 | 2011-12-08 | Pfizer Inc. | Oxyindole derivatives as 5HT4 receptor agonists |
| CA2601458C (en) | 2005-03-15 | 2011-04-26 | Pfizer Inc. | Benzimidazolone derivatives as cb2 receptor ligands |
| ES2691671T3 (en) * | 2010-06-24 | 2018-11-28 | Alkermes Pharma Ireland Limited | Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3687980T2 (en) * | 1986-01-07 | 1993-06-17 | Beecham Group Plc | INDOLDER DERIVATIVES WITH AN AZABICYCLIC SIDE CHAIN, METHOD FOR THEIR PRODUCTION, INTERMEDIATE PRODUCTS AND PHARMACEUTICAL COMPOSITIONS. |
| IT1231413B (en) * | 1987-09-23 | 1991-12-04 | Angeli Inst Spa | BENZIMIDAZOLIN-2-BONE-1-CARBOXYLIC ACID DERIVATIVES USEFUL AS 5-HT RECEPTOR ANTAGONISTS |
-
1992
- 1992-03-03 GB GB929204565A patent/GB9204565D0/en active Pending
-
1993
- 1993-02-25 NZ NZ249217A patent/NZ249217A/en unknown
- 1993-02-25 EP EP93904259A patent/EP0629198A1/en not_active Withdrawn
- 1993-02-25 CA CA002131381A patent/CA2131381A1/en not_active Abandoned
- 1993-02-25 JP JP5515422A patent/JPH07504428A/en active Pending
- 1993-02-25 WO PCT/GB1993/000395 patent/WO1993018027A1/en not_active Application Discontinuation
- 1993-02-25 AU AU35718/93A patent/AU666357B2/en not_active Ceased
- 1993-03-01 ZA ZA931430A patent/ZA931430B/en unknown
- 1993-03-02 MX MX9301157A patent/MX9301157A/en unknown
- 1993-03-20 TW TW082102087A patent/TW279857B/zh active
-
1994
- 1994-09-02 KR KR1019940703105A patent/KR950700285A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993018027A1 (en) | 1993-09-16 |
| NZ249217A (en) | 1996-06-25 |
| JPH07504428A (en) | 1995-05-18 |
| TW279857B (en) | 1996-07-01 |
| ZA931430B (en) | 1993-10-22 |
| EP0629198A1 (en) | 1994-12-21 |
| MX9301157A (en) | 1994-07-29 |
| AU666357B2 (en) | 1996-02-08 |
| GB9204565D0 (en) | 1992-04-15 |
| AU3571893A (en) | 1993-10-05 |
| KR950700285A (en) | 1995-01-16 |
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