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WO1994008995A1 - Heterocyclic condensed benzoic acid derivatives as 5-ht4 receptor antagonists - Google Patents

Heterocyclic condensed benzoic acid derivatives as 5-ht4 receptor antagonists Download PDF

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Publication number
WO1994008995A1
WO1994008995A1 PCT/EP1993/002809 EP9302809W WO9408995A1 WO 1994008995 A1 WO1994008995 A1 WO 1994008995A1 EP 9302809 W EP9302809 W EP 9302809W WO 9408995 A1 WO9408995 A1 WO 9408995A1
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Prior art keywords
hydrogen
alkyl
amino
halo
piperidinylmethyl
Prior art date
Application number
PCT/EP1993/002809
Other languages
French (fr)
Inventor
Laramie Mary Gaster
Keith Raymond Mulholland
Original Assignee
Smithkline Beecham Plc
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Publication date
Priority claimed from GB929221482A external-priority patent/GB9221482D0/en
Priority claimed from GB929221769A external-priority patent/GB9221769D0/en
Priority claimed from GB929223139A external-priority patent/GB9223139D0/en
Priority claimed from GB929223137A external-priority patent/GB9223137D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to EP93924035A priority Critical patent/EP0664806A1/en
Priority to AU53695/94A priority patent/AU5369594A/en
Publication of WO1994008995A1 publication Critical patent/WO1994008995A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Compounds of formula (I), wherein formula (I) consists of formulae (I-1) to (I-4), and pharmaceutically acceptable salts thereof, and the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, (I-1), (I-2), (I-3), (I-4) and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders. The compounds are 5-HT4 receptor antagonists.

Description


  
 



  HETEROCYCLIC CONDENSED BENZOIC ACID DERIVATIVES AS 5-HT4 RECEPTOR ANTAGONISTS
 This invention relates to novel compounds having pharmacological activity, to
 a process for their preparation and to their use as pharmaceuticals.



   European Journal of Pharmacology 146 (1988), 187-188, and
 Naunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non
 classical 5-hydroxytryptamine receptor, now designated the 5-HT4 receptor, and that
 ICS 205-930, which is also a 5-HT3 receptor antagonist, acts as an antagonist at this
 receptor. WO 91/16045   (SmithKiine    and French Laboratories Limited) describes the
 use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrhythmias and
 stroke.



   EP-A-501322 (Glaxo Group Limited) describes indole derivatives having
 5-HT4 antagonist activity.



   WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and
 PCT/GB93/00506 (SmithKline Beecham plc) describe compounds having 5-HT4
 receptor antagonist activity.



   EP-A-234872 (Adria Laboratories Inc.) and EP-A-493041 (Erabomont Inc.),
 describe benzobicyclic   carboxamides.    EP-A-339950 (Rorer International Overseas
 Inc.) describes dibenzofurancarboxamides as   5-HT3    receptor antagonists.



   WO 92/09284 describes a process for preparing multicyclic oxy-containing ring
 system compounds as   5-HT3    receptor antagonists.



   It has now been discovered that certain novel compounds also have 5-HT4
 receptor antagonist properties.



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



   Accordingly, the present invention provides compounds of formula (I),
 wherein formula (I) consists of formulae   (In1)    to   (I-4),    and pharmaceutically
 acceptable salts thereof, and the use of a compound of formula (I) or a
 pharmaceutically acceptable salt thereof:

  :
EMI1.1     
 wherein   X is O or S;   
R1 is hydrogen, amino, halo,   C16    alkyl, hydroxy   or C 1-6    alkoxy;  
R2 is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy, nitro, amino or C1-6 alkylthio;
R3 is hydrogen, halo,   C16    alkyl, C1-6 alkoxy or amino;   R4    is hydrogen or C1-6 alkyl;
EMI2.1     
 wherein
X is O or S;
A represents a single bond, -CH2-, or CO or A is (CH2)a-E-(CH2)b where one of a
 and   b is 0 and the other is 0 or    1 and E is O, S or NH;
R1 is hydrogen, amino, halo, C1-6   alkyl,    hydroxy or C1-6 alkoxy;
R2 is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy, nitro, amino or C1-6 alkylthio;
R3 is hydrogen, halo,   C 1 -6    alkyl,   C 1 -6    alkoxy or amino;

  ;   R4    is hydrogen or   C1.6    alkyl;
EMI2.2     
 wherein
X is O or S;
A represents a single bond, -CH2-, or CO or A is (CH2)a-E-(CH2)b where one of a
 and b is 0 and the other is   0    or 1 and E is O, S or   NH;    f and g are both hydrogen or together are a bond;
R 1 is hydrogen, amino, halo, C 1-6   alkyl,    hydroxy or C 1-6 alkoxy;
R2 is hydrogen, halo, C1-6 alkyl,   C1 6    alkoxy, nitro, amino or   C1 6    alkylthio;
R3 is hydrogen, halo,   C 1 -6    alkyl,   C 1 -6    alkoxy or amino;   R4    is hydrogen or C 1-6 alkyl;
EMI2.3     
  
 wherein
 X is O or S;
 R1 is hydrogen, amino, halo,   C1 6    alkyl, hydroxy or C1-6 alkoxy;

  ;
 R2 is hydrogen, halo,   C1 6    alkyl,   C1 6    alkoxy, nitro, amino or   C1 6    alkylthio;
 R3 is hydrogen, halo,   C1 6    alkyl, C1-6 alkoxy or amino;
 R4' and   R4    are independently hydrogen or   C1 6    alkyl;
In formulae (I-1) to (I-4) inclusive:
 Y is O or NH;
 Z is of sub-formula (a), (b) or (c):
EMI3.1     

 wherein
 nÚ is 0, 1,2,3 or 4; nê is 0,   1, 2, 3 or 4; n3 is 2, 3, 4 or 5;   
   qisO,    1, 2 or 3;

   p is 0, 1 or 2;   mis      0,1    or 2;
 R5 is hydrogen,   C1 12    alkyl, aralkyl or R5 is   (CH2)Z-Rlo    wherein z is 2 or 3
 and R10 is selected from cyano, hydroxyl,   C1 6    alkoxy, phenoxy,
   C(O)C1.6    alkyl, COC6H5,   -CONR1 1R12,      NR1 1C0R12,   
   S02NR11R12    or NR11 SO2 R12 wherein   R11    and R12 are hydrogen
 or   C1 6    alkyl; and
 R6, R7 and R8 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;

   in the manufacture of a medicament having 5-HT4 receptor antagonist activity.  



   Examples of alkyl or alkyl containing groups include C1, C2, C3, C4,   Cg,    C6,
C7, Cg, Cg, C10, C11 or C12 branched, straight chained or cyclic alkyl, as appropriate.   C1 4    alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, secand 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.



  In formula   (In1):   
 R1 is preferably hydrogen or amino.



   R2 is preferably hydrogen or halo.



   R3 is preferably hydrogen or halo.



   R4 is often hydrogen.



  In formula   (I-2):   
 R1 is preferably hydrogen or amino.



   R2 is preferably hydrogen or halo.



   R3 is preferably hydrogen or halo.



   R4 is often hydrogen.



  In formula   (I-3):   
 R1 is preferably hydrogen or amino.



   R2 is preferably hydrogen or halo.



   R3 is preferably hydrogen or halo.



   R4 is often hydrogen.



  In formula   (I-4):   
 R1 is preferably hydrogen or amino.



   R2 is preferably hydrogen or halo.



   R3 is preferably hydrogen or halo.



     R4    and   R4    are often hydrogen.



   A suitable bioisostere for the amide or ester linkage containing Y in formula (I), is of formula (d):  
EMI5.1     
 wherein the dotted circle represents one or two double bonds in any position in the
 5-membered ring; H, J and I independently represent oxygen, sulphur,
 nitrogen or carbon, provided that at least one of H, J and I is other than
 carbon; U represents nitrogen or carbon.



   Suitable examples of (d) are as described for X, Y and Z in EP-A-328200 (Merck Sharp  & Dohme Ltd.), such as an oxadiazole moiety.

 

   Y is preferably 0 or   NH.   



   When Z is of sub-formula (a),   nl    is preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n1 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 (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 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 (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:
EMI5.2     
  
EMI6.1     

 The invention also provides novel compounds within formula (I) with side chains (i), (ii), (iii), (iv), (v), (vi) or (vii). In a further aspect, the piperidine ring in (i), (ii) or (iii) may be replaced by pyrrolidinyl or azetidinyl, and/or the N-substituent in (i) or   (ii)    may be replaced by C3 or larger alkyl or optionally substituted benzyl.



   In an alternative aspect, the N-substituent in formula (i) or (ii) may be replaced by (CH2)nR4 as defined in formula (I) and in relation to the specific examples of EP-A-501322.



   The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric,   a-glycernphosphoric,    and   glucose-l-phosphoric    acids.



   Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds   RX-T    wherein Rx is C 1-6 alkyl, phenyl-C 1-6 alkyl or   Cos 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.



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



   The compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.



   The compounds of formula (I) wherein CO-Y is an ester or amide linkage are prepared by conventional coupling of the Z moiety with the appropriate acid.



  Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A, EP-A-36269, EP-A-289170 and   WO    92/05174 (Beecham Group p.l.c.).



  When CO-Y is replaced by a heterocyclic bioisostere, suitable methods are described in EP-A-328200 (Merck Sharp  & Dohme Limited). Reference is also made to
EP-A-501322 (Glaxo Group Limited).



   The invention also comprises a process for preparing the novel compounds of formula (I) which comprises reacting an appropriate acid derivative with an appropriate alcohol or amine. A process comprises reacting an acid derivative wherein the aromatic substituents are as required in the end compound of formula (I), or substituents convertible thereto, with an alcohol or amine containing Z or a group convertible thereto, and thereafter if necessary, converting the benzoic acid substituents and/or Z, and optionally forming a pharmaceutically acceptable salt.



   Suitable examples of conversions in the aromatic substituents include chlorination of hydrogen to chloro, reduction of nitro to amino, dehydrohalogenation such as debromination. Any elaboration is, however, usually carried out prior to ester or amide coupling.



   Suitable examples of conversions in the Z containing moiety include conventional modifications of the N-substituent by substitution and/or deprotection or, in the case of a 2-, 3- or 4- substituted piperidinyl desired end compound, reduction of an appropriate pyridyl derivative.



   The compounds of the present invention are 5-HT4 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.



   They are of potential interest in the treatment of irritable bowel syndrome (IBS), in particular the diarrhoea aspects of IBS, i.e., these compounds block the ability of 5-HT to stimulate gut motility via activation of enteric neurones. In animal models of IBS, this can be conveniently measured as a reduction of the rate of defaecation. They are also of potential use in the treatment of urinary incontinence which is often associated with IBS.



   They may also be of potential use in other gastrointestinal disorders, such as those associated with upper gut motility, and as antiemetics. In particular, they are of potential use in the treatment of the nausea and gastric symptoms of gastro  oesophageal reflux disease and dyspepsia. Antiemetic activity is determined in known animal models of cytotoxic-agent/radiation induced emesis.



   Specific cardiac 5-HT4 receptor antagonists which prevent atrial fibrillation and other atrial arrhythmias associated with 5-HT, would also be expected to reduce occurrence of stroke (see A.J. Kaumann 1990,   Naumyn-Schmiedeberg's    Arch.



  Pharmacol. 342, 619-622, for appropriate animal test method).



   Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity can be demonstrated in standard animal models, the social interaction test and the X-maze test.



   Migraine sufferers often undergo situations of anxiety and emotional stress that precede the appearance of headache (Sachs, 1985, Migraine, Pan Books,
London). It has also been observed that during and within 48 hours of a migraine attack, cyclic AMP levels are considerably increased in the cerebrospinal fluid (Welch   et al.,    1976, Headache 16, 160-167). It is believed that a migraine,- including the prodomal phase and the associated increased levels of cyclic AMP are related to stimulation of 5-HT4 receptors, and hence that administration of a 5-HT4 antagonist is of potential benefit in relieving a migraine attack.



   Other CNS disorders of interest include schizophrenia, Parkinson's disease and
Huntingdon's chorea.



   The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.



   Such compositions are prepared by admixture and are usually adapted for enteral such as oral, nasal or rectal, or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositories, injectable and infusable solutions or suspensions. Orally administrable compositions are preferred, since they are more convenient for general use.

 

   Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.



   Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.  



   Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.

  Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.



   Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.



   The oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.



  Such operations are, of course, conventional in the art.



   For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.



   Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle.



  Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.  



   The invention further provides a method of treatment or prophylaxis of irritable bowel syndrome, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.



   An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal. However, a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.5 to 500mg, of the compound of the invention. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.



   No adverse toxicological effects are indicated within the aforementioned 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 particular for use in the treatment of irritable bowel syndrome, gastro-oesophageal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine.



   The following Examples illustrates the preparation of compounds of formula (I), and the following Descriptions relate to the preparation of intermediates. The compounds of formula (I-1) and intermediates are prepared in Examples and
Descriptions   1-1,2-1    etc, the compounds of formula   (I-2)    are prepared in Examples and Descriptions 1-2, 2-2 etc and similarly for the compounds of formulae   (I-3)    to   (1.4).   



   It will be appreciated that any compound prepared wherein Y is 0 may be provided as the corresponding compound wherein Y is   NH.   



   A preferred compound corresponds to any of the compounds prepared in the
Examples, but wherein there is an amino substituent in the 4-position and a chloro substituent in the 5-position of the benzoic acid nucleus depicted in formulae   (In1)    to   (1-4) inclusive.     



  Description 1-1 (intermediate for Example 1-1) a)   Methyl-4-acetylamino-3-allyl-5-chloro-2-hydroxybenzoate   
 A mixture of methyl 4-acetylamino-5-chloro salicylate (EP-A-0339950), (17.0g, 0.070 mol), allylbromide (6.32 ml, 0.073 mol), acetone (350 ml) and potassium carbonate (19.35g, 0.140 mol) was heated to reflux with stirring. After 23h, the reaction mixture was allowed to cool, was filtered, and the filtrate evaporated under reduced pressure and dried in vacuo to give a pale brown solid. The solid was redissolved in 1,2-dichlorobenzene (300 ml) and was heated to reflux with stirring.



  After 24h the reaction mixture was allowed to cool, and was evaporated under reduced pressure. The resultant semi-solid brown residue was then purified by silica gel chromatography (2:1 Pentane: EtOAc    <     EtOAc as eluant) to give the title   compound    (8.24g, 42%) as a yellow solid.



     H    NMR (200 MHz, CDCl3)   :    11.10 (s, 1H),   7.81 (s,      1H),    7.04 (s,   1H),    5.88 (m, 1H), 5.00 (m, 2H), 3.95 (s, 3H), 3.45 (d, 2H), 2.25 (s, 3H).



  b)   Methyl-4-acetylamino-5-chloro-2-hydroxy-3-(2-oXoethyl)    benzoate
 The product from a) (8.23g, 0.029 mol) was dissolved in acetone (300 ml) and water (60 ml), treated with N-methylmorpholine-N-oxide (6.79g, 0.058 mol), followed by 4% wt osmium tetroxide in water (1.82 ml, 0.0029 mol) and stirred at room temperature overnight. After 21 h, 10% sodium   bisulphite    solution (100 ml) was added, and the mixture was stirred for   1/2    h, before the acetone was evaporated under reduced pressure. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2X), and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give an off white solid, which was dried   in    vacuo. 

  The solid was then redissolved in methanol (250 ml) and treated with a solution of sodium periodate (9.41g, 0.044 mol) in water (60 ml) with stirring. The mixture was then stirred at room temperature overnight, before the methanol was removed in vacuo. The residue was then partitioned between EtOAc and water. The aqueous layer was then extracted with
EtOAc, and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a dark brown oil.

  The oil was then purified by the silica-gel chromatography (EtOAc as eluant) to give the title compound as a brown foam (5.90g, 71%) 1H NMR (200 MHz,   CD30D)      b:    8.00 (s,   1H),    4.92 (t, 1H), 4.10 (s, 3H), 3.12 (d, 2H), 2.33 (s, 3H)  c)   2-Acetoxy-7-carbomethoxy-5-chloro-4-diacetvlamino-2,3-    dihydrobenzofuran
 The product from b) (5.90g, 0.021 mol) was dissolved in a mixture of acetic anhydride (55 ml) and pyridine (55 ml), a few crystals of   4-dimethylaminopyridine    were added, and the mixture was stirred at room temperature overnight. After 20h, the reaction mixture was partitioned between EtOAc and water.

  The aqueous layer was then extracted with EtOAc, and the combined organic layers were dried (Na2SO4), and evaporated under reduced pressure to give a brown oil, which was dried in vacuo. The oil was then purified by silica-gel chromatography (2:1
Pentane:EtOAc as eluant) to give the title compound as a pale brown oil. (2.87g, 37%) 1H NMR (250 MHz,   CDC13),      â:    8.00 (s,   1H),    7.00 (dd,   1H),    3.92 (s, 3H), 3.38 (dd,   lH),    3.00 (dd,   1H),    2.32 (s, 3H), 2.28 (s, 3H), 2.10 (s, 3H).



  d)   7-Carbomethoxy-5-chloro-4-diacetylaminobenzo[b]furan   
 The product from c) (2.87g, 7.77 mmol) was dissolved in   trifluoroacetic    acid (50 ml) and heated to reflux with stirring. After   lh,    the reaction mixture was allowed to cool and was evaporated under reduced pressure. The residue was partitioned between aq.   NaMCO3    and dichloromethane. The aqueous layer was then extracted with dichloromethane (2x), and the combined organic layers were dried (Na2SO4), and evaporated under reduced pressure to give a brown oil, which was purified by silica-gel chromatography (1:1 Petrol: diethylether as eluant) to give the title compound as a pale yellow oil (0.765g, 32%).



  1H NMR (250 MHz, CDCl3),   6:    8.10 (s, 1H), 7.81 (d, 1H), 6.70 (d,   1H),    4.10 (s, 3H), 2.30 (s. 6H).



  Description 2-1 (intermediate for Example 2-1) a) (2-Carboxyphenylthio) Acetic Acid
 A solution of thiosalicylic acid   (10.on;    64.9 mmol) in   H2O    (200 ml) containing sodium carbonate (34.5g; 0.32 mol) was treated   with    sodium chloroacetate (7.56g; 64.9 mmol) in   H2O    (100 ml). The whole was heated at reflux (2 hours), cooled and acidified to pH2 with c.HCl.

  The material that crystallised was collected by filtration and dried in vacuo to yield the title compound as an orange powder (12.5g; 91%) 1H NMR (250MHz; CD3SOCD3)   â:    13.10 - 12.85 (bs, 2H), 7.90 (d, 1H), 7.50 (t, 1H), 7.35 (d,   1H),    7.20 (t,   1H),    3.80 (s, 2H)  b)   Thioindoxyl.7-carboxylic    Acid
 (2-Carboxyphenylthio)acetic acid (6.5g; 30.66 mmol) was heated at reflux in thionyl chloride (45 ml) for 1 hour, cooled, evaporated in vacuo and the residue azeotroped with toluene. The residue was redissolved in 1,2-dichlorobenzene (8.0 ml) and treated with aluminium chloride   (8. 18g;    61.3 mmol) portionwise. The whole was heated to   45-50"    C (1 hour) then treated with ice and sodium hydroxide until the mixture was basic.

  The aqueous layer was separated, extracted with diethyl ether and then acidified with cHCl to pH1 and left to stand. The precipitate that formed was collected by filtration and dried in vacuo to yield the title compound as a red powder (2.45g; 41%) 1H NMR (250MHz; CD3SOCD3)   6:    8.05-7.95 (m, 2H), 7.50 (t, 1H), 6.55 (s, 1H) c) Benzothiophene-7-carboxylic Acid
 A solution of thioindoxyl-7-carboxylic acid (0.3g; 1.55 mmol) in glacial acetic acid   (5ml)    was treated with   zine    amalgam (made from zinc dust (1.14g) and the whole heated at reflux (18h), cooled, filtered through kieselguhr and the filtrate evaporated in vacuo to yield the title compound and 2,3-dihydrobenzothiophene-7carboxylic acid (1:1) as a red solid (0.152g; 55%).



  1H NMR (250 MHz, CD3SOCD3)   6:    8.15 (d, 1H), 8.05 (d,   1H),    7.85 (d, 1H), 7.50 (t,   2H)      
Example 1-1 [R1 =NH2,R2=Cl,R3=M,R4=M,X=O,Y=NM,Z=(i)] (1.Butyl.4.piperidinylmethyl).4.amino.5.chloro-benzo[b] furan.7-carboxamide   
 The product from Description 1 (0.765g, 2.47mmol) was dissolved in a mixture of 10% sodium hydroxide (15 ml) and ethanol (15 ml). The reaction mixture was then heated to reflux. After 23 h, the reaction mixture was allowed to cool. The ethanol was then removed by evaporation under reduced pressure and the aqueous residue acidified to pH2 using c. HCI. The resulting grey solid was then filtered off and dried in vacuo.

  The solid was then suspended in a mixture of acetonitrile (10 ml) and DMF (10 ml) and was treated with   1,1,carbonyldiimidazole    (0.440g, 2.71 mmol) with stirring. After 20h, the reaction mixture was evaporated under reduced pressure and dried in vacuo. The crude imidazolide was then suspended in dry   TMF    (20 ml) and N-butyl-4-piperidinylmethylamine (0.461g, 2.71 mmol) (W093/05038) in dry   TMF    (5 ml) was added. The mixture was then heated to reflux under argon. After 4 h, the reaction mixture was allowed to cool and was evaporated under reduced pressure. The residue was partitioned between EtOAc and 10% NaOH.

  The aqueous layer was then extracted with EtOAc, and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a brown solid, which was  purified by silica-gel chromatography (20% MeOH/EtOAc as eluant) to give the title compound as a white foam (0.425g, 46%) m.pt   88-89"    C (from CH2C12/60-80 petrol) 1H NMR (200MHz,   CDC13),      o:    8.04 (s,   1H),    7.64 (d,   1H),7.35    (brt,   1H),    6.81 (d,   1H),    4.71 (s, 2H), 3.43 (t, 2H), 2.97 (d, 2H), 2.33 (t, 3H),   2.05. 1.60    (m,   5H),    1.55- 1.20 (m, SH), 0.91 (t, 3H).



  Example 2-1 [R1   =H,R2=H,R3=H,R4=H,X=S,Y=O,Z=(i)]    (1-Butyl-4-piperidinylmethyl)benzothiophene.7.carboxylate
 A 1:1 mixture of benzothiophene-7-carboxylic acid and 2,3-dihydrobenzothiophene-7-carboxylic acid (0.262g; 1.46 mmol) was dissolved in dry DMF   (semi)    and treated with 1,1-carbonyldiimidazole   (0.161g;    1.61 mmol). The mixture was stirred (72 hours).   N-butyl.4-piperidinylmethanol    (WO 93/05038) (0.275g; 1.61 mmol) was dissolved in dry THF (10 ml) under Ar and treated with methyllithium (1.18 ml of a 1.5M solution in Et2O; 1.77 mmol) then stirred for 15 minutes. This was treated with the solution of imidazolides and the whole stirred (72 hours). Evaporated in vacuo and partitioned H2O/EtOAc.

  The organic layer was separated, dried over Na2SO4 and filtered, then the filtrate evaporated in vacuo to an orange oil. The oil was purified by flash silica-gel chromatography and eluted with   CHC13      o      3%      MeOH/CHC13    to yield a brown oil which was purified by   HPLC    separation to y ield the title compound as a clear gum (0.009g; 2%).



  1H NMR (250 MHz;   CDC13)    6: 8.15 (d, 1H), 8.05 (d,   1H),    7.60 (d, 1H), 7.30 (d, 1H), 7.05 (t, 1H), 4.30 (d, 2H), 3.05-2.95 (m, 2H), 2.35 (t, 2H), 2.00-1.75 (m,   5H),    1.60-1.25 (m, 6H), 0.90 (t, 3H).



     
Example3-1 [Rl=H,R2=Cl,R3=H,R4=H,X=O,Y=O,Z=(i)] (1 -Butyl4-piperidinylmethyl)-5-chlorobenzo[b]furan-7-carboxylate   
 5-Chlorobenzo[b]furan-7-carboxylic acid [US patent 4888353; 33f] (0.5g; 2.54 mmol) was suspended in thionyl chloride (20 ml) and heated at reflux (30 minutes) until clear. The solution was evaporated in vacuo and the residue redissolved in dry THF (10 ml).   N-butyl-4-piperidinylmethanol    (WO 93/05038) (0.479g; 2.80 mmol) was dissolved in dry THF (5 ml) under Ar and treated with methyllithium (2.05 ml of a   1.5M    solution in diethyl ether; 3.08 mmol). The mixture was stirred at (15 minutes) and treated with the acid chloride solution dropwise. 

  The solution was stirred (18 hours) evaporated in vacuo and the residue purified by flash silica gel chromatography with   CHC13       <     5% EtOH/CHC13 as eluant to yield a pale yellow oil/solid. This material was triturated with pentane, cooled to   -78"    C and the solid that formed collected by filtration and dried in vacuo to yield the title  compound as a pale yellow solid (0.1   lg;    13%), mp =   39-40"    C.



  1H NMR (CDCl3, 250 MHz) 6: 7.90 (d,   1H),    7.80 (dd, 2H), 6.80 (d, 1H), 4.30 (d, 2H), 3.05 (d, 2H), 2.40 (t, 2H), 2.10-1.80 (m, SH), 1.65-1.25 (m, 6H), 0.95 (t,   3H)      
Example4.1 [R1=H,R2=Cl,R3=H,R4=M,X=O,Y=NH,Z=(i)j (1-Butyl-4-piperidinylmethyl)-5-chlorobenzo[b]furan-7-carboxamide    5-chlorobenzo[b]furan-7-carboxylic acid [US patent 4888353; 33f] (0.18g; 0.92 mmol) was suspended in thionyl chloride (2 ml) and heated at reflux (30 minutes) until clear. The mixture was cooled, evaporated in vacuo and the residue azeotroped with toluene. The residue was redissolved in dry   TMF    (4 ml) and treated with triethylamine (0.13 ml; 0.92 mmol) and   N-butylA-piperidinylmethylamine    (W093/05038) (0.171g; 1.01 mmol).

  The solution was stirred at RT (1 hour), evaporated in vacuo and partitioned H2O/CHCl3. The organic phase was dried over
Na2SO4, filtered and evaporated in vacuo to a yellow oil. The oil was purified by flash silica-gel chromatography with CHCl3    <     2%   MeOH/CMCl3    as eluant to yield the title compound as a pale yellow oil (0.3g; 94%), which was converted to the oxalate salt, mp =   109-110     C.



  1H NMR (250 MHz, CDCl3) (free base)   :    8.10 (d,   1H),    7.75 (d, 1H), 7.70 (d,   1H),    7.55- 7.45 (m,   1H),    6.85 (d,   1H),    3.45 (t, 2H), 3.00 (d, 2H), 2.35 (t, 2H), 2.05 - 1.65 (m, SH), 1.55 - 1.25 (m, 6H), 0.90 (t, 3H).



  Description 1-2 (intermediate for Example 1-2)   Dibenzofuran.4.carboxylic    acid
 A solution of nBuLi (9.7 ml, 1.36 M in hexanes) in hexane (30 ml) was treated with N,N,N',N'-tetramethylethylenediamine (2.0 ml), followed by addition of dibenzofuran (2g). Stirring was continued at room temperature overnight. The mixture was poured onto solid   CO2    and diluted with water. The layers were separated, the aqueous layer acidified to pH2 with   5N    HCl and extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford title compound as an off-white solid (1.60g).



  1H NMR 250 MHz (d6-DMSO)   613.34(bs,1H),    8.42(d,1H),   8.21(d,1H),    8.04(d,1H),   7.80(d, 1H),    7.36-7.52(m,3H).  



     Example 1-2 [R1 = H, R2 = H, R3 = H, Rq = H, X = O, A is a single bond, Y = 0,
Z=(i)]    1-Butylpiperidin-4-ylmethyldibenzofuran-4-carboxylate hydrochloride
 To a solution of dibenzofuran-4-carboxylic acid (1.00g) in acetonitrile (50 ml) was added   1,lcarbonyldimidazole    (763 mg). Stirring was continued at room temperature for 2h. The solvent was concentrated in vacuo to afford crude imidazolide.



   Methyllithium (3.13 ml, 1.5 M in diethyl ether) was added dropwise to a solution of l-butyl-4-hydroxymethylpiperidine (808 mg) in dry THF (15 ml) at   OOC.   



  Stirring was continued at 0 C under a nitrogen atmosphere for 30 min. A solution of crude imidazolide in dry THF (20 ml) was added to the reaction mixture and stirring continued at room temperature overnight. Water (2 ml) was added and the solvent concentrated in vacuo. The residue was partitioned between chloroform and water.



  The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed on silica using chloroform and ethanol as eluant to afford pure ester. Treatment with ethereal   HCl    gave the title compound as a solid   (1.00g).   



  1H NMR 250   MMz    (CDCl3) (Free base) 6:   8.12((t,2H),      7.98(d,1H),      7.68(d,1H),    7.50(t,1H), 7.34-7.45(m,2H), 4.32(d,2H),   3.02(d,2H),      2.35(t,2H),    1.82-2.08(m,5H), 1.44-1.63(m,4H), 1.26-1.39(m,2H),   0.94(t,3H).   



  Example 2-2 [R1 = H, R2 = H, R3 = H, R4 = H, X = 0, A is-CM2-,   Y = 0, Z = (i)]      (1-Butyl 1-piperidinylmethyl)-9H-xanthene-4-carboxvlate   
 The title compound is prepared from 9H-xanthene-4-carboxylic acid (P.Yates et al., Can J. Chem., 1975, 53, 2045 and lithium   (1.butylpiperidin-4-yl)    methoxide via the imidazolide.



  Example 3-2   [R1 = H, R2 = H, R3 = H, R4 = H, X = O, A is -CO-, Y = O, Z = (i)]      (I-Butyl-4-piperidinylmethyl)-9-oxo-5 > H-xanthene-4-carboxylate   
 The title compound is prepared from 9-oxo-9H-xanthene-4-carboxylic acid (S.Akagi et   al.,J.Pharm.    Soc.

  Jpn., 1954, 74, 610) (R.Anschutz et al., Ber., 1922, 55, 686) and lithium   (1-butylpiperidin.4.yl)    methoxide via the imidazolide   Example4-2    [R1   =H,R2=H,R3=H,R4=H,X=O,Ais-NM-,Y=O,Z=(i)j    (1 -Butyl-4-piperidinylmethyl)-10H-phenoxazine-4-carboxylate
 The title compound is prepared from 10H -phenoxazine-4-carboxylic acid and lithium   (1-butylpiperidin-4-yl)    methoxide via the imidazolide  
Example 5-2 [R1 = H, R2 = H, R3 = H,   R4    = H, X = O, A is a single bond, Y = NH,
Z=(i)]   (1-Butyl"4-piperidinylmethyl)-1    -amino-2-chlorodibenzofuran-4-carboxamide
 The title compound was prepared from   1-amino-2-chlorodibenzofuran-4-    carboxylic acid (EP-A-0339950) according to the methodology described in Example 2-3,

   and was converted to its oxalate salt.



     m.pt 177-178  C    1H NMR (250 MHz, CDCl3), (Free base)   6:    8.12 (s,   1H),    7.78 (d, 1H), 7.54 (d,   1H),    7.42 (m, 3H), 4.93 (s, 2H), 3.43 (t, 2H), 2.92 (d, 2H), 2.28 (t, 2H), 1.91-1.65 (m,   5H),    1.48-1.35 (m, 6H), 0.87 (t, 3H).



  Example 6-2 [R1 = H, R2 = Cl, R3 = NH2,   R4    = H, X = O, A is a single bond, Y =
O,Z=(i)] (1.Butyl.4.piperidinylmethyl)-1-amino-2-chlorodibenzofuran-4-carboxylate
 The title compound was prepared from 1-amino-2-chlorodibenzofuran-4carboxylic acid (EP-A-0339950) according to the methodology described in Example 1-3 and was converted to its oxalate salt.



  mpt.   199.2000 C    1H NMR (250 MHz, CDCl3) (Free base) 6: 8.08 (s,   1H),    7.80 (d,   1H),    7.70 (d,   1H),    7.47 (m, 2H),   5.11 (S,    2H), 4.19 (d, 2H), 3.05 (bd, 2H), 2.39 (t, 2H), 2.12-1.80 (m,   5H),    1.54 (m, 4H), 1.32 (m, 2H), 0.94 (t, 3H).

 

  Example 7-2 [R1 = H,R2=Cl,R3 = R4 = H, X = O, A is a single bond, Y   =0,      Z=(i)]    (I-Butyl-4.piperidinylmethyl)-2-chlorodibenzofuran.4-carboxylate
 The title compound was prepared from   2-chlorodibenzofuran-4-carboxylic    acid (EP-A-0339950) according to the methodology described in Example 3-3.



  mpt.   80-82  C    1H NMR (250 MHz), CDCl3 (Free base)   6    8.12 (d, 1H), 8.05 (d,   1H),    7.92 (d,   1H),    7.68 (d,   1H),    7.53 (t,   1H),    7.40 (t,   1H),    4.32 (d, 1H), 3.03 (d, 2H), 2.38 (t, 2H), 2.10-1.82 (m, 5H), 1.55 (m, 4H), 1.32 (m, 2H), 0.90 (t, 3H).  



  Example 1-3   [R1 = H, R2 = H, R3 = H, R4 = H, X = 0, A is a single bond, f, g = H,      
Y=0,Z=(i)] (l-Butyl-4-piperidinylmethyl)-1-amino-2-chloro-Sa,6,7,8,9,9a- tetrahydrodibenzofuran-4-carboxylate   
   l-Amino-2-chloro-Sa,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic    acid (EP-A-0339950) (0.267g, 0.998 mmol) was suspended in acetonitrile and treated with bis-carbonyldiimidazole (0.178g, 1.098 mmol) with stirring. After 4 h, the reaction mixture was evaporated under reduced pressure and dried in vacuo to give the crude imidazolide as a white solid. Meanwhile, a solution of   l-butyl-4-piperidinemethanol    (WO 93/103725) (0.171g, 0.998 mmol) in dry THF (8 ml) was treated with   1.5M    methyllithium in Et2O (0.665 ml, 0.998 mmol) with stirring under argon.

  After 0.25 h, a suspension of the crude imidazolide in dry   TMF    (5 ml) was added slowly. After 24 h, the reaction mixture was evaporated under reduced pressure and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc and the combined organic layers were dried (Na2S04) and evaporated under reduced pressure to give a yellow oil, which was purified by silica-gel chromatography (5%
MeOH/CH2C12 as eluant) to give the title   compound    as a pale yellow oil (0.082g, 20%), which was converted to its oxalate salt m.pt.   105-107"C.   



  1H NMR (200 MHz,   CDC13)    (free base)   â:    7.68 (s,   1H),    4.70 (m,   1H),    4.35 (s, 2H), 4.12 (d, 2H), 3.13 (bd, 2H), 3.00 (m,   1H),    2.55-1.45 (m, 17H), 1.43-1.15 (m, 4H), 0.93 (t, 3H).



  Example 2-3 [R1 = H, R2 = Cl, R3 =   NH2,      R4    = H, X = O, A is a single bond, f, g, together are a bond, Y = NH, Z = (i)]   (1-Butyl-4.piperidinylmethyl)-    1-amino-2-chloro-5a,6,7,8,9,9a   tetrahydrodibenzofuran.4-carboxamide   
   1 -Amino-2-chloro-Sa,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic    acid (EP-A-339950) (0.292g, 1.092 mmol) was suspended in acetonitrile (20 ml) and treated with bis-carbonyldiimidazole   (0.1860,    1.46 mmol) with stirring. After 20h, the reaction mixture was evaporated under reduced pressure and dried in vacuo to give the crude imidazolide as a white solid.

  The imidazolide was then redissolved in dry   TMF    (10 ml) and   (l-butyl-4-piperidinyl)    methylamine (WO 93/05038) (0.204 g, 1.201 mmol) in dry THF (2 ml) was added under Ar. The mixture was then heated under reflux. After 8 h, the reaction mixture was allowed to cool, and was evaporated under reduced pressure. The residue was then partitioned between CH2C12 and aq.



  NaHC03. The aqueous layer was then extracted with CH2C12 (1X), and the combined organic layers were dried (Na2S04), and evaporated under reduced pressure to give a colourless oil, which was purified by chromatography (10%  
MeOH/CH2Cl2 as eluant) to give the title   compound    as a colourless oil (0.161 g, 35%) that was converted to its oxalate salt.



  m. pt   214-215"    C 1H NMR (250 MHz   CDC13)    (free base)   o:    7.82 (s, 1H), 7.54 (t, 1H), 4.72 (m, 1H), 4.29 (s, 2H), 3.32 (t, 2H), 3.03 (m, 3H), 2.32 (m, 3H), 2.12-1.15 (m, 18H), 0.91 (t, 3H)
Example 3-3 [R1 = H, R2 = Cl, R3 = H,   R4    = H, X = O, A is a single bond, f, g = H,   
Y =0, Z = (i)] (1-Butyl-4-piperidinylmethyl)-2-chloro-cts-5a,6,7,8,9,9a-    hexahydrodibenzofuran-4-carboxylate
   2-Chloro-cis-Sa,6,7,8,9,9a.hexahydrodibenzofuran-4-carboxylic    acid (EP-A-0339950),   (0.100g,    0.396 mmol) was suspended in thionyl chloride (5 ml) and heated to reflux with stirring.

  After Ih, the reaction mixture was allowed to cool, and was evaporated under reduced pressure to give a pale brown oil, which was dried in vacuo in give the crude acid chloride. Meanwhile a solution of   l-butyl-4-    piperidinylmethanol (0.075g,   0.436    mmol) in dry THF (3 ml) under argon was treated with 1.6M n-butyllithium (0.272 ml, 0.436 mmol). After 0.25h, a solution of the crude acid chloride in dry THF (5 ml) was added, and the resultant mixture stirred at room temperature overnight. The reaction mixture was then evaporated under reduced pressure and purified by silica-gel chromatography (2%   MeOH/CH2C12    as eluant) to give the title compound (0.071g, 44%) as a colourless oil, which was converted to its oxalate salt.



     m.pt 154-155  C    1H NMR (250 MHz,   CDC13)    (free base)   b:    7.70 (d,   1H),    7.20 (d,   1H),    4.85 (m, 1H), 4.18 (d, 2H), 3.25 (m,   1H),    3.05 (d, 2H), 2.43 (t, 2H), 2.13-1.70 (m, 8H), 1.65-1.25 (m, 11H), 0.95 (t, 3H).



  Example 4-3 [R1 = H, R2 = Cl, R3 = H,   R4    = H, X = O, A is a single bond,   f,g,    together are a bond, Y = 0, Z = (i)]   (1 .Butyl-4-piperidinylmethyl)-2-Chloro-6,7,8,9.tetrahydrodihenzofuran-4-    carboxylate
 The title compound was prepared from 2-chloro-6,7,8,9   tetrahydrodibenzofuran4-carboxylic    acid (EP-A-0339950) according to the methodology described in Example 3-3 and was converted to its oxalate salt.



     m.pt 188.1900 C     1H NMR (200 MHz,   CDC13)    (free base)    :    7.78 (d,   1H),    7.53 (d,   1H),    4.28 (d, 2H), 3.03 (d, 2H), 2.80 (t, 2H), 2.58 (t, 2H), 2.101.75 (m, 9H), 1.52-1.25 (m, 6H), 0.90 (t, 3H).



     Example 1-4 [X = O, R1 = H, R2 = Cl, R3, R4,, R4,,= H, Y = 0, Z = (i)]    10-(1-Butylpiperidin-4-ylmethyl)-8-chloro-3,4,5,6-tetrahydro-2,6-methano-2H-1-   benzoxadnecarboxylate   
The title compound is prepared from   8-chloro-3,4,5,6-tetrahydro-2,6-metliano-2H.1-    benzoxacin-10-carboxylic acid (R.D. Youssefyeh et al., J.Med.Chem. 1992, 35, 903) and lithium   (l-butylpiperidin-4-yl)    methoxide via the imidazolide.



     S-HT4    RECEPTOR ANTAGONIST ACTIVITY 1) Guinea pig colon
 Male guinea-pigs, weighing 250-400g are used. Longitudinal   muscie-    myenteric plexus preparations, approximately 3cm long, are obtained from the distal colon region. These are suspended under a   0.5g    load in isolated tissue baths containing Krebs solution bubbled with 5%   CO2    in    2    and maintained at   37"C.    In all experiments, the Krebs solution also contains methiothepin 10-7M and granisetron   1 0-6M    to block effects at   5-HT1,      5-HT2    and   5-HT3    receptors.



   After construction of a simple concentration-response curve with 5-HT, using 30s contact times and a 15min dosing cycle, a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40-70%   maximum(10-9M    approx). The tissue is then alternately dosed every   15min    with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant, dimethylphenylpiperazinium (DMPP). After obtaining consistent responses to both 5-HT and DMPP, increasing concentrations of a putative 5-HT4 receptor antagonist are then added to the bathing solution. The effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. 

  From this data,   pICso    values are determined, being defined as the -log concentration of antagonist which reduces the contraction by 50%. A compound which reduces the response to 5-HT but not to DMPP is believed to act as a 5-HT4 receptor   antagonist   
 The compounds generally had a   pICso    of at least 7.

Claims

Claims
1. Compounds of formula (I), wherein formula (I) consists of formulae (I-1) to (I-4), and pharmaceutically acceptable salts thereof, and the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: EMI21.1 wherein X is O or S; R1 is hydrogen, amino, halo, C1.6 alkyl, hydroxy or C1-6 alkoxy; R2 is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy, nitro, amino or C1.6 alkylthio; R3 is hydrogen, halo, C1.6 alkyl, C1.6 alkoxy or amino; R4 is hydrogen or C1.6 alkyl; EMI21.2 wherein X is O or S; A represents a single bond, -CH2-, or CO or A is (CH2)a-E-(CH2)b where one of a and b is 0 and the other is 0 or 1 and E is O, S or NH;
; R1 is hydrogen, amino, halo, C 1-6 alkyl, hydroxy or C1.6 alkoxy; R2 is hydrogen, halo, C1 6 alkyl, C1 6 alkoxy, nitro, amino or C1 -6 alkylthio; R3 is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy or amino; R4 is hydrogen or C1-6 alkyl; EMI21.3 wherein X is O or S; A represents a single bond, -CH2-, or CO or A is (CH2)a-E-(CH2)b where one of a and b is 0 and the other is 0 or 1 and E is O, S or NH;
f and g are both hydrogen or together are a bond; R1 is hydrogen, amino, halo, C16 alkyl, hydroxy or C16 alkoxy; R2 is hydrogen, halo, C16 alkyl, C16 alkoxy, nitro, amino or C16 alkylthio; R3 is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy or amino; R4 is hydrogen or C 1-6 alkyl; EMI22.1 wherein XisOorS; R1 is hydrogen, amino, halo, C1-6 alkyl, hydroxy or C1-6 alkoxy; R2 is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy, nitro, amino or C1-6 alkylthio; R3 is hydrogen, halo, C1 6 alkyl, C1 6 alkoxy or amino; R4' and R4,, are independently hydrogen or C1.6 alkyl; In formulae (I-1) to (I-4) inclusive:
: YisOorNH; Z is of sub-formula (a), (b) or (c): EMI22.2 EMI23.1 wherein n1 isO, 1,2,3or4;n2is0, 1,2,3 or 4;n 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-R1o 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, S 2NR1 1R12 or NR11S02R12 wherein R11 and R12 are hydrogen or C1-6 alkyl;
and R6, R7 and R8 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; in the manufacture of a medicament having 5-HT4 receptor antagonist activity.
2. A compound according to claim l wherein: In formula (I-): R1 is hydrogen or amino, R2 is hydrogen or halo, R3 is hydrogen or halo, R4 is hydrogen; In formula (I-2): R1 is hydrogen or amino, R2 is hydrogen or halo, R3 is hydrogen or halo, R4 is often hydrogen; In formula (I-3): R1 is hydrogen or amino, R2 is hydrogen or halo, R3 is hydrogen or halo, R4 is hydrogen; In formula (I-4): R1 is hydrogen or amino, R2 is hydrogen or halo, R3 is hydrogen or halo, R4 and R4 are hydrogen.
3. A compound according to claim 1 or 2 wherein the moiety attached to CO-Y-Z is that which is as contained in any of the Examples described herein.
4. A compound according to any one of claims 1 to 3 wherein Z is of sub-formula (a) and (CH2)n 1 is attached at a carbon atom of the azacycle.
5. A compound according to claim 4 wherein Z is N-substituted 4-piperidylmethyl.
6. A compound according to claim 5 wherein the N-substituent is C2 or greater alkyl, or optionally substituted benzyl.
7. (1 -Butyl-4-piperidinylmethyl)-4-amino-5-chlorobenzo[b]furan-7carboxamide, (1 -butyl-4-piperidinylmethyl)benzothiophene-7-carboxylate, (1 -butyl-4-piperidinylmethyl)-5-chlorobenzo[b]furan-7-carboxylate, or (1 -butyl-4-piperidinylmethyl)-5-chlorobenzo[b]furan-7-carboxamide.
8. 1-Butylpiperidin-4-ylmethyldibenzofuran-4-carboxylate, (1 -butyl-4-piperidinylmethyl)-9H-xanthene-4-carboxylate, (1 -butyl-4-piperidinylmethyl)-9-oxo-9M-xanthene.4-carboxylate, (1 -butyl-4-piperidinylmethyl)- 1 OH-phenoxazine-4-carboxylate, (1 -butyl-4-piperidinylmethyl)- 1 -amino-2-chlorodibenzofuran-4-carboxamide, (1 -butyl-4-piperidinylmethyl).1 -amino-2-chlorodibenzofuran-4-carboxylate, or (1 -butyl4-piperidinylmethyl)-2.chlorodibenzoThranA.carboxylate.
9. (1-Butyl-4-piperidinylmethyl)- 1 -amino-2-chlorn-Sa,6,7,8 ,9,9a- tetrahydrodibenzofuran-4-carboxylate, (1 -butyl-4-piperidinylmethyl). 1 -amino-2-chloro-Sa,6,7 8 ,9,9a- tetrahydrodibenzofuran-4-carboxamide, (1 -butyl-4-piperidinylmethyl)-2-chloro-cis-Sa,6,7,8,9,9a-hexahydrodibenzofuran-4- carboxylate, or (1 -butyl-4-piperidinylmethyl)-2.chloro-6,7 ,8,9-tetrahydrodibenzofuran-4- carboxylate.
10. 10-(1 -Butylpiperidin-4-ylmethyl)-8-chloro-3,4,5,6-tetrahydro-2,6-methano- 2H- 1 -benzoxacinecarboxylate.
11. A compound according to any one of claims 7 to 10 in the form of a pharmaceutically acceptable salt.
12. A compound according to any one of claims 7 to 10 but wherein Y is NH.
13. A process for preparing the ester or amide compounds (where Y is O or NH) according to claim 1, which comprises reacting an appropriate acid derivative with an appropriate alcohol or amine.
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, and a pharmaceutically acceptable carrier.
15. A compound according to claim 1 for use as an active therapeutic substance.
16. The use of a compound according to claim 1 in the manufacture of a medicament for use as a 5-HT4 receptor antagonist.
17. The use according to claim 16 for use as a 5-HT4 receptor antagonist in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.
PCT/EP1993/002809 1992-10-13 1993-10-12 Heterocyclic condensed benzoic acid derivatives as 5-ht4 receptor antagonists WO1994008995A1 (en)

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