Quiniclidine derivatives of (hetero) arylcycloheptanecarboxylic acid as muscarinic receptor antagonists

Abstract

The invention provides compounds of formula (I) wherein R 4 is a group of formula (II) or (IIIa) or (IIIb) and R 1 , R 2 , R 3 , R 5 , a, b and X are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions, their use in therapy and intermediates of use in their preparation

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 (i) R 1  is C 1 -C 6 -alkyl or hydrogen; and R 2  is hydrogen or a group —R 7 , —Z—Y—R 7 , —Z—NR 9 R 10 ; —Z—CO—NR 9 R 10 , —Z—NR 9 — [AE8] C(O)O—R 7 , or —Z—C(O)—R 7 ; and R 3  is a lone pair, or C 1 -C 6 -alkyl; or 
 (ii) R 1  and R 3  together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R 2  is a lone pair or a group —R 7 , —Z—Y—R 7 , —Z—NR 9 R 10 , —Z—CO—NR 9 R 10 , —Z—NR 9 — [AE9] C(O)O—R 7 ; or; —Z—C(O)—R 7 ; or 
 (iii) R 1  and R 2  together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group —Y—R 7 , —Z—Y—R 7 , —Z—NR 9 R 10 ; —Z—CO—NR 9 R 10 ; —Z—NR 9—   [AE10] C(O)O—R 7 ; or; —Z—C(O)—R 7 ; and R 3  is a lone pair, or C 1 -C 6 -alkyl; 
 R 4  and R 5  are independently selected from the group consisting of aryl, aryl-fused-heterocycloalkyl, heteroaryl, C 1 -C 6 -alkyl, cycloalkyl; 
 R 6  is —OH, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxy-C 1 -C 6 -alkyl, nitrile, a group CONR 8   2  or a hydrogen atom; 
 A is an oxygen or a sulfur atom; 
 X is an alkylene, alkenylene or alkynylene group; 
 R 7  is an C 1 -C 6 -alkyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(C 1 -C 6 -alkyl)-, heteroaryl(C 1 -C 6 -alkyl)-, cycloalkyl or heterocycloalkyl group; 
 R 8  is C 1 -C 6 -alkyl or a hydrogen atom; 
 Z is a C 1 -C 16 -alkylene, C 2 -C 16 -alkenylene or C 2 -C 16 -alkynylene group; 
 Y is a bond or oxygen atom; 
 R 9  and R 10  are independently a hydrogen atom, C 1 -C 6 -alkyl, aryl, aryl-fused-heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(C 1 -C 6 -alkyl)-, or heteroaryl(C 1 -C 6 -alkyl)- group; or R 9  and R 10  together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom; 
 
       or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof. 
     
     
         2 . A compound as claimed in  claim 1  wherein:
 R 1  is C 1 -C 6 -alkyl or a hydrogen atom; R 2  is C 1 -C 6 -alkyl, a hydrogen atom or a group —Z—Y—R 7  and R 3  is a lone pair or C 1 -C 6 -alkyl, or 
 R 1  and R 2  together with the nitrogen to which they are attached represent a heterocycloalkyl ring, or R 1  and R 3  together with the nitrogen to which they are attached represent a heterocycloalkyl ring; 
 R 4  and R 5  are independently selected from the group consisting of aryl, heteroaryl, C 1 -C 6 -alkyl, cycloalkyl; 
 R 9  is —OH, halogen, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl or a hydrogen atom; 
 A is an oxygen or a sulfur atom; 
 X is an alkylene, alkenylene or alkynylene group; 
 Z is an alkylene, alkenylene or alkynylene group; 
 Y is a bond or oxygen atom; 
 R 7  is aryl, heteroaryl, heterocycloalkyl. 
 
     
     
         3 . A compound as claimed in  claim 1  or  claim 2  wherein R 1  is methyl or ethyl, or a hydrogen atom; R 2  is hydrogen, C 1 -C 6 -alkyl, or a group —R 7 , —Z—Y—R 7 , —Z—NR 9 R 10 , —Z—CO—NR 9 R 10 , —Z—NR 9 —CO—R 7  or; —Z—C(O)—R 7 ; and R 3  is a lone pair, or C 1 -C 6 -alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge. 
     
     
         4 . A compound as claimed in  claim 3  wherein R 3  is methyl, so that the nitrogen atom to which it is attached is a quaternary, nitrogen and carries a positive charge. 
     
     
         5 . A compound as claimed in  claim 1  or  claim 2  wherein R 1  and R 3  together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl ring of from 3 to 7 ring atoms, in which the hetero-atoms are nitrogen; and R 2  is a lone pair or C 1 -C 6 -alkyl, or a group —R 7 , —Z—Y—R 5 , —Z—NR 9 R 10 , —Z—NR 9 —C(O)O—R 7  or —Z—C(O)—R 7 . 
     
     
         6 . A compound as claimed in  claim 5  wherein R 1  and R 3  together with the nitrogen to which they are attached form an azetidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, or pyrrolidinyl ring. 
     
     
         7 . A compound as claimed in  claim 5  or  claim 6  wherein the nitrogen atom to which R 1  and R 3 , or R 1  and R 2 , are attached is a quaternary nitrogen and carries a positive charge. 
     
     
         8 . A compound as claimed in any of the preceding claims wherein, in any group —R 7 , —Y—R 7 , —Z—Y—R 7 , —Z—NR 9 R 10 , —Z—CO—NR 9 R 10 , —Z—NR 9 —C(O)O—R 7  or; —Z—C(O)—R 7 :
 Z is —(CH 2 ) 1-8 —, optionally substituted on up to three carbons by methyl, 
 Y is a bond or —O—; 
 R 7  is methyl, ethyl, n- or isopropyl, n-, sec- or tertbutyl; or
 phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, naphthyl; or 
 pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl or Indazolyl; or 
 arylalkyl wherein the aryl part is phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, or naphthyl, and the —(C 1 -C 6 -alkyl)-part is —CH 2 — or —CH 2 CH 2 —; or 
 heteroarylalkyl wherein the heteroaryl part is pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl or indazolyl, and the —(C 1 -C 6 -alkyl)- part is —CH 2 — or —CH 2 CH 2 —; or 
 indanyl or 1,2,3,4-tetrahydronaphthalenyl; or 
 heterocycloalkyl(C 1 -C 6 -alkyl)-, wherein the heterocycloalkyl part is azetidinyl, piperidinyl, piperazinyl, N-substituted piperazinyl such as methylpiperazinyl, or tetrahydropyrrolyl and the —(C 1 -C 6 -alkyl)- part is —CH 2 — or —CH 2 CH 2 —. or 
 cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and 
 R 9  and R 10  are independently 
 hydrogen; methyl, ethyl or n- or isopropyl; 
 phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, naphthyl; 
 pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl or indazolyl; or 
 arylalkyl wherein the aryl part is phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, or naphthyl, and the —(C 1 -C 6 -alkyl)-part is —CH 2 — or —CH 2 CH 2 —; or R 9  and R 10  together with the nitrogen atom to which they are attached form an azetidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl ring. 
 R 9  and R 10  are independently selected from hydrogen; C 1 -C 6 -alkyl; or any of those optionally substituted aryl, aryl-fused-heterocycloalkyl heteroaryl or aryl(C 1 -C 6 -alkyl)- groups specifically defined for R 7  in this claim; or 
 R 9  and R 10  together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 ring atoms optionally containing a further nitrogen or oxygen atom. 
 
 
     
     
         9 . A compound as claimed in  claim 1  wherein, in the group —NR 1 R 2 R 3 , R 1  is methyl or ethyl, R 2  is —Z—NR 9 R 10  or —Z—Y—R 7 , Y is a bond or —O—, and —Z— is a straight or branched alkylene radical linking the nitrogen and —NR 9 R 10  or —YR 7  by a chain of up to 16 carbon atoms, and R 3  is methyl. 
     
     
         10 . A compound as claimed in  claim 9  wherein R 7  is phenyl, benzyl, dihydrobenzofuryl or phenylethyl. 
     
     
         11 . A compound as claimed in  claim 9  or  claim 10  wherein R 9  and R 10  are as defined in  claim 8   
     
     
         12 . A compound as claimed in  claim 1  wherein, in the group —NR 1 R 2 R 3 , R 2  is —Z—NR 9 R 10  or —Z—Y—R 7 , Y is a bond or —O—, and —Z— is a straight or branched alkylene radical linking the nitrogen and —NR 9 R 10  or —YR 7  by a chain of up to 16 carbon atoms, and R 1  and R 3  together with the nitrogen to which they are attached form a heterocyclic ring of 4-8 ring atoms, optionally containing a further nitrogen or oxygen atom. 
     
     
         13 . A compound as claimed in  claim 12  wherein R 1  and R 3  together with the nitrogen to which they are attached form an azetidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl ring. 
     
     
         14 . A compound as claimed in  claim 12  or  claim 13  wherein R 7  is preferably a cyclic lipophilic group such as phenyl, benzyl, dihydrobenzofuryl or phenylethyl. 
     
     
         15 . A compound as claimed in any of  claims 12  to  14  wherein R 9  and R 10  are as defined in  claim 8 . 
     
     
         16 . A compound as claimed in any of the preceding claims wherein R 4  and R 5  are independently selected from methyl, ethyl, n- or isopropyl, n-, sec- and tertbutyl; phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, naphthyl; pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl or indazolyl; indanyl and 1,2,3,4-tetrahydronaphthalenyl; cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and R 6  is —OH, a hydrogen atom, methyl, ethyl, hydroxymethyl, nitrile, or a group CONR 8   2  wherein each R 8  is independently methyl, ethyl, or a hydrogen atom. 
     
     
         17 . A compound as claimed in any of the preceding claims wherein (i) each of R 4  and R 5  is thienyl; or (ii) each of R 4  and R 5  is phenyl; or (iii) one of R 4  and R 5  is phenyl and the other is cyclopentyl or cyclohexyl; or (iv) one of R 4  and R 5  is thienyl, and the other is cyclopentyl or cyclohexyl. 
     
     
         18 . A compound as claimed in  claim 17  wherein R 6  is —OH. 
     
     
         19 . A compound as claimed in any of the preceding claims wherein R 8  is hydrogen. 
     
     
         20 . A compound as claimed in any of the preceding claims wherein X is —CH 2 — or —CH 2 CH 2 —. 
     
     
         21 . A compound as claimed in  claim 1  which has formula (IA) 
       
         
           
           
               
               
           
         
       
       wherein A is —O— or —S—; m is 1 or 2; ring A is an optionally substituted phenyl ring, or monocyclic heterocyclic ring of 5 or 6 ring atoms, or phenyl-fused-heterocycloalkyl ring system wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms; R 4  is phenyl, thienyl, cyclopentyl or cyclohexyl; R 5  is phenyl; thienyl, cyclopentyl or cyclohexyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 provided that s+t is not greater than 16; Y is a bond or —O—, and X −  is a pharmaceutically acceptable anion. 
     
     
         22 . A compound as claimed in  claim 1  which has formula (IB) 
       
         
           
           
               
               
           
         
       
       wherein A is —O— or —S—; m is 1 or 2; ring B is a pyrrolidinium or piperidinium ring; ring A is an optionally substituted phenyl ring, or monocyclic heterocyclic ring of 5 or 6 ring atoms, or phenyl-fused-heterocycloalkyl ring system wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms; R 4  is phenyl, thienyl, cyclopentyl or cyclohexyl; R 6  is phenyl; thienyl, cyclopentyl or cyclohexyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 provided that s+t is not greater than 16; Y is a bond or —O—, and X −  is a pharmaceutically acceptable anion. 
     
     
         23 . A compound as claimed in  claim 21  or  claim 22  wherein ring A is (i) optionally substituted phenyl, wherein optional substituents are selected from C 1 -C 3 alkoxy, halo, C 1 -C 3 -alkyl, amino C 1 -C 3 -acyl, and amino C 1 -C 3 -alkyl, or (ii) a phenyl-fused-heterocycloalkyl ring system wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms, such as dihydrobenzofuranyl. 
     
     
         24 . A compound as claimed in  claim 1  which has formula (IC) 
       
         
           
           
               
               
           
         
       
       wherein A is —O— or —S—; m is 1 or 2; ring B is a pyrrolidinium or piperidinium ring; R 4  is phenyl, thienyl, cyclopentyl or cyclohexyl; R 5  is phenyl; thienyl, cyclopentyl or cyclohexyl; R 9  and R 10  are independently a hydrogen atom, or optionally substituted C 1 -C 6 -alkyl or aryl, such as optionally substituted phenyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 provided that s+t is not greater than 16; Y is a bond or —O—, and X −  is a pharmaceutically acceptable anion. 
     
     
         25 . A compound as claimed in any of  claims 21  to  23  wherein t is 0, 1, 2, 3, 4, 5 or 6 and s is 1, 2, 3, 4, 5, 6 or 7 and s+t is 1, 2, 3, 4, 5, 6, or 7. 
     
     
         26 . A compound as claimed in  claim 21  or  claim 22  wherein t is 0, s is 3, and Y is —O—. 
     
     
         26 . A compound as claimed in  claim 21  or  claim 22  wherein Y is a bond and s+t is 2, 3 or 4. 
     
     
         27 . A compound as claimed in  claim 24  wherein Y is a bond and s+t is 8, 9 or 10. 
     
     
         28 . A compound as claimed in  claim 1 , selected from the group consisting of
 [2-(Hydroxy-diphenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium salts   [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium salts   [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-phenethyl-ammonium salts   [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(4-methyl-pent-3-enyl)-ammonium salts   [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-dimethyl-ammonium salts   [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(6-methyl-pyridin-2-ylmethyl)-ammonium salts   [2-(Cyclopentyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium salts   [2-(Cyclopentyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium salts   1-[2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-1-(3-phenoxy-propyl)-pyrrolidinium salts   [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(4-phenoxy-butyl)-ammonium salts   (2-Benzyloxy-ethyl)-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-ammonium salts   [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(4-phenyl-butyl)-ammonium salts   [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[3-(4-fluoro-phenoxy)-propyl]-dimethyl-ammonium salts   [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenyl-propyl)-ammonium salts   [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(2-phenoxy-ethyl)-ammonium salts   [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-p-tolyloxy-propyl)-ammonium salts   [3-(4-Chloro-phenoxy)-propyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-ammonium salts   [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[3-(3,4-dichloro-phenoxy)-propyl]-dimethyl-ammonium salts   [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(8-methylamino-octyl)-ammonium salts   [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-[2-(4-methylaminomethyl-phenyl)-ethyl]-ammonium salts   {2-[2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl]-ethyl}-dimethyl-(3-phenoxy-propyl)-ammonium salts   {2-[2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl]-ethyl}-dimethyl-(3-phenoxy-propyl)-ammonium salts, and   {2-[2-(Hydroxy-diphenyl-methyl)-oxazol-5-yl]-ethyl}-dimethyl-(3-phenoxy-propyl)-ammonium salts   [2-(Hydroxydiphenylmethyl)thiazol-5-ylmethyl]dimethyl-(3-phenoxypropyl)ammonium salts   (3-Benzyloxypropyl)-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-ammonium salts   [2-(4-Chloro-benzyloxy)-ethyl]-(2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl)-dimethyl-ammonium salts   
     
     
         29 . A compound as claimed in any of the preceding claims, modified by replacement of the R 2  group by a -L-B group wherein L is a linker radical and B is a moiety having β2 adrenoreceptor agonist activity. 
     
     
         30 . A compound as claimed in any of the preceding claims, for use in therapy. 
     
     
         31 . A pharmaceutical composition comprising a compound as claimed in any of  claims 1  to  29  and a pharmaceutically acceptable carrier or excipient. 
     
     
         32 . A pharmaceutical composition as claimed in  claim 31  in a form suitable for inhalation. 
     
     
         33 . Use of a compound as claimed in any of  claims 1  to  29  for the manufacture of a medicament for use in the treatment of prevention of a disease or condition in which M3 muscarinic receptor activity is implicated. 
     
     
         34 . A method of treatment of a disease or condition in which M3 muscarinic receptor activity is implicated comprising administration to a subject in need thereof of an effective amount of a compound as claimed in any of  claims 1  to  29   
     
     
         35 . Use as claimed in  claim 33  or a method of treatment as claimed in  claim 34 , wherein the disease or condition is a respiratory-tract disorder. 
     
     
         36 . Use as claimed in  claim 33  or a method of treatment as claimed in  claim 34 , wherein the disease or condition is a gastrointestinal-tract disorder. 
     
     
         37 . Use as claimed in  claim 33  or a method of treatment as claimed in  claim 34 , wherein the disease or condition is a cardiovascular disorder. 
     
     
         39 . Use as claimed in  claim 33  or a method of treatment as claimed in  claim 34 , wherein the disease or condition is chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, or allergic rhinitis; 
     
     
         38 . Use as claimed in  claim 33  or a method of treatment as claimed in  claim 34 , wherein the disease or condition is irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal convulsions or hyperanakinesia, diverticulitis, pain accompanying spasms of gastrointestinal smooth musculature; urinary-tract disorders accompanying micturition disorders including neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urinary urgency or pollakiuria; motion sickness; and cardiovascular disorders such as vagally induced sinus bradycardia. 
     
     
         40 . Use as claimed in  claim 33  or a method of treatment as claimed in  claim 34 , wherein the disease or condition is vagally induced sinus bradycardia.