Bicyclo[2.2.1]hept-7-ylamine derivatives and their uses

Abstract

Compounds of formula (I) have muscarinic M3 receptor modulating activity; wherein A is an oxygen atom or group —N(R 12 )—; (i) R 1 is C 1 -C 6 -alkyl or a hydrogen atom; and R 2 is a hydrogen atom or a group —R 5 , —Z—Y—R 5 , —Z—NR 9 R 10 ; —Z—CO—NR 9 R 10 ; —Z—NR 9 —CO—R 5 ; or —Z—CO 2 H; 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; 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 hydrogen atom; or a group —R 5 , —Z—Y—R 5 , —Z—NR 9 R 10 , —Z—CO—NR 9 R 10 , —Z—NR 9 —CO—R 5 , or —Z—CO 2 H, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; 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 5 , —Z—Y—R 5 , —Z—NR 9 R 10 ; —Z—CO—NR 9 R 10 ; —Z—NR 9 —CO—R 5 ; or —Z—CO 2 H 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; R 4 is a group of formula (a), (b), (c) or (d); is an C 1 -C 6 -alkyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(C 1 -C 8 -alkyl)-, heteroaryl(C 1 -C 8 -alkyl)-, cycloalkyl or heterocycloalkyl group, and the remaining variables are as defined in the specification.

1 . A compound of formula (I); 
       
         
           
           
               
               
           
         
         wherein 
         A is an oxygen atom or group —N(R 12 )—; 
         (i) R 1  is C 1 -C 6 -alkyl or a hydrogen atom; and R 2  is a hydrogen atom or a group —R 5 , —Z—Y—R 5 ,—Z—NR 9 R 10 ; —Z—CO—NR 9 R 10 ; —Z—NR 9 —CO—R 5 ; or —Z—CO 2 H; 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; 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 hydrogen atom; or a group —R 5 , —Z—Y—R 5 , —Z—NR 9 R 10 , —Z—CO—NR 9 R 10 , —Z—NR 9 —CO—R 5 , or —Z—CO 2 H, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; 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 5 , —Z—NR 9 R 10 ; —Z—CO—NR 9 R 10 ; —Z—NR 9 —CO—R 5 ; or —Z—CO 2 H 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; 
         R 4  is a group of formula (a), (b), (c) or (d); 
       
       
         
           
           
               
               
           
         
         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 5  is an C 1 -C 6 -alkyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(C 1 -C 8 -alkyl)-, heteroaryl(C 1 -C 8 -alkyl)-, cycloalkyl or heterocycloalkyl group; 
         R 6  is C 1 -C 6 -alkyl or a hydrogen atom; 
         R 7a  and R 7b  are a C 1 -C 6 -alkyl group or halogen; 
         n and m are independently 0, 1, 2 or 3; 
         R 8a  and R 8b  are independently selected from the group consisting of aryl, aryl-fused-heterocycloalkyl, heteroaryl, C 1 -C 6 -alkyl, cycloalkyl; 
         R 8c  is —OH, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, nitrile, a group CONR 8d   2  or a hydrogen atom; 
         R 8d  is C 1 -C 6 -alkyl or a hydrogen 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; 
         R 12  is C 1 -C 6 -alkyl or a hydrogen atom; 
         Ar 1  is aryl, heteroaryl or cycloalkyl; 
         Ar 2  are independently aryl, heteroaryl or cycloalkyl; and 
         Q is an oxygen atom, —CH 2 —, —CH 2 CH 2 — or a bond; 
         or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof. 
       
     
     
         2 . A compound as claimed in  claim 1  wherein
 A is an oxygen atom or group —N(R 12 )—; 
 R 1  is C 1 -C 6 -alkyl or a hydrogen atom and R 2  is C 1 -C 6 -alkyl, a hydrogen atom or a group —Z—Y—R 5 , or a group —Z—NR 9 R 10 ; or R 1  and R 2  together with the nitrogen to which they are attached form a heterocycloalkyl ring; 
 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; or R 1  and R 3  together with the nitrogen to which they are attached form a heterocycloalkyl ring and R 2  is C 1 -C 6 -alkyl, in which case the nitrogen atom is quaternised and carries a positive charge; 
 R 4  is a group of formula (a) or (b). 
 
       
         
           
           
               
               
           
         
         Z is a C 1 -C 8 -alkylene, C 2 -C 8 -alkenylene or C 2 -C 8 -alkynylene group; 
         Y is a bond or oxygen atom; 
         R 5  is an aryl, heteroaryl, aryl(C 1 -C 8 -alkyl)-, or heteroaryl(C 1 -C 8 -alkyl)-group; 
         R 6  is C 1 -C 6 -alkyl or a hydrogen atom; 
         R 7a  and R 7b  are independently a C 1 -C 6 -alkyl group or halogen; 
         n and m are independently 0, 1, 2 or 3; 
         R 8a  and R 8b  are independently selected from the group consisting of aryl, heteroaryl, C 1 -C 6 -alkyl, cycloalkyl; 
         R 8c  is —OH, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, or a hydrogen atom; 
         R 9  and R 10  are independently a hydrogen atom, C 1 -C 6 -alkyl, aryl, 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; and 
         R 12  is C 1 -C 6 -alkyl or a hydrogen atom. 
       
     
     
         3 . A compound as claimed in  claim 1  or  claim 2  wherein R 1  is methyl or ethyl, or a hydrogen atom and R 2  is methyl or ethyl, a hydrogen atom or a group —Z—Y—R 5 , or a group —Z—NR 9 R 10 . 
     
     
         4 . A compound as claimed in  claim 2  wherein R 1  is methyl or ethyl, or a hydrogen atom and R 2  is a group —Z—CO—NR 9 R 10 ; or a group —Z—NR 9 —CO—R 5 ; or a group —Z—CO 2 H. 
     
     
         5 . A compound as claimed in  claim 3  or  claim 4  wherein R 3  is methyl, so that the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge. 
     
     
         6 . A compound as claimed in  claim 1  or  claim 2  wherein R 1  and R 3 , or R 1  and R 2 , together with the nitrogen to which they are attached form a monocyclic heterocyclic ring of from 3 to 7 ring atoms, in which the hetero-atom(s) are nitrogen. 
     
     
         7 . A compound as claimed in  claim 5  wherein R 1  and R 3 , or R 1  and R 2 , together with the nitrogen to which they are attached form an azetidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, or pyrrolidinyl ring. 
     
     
         8 . A compound as claimed in  claim 6  or  claim 7  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. 
     
     
         9 . A compound as claimed in any of the preceding claims wherein, in any group —R 5 , —Y—R 5 , —Z—Y—R 5 , —Z—NR 9 R 10 , —Z—CO—NR 9 R 10 , —Z—NR 6 —CO—R 6 , or —Z—CO 2 H:
 Z is —(CH 2 ) 1-16 —, optionally substituted on up to three carbons in the chain by methyl; 
 Y is a bond or —O—; 
 R 5  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 hetroaryl 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. 
 
 
     
     
         10 . A compound as claimed in  claim 1  or  claim 2  wherein, in the group —NR 1 R 2 R 3 , R 1  is methyl or ethyl, R 2  is a group —Z—Y—R 5 , and R 3  is methyl, so that the nitrogen to which it is attached is quaternised and carries a positive charge. 
     
     
         11 . A compound as claimed in  claim 10  wherein R 5  is phenyl or phenyl(C 1 -C 6 -alkyl-, Y is a bond or —O—, and —Z-is a straight or branched alkylene radical linking the nitrogen and —YR 5  by a chain of up to 12, or up to 9, carbon atoms. 
     
     
         12 . A compound as claimed in any of the preceding claims wherein A is an oxygen atom 
     
     
         13 . A compound as claimed in any of  claims 1  to  12  wherein A is a group —N(R 12 )— wherein R 12  is methyl or ethyl, or a hydrogen atom. 
     
     
         14 . A compound as claimed in any of the preceding claims wherein R 4  is a group (a), R 6  is methyl or ethyl or a hydrogen atom; Ar 1  is phenyl, thienyl, cyclohexyl, cyclopentyl, cyclopropyl, or cyclobutyl; R 7a  and R 7b  are independently methyl, ethyl, n- or isopropyl, n-, sec- or tertbutyl, fluoro, chloro or bromo; and m and n are independently 0, 1, 2 or 3. 
     
     
         15 . A compound as claimed in any of  claims 1  to  13  wherein R 4  is a group (b) and R 8a  and R 8b  may be 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; R 8C  is —OH, a hydrogen atom, methyl, ethyl, hydroxymethyl, nitrile, or a group CONR ad   2  wherein each R ad  is independently methyl, ethyl, or a hydrogen atom. 
     
     
         16 . A compound as claimed in any of  claims 1  or  3  to  13  wherein R 4  is a group (d) and R 8a  and R 8b  may be 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; R 8c  is —OH, a hydrogen atom, methyl, ethyl, hydroxymethyl, nitrile, or a group CONR 8d   2  wherein R 8d  each is independently methyl, ethyl, or a hydrogen atom. 
     
     
         17 . A compound as claimed in  claim 15  or  claim 16  wherein R 8c  is —OH. 
     
     
         18 . A compound as claimed in any of  claims 15  to  16  wherein (i) each of R 8a  and R 8b  is optionally substituted pyridyl, oxazolyl, thiazolyl, furyl, thienyl or phenyl; or (ii) one of R 8a  and R 8b  is optionally substituted phenyl and the other is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or (iii) one of R 8a  and R 8b  is optionally substituted pyridyl, thienyl, oxazolyl, thiazolyl, or furyl and the other is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
     
     
         19 . A compound as claimed in any of  claims 15  to  17  wherein each of R 8a  and R 8b  is 2-thienyl or phenyl; or one of R 8a  and R 8b  is phenyl and the other is 2-thienyl. 
     
     
         20 . A compound as claimed in any of  claims 1  or  3  to  13  wherein R 4  is a group (c), and R 8c  is —OH, a hydrogen atom, methyl, ethyl, hydroxymethyl, nitrile, or a group —CONR 8d   2  wherein each R 8d  is independently methyl, ethyl, or a hydrogen atom; each Ar 2  is selected from 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; cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl rings; and the bridge -Q-between the two Ar 2  rings is —O—, —CH 2 — or —CH 2 CH 2 —. 
     
     
         21 . A compound as claimed in  claim 20  wherein each Ar 2  ring is a phenyl ring 
     
     
         22 . A compound as claimed in  claim 20  or  claim 21  wherein R 8c  is —OH. 
     
     
         23 . A compound as claimed in  claim 1  having the formula (IA) 
       
         
           
           
               
               
           
         
       
       wherein ring A is an optionally substituted phenyl ring, or a monocyclic heterocyclic ring of 5 or 6 ring atoms ring, or a phenyl-fused-heterocycloalkyl ring system wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms; R 8a  is phenyl, thienyl, cyclopentyl or cyclohexyl; R 8b  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 10; Y is a bond or —O—, and X −  is a pharmaceutically acceptable anion. 
     
     
         24 . A compound as claimed in  claim 1  having the formula (IB) 
       
         
           
           
               
               
           
         
       
       wherein ring B is an optionally substituted phenyl ring, or a monocyclic heterocyclic ring of 5 or 6 ring atoms, or a phenyl-fused-heterocycloalkyl ring system wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms; 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 10; Y is a bond or —O—; and X −  is a pharmaceutically acceptable anion. 
     
     
         25 . A compound as claimed in any of the preceding claims which is predominantly in the anti-endo configuration. 
     
     
         26 . A compound as claimed in  claim 1 , selected from the group consisting of:
 anti-2-(Biphenyl-2-ylcarbamoyloxy)bicyclo[2.2.1]hept-7-yl]-dimethyl-(3-phenoxy-propyl)-ammonium salts,   anti-[(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-(3-phenyl-propyl)-ammonium salts,   anti-(±)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-(3-phenyl-propyl)-ammonium salts,   anti-(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-(3-phenoxy-propyl)-ammonium salts,   anti-[(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-phenethyl-ammonium salts,   anti-[(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-(4-phenyl-butyl)-ammonium salts,   anti-[(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-trimethyl-ammonium salts,   (2-Benzyloxy-ethyl)-anti-[(1S,2R)-2-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium salts,   anti-(1S,2R) 2-(2-Hydroxy-2,2-diphenyl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-(3-phenoxy-propyl)-ammonium salts,   anti-(1S,2R) Dimethyl-(3-phenoxy-propyl)-[2-(9H-xanthene-9-carbonyloxy)-bicyclo[2.2.1]hept-7-yl]-ammonium salts,   anti-(1S,2R) 2-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-(3-phenoxy-propyl)-ammonium salts, and   anti-[(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-indan-2-yl-dimethyl-ammonium salts.   
     
     
         27 . 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 132 adrenoreceptor agonist activity. 
     
     
         28 . A compound as claimed in any of the preceding claims, for use in therapy. 
     
     
         29 . A pharmaceutical composition comprising a compound as claimed in any of  claims 1  to  28  and a pharmaceutically acceptable carrier or excipient. 
     
     
         30 . A pharmaceutical composition as claimed in  claim 29  in a form suitable for inhalation. 
     
     
         31 . Use of a compound as claimed in any of  claims 1  to  28  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. 
     
     
         32 . 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  28   
     
     
         33 . Use as claimed in  claim 31  or a method of treatment as claimed in  claim 32 , wherein the disease or condition is a respiratory-tract disorder. 
     
     
         34 . Use as claimed in  claim 31  or a method of treatment as claimed in  claim 32 , wherein the disease or condition is a gastrointestinal-tract disorder. 
     
     
         35 . Use as claimed in  claim 31  or a method of treatment as claimed in  claim 32 , wherein the disease or condition is a cardiovascular disorder. 
     
     
         36 . Use as claimed in  claim 31  or a method of treatment as claimed in  claim 32 , 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. 
     
     
         37 . Use as claimed in  claim 31  or a method of treatment as claimed in  claim 32 , 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. 
     
     
         38 . Use as claimed in  claim 31  or a method of treatment as claimed in  claim 32 , wherein the disease or condition is vagally induced sinus bradycardia.