Novel quinuclidine carbamate derivatives and medicinal compositions containing the same

Abstract

Carbamates of formula (I) or pharmaceutically acceptable salts thereof, including quaternary ammonium salts of formula (II) are disclosed; as well as processes for their preparation, pharmaceutical compositions comprising them and their use in therapy as antagonists of M3 muscarinic receptors.

1 - 35 . (canceled) 
   
   
       36 . A compound having the following formula (Ia): 
     
       
         
         
             
             
         
       
     
     wherein
 R1 represents a group chosen from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, and thiophen-3-ylmethyl; 
 R2 represents an unsubstituted group chosen from lower alkyl, lower alkenyl, lower alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl, and pyridylmethyl; wherein the carbocyclic moieties in the cycloalkyl, cycloalkylmethyl, phenyl, benzyl or phenethyl groups are optionally bridged or fused to another saturated, unsaturated or aromatic carbocyclic moiety or to a cyclic moiety comprising carbon atoms and 1 or 2 oxygen atoms; 
 wherein R1 is substituted by one substituent chosen from hydroxy; straight or branched, optionally substituted lower alkoxy; —SH; straight or branched optionally substituted lower alkylthio; nitro; —NR′R″; —CO 2 R′; —C(O)—NR′R″; —N(R′″)C(O)—R′; and —N(R′″)—C(O)NR′R″; wherein R′, R″ and R′″, which may be identical or different, are each independently chosen from a hydrogen atom, and a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group; and 
 p is 1 or 2 and the carbamate group is attached at positions 2, 3 or 4 of the azabicyclic ring; 
 wherein when 
 p is 2; 
 the carbamate group is attached at position 3 of the azabicyclic ring; and 
 R1 is a phenyl group which is substituted with hydroxy; 
 then R2 cannot be a benzyl group; 
 
     or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a salt of compound of formula (Ia) having the formula (IIa): 
     
       
         
         
             
             
         
       
     
     wherein:
 m is an integer ranging from 0 to 8; 
 n is an integer ranging from 0 to 4; 
 A represents a group chosen from —CH 2 —; —CH═CR′—; —CR′═CH—; —CR′R″—; 
 C(O)—, —O—, —S—, —S(O)—, —S(O) 2 —, and —NR′—, wherein R′ and R″, which may be identical or different, are each independently chosen from a hydrogen atom and a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group; 
 B represents a hydrogen atom, or a group chosen from straight or branched, optionally substituted lower alkyl; hydroxy; straight or branched, optionally substituted lower alkoxy; cyano; nitro; —CH═CR′R″; —C(O)OR; —OC(O)R′; —SC(O)R′; —C(O)NR′R″; —NR′C(O)OR″; —NR′C(O)NR″; cycloalkyl; phenyl; naphthanelyl; 5,6,7,8-tetrahydronaphthanelyl; benzo[1,3]dioxolyl; heteroaryl; and heterocyclyl; wherein R′ and R″, which may be identical or different, are each independently chosen from a hydrogen atom and a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group; and 
 wherein the cyclic groups represented by B are optionally substituted by one, two or three, identical or different, substituents chosen from halogen; hydroxy; straight or branched, optionally substituted lower alkyl; phenyl; —OR′; —SR′; —NR′R″; —NHCOR′; —CONR′R″; —CN; —NO 2 ; and —COOR′; wherein R′ and R″ are each independently chosen from a hydrogen atom, or a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group; and 
 X −  represents a pharmaceutically acceptable anion of a mono or polyvalent acid; 
 
     or a stereoisomer thereof; or a mixture of stereoisomers thereof, or a mixture of at least one stereoisomer of a compound of formula (IIa) and at least one stereoisomer of a compound of formula (Ia). 
   
   
       37 . A compound having the following formula (Ib): 
     
       
         
         
             
             
         
       
     
     wherein
 R1 represents a group chosen from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, and thiophen-3-ylmethyl; 
 R2 represents an unsubstituted group chosen from lower alkynyl, unsaturated cycloalkyl, saturated or unsaturated cycloalkylmethyl, pyridyl, and pyridylmethyl; wherein the carbocyclic moieties in the cycloalkyl or cycloalkylmethyl groups are optionally bridged or fused to another saturated, unsaturated or aromatic carbocyclic moiety or to a cyclic moiety comprising carbon atoms and 1 or 2 oxygen atoms; and 
 wherein R1 is optionally substituted by one substituent chosen from halogen; straight or branched, optionally substituted lower alkyl; hydroxy; straight or branched, optionally substituted lower alkoxy; —SH; straight or branched optionally substituted lower alkylthio; nitro; cyano; —NR′R″; —CO 2 R′; —C(O)—NR′R″; —N(R′″)C(O)—R′; and —N(R′″)—C(O)NR′R″, wherein R′, R″, and R′″, which may be identical or different, are each independently chosen from a hydrogen atom, and a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group; 
 p is 1 or 2 and the carbamate group is attached at positions 2, 3, or 4 of the azabicyclic ring; 
 wherein when:
 p is 2; 
 the carbamate group is attached at position 3 of the azabicyclic ring; and 
 R1 is a phenyl group, which is optionally substituted with one substituent chosen from chlorine, fluorine, and methyl; 
 
 then R2 cannot be one of: unsubstituted cyclopropylmethyl; unsubstituted cyclobutylmethyl; unsubstituted cyclopentylmethyl; unsubstituted cyclohexylmethyl; unsubstituted cyclohexenyl; unsubstituted norbornenyl; unsubstituted bicyclo[2,2,1]heptanyl; 
 
     or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
 with the proviso that the compound of formula (I) is not one of 
 Quinuclidin-3-yl benzo[d][1,3]dioxol-5-ylmethyl(phenyl)carbamate, or 
 Quinuclidin-3-yl (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl(m-tolyl)carbamate; 
 
     or a salt of a compound of formula (Ib) having the formula (IIb): 
     
       
         
         
             
             
         
       
     
     wherein:
 m is an integer ranging from 0 to 8; 
 n is an integer ranging from 0 to 4; 
 A represents a group chosen from —CH 2 —; —CH═CR′—; —CR′═CH—; —CR′R″—; —C(O)—, —O—, —S—, —S(O)—, —S(O) 2 — and —NR′—, wherein R′ and R″, which may be identical or different, are each independently chosen from a hydrogen atom and a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group; 
 B represents a hydrogen atom, or a group chosen from straight or branched, optionally substituted lower alkyl; hydroxy; straight or branched, optionally substituted lower alkoxy; cyano; nitro; —CH═CR′R″; —C(O)OR; —OC(O)R′; —SC(O)R′; —C(O)NR′R″; —NR′C(O)OR″; —NR′C(O)NR″; cycloalkyl; phenyl; naphthanelyl; 5,6,7,8-tetrahydronaphthanelyl; benzo[1,3]dioxolyl; heteroaryl; and heterocyclyl; wherein R′ and R″, which may be identical or different, are each independently chosen from a hydrogen atom and a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group; and 
 wherein the cyclic groups represented by B are optionally substituted by one, two or three, identical or different, substituents chosen from halogen; hydroxy; straight or branched, optionally substituted lower alkyl; phenyl; —OR′; —SR′; —NR′R″; —NHCOR′; —CONR′R″; —CN; —NO 2 ; and —COOR′; wherein R′ and R″ are each independently chosen from a hydrogen atom, or a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group; and 
 X −  represents a pharmaceutically acceptable anion of a mono or polyvalent acid; 
 or a stereoisomer thereof; or a mixture of stereoisomers thereof, or a mixture of at least one stereoisomer of a compound of formula (IIb) and at least one stereoisomer of a compound of formula (Ib); 
 with the proviso that the compound of formula (IIb) is not (3R)-3-[cyclohexylmethyl-(2-fluorophenyl)carbamoyloxy]-1-methyl-1-azoniabicyclo[2.2.2]octane iodide. 
 
   
   
       38 . The compound of  claim 36 , wherein p is 2. 
   
   
       39 . The compound of  claim 36 , wherein the azabicyclic ring is substituted in the 3-position. 
   
   
       40 . The compound of  claim 37 , wherein p is 2. 
   
   
       41 . The compound of  claim 37 , wherein the azabicyclic ring is substituted in the 3-position. 
   
   
       42 . The compound of  claim 36 , wherein R2 represents a group chosen from pent-4-enyl, pentyl, butyl, allyl, benzyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, furan-2-ylmethyl, furan-3-ylmethyl, phenethyl, cyclopentyl, cyclohexyl, and cyclohexylmethyl. 
   
   
       43 . The compound of  claim 36 , wherein
 A is —CH 2 —;   m and n are both 0;   B represents a group chosen from straight or branched, optionally substituted lower alkyl; hydroxy; straight or branched, optionally substituted lower alkoxy; cyano; nitro; —CH═CR′R″; —C(O)OR′; —OC(O)R; —SC(O)R′; —C(O)NR′R″; —NR′C(O)OR″; —NR′C(O)NR″; cycloalkyl; phenyl; naphthanelyl; 5,6,7,8-tetrahydronaphthanelyl; benzo[1,3]dioxolyl; heteroaryl; and heterocyclyl; and   R′ and R″ are each independently chosen from a hydrogen atom and a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group;   and wherein the cyclic groups represented by B are optionally substituted by one, two or three, identical or different, substituents chosen from halogen; hydroxyl; straight or branched, optionally substituted lower alkyl; phenyl; —OR′; —SR′; —NR′R″; —NHCOR′; —CONR′R″; —CN, —NO 2  and —COOR′; wherein R′ and R″ are each independently chosen from a hydrogen atom, or a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group.   
   
   
       44 . The compound of  claim 37 , wherein
 A is —CH 2 —;   m and n are both 0;   B represents a group chosen from straight or branched, optionally substituted lower alkyl; hydroxy; straight or branched, optionally substituted lower alkoxy; cyano; nitro; —CH═CR′R″; —C(O)OR′; —OC(O)R; —SC(O)R′; —C(O)NR′R″; —NR′C(O)OR″; —NR′C(O)NR″; cycloalkyl; phenyl; naphthanelyl; 5,6,7,8-tetrahydronaphthanelyl; benzo[1,3]dioxolyl; heteroaryl; and heterocyclyl; and   R′ and R″ are each independently chosen from a hydrogen atom and a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group;   and wherein the cyclic groups represented by B are optionally substituted by one, two or three, identical or different, substituents chosen from halogen; hydroxyl; straight or branched, optionally substituted lower alkyl; phenyl; —OR′; —SR′; —NR′R″; —NHCOR′; —CONR′R″; —CN, —NO 2  and —COOR′; wherein R′ and R″ are each independently chosen from a hydrogen atom, or a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group.   
   
   
       45 . The compound of  claim 36 , wherein
 A is —CH 2 —;   B represents a hydrogen atom, or a group chosen from straight or branched, optionally substituted lower alkyl; hydroxy; straight or branched, optionally substituted lower alkoxy; cyano; nitro; —CH═CR′R″; —C(O)OR′; —OC(O)R′; —SC(O)R′; —C(O)NR′R″; —NR′C(O)OR″; —NR′C(O)NR″; cycloalkyl; phenyl; naphthanelyl; 5,6,7,8-tetrahydronaphthanelyl; benzo[1,3]dioxolyl; heteroaryl; and heterocyclyl;   wherein R′ and R″ are each independently chosen from a hydrogen atom and a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group;   and wherein the cyclic group represented by B is optionally substituted by one, two or three, identical or different, substituents chosen from halogen; hydroxy; straight or branched, optionally substituted lower alkyl; phenyl; —OR′; —SR′; —NR′R″; —NHCOR′; —CONR′R″; —CN; —NO 2 ; and —COOR′; wherein R′ and R″ are each independently chosen from a hydrogen atom, or a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group; and   at least one of m or n is not 0.   
   
   
       46 . The compound of  claim 37 , wherein
 A is —CH 2 —;   B represents a hydrogen atom, or a group chosen from straight or branched, optionally substituted lower alkyl; hydroxy; straight or branched, optionally substituted lower alkoxy; cyano; nitro; —CH═CR′R″; —C(O)OR′; —OC(O)R′; —SC(O)R′; —C(O)NR′R″-NR′C(O)OR″; —NR′C(O)NR″; cycloalkyl; phenyl; naphthanelyl; 5,6,7,8-tetrahydronaphthanelyl; benzo[1,3]dioxolyl; heteroaryl; and heterocyclyl;   wherein R′ and R″ are each independently chosen from a hydrogen atom and a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group;   and wherein the cyclic group represented by B is optionally substituted by one, two or three, identical or different, substituents chosen from halogen; hydroxy; straight or branched, optionally substituted lower alkyl; phenyl; —OR′; —SR′; —NR′R″; —NHCOR′; —CONR′R″; —CN; —NO 2 ; and —COOR′; wherein R′ and R″ are each independently chosen from a hydrogen atom, or a straight or branched, optionally substituted lower alkyl group, or R′ and R″ together with the atom to which they are attached form a cyclic group; and   at least one of m or n is not 0.   
   
   
       47 . The compound of  claim 36 , wherein B represents a group chosen from phenyl, 4-fluorophenyl, 3-hydroxyphenyl, and thiophen-2-yl. 
   
   
       48 . The compound of  claim 37 , wherein B represents a group chosen from phenyl, 4-fluorophenyl, 3-hydroxyphenyl, and thiophen-2-yl. 
   
   
       49 . The compound of  claim 36 , wherein n=0 or 1; m is an integer ranging from 1 to 6; and A represents a group chosen from —CH 2 —, —CH═CH—, —CO—, —NMe—, —O—, and —S—. 
   
   
       50 . The compound of  claim 37 , wherein n=0 or 1; m is an integer ranging from 1 to 6; and A represents a group chosen from —CH 2 —, —CH═CH—, —CO—, —NMe—, —O—, and —S—. 
   
   
       51 . The compound of  claim 36 , wherein B—(CH 2 ) n -A-(CH 2 ) m — represents a group chosen from 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 3-thiophen-2-ylpropyl, allyl, heptyl, 3-cyanopropyl, and methyl. 
   
   
       52 . The compound of  claim 37 , wherein B—(CH 2 ) n -A-(CH 2 ) m — represents a group chosen from 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorophenoxy)propyl, 3-thiophen-2-ylpropyl, allyl, heptyl, 3-cyanopropyl, and methyl. 
   
   
       53 . The compound of  claim 36 , wherein X −  represents an anion chosen from chloride, bromide, trifluoroacetate, and methanesulphonate. 
   
   
       54 . The compound of  claim 37 , wherein X −  represents an anion chosen from chloride, bromide, trifluoroacetate, and methanesulphonate. 
   
   
       55 . A pharmaceutical composition comprising at least one compound of  claim 36 , and at least one pharmaceutically acceptable carrier or diluent. 
   
   
       56 . A pharmaceutical composition comprising at least one compound of  claim 37 , and at least one pharmaceutically acceptable carrier or diluent. 
   
   
       57 . A combination product comprising,
 (i) at least one first compound of  claim 36 ; and   (ii) at least one second compound effective in the treatment of at least one pathological condition chosen from respiratory, urological, and gastrointestinal disease or disorder, wherein the at least one first compound and the at least one second compound are administered simultaneously, separately, or sequentially.   
   
   
       58 . A combination product comprising,
 (i) at least one first compound of  claim 37 ; and   (ii) at least one second compound effective in the treatment of at least one pathological condition chosen from respiratory, urological, and gastrointestinal disease or disorder, wherein the at least one first compound and the at least one second compound are administered simultaneously, separately, or sequentially.   
   
   
       59 . A combination product comprising,
 (i) at least one first compound of  claim 36 ; and   (ii) at least one second compound chosen from a ∃2 agonist, steroid, antiallergic drug, phosphodiesterase IV inhibitor, and a leukotriene D4 (LTD4) antagonist, wherein the at least one first compound and the at least one second compound are administered simultaneously, separately, or sequentially in the treatment of a respiratory disease.   
   
   
       60 . A combination product comprising,
 (i) at least one first compound of  claim 37 ; and   (ii) at least one second compound chosen from a ∃2 agonist, steroid, antiallergic drug, phosphodiesterase IV inhibitor, and a leukotriene D4 (LTD4) antagonist, where the at least one first compound and the at least one second compound are administered simultaneously, separately, or sequentially in the treatment of a respiratory disease.   
   
   
       61 . A method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by antagonism of M3 muscarinic receptors chosen from respiratory, urological, and gastrointestinal diseases or disorders, comprising administering to said subject an effective amount of at least one compound of  claim 36 . 
   
   
       62 . A method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by antagonism of M3 muscarinic receptors chosen from respiratory, urological, and gastrointestinal diseases or disorders, comprising administering to said subject an effective amount of at least one compound of  claim 37 .