Guanidine compounds as anesthetics and for treatment of nervous system disorders

Abstract

Novel guanidine compounds having the formula in which R 1 , R 2 , and R 4 are as defined, are effective as sodium channel dockers in neuronal mammalian cells and as anesthetics and/or analgesics, particularly local spinal and/or epidural anesthetics, for alleviation of neuropathic pain, for providing a neuroprotective effect, and for producing anti-convulsant effects.

1 . A method for producing anesthesia or analgesia in a subject comprising administering to said subject an anesthetically or analgesically effective amount of a compound having the formula 
       
         
           
           
               
               
           
         
       
       in which:
 R 1  is 
 (a) substituted or unsubstituted alkyl; 
 (b) substituted or unsubstituted cycloalkyl; 
 (c) substituted or unsubstituted alkenyl; 
 (d) adamantyl; 
 (e) substituted or unsubstituted phenyl; 
 a 5- or 6-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; 
 (g) substituted or unsubstituted benzyl; 
 (h) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; or 
 (i) CH 2 XR 5 , where X is oxygen, sulfur, —NH— or —CH 2 — and R 5  is substituted or unsubstituted alkyl; substituted or unsubstituted cycloalkyl; substituted or unsubstituted phenyl; substituted or unsubstituted benzyl; 2-carbsunide-indolyl; or a 5-to 9-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; 
 R 2  is 
 (a) substituted or unsubstituted alkyl; 
 (b) substituted or unsubstituted cycloalkyl; 
 (c) substituted or unsubstituted alkenyl; 
 (d) substituted or unsubstituted alkoxyalkyl 
 (e) a 5- or 6-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, 
 (f) —(CH 2 ) n R 3 , where R 3  is (i) a 5- to 9-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; (ii) —NR 6 R 7  where R 6  and R 7  are independently selected from hydrogen, methyl, ethyl and benzyl; or (iii) COOR 8  where R 8  is alkyl; and n is 2 or 3; 
 (h) substituted or unsubstituted phenyl; 
 (i) substituted or unsubstituted benzyl; 
 (f) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; or 
 (k) methylene-1-naphthyl; 
 and R 4  is 
 a) hydrogen; 
 b) (CH 2 ) m COOR 15  where R 15  is alkyl or substituted alkyl; and m is 0, 1 or 2; 
 c) CONR 16 R 17  where R 16  and R 17  are independently (i) hydrogen; (ii) alkyl or substituted alkyl; (iii) cycloalkyl; (iv) alkoxyalkyl; (v) a 5- to 10-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; (vi) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; (vii) substituted or unsubstituted phenyl; (viii) (CH 2 ) p R 18  where R 18  is a 5-or 6-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, and p is 1, 2 or 3; (ix) optionally substituted benzyl; or (x) an aralkyl group comprising a chain of from 1 to 4 methylene groups substituted by one or two phenyl groups; 
 d) C 1 —C 4  alkoxy; 
 e) optionally substituted phenoxy; 
 f) SO2NR19R 20  where R 19  and R 20  are independently hydrogen, optionally substituted alkyl or phenyl; 
 g) NR 21 R 22 ; 
 h) COR 23  where R 23  is alkyl or is NR 21 R 22 ; 
 i) COOR 23  where R 23  is hydrogen, alkyl, or benzyl; 
 j) SO2R 25  where R 25  is alkyl or NR 21 R 22 ; 
 wherein R 21  and R 22  are independently hydrogen, alkyl, optionally substituted phenyl or optionally substituted benzyl; 
 or a pharmaceutically acceptable salt thereof; 
 or a composition containing an anesthetically or analgesically effective amount of said compound or salt. 
 
     
     
         2 . A method according to  claim 1  in which
 R 1  is 
 (a) C 1 —C 6  alkyl, optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH 3 ; 
 (b) C 2 —C 6  alkenyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COON and COOCH 3 ; 
 (c) C 3 —C 6  cycloalkyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH 3 ; 
 (d) adamantyl; 
 (e) optionally substituted phenyl in which the substituents are selected from mono-and dihalo, mono- and di-(C 1 —C 4  alkoxy), mono- and di-(C1-C2 alkylthio), C 1 —C 2  alkyleneoxy; C 1 —C 2  alkylenedioxy, mono-and di-(C 1 —C 4  alkyl), mono- and di-(trifluoromethyl), mono- and di-(C 1 —C 4  hydroxyalkyl), mono-and di-(C 1 —C 4  alkoxyalkyl), mono- and di-hydroxy, mono- and di-cyano, mono- and di-(COCH 3 ), and mono- and di-NHR 26 ; 
 (f) a 5- or 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C 1 —C 4  alkyl, C 1 —C 4  alkoxy, oxo and hydroxy; 
 (g) optionally substituted benzyl in which the substituents are selected from mono-and dihalo, mono- and di-(C 1 —C 4  alkoxy), mono- and di-(C 1 —C 4  alkylthio), C 1 —C 2  alkyleneoxy; C 1 —C 2  alkylenedioxy, mono-and di-(C 1 —C 4  alkyl), mono- and di-(trifluoromethyl), mono- and di-(C 1 —C 4  hydroxyallcyl), mono-and di-(C 1 —C 4  alkoxyalkyl), mono- and di-hydroxy, mono- and di-cyano, mono- and di-(COCH 3 ), and mono- and di-NHR 26 ; 
 (g) naphthyl; or 
 (h) CH 2 XR 5 , where X is oxygen, sulfur, —NH— or —CH 2 — and R 5  is selected from (i) C 1 —C 6  alkyl; (ii) C 3 —C 6  cycloalkyl; (iii) optionally substituted phenyl in which the substituents are selected from mono- and di-(C 1 —C 4  alkyl), mono- and dihalo, mono- and di-(C 1 —C 4  alkoxy), C 1 —C 2  alkyleneoxy, C 1 —C 2  alkylenedioxy, mono- and di-(trifluoromethyl), nitro, hydroxy, mono- and di-(C 1 —C 4  hydroxyalkyl), mono- and di-(C 1 —C 4  alkoxyalkyl), mono- and di-hydroxy, mono- and dicyano, mono- and di-(COCH 3 ), and mono- and di-NHR 26 ; (iv) benzyl; (v) 2-carbamide-indolyl; or (vi) a 5- to 9-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur optionally substituted by from 1 to 3 groups independently selected from halo, C 1 —C 4  alkyl, C 1 —C 4  alkoxy, oxo and hydroxy; 
 R 2  is 
 (a) C 1 —C 12  alkyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH 3 ; 
 (b) C 2 —C 8  cycloalkyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH 3 ; 
 (c) C 2 —C 12  alkenyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH 3 ; 
 (d) C 2 —C 12  alkoxyalkyl; 
 (e) a 5- or 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C 1 —C 4  alkyl, C 1 —C 4  alkoxy, oxo, and hydroxy; 
 (f) —(CH 2 ) n R 3 , where R3 is (i) a 5- to 9-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C 1 —C 4  alkyl, C 1 —C 4  alkoxy, oxo, and hydroxy; (ii) —NR 6 R 7  where R 6  and R 7  are independently selected from hydrogen, methyl, ethyl and benzyl; or (iii) COORS where R 8  is C 1 —C 4  alkyl; and n is 2 or 3; 
 (g) optionally substituted phenyl, where the substituents are independently selected from mono- and di-(C 1 —C 4  alkyl); mono- and dihalo; mono-, di-, and tri-C 1 —C 4  alkoxy); mono- and dicyano; nitro; methylsulfonyl; mono-, di-, and tri-(trifluoromethyl); C 1 —C 2  alkyleneoxy; C 1 —C 2  alkylenedioxy; —(CH 2 ) q COOR 9  where R 9  is C 1 —C 4  alkyl; or —(CH 2 ) q NR 10 R 11  where R 10  and R 11  are independently hydrogen, (C 1 —C 4 ) alkyl, COR 12  where R 12  is C 1 —C 4  alkyl, SO 2 R 13  where R 13  is C 1 —C 4  alkyl, or COOR 14  where R 14  is C 1 —C 4  alkyl and CONR′R″; and q is an integer from 1 to 4; 
 (h) optionally substituted benzyl, where the substituents are selected from mono-, di-, and tri-(C 1 —C 4 ) alkyl; mono-, di-, and tri-halo; mono, di-, and tri-(C 1 —C 4  alkoxy); mono-, di-, and tri-(C 1 —C 4  alkylthio); mono- and di-cyano; nitro; methylsulfonyl; mono-, di-, and tri-(trifluoromethyl); mono-, di-, and tri-COOR′; mono-, di-, and tri-CONR′R″; mono-, di-, and tri-NR 27 R 28  where R 27  and R 28  are independently selected from hydrogen, C 1 —C 4  alkyl, acetyl, and methylsulfonyl; C 1 —C 2  alkyleneoxy; C 1 —C 2  alkylenedioxy; and mono-, di-, and tri-(C 1 —C 6  alkoxyalkyl); 
 (j) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; or 
 (k) methylene-1- or 2-naphthyl; and 
 R 4  is 
 (a) hydrogen; 
 (h) (CH 2 ) m COOR′ where m is 0, 1 or 2; 
 (c) CONR 16 R 17  where R 16  and R 17  are independently (i) hydrogen; (ii) C 1 —C 5  alkyl optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, COOH and COOCH 3 ; (iii) C 3 —C 6  cycloalkyl; (iv) C 2 —C 8  alkoxyalkyl; (v) a 5- to 10-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur optionally substituted by from 1 to 3 groups independently selected from halo, hydroxy, oxo, C 1 —C 4  alkyl, C 1 —C 4  alkoxy, COCH 3 , COOR′, and NR 29 R 30  where R 29  and R 30  are independently selected from hydrogen, C 1 —C 4  alkyl, acetyl, or methylsulfonyl; (vi) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; (vii) (CH 2 ) p R 18  where R 18  is a 5- or 6- membered saturated or unsaturated heterocyclic group having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, hydroxy, C 1 —C 4  alkyl, C 1 —C 4  alkoxy and oxo, and p is 1, 2 or 3; (viii) phenyl optionally substituted by one or more groups independently selected from mono-, di-, and tri- halo, mono-, di-, and tri-hydroxy, mono-, di-, and tri-(C 1 —C 4  alkyl), C 1 —C 2  alkyleneoxy, C 1 —C 2  alkylenedioxy, COOR′, and NR 29 R 30  where R 29  and R 30  are independently selected from hydrogen, C 1 —C 4  alkyl, acetyl, and methylsulfonyl; (ix) optionally substituted benzyl where the substituents are selected from mono-, di-, and tri-(C 1 —C 4  alkyl); mono-, di-, and tri- halo; mono-, di-, and tri-(C 1 —C 4  alkoxy); nitro; methylsulfonyl; mono-, di-, and tri-(trifluoromethyl); NR′R″; C 1 —C 2  alkyleneoxy; C 1 —C 2  alkylenedioxy; or (x) an aralkyl group comprising a chain of from 1 to 4 methylene groups substituted by one or two phenyl groups; 
 (d) C 1 —C 4  alkoxy; 
 (e) optionally substituted phenoxy, where the substituents are independently selected from mono- and di-(C 1 —C 4 ) alkyl; mono- and dihalo; mono-, di-, and tri-(C 1 —C 4  alkoxy); cyano; nitro; methylsulfonyl; mono-, di-, and tri- trifluoromethyl; C 1 —C 2  alkyleneoxy; C 1 —C 2  alkylenedioxy; —(CH 2 ),COOR 9  where R 9  is C 1 —C 4  alkyl; or —(CH 2 ) r NR 30 R 31  where R 30  and R 31  are independently hydrogen, (C 1 —C 4 )alkyl, COR 32  where R 32  is C 1 —C 4  alkyl, SO 2 R 33  where R 33  is C 1 —C 4  alkyl, or COOR 34  where R 34  is C 1 —C 4  alkyl; 
 (i) SO 2 NR 35 R 36  where R 35  and R 36  are independently hydrogen, C 1 —C 4  alkyl or phenyl; or 
 (g) NR 37 R 38  where R 37  and R 38  are independently hydrogen; C 1 —C 4  alkyl; phenyl; COR 39  where R 39  is C 1 —C 47  alkyl; or SO 2 R 40  where R 40  is hydrogen or C 1 —C 4  alkyl; 
 wherein R 26  is COCH 3 , SO 2 CH 3 , SO 2 C 6 H 3 , COOR' or CONR′R″; and 
 wherein R′ and R″ are independently hydrogen or C 1 —C 4  alkyl; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         3 . A method according to  claim 1  in which R 1  is phenyl, substituted phenyl, a 5- or 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur optionally substituted by from 1 to 3 groups independently selected from halo, alkyl, alkoxy, oxo or hydroxy, or CH 2 XR 5 ; R 2  is benzyl, substituted benzyl, C 2 —C 4  alkyl, or —(CH 2 ) 2 R 3 , where R 3  is a 5- to 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; and R 4  is hydrogen. 
     
     
         4 . A method according to  claim 1  in which R 1  is phenyl. 
     
     
         5 . A method according to  claim 1  in which R 1  is substituted phenyl. 
     
     
         6 . A method according to  claim 1  in which R 1  is mono- or dihalophenyl. 
     
     
         7 . A method according to  claim 6  in which R 1  is 3,4-dichlorophenyl. 
     
     
         8 . A method according to  claim 1  in which R 1  is a 5- or 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C 1 —C 4  alkyl, C 1 —C 4  alkoxy, oxo or hydroxy. 
     
     
         9 . A method according to  claim 1  in which R 1  is thienyl. 
     
     
         10 . A method according to  claim 1  in which R 1  is CH 2 XR 5 , where X is oxygen, sulfur, —NH— or —CH 2 — and R 5  is selected from (i) C 1 —C 6  alkyl; (ii) C 3 —C 6  cycloalkyl; (iii) optionally substituted phenyl in which the substituents are selected from mono- and di-(C 1 —C 4  alkyl), mono- and dihalo, mono- and di-(C 1 —C 4  alkoxy), C 1 —C 2  alkyleneoxy, C 1 —C 2  alkylenedioxy, mono- and di-(trifluoromethyl), nitro, hydroxy, mono- and di-(C 1 —C 4  hydroxyalkyl), mono- and di-(C 1 —C 4  alkoxyalkyl), mono- and di-hydroxy, mono- and dicyano, mono- and di-(COCH 3 ), and mono- and di-NHR 26 ; (iv) benzyl; (v), 2-carbamide-indolyl; or (vi) a 5- to 9-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by from 1 to 3 groups independently selected from halo, C 1 —C 4  alkyl, C 1 —C 4  alkoxy, oxo and hydroxy. 
     
     
         11 . A method according to  claim 10  in which R 1  is CH 2 XR 5  and R 5  is phenyl, substituted phenyl, or benzyl. 
     
     
         12 . A method according to  claim 10  in which X is oxygen. 
     
     
         13 . A method according to  claim 12  in which R 5  is benzyl, phenyl, or substituted phenyl. 
     
     
         14 . A method according to  claim 13  in which R 5  is phenyl. 
     
     
         15 . A method according to  claim 13  in which R 5  is 4-chlorophenyl. 
     
     
         16 . A method according to  claim 13  in which R 3  is benzyl. 
     
     
         17 . A method according to  claim 1  in which R 2  is benzyl. 
     
     
         18 . A method according to  claim 1  in which R 2  is substituted benzyl. 
     
     
         19 . A method according to  claim 2  in which R 2  is benzyl or substituted benzyl 
     
     
         20 . A method according to  claim 19  in which R 2  is benzyl substituted by a C 1 —C 4  alkyl group, a C 1 —C 4  alkoxy group, or a halogen. 
     
     
         21 . A method according to  claim 19  in which R 2  is 4-methylbenzyl. 
     
     
         22 . A method according to  claim 19  in which R 2  is 4-methoxybenzyl. 
     
     
         23 . A method according to  claim 19  in which R 2  is 4-fluorobenzyl. 
     
     
         24 . A method according to  claim 1  in which R 2  is a C 2 —C 4  alkyl group. 
     
     
         25 . A method according to  claim 24  in which R 2  is ethyl. 
     
     
         26 . A method according to  claim 24  in which R 2  is n-butyl. 
     
     
         27 . A method according to  claim 1  in which R 2  is —(CH 2 ) 2 R 3 , where R 3  is a 5- to 6-membered saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur. 
     
     
         28 . A method according to  claim 27  in which R 3  is -piperidino. 
     
     
         29 . A method according to  claim 1  in which R 4  is hydrogen. 
     
     
         30 . A method according to  claim 1 , further providing that:
 if R 1  is 4-chlorophenoxymcthyl and R 4  is hydrogen, then R 2  is not methyl or 2-(N,N,-diethylamino)ethyl;   if R 1  is phenoxymethyl and R 4  is hydrogen, then R 2  is not 2-(N,N,-dicthylamino)ethyl;   if R 1  is phenyl and R 4  is hydrogen, then R 2  is not methyl;   if R 1  is 4-chlorophenyl and R 4  is hydrogen then R 2  is not methyl, n-butyl or allyl;   if is 4-bromophenyl and R 4  is hydrogen, then R 2  is not n-butyl or benzyl;   if R 1  is 4-methylphenyl and R 4  is hydrogen, then R 2  is not n-propyl;   if R 1  is 2-furyl and R 4  is hydrogen, then R 2  is not benzyl or (4-chlorobenzyl);   if R 1  is methyl and R 4  is hydrogen, then R 2  is not methyl or ethyl;   if R 1  is t-butyl and R 4  is hydrogen, then R 2  is not 4-chlorobenzyl; and   if R 1  is 1-naphthyl and R 4  is hydrogen, then R 2  is not methyl.   
     
     
         31 . A method according to  claim 1 , further providing that:
 if R 1  is 4-chlorophenoxymethyl, then R 2  is not methyl or 2-(N,N,-diethylamino)ethyl;   if R 1  is phenoxymethyl, then R 2  is not 2-(N,N,-diethylamino)ethyl;   if R 1  is phenyl, then R 2  is not methyl;   if R 1  is 4-chlorophenyl, then R 2  is not methyl, n-butyl or allyl;   if R 1  is 4-bromophenyl, then R 2  is not n-butyl or benzyl;   if R 1  is 4-methyiphenyl, then R 2  is not n-propyl;   if R 1  is 2-furyl, then R 2  is not benzyl or (4-chlorobenzyl);   if R 1  is methyl, then R 2  is not methyl or ethyl;   if R 1  is t-butyl, then R 2  is not 4-chlorobenzyl; and   if R 1  is 1-naphthyl, then R 2  is not methyl.   
     
     
         32 . A method according to  claim 1  for producing local or regional anesthesia.