Guanidine compounds as anesthetics and for treatment of nervous system disorders

Abstract

Novel guanidine compounds having the formula in which R1, R2 and R4 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 .- 91 . (canceled) 
     
     
         92 . 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; 
 (f) 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-carbamide-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; 
 (j) 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) (CH 2 ) m COOR 15  where R 15  is alkyl or substituted alkyl; and m is 0, 1 or 2 
 (b) 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; 
 (c) C 1 -C 4  alkoxy; 
 (d) optionally substituted phenoxy; 
 (e) SO 2 NR 19 R 20  where R 19  and R 20  are independently hydrogen, optionally substituted alkyl or phenyl; 
 (f) NR 21 R 22 ; 
 (g) COR 23  where R 23  is alkyl or is NR 21 R 22 ; 
 (h) COOR 23  where R 23  is hydrogen, alkyl, or benzyl; or 
 (i) SO 2 R 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. 
 
       
     
     
         93 . A compound having the formula 
       
         
           
           
               
               
           
         
         in which R 1  is phenoxymethyl, R 2  is 4-fluorobenzyl, 4-methoxybenzyl, 2-(N-piperido)ethyl, octyl, 1-naphthylmethyl, n-undecyl, benzyl or 2-(N,N-dibenzylamino)ethyl and R 4  is hydrogen. 
       
     
     
         94 . A compound having the formula 
       
         
           
           
               
               
           
         
         in which
 R 1  is benzyloxymethyl; 
 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 R 3  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) COOR 8  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 (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 g 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 dicyano; 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); 
 (i) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; or 
 (j) methylene-1- or 2-naphthyl; 
 and R 4  is hydrogen. 
 
       
     
     
         95 . A compound having the formula 
       
         
           
           
               
               
           
         
         in which R 1  and R 2  are both benzyl and R4 is hydrogen. 
       
     
     
         96 . The compound of  claim 92 , wherein
 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-(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  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  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 ;   (h) naphthyl; or   (i) 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 R 3  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);   (i) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; or   (j) methylene-1- or 2-naphthyl; and   R 4  is   (a) hydrogen;   (b) (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-(C1-C4 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 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;   (f) 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.   
     
     
         97 . The compound of  claim 92 , wherein
 R1 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.   
     
     
         98 . The composition of  claim 92 , wherein R 1  is phenyl. 
     
     
         99 . The composition of  claim 92 , wherein R 1  is substituted phenyl. 
     
     
         100 . The composition of  claim 92 , wherein R 1  is mono- or dihalophenyl. 
     
     
         101 . The composition of  claim 100 , wherein R 1  is 3,4-dichlorophenyl. 
     
     
         102 . The composition of  claim 92 , wherein 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. 
     
     
         103 . The composition of  claim 92 , wherein R 1  is thienyl. 
     
     
         104 . The composition of  claim 92 , wherein 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. 
     
     
         105 . The composition of  claim 104 , wherein R 1  is CH 2 XR 5  and R 5  is phenyl, substituted phenyl, or benzyl. 
     
     
         106 . The composition of  claim 104 , wherein X is oxygen 
     
     
         107 . The composition of  claim 106 , wherein R 5  is benzyl, phenyl, or substituted phenyl. 
     
     
         108 . The composition of  claim 107 , wherein R 5  is phenyl. 
     
     
         109 . The composition of  claim 107 , wherein R 5  is 4-chlorophenyl. 
     
     
         110 . The composition of  claim 107 , wherein R 3  is benzyl. 
     
     
         111 . The composition of  claim 92 , wherein R 2  is benzyl. 
     
     
         112 . The composition of  claim 92 , wherein R 2  is substituted benzyl. 
     
     
         113 . The composition of  claim 96 , wherein R 2  is benzyl or substituted benzyl. 
     
     
         114 . The composition of  claim 113 , wherein R 2  is benzyl substituted by an a C 1 -C 4  alkyl group, a C 1 -C 4  alkoxy group, or a halogen. 
     
     
         115 . The composition of  claim 113 , wherein R 2  is 4-methylbenzyl. 
     
     
         116 . The composition of  claim 113 , wherein R 2  is 4-methoxybenzyl. 
     
     
         117 . The composition of  claim 113 , wherein R 2  is 4-fluorobenzyl. 
     
     
         118 . The composition of  claim 92 , wherein R 2  is a C 2 -C 4  alkyl group. 
     
     
         119 . The composition of  claim 118 , wherein R 2  is ethyl. 
     
     
         120 . The composition of  claim 118 , wherein R 2  is n-butyl. 
     
     
         121 . The composition of  claim 92 , wherein 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. 
     
     
         122 . The composition of  claim 121 , wherein R 3  is 1-piperidino. 
     
     
         123 . The composition of  claim 92 , wherein R 4  is hydrogen. 
     
     
         124 . The composition of  claim 92 , wherein further providing that:
 if R 1  is 4-chlorophenoxymethyl 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,-diethylamino)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.   
     
     
         125 . The composition of  claim 92 , wherein 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-methylphenyl, 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.   
     
     
         126 . The composition of  claim 92  further comprising a pharmaceutically acceptable diluent or carrier. 
     
     
         127 . The composition of  claim 92  further comprising (a) an anesthetically or analgesically effective amount of the compound and (b) a pharmaceutically acceptable diluent or carrier.