Alpha-aminoamide derivatives useful as analgesic agents

Abstract

The present invention relates to novel and known alpha-aminoamide compounds, to a process for their preparation, to pharmaceutical composition containing them and to their use as therapeutic agents. In particular, the compounds of the present invention are endowed with analgesic properties and are particularly useful for the treatment and alleviation of chronic and neuropathic pain. Accordingly, one object of the present invention is to provide the use of a compound of formula (I) wherein: A is a —(CH 2 ) m —, —(CH 2 ) n —X— or —(CH 2 ) v —O— group wherein m is an integer of 1 to 4, n is zero or an integer of 1 to 4, X is —S— or —NH—, and v is zero or an integer of 1 to 5; s is 1 or 2; R is a furyl, thienyl, or pyridyl ring or a phenyl ring optionally substituted by one or two substituents independently chosen from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and trifluoromethyl; R 1 is hydrogen or C 1 -C 4 alkyl; one of R 2 and R 3 is hydrogen and the other is hydrogen or C 1 -C 4 alkyl optionally substituted by hydroxy or phenyl; or R 2 and R 3 taken together with the carbon atom to which they are linked form a C 3 -C 6 cycloalkyl ring; or R 2 and R 3 are both methyl; R 4 is hydrogen or C 1 -C 4 alkyl.

1. A method of treating acute or chronic pain in a patient in need thereof, said method comprising administering to the  a patient in need of such treatment a medicament comprising an analgesically effective amount of an analgesic which is  an alpha-aminoamide compound of formula (I) 
                 
 
       wherein:
 A is a —(CH 2 ) m —, —(CH 2 ) n —X— or —(CH 2 ) v —O— group wherein m is an integer of 1 to 4, n is zero or an integer of 1 to 4, X is —S— or —NH—, and v is zero or an integer of 1 to 5;  
 s is 1 or 2;  
 R is a ring or  a phenyl ring optionally substituted by one or two substituents independently chosen  selected from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and trifluoromethyl;  
 R 1  is hydrogen or C 1 -C 4  alkyl;  
 one of R 2  and R 3  is hydrogen and the other is hydrogen or C 1 -C 4  alkyl optionally substituted by hydroxy or phenyl; or R 2  and R 3  taken together with the carbon atom to which they are linked form a C 3 -C 6  cycloalkyl ring; or R 2  and R 3  are both methyl;  
 R 4  is hydrogen or C 1 -C 4  alkyl;  
 
       or a pharmaceutically acceptable salt thereof; 
       with the proviso that,  when A is a —(CH 2 ) 5 —O— group then s is 1, R is a phenyl group optionally substituted by one or two substituents selected independently from halogen, trifluoromethyl and C 1 -C 4  alkoxy, R 1  is hydrogen and one of R 2  and R 3  is hydrogen and the other is hydrogen or C 1 -C 4  alkyl optionally substituted by hydroxy. 
     
     
       2. A method of treating chronic or neuropathic pain in a patient in need thereof, said method comprising the method according to  claim 1 . 
     
     
       3. The method according to  claim 1  or  claim 6 , wherein in the compound of formula (I),
 A is a group chosen  selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 —S—, —CH 2 —CH 2 —S— and —(CH 2 ) v —O— in which v is an integer of 1 to 5;  
 s is 1 or 2;  
 R is a phenyl ring optionally substituted by one or two substituents independently chosen  selected from halogen and cyano or a thienyl ring ;  
 R 1  is hydrogen or C 1 -C 4  alkyl; one of R 2  and R 3  is hydrogen and the other is C 1 -C 4  alkyl optionally substituted by hydroxy or phenyl; or R 2  and R 3  are both methyl; and  
 R 4  is hydrogen or C 1 -C 4  alkyl.  
 
     
     
       4. A method of treating pain in a patient in need thereof, said method comprising administering to the patient a medicament comprising an effective amount of an analgesic which is selected from the group consisting of: 
       2-[4-(3-fluorobenzyloxy)benzylamino]-2-methyl-propanamide;  
       2-[4-(3-fluorobenzyloxy)benzylamino]propanamide;  
       2-(4-benzyloxybenzylamino)propanamide;  
       2-[4-(2-fluorobenzyloxy)benzylamino]propanamide;  
       2-[4-(4-fluorobenzyloxy)benzylamino]propanamide;  
       2-[4-(2-chlorobenzyloxy)benzylamino]propanamide;  
       2-[4-(3-chlorobenzyloxy)benzylamino]propanamide;  
       2-[4-(3-fluorobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;  
       2-[4-(2-fluorobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;  
       2-[4-(2-chlorobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;  
       2-[4-(3-cyanobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;  
       2-[4-(3-chlorobenzyloxy)phenylethylamino]-propanamide;  
       2-(4-benzyloxybenzylamino)-3-hydroxy-N-methyl-propanamide;  
       2-[4-(2-thenyloxy)benzylamino]-propanamide;  
       2-[4-(3-fluorobenzyloxy)benzylamino]-N-methylpropanamide;  
       2-[4-(3-fluorobenzyloxy)benzylamino]-3-hydroxy-propanamide;  
       2-[4-(2-(3-fluorophenyl)ethyloxy)benzylamino]-propanamide;  
       2-[4-(2-(3-fluorophenyl)ethyl)benzylamino]-propanamide;  
       2-[N-4-benzyloxybenzyl-N-methyl-amino]-propanamide;  
       2-[2-(4-(3-chlorobenzyloxy)phenylethyl)amino]-propanamide;  
       2-[4-benzylthiobenzylamino]-propanamide;  
       2-[4-(3-phenylpropyloxy)benzylamino]-propanamide;  
       2-[4-(4-phenylbutyloxy)benzylamino]-propanamide;  
       2-[4-(5-phylpentyloxy)benzylamino]-propanamide;  
       2-[4-benzyloxybenzylamino]-3-phenyl-N-methylpropanamide;  
       2-[4-benzyloxybenzylamino]-3-methyl-N-methylbutanamide, isomers, mixtures and pharmaceutically acceptable salts  
       The method of  claim 1  or  claim 6  in which the alpha- aminoamide compound is selected from the group consisting of:        2   - [ 4   -(   2   - fluorobenzyloxy ) benzylamino]propanamide      
         and individual optical isomers and pharmaceutically acceptable salts  thereof. 
     
     
       5. A pharmaceutical composition having analgesic activity,  comprising a pharmaceutically acceptable excipient and, as an active agent,  a compound as defined in  claim 1    claim 9 . 
     
     
       6. A method of treating acute or chronic pain in a patient in need thereof, said method comprising administering to the  a patient in need of such treatment an analgesically effective amount of an alpha-aminoamide compound of formula (I), 
                 
 
       or a pharmaceutically acceptable salt thereof, 
       
         wherein:  
           A is a — ( CH   2 ) m —, —( CH   2 ) n   —X— or — ( CH   2 ) v   —O— group wherein m is an integer of  1  to  4 , n is zero or an integer of  1  to  4 , X is —S— or —NH—, and v is zero or an integer of  1  to  5 ;    
         
           s is  1  or  2 ;  
         
           R is a phenyl ring optionally substituted by one or two substituents independently selected from halogen, cyano, C   1 - C   4    alkyl, C   1 - C   4    alkoxy and trifluoromethyl;    
           R   1    is hydrogen or C   1 - C   4    alkyl;    
           one of R   2    and R   3    is hydrogen and the other is hydrogen or C   1 - C   4    alkyl optionally substituted by hydroxy or phenyl; or R   2    and R   3    taken together with the carbon atom to which they are linked form a C   3 - C   6    cycloalkyl ring; or R   2    and R   3    are both methyl;    
           R   4    is hydrogen or C   1 - C   4    alkyl,    
           with the proviso that when A is a — ( CH   2 ) 5   —O— group then s is  1 , R is a phenyl group optionally substituted by one or two substituents selected independently from halogen, trifluoromethyl and C   1 - C   4    alkoxy, R   1    is hydrogen and one of R   2    and R   3    is hydrogen and the other is hydrogen or C   1 - C   4    alkyl optionally substituted by hydroxy.    
       
     
     
       7. A compound which is an alpha-aminoamide of formula (IA) 
                 
 
       wherein:
 A is a —(CH 2 ) m — or —(CH 2 ) n —E— group wherein m is an integer of 1 to 4, n is zero or an integer of 1 to 4 and E is —O—, —S— or —NH—;  
 s is 1 or 2;  
 one of R 10  and R 11  is cyano and the other is independently selected from hydrogen, halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and trifluoromethyl;  
 R 1  is hydrogen or C 1 -C 4  alkyl;  
 one of R 2  and R 3  is hydrogen and the other is hydrogen or C 1 -C 4  alkyl optionally substituted by hydroxy or phenyl; or R 2  and R 3  taken together with the carbon atom to which they are linked form a C 3 -C 6  cycloalkyl ring; or R 2  and R 3  are both methyl;  
 R 4  is hydrogen or C 1 -C 4  alkyl ring; or a pharmaceutically acceptable salt thereof.  
 
     
     
       8. A compound according to  claim 7 , wherein
 A is a group —CH 2 —O— or —CH 2 —CH 2 —O—,  
 s is 1;  
 one of R 10  and R 11  is cyano and the other is hydrogen, cyano or halogen; and  
 one of R 2  and R 3  is hydrogen and the other is C 1 -C 4  alkyl optionally substituted by hydroxy; or R 2  and R 3  are both methyl.  
 
     
     
       9. A compound selected from the group consisting of: 
       2-[4-(3-cyanobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide; and  
       2-[4-(3 cyanobenzyloxy)benzyl]-2-methyl-amino]-3-hydroxy-N-methyl-propanamide;  
         2 - [ 4   -(   3   - cyanobenzyloxy ) benzylamino] -   3   - hydroxy - N - methylpropanamide; and    
           2   - [ 4   -(   3  cyanobenzyloxy ) benzyl -   2   - methyl - amino] -    3   - hydroxy - N - methyl - propanamide;    
         optical  isomers, mixtures and pharmaceutically acceptable salts thereof.  
     
     
       10. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and, as an active agent, a compound as defined in  claim 7 . 
     
     
       11. A method of treating acute or chronic pain in a patient in need thereof, said method comprising administering to the  a patient in need of such treatment an analgesic which comprises an effective amount of the compound according to  claim 7  and a pharmaceutically acceptable carrier. 
     
     
       12. A method of treating acute or chronic pain in a patient in need thereof, said method comprising administering to the  a patient in need of such treatment an effective amount of the compound according to  claim 7 . 
     
     
       13. The method of  claim 1  or  claim 6  in which the alpha- aminoamide compound is selected from the group consisting of:        2   - [ 4   -(   3   - fluorobenzyloxy ) benzylamino] -   2   - methylpropanamide;          2   - [ 4   -(   3   - fluorobenzyloxy ) benzylamino]propanamide;          2   -(   4   - benzyloxybenzylamino ) propanamide;          2   - [ 4   -(   4   - fluorobenzyloxy ) benzylamino]propanamide;          2   - [ 4   -(   2   - chlorobenzyloxy ) benzylamino]propanamide;          2   - [ 4   -(   3   - chlorobenzyloxy ) benzylamino]propanamide;          2   - [ 4   -(   3   - fluorobenzyloxy ) benzylamino] -   3   - hydroxy - N - methylpropanamide;          2   - [ 4   -(   2   - fluorobenzyloxy ) benzylamino] -   3   - hydroxy - N - methylpropanamide;          2   - [ 4   -(   2   - chlorobenzyloxy ) benzylamino] -   3   - hydroxy - N - methylpropanamide;          2   - [ 4   -(   3   - cyanobenzyloxy ) benzylamino] -   3   - hydroxy - N - methylpropanamide;          2   - [ 4   -(   3   - chlorobenzyloxy ) phenylethylamino]propanamide;          2   -(   4   - benzyloxybenzylamino )-   3   - hydroxy - N - methylpropanamide;          2   - [ 4   -(   3   - fluorobenzyloxy ) benzylamino] - N - methylpropanamide;          2   - [ 4   -(   3   - fluorobenzyloxy ) benzylamino] -   3   - hydroxypropanamide;          2   - [ 4   -(   2   -(   3   - fluorophenyl ) ethyloxy ) benzylamino]propanamide;          2   - [ 4   -(   2   -(   3   - fluorophenyl ) ethyl ) benzylamino]propanamide;          2   - [N -   4   - benzyloxybenzyl - N - methyl - amino]propanamide;          2   - [ 2   -(   4   -(   3   - chlorobenzyloxy ) phenylethyl ) amino]propanamide;          2   - [ 4   - benzylthiobenzylamino]propanamide;          2   - [ 4   -(   3   - phenylpropoxy ) benzylamino]propanamide;          2   - [ 4   -(   4   - phenylbutoxy ) benzylamino]propanamide;          2   - [ 4   -(   5   - phenylpentoxy ) benzylamino]propanamide;          2   - [ 4   - benzyloxybenzylamino] -   3   - phenyl - N - methylpropanamide;          2   - [ 4   - benzyloxybenzylamino] -   3   - methyl - N - methylbutanamide;        and optical isomers, mixtures and pharmaceutically acceptable salts thereof.     
     
     
       14. The method of  claim 1  or  claim 6  in which the alpha- aminoamide compound is selected from the group consisting of:        2   - [ 4   -(   3   - fluorobenzyloxy ) benzylamino]propanamide      
       
         and individual optical isomers and pharmaceutically acceptable salts thereof. 
       
     
     
       15. The method of  claim 1  or  claim 6 , wherein the pain is neuropathic pain. 
     
     
       16. The method of  claim 15 , wherein the neuropathic pain is a peripheral neuropathic pain. 
     
     
       17. The method of  claim 15 , wherein the pain is trigeminal neuralgia pain. 
     
     
       18. The method of  claim 15 , wherein the pain is postherpetic neuralgia pain. 
     
     
       19. The method of  claim 15 , wherein the pain is diabetic neuropathy pain. 
     
     
       20. The method of  claim 15 , wherein the pain is radiculopathy pain. 
     
     
       21. The method of  claim 15 , wherein the pain is glossopharyngeal neuralgia pain. 
     
     
       22. The method of  claim 15 , wherein the pain is neuropathic pain secondary to metastatic infiltration. 
     
     
       23. The method of  claim 1  or  claim 6 , wherein the pain is burn pain. 
     
     
       24. The method of  claim 1  or  claim 6 , wherein the pain is chronic pain. 
     
     
       25. The method of  claim 1  or  claim 6 , wherein the pain is inflammatory pain. 
     
     
       26. The method of  claim 1  or  claim 6 , wherein the pain is adiposis dolorosa pain. 
     
     
       27. The method of  claim 1  or  claim 6 , wherein the pain is post- stroke central pain.   
     
     
       28. The method of  claim 1  or  claim 6 , wherein the pain is thalamic lesion pain. 
     
     
       29. The method of  claim 1  or  claim 6 , wherein the pain is multiple sclerosis pain. 
     
     
       30. The method of  claim 1  or  claim 6 , wherein the pain is acute pain. 
     
     
       31. The method of  claim 4 , wherein the pain is neuropathic pain. 
     
     
       32. The method of  claim 31 , wherein the neuropathic pain is a peripheral neuropathic pain. 
     
     
       33. The method of  claim 31 , wherein the pain is trigeminal neuralgia pain. 
     
     
       34. The method of  claim 31 , wherein the pain is postherpetic neuralgia pain. 
     
     
       35. The method of  claim 31 , wherein the pain is diabetic neuropathy pain. 
     
     
       36. The method of  claim 31 , wherein the pain is radiculopathy pain. 
     
     
       37. The method of  claim 31 , wherein the pain is glossopharyngeal neuralgia pain. 
     
     
       38. The method of  claim 31 , wherein the pain is neuropathic pain secondary to metastatic infiltration. 
     
     
       39. The method of  claim 4 , wherein the pain is burn pain. 
     
     
       40. The method of  claim 4 , wherein the pain is chronic pain. 
     
     
       41. The method of  claim 4 , wherein the pain is inflammatory pain. 
     
     
       42. The method of  claim 4 , wherein the pain is adiposis dolorosa pain. 
     
     
       43. The method of  claim 4 , wherein the pain is post- stroke central pain.   
     
     
       44. The method of  claim 4 , wherein the pain is thalamic lesion pain. 
     
     
       45. The method of  claim 4 , wherein the pain is multiple sclerosis pain. 
     
     
       46. The method of  claim 4 , wherein the pain is acute pain. 
     
     
       47. The method of  claim 14 , wherein the pain is neuropathic pain. 
     
     
       48. The method of  claim 47 , wherein the neuropathic pain is a peripheral neuropathic pain. 
     
     
       49. The method of  claim 47 , wherein the pain is trigeminal neuralgia pain. 
     
     
       50. The method of  claim 47 , wherein the pain is postherpetic neuralgia pain. 
     
     
       51. The method of  claim 47 , wherein the pain is diabetic neuropathy pain. 
     
     
       52. The method of  claim 47 , wherein the pain is radiculopathy pain. 
     
     
       53. The method of  claim 47 , wherein the pain is glossopharyngeal neuralgia pain. 
     
     
       54. The method of  claim 47 , wherein the pain is neuropathic pain secondary to metastatic infiltration. 
     
     
       55. The method of  claim 14 , wherein the pain is burn pain. 
     
     
       56. The method of  claim 14 , wherein the pain is chronic pain. 
     
     
       57. The method of  claim 14 , wherein the pain is inflammatory pain. 
     
     
       58. The method of  claim 14 , wherein the pain is adiposis dolorosa pain. 
     
     
       59. The method of  claim 14 , wherein the pain is post- stroke central pain.   
     
     
       60. The method of  claim 14 , wherein the pain is thalamic lesion pain. 
     
     
       61. The method of  claim 14 , wherein the pain is multiple sclerosis pain. 
     
     
       62. The method of  claim 14 , wherein the pain is acute pain. 
     
     
       63. The method of  claim 1  or  claim 6 , wherein the administering is by oral administration. 
     
     
       64. The method of  claim 63 , wherein the administering is by oral administration of a tablet. 
     
     
       65. The method of  claim 63 , wherein the administering is by oral administration of a capsule. 
     
     
       66. The method of  claim 63 , wherein the administering is by oral administration of liquid solution or liquid suspension. 
     
     
       67. The method of  claim 1  or  claim 6 , wherein the administering is by parenteral administration. 
     
     
       68. The method of  claim 67 , wherein the parenteral administration is intravenous administration. 
     
     
       69. The method of  claim 68 , wherein the intravenous administration is by intravenous infusion. 
     
     
       70. The method of  claim 68 , wherein the intravenous administration is by intravenous injection. 
     
     
       71. The method of  claim 67 , wherein parenteral administration is by intramuscular injection. 
     
     
       72. The method of  claim 1  or  claim 6 , wherein the administering is by rectal administration. 
     
     
       73. The method of  claim 4 , wherein the administering is by oral administration. 
     
     
       74. The method of  claim 73 , wherein the administering is by oral administration of a tablet. 
     
     
       75. The method of  claim 73 , wherein the administering is by oral administration of a capsule. 
     
     
       76. The method of  claim 73 , wherein the administering is by oral administration of liquid solution or liquid suspension. 
     
     
       77. The method of  claim 4 , wherein the administering is by parenteral administration. 
     
     
       78. The method of  claim 77 , wherein parenteral administration is intravenous administration. 
     
     
       79. The method of  claim 78 , wherein intravenous administration is by intravenous infusion. 
     
     
       80. The method of  claim 78 , wherein intravenous administration is by intravenous injection. 
     
     
       81. The method of  claim 77 , wherein parenteral administration is by intramuscular injection. 
     
     
       82. The method of  claim 4 , wherein the administering is by rectal administration. 
     
     
       83. The method of  claim 14 , wherein the administering is by oral administration. 
     
     
       84. The method of  claim 83 , wherein the administering is by oral administration of a tablet. 
     
     
       85. The method of  claim 83 , wherein the administering is by oral administration of a capsule. 
     
     
       86. The method of  claim 83 , wherein the administering is by oral administration of liquid solution or liquid suspension. 
     
     
       87. The method of  claim 14 , wherein the administering is by parenteral administration. 
     
     
       88. The method of  claim 87 , wherein parenteral administration is intravenous administration. 
     
     
       89. The method of  claim 88 , wherein intravenous administration is by intravenous infusion. 
     
     
       90. The method of  claim 88 , wherein intravenous administration is by intravenous injection. 
     
     
       91. The method of  claim 87 , wherein parenteral administration is by intramuscular injection. 
     
     
       92. The method of  claim 14 , wherein the administering is by rectal administration. 
     
     
       93. The method of  claim 63 , wherein  1 -   500  mg of the alpha - aminoamide compound is administered orally per day.   
     
     
       94. The method of  claim 63 , wherein  500  mg-   1000  mg of the alpha - aminoamide compound is administered orally per day.   
     
     
       95. The method of  claim 63 , wherein  1000 -   1500  mg of the alpha - aminoamide compound is administered orally per day.   
     
     
       96. The method of  claim 63 , wherein  1500 -   2000  mg of the alpha - aminoamide compound is administered orally per day.   
     
     
       97. The method of  claim 73 , wherein  1 -   500  mg of the alpha - aminoamide compound is administered orally per day.   
     
     
       98. The method of  claim 73 , wherein  500  mg-   1000  mg of the alpha - aminoamide compound is administered orally per day.   
     
     
       99. The method of  claim 73 , wherein  1000 -   1500  mg of the alpha - aminoamide compound is administered orally per day.   
     
     
       100. The method of  claim 73 , wherein  1500 -   2000  mg of the alpha - aminoamide compound is administered orally per day.   
     
     
       101. The method of  claim 1  or  claim 6 , wherein the pharmaceutically acceptable salt is a methanesulfonate salt. 
     
     
       102. The method of  claim 4 , wherein the pharmaceutically acceptable salt is a methanesulfonate salt. 
     
     
       103. The method of  claim 14 , wherein the pharmaceutically acceptable salt is a methanesulfonate salt. 
     
     
       104. The method of  claim 4 , wherein  2 - [ 4   -(   2   - fluorobenzyloxy ) benzylamino]propanamide methanesulfonate is administered orally to a human patient at a dose of  1   -   2000  mg/day.   
     
     
       105. The method of  claim 104 , wherein  2 - [ 4   -(   2   - fluorobenzyloxy ) benzylamino]propanamide methanesulfonate is administered orally to a human patient at a dose of  500   -   1000  mg/day.   
     
     
       106. The method of  claim 104 , wherein the pain is neuropathic pain. 
     
     
       107. The method of  claim 105 , wherein the pain is neuropathic pain. 
     
     
       108. The method of  claim 104 , wherein the pain is inflammatory pain. 
     
     
       109. The method of  claim 105 , wherein the pain is inflammatory pain. 
     
     
       110. The method of  claim 104 , wherein the pain is chronic pain. 
     
     
       111. The method of  claim 105 , wherein the pain is chronic pain. 
     
     
       112. The method of  claim 104 , wherein the pain is radiculopathy pain. 
     
     
       113. The method of  claim 105 , wherein the pain is radiculopathy pain.