Novel use of peptide compounds for treating amyotrophic lateral sclerosis

Abstract

The present invention is directed to the use of a class of peptide compounds for treating amyotrophic lateral sclerosis (ALS) and other forms of motoneuron diseases and peripheral neuropathies.

1 . Use of a compound having the Formula (Ib)  
       
         
           
           
               
               
           
         
       
       wherein  
       R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or/and at least one electron donating group;  
       R 1  is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with at least one electron donating group or/and at least one electron withdrawing group; R 2  and R 3  are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R 2  and R 3  may be unsubstituted or substituted with at least one electron withdrawing group or/and at least one electron donating group; and wherein heterocyclic in R 2  and R 3  is furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl or, when N is present in the heterocyclic, an N-oxide thereof;  
       Z is O, S, S(O) a , NR 4 , NR 6 ′ or PR 4  or a chemical bond;  
       Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic and Y may be unsubstituted or substituted with at least one electron donating group or/and at least one an electron withdrawing group, wherein heterocyclic has the same meaning as in R 2  or R 3  and, provided that when Y is halo, Z is a chemical bond, or ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5 , PR 4 SR 7 , NR 4 PR 5 R 6 , PR 4 NR 5 R 7 , or N + R 5 R 6 R 7 ,  
       
         
           
           
               
               
           
         
       
       R 6 ′ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl which may be unsubstituted or substituted with at least one electron withdrawing group or/and at least one electron donating group;  
       R 4 , R 5  and R 6  are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4 , R 5  and R 6  may independently be unsubstituted or substituted with at least one electron withdrawing group or/and at least one electron donating group; and  
       R 7  is R 6  or COOR 8  or COR 8 , which R 7  may be unsubstituted or substituted with at least one electron withdrawing group or/and at least one electron donating group;  
       R 8  is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with at least one electron withdrawing group or/and at least one electron donating group; and  
       n is 1-4; and  
       a is 1-3,  
       or of a pharmaceutically acceptable salt thereof,  
       for the preparation of a pharmaceutical composition useful for the prevention, alleviation or/and treatment of motoneuron disorders or/and peripheral neuropathies.  
     
     
         2 . Use according to  claim 1 , wherein the disorder is amyotrophic lateral sclerosis (ALS).  
     
     
         3 . Use according to  claim 1  wherein one of R 2  and R 3  is hydrogen.  
     
     
         4 . Use according to  claim 1  wherein n is 1.  
     
     
         5 . Use according to  claim 1  wherein one of R 2  and R 3  is hydrogen and n is 1.  
     
     
         6 . Use according to  claim 1  wherein R is aryl lower alkyl and R 1  is lower alkyl.  
     
     
         7 . Use according to  claim 1  wherein  
       R 2  and R 3  are independently hydrogen, lower alkyl, or ZY;  
       Z is O, NR 4  or PR 4 ;  
       Y is hydrogen or lower alkyl or  
       ZY is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 ,  
       
         
           
           
               
               
           
         
       
     
     
         8 . Use according to  claim 7  wherein R 2  is hydrogen and and R 3  is lower alkyl, or ZY;  
       Z is O, NR 4  or PR 4 ;  
       Y is hydrogen or lower alkyl;  
       ZY is NR 4 NR 5  NR 7 , NR 4 OR 5 , ONR 4 R 7 ,  
       
         
           
           
               
               
           
         
       
     
     
         9 . Use according to  claim 1  wherein R 2  is hydrogen and R 3  is lower alkyl, which may be substituted or unsubstituted with at least one electron donating group or/and at least one electron withdrawing group, NR 4 OR 5 , or ONR 4 R 7 .  
     
     
         10 . Use according to  claim 1  wherein R 3  is lower alkyl which is unsubstituted or substituted with hydroxy or loweralkoxy, NR 4 OR 5  or ONR 4 R 7 , wherein R 4 , R 5  and R 7  are independently hydrogen or lower alkyl, R is aryl lower alkyl, which aryl group may be unsubstituted or substituted with at least one electron withdrawing group and R 1  is lower alkyl.  
     
     
         11 . Use according to  claim 1  wherein aryl is phenyl and is unsubstituted or substituted with halo.  
     
     
         12 . Use according to  claim 1  wherein the compound is  
       (R)-2-acetamido-N-benzyl-3-methoxy-propionamide; 
 O-methyl-N-acetyl-b-serine-m-fluorobenzylamide;  
 O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;  
 N-acetyl-D-phenylglycinebenzylamide;  
 D-1,2-(N, O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; or  
 D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide.  
 
     
     
         13 . Use of  claim 1  wherein the compound has the Formula (IIb)  
       
         
           
           
               
               
           
         
       
       wherein  
       Ar is phenyl which is unsubstituted or substituted with at least one halo group;  
       R 3  is CH 2 -Q, wherein Q is lower alkoxy containing 1-3 carbon atoms and R 1  is lower alkyl containing 1-3 carbon atoms  
       or of a pharmaceutically acceptable salt thereof.  
     
     
         14 . Use according to  claim 13  wherein Ar is unsubstituted phenyl.  
     
     
         15 . Use according to  claim 13  wherein halo is fluoro.  
     
     
         16 . Use according to  claim 13  wherein R 3  is CH 2 -Q, wherein Q is alkoxy containing 1-3 carbon atoms and Ar is unsubstituted phenyl.  
     
     
         17 . Use of  claim 1  wherein the compund is in the R configuration and has the formula  
       
         
           
           
               
               
           
         
       
       wherein  
       R is benzyl which is unsubstituted or substituted with at least one halo group;  
       R 3  is CH 2  -Q, wherein Q is lower alkoxy containing 1-3 carbon atoms and R 1  is methyl  
       or a pharmaceutically acceptable salt thereof.  
     
     
         18 . Use according to  claim 17  which is substantially enantiopure.  
     
     
         19 . Use according to  claim 17  wherein R is unsubstituted benzyl.  
     
     
         20 . Use according to  claim 17  wherein halo is fluoro.  
     
     
         21 . Use according to  claim 17  wherein R 3  is CH 2 -Q, wherein Q is alkoxy containing 1-3 carbon atoms and R is unsubstituted benzyl.  
     
     
         22 . Use according to  claim 1 , wherein the compound of Formula (Ib) is (R)-2-Acetamido-N-benzyl-3-methoxypropionamide or a pharmaceutically acceptable salt thereof.  
     
     
         23 . Use according to  claim 22  wherein the compund is substantially enantiopure.  
     
     
         24 . Use according to  claim 1 , wherein the pharmaceutical composition is prepared for treatment with doses of the compound at least of 100 mg/day, preferably at least of 200 mg/day, more preferably at least of 300 mg/day, most preferably at least of 400 mg/day.  
     
     
         25 . Use according to  claim 1 , wherein the pharmaceutical composition is prepared for treatment with doses of the compound at a maximum of 6 g/day, more preferably at a maximum of 1 g/day and most preferably at a maximum of 600 mg/day.  
     
     
         26 . Use according to  claim 1 , wherein the pharmaceutical composition is prepared for treatment with increasing daily doses until a predetermined daily dose is reached which is maintained during the further treatment.  
     
     
         27 . Use according to  claim 1 , wherein the pharmaceutical composition is prepared for treatment in three doses per day, preferably two doses per day, more preferably in a single dose per day.  
     
     
         28 . Use according to  claim 1 , wherein the pharmaceutical composition is prepared for an administration resulting in a plasma concentration of 0.1 to 15 μg/ml (trough) and 5 to 18.5 μg/ml (peak), calculated as an average over a plurality of treated subjects.  
     
     
         29 . Use according to  claim 1 , wherein the pharmaceutical composition is prepared for oral or i.v. administration.  
     
     
         30 . Use according to  claim 1 , wherein the pharmaceutical composition further comprises an active agent for the prevention, alleviation or/and treatment of motoneuron disorders or/and peripheral neuropathies.  
     
     
         31 . Use according to  claim 30  wherein the pharmaceutical composition comprises a single dose form, or comprises a separate dose form comprising a first composition comprising said compound of Formula (Ib) and a second composition comprising the further active agent.  
     
     
         32 . Use according to  claim 1  wherein the pharmaceutical composition is prepared for administration in mammals.  
     
     
         33 . Use according to  claim 33  wherein the pharmaceutical composition is prepared for administration in humans.  
     
     
         34 . A pharmaceutical composition comprising 
 (a) a compound as defined in  claim 1 , and    (b) a further active agent for the prevention, alleviation or/and treatment of motoneuron disorders or/and peripheral neuropathies.    
     
     
         35 . The pharmaceutical composition according to  claim 34  which is a single dose form, or comprises a separate dose form comprising a first composition comprising said compound of Formula (Ib) and a second composition comprising the further active agent (b).