N-acyldipeptide derivatives and their uses

Abstract

N-acyldipeptide derivatives are described. Compositions comprising the N-acyldipeptide derivatives are therapeutically effective for treating disorders and condition associated with the nervous system or musculoskeletal system, such as pain, weakness, numbness, arthritis, joint inflammation, weakness of muscles or joints, and myopia.

We claim: 
     
         1 . A method of treating a disorder or condition selected from the group consisting of pain, weakness, numbness, arthritis, joint inflammation, weakness of muscles or joints, and myopia in a subject in need thereof, the method comprising topically or systemically administering to the subject a composition comprising a therapeutically effective amount of a dipeptide derivative of formula (I):
   R 1 -AAB-AAC-R 2   (I)
   or an isomer or salt thereof, and optionally a pharmaceutically or cosmetically acceptable carrier, wherein R 1  is an acyl radical having up to 9 carbon atoms; AAB is tyrosine and AAC is tyrosine, or AAB is valine and AAC is alanine; R 2  is OR 3 , NHR 4 , or NHNHR 5 ; R 3  is H, or an alkyl, aralkyl, or aryl radical having up to 19 carbon atoms; and R 4  and R 5  are independently H, OH, or an alkyl, aralkyl, or aryl radical having up to 19 carbon atoms.   
     
     
         2 . The method of  claim 1 , wherein the dipeptide derivative of formula (I) is selected from the group consisting of N-Ac-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-NHNHAc, N-Ac-Tyr-Tyr-NHOH, N-Pr-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-OH, N-Pr-Tyr-Tyr-OEt, N-Pr-Tyr-Tyr-NHNH 2 , and N-Pr-Tyr-Tyr-NHNHPr. 
     
     
         3 . The method of  claim 1 , wherein the dipeptide derivative of formula (I) is selected from the group consisting of N-Ac-Val-Ala-NH 2 , N-Ac-Val-Ala-OH, N-Ac-Val-Ala-NHOH, N-Pr-Val-Ala-NH 2 , and N-Pr-Val-Ala-OH. 
     
     
         4 . The method of  claim 1 , wherein the disorder or condition is selected from the group consisting of pain, weakness, numbness, arthritis, joint inflammation, and weakness of muscles or joints. 
     
     
         5 . The method of  claim 1 , wherein the disorder or condition is selected from the group consisting of pain, arthritis, and weakness of muscles or joints. 
     
     
         6 . The method of  claim 5 , wherein the pain is joint pain or muscle pain. 
     
     
         7 . The method of  claim 1 , wherein the composition is adminstered topically to skin of the subject. 
     
     
         8 . A method of treating a disorder or condition selected from the group consisting of arthritis, joint inflammation, joint or muscle pain, and weakness of muscles or joints in a subject in need thereof, the method comprising topically administering to skin of the subject a composition comprising a therapeutically effective amount of a dipeptide derivative of formula (I):
   R 1 -AAB-AAC-R 2      or an isomer or salt thereof, and optionally a pharmaceutically or cosmetically acceptable carrier, wherein R 1  is an acyl radical having up to 9 carbon atoms; AAB is tyrosine and AAC is tyrosine, or AAB is valine and AAC is alanine; R 2  is OR 3 , NHR 4 , or NHNHR 5 ; R 3  is H, or an alkyl, aralkyl, or aryl radical having up to 19 carbon atoms; and R 4  and R 5  are independently H, OH, or an alkyl, aralkyl, or aryl radical having up to 19 carbon atoms.   
     
     
         9 . The method of  claim 8 , wherein the dipeptide derivative of formula (I) is selected from the group consisting of N-Ac-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-NHNHAc, N-Ac-Tyr-Tyr-NHOH, N-Pr-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-OH, N-Pr-Tyr-Tyr-OEt, N-Pr-Tyr-Tyr-NHNH 2 , and N-Pr-Tyr-Tyr-NHNHPr. 
     
     
         10 . The method of  claim 8 , wherein the dipeptide derivative of formula (I) is selected from the group consisting of N-Ac-Val-Ala-NH 2 , N-Ac-Val-Ala-OH, N-Ac-Val-Ala-NHOH, N-Pr-Val-Ala-NH 2 , and N-Pr-Val-Ala-OH. 
     
     
         11 . The method of  claim 8 , wherein the disorder or condition is arthritis. 
     
     
         12 . The method of  claim 8 , wherein the disorder of condition is joint or muscle pain. 
     
     
         13 . The method of  claim 8 , wherein the disorder or condition is weakness of the muscles or joints. 
     
     
         14 . A method of treating a disorder or condition selected from the group consisting of arthritis, joint inflammation, joint or muscle pain, and weakness of muscles or joints in a subject in need thereof, the method comprising topically administering to skin of the subject a composition comprising a therapeutically effective amount of a dipeptide derivative selected from the group consisting of N-Ac-Tyr-Tyr-NH 2 , N-Ac-Tyr-Tyr-OH, N-Ac-Tyr-Tyr-OEt, N-Ac-Tyr-Tyr-NHNH 2 , N-Ac-Tyr-Tyr-NHNHAc, N-Ac-Tyr-Tyr-NHOH, N-Pr-Tyr-Tyr-NH 2 , N-Pr-Tyr-Tyr-OH, N-Pr-Tyr-Tyr-OEt, N-Pr-Tyr-Tyr-NHNH 2 , N-Pr-Tyr-Tyr-NHNHPr, N-Ac-Val-Ala-NH 2 , N-Ac-Val-Ala-OH, N-Ac-Val-Ala-NHOH, N-Pr-Val-Ala-NH 2 , and N-Pr-Val-Ala-OH or an isomer or salt thereof, and optionally a pharmaceutically or cosmetically acceptable carrier.