Tripeptide derivatives with central nervous system activity and preparation thereof

Abstract

The tripeptide derivatives of formula H--L--Pro--N(R.sup.1)CH(R.sup.2)CO--Y--R.sup.3 (1) in which R 1 is hydrogen, lower alkyl or NR 4 R 5 wherein R 4 and R 5 each are lower alkyl, R 2 is hydrogen or lower alkyl, R 3 is amino, lower alkylamino, di(lower)alkylamino or amino(lower)alkylamino and Y is one of the amino acid residues Gly or D-Ala with the proviso that when R' is NR 4 R 5 wherein R 4 and R 5 are as defined herein and R 2 and Y are as defined herein, R 3 is lower alkylamino, di(lower)alkylamino or amino(lower)alkylamino, .Iadd.and with the further proviso that when R 1 is hydrogen, R 2 is hydrogen or lower alkyl and Y is Gly then R 3 is amino(lower)alkylamino, .Iaddend.and a method for their preparation are disclosed. The tripeptide derivatives of formula 1 possess central nervous system activity and methods for their use are given.

We claim: 
     
       1. A compound .[.of formula 1.]. .[. .]. .[.in which R 1  is hydrogen, lower alkyl or NR 4  R 5  wherein R 4  and R 5  each are lower alkyl, R 2  is hydrogen or lower alkyl, R 3  is amino, lower alkylamino, di(lower)alkylamino or amino(lower)alkylamino, and Y is one of the amino acid residues Gly or D--Ala with the proviso that when R 1  is NR 4  R 5  is lower alkylamino, di(lower)alkylamino or amino(lower)alkylamino and with the further proviso that when R 1  is hydrogen, R 2  is CH 2  CH(CH 3 ) 2 , R 3  is amino then Y is D--Ala..]. .Iadd.selected from the group consisting of L-prolyl-D-(N-methyl)leucyl-glycinamide, L-prolyl-L-(N-methyl)leucyl-glycinamide, L-propyl-(N-isobutyl)glycyl-glycinamide, L-prolyl-DL-(N-dimethylamino)leucyl-glycine-4-amino-n-butylamide, L-prolyl-L-(N-methyl)leucyl-D-alaninamide, L-prolyl-N-(D-methyl)-leucyl-D-alaninamide and L 
     
     
       2. A pharmaceutically acceptable acid addition salt of the compound .[.of 
     
     
       3. The corresponding amino protected derivative of the compound .[.of formula 1.]. as claimed in claim 1 wherein the protecting group is selected from the group consisting of benzyloxycarbonyl, t-butoxycarbonyl, α,α-dimethyl-3,4,-dimethoxybenzyloxycarbonyl, triphenylmethyl 
     
     
       7. L-Prolyl-DL-(N-dimethylamino)leucyl .Iadd.-glycine-4-amino- .Iaddend.n-butyl-amide, as claimed in claim 1 having a rotation of 
     
     
       8. L-Prolyl-DL-(N-dimethylamino)leucyl-glycine-4-amino- n-butyl-amide, as claimed in claim 1 having a rotation of  D   25  ═18.6° 
     
     
       11. L-Prolyl-L-leucyl-glycine-4-amino-n-butyl-amide as claimed in claim 1. 
     
     
       12. A process for preparing a compound of formula 1 ##STR3## in which R 1  is lower alkyl or NR 4  R 5  wherein R 4  and R 5  each are lower alkyl; R 2  is hydrogen or lower alkyl; R 3  is amino, lower alkylamino, di(lower)alkylamino or amino(lower)alkylamino and Y is the amino acid residue Gly with the proviso that when R 1  is NR 4  R 5 , R 3  is lower alkylamino di(lower)alkylamino or amino(lower)alkylamino which comprises: condensation of an enamine or hydrazone of formula 3, R 1  N═CHR 2  (3), in which R 1  and R 2  are as defined herein with an amino acid of formula R 6  --L--Pro--OH in which R 6  is an amino protecting group selected from the group consisting of benzyloxycarbonyl, t-butoxycarbonyl, α,α-dimethyl-3,4-dimethoxy benzyloxycarboxyl, triphenylmethyl and benzyl in the presence of an isonitrile of the formula CNCH 2  COR 7  in which R 7  is lower alkoxy, to obtain the corresponding intermediate of formula 2   R.sup.6 --L--Pro--N(R.sup.1)CH(R.sup.2)CO--Gly--R.sup.7    ( 2)     in which R 1 , R 2 , R 6  and R 7  are as defined herein, followed by subjecting the last-named compound to amidation to give the corresponding amide or substituted amide and removal of the protective group(s) to obtain the corresponding peptide derivative of formula 1 in which R 1 , R 2 , R 3  and Y are as defined herein.     
     
     
       13. A process as claimed in claim 12 in which the transformation of the intermediate of formula 2   R.sup.6 --L--Pro--N(R.sup.1)CH(R.sup.2)CO--Gly--R.sup.7    ( 2)     in which R 1 , R 2 , R 6  and R 7  are as defined therein is carried out by treating said intermediate with ammonia to obtain the corresponding amide, followed by removel of the protective group R 6  selected from the group consisting of benzyloxycarbonyl, t-butoxycarbonyl, α,α-dimethyl-3,4-dimethoxy benzyloxycarbonyl, triphenylmethyl and benzyl to obtain the corresponding peptide derivative of formula 1 in which R 1  and R 2  are as defined therein, R 3  is amino and Y is the amino acid residue Gly.   
     
     
       14. A process as claimed in claim 13 in which the transformation of the intermediate of formula 2   R.sup.6 --L--Pro--N(R.sup.1)CH(R.sup.2)CO--Gly--R.sup.7    ( 2)     in which R 1 , R 2 , R 6  and R 7  are as defined therein is carried out by treating said intermediate with a hydrolyzing agent to obtain the corresponding acid, treating said acid with an activating agent to give the corresponding activated ester selected from the group consisting of 2,4,5trichlorophenyl, pentachlorophenyl, p-nitrophenyl, and 1-benzotriazolyl, and N,N 1  -carbonyldiimidazolide and .[.o-acylura.]. .Iadd.O-acylurea .Iaddend.of dicyclohexylcarboxdiimide condensing said activated compound with a lower alkylamine, di(lower)alkylamine or mono protected amino(lower)alkylamine in which the protecting group is selected from the group consisting of benzyloxycarbonyl, t-butoxycarbonyl,α,α-dimethyl 3,4-.[.dimethoxybenzyloxycarbonyol.]. .Iadd.dimethoxybenzyloxycarbonyl, .Iaddend.triphenylmethyl and benzyl to obtain the corresponding substituted amide and removing the protective group(s) from said last-named compound to obtain the corresponding peptide derivative of formula 1 in which R 1  and R 2  are as defined herein, R 3  is lower alkylamino, di(lower)alkylamino or amino(lower)alkylamino and Y is the amino acid residue Gly.   
     
     
       15. A process for preparing a compound of formula 1 ##STR4## in which R 1  is CH 3 , R 2  is CH 2  CH(CH 3 ) 2 , R 3  is NH 2  and Y is the amino acid residue D--Ala which comprises: reacting an activated ester selected from the group consisting of 2,4,5, trichlorophenyl, .[.pentachlorphe-.]. .Iadd.pentachlorophe-.Iaddend.nyl, p-nitrophenyl and 1 -benzotriazolyl of benzyloxycarbonyl-L-(N-methyl)leucine with D-alanine methyl ester to obtain the dipeptide of formula Z--L--(N--Me)Leu--D--Ala--.[.(N--Me)Leu--.]. .Iadd.OMe; .Iaddend.treating said last-name compound with hydrogen and a noble metal catalyst and isolating the dipeptide of formula H--L--(N--Me)Leu--D--Ala--OMe, reacting said last-named compound with an activated ester as defined herein of benzyloxycarbonyl- L-proline and isolating the tripeptide of formula Z--L--Pro--L--(N--Me)Leu--D--Ala--OMe; treating said last-named compound with ammonia and isolating the tripeptide of formula Z--L--Pro--L--(N--Me)Leu--D--Ala--NH 2  ; treating said last-named compound with hydrogen and a noble metal catalyst and isolating the corresponding tripeptide derivative of formula 1 in which R 1  is CH 3 , R 2  is CH 2  CH(CH 3 ) 2 , R 3  is NH 2  and Y is the amino residue D--Ala.   
     
     
       16. A pharmaceutical composition comprising an acid addition salt of a compound .[.of formula 1.]. as claimed in claim 2 and a pharmaceutically acceptable carrier. 
     
     
       17. A pharmaceutical composition comprising an amino protected derivative of a .[.copound of formula 1.]. .Iadd.compound .Iaddend.as claimed in claim 3 wherein the protecting group is selected from the group consisting of benzyloxycarbonyl t-butoxycarbonyl, α, α-dimethyl-3,4-dimethoxybenzyloxycarbonyl, triphenylmethyl and benzyl and a pharmaceutically acceptable carrier. 
     
     
       18. A method of treating Parkinsonism in warm-blooded animals comprising the oral administration thereto of 0.25-100 mg/kg of .[.an acid addition salt of.]. a compound .[.of formula 1.]. as claimed in claim 1 or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       19. A method of treating mental depression in warm-blooded animals comprising the oral administration thereto of 0.25-100 mg/kg of a compound .[.of formula 1.]. as claimed in claim 1 or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       20. A method of treating Parkinsonism in warm-blooded animals comprising the parenteral administration thereto of 0.05-20 mg/kg .[.of an acid addition salt.]. of a compound .[.of formula 1.]. as claimed in claim 1 or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       21. A method of treating mental depression in warm-blooded animals comprising the parental administration thereto of 0.05-20 mg/kg .[.of an acid addition salt.]. of a compound .[.of formula 1.]. as claimed in claim 1 or a pharmaceutically acceptable acid addition salt thereof.