Tripeptide derivatives with central nervous system activity and preparation thereof

Claim 2

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

Claim 3

A pharmaceutically acceptable acid addition salt of the compound .[.of

Claim 4

A pharmaceutically acceptable acid addition salt of the compound .[.of

Claim 5

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

Claim 6

L-Prolyl-DL-(N-dimethylamino)leucyl .Iadd.-glycine-4-amino- .Iaddend.n-butyl-amide, as claimed in claim 1 having a rotation of

Claim 7

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°

Claim 8

L-Prolyl-L-leucyl-glycine-4-amino-n-butyl-amide as claimed in claim 1.

Claim 9

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.

Claim 10

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.

Claim 11

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.

Claim 12

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.

Claim 13

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.

Claim 14

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.

Claim 15

A pharmaceutical composition comprising an acid addition salt of a compound .[.of formula 1.]. as claimed in claim 2 and a pharmaceutically acceptable carrier.

Claim 16

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.

Claim 17

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.

Claim 18

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.

Claim 19

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.

Claim 20

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.