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 , R 3 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.

Claim 3

A pharmaceutically acceptable acid addition salt of the compound of formula 1 as claimed in claim 1.

Claim 4

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 and benzyl.

Claim 5

L-Prolyl-D-(N-methyl)leucyl-glycinamide, as claimed in claim 1.

Claim 6

L-Prolyl-L-(N-methyl)leucyl-glycinamide, as claimed in claim 1.

Claim 7

L-Prolyl-(N-isobutyl)glycyl-glycinamide as claimed in claim 1.

Claim 8

L-Prolyl-DL-(N-dimethylamino)leucyl-glycine-4-amino n-butyl-amide, as claimed in claim 1 having a rotation of D .sup. 25 = -43.6° (c = 2,dimethylformamide).

Claim 9

L-Prolyl-DL-(N-dimethylamino)leucyl-glycine-4-amino-n-butyl-amide as claimed in claim 1 having a rotation of D .sup. 25 = -18.6° c = 2,dimethylformamide).

Claim 10

L-Prolyl-L-(N-methyl)leucyl-D-alaninamide as claimed in claim 1.

Claim 11

L-Prolyl-D-(N-methyl)leucyl-D-alaninamide, as claimed in claim 1.

Claim 12

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

Claim 13

A process for preparing a compound of formula 1 ##STR3## in which R.sup. 1 is lower alkyl or NR.sup. 4 R.sup. 5 wherein R.sup. 4 and R 5 each are lower alkyl; R.sup. 2 is hydrogen or lower alkyl; R.sup. 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.sup. 1 is NR.sup. 4 R.sup. 5, R.sup. 3 is lower alkylamino di(lower)alkylamino or amino(lower)alkylamino which comprises: condensation of an enamine or hydrazone of formula 3, R.sup. 1 N=CHR.sup. 2 (3), in which R.sup. 1 and R.sup. 2 are as defined herein with an amino acid of formula R.sup. 6 --L--Pro--OH in which R.sup. 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.sub. 2 COR.sup. 7 in which R.sup. 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.sup. 1, R.sup. 2, R.sup. 6 and R.sup. 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.sup. 1, R.sup. 2, R 3 and Y are as defined herein.

Claim 14

A process for preparing a compound of formula 1 ##STR3## in which R.sup. 1 is lower alkyl or NR.sup. 4 R.sup. 5 wherein R.sup. 4 and R 5 each are lower alkyl; R.sup. 2 is hydrogen or lower alkyl; R.sup. 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.sup. 1 is NR.sup. 4 R.sup. 5, R.sup. 3 is lower alkylamino di(lower)alkylamino or amino(lower)alkylamino which comprises: condensation of an enamine or hydrazone of formula 3, R.sup. 1 N=CHR.sup. 2 (3), in which R.sup. 1 and R.sup. 2 are as defined herein with an amino acid of formula R.sup. 6 --L--Pro--OH in which R.sup. 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.sub. 2 COR.sup. 7 in which R.sup. 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.sup. 1, R.sup. 2, R.sup. 6 and R.sup. 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.sup. 1, R.sup. 2, R 3 and Y are as defined herein.

Claim 15

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.sup. 2, R.sup. 6 and R.sup. 7 are as defined therein is carried out by treating said intermediate with ammonia to obtain the corresponding amide, followed by removal of the protective group R.sup. 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.sup. 1 and R.sup. 2 are as defined therein, R.sup. 3 is amino and Y is the amino acid residue Gly.

Claim 16

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.sup. 1, R.sup. 2, R.sup. 6 and R.sup. 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.sup. 1 -carbonyldiimidazolide and o-acylurea 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-dimethoxybenzyloxycarbonyl, 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.sup. 1 and R.sup. 2 are as defined herein, R.sup. 3 is lower alkylamino, di(lower)alkylamino or amino(lower)alkylamino and Y is the amino acid residue Gly.

Claim 17

A process for preparing a compound of formula 1 ##STR4## in which R.sup. 1 is CH.sub. 3, R.sup. 2 is CH.sub. 2 CH(CH.sub. 3).sub. 2, R.sup. 3 is NH.sub. 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, pentachlorophenyl, 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--OMe; treating said last-named 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.sub. 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.sup. 1 is CH.sub. 3, R.sup. 2 is CH.sub. 2 CH(CH.sub. 3).sub. 2, R.sup. 3 is NH.sub. 2 and Y is the amino acid residue D--Ala.

Claim 18

A process for preparing a compound of formula 1 ##STR4## in which R.sup. 1 is CH.sub. 3, R.sup. 2 is CH.sub. 2 CH(CH.sub. 3).sub. 2, R.sup. 3 is NH.sub. 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, pentachlorophenyl, 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--OMe; treating said last-named 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.sub. 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.sup. 1 is CH.sub. 3, R.sup. 2 is CH.sub. 2 CH(CH.sub. 3).sub. 2, R.sup. 3 is NH.sub. 2 and Y is the amino acid residue D--Ala.

Claim 19

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 20

A pharmaceutical composition comprising an amino protected derivative of a compound of formula 1 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 21

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 22

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 23

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 24

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.