Novel derivatives of alpha-endorphin, intermediates therefor and compositions and methods employing said derivatives

Claim 2

A hexadecapeptide represented by the formula H-Tyr-X-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Y wherein X is a chiral residue of a D-amino acid selected from the group consisting of D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tryosine, D-tryptophan, D-Serine, D-threonine, D-methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-asparagine, D-lysine, D-proline, D-histidine and D-arginine; Y is selected from the group consisting of hydroxy, amino, loweralkylamino, diloweralkylamino and loweralkoxy; and the pharmaceutically acceptable salts thereof.

Claim 3

A hexadecapeptide of claim 1 wherein Y is hydroxy.

Claim 4

A hexadecapeptide of claim 1 wherein Y is amino.

Claim 5

A hexadecapeptide of claim 1 wherein Y is loweralkylamino.

Claim 6

A hexadecapeptide of claim 1 wherein Y is lower dialkylamino.

Claim 7

A hexadecapeptide of claim 1 wherein Y is lower alkoxy.

Claim 8

A hexadecapeptide represented by the formula H-Tyr-D-Ala-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Y wherein Y is selected from the group conisting of hydroxy, amino, loweralkylamino, lower dialkylamino, or lower alkoxyl or a pharmaceutically acceptable salt thereof.

Claim 9

A hexadecapeptide represented by the formula H-Tyr-D-Ala-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Y wherein Y is selected from the group conisting of hydroxy, amino, loweralkylamino, lower dialkylamino, or lower alkoxyl or a pharmaceutically acceptable salt thereof.

Claim 10

A hexadecapeptide of claim 6 wherein Y is loweralkylamino.

Claim 11

A hexadecapeptide of claim 6 wherein Y is lower dialkylamino.

Claim 12

A hexadecapeptide of claim 6 wherein Y is lower alkoxy.

Claim 13

D-Ala 2 -α-endorphin and the pharmaceutically acceptble salt thereof.

Claim 14

D-Ala 2 -α-endorphin and the pharmaceutically acceptble salt thereof.

Claim 15

D-Ala 2 -α-endorphin amide and the pharmaceutically acceptable salt thereof.

Claim 16

D-Ala 2 -α-endorphin amide and the pharmaceutically acceptable salt thereof.

Claim 17

A pharmaceutical composition suitable for oral, parenteral, nasal, rectal, vaginal or sublingual administration comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

Claim 18

A pharmaceutical composition in accordance with claim 13 suitable for oral administration.

Claim 19

A pharmaceutical composition in accordance with claim 13 adapted for parenteral administration.

Claim 20

A pharmaceutical composition in accordance with claim 13 adapted for nasal administration.

Claim 21

A pharmaceutical composition in accordance with claim 13 adapted for rectal administration.

Claim 22

A pharmaceutical composition in accordance with claim 13 adapted for vaginal administration.

Claim 23

A pharmaceutical composition in accordance with claim 13 adapted for sublingual administration.

Claim 24

Novel hexadecapeptides of the formula R.sub.1 -Tyr(R.sub.2)-X' -Gly-Phe-Met-Thr(R.sub.3)-Ser(R.sub.3)-Glu(R.sub.4)-Lys(R.sub.5)-Ser(R.sub.3)-Gln-Thr(R.sub.3)-Pro-Leu-Val-Thr(R.sub.3)-Y wherein X' is a chiral residue of a D-amino acid selected from the group consisting of D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-histidine, D-proline, D-threonine, D-methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-asparagine, D-lysine and D-arginine with the limitation that when X' is D-tyrosine, D-threonine, D-serine, D-glutamine, D-lysine, D-aspartic acid or D-arginine, X' is a chiral amino acid residue protected by an R 2 , R 3 , R 4 , R 5 , R 6 protecting group; R 1 is a N-terminus solid phase peptide synthesis protecting group selected from the group consisting of acyl-type protecting groups, aromatic urethan-type protecting groups, alkyl-type protecting groups, trialkylsilane groups, or aliphatic urethan protecting groups; R 2 is a protecting group for the phenolic hydroxyl group of tyrosine selected from the group consisting of tetrahydropyranyl, tert-butyl, trityl, benzyl, 2,4-dichlorobenzyl, benzyloxycarbonyl or 2-bromobenzyloxycarbonyl; R 3 is a protecting group for the alcohol hydroxy functions of serine and threonine; R 4 is a protecting group for the gamma carboxyl group of glutamic acid; R 5 is a protecting group for the epsilon amino group of lysine selected from the group consisting of trifluoracetyl, benzyloxycarbonyl, and 2-chlorobenzyloxycarbonyl; and R 6 is a protecting group for the guanidine group of arginine; Y is selected from the group consisting of hydroxy, amino, loweralkylamino, diloweralkylamino, or lower alkoxy and a derivatized insoluble polystyrene resin support represented by the formulae ##STR2##

Claim 25

Novel hexadecapeptides of the formula R.sub.1 -Tyr(R.sub.2)-X' -Gly-Phe-Met-Thr(R.sub.3)-Ser(R.sub.3)-Glu(R.sub.4)-Lys(R.sub.5)-Ser(R.sub.3)-Gln-Thr(R.sub.3)-Pro-Leu-Val-Thr(R.sub.3)-Y wherein X' is a chiral residue of a D-amino acid selected from the group consisting of D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-histidine, D-proline, D-threonine, D-methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-asparagine, D-lysine and D-arginine with the limitation that when X' is D-tyrosine, D-threonine, D-serine, D-glutamine, D-lysine, D-aspartic acid or D-arginine, X' is a chiral amino acid residue protected by an R 2 , R 3 , R 4 , R 5 , R 6 protecting group; R 1 is a N-terminus solid phase peptide synthesis protecting group selected from the group consisting of acyl-type protecting groups, aromatic urethan-type protecting groups, alkyl-type protecting groups, trialkylsilane groups, or aliphatic urethan protecting groups; R 2 is a protecting group for the phenolic hydroxyl group of tyrosine selected from the group consisting of tetrahydropyranyl, tert-butyl, trityl, benzyl, 2,4-dichlorobenzyl, benzyloxycarbonyl or 2-bromobenzyloxycarbonyl; R 3 is a protecting group for the alcohol hydroxy functions of serine and threonine; R 4 is a protecting group for the gamma carboxyl group of glutamic acid; R 5 is a protecting group for the epsilon amino group of lysine selected from the group consisting of trifluoracetyl, benzyloxycarbonyl, and 2-chlorobenzyloxycarbonyl; and R 6 is a protecting group for the guanidine group of arginine; Y is selected from the group consisting of hydroxy, amino, loweralkylamino, diloweralkylamino, or lower alkoxy and a derivatized insoluble polystyrene resin support represented by the formulae ##STR2##