Long-lasting agonists of enkephalin

Claim 2

A novel peptide of the formula: ##STR15## where, unless otherwise indicated, an amino acid substituent identified below has the "S--" stereoconfiguration: X is S or (CH 2 ) n , where n is 0, 1 or 2; R 1 is hydrogen; C 1-6 alkyl; H-Arg; or H-Lys-Arg; R 2 is hydrogen; C 1-6 alkyl; or, when R 1 is hydrogen, may be allyl or cyclopropylmethyl; R 3 is hydrogen or methyl; R 4 is benzyl; benzyl substituted with halo, nitro, hydroxy, amino, C 1-4 alkyl, or cyano; indolylmethyl; imidazolylmethyl; or isopropylmethyl; R 5 is hydrogen or methyl; R 4 and R 5 taken together are phenylmethylene; and R 6 is (a) OM, where M is hydrogen, C 1-6 alkyl, or a cation; (b) NR 7 R 8 , where R 7 and R 8 are independently selected from the group consisting of hydrogen; C 1-6 alkyl, and, when either of R 7 or R 8 is hydrogen, --CH 2 CH 2 N(CH 3 ) 2 and ##STR16## (c) (Met-OH; (d) Met-NH 2 ; (e) Met-ol; (f) D-Met-NH 2 ; (g) N-methyl-Met-NH 2 ; (h) Met(O)-NH 2 ; (i) Met(O)-ol; (j) Leu-NH 2 ; (k) N-methyl-Leu-NH 2 ; (1) D-Leu-NH 2 ; or (m) Pro-NH 2 .

Claim 3

A peptide according to claim 1 wherein: X is S or (CH 2 ) n where n is 1 and the resulting lactam has an "R" steroconfiguration; and R 1 and R 2 are hydrogen; R 3 and R 5 are hydrogen or methyl; R 4 is benzyl; R 4 and R 5 taken together are phenylmethylene; and R 6 is NR 7 R 8 where one of R 7 or R 8 is hydrogen and the other is --CH 2 CH 2 N(CH 3 ) 2 or ##STR17## Met-OH; Met-NH 2 ; Met-ol; D-Met-NH 2 ; N-methyl-Met-NH 2 ; Met(O)-NH 2 ; Met(O)-ol; Leu-NH 2 ; N-methyl-Leu-NH 2 ; D-Leu-NH 2 ; or Pro-NH 2 .

Claim 4

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-Met-NH 2 .

Claim 5

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[Nmethyl-Phe]-Met-ol.

Claim 6

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-Met(O)-NH 2 .

Claim 7

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-Met(O)-ol.

Claim 8

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-N-methyl-Met-NH 2 .

Claim 9

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-D-Met-NH 2 .

Claim 10

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-Leu-NH 2 .

Claim 11

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[Nmethyl-Phe]-N-methyl-Leu-NH 2 .

Claim 12

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-D-Leu-NH 2 .

Claim 13

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-Pro-NH 2 .

Claim 14

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe] ##STR18##

Claim 15

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-NH-CH 2 CH 2 N(CH 3 ) 2 .

Claim 16

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Met-NH 2 .

Claim 17

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Met-ol.

Claim 18

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Met(O)-NH 2 .

Claim 19

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Met(O)-ol.

Claim 20

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-N-methyl-Met-NH 2 .

Claim 21

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-D-Met-NH 2 .

Claim 22

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Leu-NH 2 .

Claim 23

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-N-methyl-Leu-NH 2 .

Claim 24

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-D-Leu-NH 2 .

Claim 25

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Pro-NH 2 .

Claim 26

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe] ##STR19##

Claim 27

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-NH-CH 2 CH 2 N(CH 3 ) 2 .

Claim 28

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[2,3-dehydro Phe]-Met-NH 2 .

Claim 29

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[2,3-dehydro Phe]-Met(O)-ol.

Claim 30

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-2,3-dehydro Phe]-N-methyl-Leu-NH 2 .

Claim 31

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[2,3-dehydro Phe] ##STR20##

Claim 32

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[2,3-dehydro Phe]-NH-CH 2 CH 2 N(CH 3 ) 2 .

Claim 33

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R(5-amino-4-oxo-1,3-thiazine)acetic acid]-[N-methyl-Phe]-Met-NH 2 .

Claim 34

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(5-amino-4-oxo-1,3-thiazine)acetic acid]-[N-methyl-Phe]-Met(O)-ol.

Claim 35

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R(5-amino-4-oxo-1,3-thiazine)acetic acid]-[N-methyl-Phe]-N-methyl-Leu-NH 2 .

Claim 36

A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(5-amino-4-oxo-1,3-thiazine)acetic acid]-N-methyl-Phe] ##STR21##

Claim 37

A peptide according to claim 1 wherein the peptide is H-Tyr-2[R-(5-amino-4-oxo-1,3-thiazine)acetic acid]-[N-methyl-Phe]-NH-CH 2 CH 2 N(CH 3 ) 2 .

Claim 38

A pharmaceutical composition for treating pain comprising a non-toxic, pharmaceutically acceptable carrier and a therapeutically effective amount of a peptide of the formula: ##STR22## where, unless otherwise indicated, an amino acid substitutent identified below has the "S--" stereoconfiguration: X is S or (CH 2 ) n , where n is 0, 1 or 2; R 1 is hydrogen; C 1-6 alkyl; H-Arg; or H-Lys-Arg; R 2 is hydrogen; C 1-6 alkyl; or, when R 1 is hydrogen, may be allyl or cyclopropylmethyl; R 3 is hydrogen or methyl; R 4 is benzyl; benzyl substituted with halo, nitro, hydroxy, amino, C 1-4 alkyl, or cyano; indolylmethyl; imidazolylmethyl; or isopropylmethyl; R 5 is hydrogen or methyl; R 4 and R 5 taken together are phenylmethylene; and R 6 is (a) OM, where M is hydrogen, C 1-6 alkyl, or a cation; (b) NR 7 R 8 , where R 7 and R 8 are independently selected from the group consisting of hydrogen; C 1-6 alkyl, and, when either of R 7 or R 8 is hydrogen, --CH 2 CH 2 N(CH 3 ) 2 and ##STR23## (c) Met-OH; (d) Met-NH 2 ; (e) Met-ol; (f) D-Met-NH 2 ; (g) N-methyl-Met-NH 2 ; (h) Met(O)--NH 2 ; (i) Met(O)-ol; (j) Leu-NH 2 ; (k) N-methyl-Leu-NH 2 ; (l) D-Leu-NH 2 ; or (m) Pro-NH 2 .

Claim 39

A pharmaceutical composition for treating pain comprising a non-toxic, pharmaceutically acceptable carrier and a therapeutically effective amount of a peptide of the formula: ##STR22## where, unless otherwise indicated, an amino acid substitutent identified below has the "S--" stereoconfiguration: X is S or (CH 2 ) n , where n is 0, 1 or 2; R 1 is hydrogen; C 1-6 alkyl; H-Arg; or H-Lys-Arg; R 2 is hydrogen; C 1-6 alkyl; or, when R 1 is hydrogen, may be allyl or cyclopropylmethyl; R 3 is hydrogen or methyl; R 4 is benzyl; benzyl substituted with halo, nitro, hydroxy, amino, C 1-4 alkyl, or cyano; indolylmethyl; imidazolylmethyl; or isopropylmethyl; R 5 is hydrogen or methyl; R 4 and R 5 taken together are phenylmethylene; and R 6 is (a) OM, where M is hydrogen, C 1-6 alkyl, or a cation; (b) NR 7 R 8 , where R 7 and R 8 are independently selected from the group consisting of hydrogen; C 1-6 alkyl, and, when either of R 7 or R 8 is hydrogen, --CH 2 CH 2 N(CH 3 ) 2 and ##STR23## (c) Met-OH; (d) Met-NH 2 ; (e) Met-ol; (f) D-Met-NH 2 ; (g) N-methyl-Met-NH 2 ; (h) Met(O)--NH 2 ; (i) Met(O)-ol; (j) Leu-NH 2 ; (k) N-methyl-Leu-NH 2 ; (l) D-Leu-NH 2 ; or (m) Pro-NH 2 .