Claims
- 1. A compound of the formula
- A-B-Gly-D-E
- wherein A is a residue of formula ##STR18## wherein R.sub.1 is hydrogen or alkyl of 1 to 4 carbon atoms,
- R.sub.2 is hydrogen or, together with R.sub.1, forms an ethylene bridge, and
- R.sub.3 is hydrogen, alkyl of 1 to 4 carbon atoms or an R.sub.4 CO-- group, wherein
- R.sub.4 is a saturated or unsaturated branched or unbranched alkyl residue of 1 to 17 carbon atoms, phenyl or phenylalkyl of 7 to 12 carbon atoms in which the phenyl residue can be mono- or disubstituted with fluorine, chlorine or bromine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, whereby the R.sub.3 O group is in a position meta- or para- to the ##STR19## Z is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, cyclopropylmethyl, cyclobutylmethyl, R.sub.4 CO, wherein R.sub.4 is as previously defined, H-Arg, H-Lys, H-Phe or H-Tyr,
- B is -(D)Ala-,
- D is a residue of formula ##STR20## wherein R.sub.5 is hydrogen or alkyl of 1 to 4 carbon atoms,
- R.sub.6 is hydrogen, fluorine, chlorine, bromine, nitro, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and
- z is 1 or 2,
- E is
- (i) -Met-X, -Leu-X, -Nle-X, -Nva-X, -Ile-X, or ##STR21## wherein X is ##STR22## and each of R', R", and R'" independently signifies hydrogen or alkyl of 1 to 5 carbon atoms, or
- (ii) a residue of formula ##STR23## wherein R.sub.3 ' is hydrogen or R.sub.4 CO--, wherein R.sub.4 is as previously defined,
- R.sub.7 is hydrogen or alkyl of 1 to 4 carbon atoms, and
- R.sub.8 is (a) ##STR24## (b) --(CH.sub.2).sub.m --CH.sub.2 OR.sub.3 ' wherein R.sub.3 ' is as previously defined, and m is from 0 to 6,
- (c) ##STR25## wherein R.sub.3 ' is as previously defined, (d) --CH.sub.2 --S--H,
- (e) ##STR26## wherein R.sub.9 is alkyl of 1 to 5 carbon atoms, r is 0, 1 or 2, and s is 0, 1 or 2,
- (f) --(CH.sub.2).sub.4 --NH.sub.2, --(CH.sub.2).sub.4 --NHCOR.sub.4, wherein R.sub.4 is as previously defined, ##STR27## (g) --(CH.sub.2).sub.n --CONH.sub.2, wherein n is 1 or 2, (h) --(CH.sub.2).sub.n --COOR.sub.10, wherein n is as previously defined, and R.sub.10 is hydrogen or alkyl of 1 to 5 carbon atoms, or
- or (iii) a residue of formula ##STR28## wherein n and R.sub.7 are as previously defined, whereby the A and D residues possess either the L- or D,L-configuration and the residue E possesses
- (1) the L-, D- or D,L-configuration, where E is ##STR29## r is 1 or 2 and s, X, R.sub.3 ', R.sub.7 and R.sub.9 are as previously defined or
- (2) the D-configuration when E is other than as defined in 1
- or a pharmaceutically acceptable salt or complex form thereof.
- 2. H-Tyr-(D)Ala-Gly-MePhe-methioninolsulphoxide.
- 3. A pharmaceutical composition 8 or treating pain comprising a compound of claim 1, in free base form or in the form of a pharmaceutically acceptable salt or complex, in association with a pharmaceutically acceptable carrier or diluent.
- 4. A method of treating pains in animals, which comprises administering to an animal in need of such treatment, a therapeutically effective amount of a compound of claim 1.
- 5. A compound according to claim 1 having the formula
- A-B-Gly-D-E
- wherein A is a residue of formula ##STR30## wherein R.sub.1 is hydrogen,
- R.sub.2 is hydrogen, and
- R.sub.3 is hydrogen, methyl or a R.sub.4 CO-- group, wherein R.sub.4 is alkyl of 1 to 6 carbon atoms,
- Z is hydrogen, methyl or R.sub.4 CO, wherein R.sub.4 is alkyl of 1 to 6 carbon atoms,
- B is -(D)Ala-,
- D is a residue of formula ##STR31## wherein R.sub.5 is hydrogen or methyl,
- R.sub.6 is hydrogen, chlorine, or nitro,
- z is 1 or 2, and
- E is ##STR32## wherein X is ##STR33## and each of R', R", and R'", independently, signifies hydrogen or alkyl of 1 to 5 carbon atoms, or ##STR34## where a is 1 or 2, or a pharmaceutically acceptable acid addition salt thereof.
- 6. A compound according to claim 1 of the formula
- A-B-Gly-D-E
- wherein A is a residue of formula ##STR35## wherein R.sub.1 is hydrogen,
- R.sub.2 is hydrogen or, together with R.sub.1, forms an ethylene bridge, and
- R.sub.3 is hydrogen, alkyl of 1 to 4 carbon atoms or an R.sub.4 CO-- group, wherein R.sub.4 is alkyl of 1 to 6 carbon atoms, whereby the R.sub.3 O group is in a position meta- or para- to the ##STR36## Z is hydrogen, alkyl of 1 to 5 carbon atoms, cyclopropylmethyl, cyclobutylmethyl, R.sub.4 CO, wherein R.sub.4 is alkyl of 1 to 6 carbon atoms, H-Arg, H-Lys, H-Phe or H-Tyr,
- B is -(D)Ala-,
- D is a residue of formula ##STR37## wherein R.sub.5 is hydrogen or alkyl of 1 to 4 carbon atoms,
- R.sub.6 is hydrogen, fluorine, chlorine, bromine, nitro, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and
- z is 1 or 2,
- E is
- (i) -Met-X, -Leu-X, -Nle-X, -Nva-X, -Ile-X, ##STR38## wherein X is ##STR39## and each of R', R", and R'" independently signifies hydrogen or alkyl of 1 to 5 carbon atoms, or
- (ii) a residue of formula ##STR40## wherein R.sub.3 ' is hydrogen or R.sub.4 CO--, wherein R.sub.4 is as previously defined,
- R.sub.7 is hydrogen or alkyl of 1 to 4 carbon atoms, and
- R.sub.8 is (a) ##STR41## (b) --(CH.sub.2).sub.m --CH.sub.2 OR.sub.3 ' wherein R.sub.3 ' is as previously defined, and m is from 0 to 6,
- (c) ##STR42## wherein R.sub.3 ' is as previously defined, (d) --CH.sub.2 --S--H,
- (e) ##STR43## wherein R.sub.9 is alkyl of 1 to 5 carbon atoms, r is 0, 1 or 2, and s is 0, 1 or 2,
- (f) --(CH.sub.2).sub.4 --NH.sub.2, ##STR44## (g) --(CH.sub.2).sub.n --CONH.sub.2, wherein n is 1 or 2, (h) --(CH.sub.2).sub.n --COOR.sub.10, wherein n is as previously defined, and R.sub.10 is hydrogen or alkyl of 1 to 5 carbon atoms, or
- (iii) a residue of formula ##STR45## wherein n and R.sub.7 are as previously defined, whereby the A and D residues possess either the L- or D,L-configuration and the residue E possesses
- (1) the L-, D- or D,L-configuration, when E is ##STR46## r is 1 or 2 and s, X, R.sub.3 ', R.sub.7 and R.sub.9 are as previously defined or
- (2) the D-configuration when E is other than as defined in (1),
- or a pharmaceutically acceptable salt or complex form thereof.
- 7. A compound according to claim 6 of the formula
- A-B-Gly-D-E
- wherein A is a residue of formula ##STR47## wherein R.sub.1 is hydrogen,
- R.sub.2 is hydrogen or, together with R.sub.1, forms an ethylene bridge, and
- R.sub.3 is hydrogen, alkyl of 1 to 4 carbon atoms or an R.sub.4 CO-- group, wherein R.sub.4 is alkyl of 1 to 6 carbon atoms, whereby the R.sub.3 O group is in a position para- to the ##STR48## Z is hydrogen, alkyl of 1 to 5 carbon atoms, cyclobutylmethyl, R.sub.4 CO, wherein R.sub.4 is alkyl of 1 to 6 carbon atoms or H-Arg,
- B is -(D)Ala-,
- D is a residue of formula ##STR49## wherein R.sub.5 is hydrogen or alkyl of 1 to 4 carbon atoms,
- R.sub.6 is hydrogen, chlorine, nitro, or alkoxy of 1 to 4 carbon atoms, and
- z is 1 or 2,
- E is
- (i) -Met-X, Leu-X, or ##STR50## wherein X is ##STR51## and each of R', R", and R'" independently signifies hydrogen or alkyl of 1 to 5 carbon atoms, or
- (ii) a residue of formula ##STR52## wherein R.sub.3 ' is hydrogen or R.sub.4 CO--, wherein R.sub.4 is as previously defined,
- R.sub.7 is hydrogen or alkyl of 1 to 4 carbon atoms, and
- R.sub.8 is (a) ##STR53## (b) --(CH.sub.2).sub.m --CH.sub.2 OR.sub.3 ' wherein R.sub.3 ' is as previously defined, and m is 1 or 2,
- (c) ##STR54## wherein R.sub.9 is alkyl of 1 to 5 carbon atoms, r is 0, 1 or 2, and s is 0 or 1,
- (d) ##STR55## (e) --(CH.sub.2).sub.n --CONH.sub.2, wherein n is 1, or (iii) a residue of formula ##STR56## wherein n and R.sub.7 are as previously defined, whereby the A and D residues possess either the L- or D,L-configuration and the residue E possesses
- (1) the L-, D- or D,L-configuration, when E is ##STR57## r is 1 or 2 and s, X, R.sub.3 ', R.sub.7 and R.sub.9 are as previously defined or
- (2) the D-configuration when E is other than as defined in (1),
- or a pharmaceutically acceptable salt or complex form thereof.
- 8. A compound according to claim 7 of the formula
- A-B-Gly-D-E
- wherein A is a residue of formula ##STR58## wherein R.sub.1 is hydrogen,
- R.sub.2 is hydrogen or, together with R.sub.1, forms an ethylene bridge, and
- R.sub.3 is hydrogen, alkyl of 1 to 4 carbon atoms or an R.sub.4 CO-- group,
- wherein R.sub.4 is alkyl of 1 to 6 carbon atoms,
- Z is hydrogen or alkyl of 1 to 5 carbon atoms, cyclobutylmethyl, R.sub.4 CO, wherein R.sub.4 is alkyl of 1 to 6 carbon atoms or H-Arg,
- B is -(D)Ala-,
- D is a residue of formula ##STR59## wherein R.sub.5 is hydrogen or alkyl of 1 to 4 carbon atoms,
- R.sub.6 is hydrogen, chlorine or nitro or alkoxy of 1 to 4 carbon atoms, and
- z is 1 or 2,
- E is
- (i) -Met-X ##STR60## wherein X is ##STR61## and each of R', R", and R'" signifies hydrogen, or (ii) a residue of formula ##STR62## wherein R.sub.3 ' is hydrogen
- R.sub.7 is hydrogen or alkyl of 1 to 4 carbon atoms, and
- R.sub.8 is ##STR63## wherein R.sub.9 is methyl, r is 0, 1 or 2, and s is 1, whereby the A and D residues possess either the L- or D,L-configuration and the residue E possesses
- (1) the L-, D- or D,L-configuration, when E is ##STR64## r is 1 or 2 and s, X, R.sub.3 ', R.sub.7 and R.sub.9 are as previously defined or
- (2) the D-configuration when E is other than as defined in (1),
- or a pharmaceutically acceptable salt or complex form thereof.
- 9. A compound according to claim 1 of the formula
- A-B-Gly-D-E
- wherein A is a residue of formula ##STR65## wherein R.sub.1 is hydrogen,
- R.sub.2 is hydrogen, and
- R.sub.3 is hydrogen, alkyl of 1 to 4 carbon atoms or an R.sub.4 CO-- group,
- wherein
- R.sub.4 is alkyl of 1 to 17 carbon atoms, whereby the R.sub.3 O group is in a position meta- or para- to the ##STR66## Z is hydrogen, alkyl of 1 to 5 carbon atoms, or R.sub.4 CO, wherein R.sub.4 is as previously defined,
- B is -(D)Ala-,
- D is a residue of formula ##STR67## wherein R.sub.5 is hydrogen or alkyl of 1 to 4 carbon atoms,
- R.sub.6 is hydrogen, fluorine, chlorine, bromine, nitro, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and
- z is 1 or 2,
- E is
- (i) -Met-X, ##STR68## wherein X is ##STR69## and each of R', R", and R'" independently signifies hydrogen or alkyl of 1 to 5 carbon atoms, or
- (ii) a residue of formula ##STR70## wherein R.sub.3 ' is hydrogen or R.sub.4 CO--, wherein R.sub.4 is as previously defined,
- R.sub.7 is hydrogen or alkyl of 1 to 4 carbon atoms, and
- R.sub.8 is ##STR71## wherein R.sub.9 is alkyl of 1 to 5 carbon atoms, r is 0, 1 or 2 and s is 1,
- whereby the A and D residues possess either the L- or D,L-configuration and the residue E possesses
- (1) the L-, D- or D,L-configuration, when E is ##STR72## r is 1 or 2 and s, X, R.sub.3 ', R.sub.7 and R.sub.9 are as previously defined or
- (2) the D-configuration when E is other than as defined in (1),
- or a pharmaceutically acceptable salt or complex form thereof.
- 10. A compound according to claim 8 of the formula ##STR73## where Z is hydrogen, methyl or R.sub.4 CO--,
- R.sub.3 is hydrogen, methyl or R.sub.4 CO--,
- D is Phe or MePhe, unsubstituted or substituted with chloro or nitro;
- X is OH, NH.sub.2 or CH.sub.2 OR.sub.3 ' where R.sub.3 ' is hydrogen or R.sub.4 CO--, and
- R.sub.4 is alkyl of 1 to 6 carbon atoms
- or a pharmaceutically acceptable salt thereof.
- 11. A compound according to claim 8 of the formula ##STR74## where Z is hydrogen, methyl or R.sub.4 CO--,
- R.sub.3 is hydrogen, methyl or R.sub.4 CO--,
- D is Phe or MePhe, unsubstituted or substituted with chloro or nitro,
- E is Met(O) or Met(O.sub.2), and
- X is OH, NH.sub.2 or CH.sub.2 OR.sub.3 ' where R.sub.3 is hydrogen or R.sub.4 CO--, and
- R.sub.4 is alkyl of 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.
- 12. The compound of claim 8, which is H-Tyr-(D)Ala-Gly-MePhe-methioninolsulphone or a pharmaceutically acceptable salt or complex thereof.
- 13. The compound of claim 8, which is H-Tyr-(D)Ala-Gly-Phe(p-NO.sub.2)-methioninolsulphoxide or a pharmaceutically acceptable salt or complex thereof.
- 14. The compound of claim 8, which is H-Tyr(Me)-(D)Ala-Gly-MePhe-methioninolsulphoxide or a pharmaceutically acceptable salt or complex thereof.
- 15. The compound of claim 8, which is MeTyr-(D)Ala-Gly-MePhe-methioninolsulphoxide or a pharmaceutically acceptable salt or complex thereof.
- 16. A compound according to claim 8 of the formula
- H-Tyr-(D)Ala-Gly-Phe-E
- where E is selected from the group consisting of (a) methioninolsulphoxide, (b) D-methioninol, (c) D-methioninosulphoxide, (d) N-methylmethioninesulphoxide and (e) N-methylmethioninesulphone or a pharmaceutically acceptable salt or complex thereof.
- 17. A compound according to claim 8 of the formula
- H-Tyr-(D)Ala-Gly-D-E
- where D-E is selected from the group consisting of
- (a) -(D,L)Phe(p.Cl)-methioninolsulphoxide;
- (b) -Phe(p-NO.sub.2)-methioninolsulphone;
- (c) -Phe(3,4-diMeO)-methioninolsulphoxide;
- (d) -MePhe(p-NO.sub.2)-methioninolsulphoxide and
- (e) -MePhe-methioninamidesulphoxide,
- or a pharmaceutically acceptable salt or complex thereof.
- 18. A compound according to claim 8 of the formula
- A-(D)Ala-Gly-D-methioninolsulphoxide
- where A and D are selected from the group consisting of
- (a) H-(D,L)Ata(6-OH)-and-Phe-;
- (b) H-(D,L)Ata(6-OH)-and-MePhe-;
- (c) H-Arg-Tyr-and-MePhe-;
- (d) N-cyclobutylmethyl-Tyr-and-MePhe-;
- (e) H-(D,L)Ata(7-OH)-and-MePhe-;
- (f) H-(D,L)-m-Tyr-and-MePhe- and
- (g) AcTyr-and-MePhe-,
- or a pharmaceutically acceptable salt or complex thereof.
- 19. A compound according to claim 7 selected from
- (a) H-Tyr-(D)Ala-Gly-Phe-S-methylcysteinolsulphoxide and
- (b) H-Tyr-(D)Ala-Gly-MePhe-S-methylcysteinolsulphoxide,
- or a pharmaceutically acceptable salt or complex thereof.
Priority Claims (10)
Number |
Date |
Country |
Kind |
1266/76 |
Feb 1976 |
CHX |
|
7524/76 |
Jun 1976 |
CHX |
|
7525/76 |
Jun 1976 |
CHX |
|
8955/76 |
Jul 1976 |
CHX |
|
8956/76 |
Jul 1976 |
CHX |
|
9206/76 |
Jul 1976 |
CHX |
|
9208/76 |
Jul 1976 |
CHX |
|
10763/76 |
Aug 1976 |
CHX |
|
10764/76 |
Aug 1976 |
CHX |
|
12064/76 |
Sep 1976 |
CHX |
|
Parent Case Info
This is a continuation of application Ser. No. 762,646 filed Jan. 26, 1977, now abandoned.
US Referenced Citations (12)
Continuations (1)
|
Number |
Date |
Country |
Parent |
762646 |
Jan 1977 |
|