Claims
- 1. A compound of formula I ##STR199## wherein A is A.sup.1 or A.sup.2 ;
- G is G.sup.1 or G.sup.2 ;
- D is ##STR200## wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 independently are hydrogen, halogen, aryl, C.sub.1-6 -alkyl or C.sub.1-6 -alkoxy;
- E is hydrogen, --O--(CH.sub.2).sub.I --R.sup.10a, ##STR201## wherein R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 independently are hydrogen, halogen, aryl, C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, --CONR.sup.15 R.sup.16, --(CH.sub.2).sub.v --NR.sup.15 SO.sub.2 R.sup.17, --(CH.sub.2).sub.v --NR.sup.15 COR.sup.16, --(CH.sub.2).sub.v --OR.sup.17, --(CH.sub.2).sub.v --OCOR.sup.16, --(CH(R.sup.15)R.sup.16, --(CH.sub.2).sub.v --NR.sup.15 --CS--NR.sup.16 R.sup.18, --(CH.sub.2).sub.v --NR.sup.15 --CO--NR.sup.16 R.sup.18,
- R.sup.15 and R.sup.16 independently are hydrogen or C.sub.1-6 -alkyl optionally substituted with halogen, --N(R.sup.26)R.sup.27, hydroxyl, C.sub.1-6 -alkoxy, C.sub.1-6 -alkoxycarbonyl, C.sub.1-6 -alkyl-carbonyloxy or aryl,
- or R.sup.16 is ##STR202## wherein Q.sup.1 is --CH<,
- T.sup.1 and J.sup.1 are independently --CH.sub.2 --, --CO--, or a valence bond,
- t and u are independently 0, 1, 2, 3 or 4;
- R.sup.17 is C.sub.1-6 alkyl or phenyl optionally substituted with hydroxyl or aryl;
- R.sup.18 is C.sub.1-6 alkyl;
- R.sup.26 and R.sup.27 are independently hydrogen or C.sub.1-6 -alkyl;
- v is 0, 1, 2 or 3;
- R.sup.10a is hydrogen, aryl optionally substituted with halogen or C.sub.1-6 -alkyl, or C.sub.1-6 -alkyl optionally substituted with halogen or C.sub.1-6 -alkyl,
- I is 0, 1, 2, or 3;
- A.sup.1 is ##STR203## wherein R.sup.29, R.sup.33, R.sup.34, R.sup.35 and R.sup.36 are independently hydrogen or C.sub.1-6 alkyl optionally substituted with halogen, amino, hydroxyl or aryl;
- R.sup.34 and R.sup.35 may optionally form --(CH.sub.2).sub.i --Z--(CH.sub.2).sub.j --, wherein i and j independently are 1 or 2 and Z is a valence bond;
- n, m and q are independently 0, 1, 2, or 3;
- o and p are independently 0 or 1;
- M is --CR.sup.37 .dbd.CR.sup.38 --, --O--, --S--, or a valence bond;
- R.sup.37 and R.sup.38 are independently hydrogen, or C.sub.1-6 -alkyl optionally substituted with aryl;
- A.sup.2 is ##STR204## wherein R.sup.29, R.sup.33, R.sup.34, R.sup.35 and R.sup.36 are independently hydrogen or C.sub.1-6 -alkyl optionally substituted with halogen, amino, hydroxyl or aryl;
- R.sup.34 and R.sup.35 may optionally form --(CH.sub.2).sub.i --Z--(CH.sub.2).sub.j --, wherein i and j independently are 1 or 2 and Z is a valence bond;
- n, m and q are independently 0, 1, 2, or 3;
- o and p are independently 0 or 1;
- M is --CR.sup.37 .dbd.CR.sup.38 --, --O--, or --S--;
- R.sup.37 and R.sup.38 are independently hydrogen, or C.sub.1-6 -alkyl optionally substituted with aryl;
- G.sup.1 is hydrogen, halogen, aryl, C.sub.1-6 --alkyl, C.sub.1-6 --alkoxy, --CONR.sup.39 R.sup.40, --(CH.sub.2).sub.e --NR.sup.39 SO.sub.2 R.sup.41, --(CH.sub.2).sub.e --NR.sup.39 COR.sup.40, --(CH.sub.2).sub.e --OR.sup.41, --(CH.sub.2).sub.e --OCOR.sup.40, --CH(R.sup.39)R.sup.40, --CON.sup.39 --NR.sup.40 R.sup.42, --(CH.sub.2).sub.e --NR.sup.39 --CS--NR.sup.40 R.sup.42, --(CH.sub.2).sub.e --NR.sup.39 --CO--NR.sup.40 R.sup.42,
- R.sup.39 and R.sup.40 independently are hydrogen or C.sub.1-6 -alkyl optionally substituted with halogen,
- --N(R.sup.50)R.sup.51, hydroxyl, C.sub.1-6 -alkoxy, C.sub.1-6 -alkoxycarbonyl, C.sub.1-6 -alkylcarbonyloxy or aryl,
- or R.sup.40 is ##STR205## wherein Q.sup.2 is --CH<,
- J.sup.2 and T.sup.2 are independently --CH.sub.2 --, --CO--, or a valence bond,
- x and y are independently 0, 1, 2, 3 or 4;
- R.sup.41 is C.sub.1-6 alkyl substituted with aryl;
- R.sup.42 is C.sub.1-6 alkyl;
- R.sup.50 and R.sup.51 are independently hydrogen or C.sub.1-6 -alkyl;
- e and f are independently 0, 1, 2 or 3;
- G.sup.2 is hydrogen or C.sub.1-6 -alkyl;
- R.sup.1 is hydrogen, or C.sub.1-6 -alkyl;
- R.sup.2 is hydrogen, --C(.dbd.O)--R.sup.54 or C.sub.1-6 -alkyl;
- R.sup.54 is hydrgen or C.sub.1-6 -alkyl,
- R.sup.3 and R.sup.4 are taken together to form .dbd.S or .dbd.O;
- L.sup.1 is CR.sup.57 ;
- L.sup.2 is CR.sup.58 or N;
- R.sup.57 and R.sup.58 independently are hydrogen, C.sub.1-6 -alkyl, optionally substituted with hydroxyl, halogen, C.sub.1-6 -alkoxy, or aryl;
- a and b independently are 0, 1, 2, or 3;
- with the proviso that:
- when G is G.sup.2 and L.sup.1 is CR.sup.57 and L.sup.2 is CR.sup.58, then A is A.sup.2 ;
- when G is G.sup.1 and L.sup.1 is CR.sup.57 and L.sup.2 is CR.sup.58, then A is A.sup.1 and R.sup.2 is --C(.dbd.O)--R.sup.54
- when L.sup.2 is N, then G is G.sup.1 and A is A.sup.1 ;
- or a pharmaceutically acceptable salt thereof.
- 2. The compound according to claim 1, wherein A is R.sup.33 --NH--(CR.sup.34 R.sup.35).sub.p(CH.sub.2).sub.m --M--(CHR.sup.36).sub.o --(CH.sub.2).sub.n --
- wherein R.sup.33 is hydrogen or C.sub.1-6 alkyl optionally substituted with hydroxyl,
- R.sup.34 and R.sup.35 are independently of each other C.sub.1-6 alkyl,
- R.sup.36 is hydrogen,
- M is --CR.sup.37 .dbd.CR.sup.38 --or --O--, wherein R.sup.37 and R.sup.38 are hydrogen or C.sub.1-6 alkyl, p is 1, m is 1, o is 0 or 1 and n is 0 or 1.
- 3. The compound according to claim 1, wherein A is ##STR206## wherein R.sup.33 is hydrogen or C.sub.1-6 alkyl, R.sup.34 and R.sup.35 independently of each other are hydrogen or C.sub.1-6 alkyl,
- m is 0 or 1, n is 0 or 1, and p is 0 or 1.
- 4. The compound according to claim 1, wherein D is ##STR207## wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 independently of each other are hydrogen or aryl.
- 5. The compound according to claim 1, wherein D is ##STR208## wherein R.sup.5 and R.sup.6 independently of each other are hydrogen or C.sub.1-6 alkyl.
- 6. The compound according to claim 1, wherein E is ##STR209## wherein R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 independently of each other are hydrogen, --(CH.sub.2).sub.v --NR.sup.15 SO.sub.2 R.sup.17, --(CH.sub.2).sub.v --NR.sup.15 COR.sup.16 or --(CH.sub.2).sub.v --OR.sup.17, wherein v is 0 or 1, R.sup.15 is hydrogen or C.sub.1-6 alkyl, R.sup.16 is hydrogen or C.sub.1-6 alkyl optionally substituted with --N(R.sup.26)R.sup.27, wherein R.sup.26 and R.sup.27 independently of each other are hydrogen or C.sub.1-6 alkyl, R.sup.17 is C.sub.1-6 alkyl or phenyl optionally substituted with hydroxyl or phenyl.
- 7. The compound according to claim 1, wherein G is hydrogen or --CONR.sup.39 R.sup.40, wherein R.sup.39 and R.sup.40 independently of each other are hydrogen or C.sub.1-6 alkyl.
- 8. The compound according to claim 1, wherein R.sup.2 is hydrogen, --C(.dbd.O)--R.sup.54 or C.sub.1-6 alkyl, wherein R.sup.54 is C.sub.1-6 alkyl.
- 9. The compound according to claim 1, wherein R.sup.3 and R.sup.4 are taken together to form .dbd.O.
- 10. The compound according to claim 1, wherein a is 1.
- 11. The compound according to claim 1, wherein b is 0 or 1.
- 12. The compound according to claim 1, wherein L.sup.1 is --CH--.
- 13. The compound according to claim 1, wherein L.sup.1 is --CH-- or >N--.
- 14. The compound according to claim 1, selected from the group consisting of
- 1-((2R)-2-(N-((2E)-5-amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-2-benzyl-4-ethylsemicarbazide,
- 1-((2R)-2-(N-((2-amino-2-methylpropoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-2-benzyl-4-ethylsemicarbazide,
- (2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionic acid N-methyl-N-phenethylamide, or the trifluoroacetate salt thereof,
- (2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionic acid N-methyl-N-(2-(2-(methylsulfonylamino)phenyl)ethyl)amide,
- (2R)-2-(N-((2E)-5-((2R)-2-hydroxypropylamino)-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-phenethylpropionamide, or the trifluoroacetate salt thereof,
- (2E)-5-Amino-5-methylhex-2-enoic acid N-((1R)-2-(N-acetyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)amino)-1-((2-naphthyl)methyl)ethyl)amide,
- (2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,
- (2E)-5-Methyl-N-methyl-5-(methylamino)-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide,
- (2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide,
- (2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-(2-(2-methylsulfonylaminophenyl)ethyl)propionamide,
- (2E)-N-((1R)-1-(N-(2-(2-(2-Hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methyl-5-methyl-5-(methylamino)hex-2-enamide,
- 3-Aminomethyl-N-�(1R)-1-(N-{2-�2-(2-hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!benzamide,
- (2E)-5-Amino-5-methylhex-2-enoic acid N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbomoyl)-2-(2-naphthyl)ethyl)-N-methylamide,
- (2E)-5-Amino-5-methylhex-2-enoic acid N-((1R)-1-{N-�2-(2-(benzenesulfonylamino)phenyl)ethyl!-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide,
- 2-Amino-N-(2-(2-(N-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)ethyl)phenyl)acetamide,
- (2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-(2-(2-(3-hydroxypropoxy)phenyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide,
- 3-Aminomethyl-N-�(1R)-1-(N-{2-�2-(2-hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!benzamide, and
- (2E)-5-Amino-5-methylhex-2-enoic acid N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbomoyl)-2-(2-naphthyl)ethyl)amide; or a pharmaceutically acceptable salt thereof.
- 15. A pharmaceutical composition comprising, as an active ingredient, a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
- 16. A method of stimulating the release of growth hormone from the pituitary, the method comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
Priority Claims (1)
Number |
Date |
Country |
Kind |
0803/96 |
Jul 1996 |
DKX |
|
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. 119 of Danish application Ser. No. 0803/96 filed Jul. 22, 1996, the contents of which are fully incorporated herein by reference.
Foreign Referenced Citations (3)
Number |
Date |
Country |
WO 9517423 A1 |
Jun 1995 |
WOX |
WO 9622997 A1 |
Aug 1996 |
WOX |
WO 9723508 A1 |
Jul 1997 |
WOX |