Peptides as oxytocin agonists

Abstract

The invention relates to compounds of formula ##STR00001##
wherein variables are defined herein. It has been found that the present compounds are oxytocin receptor agonists for the treatment of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrom.

Claims

1. A compound of formula ##STR00073## wherein R.sup.1 is hydroxy or amino; R.sup.2 is sec-butyl or isobutyl; R.sup.3 is lower alkyl, lower alkyl substituted by hydroxy, (CH.sub.2).sub.2C(O)NH.sub.2, (CH.sub.2).sub.3NH.sub.2 or CH.sub.2-five membered aromatic heterocyclic group; R.sup.4 is hydrogen or lower alkyl; R.sup.5 is hydrogen or lower alkyl; or R.sup.4 and R.sup.5 may form together with the N and C atom to which they are attached a pyrrolidine ring, optionally substituted by hydroxy or halogen, a piperidine ring or an azetidine ring; R.sup.6 is hydrogen, lower alkyl, lower alkyl substituted by hydroxy, (CH.sub.2).sub.2C(O)OH, (CH.sub.2).sub.2C(O)NH.sub.2, benzyl optionally substituted by amino or hydroxy, CH.sub.2-five membered aromatic heterocyclic group, indolyl, CH.sub.2-cycloalkyl, cycloalkyl, (CH.sub.2).sub.2S lower alkyl or is (CH.sub.2).sub.1-4NH.sub.2; R.sup.6 is hydrogen or lower alkyl; or R.sup.6 and R.sup.6 are together cycloalkyl; X is C(O)CHRNRC(O); R/R are independently from each other hydrogen or lower alkyl; m is 2; o is 0 or 1; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer thereof.

2. A compound of formula I according to claim 1 or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer thereof, wherein R.sup.2 is sec-butyl.

3. A compound of formula I according to claim 1 or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer thereof, wherein the five-membered heterocyclic ring is an imidazole ring.

4. A compound of formula I according to claim 1 or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer thereof, wherein o is 0.

5. A compound of formula I according to claim 1 or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer thereof, wherein the compound is selected from ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088##

6. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer thereof, and a pharmaceutical acceptable carrier and/or adjuvant.

Description

EXAMPLE 1

(1) ##STR00018##

(2) The following amino acids were used: Fmoc-Gly-OH, FMOC-Phe(4-NHBoc)-OH, Fmoc-SAR-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(3) MS (M+H.sup.+): expected 994.1; observed 994.9

EXAMPLE 2

(4) ##STR00019##

(5) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-SAR-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, FMOC-Phe(4-NHBoc)-OH

(6) MS (M+H.sup.+): expected 944.1; observed 944.4

EXAMPLE 3

(7) ##STR00020##

(8) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ala-OH

(9) MS (M+H.sup.+): expected 985.1; observed 986.3

EXAMPLE 4

(10) ##STR00021##

(11) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc--Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(12) MS (M+H.sup.+): expected 984.5; observed 984.9

EXAMPLE 5

(13) ##STR00022##

(14) The following amino acids were used: Fmoc-SAR-OH, Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Gly-OH

(15) MS (M+H.sup.+): expected 984.5; observed 984.9

EXAMPLE 6

(16) ##STR00023##

(17) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(18) MS (M+H.sup.+): expected 931.0; observed 932.0

EXAMPLE 7

(19) ##STR00024##

(20) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(21) MS (M+H.sup.+): expected 914.9; observed 915.9

EXAMPLE 8

(22) ##STR00025##

(23) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Tyr(tBu)-OH

(24) MS (M+H.sup.+): expected 971.1; observed 971.5

EXAMPLE 9

(25) ##STR00026##

(26) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(27) MS (M+H.sup.+): expected 980.1; observed 981.5

EXAMPLE 10

(28) ##STR00027##

(29) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, FMOC-Phe(4-NHBoc)-OH

(30) MS (M+H.sup.+): expected 970.1; observed 970.8

EXAMPLE 11

(31) ##STR00028##

(32) The following amino acids were used: Fmoc-Gly-OH, FMOC-Phe(4-NHBoc)-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(33) MS (M+H.sup.+): expected 1020.0; observed 1021.0

EXAMPLE 12

(34) ##STR00029##

(35) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH, Fmoc-SAR-OH

(36) MS (M+H.sup.+): expected 985.1; observed 985.4

EXAMPLE 13

(37) ##STR00030##

(38) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-SAR-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(39) MS (M+H.sup.+): expected 945.1; observed 945.4

EXAMPLE 14

(40) ##STR00031##

(41) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-D-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(42) MS (M+H.sup.+): expected 971.1; observed 971.5

EXAMPLE 15

(43) ##STR00032##

(44) The following amino acids were used: Fmoc-Gly-OH, Fmoc-D-Leu-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(45) MS (M+H.sup.+): expected 971.1; observed 971.3

EXAMPLE 16

(46) ##STR00033##

(47) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(48) MS (M+H.sup.+): expected 902.9; observed 903.8

EXAMPLE 17

(49) ##STR00034##

(50) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(51) MS (M+H.sup.+): expected 944.5; observed 945.0

EXAMPLE 18

(52) ##STR00035##

(53) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(54) MS (M+H.sup.+): expected 928.9; observed 929.7

EXAMPLE 19

(55) ##STR00036##

(56) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(57) MS (M+H.sup.+): expected 957.1; observed 957.8

EXAMPLE 20

(58) ##STR00037##

(59) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(60) MS (M+H.sup.+): expected 957.1; observed 957.9

EXAMPLE 21

(61) ##STR00038##

(62) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Lys(Boc)-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(63) MS (M+H.sup.+): expected 986.1; observed 986.9

EXAMPLE 22

(64) ##STR00039##

(65) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-D-Ile-OH, Fmoc-Tyr(tBu)-OH

(66) MS (M+H.sup.+): expected 971.1; observed 971.5

EXAMPLE 23

(67) ##STR00040##

(68) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-D-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(69) MS (M+H.sup.+): expected 971.1; observed 971.5

EXAMPLE 24

(70) ##STR00041##

(71) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(72) MS (M+H.sup.+): expected 971.1; observed 971.8

EXAMPLE 25

(73) ##STR00042##

(74) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thr(tBu)-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(75) MS (M+H.sup.+): expected 932.9; observed 933.6

EXAMPLE 26

(76) ##STR00043##

(77) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(78) MS (M+H.sup.+): expected 931.0; observed 931.6.

EXAMPLE 27

(79) ##STR00044##

(80) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Phe-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(81) MS (M+H.sup.+): expected 979.0; observed 979.5

EXAMPLE 28

(82) ##STR00045##

(83) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(84) MS (M+H.sup.+): expected 918.9; observed 919.7

EXAMPLE 29

(85) ##STR00046##

(86) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Glu(tBu)-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(87) MS (M+H.sup.+): expected 960.9; observed 962.1

EXAMPLE 30

(88) ##STR00047##

(89) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Dab(Boc)-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(90) (M+H.sup.+): expected 932.0; observed 932.6

EXAMPLE 31

(91) ##STR00048##

(92) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(93) (M+H.sup.+): expected 960.0; observed 960.9

EXAMPLE 32

(94) ##STR00049##

(95) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(96) MS (M+H.sup.+): expected 995.0; observed 996.0

EXAMPLE 33

(97) ##STR00050##

(98) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH

(99) MS (M+H.sup.+): expected 945.0; observed 945.0

EXAMPLE 34

(100) ##STR00051##

(101) The following amino acids were used: Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(102) (M+H.sup.+): expected 969.0; observed 969.7

EXAMPLE 35

(103) ##STR00052##

(104) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Met-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(105) (M+H.sup.+): expected 995.0; observed 996.0

EXAMPLE 36

(106) ##STR00053##

(107) The following amino acids were used: Fmoc-Gly-OH, Fmoc-MeLeu-OH, Fmoc-Pro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(108) (M+H.sup.+): expected 955.1; observed 985.1

EXAMPLE 37

(109) ##STR00054##

(110) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(111) (M+H.sup.+): expected 888.0; observed 888.6

EXAMPLE 38

(112) ##STR00055##

(113) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Trp-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(114) (M+H.sup.+): expected 1018.1; observed 1018.8

EXAMPLE 39

(115) ##STR00056##

(116) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Cha-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(117) (M+H.sup.+): expected 985.1; observed 985.6

EXAMPLE 40

(118) ##STR00057##

(119) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Nle-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(120) (M+H.sup.+): expected 945.0; observed 945.5

EXAMPLE 41

(121) ##STR00058##

(122) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Chg-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(123) (M+H.sup.+): expected 971.1; observed 971.9

EXAMPLE 42

(124) ##STR00059##

(125) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Dap-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(126) (M+H.sup.+): expected 918.0; observed 918.7

EXAMPLE 43

(127) ##STR00060##

(128) The following amino acids were used: Fmoc-Gly-OH, Fmoc-HoLeu-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(129) (M+H.sup.+): expected 959.1; observed 959.9

EXAMPLE 44

(130) ##STR00061##

(131) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Tle-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(132) (M+H.sup.+): expected 945.0; observed 944.7

EXAMPLE 45

(133) ##STR00062##

(134) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Hyp-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(135) (M+H.sup.+): expected 987.1; observed 988.0

EXAMPLE 46

(136) ##STR00063##

(137) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-FluoroPro-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(138) (M+H.sup.+): expected 989.1; observed 989.3

EXAMPLE 47

(139) ##STR00064##

(140) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Hpr-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(141) (M+H.sup.+): expected 985.1; observed 985.1

EXAMPLE 48

(142) ##STR00065##

(143) The following amino acids were used: Fmoc-Gly-OH, Fmoc-cyLeu-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(144) (M+H.sup.+): expected 943.0; observed 943.1

EXAMPLE 49

(145) ##STR00066##

(146) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Aib-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(147) (M+H.sup.+): expected 917.0; observed 917.8

EXAMPLE 50

(148) ##STR00067##

(149) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Aze-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(150) (M+H.sup.+): expected 957.0; observed 957.1

EXAMPLE 51

(151) ##STR00068##

(152) The following amino acids were used: Fmoc-Gly-OH, Fmoc-MeLeu-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(153) (M+H.sup.+): expected 959.1; observed 959.7

EXAMPLE 52

(154) ##STR00069##

(155) The following amino acids were used: Fmoc-Gly-OH, Fmoc-MeLeu-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(156) (M+H.sup.+): expected 903.0; observed 903.2

EXAMPLE 53

(157) ##STR00070##

(158) The following amino acids were used: Fmoc-Gly-OH, Fmoc-2AOC-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(159) (M+H.sup.+): expected 973.0; observed 973.5

EXAMPLE 54

(160) ##STR00071##

(161) The following amino acids were used: Fmoc-Gly-OH, Fmoc-2ADC-OH, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(162) (M+H.sup.+): expected 1001.1; observed 1000.5

EXAMPLE 55

(163) ##STR00072##

(164) The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu, Fmoc-Sar-OH, Fmoc-Glu(Allyl)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Val-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OHMS

(165) (M+H.sup.+): expected 916.0; observed 917.2

(166) Material and Methods

(167) Cell Culture and Stable Clone Production

(168) Chines Hamster Ovary (CHO) cells were transfected with expression plasmids encoding either the human V1a, the human Oxytocin (OTR) or the humanV2 receptor, the later in combination with the chimeric Gqs5 G protein to redirect the signal to Calcium flux. Stable cells were cloned by limiting dilution to yield monoclonal cell lines expressing either human V1a, human V2+Gqs5 or human OTR receptors and selected based on functional responses detected on a fluorometric imaging plate reader (FLIPR) detecting Calcium flux in the cell after receptor activation. The stable cell lines were grown in F-12 K Nutrient Mixture (Kaighns Modification), containing 10% foetal bovine serum (FBS), 1% penicillin-streptomycin, 1% L-glutamate, 200 ug/ml Geneticin at 37 C. in a 10% CO.sub.2 incubator at 95% humidity.

(169) Calcium Flux Assays Using Fluorescent Imaging (Fluorometric Imaging Plate Reader, FLIPR)

(170) On the afternoon before the assay, cells were plated at a density of 50,000 cells/well into black 96 well plates with clear bottoms to allow cell inspection and fluorescence measurements from the bottom of each well. The density of cells was sufficient to yield a confluent monolayer the next day. Hanks balanced salt solution, without phenol red, containing 20 mM HEPES (pH 7.3) and 2.5 mM probenecid (assay buffer) was prepared fresh for each experiment. Compound dilutions were made using a Beckman Biomek 2000 laboratory automation workstation, in assay buffer containing 1% DMSO. The dye-loading buffer consisted of a final concentration of 2 M Fluo-4-AM (dissolved in DMSO and pluronic acid) in assay buffer. The existing culture media was removed from the wells and 100 l of the dye-loading buffer was added to each well and incubated for approximately 60 min at 37 C. in a 5% CO.sub.2 incubator at 95% humidity. Once dye-loaded, the cells were washed thoroughly on an Embla cell washer with the assay buffer to remove any unincorporated dye. Exactly 100 l assay buffer was left in each well.

(171) Each 96 well plate containing dye-loaded cells was placed into the FLIPR machine and the laser intensity set to a suitable level to detect low basal fluorescence. To test compounds as agonists, 25 l diluted compound was added to the plate 10 seconds into the fluorescent measurements and fluorescent response was recorded for 5 minutes. The fluorescence data was normalized to the endogenous full agonist dose-response set at 100% for the maximum response and 0% for the minimum. Each agonist concentration-response curve was constructed using a four parameter logistic equation with Microsoft Excel XLFit as follows: Y=Minimum+((MaximumMinimum)/(1+10.sup.(Log EC50-X)nH)), where y is the % normalized fluorescence, minimum is the minimum y, maximum is the maximum y, log EC.sub.50 is the log.sub.10 concentration which produces 50% of the maximum induced fluorescence, x is the log.sub.10 of the concentration of the agonist compound and H is the slope of the curve (the Hill Coefficient). The maximum value gives the efficacy of the agonist test compound in percentage. The concentration of agonist that produced a half-maximal response is represented by the EC.sub.50 value, the logarithm of which yielded the pEC.sub.50 value.

(172) The following EC.sub.50 (nM), and efficacy (%) for the specific peptides may be provided, together with comparative data for hV1a and hV2:

(173) TABLE-US-00001 hOT hV2 hOT hV1a hV2 EC.sub.50(nM)/ hV1a EC.sub.50 (nM)/ EC.sub.50(nM)/ EC.sub.50 (nM)/ EC.sub.50 (nM) efficacy EC.sub.50 efficacy efficacy efficacy efficacy Expl. (%) (nM) (%) Expl. (%) (%) (%) 1 10/111 >27000 4800/107 29 32/130 >10000 10682/39 2 9/112 >27000 7906/74 30 .sup.6/119 >10000 142/104 3 4/94 31 .sup.9/131 >10000 2708/91 4 31/102 32 .sup.4/119 >10000 1985/106 5 181/108 33 .sup.2/119 >27000 3821/101 6 11/95 >27000 34 10/136 >10000 145/120 7 124/87 35 .sup.3/111 >10000 1672/104 8 100/92 36 41/138 9 118/93 37 .sup.4/137 10 17/91 >2700 38 .sup.1/126 11 11/94 >27000 39 0.4/122 >27000 3707/111 12 48/82 40 0.4/124 >27000 2194/117 13 0.2/111 >27000 5110/97 41 69/117 14 250/92 42 .sup.1/119 15 52/102 >12000 43 26/124 16 30/105 >12000 44 0.5/117 >27000 1230/112 17 45/92 >12000 45 0.6/113 >27000 3806/91 18 24/91 >12000 46 10/104 19 1.5/122 127/33 47 1.5/111 20 40 >12000 48 3.6/108 21 12/105 32/55 49 5.9/97 22 98/116 50 3.6/99 >27000 23 88/64 51 13/97 >27000 24 2.2/152 >27000 2505/98 52 4.3/121 25 3/125 >10000 3823/103 53 1.1/127 26 2/124 >10000 2624/102 54 0.8/134 27 5/128 >10000 1498/101 55 20/104 28 5/122 >10000 4173/87
The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered preferably transdermal, intranasal, subcutaneous or intra venous (iv).

(174) Transdermal is a route of administration wherein active ingredients are delivered across the skin for systematic distribution. Examples include transdermal patches used for medicine delivery, and transdermal implants used for medical or aesthetic purposes.

(175) Nasal administration can be used to deliver drugs for either local or systemic effects, nasal sprays for local effect are quite common. Peptide drugs may be administered as nasal sprays to avoid drug degradation after oral administration.

(176) Subcutaneous injections are also common for the administration of peptide drugs. An intramuscular injection is the injection of a substance directly into the muscle. It is one of several alternative methods for the administration of medications. It is often used for particular forms of medication that are administered in small amounts. The injections should be given under the skin.

(177) The intravenous route is the infusion of liquid substances directly into a vein. Compared with other routes of administration, the intravenous route is the fastest way to deliver fluids and medications throughout the body.

(178) The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

(179) Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

(180) The most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory, loss alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrom.

(181) The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. The dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.