PEPTIDES AS OXYTOCIN AGONISTS

Abstract

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 Syndrome.

Claims

1. A compound of formula ##STR00043## wherein R.sup.1 is hydrogen, lower alkyl, CH.sub.2-cycloalkyl or cycloalkyl; R.sup.2 is hydrogen, lower alkyl, lower alkyl substituted by hydroxy or R.sup.1 and R.sup.2 may form together with the N and C atom to which they are attached a pyrrolidine ring optionally substituted by one or two F-atoms or by hydroxy, or may form an azetidine or a piperidine ring; R.sup.3 is hydrogen, lower alkyl, lower alkyl substituted by hydroxy, (CH.sub.2).sub.oNH.sub.2, benzyl optionally substituted by hydroxy, phenyl, CH.sub.2-cycloalkyl or cycloalkyl; R.sup.3 is hydrogen or lower alkyl; n is 1; m is 0 or 1; o is 1 to 4; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

2. A compound of formula I according to claim 1, wherein m is 1.

3. A compound of formula I according to claim 1, wherein R.sup.1 is hydrogen, lower alkyl, CH.sub.2-cycloalkyl or cycloalkyl and R.sup.2 is hydrogen, lower alkyl, lower alkyl substituted by hydroxy and the other definitions are as described in claim 1.

4. A compound of formula I according to claim 1, wherein R.sup.1 and R.sup.2 may form together with the N and C atom to which they are attached a pyrrolidine ring optionally substituted by one or two F-atoms or by hydroxy, or may form an azetidine or a piperidine ring, and the other definitions are as described in claim 1.

5. A compound of formula I according to claim 1, selected from the group consisting of ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051##

6. A pharmaceutical composition comprising a compound of formula I according to claim 1, and a pharmaceutical acceptable carrier and/or adjuvant.

7. A method inhibiting the oxytocin receptor in a cell, comprising administering to the cell a compound of formula I according to claim 1.

8. A method of treating a disorder selected from autism, stress, an anxiety disorder, depression, schizophrenia, a psychiatric disorder, memory loss, alcohol withdrawal, drug addiction, or Prader-Willi Syndrome, comprising administering to the subject in need thereof a compound of formula I according to claim 1.

9. The method of claim 8, wherein the disorder is stress or an anxiety disorder.

10. The method of claim 9, where in the disorder is post-traumatic stress disorder or anxiety.

Description

EXAMPLE 1

[0044] ##STR00011##

[0045] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0046] MS (M+H.sup.+): expected 1006.1; observed 1006.4

EXAMPLE 2

[0047] ##STR00012##

[0048] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0049] MS (M+H.sup.+): expected 980.1; observed 981.2

EXAMPLE 3

[0050] ##STR00013##

[0051] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, (2S)-Fmoc-4,4-Difluoro-Pyrrolidine-2-Carboxylic Acid, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0052] MS (M+H.sup.+): expected 1042.1; observed 1043.1

EXAMPLE 4

[0053] ##STR00014##

[0054] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, (S)N-Fmoc-Azetidine-2-Carboxylic Acid, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0055] MS (M+H.sup.+): expected 992.2; observed 993.4

EXAMPLE 5

[0056] ##STR00015##

[0057] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pipecolic Acid, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0058] MS (M+H.sup.+): expected 1020.2; observed 1020.5

EXAMPLE 6

[0059] ##STR00016##

[0060] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, (2S,4S)-Fmoc-4-Fluoro-Pyrrolidine-2-Carboxylic Acid, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0061] MS (M+H.sup.+): expected 1024.1; observed 1024.5

EXAMPLE 7

[0062] ##STR00017##

[0063] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Trans-4-Fluoro-Proline, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0064] MS (M+H.sup.+): expected 1024.1; observed 1024.5

EXAMPLE 8

[0065] ##STR00018##

[0066] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Hyp(tBu)-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0067] MS (M+H.sup.+): expected 1022.1; observed 1022.5

EXAMPLE 9

[0068] ##STR00019##

[0069] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Nle-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0070] MS (M+H.sup.+): expected 980.1; observed 980.4

EXAMPLE 10

[0071] ##STR00020##

[0072] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Aib-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0073] MS (M+H.sup.+): expected 952.0; observed 952.4

EXAMPLE 11

[0074] ##STR00021##

[0075] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Cha-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0076] MS (M+H.sup.+): expected 1020.2; observed 1020.6

EXAMPLE 12

[0077] ##STR00022##

[0078] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0079] MS (M+H.sup.+): expected 966.1; observed 966.5

EXAMPLE 13

[0080] ##STR00023##

[0081] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0082] MS (M+H.sup.+): expected 980.1; observed 980.4

EXAMPLE 14

[0083] ##STR00024##

[0084] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Nva-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0085] MS (M+H.sup.+): expected 966.1; observed 966.5

EXAMPLE 15

[0086] ##STR00025##

[0087] The following amino acids were used: Fmoc-Gly-OH, Fmoc-homoVal-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0088] MS (M+H.sup.+): expected 994.1; observed 994.5

EXAMPLE 16

[0089] ##STR00026##

[0090] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Phe-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0091] MS (M+H.sup.+): expected 1014.1; observed 1014.4

EXAMPLE 17

[0092] ##STR00027##

[0093] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0094] MS (M+H.sup.+): expected 1030.1; observed 1030.4

EXAMPLE 18

[0095] ##STR00028##

[0096] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0097] MS (M+H.sup.+): expected 954.0; observed 954.4

EXAMPLE 19

[0098] ##STR00029##

[0099] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0100] MS (M+H.sup.+): expected 938.0; observed 938.4

EXAMPLE 20

[0101] ##STR00030##

[0102] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Dap(BOC)-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0103] MS (M+H.sup.+): expected 953.0; observed 953.4

EXAMPLE 21

[0104] ##STR00031##

[0105] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Chg-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0106] MS (M+H.sup.+): expected 1006.1; observed 1006.4

EXAMPLE 22

[0107] ##STR00032##

[0108] The following amino acids were used: Fmoc-Gly-OH, Fmoc--MeLeu-OH, Fmoc-Sar-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0109] MS (M+H.sup.+): expected 994.1; observed 994.5

EXAMPLE 23

[0110] ##STR00033##

[0111] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Nva-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0112] MS (M+H.sup.+): expected 1008.1; observed 1008.4

EXAMPLE 24

[0113] ##STR00034##

[0114] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Nle-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0115] MS (M+H.sup.+): expected 1022.2; observed 1022.4

EXAMPLE 25

[0116] ##STR00035##

[0117] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0118] MS (M+H.sup.+): expected 996.1; observed 996.3

EXAMPLE 26

[0119] ##STR00036##

[0120] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-homoSer(tBu)-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0121] MS (M+H.sup.+): expected 1010.1; observed 1010.4

EXAMPLE 27

[0122] ##STR00037##

[0123] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-CyclopropGly-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0124] MS (M+H.sup.+): expected 1006.1; observed 1006.4

EXAMPLE 28

[0125] ##STR00038##

[0126] The following amino acids were used: Fmoc-Gly-OH, Fmoc-a-MeLeu-OH, Fmoc-CyclopropGly-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0127] MS (M+H.sup.+): expected 1020.1; observed 1020.5

EXAMPLE 29

[0128] ##STR00039##

[0129] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-CyclopropGly-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0130] MS (M+H.sup.+): expected 992.1; observed 992.5

EXAMPLE 30

[0131] ##STR00040##

[0132] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Aib-OH, Fmoc-CyclopropGly-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0133] MS (M+H.sup.+): expected 978.1; observed 978.5

EXAMPLE 31

[0134] ##STR00041##

[0135] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-CyclopropGly-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0136] MS (M+H.sup.+): expected 1006.1; observed 1006.4

EXAMPLE 32

[0137] ##STR00042##

[0138] The following amino acids were used: Fmoc-Gly-OH, Fmoc-Chg-OH, Fmoc-CyclopropGly-OH, Fmoc-(S)-2-Amino-4-(2-tert-butoxycarbonyl-ethanesulfonyl)-butyric acid, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH and Fmoc-Tyr(tBu)-OH.

[0139] MS (M+H.sup.+): expected 1032.2; observed 1032.4

Material and Methods

Cell Culture and Stable Clone Production

[0140] Chines Hamster Ovary (CHO) cells were transfected with expression plasmids encoding either the human Vla, 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 Vla, 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.

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

[0141] 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.

[0142] 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.(LogEC50X)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.

The Following EC.sub.50 (nM), and Efficacy (%) for the Specific Peptides May be Provided, Together with Comparative Data for hV1a and hV2:

TABLE-US-00001 hV2 hV1a hV2 hOT EC.sub.50 hOT EC.sub.50 EC.sub.50 EC.sub.50(nM)/ hV1a (nM)/ EC.sub.50(nM)/ (nM)/ (nM) efficacy EC.sub.50 efficacy efficacy efficacy efficacy Expl. (%) (nM) (%) Expl. (%) (%) (%) 1 0.8/120 1633 2982/101 18 3.3/102 2 0.8/107 >27000 3984/86 19 1.4/110 3 1.7/144 20 12.9/113 4 3.0/128 21 0.4/117 5 3.8/130 22 2.5/109 6 1.6/145 23 23/123 7 2.6/141 24 40/114 8 0.8/129 25 16/137 9 1.0/104 26 .sup.7/140 10 4.7/100 27 0.5/125 >27000 3730/110 11 1.4/115 28 0.7/105 >27000 9423/129 12 1.4/112 29 0.5/105 3344/143 13 1.1/117 30 1/97 6339/131 14 0.7/117 31 0.4/115 2942/150 15 1.0/107 32 0.26/120 2233/38 2365/155 16 5.6/104 17 2.2/105
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).

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

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 Syndrome.

[0149] 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.