Title of Invention	COMPOUNDS WITH GROWTH HORMONE RELEASING PROPERTIES
Abstract	The present invention relates to disclosed novel compounds of the general formula I

Full Text

COMPOUNDS WITH GROWTH HORMONE RELEASING PROPERTIES FIELD OF INVENTION The present invention relates to novel compounds, compositions containing them, and their use for treating nedical disorders resulting from a deficiency in growth horncne. ' BACKGROUND OF THE INVENTION Growth hormone is a hormone which stimulate, growth of all tissues capable of growing. In addition, growth hortone is known to have a . 'number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilization and to cause a switch in energy metabolism from carbohydrate tc fatty acid • metabolism. Deficiency in growth hormone result in a number of severe medical disorders, e.g., dwarfism. Growth hormone is released from the pituitary. Tha release is under tight control of a number of hormones and neurotransmitters either directly or indirectly. Growth hormone release can b-2 stimulated by growth hormone releasing hormone (GJQH) inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primerily via specific receptors located in the pituitary. Other compounds uhich stimulate the release of growth hormone from the also been described. For example arginine, L-3, J-dihycroyphenylalanine (L-Dopa) , glucagon, vasopressin, PACAP (pituitary aclenylyl cyclase activating peptide), muscarinic receptor agonist;; and a synthethic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direc; effect on the pituitary or by affecting the release of GF.RH ard/cr somatostatin from the hypothalamus. In disorders or conditions where increased, levels of growth hormone is desired, the protein nature of growth hormone anything but ./ parenteral administration non-viable. Furthermore, other directly acting natural secretagogues, e.g., GHRH and PACAP, are longer polypeptides for which reason oral administration of them is not viable. The use of certain compounds for increasing the levels of growth hormone in mammals has previously been proposed, e.g. in EP 18 072, EP 83 864, WO 89/07110, WO 89/01711, WO 89/10933, WO 88/9780, WO 83/02272, WO 91/18016, WO 92/01711, WO 93/04081, WO 95/17422, WO 95/17423 and WO 95/14666. The composition of growth hormone releasing compounds is important for their growth hormone releasing potency as well as their bioavailability. It is therefore the object of the present invention to provide compounds with growth hormone releasing properties which have improved properties rolative to known peptides of this type. SUMMARY OF THE INVENTION Accordingly, the present invention relates to a compound of general formula I wherein R3, R\ R5, R6, R7 and R8 independently ara hydrogen or Cj.j-alkyl optionally substituted with halogen, amino, hydroxy or aryl ,• R5 and R6, R6 and R1, R5 and R8 or R7 and R8 optionally' forming -(CH2)i-U-(CH2)3-, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, * optionally substituted with halogen, amino, hydroxy, cμ-alkyl or Cμ-alkoxy; o, r and t are independently o, 1, 2, 3 or 4; q and s are independently 0 or l; arid r+s+t is 1, 2, 3 or 4; 6, U' is ~0~» ~S- or a valence bond; X is -N(Rn)-, -0- or -S-, V is -C(R12)= or -N=, Y is -C(Rl3)= or -N=, 2 is -C(R14)= or -N=, R"; Rn and R14 independently are hydrogen, -CCOR1*, -CONR16Rn, -(CH2)VNR16R17, -(CH2)uOR15, halogen, hydroxy, branched or linear Cj_6-alkyl, phenyl, oxazol-5-yl, 5~raethyl-[l,2,4]o>:adiazol-3-yl, R11, R15, R16 and R17 independently are hydrogen or branched, or linear CU6-alkyl . obtionally substituted with aryl, an3 u and v are independently 0 or l, 2, 3, 4, 5 or 6; wherein R18, R19, R20 and R21 are independently hydrogen, c,.s-alkyl optionally substituted with halogen, amino, c,.6-alky:Lamino, hydroxy or aryl; Ria and R"f R19 and R21f R19 and R20 cr R20 c.nd R21 optiqnally forming "(CH2)k,-Z-(CH2)i--where k' and 1* independently are 1, 2 or 3, and k'+l' are 3, 4, 5 or 6; Z is -0-, -S- or a valence bond; b is 0 or 1; a and d are independently 0, 1, 2, 3 or 4; and a+b is 1 to 4; Q is >CR22- or >N-, wherein R22 is hydrogen or cx.6-alkyl. -..optionally substituted with halogen, amino, hydroxy, Cμg-alkyl or .Cμ-alkoxy; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical is omers or racemic mixtures thereof. Regarding the above compounds of the general foi-mula I preferred substituents are mentioned in the dependent. cla:.ms Furthermore, especially preferred substituents are those xentjoncsd below. wherein R1 and W are as defined above. Preferred groups of R1 is C1-6-alkyl, and more praferred C1-6-alky! such as methyl, ethyl, cyclopropyl and isopropyl. Preferably m is 1 and/or p is 1. wherein R5, R6, R7, Re, M, s, t, q and o are as defined above. Preferably R5 and R6, R6 and R7, R5 and R8 or R7 and R8 are optionally forming -(CH2)i-U-(CH2)μ-, wherein U, i and j are as defined above. Preferably o, r and t are independently 0, 1, 2 cr 3. Specifically preferred D is 4-piperidinyl, 3-pi;?eridinyl, or 3- aminomethylphenyl. Specifically prefered D-B- is 3-amino-3-methyl-bxr:enyl or 4-amino-4-methy1-penteny1. Preferably K is hydrogen. The meanings of the above preferred substituents should in no way be construed as limiting the invention to such sv.bstituents Representative compounds of the present invention include the following: 3-Aminomethyl-N- {(1R, 2E, 4S) -4-carbamoyl-5- (2-naphthyl) -1-(2 -naphtμhy 1) methy lpent-2 -eny 1) benzamide: Piperidine-4-carboxylic acid ((lR,2E/4S)-4-carbamoyl-5-(2-haphthyl)-l-(2-naphthyl)methylpent-2-enyl) amide: N-((1R)-l-((1R)-l-((IS)-5-Amino-l- (diraethylcarbamoyl)pentylcarbainoyl)-2-phenyletnoxy)methyl-2-(2-naph thy 1)ethy1)-3-aminomethy1benz amide: (dimethylcarbamoyl)pentyl) carbamoyl) -1-((2-naphthyl)methyl) -2-oxo-Srphenylpenty1)-3-aminomethylbenzamide: ? 5- ( [l,3,4]oxadiazole-2-carboxylic acid amide: * It is believed that compounds of formula I exhibit an improved resistance to proteolytic degradation by enzymes because they are non-natural, in particular because the natural amide bonds are replaced by non-natural amide bond mimetics. The increased resistance to proteolytic degradation combined with the reduced size of the compounds of the invention in comparison with known growth hormone releasing peptides is expected to improve their bioavailability compared to that of the peptides suggested in the prior literature. In the above structural formulas and throughout the present specification, the following terms have the indicated meanings: The Ci.g-alkyl groups specified above are intended tc include those alkyl groups of the designated length in either a linear or branched or cyclic configuration. Examples of linear alkyl are methyl, ethyl, propyl, butyl, pentyl and hexyl. Examples of branched alkyl are isopropyl, sec-butyl, tert.-butyl, isopentyl and isohexyl. Examples of cyclic alkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Especially preferred C1-6-alkyl groups are the C1-6--alkyl groups. Preferred C1-6-alkyl groups are methyl, ethyl, isopropyl and cyclopropyl. The C1-6-alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a linear or branched or cyclic configuration. Examples of linear alkoxy are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Examples of branched alkoxy are isopropoxy, sec-butoxy, ter.-butoxy, isopentoxy and isohexoxy. Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. Especially preferred d-s-alkoxy groups are the d-i~alkoxy groups. Preferred C1-6-alkoxy groups are methoxy, ethoxy, isopropoxy and cyclopropoxy. The C1.6-alkylamino groups specified above are intended to include those alkylamino groups of the designated length In either a linear or branched or cyclic configuration. Examples of linear alkylamino are methylamino, ethylamino, propylamino, butylamiro, pentylamino and hexylamino. Examples of branched alkylamino are isopropylamino, s ec -butyl ami no, tert.-butylamino, isopentyl amino and isohexylamino. Examples of cyclic alkylamino are eye1opropylamino, eyelobutylamino, cyclopentylamino and cyclohexylamino. Especially preferred Cμj-alkylamino groups are the d-3-alkylamino groups, preferred groups are methylamino, ethylamino, isopropylamino and cyclopropylamino. In the present context, the term "aryl" is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings selected from the group consisting of phenyl, naphthyl, pyridyl, 1-H-tetrazol-5~yl, thiazolyl, imidazolyl, indolyl, quinoline, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxalyl, thiopheneyl, quinolinyl, pyrazinyl or isothia2;olyl, optionally substituted by one or more d.6-alkyl, aminohalogen or aryl. Aryl is preferably phenyl, thienyl, imidazolyl, pyridyl, indolyl or naphthyl optionally substituted with halogen, amino, hydroxy, d_6-alkyl or d_6-alkoxy. Tne term "halogen" is intended to include CI, F, Br and I. The compounds of the present invention ne.y have one or more asymmetric centres and it is intended -ciat stereoisomers, as separated, pure or partially purified {stereoisomers or racemic mixtures thereof are included in the scope o:' thj invention. Compounds of the present invention may be prepared from natural and unnatural amino acid residues as described in the fo]lowing general • methods A to E, and where the starting amino aclcs can be prepared as Known in the arts Compounds of formula I may be prepared as shown i:i reaction scheme I starting with an appropriate N-protected amino acid which can be converted to sulfone 1 using a known procedure (e.g. Spaltenstein, J. Org. Chem. 1987, 52, 3759). The other starting material 2 may be prepared from dimethyl malonate and an aromatic alkyl halide followed by reduction by LiAlH The intermediate 3 may be oxidized by e.g. Jones reagent to a carboxylic acid 4 which may be converted to an am:.de 5 by treatment with e.g. thionyl chloride and ammonia. Compound 5 may finally be reacted with a protected amino acid using a suitable condensing agent (e.g. DCC) and deprotected by methods which are described by e.g. T.W. Greene (Protective Groups in Organic Chemistry, 2.ed. John Wiley and Sons, 1991) to form compound 6 which is a compound of formula I. General Method B Reaction Scheme II Compound of formula I may be prepared as shown in reaction scheme II starting with the synthesis of intermediate 10 using the procedure of e.g. A. E. Decamp et al. (Tetrahedron Letters, 1991, 32, 1867 - 1870.): The titanium-homoenolate 9 may be generated from 3-iodopropionic acid 8 and added onto a suitable aldehyde 7. A cyclization in e.g acetic acid may furnish the lactone 11. Alkylation of the lactone may be done as described by e.g. A. H. Fray et al. (J. Org. Chem., 1986, 51, 4828 - 4833). The enolate may be generated by treatment with base such as lithium hexamethyldisilazane (LHDS) or Lithium diisopropylamide (LDA) and reacted with a suitable alkylating reagent such as; alkylchloride to give a compound of type 12. The lactone may be transferred into a • silyl-protected hydroxy acid 13 as described by €=.g. A. H. Fray et .' al {J. Org. Chem., 1986, 51, 4828 - 4833). Coupling with an amine, which may contain amino protective groups as e.j. phthalimido or FMOC, by reaction with EDAC and HOBT may give an amide of type 14. Deprotection of the amino group using procedures known in the art (e.g. T.W. Greene, Protective Groups in Organic Chemistry, 2.ed. John Wiley and Sons 1991) is followed by coupling to a suitable acid, which may include a protection group, by reaction with e.g. EDAC and HOBT to give a compound of type 16. Finally, protection groups on the variable fragments may be renoved by methods described in the art (e.g. T. W. Greene, Protective Groups in Organic Synthesis, 2nd. edition, John Wiley and Sons, New York 1991.) to give the final product 17 which is a compound of formula I. T Compounds of formula I may be prepared as shown in scheme III starting with deprotection of an amide of type 14 by reaction with e.g. tetrabutyIammonium fluoride and subsequent oxidation with a suitable reagent such as PCC or PDC to. give a compound 19. The amino group may be deprotected with e.g. hydrochloric acid in ethyl acetate followed by coupling with a suitable acid wh;.ch may contain a protection group. Finally, protection groups on the variable . fragments may be removed by methods described in the art (e.g. T. W. Greene, Protective Groups in Organic Synthesis, 2nd. edition, John Wiley and Sons, New York 1991.) to give the final product 20 which is a compound of formula I. Compounds of formula—I-may be prepared as shown in scheme IV starting with an amino-alcohol of type 21 which may be reacted with chloroacetyl chloride as described in the literature! by e.g. E. D. Nicolaides et al. (J. Med. Chem. 1986, 29, 959 - 971.). Reaction with a base such as sodium hydride in THJ may furnish a morpholinone 23 which can be alkylated by using s base such as LDA or LHDS and subsequent addition of a suitable alkylating reagent such as alkyl chloride. After separation of diastereoisomeres, the ring can be opened by reaction with acid as described by e.g." R. E. TenBrinJc (J. Org. Chew. 1987, 52, 418 - 422.) and the araino-group can be protected to give a compound 25. The E-fragraent, that may contain protected functionalities, can be attached by reaction of a suitable amine using e.g. l-ethy1-3 -(3-dimethylaminopropyl)carbodiimide (EDAC) and 1-hydroxybenzotriazole (HOBT). The amino group in 26 can be deprotected by suitable conditions, such as hydrogene chloride in etnyl acetate, and reacted with a suitable acid, that may contain protection groups, EDAC, and HOBT. Removal of all protection groups by methods described in the art (e.g. T. W. Greene, Protective Groups in Organic Synthesis, 2nd. edition, John Wiley and Sons, New York 1991.), may yield the final product 28 which is a compound of general formula I. Compounds of formula I may be prepared as shown :.n reaction scheme V starting with an N-protected amino acid 29 whica may be activated with, e.g. EDAC and then reacted with an amido oxime 30 in e.g. pyridine using a known procedure (e.g. J. Heterocyclic Chem. 1989, 26, 125) to give 1,2,4-oxadiazole derivative 31. After deprotection of the amino group using methods known in the art and described by . e.g. T.W. Greene (Protective Groups in Organic Synthesis, 2. ed. John Wiley and Sons 1991) the compound can be reductive alkylated using an aldehyde and a mild reducing reagent, such as sodium cyanoborohydride to give the desired intermediate 33. Further reaction of 33 with an N-protected natural or unratural amino acid 34 using peptide coupling methodologies as described in the art (e.g. DCC coupling in DMF) can give intermediate 35, which after deprotection with e.g. hydrochloric acid in an appropriate solvent, such as ethyl acetate can be coupled with another N-protected aminoacid 37 using a known peptide coupling methodology such as DCC coupling in DMF to give an intermediate which after deprotection of the amino group with e.g. hydrochloric acid in an appropriate solvent, such as ethyl acetate can give the desired product 38 which is a compound of formula I. When R12 is a functional group (e.g. an ester) this group may be derivatized at an appropriate step in the reaction sequence. A compound of formula I may be prepared as shown in scheme V starting with lactone 40 which may be reacted with cunmonia to give the amide 41. A reaction under Mitsunobu conditions as described by M. S. Mannas et al. (J. Chem. Soc. Perkin Trars X, 1975, 461 -4 63.) may give an ether 42 which may be deprotected under acidic conditions. Coupling with a suitable acid, thai: might contain a protected functionality, may give a compound of t/pe 43, which may be deprotected by methods described in the art («t.g. T. W. Greene, : Protective Groups in Organic Synthesis, 2nd. edition, John Wiley and Sons, New York 1991,) to give the final product 44 which is a A compound of formula .1.,, may be prepared as shown. in scheme VII, starting with an amino acid 45, which may be acylated with e.g. an acid anhydride and - after work up - may be subsequently reduced with e.g. diborane, sodium borohydride/iodine or lithium lurainumhydride as described by e.g. M. J. McKtmnon et. al. (J. Org. Chem, 1993, 58, 3568 - 3571) in an appropriate solvent such as 'THF, diethylether, dioxane or hydrocarbons to give an aminoalcohol 46. It may be protected with a method known in the art and described by e.g. T. W. Greene {Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, New York 1991), with e.g. di-tert-butoxy dicarbonate or benzoylcarbonyl ch:.or:.de to give the protected alcohol 47. A reaction with ethyl diazaacetate under rhodium acetate catalysis (preferentially 0.01 - 15%) as described by e.g. J. HlavaSeck and V. Krai (Collect. Czech. Chem. Coirauun., 1992, 57, 525 - 530) may furnish the ester 48. The ester may be saponified with a method known in the art and. described by e.g. T. W. Greene (Protective Groups in Organic synthesis, 2. ed., John Wiley and Sons, New York 1991) with bases such as lithium hydroxide or potassium hydroxide to give the acid 49, which me.y be activated by e.g. l-ethyl-3~(3-dimethylaminopropyL)carbodiimide hydrogenchloride or a combination of i-ethyl-3-(3-dimethylarainopropyl) carbodiimide hydrogenchloric.e and 1-hydroxy-benzotriazole or l-hydroxy-7-azabenzotriazole and reacted with an amine 50 to give an amide 51. The amino group in 51 may be deprotected by a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, ?2. ed., John Wiley and Sons, New York 1991) e.g. hydrogen chloride in ethyl acetate or trifluoroacetic acid. An acid 34a may be activated by e.g. l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrogenchloride or a combination of l-ethyl-3-(3-diraethylaminopropyl) carbodiimide hydrogenchloric.e and l-hydroxy-benzotriazole or l-hydroxy-7-azabenzotriazole and reacted in an appropriate solvent such as e.g. DMF of dichloromethane with 52 to give the amide 53. The amine-protection group may be removed by a method known in the art and described by e.g. T. W. Greene (Protective Groups in organic synthesis, 2. ed,., John Wiley and. Sons, New York 1991) such as e.g. hydrogenchloride in ethyl acetate or trifluoroacetic acid. A. protected acid 37 may b-a activated by e.g. 1-ethyl-3- (3-dimethylamino-propyl) carbodiiinide hydrogenchloride or a combination o:: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrogenchloride and 1-.hydroxybenzotriazole or l-hydroxy-7-azabenzotriazole and may be reacted with the amine 54 in an appropriate solvent such as DMF or dichloromethane to give - after deprotection by a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, Neiw York 1991) such as e.g. hydrogen chloride in ethyl acetate or tifluoroacetic acid -55, which is a compound of formula I. A compound of formula I may be prepared as shown in scheme VIII, starting with an amino acid 56. As described by e.g. S. Borg et al. (J. Org. Chem. 1995, 60, 3112 - 3120.) 56 may be transformed into Van ester 57 by e. g. reaction with ethanol in the presence of N-(3-dimethylaminopropyl)-N"-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine, which may be subsequently reacted with hydrazine hydrate to give the hydrazide 58. The ester 60 may be obtained from 58 by reaction with ethyl oxalyl cloride (59) in the presence of a base such as e.g. triethylamine. Th«j ring closure may proceed e.g. with thionyl chloride/pyridine and subsequent heat, furnishing and [l,3,4]oxadiazole 61. The airide 62 it ay be obtained by aminolysis of the ester moiety in e.g. liquid ammonia. Deprotection of the amino group by a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, New York 1991.) e. g. , hydrogen chloride in ethyl acetate or trifluoroacetic acid may furnish the amine 63. A suitable protected amino acid 34a may be coupled to 63 using a coupling reagent 3cnown in the art such as e.g. N-(3-dimethylarainopropyl)-N'-ethylcarbodiimide hydrochloride or a combination of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole or l-hydroxy-7-azabenzotriazole to give 64. A deprotection, Ccirried out with a method known in the art and described by e.g. T. W. Green (Protective Groups in Organic Synthesis, 2. ed. , John Wiley and Sons, New York 1991.) e. g. hydrogen chloride in ethyl acetate or trifluoracetic acid, may furnish the amine 65. This may be coupled with a coupling reagent known in the art such as e.g. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride or a combination of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole or l-hydroxy-7-azabenzotriazole with a suitable protected amino ac:.d 37 to give -, after deprotection with a method known in the art. and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, New York 1991.) e. g. hydrogan chloride in ethyl acetate or trifluoracetic acid - 66, which is a cbmpound of A compound of formula I may be prepared a? shown in scheme IX, starting with a suitable protected amino alcohol €,g. 47, which may be oxidized by methods known in the art with reagents such as e.g. DMSO/oxalyl chloride/triethylamine (A. E. DeCamp, A. T. Kawaguchi, R. P. Volante, I. shinkai, Tetrahedron Letters, 1991, 32, 1867 -1870; J. R. Luly, J. F. Dellaria, J. j. Plattner, J. L. Soderguist, N. Yi, J. Org. Chem. 1987, 52, 1487 -• 1492.) or DMSO/sulfur(IV)oxide pyridinium complex/triethylamire (J. S. Ng, C. A. Przybyla, C. Liu, J. C. Yen, F. W. Mueilner, C. L. Weyker, Tetrahdron 1995, 51, 6397 - 6410; P. L. Beaulieu, D. Wernic, J.-S. Duceppe, Y. Guindon, Tetrahedron Letters, 1995, 36, 3317 - 3320.) to give the aldehyde 67. The aldehyde might ba reacted with a Grignard reagent, e.g. allylmagnesium bromide to give an unsaturated compound 68. A hydroboration //ith e.g. 9~ borabicyclo[3.3.l]nonane and subsequent treatment with hydrogen peroxide and sodium hydroxide may furnish the dlol 69. The amino group may be deprotected with a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, New York 1991)by reaction with e.g. hydrogen chloride in ethyl acetate or trifluoro acetic acid to give 70. A suitable protected amino acid :14a may be coupled to 70 using a coupling reagent known in the art such as e.g. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride or a combination of l-ethyl-3-(3-dimethy!aminofropyl)carbodiimid hydrochloride and 1-hydroxybenzotriazole or l-hydroxy-7-azabenzotriazole in an appropriate solve*it suc'i as e.g. DMF of dichloromethane to give 71. A deprotectior. carried out with a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed, , John Wiley and Sons, New York 1991) e.g. trifluoro acetic acid may furnish the amine 72. A suitable protected amino acid 3 7 may be coupled to 72 with a coupling reagent known in the art such as e.g. l-ethyl-3-(3-dimethylaroinopropyl) carbodiimid hydrochloride o:: a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride and 1-hydroxybenzotriazole or appropriate solvent such as e.g. DMF of dichloroirethane to give -after deprotection with a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, New York 1991) by reaction with e.g. trifluoro actic acid - 73. 73 may be saponified by a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, New York 1991) by reaction with e.g. potassium hydroxide or sodium hydroxide to give 74, which is a compound of formula I. r a The ether 48 may be reduced with a method known in the art e.g. lithium boronhydride, sodium borohydride, or diisobutylaluminum hydride to give an alcohol 75. The amino group iray be deprotected by a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed. , John Wiley and Sons, New York 1991)by reaction with e.g. hydrogen chloride in ethyl acetate or trifluoro acetic acid to give the amine 76. A suitable protected amino acid 34a may be coupled to 76 using a coupling reagent known in the art such as e.g. l-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride or a combination of l~ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride and .1-hydroxybenzotriazole or l-hydroxy-7-azabenzotriazole in an appropriate solvent such as e.g. DMF of dichlorom.3th.ane to give 77. A deprotection carried out with a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, New York 1991) e.g. trifluoro acetic acid or hydrogen chloride in ethyl acetate may furnish the amine 78. A suitable protected amino acid 37 may be coupled to 78 with a coupling reagent known in the art such as e.g. l-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride or a comb ination of 1-ethy1-3-(3-dimethy1aminopropyl)carbodiimid hydrochloride and 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole in an appropriate solvent such as e.g. DMF or dichloromethane to give - after deprotection with a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, New York 1991) by reaction with e.g. trifluoro actic acid - 79, which is a compound of. formula I. To enhance the yield, it may be feasible to subject the crude product to a saponification with reagents known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, Now York 1991) such as e.g. potassium hydroxide in methanol to cleave; esters, that may have formed during the amide coupling steps. Thioamides 81 can be incorporated by the same methods as in method K. They can be made from the corresponding amides 80 by the action, of Lawesson's reagent (LR). This methodology is described in S. Scheiby, B. s. Pedersen, S.O. Lawesson, Bull. Chim. Sac. Belg., 1978, 229-38. Tetrazole analogs 83 of amides 82 can be incorporated by much the same methods as in method K, They may be prepared by the action of triphenylphosphine, diethylazodicarboxylats andtrimethylsilylazide on amides like 82. This methodology is describee, in \J. V. Dunica, M. E. Pierce, J. B. Santella III, J. Org. Chem. 1991, 56, 2395-2400. Thiazoles 89 may be incorporated by the same methodology as in method F. 89 may be synthesized by acylation of the imine 84 using a strong base such as potassium tert butcxide or lithium diisopropylamide and an acylating reagent such as an -acid chloride 85. The resulting 3-keto-aminoacid 86 could be coupled to the dipeptide 88 by known methods such as the asymmetrical anhydride method using a reagent such as isobutylchlo.roformate as coupling agent. The dipeptide 88 could be cyclised by a nunber of methods e.g. with Lawessons reagent (LR) to give the desired thiazoles 89. This methodology has been described in T. D. Gordor, J. Singh, P. H. Hansen, B. A. Morgan, Tett. Lett., 1993, 1901-1904. Pharmaceutically acceptable acid addition salt;; of compounds of formula I include those prepared by reacting the compound with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, roaleic, phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesulfonic, trifluoracetic, sulfamic or fumaric acid. In another aspect, the present invention relates to a pharmaceutical composition comprising, as an active'ingredient, a compound of the general formula I or a pharmaceucically acceptable salt thereof together with a pharmaceutical ly acceptable carrier or diluent. Pharmaceutical compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences, ,1985. The compositions may appear in conventional f o;rms. for example capsules, tablets, aerosols, solutions, suspensions or topical applications. The pharmaceutical carrier or diluent employad may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alky! ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. If a solid carrier is used for oral administrate 01, "he preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier'will vary widely but wi]l usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. A typical tablet which may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) lOOmg Colloidal silicon dioxide (Aerosil) . i.5mg Cellulose, microcryst. (Avicel) 70mg Modified cellulose gum (Ac-Di-Sol) 7.5mg Magnesium stearate Coating: HPMC approx. 9mg *Mywacett 9-40 T approx. 0.9mg *Acylated monoglyceride used as plasticizer for film coating. For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes. Generally, the compounds of the present invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage. The dosage of the compounds according to this invantion is suitably 0.1-500 mg/day, e.g." from about 5 to about 50 mg, such as about 10 i mg per dose, when administered to patients, e.g. humans, as a drug. It has been demonstrated that compounds of the general formula I possess the ability to release endogenous growth hormone in vivo. The compounds may therefore be used in the treatment of conditions which require increased plasma growth hormone levels such as in growth hormone deficient humans or in elderly patients or livestock. Thus, in a particular aspect, the present invention relates to a pharmaceutical composition for stimulating the release of growth hormone from the pituitary, the composition comprising, as an active ingredient, a compound of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. In a further aspect, the present invention relates to 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 of the general formula I or a pharmaceutically acceptable salt thereof. In a still further aspect, the present invention relates to the use of a compound of the general formula I or a pharmaceuticalμ acceptable salt thereof for the preparation of a medicament for stimulating the release of growth hormone from the pituitary. To those skilled in the art, it is well known that the current and potential uses of growth hormone in humans are varied and multitudinous. Thus, compounds of formula I can beμ administered for purposes stimulating release of growth hormone from the pituitary and would then have similar effects or uses as growth hormone itself. The uses of growth hormone may be summarized as follows: stimulation of growth hormone release in the elderly; prevention of catabolic side effects'of "glucocorticoids, prevention and treatment of osteoporosis, stimulation of the immune system, acceleration of wound healing, accelerating bone fracture repair, treatment of growth retardation, treating renal failure or insufficiency ' resulting from growth retardation, treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness, treatment of obesity and growth retardation associated with obesity, treating growth retardation associated with the Prader-Willi syndrome and Turner's syndrome; accelerating the recovery and reducing hospitalization of burn patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cunning's syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients, treatment of osteochondrodysplasias, Noonan's syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation, treatment of pulmonary dysfunction and ventilator dependency, attenuation of protein catabolic responses after major surgery, reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; treatment of hyperinsulinemia including nesidioblastosis, adjuvant treatment for ovulation induction; to stimulate thymic development and prevent the age-related decline of thymic function, treatment of immunosuppressed patients, improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the frail elderly, stimulation of osteoblasts, bone remodelling and cartilage growth, stimulation of the immune system in companion animals and treatment of disorder of aging in companion animals, growth promoter in livestock and stimulation of wool growth in sheep. For the above indications the dosage will vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired. However, generally dosage levels between 0.0001 and 100 mg/kg body weight daily are administered to patients and animals to , obtain....effective release of endogenous growth hormone. Usually, dosage forms suitable for oral, nasal, pulmonal 9 or transdermal administration comprise from atout. 0.0001 mg to about 100 mg, preferably from about 0.001 mg to about 50 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent. The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form or, where appropriate, as a alkali metal or alkaline earth metal or lower alkylammonium salt. Such salt forms are believed to exhibit approximately the same order of activity as the free base forms. Optionally, the pharmaceutical composition of rhe invention may comprise a compound of formula I combined vith one or more compounds exhibiting a different activity, e.g., an antibiotic or 'other, pharmacologically active material. The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral, the oral route being preferred. Apart from the pharmaceutical use of the compounds of formula I, they may be useful in vitro tools for investigating the regulation of growth hormone release. Compounds of formula I may also be useful in vivo tools for evaluating the growth hormone releasing capability of the pituitary. For example, serum samples taken before and after administration of these compounds to humans cen be assayed for growth hormone. Comparison of the growth hbrmcne in each serum sample would directly determine the ability of the patients pituitary to release growth hormone. Compounds of formula I--may be administered to commercially * important animals to increase their rate and extent of growth, and to increase milk production. A further use of growth hormone secretagogue con-pounds of formula I is in combination with other secretagogues suc:h as GHRP (2 or 6), GHRH and its analogues, growth hormone and its analogues or 9 somatomedins including IGF-1 and IGF-2. Pharmacological Methods Compounds of formula I may be evaluated in vitro ::or their efficacy and potency to release growth hormone in rat pituitary primary cultures. The isolation of rat pituitary cells is a modificatian of 0. sartor et al., Endocrinology 116, 1985, pp. 952-957. Mal-.e albino Sprague-Dawley rats (250 +/- 25 grams) were purchased from M0llegaard, Lille Skensved, Denmark. The rats were housed in group cages (four animals/cage) and placed in rooms with 12 hour light cycle. The room temperature varied from 19-24'C and the humidity from 3 0 -60%. The rats were decapitated and the pituitaries dissected. The neurointermediate lobes were removed and the remaining tissue was immediately placed in icecold isolation buffar (Gey's medium (Gibco 041-04030) supplemented with 0.25% D-jlucose, 2% non¬essential amino acids (Gibco 043-01140) and 1% bovine serum albumine (BSA) (Sigma A-4503)). The tissue was cut into small pieces and transferred to isolation buffer supplemented with 3.8 mg/ml of trypsin (Worthington #3707 TRL-3; and 2 30 Jig/ml of DNase (Sigma D-4527). This mixture was incubated at 7 0 rotations/min for 35 min at 37°C in a 95/5% atmosphere of Oμ/CO,. The tissue was then washed three times in the above buffer. Using a standard pasteur pipet, the tissue was then aspirated into single cells. After dispersion, cells were filtered through a nylon filter (160 ,um) to remove undigested, tissue. The cell suspension was washed 3 times i with isolation buffer supplemented with trypsin inhibitor (0.75 mg/ml, Worthington #2829) and finally resuspanded in culture medium; DMEM (Gibco 041-01965) supplemented with 25 mM HEPES (Sigma H-3375), 4 mM glutamine (Gibco 043-05030H), 0.075% sodium bicarbonate (Sigma S-8875), 0.1% non-essential amino acid, 2.5% fetal calf serum (FCS, Gibco 011-06290), 3% horse serum (Gibco 034-06050) , 10% fresh rat serum, l nM T3 (Sigma T-2752) and 40 pq/l> dexamethasone (Sigma D-4902) pH 7.3, to a density of 2 x 105 cells/ml. The cells were seeded into raicrotiter plates (Nunc, Denmark), 200 jil/well, and cultured for 3 days at 37*C and 8% C02. Compound testing After cultaring, the cells were washed twice with stimulation buffer (Hanks Balanced Salt Solution (Gibco 041-04020) supplemented with 1% BSA (Sigma A-4503), 0.25% D-glucose (Sicma G-5250) and 25 mM HEPES (Sigma H-3375) pH 7.3) and preincubated for 1 hour at 37 °C. The buffer was exchanged with 90 ,ul stimulation buffer (37C). Ten jil test compound solution was added and the plates were incubated for 15 min at 37DC and 5% C02. The median was decanted and analyzed for GH content in an rGH SPA test system. . All compounds were tested in doses ranging from 10 pM to IOO M. A dose-response relation was constructed using the HilL equation (Fig P, Biosoft) . The efficacy (maximal GH released, Emax) was expressed in % of the E„ax of GHRP-6. The potency (EC50) was determined as the concentration inducing half maximal stimulation of the GH release. Compounds of formula I may be evaluated for their ' metabolic stability. Compounds were dissolved at a concentration of 1 ,ig/.'-il in water. 25 of this solution is added to 175 of the respective enzyme-solution (resulting in an enzyme:substrate ratio (w/w) of approximately 1:5). The solution is left at 37DC overnight. 10 of the various degradation solutions is analyzed against a corresponding zero-sample using flow injection electrospray mass spectrometry (ESMS) with selected ion monitoring of the molecular ion. If the signal has decreased more than 20?; compared to the zero-sample, the remainder of the solution is analyzed by HPLC and mass spectrometry in order to identify the extent and site(s) of degradation precisely. Several standard peptides (ACTH 4-10, Angiotensin 1-14 and Glucagon) have been included in the stability tests in order to verify the ability of the various solutions to degrade peptides. Standard peptides (angiotensin 1-14, ACTH 4-10 and glucagon) were purchased from Sigma, MO, USA) Enzymes (trypsin, chymotrypsin, elastase arainopeptidase M and carboxypeptidase Y and B) were all purchased from Boehringer : Mannheim GmbH (Mannheim, Germany) Pancreatic enzyme mix: trypsin, chymotrypsin and elastase in 100 mM ammoniumbicarbonate pH 8.0 (all concentrations 0.025 pg/fil) . Carboxypeptidase mix: carboxypeptidase 1 and B in 50 raM . ammoniumacetate pH 4.5 (all concentrations 0.025 μg//il) . Aminopeptidase M solution: aminopeptidase M (0.025g/jil) in 100 mM ammoniumbicarbonate pH 8.0 Mass spectrometric analysis was performed using two different mass spectrometers. A Sciex API III triple quadrupole LC-MS instrument (Sciex instruments, Thornhill, Ontario) equipped with an electrospray ion-source and a Bio-Ion 20 time-of-flight Plasma Desorption instrument (Bio-Ion Nordic AB, Uppsala, Sweden). Quantification of the compounds (before and after degradation) was done on the API III instrument using single ion monitoring of the molecular ion in question with flow injection of the analyte. The liquid flow (MeOH:water 1:1) of 100 min was controlled by an ABI 140B HPLC unit (Perkin-Elmer Applied Biosystems Divisions, Foster City, CA) . The instrument parameters were set to standard operation conditions, and SIM monitoring was performed using the most intense molecular ion (in most cases this corresponded to the doubly charged molecular ion). Identification of degradation products furthermore involved the use of plasma desorption mass spectrometry (PDMS) with sample application on nitrocellulose coated targets and standard instrumental settings. The accuracy of the hereby determined masses is generally better than 0.1%. Separation and isolation of degradation products was done using a HY-TACH C-18 reverse phase 4.6x105 mm HPLC column (Hewlett-Packard Company, Palo Alto, CA) with a standard acetonitril: TFA separation gradient. The HPLC system used was HP1090M (Hewlett-Packard Company, Palo Alto, CA). Any novel feature or combination of features described herein is considered essential to this invention. EXAMPLES: The process for preparing compounds of formula 1 and preparations containing them is further illustrated in the fallowing exampels, which however, are not to be construed as limiting. The structures of the compounds are confirmed by either elemental analysis (MA) nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts (5) are given in parts per million (ppm) and only selected peaks are given, mp is meLti.-.g point ,and is given in °c. Column chromatography was carried out using the technique described by W.C. still at al, J. ore. t:hem. 1978, 43, 2923-2925 on Merck silica gel 60 (Art 9385). Compounds used as starting materials are either known compounds or compounds which can readily be prepared by methods known per se. Abbrevations: TLC: thin layer chromatography DMSO: dimethylsulfoxide rain: minutes h: hours HPLC-Analysis: Method a. The RP-HPLC analysis was performed using UV detection at 254nm and a Lichrosorp RP-18 5uM column, which was eluted at j.ml/minute. Two solvent systems were used: Solvent system I: 0.1% Trifluoro acetic acid in acetonitrile. Solvent system II: 0.1% Trifluoroacetic acid in water. The column was equilibrated with a mixture composed of 20% of solvent system I and 80% of solvent system II. After injection of the sample a gradient of 20% to 80% of solvent system I in solvent system II was run over 30 minutes. The gradient was then extended to 100% of solvent system I over 5 minutes followed by isocratic elution with 100% of this system for 6 minutes. Method b. The RP-analysis was performed using UV detections at 214, 2 54, 276, and 301 nm on a 218T/P54 4.6 mm x 250 mm 5H C-18 ssilica column (The Seperations Group, Hesperia), which was eluted at: 1 mL/min at 42°C. The column was equilibrated with 5% acetoni t rile in a buffer consisting of 0.1 M ammonium sulfate, which was adjusted to pH 2.5 with 4M sulfuric acid, after injection the sample was eluted by a gradient of 5% to 60% acetonitrile in the same buffer during 50 rain. > r 1,3-Dicyclohexylcarbodiimide (10.lg, 49mmol) *as dissolved in dichloromethane (100ml) and added to a solution of (R) N-tert-butoxycarbonyl-phenylalanine (10. Og, 37.7mmol) :.n dichloromethane (250ml) at 0-5°C. The reaction mixture was heated to 20°C and stirred at this temperature for lh. Acetamide oxitne (3.63g, 49mmol) was suspended in pyridine (200inl) and N,N-dimethylformamide (40ml) and added to the reaction mixture. The dichloromethane was evaporated and the reaction mixture was heated to reflux temperature for 18h. The reaction mixture was cooled to 0°C and filtered. The eluent was diluted with er.hyl acetate (100ml) and washed with aqueous citric acid (10%, 3x50ml) and water (3x50ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and crystallized from ethyl acetate and heptane to give 5.48g of (R) [1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]carbamic acid tertbutyl ester. mp 94-98°C 'H-NMR (DMSO-d6) 8 1.30(s, 9H) ; 2.32(s, 3H) ; 4.90-5. 10(m, 1H) ; 7.15-7.30(m, 5H). HPLC: Rc= 26.7 min (Method a) (R) 1-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylamine hydrochloride: (R) [1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyljcarbamic acid tertbutyl ester (2.4g, 7.9mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate ('lOmi) . After 5h at 20°C the reaction mixture was concentrated in vacuo. The residue was crystallized from ethyl acetate to give 2.05g oi: (R) l-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylamine hydrochlor ide. U.'p. 144-148°C. H-NMR (DMSO-d6) 5 2.35(s, 3H) ; 3.21(dd, 1H) ; 3.49(dd, 1H) ; 5.05(dd, 1H); 7.13-7.35(m, 5H). HPLC: Rt= 9.2 min (Method a) N-(3-Dimethylaminopropyl) -N'-ethylcarbodiimidehvdrcchloride (6.3g, 32.9mmol) and l-hydroxybenzotriazole monohydrate- (5.0g, 32.9mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2-naphthyl)-alanine (10.4g, 32.9mmol) in N,N-dimethylformamide (140ml). After lh at 20'c a mixture of 1-(3-raethyl-[l,2,4]oxadiazole-5-yl) -2-phenylethylaminehydrochloride (5.6g, 23.5 nunol) and triethylamine (2.37g, 23.5mmol) in N,N-dimethylformamide (100ml) were added. After 18h at 20°c the reaction mixture was poured on water (1.4L) and extracted several times with ethyl acetate (total 1.4L) . The collected organic phases we're washed with aqueous citric acid (1.0%, 200ml), a siaturated solution of sodium hydrogencarbonate (200ml) and water (3x200ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and crystallized from ethyl acetate and heptane to give 9.45g of { ( 1R) -1-{ (1R) -l-(3-methyl-[l,2 ,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl}-2-(2-naphthyl)ethyl}carbaroic acid tertbutyl ester. m.p. 148-150°C. H-NMR (DMS0-d6) 5 1.25(s, 9H) ; 2.29(s, 3H) ; 4.25—1.35(m, 1H) ; 5.25-5.35 (s, 1H); 7.15-7.85 (m, 12H). HPLC: Rt= 29.6 min (Method a) Calculated for Cj9H3jN404: C, 69.58; H, 6.44; N, 11.19%; found: C, 69,40; H, 6.65; N, 10.93%. 7 {(lR)-l-{(lR)-l-(3-Methyl-[l,2,4Joxadiazol-5-yl)-2-phenylethylcarbamoyl}-2-(2-naphthyl) ethyl }carbairic acid tertbutyl ester (4.5g, 8.99mmol) was suspended in ethyl acetate (50ml) and a saturated mixture of hydrogen chloride in ethyl acetate (45ml) was added. After 3h at 20°c/ the reaction mixture was filtered to give 3.17g of (2R)-2-amino-N-[ (lR)-l-(3-jnethyl-[l,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthyl)propionamide hydrochloride. mp 197-199°C. lH-NMR (DMS0-ds) 8 2.28(s, 3H) ; 3.15-3.35(111, 4H) ? 4.15(t, 1H) ; ' 5.35(q, 1H); 7.20-7.90(m, 12H). HPLC: Rt= 18.5 rain (Method a) Calculated for C2,H21N«0;,HC1: C, 65.97; H, 5.77; N, 12.82%; found: C, 66,20; H, 5.90; N, 12.57%. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.42g, 2.ISmmol) and 1-hydroxybenzotriazole monohydrate (0.33g, 2.18mmol) were added to a solution of (R)-N-tertbutoxycarbonyl-3-piperidine carboxylic acid (0.50g, 2.18mmcl) in N,N-dimethylforraamide (7ml). After 30 min at ;.o°C a mixture of (2R)-2-amino-N-[(lR)-l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthyl)propionamide hydrochloride (0.68g, 1.56mmol) and triethylamine (0.i6g, i.56mmol) in N,N-dimethylformamide (8ml) were added. After 18h at 2 0°C the reaction mixture was poured on ice water (90ml) and extracted several times with ethyl acetate (total 90ml). The organic phases were collected and washed with aqueous citric acid (10%, 15ml), a saturated solution of sodium hydrogen carbonate (3xl5ml) and water (3xl5mJ.). After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (90g) using ethyl acetate and heptane (3:2) as eluent to give 0.83q o-* (3R) -3-{ (1R) -1 - [ (1R) -1- (3-methyl-[ 1,2,4] oxadiazol-5-yl) -2-phenyl ethyl carbamoyl ] -2-(2-naphthyl)ethylcarbamoyl}piperidine-1-carboxylicacidtertbutyl ester. lH-HMR (DMSO-d6) 5 1.37(s, 9H) ; 2.30(s, 3H) ; 4.60-4.70(m, 1H) ; 5.25-5.35(m, 1H) ; 7.15-7.85(m, 12H). HPLC: Rt= 31.6 min (Method a) 3-{(lR)-[(lR)-l-(3-Methyl-[l,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl]-2- (2-naphthyl) ethylcarbamoyl}piperidine-1-carboxylic acid tertbutyl ester (0.80g, l.31mmol) was dissolved in ethyl acetate (20ml) and a saturated solution of hydrogen chloride in ethyl acetate (20ml) was added. After 2h at 20°C the reaction mixture was concentrated in vacuo. The compound was crystallized from a mixture of methanol and ethyl acetate to give 0.66g of the title compound, m.p. 198-200°C lH-NMR (DMSO-d6) 8 1.10-1.80(m, 4H); 2.30(s, 3H); 4.60-4.70(m, 1H); 5.25-5.35(m, 1H); 7.20-7.9 0(m, 12H). HPLC: Rt= 20.9 min (Method a) Calculated for C30H33N5O5,HCl: C, 65.74; H, 6.25; N, 12.78%; found: C, 65,57; H, 6.35; N, 12.46%. F . 2-Amino-2-methylpropan-l-ol (10.0 g, 112 mmol) was dissolved in tetrahydrofuran (100 ml). A IN solution of sodium hydroxide in water (112 ml, 112 mmol) was added. A solution of di-tert-butyl dicarbonate (29.3 g, 134 mmol) in tetrahydrofuran {100 ml) was added over a period of 15 min. The solution was stirred at 20°C for 16 h. Water (100 ml) was added. The phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 150 ml) and the combined organic phases were dried (magnesium sulfate). The solvent was removed in vacuo and the crude product was chromatographed on silica gel (180 g) with ethyl acetate/heptane 1:1 as eluent to give DMSO (12.4 ml, 174.4 mmol) was dissolved in diehloromethane (240 ml)and the solution was cooled to -73 °C. Oxalyl chloride (7.6 nil, 87 mmol) was added dropwise. The solution was st:_rr«d at -78 °C for 15 min. A solution of N-2-hydroxy-l,l-dimethylethyl carbamic acid tert-butyl ester in diehloromethane (30 ml) was added dropwise. The solution was stirred for 30 min at -78 °C. Triethylamine (55.23 ml, 396.3 mmol) was added slowly. After 5 min at -78 °c the solution was allowed to warm to 20°C, diluted with diehloromethane (300 ml) and washed with IN hydrochloric acid (3 x 200 ml) . The combined aqueous phases were extracted with diehloromethane (2 x 200 ml). The combined organic layers were washed with a saturated solution of sodium hydrogencarbonate (2 x 200 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the crude product was chromatographed on silica gel (180 g) with ethyl acetate/heptane 1:4 as eluent to give 13.4gj of 2-tert-> butoxycarbonylamino-2-methylpropanal. mp 84 - 85°C 'H-NMR (CDClj) 5 1.35 (s, 6 H); 1,45 (s, 9 H); 5.00 (br, 1H); 9.45 (s, 1 H). i f i Triethyl phosphonoacetate (9.6ml, 48mmol) was added slowly to a suspension of pottasium tert-butoxide (5. 39g, 4Smmol) in tetrahydrofuran (14 0ml). After 30min at 20°c 2-tert-butoxycarbonylamino-2-methylpopanal (5.0g, 26mmo!-) was added. After 2.5h at 20°C IN hydrochloric acid (80ml) was added slowly. The mixture was extracted with ethyl acetate (120ml, 2 :t 50ml) and the combined organic layers were washed with a saturated solution of sodium hydrogencarbonate (100ml) and dried (mscgnesium sulfate) . The solvent was removed in vacuo and the crude product was chromatographed on silica gel (lOOg) with ethyl acetate/heptane 1:4 as eluent to give 5.7g of (2E)-4-tert-butoxycarbonylamino-4- methylpent-2-enoic acid ethyl ester, mp 40 - 41°C (Heptane) H-NMR (CDC13) : 8 1.29 (t, 3 H) ; 1.41 (s, 6 H) ; 1.43 (s, 9H) ; 4.19 (q, 2 H) ; 4.65 (br, 1H) ; 5.84 (d, J = 15.9 Hz, 3 H) ; 6.99 (d, J = 16.0 Hz, 1 H). (2E)-4-tert-Butoxycarbonylamino-4-methylpent-2-enoic acid ethyl ester (5.0g, 19.4mmol) was dissolved in dioxane t50nil). A solution of lithium hydroxide (0.61 g, 25.3 mmol) in water (25 ml) was added. The solution was stirred for 16 h at 20°C. Ethyl acetate (75 ml) and water (20 ml) were added. The phases were seperated, and the aqueous phase was extracted with ethyl acetate (2 0 ml). The combined organic phases were extracted with IN sodium hydroxide solution (30 ml) . The combined aqueous phases wesre acidified with IN sodium hydrogensulfate solution until pH = 2. The aqueous phase was extracted with ethyl acetate (2 x 50 ml). Thu combined organic phases were dried (magnesium sulfate) and the solvent removed in vacuo. The crude (2E)-4-tert-butoxycarbonylamino-4-methylpent-2-enoic acid was used for further syntheses. :H-NMR (CDC13) : 8 1.39 (s, 6 H); 1.43 (S, 9 H); 4.79 (br, 1 HJ ; 5.75 (d, 1 H); 7.12 (d, 1 H); 9.50 - 11.50 (br, 1 H). N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.42g, 2.18mmol) and 1-hydroxybenzotriazole monohydrate (0.33g, 2.18mmol) were added to a solution of 4-tertbutoxycarbonylamino-4- methylpent-2-enoic acid (0.50g, 2.i8mmol) in N,N-dimethylformamide (7ml). After 30 min at 20°C a mixture of (2R)-2-amino-N-[(1R)-1-(3- methyl-[ 1, 2 , 4]oxadiazol-5-yl) -2-phenylethyl]-3-(2- « 1 naphthyl)propionaraide hydrochloride (0.68g, 1.56mmol) and triethylamine (0.16g, 1.56mmol) in N,N-dimethylformamide (8ml) were added. After 18h at 20°C the reaction mixture was poured on ice water (90ml) and extracted several times with ethyl acetate (total 90ml). The organic phases were collected and washed with aqueous citric acid (10%, 15ml), a saturated solution of sodium hydrogencarbonate (3x15ml) and water (3x15m:). After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (95g) using ethyl acetate and heptane (1:1) as eluent to give 0.90g of {1,l-dimethyl-S-C (1R) -l-( (1R) -1- (3-methyl-[l, 2,4 ]oxadiazol-5-yl) -2-phenylethylcarbamoyl)-2-(2-naphthyl)-eth.ylcarbaraoyl]allyl}carbamic acid tertbutyl ester. H-NMR (DMS0-d6) 5 1.22(s, 3H) ; 2.28(s, 3H) ; 4.70-1.80 (m, 1H) ; 5.72-5.82(m, 1H); 5.89(d, 1H); 6.72(d, 1H); 7.15-7.85(m, 12H). HPLC: Rt= 30.3 min (Method a) (1, l-Dimethyl-3- [ (1R) -1-((1R) -l-(3-methyl-[l,2,4] oxadiazdl-5-yl) -2-phenylethylcarbamoyl) -2- (2-naphthyl)ethylcarbamoyl]-allyl}carbamic acid tertbutyl ester (0.90g, 1.47mmol) was dissolved in ethyl acetate (10ml) and a saturated solution of hydrogen chloride in ethyl acetate* (20ml) was added. After 3h at 20°C the reaction mixture was concentrated in vacuo to give 0.70g of the title compound. mp I61-167°c H-NMR (DMSO-d6) S 1.32(s, 3H) ; 1.34(s, 3H) ; 2.28;s, 3H) ; 4.75- 4.83(ra, 1H) ; 5.23-5.33(tn, 1H) ; 6.12(d, 1H) ; 6. 61(d, 1H) ; 7.15-7.88(m, 12H). HPLC: Rt= 20.6 min (Method a) Calculated for C3DH33N505,HC1,0.75H20: C, 64.16; H, 6.45; N, 12.47%; found: C, 64,42; H, 6.43; N, 12.03%. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.92g, 4.82mmol) and 1-hydroxybenzotriazole monohydrate (0.74g, 4.83mmol) were added to a solution of N-tert.butoxycarbonyl-3-arainobenzoic acid (1.2lg, 4.82mmol) in H,N-dimeithylfoririamide (15ml). After lh at 20°c a mixture of (2R)-2-andno-N-C(1R)-l-(3- methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3 - { 2- naphthyl)propionamide hydrochloride (1.50g, 3.43mmol) and triethylamine (0.35g, 3. 46mmol) in N,N-dimethylformamide (15ml) were added. After 18h at 2Q°C the reaction mixture was poured on ice water (180ml) and extracted several times with dichloromethane (total 180ml). The organic phases were collected and washed with aqueous citric acid (10%, 25ml), a saturated solution of sodium hydrogencarbonate (3x25ml) and water (3x25ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and 1.80g of (3-{(lR)-l-[(lR)-l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2- phenylethylcarbamoyl]-2-(2-naphthyl)ethylcarbamoyl}- benzyl)carbamic acid tertbutyl ester was isolated from ethyl acetate. mp = 176-178°C lH-NMR (DMS0-d6) 6 1.39(S, 9H) ; 2.30(s, 3H); 4.70-4.80(m, 1H); 5.29- "5.39(m, 1H) ; 7.15-7,85(m, 17H) . HPLC: Rt= 31.4 min (Method a) Calculated for Cj,H39N505: C, 70.12; H, 6.20; N, 11.05%; found: C, 70.20; H, 6.34; N, 10.86%. (3-{(lR)-l-[(lR)-l-(3-Methyl-[l,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl]-2-(2-naphthyl)ethylcarbamoyl)-benzyl)carbamic acid tertbutyl ester (5.5lg, 2.38mmol) was suspended in ethyl acetate (20ml) and a saturated solution of hydrogen chloride in ethyl acetate (30ml) was added. After 4h at 20°C the reaction mixture was concentrated in vacuo and crystallized from ethyl acetate to give l.26g of the title compound, mp 240-241°C H-NMR (DMS0-d6) 8 2.31(s, 3H) ; 4.03(s, 2H) ; 4 .75- HPLC: Rt= 24.6 min (Method a) N-(3-Dimethylaminopropyl)-N1-ethylcarbodiimide hydrochloride (0.92g, 4.82nunol) and 1-hydroxybenzotriazole monohydrate (0.74g, 4.83mmol) were added to a solution of N-tertbutoxycarbonyl-4- piper idine carboxylic acid (1.10g, 4.80mmol) in N,N- dimethylformamide (15ml) . After 30 rain at 20°C a mixture of (2R)-2- amino-N-[ (1R) -1-(3-methyl-[ 1,2,4] oxadiazol-5-yl) -2-phenylethylJ -3- (2-naphthyl)propionamide hydrochloride (1.50g, 3.43mmol) and triethylamine (0.35g, 3.46mraol) in N,N- dimethylformamide (15ml) were added. After 18h at 20°C the reaction mixture was poured on ice water (180ml) and extracted several times with ethyl acetate (total 180ml). The organic phases were collected and washed with aqueous citric acid (10%, 25ml), a saturated solution of sodium hydrogencarbonate (3x25ml) and water (3x25ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and crystallized from ethyl acetate to give 1.84g of 4-{(lR)- 1- [ (1R) -1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl]- 2-(2- naphthyl)ethylcarbamoyl)piperidine-1-carboxylie acid tertbutyl ester. mp 152-155DC H-NMR (DMS0-d6) 6 1.35(8, 9H) ; 2.29(s, 3H) ; 4.60-4.70(m, 1H) ; 5.25- 5.35(m, 1H); 7.15-7.85(m, 12H). HPLC: Rt= 31.3 min (Method a) calculated for CJSHHNSOS: C, 68.72; H, 6.76; N, 11.45%; found: C, 68.65; H, 6.95; N, 11.34%. 4-((lR)-l-[(lR)-l-(3-Methyl-[l,2,4]oxadiazol-5-yl)-2- phenylethylcarbamoyl ] -2- (2-naphthyl) ethylcarbamoyl} piperidine-i- carboxylic acid tertbutyl ester (l.57g, 2.57mmoi;. was dissolved in ethyl acetate (20ml) and a saturated solution of hydrogen chloride in ethyl acetate (30ml) was added. After 4h at 20°C the reaction mixture was filtered affording 1.34g of the title compound. mp 238-241°C 'H-NMR (DMSO-d6) 5 2.30(s, 3H); 4.60-4.70(m, 1H); 5.25-5.35(m, 1H); 7.20-7.85(m, 12H). HPLC: Rc= 23.7 min (Method UJ Calculated for C30H33N5O5,HCl: C, 64.74; H, 6.25; N, 12.78%; found: C, 65,91; H, 6.39; N, 12.42%. Example 5: 5-( (lR)-l-[ (2R)-2-(3-AminoBiethylbenzoylamino)-3-(2-naphthyl)propionylamino]-2-phenylethyl}-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester, triflouroacetic acid: 1,3-Dicyclohexylcarbodiimide (2.lg, lOmmol) was dissolved in dichloromethane (25ml) and added to a solution of (R) N-tert-butoxycarbonylphenylalanine (2.2g, lOmmol) in dichloromethane (50ml) at 0-5°C. The reaction mixture was heated to 20cc and stirred at this temperature for 30 min. Ethyl 2-amino-2-(hydroxyimino)acetate (1.3g, lOmmol) was dissolved in pyridine (50ml) and added to the reaction mixture. The dichloromethane was evaporated and the reaction mixture was heated to reflux temperature for 18h. The reaction mixture was cooled to 0°C and filtered. The filtrate was diluted with ethyl acetate (25ml) and washed with aqueous citric acid (10%, 3x15ml) and water (3x15ml). After drying (magnesium sulfate) the solution wa.s concentrated in vacuo and purified by flash chromatography on silica gel (90g) using ethyl acetate and heptane (1:1) to give 1.68g of (R) 5-(l-tert-butoxycarbonylamino-2-phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester, mp 72-76°C H-NMR (DMSO-d6) 5 1.30(S, 9H) ; 1.32(t, 3H) ; 3.10-3.30(m, 2H) ; 4.41(g, 2H); 5.10(g, 1H); 7.20-7.50fm, 5H). f (R) 5-(l-Amino-2-phenylethyl)-[1,2,4}oxadiazole-3-carboxylic acid ethyl ester hydrochloride: (R) 5-(l-tert-Butoxycarbonylamino-2-phenylethyl)- [1,2,4]oxadiazole-3-carboxylic acid ethyl ester (1.5g, 4.2mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (4 0ml) . After 5h at 2 0°C the. reaction mixture was concentrated in vacuo to give 1. 2g of (R) 5- (l-amino-2- phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride. lH-NMR (DMSO-d6) 5 1.32(t, 3H) ; 4.41(q, 2H) , 5.20(dd, 1H) ; 7.10- 7,30(m, 5H). ! 5-[(lR)-l-{(2R)-2-tert-Butoxycarbonylamino-3- naphthyl)propionylamino}-2-phenylethyl]-[1, 2,4]oxadiazole-3- carboxylic acid ethyl ester: N-(3-Dimethylaminopropyl)-N•-ethylcarbodiimide hydrochloride (0.77g, 4. 03mmol) and 1-hydroxybenzotriazole mcnohydrate (o.62g, 32.9mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2-naphthyl) alanine (1.27g, 4.03mmol) in N,N-dimethylformamide (20ml). After 30min at 20°C a solution of (R) ethyl 5-(l-amino-2-phenylethyl) -[1,2,4] oxadiazole-3-carboxylate hydrochloride (l. 20g, 4.03mmol) in N,N-dimethylformamide (15ml) was added. The reaction mixture was heated to 50°C for 3h, poured on water (400ml) and extracted several times with dichloromethane (total 35"0ml) . The collected organic phases were washed with a saturated solution of sodium hydrogencarbonate (2x50ml)and dried (magnesium sulfate). The solution was concentrated in vacuo and and purified by flash chromatography on silica gel (40g) using ethyl acetate and heptane (3:7) to give o.4lg of 5-[(1R)-l-{(2R)-2-tert-butoxycarbonylamino-3-(2-naphthyl)propionylamino}-2-phenylethyl]-[l,.2,4]o_xadiazole-3-carboxylic acid ethyl ester. naphthyl)propionylamino}-2-phenylethyl]-[1,2,4]cxadiazole-3- carboxy1ic acid ethyl ester (0.4lg, 0.7mmol) was suspended in a saturated mixture of hydrogen chloride in ethyl acetate (10ml). After 18h at 20°C, the reaction mixture was filtered to give 0.39g of 5-[(lR)-l-{(2R)-2-amino-3-(2- naphthy1)propionylamino}-2-phenylethyl]-[l,2,4]cxadiazole-3- carboxylic acid ethyl ester hydrochloride. lH-MMR (DMSO-dj) 5 1.32(t, 3H); 4.10-4.20(m, 1H); 4.40-4.45(m, 2H); 5.40-5.50(m, 1H). N-(3-Dimethylaminopropyl)-N1-ethylcarbodiimide hydrochloride (0.23g, 1.20mmol) and 1-hydroxybenzotriazole monohydrate (0.18g, 1.2mmol) were added to a solution of 3-(tert-butoxycarbonylaminomethy1)benzoic acid (0.30g, 1.2mmol) in N,N-ilimethylformamide (8ml). After lh at 20CC a mixture of 5-[(lR)-l-{ (2R) -2-amino-3- (2-naphthyl)propionylamino}-2-phenylethyl]-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride (0.39g, 0.79mmol) and triethylamine (0.08g, 0.79mmol) in N,N-dimethylformainide (2ml) were added. After 18h at 20"C the reaction mixture was poured on water (70ml) and extracted several times with ethyl acetate (total 80ml). The organic phases were collected and washed with aqueous citric acid (10%, 15ml), a saturated solution of sodium hydrogencarbonate (10ml) and water (3x10ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and crystallized from a mixture of ethyl aceta-ce and heptane to give 0 . 4 4 g of 5-[(lR)-l-{ ( 2R) -2- ( (3-tert-butoxycarbonylaminomethyl)benzoylamino)-3-(2-naphthyl) propionylamino} -2 -phenyl ethyl] -[l,2,4]oxadiazole—3-carboxylic acid ethyl ester, mp = 170-176°C rH-NMR (DMS0-d6) S 1.30-1.40 (m, 12H) ; 4.42(q, 2H) , 4.80-4.90 (m, 1H); 5.40-5.50(m, 1H). 5-[(lR)-l-{(2R)-2-((3-tert-Butoxycarbonyl- aminomethyl)benzoylamino)-3-(2-naphthyl)propionylamino)-2-phenylethyl]-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester (0.40g, 0.58mmol) was suspended in a saturated soLutipn of hydrogen chloride in ethyl acetate (10ml). After 5h at 20°C the reaction mixture was concentrated in vacuo. The compound was purified by flash chromatography with silica gel (40y) using a mixture of dichloromethane and 10% ammonia in ethanol (9:1) as eluent to give 0.14g of the title compound. The compound was further purified by semipreparative HPLC in three runs on a 25mm x 25D mm column packed with l\x C-18 silica which was preequilibrated witi 30% acetonitrile in a 0.5M solution of ammonium sulfate, which was adjusted to pH 2.5 with sulfuric acid (4M) . The column was elut ; 'H-NMR (DMS0-d6) 8 1.35(t, 3H) ; 4.40(q, 2H) ,* 4.85-4.95(m, 1H) ; 5.35-5.45 HPLC: Rt= 28.4 min (method: 0-90% 0.1% TFA in acetonitrile over 50 . min) Calculated for CHHJJNJOS.TFA, 1. 5H20: C, 59.01; H, 5.09; N, 9.56%; found: C,' 68,89; H, 5.10; N, 9.74%. suspension of (R)-3-(2-naphthyl)alanine (5.0 g) in methanol (50ml) at 35°C. After addition the mixture was heated at 60°c for 1 h, cooled and the solvent removed in vacuo. Water (75 ml) and ethyl acetate (125 ml) were added and pH was adjusted to 8.5 with 'sodium carbonate. The organic phase was separated and dried (magnesium sulfate) to afford 4.86 g of (R)-3-(2-naphthyl)alanine methyl ester. 3-(tert-Butoxycarbonylaminomethyl)benzoic acid (5.32 g; 21.2 mmol) was dissolved in N,N-dimethylformamide (20 ml) . l-Ethyl-3-(3-dimethylaminopropyl) -carbodiimide hydrochloride (EE1AC) (4.06 g, 21.2 mmol) was added and the mixture was stirred for 20 min. A solution of (R)-3-(2-naphthyl)alanine methyl ester (4.85 g, 21.2 mmol) in N,N-dimethylformamide (20 ml) and triethylamine (4.4 ml) was added and stirring was continued for 18h. The mixture was diluted with ethyl acetate (400 ml) and the organic phase was washed with water (200 ml) , 10% aqueous sodium hydrogensulfate (50 ml), 5 % aqueous sodium hydrogencarbonate (100 ml) and water (100 ml) . The phases were separated and the organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to afford 8.9g of (R)-2-(3-(tert-butoxycarbonylaminomethyl)benzoylaraino)-3-(2-naphthyl)propionic acid methyl ester. H-NMR (CDC13) 8 1.44 (s, 9H) ; 3.40 (t, 2H) ; 3.76 (s, 3H) 4.28 (d, 2H); 5.00 (s(br), 1H); 5.18 (q, 1H); 6.75 (d, 1H); 7.20-7.80 (m, 11H) (R) -2-(3-(tert-Butoxycarbonylaminomethyl)ben2oylamino)-3-(2-naphthyl)propionic acid methyl ester (S. 8 g, 13.1 mmol) was dissolved in methanol (100 ml) and lithium hydro::id« (0.55 g, 22.2 mmol) was added. After 2 h dichloromethane (200 ml), water (200 ml) and 3 M sodium hydrogen sulfate (50 ml) were aided. The organic phase was separated and washed with water (100 ml)'. The organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to yield 7.9g of (R)-2-(3-(tert-butoxycarbonylaminomethyl)benzoylamino)-3-(2-naphthyl)propionic acid. 1,3-Dicyclohexylcarbodiimide (1.88g, 9.lmmol) was dissolved in dichloromethane (25ml J and added to a solution of (RJ N-tert-butoxycarbonyl-(2-naphthyl)alanine (3.0g, 9.lmmol) in dichloromethane (50ml) at 0-5°C. The reaction mixture was heated to 20°C and stirred at this temperature for 30 min. Ethyl 2-amino-2-(hydroxyimino)acetate (1.2g, 9.lmmol) was dissolved in pyridine (50ml) and added to the reaction mixture. The dichloromethane was evaporated and the reaction mixture was heated to reflux temperature for 18h. The reaction mixture was cooled to 0°C and filtered. The eluent was concentrated in vacuo, redisolved in ethyl acetate (25ml) and washed with aqueous citric acid (10%, 3x15ml) and water (3x15ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (90g) using ethyl acetate and heptane (1:4) to give l.-59g of (R) 5- (1-(N-methyl-tert- (R) 5-(1-(N-Methyl-tert-butoxycarbonylamino)-2-(2-naphthyl)-ethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester (0.77g, l.Smmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (15ml) . After 5h at 20°C the reeiction mixture was concentrated in vacuo to give 0.72g of (R) 5-(l-3nethylamino-2-(2-naphthyl) ethyl) - [ 1,2,4 ] oxadiazole-3-carboxylic acid etjhyl ester hydrochloride. 'H-NMR (DMS0-d6) 8 1.32(t, 3H); 2.71(s, 3H); 4.40(q, 2H); 5.45(q, 1H) ; 7.30-7.90(111, 7H) . HPLC: Rc= 19.7 min (Method a) (0.51g, 2.6mmol) and l-hydroxy-7-azabenzotriazols (0.36g, 2.6mmol) were added to a solution of 2-(3-(tert-butoxycarbonylaminomethyl)benzoylamino)-3-(2-naphthyl)propionic acid (1.18g, 2.6mmol) in N,N-dimethylformamide (15ml). After 30min at 20°C a mixture of (R) 5-(l-methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride (0.69g, 1.9mmol) and triethylamine (0.19g, 1.9mmol) in N,N-dimethylformamide (10ml) were added. After 18h at 20°C the reaction mixture was poured on water (175ml) and extracted several times with ethyl acetate (total 175ml). The collected organic phases were washed with aqueous citric acid (10%, 20ml), a saturated solution of sodium hydrogencarbonate (2 5ml), water (3 x2 5ml) and dried (magnesium sulfate). The solution was concentrated in vacuo and purified by flash chromatography on silica gel (80g) using ethyl acetate and heptane (2:3) to give 0. 8g of af 1:1 mixture of two diastereoisomers of 5-{l-[2-(3-(tert-butoxycarbonylamino-methyl)benzoylamino)-3-(2-naphthyl)propionyl-N-methylamino]-2-(2-naphthyl)ethyl)-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester. 'H-NMR (DMSO-d6) 6 1.30-1.42(m, 12H), 4.40-4.48(m, 2H) ; 4.90-5.20(m, 1H); 6.00-6.10(m,-lH). 1 HPLC: diasteroisomer I ; Rt= 25.6 min (Method a) diastereoisomer II; Rt= 30.81min (Ifethod a) 5-{ l-[2- (3- (tert-Butoxycarbonylaminomethyl) benzoyl amino) -3- (2-naphthyl)propionyl-N-methylamino]-2--(2-naphthyl)ethyl}-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester (0.34g, 0.5mmol) was suspended in a mixture of trifluoroacetic acid and dichloromethane (1:1, 2 0ml). After lOmin at 2 0°C, the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (40g) using dichloromethane and a 10% mixture of ammonia in ethanol (85:15) to give 0.14g of two diastereoisroers of the title compound. *H-NMR (DMSO-d6) 5 1.35-1.50 (m, 3H) ; 4.40-4.50(m, 2H) ; 5.00-5.20(111, 1H); 5.98-6.13(m, 1H). HPLC: diasteroisomer I ; Rt= 26.9 min (Method a) diastereoisomer II; Rt= 37.7min (Method a) Calculated for c39HJ7N505: C, 71.43; H, 5.69; N, 10.68%; found: C, 71.05; H, 5.54; N, 10.41%. Example 7: 5-{(lR)-l-[(2R)-2-(piperidine-4-carbonylamino)-3-(2-naphthyl)propionyl-N-methylamino]-2-(2-naphthyl)ethyl}-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.54g, 2.8mmol) and l-hydroxy-7-azabenzotriazolei (0.38g, 2.8mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2-naphthyl)alanine (0.88g, 2.8mmol) in N,N-dimethylformamide (15ml). After 30min at 20°C a solution of (R) 5-(l-methylamino-2-(2-naphthylJethyl) -[1, 2,4]oxadiazole-3- carboxylic acid ethyl ester hydrochloride (0.7g, 2.0mmol) in N,N- dimethylformamide (15ml) was added. The reaction mixture was heated to 50°C for 3h, poured on water (180ml) and extracted several times with ethyl acetate (total 200ml). The collected organic phases were washed with aqueous citric acid (10%, 25ml), a saturated solution of sodium hydrogencarbonate (3 0ml) , water (3x30m'l) and dried (magnesium sulfate). The solution was concentrated in vacuo to give 1.3g of 5-{(1R)-l-[(2R)-2-tert-butoxycarbonylamino-3-(2- naphthyl)propionyl-N-methylamino]-2-(2-naphthyl)ethyl}-[1/2,4]oaxdiazole-3-carboxylic acid ethyl ester. lH-NMR (DMS0-d6) 5 1.00-1.40(m, 12H) ; 4.45(q, 2H) ; 5.90-6.20 (m, 1H) . 5-{(lR)-l-[(2R)-2-tert-butoxycarbonylamina-3-(2-naphthyl)-propiony1-N-methylamino]-2-(2-naphthy1)ethyl}- [l,2,4]oaxdiazole-3-carboxylic acid ethyl ester (1.3g, 2.0nuuol) was suspended in a saturated mixture of trifluotoacetic acid and dichlororaethane (1:1, 50ml). After lOmin at 20°C, ' the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (lOOg) using dichloromethane and a mixture of 10% ammonia in ethanol (95:5) as eluent to give 0.9g of 5-{ (1R) -l-[ (2R) -2-amino-3-(2-naphthyl)propionyl--N-methylaminoj-2-(2-naphthyl)ethyl}-[l,2,4]oaxdiazole-3-carboxylic acid ethyl ester. H-NMR (DMS0-d6) 8 1.35(i, 3H) ; 4.45(q, 2H) ; 5.88-6.20(m, 1H) . N-(3-Dimethylaminopropyl)-N1-ethylcarbodiimide hydrochloride (0.40g, 2.1mmol) and l-hydroxybenzotriazole monohydrate (0.32g, 2. lmmol) were added to a solution of N-tert--butoxycarbonyl-4-piperidinecarboxylic acid (0.48g, 2.lmmol) in N,N--dimeth.ylformamide (10ml) . After lhat 20°C a-solution of 5-{(lR)-l-[ .'2RJ -2-amino-3-(2- naphthyl)propionyl)-N-methy1amino]-2-(2-naphthyl)ethyl}- [l,2,4]oxadiazole-3-carboxylic acid ethyl ester (0.73g, l,4mmol) in N,N-dimethylformamide (2ml) was added. After 18h at 20°C the reaction mixture was poured on water (120ml) and extracted several times with ethyl acetate (total 140ml). The organic phases were collected and washed with aqueous citric acid (10%, 15ml), a saturated solution of sodium hydrogencarbonate (15ail) and water (3x20ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (40g) using ethyl acetate and heptane (1:1) to give 0.9g of 4-((1R)-1-{[(1R)-1-(3-ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-2- (2- naphthyl)ethyl]-N-methylcarbamoyl} -2-(2- naphthyl)ethylcarbamoyl)piperidine-1-carboxylie acid tert-butyl > ester. H-NMR (DMSO-d6) 6 1.30-1.45(m, 9H) ; 6.00-6.15(m, 1H) . HPLC: Rt= 3 3.9 min (Method a) 4-((lR)-l-{[(lR)-l-(3-Ethoxycarbonyl-[l,2,4]oxadiazol-5-yl)-2-(2- naphthyl)ethyl]-N-methylcarbamoyl}-2-(2- ( naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (0.21g, 0.29mmol) was dissolved in a mixture trifluoroacetic acid and dichloromethane (1:1, 12ml) . After 10 min at 20°c the reaction mixture was concentrated in vacuo. The compound was purified by flash chromatography with silica gel (40g) using a mixture of dichloromethane and 10% ammonia in ethanol (4:1) as eluent to give 0.12g of the title compound. lH-NMR (DMSO-ds) 5 1.30-1.40(m, 3H) ; 2.80-2.90(2s, 3H), 4.40-4.50(m, 2H); 5.98-6.20(m, 1H). HPLC; Rt= 25.0 min (Method a) Calculated for C31H39Nj05, H20: C, 68.19; H, 6.34x N, 10,75%; found: C, 68,23; H, 6.25; N, 10.60%. Example 8 : Piperidine-4-carboxylic acid (1-{[1-(3-carbamoyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2- (2-naphthyl)ethyl)amide: > 4-((1R)-X-{[(1R)-1-(3-Ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2- naphthyl)ethylcarbamoyl)piperidine-l-carboxylic acid tert-butyl ester (0.67q, 0.91nunal) was suspended in refuxing liquid ammonia at 1 atm. After 18h the reaction mixture was concentrated in vacuo to give o.58g of two diastereoisomers of 4-(l~{[i-(3-carbamoyl-[l,2,4]oxadiazol-5-yl)-2-(2-naphthyl)- ethylJ methylcarbamoyl}-2-f 2-naphthyl)ethylcarbamoyX)piperidine-1-carboxylic acid tert butyl ester, H-NMR (DMSO-d6) 8 1.30-1.40(m, 9H) ; 4.80-4.95(m, 1H) ; 6.00-6.13(m, 1H) . HPLC: diastereoisomer I: Rt= 28.9 min (Method a) diastereoisomer II: Rt= 29.4 min (Method a) The diastereomer mixture-of 4-(i-(i-(3-carbamoy]- [1,2, 4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl)methylcarbamoyl}-2-(2-naphthyl)ethylcarbamoyl)-piperidine-1-carboxylic acid tert butyl ester (0.58g, 0.29mmol) was dissolved in a mixture trifluoroacetic acid and dichloromethane (1:1, 12ml). After 5min at 20°C the reaction mixture was concentrated in vacuo. The compound was purified by flash chromatography with silica gel (80g) using a mixture of dichloromethane and 10% ammonia in ethanol (7:3) as eluent to give 0.44g of two diastereoisomers of the title compound. 'H-NMR (DMSO-d6) 5 2.88-2.92(2s, 3H); 4.79-5.00(m, 1H); 6.00-6.13(m, 1H) . HPLC: diastereoisomer I: Rt= 21.2 min (Method a) diastereoisomer II: Rt= 22.1 min (Method a) I A solution of diisopropylaluminium methoxide was prepared by placing diisobutylaluminium hydride (17.9ml of a 25% solution in toluene; 26.6mmol) under nitrogen, cooling in an Lcebath and slowly treating with dry methanol (1.1ml, 26.6mmol). ((1R)-1-Ben2enesulfonylmethyl-2-(2-naphthyl)ethyl) carbamic acid tert-butyl ester (2.14g; 5.0mmol) (prepared by the method of Spaltenstein et al., J. Org. Chem., 52, 3759-66, 1987) was refluxed in dry tetrahydrofuran (250ml) until dissolved. The solution was cooled to -70°C. n-Butyllithium (3.92 ml; 2.5M solution in hexane, 9.8mmol) was added over 10 min and the solution was left with stirring for 30 min. A solution of racemic 2-(tert-butyldimethylsilanyloxymethyl)-3-phenylpropionaldehyde (2.lg; 7.6mmol) (prepared as in Jenmalm et al. J. Org. Chem., 59, 1139-48, 1994) in dry tetrahydrofuran (10 ml) under nitrogan was cooled to -70°C and treated with the previously prepared solution of diisopropylaluminium methoxide (5.4ml; 7.6mmol). Immediately after the addition, the-aluminium complex was add«d via cannula to the sulfone-anion solution. Cooling was maintained for 30 min then aqueous ammonium chloride (40 ml; 10%), water (200 ml) and dichloromethane (200 ml) were added. The phases were separated, the organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to give 5.50g of an oil. On suspension of this oil in methanol (150 ml) a solid precipitated, was filtered off and discarded. Disodium hydrogenphosphate (1.7g) was added to the methanol solution, cooled to 5°C and treated with sodium amalgam (150g; 2%) . After 4h at 20°C the solvent was removed in vacuo and the residue was chromatographed on silica (80g) using diethylether/heptane (1:6) as eluent. This afforded 0.85g of a mixture of isomers of ((1R,2E)-4-(tert-butyldimethylsi-lanyloxymethyl)-l-(2-naphthyl)methyl-5-phenylpent-2-enyl)carbamic acid tert-butyl ester which was used in the next step without further purification. 'H-NMR (CDC13) 5 -0.02-0.08 (four s, 6H) ; 0.85-0.9G (four s, 9H); 1.40-1.45 (four S, 9H); 2.40-3.60 (m, 7H); 4.45 (s(br), 2H); 5.20-5.46 (m, 2H); 7.02-7.82 (m, 12H). ((lR,2E)-4-(tert-Butyldimethylsilanyloxymethyl)-l-(2-naphthyl)methyl-5-phenylpent-2-enyl)carbamic acid tert-butyl ester (0,75g, 1.38 mmol) was dissolved in 2% hydrogen fluoride in acetonitrile (50 ml) and stirred at room temperature for 3h. The solvent was removed in vacuo and the residue was chromatographed on silica (80g) using dichloromethane/heptane/methanol (4/10/1) as eluent. Three fractions were isolated containing compounds with Rf 0.1-0.2. The major fraction (eluting second) was concentrated in vacuo to give 0.35g of ((1R,2E)-4-hydroxymethyl-l-(2-naphthyl)methyl-5-phenylpent-2-enyl)carbamic acid tert butyl ester as a mixture of diastereomers. ((1R, 2E)4-Hydroxymethyl-l-(2-naphthyl)methyl-5-phenylpent-2-enyl)carbamic acid tert butyl ester (350mg, O.Slmmol) was dissolved in dichloromethane and trifluoroacetic acid (5 ml) was added. After 90 min the solvent was removed in vacuo and the residue was dissolved in dichloromethane (5 ml) and reevaporated. Finally the mixture was lyophilized in water acidified with 4 M HC1 (2 ml) to afford 0.3g of two diastereoisomers of (3E, 5R) -5-amino-2-benzyl-6-(2-naphthyl)hex-3-en-l-ol as a hydrochloride that were taken to the next step without further purification. lH-NMR (CDClj) d 1.8 (s(br), 2H); 2.45-3.70 (m, 7H);14.35 (m, 1H); 5.32-5.60 (m, 2H) ; 7.03-7.72 (m,12 H). 3-(tert-Butoxycarbonylaminomethyl)benzoic acid (407mg) was dissolved in dichloromethane (6 ml) and then converted to the symmetrical anhydride by stirring with N-ethyl-N' - (3- dimethylaminopropyl)-carbodiimide hydrochloride (I55mg) for 10 min. A solution of (3E,5R)-5-amino-2-benzyl-6-(2-naphthyl)hex-3-en-l-ol hydrochloride (149 mg) and N,N-diisopropylethylamine (70 jul) in dichloromethane (3 ml) was added to this mixture and then reacted for 20 h at 20°C. The reaction mixture was then concentrated to an oil and redissolved in ethyl acetate (50 ml). This solution was extracted sequentially with 5% aqueous sodium hydrogen carbonate (100 ml) and with water (2 x 100 ml). The resulting organic phase was dried (sodium sulfate) and concentrated in vacuo to an oil. The oil was dissolved in dichloromethane / trifluoroacetic acid 1:1 (6 ml) and stirred. After 10 min the mixture was concentrated by a stream of nitrogen and the resulting oil was redissolved in acetic acid (1 ml). Then water (40ml) and acetonitrile (12 ml) were added. The solution of crude product of the title compound was then purified by semipreparative HPLC in five runs on a 25 mm x 250 mm column packed with ly, C-18 silica which was preequilibrated with 30% acetonitrile in 0.05M ammonium sulfate, which wasjadjusted to pH 2.5 with 4M sulfuric acid. , j The column was eluted with a gradient of 30% - 4!5% acetonitrile in 0.05M ammonium sulfate, pH 2.5 (using 4M sulfuric acid) at 10 ml/min during 47 min at 40 °C and the fractions corresponding to the two major components were each collected, diluted with 3 volumes of water and applied to two Sep-Pak® C18 cartridges connected in series (Waters part. #:51910 ) which were preequilibrated with 0.1% trifluoroacetic acid . The compounds were eluted from the Sep-Pak* cartridges with 70% acetonitrile 0.1% trifluoroacetic acid and isolated from the eluate by lyophilisation after dilution with water. The final products obtained were characterised by analytical RP-HPLC (retention time) and by plasma desorption mass spectrometry (molecular mass). The molecular masses for isomer I and isomer II were found to 464,1 and 464.5 respectively which is in agreement with the expected structure within the experimental error of the method (± 0.9 amu), The RP-HPLC analysis was performed using UV detection at 214 nm and a Vydac 218TP54 4.6mm x 250mm 5(* C-18 silica column (The Separations Group, Hesperia) which was eluted at l ml/min at 42 CC. Two different elution conditions were used: Al: The column was equilibrated with 5% acetonitrile in a buffer consisting of 0.1M ammonium sulphate, which was adjusted to pH 2.5 with 4M sulfuric acid and eluted by a gradient of 5% to 60% acetonitrile in the same buffer duiring 50 min. Bl: The column was equilibrated with 5% acetonitrile / 0.1% trifluoroacetic acid / water and eluted by a gradient of 5% acetonitrile / 0.1% trifluoroacetic acid / water to 60% acetonitrile / 0.1% trifluoroacetic acid / water during 50 min. The retention time using elution conditions Al and Bl was found to be 32.97 min and 34.52 min, respectively for isomer I and 33.67 min and 33.67 min, respectively for isomer II. r (3R) Piperidine-3-carboxylic acid {(1R,2E)-4-hydroxymethyl-l-(2-naphthyl)methyl-5-phenylpent-2-enyl)amide was prepared and characterized using similar procedures as in example 10. The molecular masses for isomer I and isomer II were found to 442.6 and 442.5 respectively which is in agreement with the expected structure within the experimental error of the method {+ 0.9 amu) . The RP-HPLC retention time using elution conditions Al and Bl were found to be 30.02 min and 31.30 min, respective!" for isomer I and 30,56 min and 31.95 min, respectively for isomer II. i ■ At 0 °C, ethyl chloroformate (1.10 ml, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 ml, 13.8 mmol) in THF (10 ml). The solution was stirred for 40 min at 0 °C. The formed precipitation was filtered off and washed with THF (20 ml). The liquid was immediately cooled to 0 °C. A 2M solution of lithium boronhydride in THF (14.4 ml, 28.8 mmol) was added dropwise. The solution was stirred at 0 °C for 2 h, and then warmed to room temp. over a period of 4 h. It was cooled to 0 °C. Methanol (5 ml) was added carefully. IN Hydrochloric acid (100 ml) was added. The solution was extracted with ethyl acetate (2 x 100 ml, 3. x 50 ml). The combined organic layers were washed with satd. sodium hydrogencarbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removea in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-l,1-dimethylpropylcarbamic acid tert-butyl ester. 400 MHz-lH-NMR (CDCl3) : 1.33 (s, 6 H) ; 1.44 (s, 9 H) ; 1.88 (t, 2 H) ; 1.94 (br, 1 H); 3.75 (q, 2 H); 4.98 (br, 1 H). At -78 °C DMSO (1.22 ml, 17.2 mmol) was added to a solution of oxalyl chloride (1.1 ml, 12.9 mmol) in dichloromethane (J5 ml). The . mixture was stirred for 15 min at -78 °C. A solution of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester (1.75 g, 8.6 mmol) in dichloromethane (10 ml) was added dropwise over a period of 15 min. The solution was stirred at -78 °C for another 15 min. Triethylamine (6.0 ml, 43 mmol) was added. The solution was stirred at -78 °C for 5 min and then warmed to room temp, The solution was diluted with dichloromethane (100 ml) and extracted with IN hydrochloric acid (100 ml). The aqueous phase was extracted with dichloromethane (50 ml). The combined organic layers were washed with satd. sodium hydrogencarbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (140 g) with ethyl acetate/heptane (1:3) to give 1.10 g of 3-(tert-butoxycarbonylamino)-3-methylbutanal. 400 MHZ-1H-NMR (CDCl3) : d = 1.39 (s, 6 H) ; 1.45 ;s, 9 H) ; 2.85 (d, 2 H); 4.73 (br. 1 H); 9.80 (t, 1 H). Triethylphosphonoacetate (1.96 ml, 9.8 mmol) was dissolved in THF (30 ml). Potassium tert-butoxide (1.10 g, 9.8 mmol) was added. The solution was starred for 40 min at room temp. A solution of 3-(tert-butoxycarbonylaraino)-3-methylbutanal (1.10 g, 5.5 mmol) in THF (6 ml) was added slowly. The solution was stirred at room temp, for 75 min. It was diluted with ethyl acetate (100 ml) and IN hydrochloric acid (100 ml). The phases were seperated. The aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with satd. sodium hydrogencarbonate solution (60 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (90 g) with ethyl acetata/heptane (1:4) to give 1.27 g of ethyl (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate. 200 MHZ-IH-NMR (CDC13) : 5 = 1.30 (s, 6 H); 1.30 it, 3 H) ; 1.46 (s, 9 H) ; 2.62 (d, 2 H) ; 4.27 (q, 2 H) ; 4.42 (br, 1 H) ; 5.88 (d, 1 H) ; 6.94 (td, 1 H). Ethyl(2E)-5-(tert-butoxycarbonylamino)-5-methylnex-2-enoate(1.233 g, 4.54 mmol) was dissolved in dioxane (20 ml). Lithium hydroxide (0.120 g, 5.00 mmol) was added as a solid. Water (10 ml) was added, until a clear solution was reached. The solution was stirred 16 h at room temp. The solution was diluted with water (70 ml) and was extracted with tert-butylmethylether (2 x 100 ml). The aqueous phase was acidified with IN sodium hydrogensulfate solution (pH = i 1) and was extracted with tert-butylmethylether (3 x 70 ml). These organic layers were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 1.05 g of (2E) -5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid. The crude product was used for further synthesis. 400 MHz-lH-NMR (DMSO d6) : 5 = 1.15 (s, 6 H) ; 1.35 (s, 9 H) ; 2.53 (d, 2 H); 5.75 (d, 1 H); 6.57 (br, 1 H); 6.75 (td, 1 H); 12.15 (s, 1 H). iso-Butylchloroformate (1.22g, 9.Ommol) was dropwise added to a solution of (R) N-methyl-N-tert-butoxycarbonyl-3-(2- naphthyl)alanine (3.0g, 9mmol) and N-methyl-morpholine (0.91g, 9.Ommol) in dichloromethane (40ml) at -20°C. Aftur 15 min at -20°C acetamidoxim (l.33g, l8mmol) was added followed by addition of N- methyl-morpholine (0.91g, 9mmol). After 30min at -205C the reaction mixture was heated to 20°C and diluted with N,N-dimethylformamide (4 0ml). The dichloromethane was evaporated ii vacuo and the reaction mixture was heated at 120°c for 16 h. This reaction mixture was poured into water (120ml) and extracted with ethyl acetate (total 180ml). The organic phases were collected, washed with water (40ml) and dried (magnesium sulfate). The solution was concentrated in vacuo to give 3.5g of crude (R) N-methyl-H-[l-(3-methyl-[1,2,4]oxadiazol-5-yl)-2- (2-naphtyl)ethyl]carbamic acid tertbutyl ester -chat was used without further purification. (R) N-methyl-N-[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphtyl)ethyl]carbamic acid tertbutyl ester (3.3g, 9.0mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (75ml). After 3h at 20°C the reaction mixture was filtered to give 1.52g of (R) N-methyl-N-{l-(3-methyl-[l,2,4joxadiazol-5-y1)-2-(2-naphthy1)ethyl}amine hydrochloride. m.p. 198-202QC. LH-NMR (DMS0-d6) 8 2.35(s, 3H); 2.68(s, 3H) ; 3.43[dd, 1H); 3.80(dd, 1H); 5.29(dd, 1H); 7.30(d, 1H); 7.45-7.90(m, 7H). HPLC: Rc= 16.3 min (Method a) (1.12g, 5.85mmol) and l-hydroxy-7-azabenzotriazole (0.8g, 5.85mmol) were added to a solution of (R) N-tert-but:oxycarbonyl-3-(2-naphthyl)-alanine (1.84g, 5.85mmol) in N,N~dimethylformamide (45ml). After 30min at 20°C a mixture of (R) N-methyl-N-{l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl}amine hydrochloride ;i.27g, 4.18mmol) and triethylamine (0.42g, 4.18mmol) in N,N-dimethylformamide (15ml) were added. After 18h at 2 0°C the reaction mixture was poured on water (200ml) and extracted several times with ethyl acetate (total 110ml) . The collected organic phases were washed, with aqueous citric acid (10%, 40ml) , a saturated solutior. of sodium hydrogencarbonate (3x40ml) and water (3x40ml). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 2.4g of crude {(1R)-l-{N-methyl-N-[(1R)-l-(3-methyl-[l,2,4]-oxadiazol-5-yl)-2-(2 -naphthy1)ethyljcarbcmoyl}-2-(2- naphthyl)ethylJcarbamic acid tertbutyl ester tha-; was used for the next step without further purification. {(lR)-l-{N-Methyl-N-[(lR)-l-(3-methyl-[l,2,4]oxadiazbl-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl}carbamic acid tertbutyl ester (2.4g, 4.2mmol) was dissolved in a mixture of trifluoroacetic acid (40ml) and dichlorometharuj (40ml) at 20°C. After lOmin the reaction mixture was concentre tec. in vacuo and coevaporated from dichloromethane (80ml). "he residue was crystallised from ethyl acetate to give I.19g cf i2R)-2-amino-N-methyl-N-[ (1R)-1-(3-methyl-[1,2,4]oxadiazol-5-y])-2-(2-naphthyl)-ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid, mp 190-191°C. HH-NMR (DMSO-d6) 5 2.33(s, 3H) ; 2.88(s, 3H) ; i.00-3.15(m, 2H) ; 3.45(dd, 1H); 3.65(dd, 1H); 4.71(t, 1H); 7.25-7.95(m, 14H). N-(3-Dimethylarainopropyl)-N'-ethylcarbodiimide hydrochloride (0.28g, 1.48mmol) and 1-hydroxybenzotriazole monohydrate (0.23g, 1.48mmol) were added to a solution of (2E) -5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (o.36g, i.48mmol) in N,N-dimethylformamide (5ml). After 30 min at 20°C a mixture of (2R)-2-aaino-N-methyl-N-[ (1R)-l-(3-methyl-[l,2,4]Dxadiazol-5-yl)-2-(2-naphthyl) -ethyl) -3-(2-naphthyl) ]propionamide, trifluoroacetic acid (0.61g, l.06mmol) and triethylamine (O.llg, I.06mmol) in N,N-dimethylformamide (7ml) were added. After 18h at 20°C the reaction mixture was poured on water (80ml) and extracted several times with ethyl acetate (total 40ml). The organic phases w«;re collected and washed with aqueous citric acid (10%, 15ml), a saturated solution of sodium hydrogencarbonate (3x15ml) and water (3xl5ml). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 0.71g of crude [1,l-dimethyl-4-((lR)-l-{N-methyl-[(1RJ-l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-(2- naphthy1)ethyl]carbamoyl J-2-(2-naphthyl)ethylcarbamoyl)but-3-enyl]carbamic acid tertbutyl ester that was used for the next step without further purification. HPLC: Rt= 34.9 min (Method a) [l,l-Dimethyl-4-((lR)-l-(N-methyl-[(lR)-l-(3-methyl-[1,2,4 ]oxadiazol-5-yl) -2-( 2-naphthyl) ethyl]carbamoyl}-2- (2-naphthyl)ethylcarbamoyl)but-3-enyl]carbamic acid tertbutyl ester (0.71g, 1.03mmol) was dissolved in a mixture trLfluoroacetic acid (10ml) and dichloromethane (10ml). After lOmin at 20°C the reaction mixture was concentrated in vacuo. The compound was chromatographed on silica (80g) using a 10% mixture of ammonia in ethanol and dichloromethane (9:91) as eluent to give 0.44g of the title compound. HPLC: Rt= 23.6 min (Method a) ; Calculated for C36H39N503, 0.75H20: C, 71.68; H, 6.77; N, 11.61%; found: C, 71.76; H, 6.73; N, 11.12%. Example 12: 4-Amino-4-methylpent-2-enoic acid [(1R)-l-{N-meehyl-N-[(lR)-l-(3- methyl-[1,2,4]oxadiazol-5-yl)-2-(2- naphthy1)ethyl]carbamoyl}-2-(2-naphthyl)ethyl]anide: N-(3-Dimethylaminopropyl)-N•-ethylcarbodiimide hydrochloride (0.26g, l.38mmol) and 1-hydroxybenzotriazole monohydrate (0.21g, 1.3Smmol) were added to a solution of N-tertbutoxycarbonyl-4~araino- 4-methylpent-2-enoic acid (0.32g, l.38njnol) in N,N- dimethylformamide (5ml). After 30 min at 20°c a mixture of (2R)-2- aTnino-N-methyl-N-[(lR)-l-(3-methyl-[l,2,4]oxaclia?.ol-5-yl)-2-t2-naphthyl)ethyl)-3-(2- naphthyl)propionamide, trifluoroacetic acid (0.57g, o.99mmol) and triethylamine (0.10g, 0,99mmol) in N,N-dimethylformamide (6ml) were added. After 18h at 20°C the reaction mixture was poured on water (75ml) and extracted several times with etnyl acetate (total 30ml). The organic phases were collected and washed w:.th aqueous citric acid (10%, 15ml), a saturated solution of sodium hyirogencarbonate (3x15ml) and water (3x15ml) . After drying (magn-ssiim sulfate) the solution was concentrated in vacuo to give 0.68g of crude {1,1-dimethyl-3-[ (1R)-l-{N-methyl-N-{ (1R)-l-(3-methyl-[l,2,4]oxadiazol-. 5-yl)-2-(2-naphthyl)ethyl)carbamoyl}-2-(2-naphthyl)ethylcarbamoyl]allyl}carbamic acid te:rtbutyl ester that was used for the next step without further purification. HPLC: Rt= 33.4 min (Method a) {1,l-Dimethyl-3-[(1R)-1-(N-methyl-N-{(1R)-1-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl}carbj1moyl}-2-(2-naphthyl)ethylcarbamoyl]allyl}carbamic acid tertbutyl ester (0.68g, l.Olmmol) was dissolved in a mixture of :rifluoroacetic acid (10ml) and dichloromethane (10ml). Af'ier lOitin at 20°C the reaction mixture was concentrated in vacuo and ohromatographed on silica gel (80g) using a 10% mixture of ammonia in ethanol and dichloromethane (1:9) as eluent to give 0.48g of the title compound. HPLC: Rt= 23.3 min (Method a) Calculated for C35H31N5Oj,0.5H2O: C, 71.90; H, 6.55; N, 11.98%; found: C, 71.82; H, 6.55; N, 11.71%. Example 13: 4-Amino-4-methyl-pent-2-enoic acid N-[(1R)-l-{N-methyl-N-[(1R)-1- (3-methyl-[l(2,4]oxadiazol-5-yl)-2-(2- naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl]-H-methylamide: N-methyl-N-( (1R) -l-{N-methyl-N-[ (1R) -l-(3-methy:.- [1,2, 4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2- naphthyl)ethyl)carbamic acid tertbutyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.34g, 7.Ommol) and l-hydroxy-7-azabenzotriazole (0.95g, 7.Ommol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2-naphthyl)-alanine (2.31g, 7.Ommol) in N,N-dimethylformamide (50ml). After 30min at 20°C a mixture of (R) N-methyl-N*-{l-(3-methyl-[1,2,4]oxadiaz ol-5-yl)-2- (2-naphthyl)ethyl}amine hydrochloride (1.52g, 5.Ommol) and triethylamine (0.51g, 5.Ommol) in N,N-dimethylformamide (10ml) was added. After 18h at 20°C the reaction mixture was poured on water (250ml) and extracted several times with ethyl acetate (total 130ml) . The collected organic phases were washed witJi aqueous citric acid (10%, 50ml), a saturated solution of sodium hydrogencarbonate (3x50ml) and water (3x50mL). ?After drying (magnesium sulfate) the solution was concentrated in vacuo and chromatographed on silica (llOg) using heptane and ethyl acetate (1:1) to give 2.4g of N-methyl-N-((1R)-l-{N-methyl-N-[(1R)-l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-(2- naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)carbamic acid tertbutyl ester. HPLC: Rt= 36.5 min (Method a) (2R)-2-Methylamino-N-methyl-N-[(lR)-l-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid: NmethylN((1R)1{NmethylN[(1R)l(3methyl [1,2,4] oxadiazol-5-yl) -2- (2-naphthyl) ethyl]carbamoyl}-2-(2 -naphthyl) ethyl) carbamic acid tertbutyl ester (:i.4g, 4 .2mmol) was dissolved in a mixture of trifluoroacetic acid (40ml) and dichloromethane (40ml) at 20°C. After lOmin the reaction mixture was concentrated in vacuo and coevaporated from dichloromethane (80ml). The residue was crystallised from ethyl acetate to give 1.9g of (2R) -2-methylamino-N-methyl-N-[ (1R) -1- (3-methyl- [1,2,4] oxadiazol-5-yl)-2-(2-naphthyl)-ethyl]-3- (2-naphthyl)propionamide, trifluoroacetic acid, mp 184-188°C 'H-NMR (DMSO-d6) 5l.53(s, 3H) ; 2.34(s, 3H) ; 2.6:i(s, 3H) ; 3.05(dd, » 1H); 3.21(dd, 1H); 3.40(dd, 1H) ; 3.55(dd, 1H); 4.60{t, 1H); 6.35 (dd, 1H) ; 7.25(d, 1H) ; 7.40-7.90(111, 14H) . HPLC: Rt= 24.9 min (Method a) Calculated for C30H30N {1,l-Dimethyl-3-[N-((1R)-1-(N-methyl-N-((1RJ-1-13-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl}carbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]allyl}carbamic acid tertbutyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.3lg, 1.6mmol) and l-hydroxy--7-azabenzotriazola (0.22g, 1.6mmol) were added to a solution of N-tertbutoxycarbonyl-4-amino-4- methylpent-2-enoic acid (0.37g, 1.6mmol) in N,H--diiiiethylformamide (5ml). After 30 min at 20°C a mixture of (2R; -2-methylamino-N- raethyl-N-[(lR)-i-(3-methyl-[1,2,4]oxadiazol-5-y:o-H-(2-naphthyl)- ethyl)-3-(2-naphthyl)]propionamide, trifluoroacetic? acid (0.68g, 1. 2mmol) and tr iethy lamine (0.12g, 1.2:rano I) in N, N- dimethylformamidef5ml) were added. After 18h at 20°c the reaction mixture was poured on water (80ml) and extracted several times with ethyl acetate (total 55ml). The organic phases were collected and washed with aqueous citric acid (10%, 15ml), a saturated solution of sodium hydrogencarbonate (3x15ml) and water (3x15ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and chromatographed on silica gel (80g) using heptane and ethyl acetate (3:7) as eluent to give 0.75g of (1, l-diinethyl-3-[N-( (1R) -l-(N-methyl-N-((1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethylJcarbamoyl)-2-(2-naphthyi)ethyl)- N -methylcarbamoyl]allyl)carbamic acid tertbutyl ester. HPLC: Rt= 33.8 min (Method a) {l,l-Dimethyl-3-[ (lR)-l-{N-methyl-N-{ (lR)-l-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl}carbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]allylJcarbamic acid tertbutyl ester (0.62g, 1.9mmol) was dissolved in a mixture of trifluoroacetic acid (9ml) and dichloromethane ;9ml). After lOmin at 20°c the reaction mixture was concentrated in vacuo and chromatographed on silica gel (80g) using a 10% mixturefof ammonia in ethanol and dichloromethane (5:95) as eluent to give 0.44g of the title compound. HPLC: Rt= 26.4 min (Method a) Calculated for C36H39N503, 0.75H?0: C, 71.68; H, 6.77; N, 11.61%; found: C, 71.81; H, 6.72; N, 11.17%. Example 14: 3-Aminomethyl-N-((1R)-1-{N-[(1R)-1- (((dimethylcarbamoyl)methoxy)methyl)-2-phenylethyl]-N- > methylcarbamoyl}-2-(2-naphthy1)ethyl)-N-methylb«mzamide (2R)-2-(Methylamino)-3-phenylpropan-l-ol: (2R)-2-(Methylamino)-3-phenylpropan-l-ol was prepared analogue to M. J. McKennon and A. I. Meyers J. Org. Chem. 1993 (58), 3568 - 3571. m.p. 69 - 69°C (lit: A. I. Meyers, J. Org. Chem. 1993 (58), 3568 - 3571: 71 - 74 °C; A. Karim, A. Mortreux, F. Petit, G. Buono, G. Pfeiffer, C. Siv, J. Organomet. Chem. 1986, 317, 93: 68 °C, for (2S)-2-(methylamino)-3-phenylpropan-l-ol). (2R)-2-(Methylamino)-3-phenylpropan-l-ol (6.00g, 36.3mmol) was dissolved in THF (80ml). IN sodium hydroxide solution (36.3ml, 36.3mmol) was added. A solution of di-tert-butyl dicarbonate (9.50g, 43.6mmol) in THF (60 ml) was slowly added at room temp. The solution was stirred 16 h at room temp. Water (2 00ml) and ethyl acetate (200ml) were added. The phases were separated. The aqueous phase was washed with ethyl acetate (2 x 100ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The product was purified on silica (170g) with ethyl aceate/heptane (1:1) to give ' 7.85g of N-((1R)-l-hydroxymethyl-2-phenylethyl)-N-methyl carbarmic acid tert-butylester. 1H-NMR (CDC13) : 5= 1.32 - 1.40 (br, 9H) ; 2.55 - 2.95 (m, 5 H) ; 3.65 - 3.67 (br, 2 H); 4.10 - 4.35 (br, 1H); 7.05 - 7.35 (ra, 5 H). solution was warmed to 75 - 8 0°C. Rhodium(IE) acetate (0.lg, 0.4mmol) was added. During a time of 6h a solution of ethyl diazoacetate (2.4ml, 22.5mmol) in dichloromethane (100ml) was added. After 3h another portion of rhodium(II) acetate (O.lg, 0.4mraol) was added. After all ethyl diazoacetate was added, the solution was cooled to room temp. It was filtrated through a plug of celite. The solvent was removed in vacuo. The crude product was chromatographed on silica (lOOg) to give 1.53g of ((2R)-2-(tert-butoxycarbonylmethylamino) -3-phenylpropoxy) acetic acid ethyl ester. 1H-NMR (CDC13) : 5 = 1.28 (m, 3 H) ; 1.39 and 1.48 (both s, together 9H); 2.65 - 2.95 (m, 9 H); 3.58 (m, 1 H); 3.6" (br, 1H); 3.98 -4.27 (m, 4 H); 4.35 - 4.55 (br, 1H); 7.10 - 7.30 (m, 5 H)- acid ethyl ester (0.60g, 1.71mmol) was dissolved in dioxane (5ml). \ solution of lithium hydroxide (0.05g, 2.20mmol) in water (2ml) was added. The solution was stirred at room tenp. for 36h. Ethyl acetate (10ml) and water (2ml) were, added. The phases were separated. The aqueous phase was extracted with ethyl acetate (10ml). The combined organic layers were extracted with IN sodium hydroxide solution (20ml). The combined aqueous phases were acidified with a 1M sodium hydrogensulfate solution (pH = 2) and Extracted with ethyl acetate (2 x 20ml). These ethyl acetate layers rfere combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 0.38g of crude ((2R)-2-(tert-autoxycarbonylmethylamino)-3-phenylpropoxy) acetic acid, that was jsed for the following steps. ((2R)-2-(tert-Butoxycarbonylmethylamino)-3-pht;nyLpropoxy)acetic acid (0.37g, 1.14mmol) and l-hydroxy-7-azaben:iotriazole (0.26g, 1.14mmol) were dissolved in N,N-dimethylformamide (7ml). N-ethyl-N'-(3-dimethylaminopropy1)carbodiimide hydrochloride (0.2 6g, 1.37mmol) was added. The solution was stirred for 30 min. A 33% solution of dimethylamine in ethanol (0.33ml, 1.26mmol) was added. The solution was stirred over night. Water (20ml) and ethyl acetate (15ml) were added. The organic phase was washed with a 1M solution of sodium hydrogensulfate (30ml) and a saturated solution of sodium hydrogencarbonate (30ml). It was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (15g). This product was dissolved in dichloromethane (3ml) and was cooled to 0"C. Trifluoroacetic acid (1ml) was added. The solution was stirred at o°C for 20min. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (10ml) and IN sodium hydroxide sclution (10ml). The phases were separated. The aqueous phase was extracted with dichloromethane (4 x 10ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo to give 140mg of crude N,N-dimethyl-2-((2R)-2-nethylamino-3-phenylpropoxy)acetamide, which was used for further syntheses. 1H-NMR (CDC13) : 8 - 2.25 (s, 1H) ; 2,45 (s, 3 H) ; 2.50 - 3.10 (m, 3 H); 3.94 (s, 1 H); 3.99 (s, 3H); 3.35 - 3.55 (m, 2 H); 4.15 (s, 2 H); 7.10 - 7.40 (m, 5 H). (12 6mg), Boc-N-Me-D-2Nal-0H (250mg) and l-hydroxy-7-azabenzotriazole (103mg) was dissolved in dichloromethane (6ml) and N,N-dimethylformamide (5ml) and then stirred 30 min at 0°C with N- i ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (146mg) . Diisopropylethyl amine (87/il) was added and stirring was continued for Ih at 0°C. After this the dichloromethane was evaporated from the mixture by a stream of nitrogen and ethyl acetate (25ml) was added. The mixture was extracted sequentially with 5% aqueous sodium hydrogen carbonate (2 x 25ml), 5% aqueous potasium hydrogen sulfate (2 x 25ml) and water (25ml) and the organic phase was dried (sodium sulfate) and concentrated in vacuum yielding 265 mg of crude N-( (1R) -l-{N-[ (1R) -l-( ((dimtjthylcarbamoyl) methoxy)methyl) -2-phenylethyl]-N-methylcirfcamoyl}-2-{2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl e&ter. (((diroethylcarbamoyl)methoxy)methyl)-2-phenylethyl]-N-roethylcarbamoy1}-2-{2-naphthy1}ethyl)-N-methylcarbamic acid tert-butyl ester (132 mg) was dissolved in a mixture of dichloromethane and trifluoroacetic acid 1:1 (2 ml) and stirred for lOmin. The mixture was concentrated by a stream of nitrogen and the resulting oil was redissolved in 1 ml IN hydrochloric acid, diluted with water to a volume of 50 ml and lyophilized. This lyophilized product was dissolved in dichloromethane (5ml) and diisopropylethyl amine (171/il) was added. To this; mixture was added a solution in dichloromethane (5ml; of 3-tert-butyloxocarbonylaminomethylbenzoic acid (503mg) which immediately before had been converted to the symmetrical anhydride by stirring with N-ethyl-N' - (3-dimethylaminopropyl) -carbodiimide hydrochloride (191.6mg) for 15 min. The reaction mixture was then concentrated to an oil and redissolved in ethyl acetate (25ral) . This mixture was extracted sequentially with 5% aqueous sodium hydrogen carbonate (50ml), 5% aqueous potassium hydrogen sulfate (50ml) and water (50ml) and the organic phase was dried (sodium sulfate) and concentrated by a stream of nitrogen to dryness . This product was dissolved in a mixture of dichloromethane and trifluoroacetic acid 1:1 (4ml) . After 10 min the mixture was concentrated by a stream of nitrogen and the resulting oil was redissolved in 5ml 70% acetonitrile / 0.1% trifluoroacetic acid and diluted with water to a volume of 50 ml. The crude product of the -.itle compound was then purified by semipreparative HPLC in four ruis on a 25 mm x 250 mm column packed with 7/i C-18 silica which was preetruilibrated with .29% acetonitrile in 0.05M ammonium sulphate, which was adjusted to pH 2.5 with 4M sulphuric acid. The column was eluted with a gradient of 29% - 39% acetonitrile in 0.05M ammonium sulphate, pH 2.5 at 10 ml/min during 47 min at 40 °c and the peptide containing fractions were collected, diluted with 3 volumes of water and applied to a Sep-Pak® C18 cartridge (Waters part. #:51910 ) which was equilibrated with 0.1% trifluoroacetic acid . The peptide was eluted from the Sep-Pak* cartridge with 70% acetonitrile 0.1% trifluoroacetic acid and isolated from the eluate by lyophilisation after dilution with water. The final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass). The molecular mass found (MH+: 592.9amu) agreed with the expected structure (teor. MH*: 5934amu) within the experimental error of the method. The RP-HPLC analysis was performed using UV detection at 214 nm and a Vydac 218TP54 4.6mm x 250mm 5y. C-18 silica column (The Separations Group, Hesperia) which was eluted at 1 ml/min at 42 °C. Two different elution conditions were used: Al: The column was equilibrated with 5% acetonitrile in a buffer consisting of 0.1M ammonium sulphate, which was adjusted to pH 2.5 with 4M sulphuric acid and eluted by e gradient of 5% to 60% acetonitrile in the same buffer durirg 50 min. Bl: The column was equilibrated with 5% acetonitrile / 0.1% r trifluoroacetic acid / water and eluted by a gradient of 5% acetonitrile / 0.1% trifluoroacetic; acid / water to 60% acetonitrile / 0.1% trifluoroacetic acid / water during 50 min. The retention time using elution conditions Al and Bl was found to be 30.92 min and 35.15 min, respectively. (2R)-2-(tert-Butoxycarbonylmethylamino)-3-phenylpropionic acid (4. Og, 14.27mmol) was dissolved in dichloron.ethane (5ml) and ethanol (0.95ml, 16.27mmol). 4-Dimethylaminopyridine (0.19g, 1.57mmol) was added. The solution was cooled to 0 °C and N-(3-dimethylarainopropyl)-H'-ethylcarbodiimide hydrochloride (2.98g, 15.55mmol) was added. The reaction mixture was stirred for 2h at 0°C for 16h at room temp. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate/water (30ml/30ml). The phases were seperated. The organic phase was washed with satd. sodium hydrogencarbonate solution and water and dried over magnesium sulfate. The crude product was purified by flash chromatography on silica (180g) with ethyl acetate/heptane 1:2 to give 1.95g of (2R)-2-(tert-butoxycarbonylmethylamino)-3-phenylpropionic acid ethyl ester. 'H-NMR (CDC13) : 6 = 1.15 - 1.50 (m, 12 H) ; 2.71 (m, 3 H) ; 3.00 (m, 1 H); 3.80 (m, 1 H); 4.20 (br q, 2 H); 4.55 and 4.90 (both br dd, together 1 H); 7.10 - 7.40 (m, 5 H). ((lR)-l-Hydrazinocarbonyl-2-phenylethyl)methylc;irbamic acid tert-butyl ester: (2R) -2-(tert-Butoxycarbonylmethylamino) -3-pheny:.propionic acid ethyl ester (1.9g, 6.16mmol) was dissolved in anhydrous ethanol (15mL). Hydrazine hydrate (3.0ml, 61.6mmol) was added dropwise. The solution was stirred at room temp, over night. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (40ml) and washed with water {40ml). The organic phase was dried over magnesium sulfate. After removal of the solvent in vacuo 1.40g of curde ((1R) -l-hydrazinocarbonyl-2-phenylethyl)mi2thylcarbamic acid tert-butyl ester was obtained, which was used for the further synthesis. HH-NMR (CDC13) : 5 = 1.20 - 1.50 (m, 9 H) ; 2.76 (s, 3 H) ; 3.00 (m, 1 H); 3.35 (m, 1 H); 3.85 (br, 2 H); 4.75 and 4.85 (both m, together 1 H); 7.10 - 7.40 (m, 5 H); 7.45 (br, 1 H). l-H( (2R)-2-(tert-Butoxycarbonylmethylamino)-3-phenylpropiony1)-2-ethoxycarbony1formylhydraz in«: ((1R)-l-Hydrazinocarbonyl-2-phenylethyl)methylcarbamic acid tert-butyl ester (1.4g, 4.76mmol) was dissolved in dichloromethane (40ml). Triethylamine (0.8ml, 5.71mmol) was added and the solution was cooled to -15°C. Ethyl oxalyl chloride (0.5S,ml, 5.24imnol) was added dropwise. The solution was stirred for I5itdi a': - 15°c. It was warmed to room temp. and extracted with water (2x 2 0ml) and 5% citric acid (30ml) and washed with satd. sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica (140gt wi-Hh ethyl acetate/dichloromethane 1:3 to give 1.40g of l--((2R)-2-(tert-Butoxycarbonylmethylamino)-3-phenylpropionyl)-2-ethoxycarbony1formylhydraz ine. 'H-NMR (CDC13) : S = 1.30 - 1.50 (m, 12 H) ; 2.80 (br, 3 H) ; 3.05 (m, 1 H); 3.35 (m, 1 H); 4.37 (br a, 2 H); 4.82 and 4.95 (br and br t, together 1H) ; 7.05 - 7.35 (m, 5 H) ; 8.60, 8.95, 9.15, 9.45 (all br, together 2 H) . l-((2R)-2-(tert-Butoxycarbonylmethylamino)-3- phenylpropionyl)ethoxycarbonylformylhydrazine (1.4g, 3.55nunol) was dissolved in ether (2 5ml) and THF (10ml). Pyridine (1.44ml 17.75mmol) was added, and the solution was cooled to 0°c. Thionyl chloride (0.3ml, 3.90mmol) was added dropwise. The reaction mixture was stirred at 0°c for 2h. The precipitation was filtered off. The solvent was removed in vacuo without warming. The res idue was dissolved in toluene (25ml) and the solution was warmed to reflux for 2h. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (70g) with ethyl acetate/dichloromethane 1:2 to give 721mg of 5-((1R)-l-(tert-butoxycarbonylmethylamino) -2-phenylethyl) -[1.3,4]oxadiazole-2-carboxylic acid ethyl ester. H-NMR (CDC13) : 6 = 1.35 (br d, 9 H) ; 1.47 (t, 3 K) ; 2.70 (br, 3 H) ; 3.30 (br, 1 H); 3.50 (br, 1 H); 4.52 (br, 2 HJ; 5.55 and 5.88 (both br, together 1H); 7.15 - 7.40 (m, 5 H). i 5-((1R)-1-(tert-Butoxycarbonylmethylamino)- 2-phenylethyl)- [1,3,4]oxadiazole-2-carboxylic acid ethyl ester (600mg, 1.6mmol) was dissolved in THF (4ml) and added to reflu: r solution was stirred for 3h. The the ammonia was removed in a stream of nitrogen. The residue was dissolved in ethyl acetate/10% sodium hydrogensulfate solution (20ml/20inL) . The phases were seperated and the organic phase was washed with satd. sodium hydrogencarbonate solution and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40g) with ethyl acetate/heptane 2:1 to give 383mg of ((1R) -l-(5-carbamoyl-[:i, 3, 4 ]cxac.iazol-2-yl) -2-phenylethyl)methyl carbamic acid tert-butyl ester. 'H-NMR (CDClj) : 8 = 1.30 (br, 9 H) ; 2.75 (br d, 3 H) ; 3.30 (dd, 1 H) ; 3.50 (br, 1 H) ; 5.55 and 5.85 (both br, together 1 H) ; 6.27 (br, 1 H) ; 7.10 (br, 1 H) ; 7.20*- 7.40 (m, 5 H) . ((1R)-1-(5-Carbamoyl-[1,3,4]oxadiazol-2-yl)-2- phenylethyl)methyl carbamic acid tert-butyl ester (350mg> l.Olmmol) was dissolved in dichloromethane (6ml). The solution was cooled to 0°C. Trifluoroacetic acid (2ml) was added dropwists. The solution was stirred for 30min. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (6ml) and the solvent was removed in vacuo. The residue was again dissolved in dichloromethane (6ml) and the solvent was removed in vacuo. The residue was dissolved in dichloromethane. This phase was washed with water. The aqueous phase was lyophilized to give 247mg of crude (1R)-5-(l-methylamino-2-phenylethyl)-[1,3,4]oxadiazole-2-carboxylic acid amide, which was used for the further synthesis. LH-NMR (DMSO d£) : 2 = 2.65 (s, 3H) ; 3.35 (dd, 1 H) ; 3.62 (dd, 1 H) ; 5.20 (dd, 1 H); 7.10 - 7.40 (m, 5 H); 8.35 (s, 1 H); 8.68 (sr 1 H). (1R) -5- (l-Methylamino-2-phenylethyl) -[1,3,4;]oxadd azcle-2-carboxylic acid amide (240mg, 0.98mmol), (R)-2-((tert- butoxycarbonyl)methylamino)-3-(2-naphthyl)propionic 0.98mmol) and l-hydroxy-7-azabenzotriazole (I3 3ing, o.98mmol) were dissolved in dichloromethane (8ml) and DMF (4ml). The solution was cooled to 0CC and N-(3-dimethylaminoprapyl) -N' -ettiylcarbodiimide hydrochloride (230mg, l.lSmmol) was added. After 10 min triethy1amine (0.35ml, 2.46mmol) was added. The solution was stirred for lh at 0CC and subsequently for 16h at room temp. The solution was diluted with ethyl acetate (30ml) and water (20ml). The phases were seperated and the aqueous phase was extracted with ethyl acetate (20ml). The combined organic layers were washed with satd. sodium hydrogencarbonate solution (30ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (50g) with ethyl acetate to give 301mg of ((1R)-l-(((13)-l-(5-carbamoyl-[l,3,4]oxadiazol-2-yl)-2- phenylethyl)methylcarbamoy1)-2-(2-naphthy1)ethyl)methylcarbamic acid tert-butyl ester. ' H-NMR (CDC13) : 5 = 0.84, 0.95, 1.07, 1.25 (all s, together 9 H) ; 2.05, 2.15, 2.42, 2.75, 2-76, 2.77, 2.87,3.98 (all s, together 6 H); 6.90 - 7.90 (m, 12 H). 1 ((1R) -1- (((1R) -1- (5-Carbamoyl-[1,3,4]oxadiazol-:>-yl) -2-phenylethyl)methylcarbaraoyl)-2-(2-naphthyl)ethyl)methylcarbaraic acid tert-butyl ester (300mg, 0.55mmol) was dissolved in dichloromethane (3ml) and cooled to 0°C. Trifluoioacetic acid (3ml) was added dropwise. The solution was stirred for 5min at 0°C. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (5ml), and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (5ml), and the solvent was removed in vacuo. The residue was dissolved in 3M hydrogen chloride in ethyl acetate (5ml), and the solvent was removed in vacuo. The residue was dissolved in 3M hydrogen chloride ir ethyl acetate (5ml), and the solvent was removed in vacuo to give 238mg of crude 5 - ( ( 1 R) -1- (methyl ( (2R)-2-methyLamino-3-(2-naphthyl)propionyl)amino)-2-phenylethyl)-[1,3,4]oxadiazol-2-.carboxylic acid amide, which was used for the further synthesis. . JH-NMR (CDC13) : 6 = 2.40 (s, 3H); 2.55 - 4.40 (m, 9 H) ; 7.10 - 7.90 (m, 9H). ((E)-3-(((lR)-l-(((lR)-l-(5-Carbamoyl-[l,3,4]oxadiazol-2-yl)-2-phenylethy1)methylcarbamoyl)-2-(2- haphthyl)ethyl)methylcarbamoyl)-1,1-dimethylallyl)carbamic acid tert-butyl ester: (2E)-4-tert-Butoxycarbonylamino-4-methylpent-2-«noic acid (14 3mg, 0.62mmol) was dissolved in dichloromethane ( azabenzotriazole (85mg, 0,62mmol) and subsequently N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (119mg, 0.62mraol) were added. The solution was stirred for I5min at room temp. 5-((lR)-i-(Methyl((2R)-2-me-hylamino-3-(2-naphthyljpropionyl) amino)-2-phenylethyl)-[1,3, H-NMR (CDC13) : fi = 1.1 - 1.5 (m, 15 H) ; 2.6 - 3.7 (m, 12H) . HPLC (Method B): 44.95 min. PDMS: 668.8 ([M]*) ((E)-3-(((lR)-l-(((lR)-l-(5-Carbamoyl-[l,3,4]oxacliazol-2-yl)-2-phenylethyljmethylcarbamoyl) -2- (2-naphthyl) ethyl] methyl-carbamoyl) -l,l-dimethylallyl)carbamic acid tert-butyl ester (120mg> o.lSmmol) was dissolved in dichloromethane (3ml). The solution was cooled to 0°C. Trifluoroacetic acid (3ml) was added dropvise. The reaction mixture was stirred for 5min at 0°C. The solvent was removed in vacuo without warming. The residue was dissolved in dichloromethane (5ml) and the solvent was removed in vacuo. This last procedure was repeated two times. The residue was dissolved in water (5ml) and IN hydrochloric acid (lml, lmmol) was added. The salvant was removed in vacuo. The residue was dissolved in 3M hydrogen chloride in ethyl acetate (3ml), and the solvent was removed in vacuo. This last procedure was repeated. The crude product was purified by HPLC-chromatography on a 25mm x 250mm 5/i CIS sii.ica column with a gradient of 28% to 38% acetonitrile in a 0.1M ammonium sulfate buffer, which was adjusted to pH 2.5 with 4M sulfuric acid to give 64mg of the title compound. HPLC (Method B): 30.133 min PDMS: 569.6 ([M+H]*) (1.34g, 7.Ommol) and l-hydroxy-7-azabenzotriazole (0.95g, 7.Ommol) were added to a solution of (R) N-methyl-N-tert-butoxycarbonyl-3-(2-naphthyl)alanine (2.31g, 7.Ommol) in N,N-dimethylformamide (50ml). After 30min at 20°C a mixture of (R) N-methyl-N-{l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl}amine hydrochloride (1.52c, 5.Ommol) and triethylamine (0.51g, 5.Ommol) in N,N-dimethylformarnide (10ml) were added. After 18h at 20°C the reaction mixture was poured on water (250ml) and extracted several times with ethyl acetate (total 130ml). The collected organic phases were washed with aqueous citric acid (10%, 50ml), a saturated solution of sodium hydrogencarbonate (50tnl) and water (3xSOral) . After drying (magnesium sulfate) the solution was concentrated in vacuo and the residue was chromatographed on silica (llOg) usiing ethyl acetate and heptane (1:1) as eluent to give 2.4g of N-uethyl-f(1R)-1-{N- methyl-N-[(1R)-1-(3-methyl-[1,2,4]-oxadiazol-5-yl)-2-(2- naphthyl)ethyl]carbamoyl}-2-(2- ' naphthyl) ethyl)carbamic acid tert-butyl ester a:i a foam. HPLC: Rc= 3 6.5 min (method a) [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl)-2-(2-naphthyl)ethylJcarbamic acid tert-butyl ester (2.4g, 4.2mraol) was dissolved in a mixture of trifluoroacetic acid (40ml) and dichloromethane (40ml) at 20°C. After lOmin the reaction mixture was concentrated in vacuo and coevaporated from heptane (80ml) and dichloromethane (80ml). The residue was crysta11ised from ethyl acetate to give 1.12g of (2R)-2-methylamino-N-methyl-N-[(1R)-l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-(2-naphthyl)-ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid. mp 184-188°C. H-NMR (DMSO-d6) 5l.52(s,3H); 2.32(s,3H); 2.68(s,3H); 3.03(dd,1H); . 3.22(dd, 1H); 3.55(dd, 1H); 4.62(t, 1H); 6.35(dd, 1H); 7.25-7.95(m, 14H) . HPLC: Rt= 24.9min (Method a) . Calculated for C30H30N4O2,CF3COOH, 0.25EtOAc: c, 64.49; H, 5.41; N, 9.12%; found: C, 65.01; H, 5.35; N, 9.32%. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.37g, l.91mmol) and 1-hydroxybenzotriazole monohydrate (0.26g, 1.91mmol) were added to a solution of N-tert-bucoxycarbonyl-4-piperidine carboxylic acid (0.44g, 1.91mmol) in N,N-dimethylformamide (5ml). After 45 min at 20°C a mixcure of (2R)-2-methylainino-N-methyl-N-[(lR)-l-(3-niethyl-[l,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl)-3-(2-naphthy1)]propionamide, trifluoroacetic acid (0.81g, 1.37mmol) and tricsthylamine (0.19g, 1.37mmol) in N,N-dimethylformamide (10ml) were added. After 18h at 20°C the reaction mixture was poured on water (100ml) and extracted several times with ethyl acetate (total 70ml). Hhe organic phases were collected and washed with aqueous citric acid (10%, 20ml), a saturated solution of sodium hydrogencarbonate (20ml) and water (3x20ml). After drying (magnesium sulfate) ihe solution was concentrated in vacuo and the residue was chromatographed on silica (80g) using ethyl acetate and heptane (3:2) as eluent to give 0.88g of 4-{N-methyl-{(lR)-l-[N-methyl-((iR)-i-(3-methyl-[1,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl)carbamoyl]-2-(2-naphthyl)ethyl)carbamoyl}piperidine-l-carboxylic acid tert-butyl i ester. HPLC: Rt = 36.1 min (Method a) 4- HPLC: diastereoisomer I: Rt = 25.24 min (Method a) diastereoisomer II: Rc= 25.26 min (Method a) Calculated for C30H39N5O3,H2O: C, 71.15; H, 6.80; N, 11.52%; found: ' C, 71.27; H, 6.68; N, 11.28%. Example 17 HNC 26-0719 Piperidine-4-carboxylic acid N-{-l( [methyl-l-(3-- methyl-[1,2,4]-oxadiazole-5-yl)-2-(2- naphthyl)ethylcarbamoy1)-2-(2-naphthyl)ethyl}amide. 4-((lR)-l-{H-Methyl-[(lR)-l-(3-methyl-[l,2,4]oxaaiazol-5-yl)-2-(2- naphthy1)ethyl]carbamoyl)-2-(2 - naphthyl)ethyl)carbamoyl)piperidine-l-carboxylit: acid tert-butyl ester: N-(3-Dimethylaminopropyl)-N1-ethylcarbodiimide hydrochloride (0.4 2g, 2.2rnmol) and 1-hydroxybenzotriazole mcnohydrate (0.34g, 2.2ramol) were added to a solution of N-tert-butoxycarbonyl-4-piperidine carboxylic acid (0.50g, 2.2nmol) in N,N-dimethylformamide (5ml). After 30 min at 20°C a mixture of (2R)-2-methylamino-N-methyl-N-[ (1R)-l-(3-methyl-[ 1,2 ,4 ] oxadiazol-5-yl)-2-(2-naphthyl)ethyl)-3-(2-naphthyl)Jpropionamide, trifluoroacetic acid (0.9g, l.54mmol) and triethylamine (0.16g, 1.54nunol) in N,N-dimethylformamide (10ml) were added. After 18h at 20°C the reaction mixture was poured on water (8 5ml) and extracted several times with ethyl acetate (total 90ml). The organic phases were collected and washed with aqueous citric acid (10%, 15ml), a saturated solution of sodium hydrogencarbonate (15ml) and water (3x15ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and the residue was chromatographed on silica (llOg) using ethyl acetate and heptane (1:1) as eluent to give 0.50g of 4-((lR)-l-{N-methyl-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl) -2-(2-naphthyl) ethyl ] carbamoyl ) -2- (2-naphthyl) ethyl)carbamoyl)piperidine-1-carboxylie: acid tert-butyl ester. H-NMR (DMS0-d6) 8 2.40(s,3H); 2.95(s,3H); 3 . 45 (dd , 1H) ; 3.60(dd,lH); 4.85(m,lH); 6.08(m, 1H); 7.10(d, 1H); 7-40-7.90;m, 13H). HPLC: Rt= 34.0 min (Method a) 4-((lR)-l-{N-Methyl-[ (lR)-l-( 3-methyl-[1,2,4 ]oxa3iazol-5-yl)-2-(2-naphthy1)ethyl]carbamoyl}-2-(2- naphthyl)ethyl)carbamoyl)piperidine-l-carboxylic acid tert-butyl ester (0.50g, 0.74mmol) was dissolved in a mixture of trifluoroacetic acid (10ml) and dichloromethane tlOnl). After lOmin at 20°C the reaction mixture was concentrated in vacuo. The compound was chromatographed on silica (38g) using a 10% mixture of ammonia in ethanol and dichloromethane (3:7) as eluent to give 0.26g of the title compound. lH-NMR (DMSO-d6) 6 3.45(dd,lH); 3.61(dd,lH); 4.72(m,lH); 6.10(dd, 1H); 7.20 HPLC: Rt= 24.8 rain (Method a) Calculated for C35H3TN5O3,0.5 H20: C, 71.90; H, 6.55; N, 11.98%; found: C, 71.77; H, 6.52; N, 12.09%. Example 18: 5-{l-[2-(piperidine-4-carbonylamino)-3-(2- naphthyl)propionyl-N-methylamino]-2-(2-naphthyl)ethyl}- (R) 5-(l-methylamino-2-(2-naphthyl)ethyl) -[1,2,]oxadiazole-3-carboxylic acid ethyl ester hydrochloride (1.54g, 4.5mmol) was suspended in 2-propanol (35ml). After addition of tetraisopropyl titanate (1.3g, 4.5mmol) the reaction mixture was. re fluxed for 18h. Hydrochloric acid (IN, 30ml) was added and the reaction mixture was extracted with ethyl acetate (150ml). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (50ml) and water (3x50ml). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 1. 3g of (R) 5-(l-methylamino-2-(2-naphthyl)ethyl)- [l,2,4]oxadiazole-3-carboxylic acid 2-propyl ester that was used for the next step without further purification. 'H-NMR (DMS0-d6) 5 1.31(d,6H); 2.21(d,3H); 3.3(n,2H); 4.40(t,lH); 5.72(m,lH); 7.35-7.95(m, 7H). HPLC: Rt= 20.5 mill (Method a) N-(3-Dimethylaroinopropyl)-N'-ethylcarbodiimide hydrochloride (2.15g, 6.8mmol) and l-hydroxy-7-azabenzotriazole (0.93g, 6.8mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2-naphthyl)alanine (2.l5g, 6.8mmol) in N,N-dimethylformaraide (50ml). After 30min at 20°C a solution of (R) 5-(1-methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid 2-propyl ester (1.65g, 4.9mmol) in N,N-dimethylformamide (15ml) was added. After 18h the reaction mixture was poured on water (500ml) and extracted several times with eth'1 acetate (total 450ml). The collected organic phases were wash id with aqueous citric acid (10%, 75ml), a saturated solution )f sodium hydrogencarbonate (75ml), water (3x75ml) and dri id (magnesium sulfate). The solution was concentrated in vacuo and the residue was chromatographed on silica (160g) using ethyl acetate and heptane (1:2) as eluent to give 2.4g of 5-{ -l-[ (2R) -2-tert-butoxycarbonylamino-3-(2-naphthyl)propionyl-N-nethylamino]-2-(2-naphthyl)ethyl)-[1,2, 4]oaxdiazole-3-carboxylic acid 2-propyl ester. ! i 5-{(1R)-l-[(2R)-2-tert-Butoxycarbonylamino-3-(2~naphthyl)-propionyl-N-methylamino]-2-(2-naphthyl)ethyl}- [l,2,4]oxadiazole-3-carboxylic acid 2-propyl ester (2.1g, 3.3mmol) was suspended in a saturated mixture of trifluoroacetic acid and dichloromethane (1:1, 60ml). After lOmin at 20°C, the reaction mixture was concentrated in vacuo to give 2.2g of 5-{(1R)-l-[(2R)-2-amino-3-(2-naphthyl)propionyl-N-methylamino]- 2 -(2-naphthyl) ethyl)-[ 1, 2,4] oaxdiazole-3-carboxylic acid 2-propyl ester, trifluoroacetate, that was used for the next step without further purification. r 4-((lR)-l-{[(lR)-l-(3-(2-propoxy)carbonyl-[i,2,4;oxadiazol-5-yl)-2-(2-naphthy 1) ethyl ] -N-methylcarbamoy1} -2- (2-naphthyI) -ethylcarbamoyl)piperidine-l-carboxylic acid tert-butyl ester: ' N-(3-Dimethylaminopropyl)-N1-ethylcarbodiimide hydrochloride (1.22g, 6.35mmol) and 1-hydroxybenzotriazole monohydrate (0.97g, 6.3 5mmol) were added to a solution of N-tert-butoxycarbonyl-4-piperidinecarboxylic acid (1.46g, 6.35mmol) in N,N-dimethylformamide (20ml) . After 30min at 20°c a solution of 5-{ (1R)-1-[(2R)-2-amino-3-(2-naphthyl)propionyl)-N-methylamino]-2-(2-naphthyl)ethyl}-[l,2,4]oxadiazole-3-cartoxylic acid 2-propyl ester (2.95g, 4.53mmol) and triethylamine (0.47g, 4.53mmol)in N,N-dimethylformamide (20ml) was added. After 18h at 20°c the reaction mixture was poured on water (240ml) and extracted several times naphthyl ) ethyl ] -N-methylcarbamoyl } - 2 - ( 2 -naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester. 'H-NMR (DMSO-d6) 6 HPLC: Rt= 35.9 mill (Method a) 4-((lR)-l-{[(lR)-l-(3-(2-Propoxy)carbonyl-[l,2,4;oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2- naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (l.Og, i.34mmol) was dissolved in a mixture trifluoroacetic acid and dichloromethane (1:1, 25ml) . After 13 win at 20°C the reaction mixture was concentrated in vacuo. The ? compound was purified by flash chromatography with silica gel (75g) using a mixture of dichloromethane and 10% ammonia in ethanol (9:1) as eluent to give 0.77g of the title compound. :H-NMR (DMS0-d6) 8 . 4-((lR)-l-{[(lR)-l-(3-Ethoxycarbonyl-[l,2,4]oxadia!ol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naph"hy1)-ethy1carbamoyl)piperidine-l-carboxylic acid tert-butyl ester(0.79g, l.06mmol) was dissolved in dioxane (5.5ml). Water (3ml) and solid lithium hydroxide (0.03g) was added. After 18h at 20°C the reaction mixture was diluted with water (15ml) and extracted with tert-butyl-methylether (2xl0inl) . The aqueous phase was acidified with IN aqueous sodium hydrogenphosphate (2.5ml) and extracted with tert-butyl-methylether (3x40ml). The collected organic phases were dried (magnesium sulfate) and concentrated in vacuo. The residue was chromatographed on silica (60g) using a mixture of dichloromethane and 10% ammonia in ethanol (4:1) as eluent to give 0.41g of 4-(l-{[l-(3-ethoxycarbonyl-[1,2,4] oxadiazol-5-yl) -2- (2-naphthyl) ethyl] -N-mtJthylcarbamoyl)-2-(2-naphthyl)-ethylcarbamoyl)piperidine-l-carboxylic;acid. 'H-NMR (DMSO-d6) 5 . 4-(l-Ul-(3-Ethoxycarbonyl-[l,2,4]oxadiazol-5-yl)-2-(2-naphthy1) ethyl ] -N-methylcarbamoy 1} -2- (2-naph'ihy L) -ethylcarbamoyl)piperidine-1-carboxylie acid (0.1lg, 0. 58mmol) was was dissolved in a mixture trifluoroacetic acid and dichloromethane (1:1, 12ml). After 10 min at 20°C the reaction mixture was concentrated in. vacuo to give 0.4g of the title compound as a crude product. 'H-NMR (DMS0-d6) 5 PDMS; (teor. MH* = 606.7; found MH+ = 605.9) Example 20: Piperidine-4-carboxylic acid (l-{[l-(3-methylcarbamoyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2- (2-naphthyl)ethyl)amide: 4-{(1R) -1-{[ (1R) -1- (3-Propoxycarbonyl-[1,2,-4] oxadi naphthyl)ethylcarbamoyl)piperidine-l-carboxylic acid tert-butyl ester (0.80g, 1.07mmol) was dissolved in 33% methylamine in ethanol and stirred at 90°C for 18h in a closed reaction vessel. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica (60g) using ethyl acetate and heptane (7:3) as eluent to give 0.15g of 4-(l-{[l-(3-methylcarbamoyl- [l,2,4]oxadiazol-5-yl)-2-(2-naphthylJ- • ethyl]methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert butyl ester. lH-NMR (DMSO-d6) S HPLC: Rt= 31.5 min (Method a) 4-(l-{[i-(3-Methylcarbamoyl-[l,2,4]oxadiazol-5-yl)-2-(2- naphthyl)-ethyl]methylcarbamoyl}-2-(2- naphthyl)ethylcarbamoyl)piperidine-1-carboxylie acid tert butyl ester (0.15g, 0.21mmol) was dissolved ir a mixture of trifluoroacetic acid and dichloromethane (1:1,4ml). After 5min at 20°C the reaction mixture was concentrated in vacuo. The compound was purified by flash chromatography with silica gel 'H-NMR (DMS0-d6) 5 HPLC: Rt= 20,9 min (Method a) acid ethyl ester (3.3g, 9.0mmol) was dissolved in ethanol (30itil). Benzylamine (3ml) was added and the reaction mixture was stirred for I8h at 20°C. The reaction mixture was concentrated in vacuo and the residue was crystallised from ethanol to give 2.07g, of (R) 5-(l-methylamino-2-phenylethyl)-[l,2,4]oxadiazole-3-carboxylic acid benzylamide. m.p. 128-128.5°c lH-NMR (DMSO-d6) 5 2.22 (s, 3H); 3.08 (dd, 1H); 3.18 (dd, 1H); 4.26 (t, 1H) ; 4.45 (d, 2H) ; 7.10-7.45 (m, 1H) ; 9.50 (t, 1H) . , N-(3-Dimethylaminopropyl)-N'-ethylcarbodi imide hydrochloride (1.64g, 8.57mmol) and i-hydroxy-7-azabenzotriazole (1.17g, 8.57mmol) were added to a solution of (R) N-tert-bircoxycarbonyl-3-(2-naphthyl)-alanine (2.70g, 8.57iwnol) in N,N~dimethylformamide (40ml). After 20min at 20°C a solution of (K) 5-(l-methylamino-2-phenylethyl) - [ 1,2,4 ] oxadiazole-3-carboxylic acic\ be.nzylamide (2.06g, 6.12mmol) in dimethylformamide (40ral) was added. After 18h at 20°C the reaction mixture was poured on water (250ml) and extracted several times with ethyl acetate (total 2 00ml). The collected organic phases were washed with aqueous citric acid (10%, 50ml), a saturated solution of sodium hydrogencarbonate (3x50ml) and water (3x50ml)After drying (magnesium sulfate) the solution was concentrated in vacuo and the residue was chromatographed on { (lR)-l-{N-methyl-N-[ (1R) -l-(3-benzylcarbamoyl-[l,2 ,4]oxadiazol-5- yl) -2-phenylethyl ] carbamoyl} -2- (2-naphthyl) ethyl } caiHbamic acid tert-butyl ester (3.9g, 6.15mmol) was dissolved in a mixture of trifluoroacetic acid (40ml) and dichloromethane (40ml) at 20°C. After lOmin the reaction mixture was concentrated in vacuo and coevaporated from heptane and them from dichloromethane to give 4g of two isomers of crude 2-amino-N-methyl-N-[l-(:i-benzylcarbamoyl- [ 1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthylJpropionamide, trifluoro acetic acid that was used for the :iext step without further purification. H-NMR (DMSO-de) 5 2.88 (s) ; 3.21 (s) ; 3.32 (m) ; 3.55 (m) ; 4.52 (m) ; 5.95 (m); 6.21 (m). N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.40g, 2.1mmol) and l-hydroxybenzotriazole mcnohydrate (0.32g, 2.lmmol) were added to a solution of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (o.5ig, 2.lmmol) in N,N-dimethylformamide (5ml). After 30 min at 20°C a mixture of 2-amino-N-methyl-N-[l- (3-benzylcarbamoyl- [1,2,4] oxadiazol-5-yl) -2-phenylethyl]-3-(2-naphthyl)propionamide, trifluoro acetic acid (l.Og, 1.5mmol) and triethylamine (0.15g, :.. 5mmol) in N,N-dimethylformamide (12ml) were added. After 18h at; 20°C the reaction mixture was poured on water (100ml) and extracted several times with ethyl acetate (total 65ml). The organic phages were collected and washed with aqueous citric acid (10%, 20ml), a saturated solution of sodium hydrogencarbonate (20ml) ani water (3x20ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and the residue was chromatographed on silica (85g) using ethyl acetate and heptane (1:1) as eluent to 0.77g of two isomers of [ 1, l-dimethyl-4- (1-(N-methyl-[1- (:i-benzylcarbamoyl-[ 1, 2 , 4 ] oxadiazol-5-yl) -2-phenylethyl Jcarbamoyl } -2 - (2 -naphthyl)ethylcarbamoyl)but-3-enyl]carbamic acid tert-butyl ester. HPLC: Isomer I: Rt= 34.1 min (Method a) Isomer II: Rc= 34.4 min (Method a) [l,l-Dimethyl-4-(l-{N-methyl-[l-(3-benzylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]carbamoyl}-2- (2 -naphthyl)ethylcarbamoyl)but-3-enyl]carbamic acid tert-butyl ester (0.77g, l.Ommol) was dissolved in a mixture tr:.fluoroacetic acid (2ml) and dichloromethane (2ml). After lOmin at 20:)c the reaction mixture was diluted with dichloromethane (25ml) and neutralised with a saturated aquoeus solution of sodium hydrogencarbonate. The organic phase was dried (magnesium sulfate) and concentrated in vacuo to give 0.7g of two isomers of the title compound. HPLC: Isomer I: Rt= 24.5 min (Method a) Isomer II: Rc= 25.3 min (Method a) Oxalyl chloride (4.24 mL, 48.61 mmol) was dissolved in iichloromethane (30 mL). The solution was cooled to -63 °C. A solution of DMSO (4.6 mL, 64.81 mmol) in dichloromethane (20 mL) sras added dropwise. The solution was stirred for 5 tnin and a solution of N-( (1R) -1-(Hydroxymethy1)-2-phsnylethyl)-N- methyl carbamic acid tert-butylester 32.41 mmol) in dichloromethane (200 mL) was added dropw over a period of 30 min. The reaction mixture was stirred for rain i£ -63 °C . A solution of triethylamine (18.07 ml, 12'). 6 2 mmol) in dichloromethane (40 mL) was added over EI JI= riac. of 25 min. The solution was warmed to -35 °c and immediately cooled (to -63 °C It was stirred at this temp, for 1 h. Acetic (8.15 mL, 142.58 mmol) was added. The reaction mixture was warned tD 10 °c and washed with water (2 x 200 mL) and satd. sodium carbonate solution (150 mL) . The org. phase was dried over it a sulfate. The solvent was removed in vacuo to give 7.536 (1R) -1-formyl-2-phenylethyl)-N-methylcarbamic acid tert-estnr H-NMR (CDC13) : 6 = 1.40 and 1.44 (both s, gether 9H) ; 2.52 and 2.58 (both s, together 3H); 2.90 and 3.00 together 1H); 3.81 (dd, 1H) ; 4.00 and 4.20 (both dd, 1H) ; 7.10 - 7.35 (m, 5H) . N-((1R)-l-Formyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester (6.0 g, 20.04 mmol) was dissolved in ether (150 mL) . The solution was cooled to -78 °c and allylmagnesium bromide (22 mL of a 1.0 M solution in ether, 22 mmol) was added dropwise. After addition, the solution was warmed to room temp. It was given onto 10% ammonium chloride solution in water (200 mL The phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 50 mL) . The organic layers were combined and washed with satd. sodium hydrogencarbonate solution (100 mL) and dried over magnsium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (260 g) with ethyl acetate/heptane 1:1 to give 4.00 g of N-((1R)-l-benzyl-2-hydroxypent-4-enyl)-N-methylcarbamic acid tert-butylester. LH-NMR (CDC13) : S = 1.10 - 1.50 (m, 9H) ; 1.90 - 3.40 (m, 8H) ; 3.50 -4.10 (m, 2H) ; 5.00 - 5.30 (m, 2H) ; 5.90 (in, 1H; ; 7,10 - 7.40 (m, 5H) . I WE CLAIM : 1. A compound of general formula I wherein R3, R4, R5, R6, R7 and R8 independently are hydrogen or C1_6-alkyl optionally substituted with halogen, amino, hydroxy or aryl; Rs and R6, R6 and R7, R5 and R8 or R7 and R8 optionally forming -(CH2)rU-(CH2)j-, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; R12, R13 and R14 independently are hydrogen, -COOR15, -CONR,6R17, -(CH2)vNR,6R17, -(CH2)uOR15, halogen, hydroxy, C1-6-alkyl, phenyl, oxazol-5-yl, 5-methyl-[l,2,4]oxadiazol-3-y[) R1', R15, R16 and R17 independently are hydrogen or C.-alkyl optionally substituted with aryl, and u and v are independently 0 or 1, 2, 3,4, 5 or 6; optionally substituted with halogen, amino, hydroxy, C1-6-alkyl or C,-alkoxy; said compounds of formula I comprising any optical isomers thereof in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof; or a pharmaceutically acceptable salt thereof; with the proviso that when n is 1, B or F is not an amide or an amine. wherein R5, R6, R7 and R8 independently are hydrogen or C1-6-alkyl optionally substituted with halogen, amino, hydroxy or aryl; R5 and R6, R6 and R7, R5 and R8 or R7 and R8 optionally forming -(CH2)i-U-(CH2)j-, wherein i and j independently are 1 or 2, and U is -O-, -S- or a valence bond; optionally substituted with halogen, amino, hydroxy, C1-alkyl or C1.6-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; andr+s+t is I, 2, 3 or 4. 4. The compound as claimed in any one of the preceding claims, wherein G and J independently are 5. The compound as claimed in any one of the preceding claims, wherein D is wherein R5, R6, R7 and R8 independently are hydrogen or C1-6-alkyl optionally substituted with halogen, amino, hydroxy or aryl; R5 and R6, R6 and R7, R5 and R8 or R7 and R8 optionally forming -(CH2)j-U-(CH2)j-, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; optionally substituted with halogen, amino, hydroxy, Cj-alkyl or C1-6-alkoxy; o, r and t are independently 0,1, 2, 3 or 4; q and s are independently 0 or 1; andr+s+tis 1,2, 3 or 4. 6. The compound as claimed in any one of the preceding claims, wherein R5, R6, R7 and R8 independently are hydrogen or Cj-6-alkyl optionally substituted with halogen, amino, hydroxy or aryl; R5 and R6, R6 and R7, R5 and R8 or R7 and R8 optionally forming -(CH2)rU-(CHi)r, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; optionally substituted with halogen, amino, hydroxy, C1-6-alkyl or C1-6-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; qis 1; s is Oor 1; andr+s+tis 1, 2, 3 or 4. wherein Xis-N(Rn)-or-0-, Vis-C(R,2)= or-N=, Y is -N=, Zis-C(Ri4)= or-N=, R12 and R14 independently are hydrogen, -COOR15, -CONR16Ri7, -(CH2)VNR16R17, -(CH2)uOR15, halogen, hydroxy, C1-6-alkyl, phenyl, oxazol-5-yl, 5-methyl-[ 1,2,4]oxadiazol-3 -y 1, R1', R15, R16 and R17 independently are hydrogen or C1-6-alky! optionally substituted with aryl, and u and v are independently 0 or 1, 2, 3, 4, 5 or 6. wherein Xis-N(Rn)-or-0-, V is -C(R!2)=, Yis-N=, Zis-C(R,4)= or-N=, Ri2 and R14 independently are hydrogen, -COOR15, -CONRl6R17, -{CH3)vNRl6R17, -(CH2)uOR15, halogen, hydroxy, C1-6-alkyl, phenyl, oxazol-5-yl, 5-methyl- [ 1,2,4]oxadiazoI-3-yl, Ru, R15, R16 and R17 independently are hydrogen or C1-6-alkyl optionally substituted with aryl, and u and v are independently 0 or 1, 2,3,4, 5 or 6. 9. The compound as claimed in any one of the preceding claims, selected from the group consisting of Piperidine-4-carboxylic aC1d (1 - {[ 1 -(3-carbamoyl-! 1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl} -2-(2-naphthyl)ethyl) amid" 5-{(lR)-l-[(2R)-2-{Piperidine-4-carbonylamtno)-3-(2-naphthyl)propionyl-N-methylamino]-2-(2-naphthyl)ethyl}-[l,2,4]oxadiazole-3-carboxylic aC1d ethyl ester, 5-{l-[2-(3-Aminomethylbenzoyl)-3(2-naphthyl)propionyl-N-methylamino]-2-(2-naphthyl)ethy[}-[l,2,4]oxadiazole-3-carboxyIic aC1d ethyi ester, 5-{(lR)-l-[(2R)-2-(3-Aminomeliiylbenzoylamino)-3-{2-naphthyl)propionylainino]-2-phenylethyl}-[l,2,4]oxadiazole-3-carboxylic aC1d ethyl ester, or the triflouroacetic aC1d salt thereof, Piperidine 4-carboxylic aC1d N-[( 1R)-1 - {(1R)-1 -(3-methyl-[ 1,2,4]oxadiazol-5-yl)-2-phenylethyIcarbamoyl}-2-(2-naphthyl)ethyl]amide, 3-AminomethyI-N-[(lR)4-{(lR)-l(3-methyl-[l,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl}-2-(2-naphthyl)ethyl]benzamide, 4-Amino-4-methyl-pent-2-enoic aC1d [(lR)-l-{(lR)-l-(3-methyl-[I,2,4]oxadiazol-5-yl)-2-phenyIethylcarbamoyl}-2-(2-naphthyl)ethyl]amide, (3R)-Piperidine 3-carboxylic aC1d [(lR)-l-((lR)-l-(3-methyl-[l,2,4]oxadiazol-5-yt)-2-phenylethylcarbamoyI)-2-(2-naphthyl)ethyl]amide, 5-((lR)-lK-Methyl-N-((2R)-3-(2-naphthyl)-2-(piperidin-4-yl-carbonylamino)propionyl)amino)-2-(2-naphthyl)ethyI)-[l,2,4]oxadiazoIe-3-carboxylic aC1d ethyl ester, 5((lR)-l-(N-((2R)2-(3-Aminomethylberoylamko)-3-(2-naphthyl)propionyl)-N-methylamino)-2-(2-naphthyl)ethyl)-[l,2,4]oxadiazole-3-carboxylic aC1d ethyl ester, 5((lR)-l-(N-((2R)-2-(3-AminomethyIbenzoylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-2-phenylethyl)-[l,3,4]oxadiazole-2-carboxylic aC1d amide, (2E)-5-Amino-5-methylhex-2-enoic aC1d {(lR)-l-[N-methyl-N-({lR)-l-(3-methyl- [l,2,4]oxadiazol-5-yl)-2-(2-naphthyl)-ethyl)carbamoyl]-2-(2-naphthyl)ethyl} amide, 4-Amino-4-methylpent-2-enoic aC1d N-[(lR)-l-{N-methyl-N-[(lR)-l-(3-methyl-[l,2,4]oxadiazol-5-yI)-2-(2-naphthyl)ethyl]carbamoyI}-2-(2-naphthyl)ethyl]-N-methylamide, 4-Amino-4-methylpent-2-enoic aC1d [(lR)-l-{N-methyl-N-[(lR)-l-(3-methyI-[l,2,4]oxadiazol-5-yl)-2-(2-naphthyl)e%l]carbamoyl}-2-(2-naphthyl)ethyl]amide, 5-((lR)-l-(((2R)-2-(((2E)-4-Amino-4-methylpent-2-enoyl)methylamino)-3-(2-naphthyl)propionyl)methylamino)-2-phenylethyl)-[l,3,4]-oxadiazoIe-2-carboxylic aC1d amide, Piperidine-4-carboxylic aC1d N-methyl-N-{1 -(methyl-[ 1 -(3-methyl-[ 1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoy l)-2-(2-naphthy I)ethyl} amide, Piperidine-4-carboxylic aC1d N- {1 -(N-methyl-N-[ 1 -(3-methyl-[l,2,4]-oxadiazoI-5-yl)-2-(2-naphthyl)ethyI]carbamoyl)-2-(2-naphthyl)ethyl}amide, 5-{l-[N-(2-(piperidine-4-carbonylamino)-3-(2-naphthyl)propionyl)-N-methylamino]-2-(2-naphthyl)ethyl}-[l,2,4]oxadiazole-3-carboxylic aC1d 2-propyl ester, 5-{l-[N-(2-(piperidine-4-carbonyIamino)-3-(2-naphthyl)propionyl)-N-methylamino]-2-(2-naphthylJetoylHlJoxadiazole-S-carboxylic aC1d, trifluoro acetate, Piperidine-4-carboxylic aC1d (l-{N-[l-(3-methylcarbamoyl-[l,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)amide, {2E)-5-Amino-5-methyIhex-2-enoic aC1d {l-[N-(l-(3-benzylcarbamoyl-[l,2,4]oxadiazol-5-yI)-2-phenylethyl)-N-methyl-carbamoyI]-2-(2-naphthyl)ethyl} amide, Piperidine-4-carboxylic aC1d ((lR)2-(2-naphthyl)-l-((lR)-2-(2-naphthyl)-l-(l- phenethyl-lH-tetrazo[-5-yI)ethyt-carbamoyl)ethyl)amide, Piperidine-4-carboxylic aC1d ((lR)-l-((lR)-H4-carbamoyl-5-phenyl-13-thia2ol-2-yl)-2-(2-naphthyl)ethylcarbamoyl)-2-(2-naphthyl)ethyl)amide, (2E)-5-Amino-5-methylhex-2-enoic aC1d {l-[N-(l-(3-methylcarbamoyl-[l,2,4]oxadiazol-5-yl)-2-phenylewyl)-N-memyl-carbamoyl]-2-(2-naphthyl)ethyl} amide, (2E)-5-Amino-5-methylhex-2-enoic aC1d {l-[N-(l-(3-dimethylcarbamoyl-[l,2,4]oxadiazol-5-yI)-2-phenylethyI)-N-methyl-carbamoyl]-2-(2-naphthyl)ethyl} amide; and any optical isomers thereof in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof; and pharmaceutically acceptable salts thereof. said compounds comprising any optical isomers thereof in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof; wherein R , R , R and R independently are hydrogen or C1-6-alkyl optionally substituted with halogen, amino, hydroxy or aryl; R5 and R6, R6 and R7, R5 and R8 or R7 and R8 optionally forming -(CH2)j-U-(CH2)j-, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, said compounds comprising any optical isomers thereof in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof; optionally substituted with halogen, amino, hydroxy, C1-6-alkyl or C1-6-alkoxy; o, r and t are independently 0,1,2, 3 or 4; q and s are independently 0 or 1; andr+s+tis 1,2, 3 or 4. 18. A pharmaceutical composition comprising, as an active ingredient, a compound as claimed in any one of claims 1 to 17 together with a pharmaceutically acceptable carrier or diluent. 19. The pharmaceutical composition as claimed in claim 18, in unit dosage form, comprising from about 10 to about 200 mg of said compound. 20. The pharmaceutical composition for stimulating the release of growth hormone from the pituitary, the composition comprising, as an active ingredient, a compound as claimed in any one of claims lto 17 together with a pharmaceutically acceptable carrier or diluent.

Documents:

125-mas-96 abstract duplicate.pdf

125-mas-96 abstract.pdf

125-mas-96 claims duplicate.pdf

125-mas-96 claims.pdf

125-mas-96 correspondence others.pdf

125-mas-96 correspondence po.pdf

125-mas-96 description (complete)-1.pdf

125-mas-96 description (complete)-2.pdf

125-mas-96 description (complete)-3.pdf

125-mas-96 description (complete).pdf

125-mas-96 form-19.pdf

125-mas-96 form-2.pdf

125-mas-96 form-26.pdf

125-mas-96 form-4.pdf

125-mas-96 form-6.pdf

125-mas-96 petition.pdf