WO1994015917A1 - Alpha-methyl-(r)-tryptophyl-arylcycloalkylalkylamides as ligands for gastrin receptors - Google Patents

Abstract

An α-methyl-R-tryptophyl-arylcycloalkylalkylamide of formula (I), wherein (B) is methylene or ethylene, (C) is a valency bond or methylene, A is a valency bond or aminocarbonyl, p is 0, 1 or 2, R1 is a 1H-tetrazol-5-yl group, a carbonyl function -CO-R2 where R2 is hydroxyl, alkoxy or a cycloalkylamine, and * is the absolute configuration, according to Cahn, Ingold and Prelog, of the carbon atom adjacent thereto. It is useful as a drug for treating gastric and/or central nervous system disorders.

Description

 ALPHA-METHYL- (R) -TRYPTOPHYL-ARYLCYCLOALKYLALKYLAMIDES AS

 GASTRINE RECEPTOR LIGANDS

The subject of the present invention is new derivatives of α-methyl-R-tryptophyl-arylcycloalkylalkylamides, their preparation process and their use in therapy, in particular for their affinity for gastric receptors.

Many functions of the organism are regulated by peptide hormones which, since the sixties, have been the subject of research aimed at both the elucidation of their structure and that of their mechanism of activity. With regard to digestive functions, several hormones from the gastrointestinal tract have been discovered, including particularly in 1964 the hormones of the gastrin group (Gregory et al.), Then in 1968 the hormones of the cholecystokinin group (Mutt and Jorpes) .

In each group there coexist several peptides corresponding to the splitting derivatives of the peptide which has the longest chain and which comprises 34 amino acids for gastrin and 33 amino acids for cholecystokinin, the compounds of the two groups all having in common their tetrapeptide sequence terminal constituted by the sequence -Trp-Met-Asp-Phe-NH ₂ . The various cholecystokinins (CCK) have been the subject of intensive studies which have demonstrated their affinity for peripheral receptors which have been termed CCK _A and / or for central receptors which have been termed CCK _B , these receptors inducing by interaction with ligand compounds with different biological effects, mainly in the gastrointestinal tract for the CCK _A interaction and mainly in the central nervous system for the CCK _B interaction ("Cholecystokinin receptors" - Cl. Nagain , Cl. Rozé -Gastroenterol. Clin. Biol, 1991, 15, 735- 743.)

Due to their common terminal tetrapeptide, peptide compounds ligands to CCK receptors can also be gastrin receptor ligands (Dockray, GJ - Quat. J. Exp. Physiol 1988, 73, 703-27).

In this state of knowledge, considerable work has been done to obtain synthetic compounds, resistant to peptidases, which are selective ligands, agonists and / or antagonists, to CCK receptors of type A or B. A state representative of these works and of the proposed compounds was established in 1989 by Ben E. Evans (Drugs of the Future, 1989, 14 (10): 971-977) and, more recently with regard to CCK _B receptor antagonist compounds, by Mark G. Bock (Drugs of the Future, 1991, 16 (7): 631-640) then by F. Makovec (Drugs of the Future, 1993, 18 (10): 919-931).

CCK _B type receptors have been predominant in many brain regions and, at this level, their involvement in the effect of dopamine has been recognized. Various non-peptide molecules with CCK _B receptor antagonist affinity, belonging to different chemical families, have been proposed to treat nervous and psychotic conditions (Mark G. Bock and F. Makovec - already cited) and, among these compounds, derivatives α-methyl-R-tryptophan have been described for remarkable activity.

 Thus, in European patent application 0405,537 A1, the acid is described in Example 20:

[R- (R *, R *) - 4 - [[2 - [[3- (1H-indol-3-yl) -2-methyl-1-oxo-2- [[(tricyclo [3.3.1.1 ^{3 , 7} ] dec-2-yloxy) carbonyl] amino] propyl] - amino] -1-phenylethyl] amino] -4-oxobutanoic of formula:

which, identified under the codes PD-134,308 then CI-988 has been the subject of extensive pharmacological studies which have demonstrated its antagonistic affinity for the CCK _B and gastrin receptors (J. Med. Chem. 1991, 34 404-414 ; ibid 1992, 35, 1472-1484, 1572-1577, 2573-2581). Particularly the anxiolytic activity of the product has been shown and seems to be specific (Singh et al., Brit. J. Pharmacol. (1991) 104. 239-245).

Also, in published applications WO 92/04045, WO 92/04320 and WO 92/04322, pseudo-peptides derived from tryptophan, of structures related to PD-134,308 and for which it is only objectively shown are described. CCK _B receptor antagonist type affinity for the various pharmacological tests presented.

As described these inventions favor, in relation to this affinity, the usefulness of the products for the treatment of various affections directly or indirectly related to psychotic states (Singh et al., Already cited).

 However, it is known that gastrins, through the stimulation of secretion of water and gastric electrolytes have their own role in the control of gastric secretions and in the control of the blood circulation intervening in the process of gastric motility.

 In addition, the role of gastrin secreting cells is implicated in certain gastrointestinal tumors.

Therefore, and independently of a coexisting CCK receptor affinity, compounds of antagonist affinity to the gastrin receptors are of great interest.

 Thus, gastric antagonists are useful in conditions involving excessive acid secretion, for the treatment and prevention of gastrin disorders dependent on the human and animal gastrointestinal system, such as peptic ulcers, Zollinger-Ellison syndrome, hyperplasia and gastric cell neoplasms.

Different from the state of the art, and in order to respond to this interest, new compounds have just been found which have a significant affinity for gastrin receptors. characterized in that it is equal if not significantly greater than their affinity for CCK B receptors.

As such, the present invention relates to new derivatives of α-methyl-R-tryptophyl-arylcycloalkylalkylamides of formula (I)

in which,

(B) represents a methylene (-CH ₂ -) or ethylene (-CH ₂ - CH ₂ -) group,

(C) represents a valence bond or a methylene group (- CH ₂ -),

A is a valence bond or an aminocarbonyl group

 (NH-CO),

p has the value 0, 1 or 2,

R ₁ represents a 1H-tetrazol-5-yl group or else a carbonyl function -CO-R ₂ in which R ₂ is hydroxyl, lower alkoxy, N-indolinyl or R _{2 also} represents a cycloalkylamine of formula (VIII),

in which R ₃ is hydrogen or a hydroxyl radical, oa for value 0 or 1 and R ₄ is hydrogen or a chlorine atom, * represents, established according to the rule of Cahn, Ingold and Prelog, the absolute configuration of the carbon in position 1 of the cycloalkyl sequence, and their optional addition salts with pharmaceutically acceptable bases.

 For simplification of the formulas in the text and the figures below:

- the sequence (tricyclo [3.3.1.1 ^3,7 ] dec-2-yloxy) carbonyl is called (2-adamantyloxy) carbonyl and represented by the commonly accepted acronym 2-Adoc,

 - the sequence (1H-indol-3yl) is represented by the acronym 3Ind, as shown below:

Also by lower alkoxy is meant alkoxy radicals comprising from 1 to 4 carbon atoms in a linear or branched chain. A distinction is made in all of the compounds (I) of the invention: - a group of compounds in which A and (C) are a valence bond, pa for value 0 and R ₁ is a carbonyl radical -CO-R ₂ which meets the formula (Ia).

in which (B), * and R ₂ have the meanings previously defined, and

 - a group of preferred compounds in which (C) is methylene which corresponds to the formula (I.b.)

in which (B), * and R ₁ have the meanings previously defined and pa for value 1 or 2.

Among the compounds (Ib), preference is given to those in which (B) is methylene and pa for value 2 and, more particularly, those in which the asymmetric carbon 1 (*) is of configuration (R) and, as such, the 4- [(1R) -1- [1- [1- [N- [(2- adamantyloxy) carbonyl] -α-methyl-tryptophyl-aminomethyl] - indanyl] amino] -4-oxo-butanoic acid. (Ib; B = -CH2-, p = 2, R1 = CO-R ₂ with R ₂ = OH, * = R) and its addition salt with N-methyl-D-glucamine.

Another aspect of the invention relates to a preparation process characterized in that it consists: a) for preparing a compound (I) in which,

A and (C) are a valence bond, pa for value O and R ₁ is a carbonyl radical -CO-R ₂ which corresponds to formula (Ia)

in which (B) and * have the meanings mentioned for (I) and R ₂ is lower alkoxy,

- or, according to the preferred method, to condense in tetrahydrofuran an intermediate (II. a)

in which R ₂ is lower alkoxy, with 2-adamantyl chloroformate, - or to react the N - [(2-adamantyloxy) carbonyl] -α-methylR-tryptophan (VI) with cyanuric fluoride to obtain the fluorinated intermediate derivative (VI ')

which, without being isolated, is condensed in methylene chloride in the presence of triethylamine with an arylcycloalkylamine (IV.a)

in which R ₂ is lower alkoxy, and,

to prepare a compound (Ia) in which R ₂ is hydroxyl, to saponify in dioxane with lithium hydroxide a compound (Ia) in which R ₂ is lower alkoxy then, optionally to react the acid thus obtained with the N-methyl-D-glucamine which is the preferred base for obtaining the corresponding addition salt, and, b) for preparing a compound (I) in which,

A is aminocarbonyl (NH-CO), C is methylene (-CH ₂ -), pa for value 1 or 2 which corresponds to the formula (Ib).

in which (B), *, p and R ₁ have meanings mentioned for (I), - or, according to the preferred method, to condense in tetrahydrofuran an intermediate (IV. b)

in which Z is an amino protecting group such as the benzyloxycarbonyl group which is preferred, with 2-adamantyl chloroformate to obtain an intermediate (III. b)

from which the protective group Z is removed by hydrogenolysis to obtain an intermediate (II. b)

which is acylated with a reagent (IX) of formula W-OC- (CH ₂ ) pR ₁ in which W represents bromine, chlorine or a hydroxyl radical and R ₁ has the meanings mentioned for (I), except when R ₇ represents a hydroxyl, to obtain a corresponding compound (Ib), or,

which is acylated by the internal anhydride of a diacid such as succinic anhydride to obtain a corresponding compound (Ib) in which pa for value 2 and R ₁ is a radical -CO-R ₂ in which R ₂ is hydroxyl, then optionally reacting the acid thus obtained with N-methyl-D-glucamine to obtain the corresponding addition salt,

 - or to condense the N - [(2-adamantyloxy) carbonyl] -α-methyl-R- tryptophan (VI) in tetrahydrofuran with an arylcycloalkylamine (VII. b)

in which Z is a protective group such as the benzyloxycarbonyl group, in order to obtain an intermediate (III. b) from which the group Z is removed to obtain a compound (II. b) and which is then acylated to obtain a compound of the invention (Ib) as previously described.

As shown in Schemes 1 and 2, the preferred methods involve the preparation of the compounds (Ia) and (Ib) of the invention:

 a reaction iii) of condensation of the 2- adamantyl chloroformate with the amino intermediates (II.a) or (IV.b), to prepare the compounds (I.a) and (III. b),

 a reaction iv) of selective hydrogenolysis of the N-protective benzyloxycarbonyl group of an intermediate (Ill.b), to prepare the compounds (II.b),

- A reaction v) of acylation of the precursor intermediates (IIb), to prepare the compounds (I.b).

The implementation of reactions iii) uses standard conditions known to those skilled in the art which are described inter alia by Geiger R. and Koenig W. (1980) in "The peptides" vol. 3, p.3-136 (Gron E. - Meienhofer J., ed.) Académie Press, New-York. Among the various possibilities, use is made of reacting in a neutral and aprotic solvent such as tetrahydrofuran or methylene chloride which is preferred, equimolecular amounts of an amino intermediate (II.a) or (IV.b) with 2-adamantyl chloroformate itself prepared from 2-adamantanol as described for example in J. of Med. Chem. 1991, vol. 34, N ° 1 p. 411. Advantageously, an equivalent of triethylamine is added to the reaction medium, the reaction being carried out at a temperature between - 10 ° and 10 ° C and more favorably at 0 ° C for approximately 16 hours; the product being finally isolated by the usual methods and purified by chromatography on silica.

The hydrogenolysis reaction iv) of the intermediates (Ill.b) is carried out in solution in a neutral protic solvent, such as a primary alcohol with a boiling point below 100 ° C and miscible with water. Ethanol is the preferred solvent, the catalyst used being 5 or 10% palladium-on-carbon activated appropriately for decarboxybenzylations. The reaction is complete after 2 to 24 hours under pressure of hydrogen from 1 to 10 bars at a temperature between 20 and 70 ° C.

 Preferably, using 10% (w / w) palladium-on-carbon, satisfactory results are obtained under a pressure of 5 bars of hydrogen, at 60 ° C. and this after 5 hours of reaction.

Also the acylation reaction v) calls upon known methods which consist:

- when in the reagent (IX) W-OC- (CH ₂ ) pR ₁ W is chlorine or bromine, to be reacted with reflux of a neutral aprotic solvent, for one mole of intermediate (Il.b) of 0.8 to 1.5 moles of the reagent (IX), in the presence of 1 to 3 moles of triethylamine, at a temperature between 0 and 80 ° C for 1 to 24 hours.

With methylene chloride which is the preferred solvent, for one mole of the intermediate (IIb), 1.1 mole of the halogenated acylation reagent is reacted in the presence of 1.2 mole of triethylamine, the reaction being complete after 5 hours at reflux of the solvent, and,

- when in the reagent (IX) W-OC- (CH ₂ ) p-R1, W is hydroxyl, the carboxylic function is condensed with the amine function of the compound (Il.b) according to well known techniques, many of which will be found examples in, among others, Houben-Weyl's work, Methoden der organischen Chemie, Synthèse von peptide, vol. 15/1, fourth edition, Georg Thieme Verlag, 1974, pages 533 to 538 and pages 836 to 845.

 Thus, various techniques calling upon the activation of the carboxylic function are proposed to achieve this condensation:

a) use a coupling agent which can be a diimide such as N, N'-diisopropylcarbodiimide (DIC), or N ', N'- dicyclohexylcarbodiimide (DCC) optionally in the presence of an additive such as hydroxybenzotriazole ( HOBT), N-hydroxy-succinimide or N-hydroxyphthalimide, which are intended to avoid side reactions,

b) transforming the carboxylic function beforehand into an activated ester with a substituted phenol such as pentafluorophenol, or else a mixed anhydride activated by reaction with an alkyl or aryl chloroformate, isobutyl chloroformate being preferred,

c) however, the particularly preferred method consists in using as a condensing agent PyBroP (R) which is bromo-tris-pyrrolidino-phosphonium hexafluorophosphate. The operating conditions then consist in carrying out the reaction in tetrahydrofuran at 20 - 25 ° C by reacting equimolecular amounts of amino intermediate (IIb) and of the acid reagent (IX) in the presence of an equimolecular amount or an excess can expect 50% PyBrop (R) and an excess (300%) of triethylamine.

 The reaction is generally complete after 16 hours of contact, the product (I.b) obtained being then isolated and then purified by chromatography, and,

 - when the acylation reagent is an anhydride of a diacid such as succinic anhydride, the preferred procedure consists in reacting in tetrahydrofuran, one mole of amine (II.b) with one mole of succinic anhydride in the presence one and a half moles of triethylamine, the reaction being complete after 4 to 8 hours of heating at reflux.

Also, a process for preparing the compounds of the invention (Ia) and (Ib) in which R ₂ is hydroxyl consists in saponifying their corresponding analogs in which R ₂ is an alkoxy radical.

 To this end, the saponification is carried out in an aqueous alkaline medium and in the presence of a water-miscible solvent. An aqueous solution of lithium hydroxide is preferred and using methanol or dioxane as solvents. The reaction is carried out at 0 ° C. with stirring and lasting from 1 to 24 hours depending on the reactivity of the ester to be saponified.

 After complete reaction of the product involved, the reaction medium is evaporated and then the residual product is generally purified by chromatography on silica.

As they have just been described, the essential precursors which allow the preparation of the compounds of the invention (Ia) and (Ib) are respectively the intermediaries (II. a) and (IV. b) which are prepared by methods which are represented in diagrams 1 and 2. They consist in condensing according to reaction i) a derivative of l α-methyl-R-tryptophan (V) and as described for example in Eur. J. Med. Chem. (1990) 25, p.57, in which Xoc represents an X-oxycarbonylated N-protecting group in which X is an alkyl, aryl or else polyaralkylalkyl, the t.butyl radical being however preferred to give protecting groups N- [ (t-butyloxy) carbonyl] (abbreviation Boc), with either an amino ester (IV.a) in which R ₂ is lower alkoxy, or a diamine (Vll.b) intermediate in order to obtain the respective pseudo dipeptides (III .a) and (Va) then carry out according to reaction ii) N-deprotection of their sequence Xoc- trifluoroacetic medium. Advantageously, the condensation reaction i) is carried out in an inert solvent such as tetrahydrofuran or dioxane and in the presence of a condensing agent such as dicyclohexylcarbodiimide or carbonyldiimidazole or also and preferably PyBroP (R) previously mentioned.

Preferably, the N-deprotection reaction ii) is carried out by the method of Sharp et al., JJ. Sharp, AB Robinson, MD Kamen, J.Am. Chem. Soc., 95, 6097 (1973), ("for the synthesis of Trp centaining fragments, anisole containing 2% EDT (ethane dithiol) was employed during the TFA -N ^α deprotection in order to suppress Indole alkylation")

to selectively eliminate the Boc group while respecting the protection Z carried by the other part of the molecule, and this in particular when Z is a benzyloxycarbonyl group.

Scheme 3 shows the routes of preparation of the amino ester intermediates (IV.a) and diamines (VII.b) in their racemic and optically active forms, which consist of a succession of syntheses known to those skilled in the art.

Thus, the preparation of an amino ester (IV.a), starting from a ketone (Pr.a) consists, by reaction with an alkaline cyanide and ammonium carbonate in an ethanolic medium, in preparing the spiro- hydantoin (Pr.b) which can be split into its enantiomers, for example according to the method described in patent application WO 92/08702, then to practice hydrolysis in an aqueous medium, at a temperature close to 140 ° C. in the presence of sodium or barium hydroxide or in the presence of sulfuric acid to obtain the α-amino acids (Pr.c) which are esterified with methanol in an acid medium to obtain the α-amino esters (IV.a) which, in their racemic forms, can be split into their enantiomers by formation of diastereoisomers with for example the acid (R) - (-) - 4-hydroxydinaphto [2,1-d: 1 ', 2'-f] [ 1,2,3] dioxaphosphepin-4-oxide.

The preparation of diamines (VII. B) is advantageously carried out from α-amino esters (IV. A) which are condensed with a reagent suitable for temporarily inactivating the reactivity of the amino function as by their reaction with benzyl chloroformate for prepare a compound (Pr. f), the ester function of which is saponified in order to obtain an intermediate acid (Pr. d), the corresponding amide of which (Pr. g) is prepared by reaction of ammonia with an activated intermediate of the acid which , according to the preferred method is a mixed anhydride obtained by preliminary reaction with an alkyl chloroformate. Finally the intermediate diamine (Vll.b) is obtained by reduction of the carbamide function of the intermediate (Pr. G) by means of a metal hydride complex such as borane-dimethylsulfide which is the preferred reducing agent. The experimental part which follows describes, without limitation, the products of the invention, their intermediates, as well as their preparation methods.

 The techniques used are common to those skilled in the art, so the purification of the products is carried out by conventional methods such as crystallization and / or preparative column chromatography.

 For the latter method (purification by chromatography in the text of the examples) the "chromatoflash" technique according to W. Clark Still et al., J. Org. Chem., 1978, 43, (14), 2933 is used using a silica gel support with a grain size of 0.043-0.063 mm and a quantitative ratio of product to be purified relative to the support of 1/20 to 1/100 depending on the separation difficulties.

The methods used to check the purity and structure of the compounds obtained are:

 - thin layer chromatography (TLC) on ready-to-use silica plates - thickness 0.25 mm - fluorescence indicator of 254 nm,

- the proton nuclear magnetic resonance spectrography which, unless specified, is recorded on a 90 MHz device, the products being dissolved in deuterodimethylsulfoxide or deuterochloroform. The displacements in ppm of the main peaks relative to tetramethylsilane are reported in the examples as well as their attribution and the nature of the signals which is expressed in a conventional manner.

In many cases, the amorphous nature and / or the high hygroscopicity of the products makes the determination of their melting point uncertain. The temperatures then indicated correspond, during the determination by the capillary tube method, to the start of the melting which is appreciated by a softening of the product and for the second value to the total melting which corresponds to the liquid state of the sample. . EXPERIMENTAL PART

COMPOUNDS OF THE INVENTION Example 1-A: (R, S) [1- [1- [N- (2-adamantyloxy) carbonyl] -α- methyl-R-tryptophyl] -1-amino] -1-methoxycarbonyl- indane. (Ia; (B) = -CH ₂ , R ₂ = OCH ₃ , * = R, S)

 Under a nitrogen atmosphere at -15 ° C, in a stirred solution of 3.0 g (7.57 mmol) of N-2Adoc-α-methyl-R-tryptophan (VI) prepared according to Eur. J. Med. Chem (1990) 25, 53-60 in 35 ml of methylene chloride, 0.6 g (7.57 mmol) of pyridine is added, then, dropwise, a solution of 5.1 g (111 mmol) of cyanuric fluoride . The mixture is stirred for another hour at -15 ° C. and a mixture of 50 g of ice and 50 g of methylene chloride is added. The emulsion is filtered on celite and after decantation the organic phase is washed with water. It is dried and evaporated in vacuo. 3.0 g of crude N-2Adoc-α-methyl-R-tryptophan fluoride are obtained, which is used without purification in the following step.

R.M.N. : (DMSO) δ = 8.15 (broad 1H exchangeable); 7.8-6.9

(m 6H including 1H exchangeable); 4.7 (m 1H); 3.2 (s 2H); 2.2-1.0 (m 17H including αmethyl at 5 = 1.55).

At 0 ° C, under a nitrogen atmosphere, to a solution of 2.12 g (11.1 mmol) of (R, S) 1-amino-1-methoxycarbonyl-indane (IV. A; (B) = - CH ₂ -, R ₂ = OCH ₃ ) prepared according to J. Med. Chem. (1988), 31 (1), 230-43, 2.7 g (22.2 mmol) of triethylamine are added, then dropwise, a solution of 4.3 g (10.8 mmol) of the crude fluoride obtained above in solution in 50 ml of methylene chloride. After 1 hour of stirring, the mixture is heated for 4 hours at reflux temperature, cooled, washed with an N / 10 solution of potassium acid sulfate and then a 5% sodium bicarbonate solution.

 The organic phase is dried, evaporated under vacuum. The residue is chromatographed on silica eluting with a gradient of ethyl acetate in methylene chloride. 3.5 g (yield = 56%) of purified product are obtained. Mp 102-115 ° C.

TLC: CH ₂ Cl ₂ / AcOEt 90/10 Rf = 0.62. NMR: (DMSO) δ = 8.40 (broad 1H exchangeable); 7.65-7.45 (m 1H); 7.4-6.8 (m 10H including 2H exchangeable); 5.48 (d 1H); 4.75 (s 1H); 3.85 (d 1H); 3.63 (s 3H); 3.05-2.8 (m 4H); 2.6-1.2 (m 17H).

Analysis: C ₃₄ H ₃₉ N ₃ O ₅ , 3 / 4H ₂ O

 Wedge%: C 70.02 H 7.00 N 7.21 O 15.77

 Tr.%: C 70.05 H 7.09 N 7.21 O 15.40

Example 1-B: (R) [1- [1- [N- (2-adamantyloxy) carbonyl] -α-methyl-R- tryptophyl] -1-amino] -1-methoxycarbonyl-indane.

(Ia; (B) = -CH ₂ , R ₂ = OCH ₃ , * = R)

The compound is prepared as described in Example 1-A above from N-2Adoc-α-methyl-R-tryptophan and from (R) 1-amino-1-methoxycarbonyl-indane (IV. A; (B ) = -CH ₂ -, R ₂ = OCH ₃ ) prepared as described in preparation 3bis. The crude product is purified by chromatography on silica, eluting with a methylene chloride-ethyl acetate mixture 90-10 (v / v).

 Yield = 70% F = 102-115 ° C.

[α] ²⁰ D = + 66 ° (c = 1.0; methanol)

CCM: CH ₂ Cl ₂ / AcOEt 90/10 Rf = 0.25.

 R.M.N. : (DMSO) identical to that of Example 1-A

Analysis: C ₃₄ H ₃₉ N ₃ O ₅

 Wedge%: C 71.68 H 6.90 N 7.38 O 14.04

 Tr.%: C 71.53 H 6.92 N 7.43 O 13.89

Example 1-C: (S) [1- [1- [N- (2-adamantyloxy) carbonyl] -α-methyl-R- tryptophyl] -1-amino] -1-methoxycarbonyl-indane.

(Ia; (B) = -CH ₂ , R ₂ = OCH ₃ , * = S)

The compound is prepared as described in Example 1-B above from N-2Adoc-α-methyl-R-tryptophan and from (S) 1-amino-1-methoxycarbonyl-indane (IV. A; (B ) = -CH ₂ -, R ₂ = OCH ₃ ) prepared as described in preparation 3bis.

 Yield = 75% F = 108-112 ° C.

[α] ²⁰ _D = + 23 ° (c = 1.0; methanol)

CCM: CH ₂ Cl ₂ / AcOEt 90/10 Rf = 0.25.

NMR: (DMSO) identical to Examples 1-A and 1-B. Analysis: C ₃₄ H ₃₉ N ₃ O ₅

 Wedge%: C 71.68 H 6.90 N 7.38 O 14.04

 Tr.%: C 71.79 H 6.93 N 7.28 O 14.14 Example 2: [1- [1- [N- (2-adamantyloxy) carbonyl] -α-methyl- R-tryptophyl] acid - 1-amino] -1-indanyl carboxylic.

(Ia; (B) = -CH ₂ -, R ₂ = OH, * = R, S)

At 0 ° C., under a nitrogen atmosphere, to a solution of 1.7 g (3.0 mmol) of the ester prepared in Example 1 in 15 ml of dioxane, a solution of 0 is added dropwise. 2 g (4.5 mmol) of lithium hydroxide monohydrate in 5 ml of water. It is allowed to return to laboratory temperature and stirred for five hours. The solvent is evaporated in vacuo and taken up in 50 ml of methylene chloride, washed with an N / 10 solution of potassium acid sulfate and then with a saturated sodium chloride solution. Dried, evaporated in vacuo then chromatographed the residue on silica, eluting with a gradient of methanol in methylene chloride. 1.2 g (yield = 72%) of purified product are obtained.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.5.

 R.M.N. : (DMSO) δ = 11.0 (s 1H exchangeable); 8.38 (s 1H exchangeable); 7.55-6.70 (m 9H); 4.7 (s 1H); 4.3-2.8 (m 8H including 2H exchangeable); 2.3-1.0 (m 17H).

- N-methyl-D-glucamine salt

 To a solution of 1.11 g (2.0 mmol) of the acid obtained above in 50 ml of anhydrous ethanol, a solution of 0.39 g (2.0 mmol) of N-methyl-D is added -glucamine in 50 ml of ethanol. The mixture is brought to reflux and then after cooling evaporates under vacuum.

 Amorphous salt is obtained in the form of a white powder.

Mp 135-140 ° C.

Analysis: C ₄₀ H ₄₄ O ₁₀ N ₄ ; 4 / 3H ₂ O

 Calc. %: C 62, 00 H 7, 37 N 7, 23 O 23, 39

Tr. %: C 61, 98 H 7, 46 N 7, 24 O 23, 32 Example 3: [1- [1- [N- (2-adamantyloxy) carbonyl] -α-methyl-R- tryptophyl] -1-amino] -1-methoxycarbonyl-tetrahydro-1,2,3,4-naphthalene. (Ia; (B) = -CH ₂ -CH ₂ -, R ₂ = OCH ₃ , * = R, S) The compound is prepared according to the protocol described in Example 1 from N-2adoc-α-methyl -R-tryptophan and (R, S) amino-1- methoxycarbony1-1-tetrahydro-1,2,3,4-naphthalene.

The crude product is purified by chromatography on a silica column, eluting with a methanol gradient in methylene chloride.

Yield 93%.

TLC: CH ₂ Cl ₂ / MeOH 95/5 Rf = 0.60.

RMM (CDCl ₃ ): δ = 8.32 (s 1H exchangeable); 7.7-7.45 (m 1H); 7.45-6.90 (m 10H including 2 exchangeable); 4.70 (s 1H);

3.70 (s 3 H); 3.55-3.3 (m 2H); 3.3-2.60 (m 2H); 2.60-2.20 (m 2H); 2.20-1.20 (m 19 H).

EXAMPLE 4 Salt of 3- [1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-R-tryptophyl-aminomethyl] -indanyl] -amino] -3-oxo-propanoic acid and N-methyl-D-glucamine. (Ib; (B) = - CH ₂ -, p = 1, R ₁ = CO-R ₂ with R ₂ = OH, * = R, S)

- stage 1: 1 - [[N - [(t.butyloxy) carbonyl] -α-methyl-R- tryptophyl] -aminomethyl] -1 - [(benzyloxycarbonyl) -amino] -indane. (Vb; X = Boc, (B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R, S)

 At 0 ° C, under a nitrogen atmosphere, 15.26 g (25.0 mmol) of N-Boc- R-α-methyl-R-tryptophan (V; Xoc = Boc) are dissolved in 150 ml of anhydrous tetrahydrofuran 7.58 g (75.0 mmol) of triethylamine and 7.41 g (25.0 mmol) of (R, S) are added

1-aminomethyl-1- (benzyloxycarbonylamino) -indane (VII. B;

(B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R, S). A solution of 11.66 g of PyBrop (25.0 mmol) in 100 ml of THF is then added dropwise. After 16 hours of stirring, the mixture is evaporated under vacuum and taken up in methylene chloride, washed with an N / 10 solution of potassium acid sulfate and then a 5% sodium bicarbonate solution. It is dried, evaporated under vacuum and then the residue is chromatographed on silica, eluting with a gradient of ethyl acetate in methylene chloride. 6.41 g are obtained (yield = 43%) of purified product in the form of a slightly yellow resin.

TLC: CH ₂ Cl ₂ / AcOEt 80/20 Rf = 0.7.

NMR: (DMSO) δ = 10.85 (broad 1H exchangeable); 8.05 (s large 1H exchangeable); 7.85 (s 1H exchangeable); 7.6-6.7 (m 15H including 1H exchangeable); 5.1 (s 2H); 3.8-2.9 (m 4H); 2.9-2.6 (m 2H); 2.3-1.4 (m 14H including tBut at δ = 1.50 and αMe at δ = 1.55). Analysis: C ₃₆ H ₄₂ N ₄ O ₅

 Calc.%: C 71.82 H 7.10 N 7.98 O 13.10

 Tr.%: C 71.90 H 7.05 N 7.90 O 13.10

Stage 2: 1 - [(α-methyl-R-tryptophyl) -aminomethyl] -1- (benzyloxycarbonylamino) -indane. (IV. B; (B) = -CH ₂ -, Z = CO-O- CH ₂ -C ₆ H ₅ , * = R, S)

 At 0 ° C., under a nitrogen atmosphere, 4.96 g (10.0 mmol) of the intermediate obtained in stage 1 above, 6 ml of anisole and 0.15 ml of ethane-dithiol are mixed.

With stirring, 30 ml of trifluoroacetic acid are poured little by little into this mixture. After 90 minutes, the mixture is evaporated under vacuum and the residual yellow oil of methylene chloride is taken up. Washed with a 5% bicarbonate solution separates the organic phase, dry, evaporate in vacuo. The residue is chromatographed on silica eluting with a gradient of methanol in methylene chloride, 3.72 g (yield = 75%) of purified product in the form of yellow resin are obtained.

TLC: CH ₂ Cl ₂ / Methanol 90/10 Rf = 0.4.

 R.M.N. : (DMSO) 8.15 (broad 1H exchangeable); 7.65 (s 1H exchangeable); 7.6-6.7 (m 15H including 1H exchangeable); 4.85 (s 2H); 3.7-2.9 (m 6H including 2H exchangeable); 3.0-2.7 (m 2H); 2.4-1.4 (m 5H).

- Stage 3: [1- [N- (2-adamantyloxy) carbonyl] -α-methyl-R- tryptophyl] -aminomethyl] -1 - [(benzyloxycarbonyl) -amino] -indane. (Fig.b; (B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R, S)

At 0 ° C., under a nitrogen atmosphere, 3.03 g (30 mmol) of triethylamine are added to a solution of 14.9 g (30 mmol) of product obtained in stage 2 in 200 ml of methylene chloride. A solution of 6.4 g (30 mmol) of 2-adamantyl chloroformate is then added dropwise. After 16 hours of stirring, washing with an N / 10 solution of potassium acid sulfate and then a 5% sodium bicarbonate solution. Dry, evaporate in vacuo, chromatograph the residue on silica, eluting with a gradient of ethyl acetate in methylene chloride. 14.0 g are obtained (yield = 69%) of purified product.

TLC: CH ₂ Cl ₂ / AcOEt 80/20 Rf = 0.5.

NMR: (CDCl ₃ ) δ = 8.15-7.95 (broad 1H exchangeable); 7.65-7.45 (m 1H); 7.6-6.7 (m 14H including 1H exchangeable); 6.05 (exchangeable s1H); 5.38 (s 1H exchangeable); 5.05 (s 2H); 4.70 (s1H); 4.0-2.2 (m 6H) 2.2-1.1 (m 19H).

- Stage 4: 1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-R- tryptophyl-aminomethyl] -indanyl] -amin. (Il.b; (B) = -CH ₂ -, * = R, S)

 In a small sealed reactor equipped with a heating system, 8.8 g (11.85 mmol) of the intermediate from stage 3 are dissolved in 50 ml of anhydrous ethanol and hydrogenated in the presence of 0.126 g of palladium on carbon at 10%, under a pressure of 5 bars at 60 ° C for 5 hours.

 After filtration and evaporation, the residue is taken up in methylene chloride and chromatography on silica, eluting with a gradient of methanol in methylene chloride. 5.4 g (yield = 84%) of product are obtained after purification.

TLC: ethyl acetate / methanol 95/5 Rf = 0.25

NMR: (CDCI ₃ ) δ = 8.55 (s 1H exchangeable); 7.2-6.9 (m 9H); 6.80-6.55 (t large 1H exchangeable); 5.36 (s 1H exchangeable); 4.82 (s 1H); 3.70-2.60 (m 6H); 2.2 (s large 2H exchangeable); 2.1-1.2 (m 19H).

- Stage 5: Ethyl ester of 3- [1- [1- [N - [(2- adamantyloxy) carbonyl] -α-methyl-R-tryptophyl-aminomethyl] - indanyl] -amino] -3-oxo acid -propanoic. (Ib; (B) = -CH ₂ -, p = 1, R ₁ = CO-R ₂ with R ₂ = C ₂ H ₅ , * = R, S) At 0 ° C., under a nitrogen atmosphere, 1.87 g (3.46 mmol) of the intermediate of stage 4 and 0.42 g (4.15 mmol) of triethylamine are dissolved in 50 ml of methylene chloride. 0.57 g (3.8 mmol) of the ethyl ester of malonyl monochloride in 20 ml of methylene chloride is added dropwise. The mixture is left stirring for one hour at this temperature and heating for 5 hours at the reflux temperature of the mixture, cooling, washing with normal hydrochloric acid, then with normal soda and finally with a saturated solution of sodium chloride.

 Dried, evaporated in vacuo, the residue is chromatographed on silica, eluting with a gradient of methanol in methylene chloride. 1.5 g (yield = 65%) of purified colorless resin are obtained.

TLC: CH ₂ Cl ₂ / MeOH 98/2 Rf = 0.3.

NMR: (CDCl ₃ ) δ = 8.45 (s 1H exchangeable); 7.7-6.9 (m 11H including 2H exchangeable); 5.40 (d 1H exchangeable); 4.80 (s 1H); 4.35-4.40 (s 2H); 3.95-3.05 (m 6H); 3.05-2.6 (m 2H); 2.6-1.35 (m 19H); 1.25 (t split 3H).

- Stage 6: 3- [1- [1- [N - [(2-adamantyloxy) carbonyl] -α- methyl-R-tryptophyl-aminomethyl] -indanyl] -amino] -3-oxopropanoic acid. (Ib; (B) = -CH ₂ -, p = 1,

R ₁ = CO-R ₂ with R ₂ = OH, * = R, S)

At 0 ° C., under a nitrogen atmosphere, 1.5 g (2.3 mmol) of the ethyl ester obtained in the preceding stage 5 are dissolved in 60 ml of anhydrous THF. A solution of hydrated lithium hydroxide N / 10 is added dropwise and the mixture is stirred for 5 hours at 0 ° C. The mixture is allowed to return to ambient temperature and acidified with citric acid N. The solvent is evaporated in vacuo and taken up in ethyl acetate, the organic phase is washed with a saturated solution of sodium chloride, dried, evaporated under empty. The residue is chromatographed for purification on silica, eluting with a methanol gradient in methylene chloride.

0.85 g is obtained (yield = 59%) of colorless meringue.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.05. NMR: (DMSO) δ = 10.95 (s 1H exchangeable); 8.65 (s 1H exchangeable); 8.4-7.9 (d large 1H exchangeable); 7.6-6.6 (m 10H including 1H exchangeable); 4.70 (s 1H); 3.75-2.6 (m 8H); 2.4-1.0 (m 19H).

- N-methyl-D-glucamine salt

 To a solution of 0.9 g (1.436 mmol) of the acid obtained above in 30 ml of anhydrous ethanol, a solution of 0.280 g (1.436 mmol) of N-methyl-D-glucamine in 25 ml of is added. ethanol. The mixture is brought to the boil and after cooling it is evaporated under vacuum. The desired salt is obtained in the form of a white powder. Mp 115-120 ° C.

Analysis: C ₄₃ H ₅₉ O ₁₁ N ₅ , H ₂ O

 Calc.%: C 61.48 H 7.32 N 8.34 O 22.86

 Tr.%: C 61.13 H 7.86 N 8.11 O 22.90.

EXAMPLE 5 Salt of 4- [1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-R-tryptophyl-aminomethyl] -indanyl] -amino] -4- oxo-butanoic acid and N-methyl-D-glucamine. (Ib; (B) = -CH ₂ -, p = 2, R ₁ = -CO-R ₂ for R ₂ = OH, * = R, S)

Under a nitrogen atmosphere, a mixture of 3.5 g (6.47 mmol) of 1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-R-tryptophyl- is stirred for sixteen hours. aminomethyl] -indanyl] -amino (Example 3, stage 4), 0.98 g (9.7 mmol) of triethylamine and 0.97 g (9.7 mmol) of succinic anhydride in 75 ml of tetrahydrofuran. Then heated to the reflux temperature of the mixture for 5 hours, then evaporated in vacuo and taken up in ethyl acetate, washed with an N / 10 solution of potassium acid sulfate, dried, evaporated in vacuo. The product is purified by chromatography on silica, eluting with a gradient of methanol in methylene chloride. 2.70 g are obtained (yield = 65%) of 4- [1- [1- [N - [(2- adamantyloxy) carbonyl] -α-methyl-R-tryptophyl-aminomethyl] - indanyl] -amino acid ] -4-oxo-butanoic in the form of a white powder.

TLC: CH ₂ Cl ₂ / MeOH / NH ₄ OH 90/9/1 Rf = 0.6. TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.1.

 R.M.N. : (DMSO) δ = 10.65 (d 1H exchangeable); 8.98 (s large 1H exchangeable); 7.65-6.9 (m 10H including 1 exchangeable); 6.75 (s large 1H exchangeable); 5.72 (s large 1H exchangeable); 4.72 (s 1H); 3.65-3.05 (m 4H); 3.05-2.65 (m 2H); 2.6-2.1 (m 6H); 2.1-1.1 (m 17H).

 - N-methyl-D-glucamine salt

 To a solution of 1.92 g (3.0 mmol) of the acid obtained in 75 ml of anhydrous ethanol, a solution of 0.585 g (3.0 mmol) of N-methyl-D-glucamine in 75 is added. ml of ethanol. The mixture is brought to the boil and after cooling it is evaporated under vacuum.

 The salt is obtained in the form of a white powder.

 Mp 115-120 ° C.

Analysis: C ₄₄ H ₆₁ O _{1 1} N ₅ ; 2H ₂ O

 Calc.%: C 60.60 H 7.51 N 8.03 O 23.85

 Tr.%: C 60.97 H 7.43 N 8.01 O 23.59

EXAMPLE 6 Acid Salt 4 - [(1R) -1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-R-triptophyl-aminomethyl] -indanyl] -amino] -4 - oxo-butanoic and N-methyl-D-glucamine. (Ib; (B) = -CH ₂ -, p = 2, R ₁ = -CO-R ₂ for R ₂ = OH, * = R)

- Stage 1: 1 - [[N - [(t.butyloxy) carbonyl] -α-methyl-R-tryptophyl] - aminomethyl] - (1R) -1- (benzyloxycarbonylamino) -indane. (V.b; X =

Boc, (B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R)

The compound is prepared as described in Example 4 - stage 1 from 3.75 g (9.45 mmol) of N-Boc-α-methyl-R-tryptophan and 2.8 g (25 mmol) of ( IR) -1-aminomethyl-1- (benzyloxycarbonylamino) -indane (VII. B; (B) = -CH ₂ -, Z = CO-O- CH ₂ -C ₆ H ₅ , * = R). The crude product is purified by chromatography on silica, eluting with a gradient of ethyl acetate in methylene chloride. 2.2 g (yield = 34%) of slightly yellow resin are obtained.

TLC: CH ₂ Cl ₂ / AcOEt 80/20 Rf = 0.7. NMR: (DMSO) δ = 10.85 (broad 1H exchangeable); 8.05 (wide 1H exchangeable); 7.85 (wide 1H exchangeable); 7.6-6.7 (m 15H including 1H exchangeable); 5.1 (s 2H); 3.8-2.9 (m 4H); 2.9-2.6 (m 2H); 2.3-1.4 (m 14H including tBut at δ = 1.50 and αMe at δ = 1.55). Analysis: C ₃₆ H ₄₂ N ₄ O ₅

 Calc%: C 71.82 H 7.10 N 7.98 O 13.10

 Tr.%: C 71.90 H 7.05 N 7.90 O 13.10

- Stage 2: 1 - [(α-methyl-R-tryptophyl) -aminomethyl] - (1R) -1- (benzyloxycarbonylamino) -indane. (IV. B; (B) = -CH ₂ -, Z = CO-O-CH ₂ - C ₆ H ₅ , * = R)

 The compound is prepared by treatment of the product obtained in the preceding stage according to the procedure described in Example 4 - stage 2. After chromatographic purification, 1.24 g (yield = 75%) of resin are obtained.

TLC: CH ₂ Cl ₂ / Methanol 90/10 Rf = 0.4.

 R.M.N. : (DMSO) δ = 8.15 (s broad 1H exchangeable); 7.65 (s broad 1H exchangeable); 7.6-6.7 (m 15H including 1H exchangeable); 4.85 (s 2H); 3.7-2.9 (m 6H including 2H exchangeable); 3.0-2.7 (m 2H); 2.4-1.4 (m 5H).

- Stage 3: 1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-R- tryptophyl] -aminomethyl] - (IR) -1- (benzyloxycarbonylamino) - indane. (Fig. B; (B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R)

At 0 ° C, under a nitrogen atmosphere, from 2.34 g (4.71 mmol) of compound of the preceding stage which is treated according to the procedure of Example 4 - stage 3 obtained after purification 2.2 g chromatographic (yield = 69%) of product. TLC: CH ₂ Cl ₂ / AcOEt 80/20 Rf = 0.5.

NMR: (CDCl ₃ ) δ = 8.15-7.95 (broad 1H exchangeable); 7.65-7.45 (m 1H); 7.6-6.7 (m 14H including 1H exchangeable); 6.05 (s 1H exchangeable); 5.38 (s 1H exchangeable); 5.05 (s 2H); 4.70 (s 1H); 4.0-2.2 (m 6H) 2.2-1.1 (m 19H).

-Stage 4: (1R) -1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-R- tryptophyl-aminomethyl] -indanyl] -aminate. (Il.b; (B) = -CH ₂ -, * =

R)

2.2 g (3.26 mmol) of the compound obtained in the preceding stage 3 are hydrogenated in a small reactor under conditions identical to those described in Example 4 - stage 4. Finally, 1.3 g (yield = 96%) of product are obtained.

TLC: ethyl acetate / methanol 95/5 Rf = 0.25

NMR: (CDCl ₃ ) δ = 8.55 (s 1H exchangeable); 7.2-6.9 (m 9H); 6.80-6.55 (t large 1H exchangeable); 5.36 (s 1H exchangeable); 4.82 (s 1H); 3.70-2.60 (m 6H); 2.2 (s large 2H exchangeable); 2.1-1.2 (m 19H).

- Stage 5: Acid 4 - [(1R) -1- [1- [N - [(2-adamantyloxy) carbonyl] - α-methyl-R-tryptophyl-aminomethyl] -indanyl] -amino] -4-oxo- butanoic. (Ib; (B) = -CH ₂ -, p = 2, R ₁ = -CO-R ₂ for R ₂ = OH, * = R)

 Under a nitrogen atmosphere, a mixture of 1.7 g (3.14 mmol) of the amine obtained in the preceding stage 4, 0.477 g (4.71 mmol) of triethylamine and 0.47 is stirred for sixteen hours. g (4.71 mmol) of succinic anhydride in 60 ml of tetrahydrofuran. Then heated to the reflux temperature of the mixture for 6 hours, then added 0.200 g (1.6 mmol) of 4-dimethylaminopyridine then evaporated in vacuo and taken up in ethyl acetate, washed with a solution N / 10 of potassium acid sulfate, dry, evaporated in vacuo. The product is purified by chromatography on silica, eluting with a gradient of methanol in methylene chloride. 1.30 g are obtained (yield = 65%) of purified product in the form of a white powder.

TLC: CH ₂ Cl ₂ / MeOH / NH ₄ OH 90/9/1 Rf = 0.6.

TLC: CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.1.

 R.M.N. : (DMSO) δ = 10.65 (d 1H exchangeable); 8.98 (s large 1H exchangeable); 7.65-6.9 (m 10H including 1 exchangeable); 6.75 (s large 1H exchangeable); 5.72 (s large 1H exchangeable); 4.72 (s 1H); 3.65-3.05 (m 4H); 3.05-2.65 (m 2H); 2.6-2.1 (m 6H); 2.1-1.1 (m 17H).

 - N-methyl-D-glucamine salt

 To a solution of 1.2 g (2.0 mmol) of the above acid in 50 ml of anhydrous ethanol, a solution of

0.390 g (2.0 mmol) of N-methyl-D-glucamine in 75 ml of ethanol. The mixture is brought to the boil and after cooling evaporated under vacuum. The salt is obtained in the form of a white powder. Mp 90-97 ° C.

Analysis: C ₄₄ H ₆₁ O ₁₁ N ₅ ; 2H ₂ O

 Calc.%: C 60.60 H 7.51 N 8.03 O 23.85

 Tr.%: C 60.97 H 7.43 N 8.01 O 23.59

EXAMPLE 7 Acid Salt 4- [1- [1- [N - [(2adamantyloxy) carbonyl] -α-methyl-R-tryptophyl] -aminomethyl] -1,2,3,4- tetrahydro-naphthyl- ] -l-amino-4-oxo-butanoic acid and N-methyl-D-glucamine. (Ib; (B) = -CH ₂ -CH ₂ -, p = 2, R ₁ = -CO-R ₂ , for R ₂ = OH, * = R, S)

- Stage 1: 1 - [- [N - [(t.butyloxy) carbonyl] -α-methyl-tryptophyl] - aminomethyl] -1 - [(benzyloxycarbonyl) -amino] -tétrahydro-1,2,3,4- naphthalene. (Vb; X = Boc, (B) = -CH ₂ -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , *

= R, S)

 The reaction is carried out according to the procedure of the example

4 - stage 1 from 15.26 g (25.0 mmol) of N-Boc-α-methyl-R-tryptophan and 9.96 g (25 mmol) of (R, S) 1- aminomethyl-1- [(benzyloxycarbonyl) -amino] -tetrahydro-1,2,3,4- naphthalene (VII. b; (B) = -CH ₂ -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R, S).

10.23 g (yield = 67%) of colorless resin are obtained.

TLC: CH ₂ Cl ₂ / AcOEt 80/20 Rf = 0.75.

 R.M.N. : (DMSO) δ = 10.65 (broad 1H exchangeable); 8.15 (s large 1H exchangeable); 7.80 (s large 1H exchangeable); 7.6-6.7 (m 15H including 1H exchangeable); 4.8 (s 2H); 3.7-2.9 (m 6H); 2.9-2.6 (m

2H); 2.3-1.4 (m 16H including tBut at δ = 1.42 and αMe at δ = 1.5).

Analysis: C ₃₆ H ₄₂ N ₄ O ₅

 Calc%: C 71.82 H 7.10 N 7.98 O 13.10

 Tr.%: C 71.90 H 7.05 N 7.90 O 13.10

 Stage 2: 1- [(α-methyl-R-tryptophyl) -aminomethyl] -1-

(benzyloxycarbonylamino) -tetrahydro-1,2,3,4-naphthalene. (IV.b;

(B) = -CH ₂ -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R, S).

The reaction is carried out according to the procedure of Example 4 - stage 2 from 12.2 g (20 mmol) of the compound prepared at the previous stage. After purification, 8.17 g (yield = 80%) of slightly yellow transparent resin are obtained.

TLC: CH ₂ Cl ₂ / Methanol 90/10 Rf = 0.4.

 R.M.N. : (DMSO) 8.05 (s large 1H exchangeable); 7.75 (s broad 1H exchangeable); 7.6-6.7 (m 15H including 1H exchangeable); 4.85 (s 2H); 3.7-2.9 (m 6H including 2H exchangeable); 2.9-2.6 (m 2H); 2.3-1.2 (m 7H).

Stage 3: [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-R- tryptophyl] -aminomethyl] -1 - [(benzyloxycarbonyl) -amino] - tétrahydro-1,2,3,4- naphthalene. (Fig. B; (B) = -CH ₂ -CH ₂ -, Z = CO-O- CH ₂ -C ₆ H ₅ , * = R, S).

The reaction is carried out according to example 4 - stage 3 starting from 1.53 g (3.0 mmol) of the intermediate obtained in the preceding stage. 1.59 g are obtained (yield = 77%) of purified product. TLC: CH ₂ Cl ₂ / AcOEt 80/20 Rf = 0.8.

 R.M.N. : (DMSO) δ = 10.85 (broad 1H exchangeable); 8.05 (s large 1H exchangeable); 7.75 (s large 1H exchangeable); 7.6-6.7 (m 14H); 4.9 (s 2H); 4.72 (s 1H); 3.7-2.9 (mH including 1H exchangeable at δ = 3.3); 2.9-2.6 (m 2H); 2.3-1.2 (m 21H).

- Stage 4: [1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-tryptophyl] -aminomethyl] -1,2,3,4-tetrahydro-naphthyl -] - 1-amine. (Il.b; (B) = -CH ₂ -CH ₂ -, * = R, S)

 3.5 g (5.08 mmol) of the intermediate obtained in the preceding stage 3 are hydrogenated as described in Example 4 - stage 4. 1.69 g are obtained (Yield = 60%) of purified product.

TLC: ethyl acetate / methanol 90/10 Rf = 0.5.

R.M.N .: (DMSO) δ = 10.84 (s 1H exchangeable); 7.6-6.7 (m 10H including 1H exchangeable); 4.7 (s 1H); 4.3 (s large 2H exchangeable); 3.6-2.55 (m 6H); 2.2-1.2 (m 21H).

- Stage 5: Acid 4- [1- [1- [N - [(2-adamantyloxy) carbonyl] -α- methyl-tryptophyl] -aminomethyl] -1,2,3,4-tetrahydro-naphthyl] -1- amino] -4-oxo-butanoic. (Ib; (B) = -CH ₂ -CH ₂ -, R ₁ = -CO-R ₂ , for R ₂ = OH, p = 2, * = R, S)

The product is prepared as described in Example 5 from 1.68 g (3.03 mmol) of the intermediate prepared in previous stage 4, 0.46 g (4.54 mmol) of triethylamine and 0.303 g (3.03 mmol) of succinic anhydride in 15 ml of tetrahydrofuran. 0.84 g is obtained (yield = 42%) of product in the form of a colorless foam.

TLC: CH ₂ Cl ₂ / MeOH / NH ₄ OH 80/18/2 Rf = 0.8.

R.M.N. : (DMSO) δ = 10.85 (broad 1H exchangeable); 8.0 (t large 1H exchangeable); 7.5-6.7 (m 10H 1 exchangeable); 6.55 (s large 1H exchangeable); 4.85 (s large 1H exchangeable); 4.65 (s 1H); 3.6-2.9 m 6H); 2.3-2.1 (m 4H); 2.1-1.1 (m 21H).

 - N-methyl-D-glucamine salt

To a solution of 0.65 g (1 mmol) of the above acid, in 25 ml of anhydrous ethanol, a solution of 0.195 g (1 mmol) of N-methyl-D-glucamine in 25 ml of is added. ethanol. The mixture is brought to the boil and after cooling it is evaporated under vacuum. The desired salt is obtained in the form of a white powder. Mp 145-150 ° C.

Analysis: C ₄₅ H ₆₃ O ₁₁ N ₅ ; 2.5H ₂ O

 Calc.%: C 60.39 H 7.67 N 7.82 O 24.15

Tr.%: C 60.62 H 7.71 N 7.56 O 24.11 Example 8: Acid salt 4 - [(1R) -1- [1- [N - [(2- adamantyloxy) carbonyl ] -α-methyl-R-tryptophyl] -aminomethyl] - 1,2,3,4-tetrahydro-naphthyl -] - 1-amino-4-oxo-butanoic acid and N-methyl-D-glucamine. (Ib; (B) = -C _H2 -CH ₂ -, p = 2, R ₁ = -CO-R ₂ for R ₂ = OH, * = R)

- Stage 1: (1R) 1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-R- trvptophyl-aminomethyl] -1 - [(benzyloxycarbonyl) -amino] -1,2,3,4- tetrahydro-naphthalene. (Fig. B; (B) = -CH ₂ -CH ₂ -, Z = CO-O-CH ₂ - C ₆ H ₅ , * = R)

The compound is prepared according to the procedure described in Example 4 - stage 1 from 6.0 g (15.15 mmol) of N- 2Adoc-α-methyl-R-tryptophan (VI) and from 4, 7 g (15, 15 mmol) of (R) -1-aminomethyl-1- (benzyloxycarbonylamino) -1,2,3,4- tetrahydro-naphthalene (VII.b; (B) = -CH ₂ -CH ₂ -, Z = CO-O-CH ₂ - C ₆ H ₅ , * = R). After purification by chromatography on silica, eluting with a gradient of ethyl acetate in methylene chloride 3.6 g (yield = 35%) of compound.

TLC: CH ₂ Cl ₂ / Ethyl acetate 80/20 Rf = 0.80

 - Stage 2: (1R) [1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl- tryptophyl] -aminomethyl] -1,2,3,4-tetrahydro-naphthyl -] - 1 -amine

(Il.b; (B) = -CH ₂ -CH ₂ -, * = R).

 3.6 g (5.23 mmol) of the compound obtained in the preceding stage are subjected to hydrogenolysis according to the procedure described in Example 4 - stage 4. 2.9 g (yield = 100%) of compound are obtained )

CMM: CH ₂ Cl ₂ / MeOH 95/5 Rf = 0.25

 - Stage 3: Acid 4 - [(IR) -1- [1- [N - [(2-adamantyloxy)

carbonyl] -α-methyl-R-tryptophyl] -aminomethyl] -1,2,3,4- tetrahydro-naphthyl -] - 1-amino-4-oxo-butanoic. (I.b;

(B) = -CH ₂ -CH ₂ -, p = 2, R ₁ = -CO-R ₂ for R ₂ OH, * = R)

 The compound obtained in the preceding stage is reacted with 0.79 g (7.85 mmol) of succinic anhydride according to the procedure of Example 7 - stage 5.

 After purification by chromatography on silica, eluting with a methanol gradient in methylene chloride, 1.95 g are obtained (Yield = 57%) of product.

CMM: CH ₂ Cl ₂ / MeOH / NH ₄ OH 90/10/2 Rf = 0.10

 R.M.N. : identical to the corresponding racemic compound (example

7 - stage 5).

- N-methyl-D-glucamine salt

 The compound is prepared as described in the salification carried out in Example 7 - stage 5.

Analysis: C ₄₅ H ₆₃ N ₅ O ₁₁ , 4H ₂ O

 Calc.%: C 58.62 H 7.76 N 7.60 O 26.03

 Tr.%: C 58.67 H 7.69 N 7.38 O 26.26

Example 9: [4- [1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl] - R-tryptophyl] -aminomethyl] -1,2,3,4-tetrahydro-naphthyl] - 1- amino] -4-oxo] - [1- [N- [1- (4-benzyl) piperidyl]]] - butanoyl

(Ib; (B) = -CH ₂ -CH ₂ , p = 2, * = R, S,

R ₁ = -CO-R ₂ for R ₂ =

In a reactor protected from humidity, 4.0 g (7.20 mmol) of the intermediate amine Il-b prepared in Example 7 - stage 4, are mixed with 60 g of anhydrous tetrahydrofuran 4.0 g (2.2 g ( 21.60 mmol) of triethylamine, 1.99 g (7.20 mmol) of [1- (4-benzyl) piperidyl] -4-oxo-butanoic acid and 3.36 g (8.65 mmol) of PyBrop .

 The mixture is stirred for 16 h at 20-25 ° C and then evaporated in vacuo. The residue is taken up in 100 ml of methylene chloride, washed with a saturated solution of sodium bicarbonate. The organic phase is dried, evaporated and the residue is purified by chromatography on silica. 6.5 g (yield = 65%) of purified product in amorphous form are obtained.

TLC: Ethyl acetate / MeOH Rf = 0.80

TLC: Ethyl acetate Rf = 0.65

R.M.M. : (DMSO) δ = 9.75 (s 1H exchangeable); 7.75-7.45 (m 2H exchangeable); 7.45-6.9 (m 14H); 5.78 (s 1H exchangeable); 4.8 s1H, 4.7-3.7 m 2H; 3.6-2.15 (m 14H); 2.15-0.8 (m 26H)

Analysis: C ₅₀ H ₆₁ N ₅ O ₅ , CH ₃ COOCH ₃ , ½ H ₂ O

 Hold. %: C 71.34 H 7.76 N 7.70 O 13.20

 Tr.%: C 71.45 H 7.64 N 7.85 O 13.06

Example 10: [4- [1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl] - R-tryptophyl] -aminomethyl-1,2,3,4-tetrahydronaphthyl] -1-amino ] - 4-oxo] - [1- [N- [1- (4-p.chlorophenyl-4-hydroxy) piperidyl]]] - butanoyl (Ib; (B) = -CH ₂ -CH ₂ , p = 2 , * = R, S,

R ₁ = -CO-R ₂ for R ₂ =

-this

The product is prepared according to the procedure of Example 9 above from 5.0 g (9.0 mmol) of amine (Example 7 - stage 4) and 2.8 g (9.0 mmol) d acid [1- (4-p.chlorophenyl-

4-hydroxy) -piperidyl] -butanoic. After purification,

3.5 g of product (yield = 46%)

TLC: Ethyl acetate. Rf = 0.39 NMR: (DMSO) δ = 9.45 (s 1H exchangeable); 7.75-7.5 (m 2H exchangeable); 7.5-6.8 (m 13H) 5.13 (s / 1H exchangeable); 4.70 (s 1H); 4.5-2.95 (m 6H); 2.9-2.1 (m 9H); 2.1 -1.1 (m 25H).

Analysis: C ₄₉ H ₅₈ Cl N ₅ O ₆ , 3/4 H ₂ O

 Hold. %: C 68.28 H 6.96 N 8.12 O 12.53 Cl 4.11

 Tr%: C 68.24 H 7.05 N 7.89 O 12.78 Cl 4.06

Example 11: 4- [1- [1- [N - [(2adamantyloxy) carbonyl] -α-methyl -R- tryptophyl] -aminomethyl] -1,2,3,4-tetrahydro-naphthyl -] - 1-amino - Ethyl 4-oxo-butanoate. (Ib; (B) = -CH ₂ -CH ₂ -, p = 2, R ₁ = -CO-R ₂ for R ₂ = C ₂ H ₅ , * = R, S)

4.7 g (8.48 mmol) of [1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl-R-tryptophyl] - aminomethyl] -1 are dissolved in a 500 ml reactor , 2,3,4-tetrahydro-naphthyl -] - 1-amine, prepared in example 7 - stage 4, in 200 ml of anhydrous methylene chloride. 1.4 ml of triethylamine are added to the solution and then, drop by drop at t <5 ° C 1.4 g (8.47 mmol) of ethyl succinate chloride dissolved in 20 ml of methylene chloride. The mixture is brought to reflux for 4 hours then cooled and extracted successively with 100 ml of N HCl solution, 100 ml of NaOH N solution, then with a saturated NaCl solution and finally dried over Na ₂ SO ₄ . After removing the solvent, 3.8 g (yield = 66%) of chromatographically pure compound are obtained.

 TLC: methylene choride-MeOH 98-2 v / v. Rf = 0.39

[α] ²⁰ _D = + 13 ° (c = 1.0; MeOH)

R.M.N .: (DMSO) δ = 10.9 (s 1H exchangeable); 8.1 (m wide 3H exchangeable); 7.6-6.9 (m 9H); 4.74 (s 1H exchangeable); 4.10 (s 2H); 3.70-2.90 (m 6H); 2.9-2.2 (m 4H); 2.2 -1.2 (m 24H).

Analysis: C ₄₀ H ₅₀ N ₄ O ₆ , 0.5 H ₂ O

 Hold. %: C 69.44 H 7.43 N 8.10 O 15.03

Tr%: C 69.41 H 7.50 N 8.14 O 14.87 Example 12: [4- [1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl] - R-tryptophyl] -aminomethyl] -1,2,3,4-tetrahydro-naphthyl] - 1- amino] -4-oxo] - (N-indolyl) -butanoyl (Ib; (B) = -CH ₂ -CH ₂ , p = 2, * = R, S, R ₁ = -CO-R ₂ for R ₂ = N-indolinyl)

The compound is prepared in the presence of PyBrop as described in Example 9 from the intermediate amine Il-b prepared in Example 7 - stage 4 and (1-indolyl) -4-oxo-butanoic acid prepared by reacting indoline with succinic anhydride in THF. After chromatography and elution by mixing

AcOEt-MeOH, 91% of purified product is obtained.

 TLC: Ethyl acetate / MeOH 90-10 v / v Rf = 0.90

[α] ²⁰ _D = +4 (c = 1.0; MeOH)

 R.M.M. : (DMSO) δ = 10.9 (s 1H exchangeable); 8.10 (m 3H exchangeable); 7.60-6.9 (m 13H); 4.75 (s 1H); 4.05 m 2H; 3.7-

2.9 m 8H; 2.9-2.2 (m 4H); 2.2-1.2 (m 21H)

Analysis: C ₄₆ H ₅₃ N ₅ O ₅ , 0.75 CH ₃ COOC ₂ H ₅

 Hold. %: C 71.60 H 7.23 N 8.92 O 12.65

 Tr.%: C 71.35 H 7.47 N 8.97 O 12.61

Example 13: [N- [1- [1- [N - [(2-adamantyloxy) carbonyl] -α-methyl] - R-tryptophyl] -aminomethyl] -1,2,3,4-tetrahydro-naphty1] - [2- (5-1H-tetrazolyl)] - acetamide. (Ib; (B) = -CH ₂ -CH ₂ -, p = 1, * = R, S, R ₁ = 1 H-tetrazol-5-yl)

The compound is prepared according to the procedure of Example 9 from 4.0 g (7.2 mmol) of amine (Example 7 - stage 4) and 1.1 g (8.65 mmol) of -lH-tetrazole-acetic acid prepared according to Nucleic Acids Research (1985) Vol 13, 23 _. 8525-26.

2.8 g of product are obtained after chromatographic purification (yield = 58%)

 TLC: Ethyl acetate / MeOH 90/10 Rf = 0.62

NMR: (DMSO) δ = 10.9 (s 1H exchangeable); 8.20 (s 1H exchangeable); 8.05 (s 1H exchangeable); 7, 2-6, 8 (m 9H); 5.80 (s1H exchangeable); 5.30 (s 1H exchangeable); 4.65 (s 1H); 3.95-3.05 (m 6H); 3.0-2.6 (m 2H); 2.55-1.1 (m 21 H) PREPARATIONS

Preparation 1

Stage 1: 1- (Benzyloxycarbonylamino) -indanyl-1-carboxylic acid. (Pr.d; (B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R, S) Under a nitrogen atmosphere and at a temperature always below 2 ° C, 30 g are dissolved (169.3 mmol of acid

1-amino-1-indanyl-carboxylic acid (Pr.c; B = -CH ₂ -, * = R, S) in a solution of 300 ml of dioxane and 150 ml of water by adjusting the pH to 10.2 at normal soda medium. To this solution are added dropwise 57.8 g (338.6 mmol) of benzyl chloroformate in 100 ml of dioxane, maintaining the pH between 7.8 and 8.2 using normal sodium hydroxide added using of a pHstat. The addition lasts 4 hours.

Acidified with 250 ml of normal hydrochloric acid and extracted with ethyl acetate (2 times by 250 ml), washed with a saturated solution of dry sodium chloride and then evaporated in vacuo.

The residue is chromatographed on silica eluting with a gradient of methanol in methylene chloride. 26.5 g are obtained (yield = 50%) of white powder.

TLC: CH ₂ Cl ₂ / MeOH 95/5 Rf = 0.4.

NMR: (DMSO) δ = 8.3 (broad 1H exchangeable); 7.4-7.0 (m 9H); 6.62 (s large 1H exchangeable); 5.10 (s 2H); 3.2-2.2 (m 4H). - stage 2: (R, S) 1-carbamoyl-1- (benzyloxy-carbonylamino) - indane. (Pr.g; (B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R, S)

At -15 ° C and under a nitrogen atmosphere, 26.5 g (85 mmol) of the acid obtained in the preceding stage are dissolved in 400 ml of methylene chloride. 17.2 g (170 mmol) of N-methylmorpholine are added and the mixture is stirred for 30 minutes. 23.25 g (85 mmol) of isobutyl chloroformate dissolved in 80 ml of methylene chloride are then added dropwise. The mixture is stirred at -20 ° C. for 2 hours and a stream of gaseous ammonia is bubbled through the solution. It is left for 1 hour 30 minutes with stirring at -15 ° C, and allowed to rise to room temperature. The organic phase is washed with an N / 10 solution of potassium acid sulfate and then a 5% sodium bicarbonate solution. Dry, evaporate in vacuo, chromatograph the residue on silica, eluting with a gradient of methanol in methylene chloride. 22.1 g (yield = 85%) of white powder are obtained.

TLC: CH ₂ Cl ₂ / MeOH 95/5 Rf = 0.60.

NMR: (CDCl ₃ ) δ = 7.4-7.0 (m 9H); 6.18 (s large 1H exchangeable); 6.0-5.5 (s large 2H exchangeable); 5.20 (s 2H); 3.2-2.3 (m 4H).

- Stage 3: (R, S) 1-aminomethyl-1- (benzyloxycarbonylamino) - indane. (VII. B; (B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R, S)

 At 0 ° C. and under a nitrogen atmosphere, 24.8 g (80 mmol) of the amide obtained in the preceding stage are dissolved in 350 ml of anhydrous THF. 20.23 g (26.6 mmol) of borane-dimethylsulfide dissolved in 30 ml of anhydrous THF are added dropwise.

The mixture is allowed to return to ambient temperature and is heated for three hours at the reflux temperature of the mixture.

 The reaction is cooled, and 250 ml of methanol are added dropwise. It is brought to reflux for 1 hour, cooled and added

100 ml of 4N hydrochloric ether. The mixture is stirred for two hours and the residue is evaporated, the residue is chromatographed on silica, eluting with a gradient of methanol in methylene chloride.

 Colorless resin is obtained (yield = 59%).

TLC: CH ₂ Cl ₂ / MeOH 95/5 Rf = 0.2.

 R.M.N. : (DMSO) δ = 7.59 (s broad 1H exchangeable); 7.4-7.0 (m

9H); 5.62 (s large 2H exchangeable); 4.95 (s 2H); 3.4-3.2 (m

2H); 3.05-2.6 (m 2H); 2.6-2.0 (m 2H). Preparation 2

- Stage 1: Acid (R, S) 1- (1- (benzyloxy-carbonylamino) -1,2,3,4- tetrahydro-naphthyl) -carboxylic. (Pr.d; (B) = -CH ₇ -CH ₂ -,

Z = CO-O-CH ₂ -C ₆ H ₅ * = R, S)

The compound is prepared according to the procedure described in preparation 1 - stage 1 from 1-amino-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (Yield = 50% - oil) TLC: H ₂ Cl ₂ / MeOH 95/5 Rf = 0.35.

 R.M.N. : (DMSO) δ = 8.3 (s broad 1H exchangeable); 7.4-7.0 (m 9H); 6.62 (s large 1H exchangeable); 5.10 (s 2H); 3.2-2.2 (m 4H).

Stage 2: (R, S) 1-carbamoyl-1- (benzyloxycarbonylamino) - tetrahydro-1,2,3,4-naphthalene. (Pr.g; (B) -CH ₂ -CH ₂ ,

Z = CO-O-CH ₂ -C ₆ H ₅ , * = R, S)

 The compound is prepared from the acid obtained in the preceding stage, with a yield of 71% using the procedure of preparation 1 - stage 2.

TLC: CH ₂ Cl ₂ / AcOEt 80/20 Rf = 0.60.

 R.M.N. : (DMSO) δ = 7.6-6.7 (m 11H including 2H exchangeable); 6.6-6.3 (s 1H exchangeable); 4.95 (s 2H); 2, 9-2, 6 (m 2H); 2.4-1.6 (m 4 H).

- stage 3: (R, S) (1-aminomethyl-1- (benzyloxy carbonyl amino) - tetrahγdro-1,2,3,4-naphthalene. (VII. b; (B) = -CH ₂ -CH ₂ , Z = CO-O-

CH ₂ -C ₆ H ₅ , * = R, S)

 Product prepared by reduction of the amide obtained in the previous stage using the procedure of preparation 1 - stage 3. Yield = 44%.

TLC: CH ₂ Cl ₂ / MeOH 95/5 Rf = 0.2.

 R.M.N. : (DMSO) δ = 7.5-7.0 (m 9H); 6.9 (s 1H exchangeable); 4.9 (s 2H); 3.7 (s large 3H including 2 exchangeable); 2.9-2.45 (m 3H); 2.4-1.5 (m 4H). Preparation 3

- Stage 1: (R) -1- (1-methoxycarbonyl) -indanyl-amine. (IV. A) (B) = -CH ₂ -, * = R)

In 320 ml of n-propanol is dissolved on the one hand 16.0 g (83.7 mmol) of (R, S) -1- (1-methoxycarbonyl) -indanyl-amine and on the other hand 29.0 g (83.7 mmol) of acid (R) - (-) - 4-hydroxydinaphto [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphosphepin-4-oxide are brought into suspension in 320 ml of n-propanol. The solution and the suspension are heated to reflux temperature and are mixed. The incompletely dissolved acid goes into solution. Let cool and then initiate crystallization by the usual means and if necessary with a primer of the diastereoisomer prepared in a previous test.

Upon cooling, a precipitate forms which is filtered and then redissolved in 1.5 liters of boiling n-propanol. Let cool, filter. The anion is exchanged on an IRA 400 column in the form Cl- (5 moles). 5.50 g of hydrochloride of the enantiomer of the amine are obtained (yield = 58%).

Absolute chirality was determined by hydrolysis of α-chymotrypsin, at 37 ° C. The isomer obtained is transformed into its corresponding amide by reaction with camphanyl chloride, which is characterized on a plate, the eluent being a mixture of cyclohexane and ethyl acetate 60/40 (Rf = 0.36 R isomer ) (Rf = 0.45 S isomer).

- Stage 2: Methyl ester of acid (IR) -1- (benzyloxycarbonylamino) -1-indanyl-carboxylic. (Pr.f; (B) = -CH ₂ -, Z =

CO-O-CH ₂ -C ₆ H ₅ , * = R)

 At 0 ° C, under a nitrogen atmosphere, to a solution of 4.6 g (24 mmol) of the above methyl ester and 7.3 g (72.18 mmol) of triethylamine in 100 ml of THF, we stirring, add a solution of 2.83 g (26.5 mmol) of benzyl chloroformate in 50 ml of toluene. It is left for 20 hours at room temperature. After cooling, the solution is filtered and then washed quickly with an N / 10 solution of potassium acid sulfate and then a 5% sodium bicarbonate solution.

Dried, evaporated in vacuo then chromatographed the residue on silica eluting with a gradient of methanol in methylene chloride. 5.6 g (yield = 72%) of colorless resin are obtained. TLC: CH ₂ Cl ₂ / MeOH 98/2 Rf = 0.85.

NMR: (CDCl ₃ ) 5 = 7.5-6.95 (m 9H); 5.72 (s1H exchangeable); 5.2 (s 2H); 3.65 (s 3H); 3.0-2.6 (m 2H); 2.4-1.8 (m 2H).

- Stage 3: Acid (IR) -1- (benzyloxy-carbonylamino) -indanyl-1-carboxylic. (Pr.d; (B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R)

At 0 ° C., under a nitrogen atmosphere, 5.6 g (17.2 mmol) of methyl ester obtained in the preceding stage are dissolved in 25 ml of dioxane. 13 ml of a solution of 1.08 g (25.75 mmol) of hydrated lithium hydroxide and stirred for 5 hours at 100 ° C. The mixture is allowed to return to ambient temperature and evaporated under vacuum. The residue is taken up in methylene chloride, washed with a N / 5 potassium acid sulfate solution, dried and the solvent evaporated in vacuo.

 The residue is chromatographed on silica eluting with a gradient of methanol in methylene chloride. 4.05 g (yield = 75%) of colorless resin are obtained.

TLC: H ₂ Cl ₂ / MeOH 95/5 Rf = 0.25.

R.M.N. : (DMSO) δ = 8.3 (s broad 1H exchangeable); 7.4-7.0 (m 9H); 6.62 (s large 1H exchangeable); 5.10 (s 2H); 3.2-2.2 (m 4H).

- Stage 4: (1R) -1-carbamoyl-1- (benzyloxycarbonylamino) -indane (Pr.g; (B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R )

 The product is obtained according to the procedure of preparation 1 - stage 2 starting from the acid obtained in the preceding stage. Yid = 97%.

TLC: CH ₂ Cl ₂ / MeOH 95/5 Rf = 0.60.

NMR: (CDCl ₃ ) δ = 7.4-7.0 (m 9H); 6.18 (s large 1H exchangeable); 6.0-5.5 (s large 2H exchangeable); 5.20 (s 2H); 3.2-2.3 (m 4H).

- Stage 5: (1R) -1-aminomethyl-1- (benzyloxycarbonylamino) - indane. (VII. B; (B) = -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ , * = R)

 At 0 ° C and under a nitrogen atmosphere, 4.0 g (12.9 mmol) of (1R) - 1-carbamoyl-1- (benzyloxy-carbonylamino) -indane are dissolved in 20 ml of anhydrous THF and added dropwise dropwise into a solution of 38 mmol of aluminum hydride prepared in 40 ml of anhydrous ether. The mixture is heated at reflux for 4 hours and then allowed to return to room temperature.

The mixture is cooled, and 50 ml of ethyl acetate and 50 ml of normal sodium hydroxide are added dropwise. Extracted with ethyl acetate, dried, evaporated and then chromatographed the residue on silica, eluting with a gradient of methanol in methylene chloride. 2.8 g (yield = 74%) of colorless resin are obtained.

CCM: CH ₂ Cl ₂ / MeOH 95/5 Rf = 0.20 NMR: (DMSO) δ = 7.59 (broad 1H exchangeable); 7.4-7.0 (m 9H); 5.62 (s large 2H exchangeable); 4.95 (s 2H); 3.4-3.2 (m 2H); 3.05-2.6 (m 2H); 2.6-2.0 (m 2H).

.

Preparation 3 bis (R) and (S) -1- (1-methoxycarbonyl) -indanyl- aminei. (IV. A) (B) = -CH ₂ -, * = R or S)

 One proceeds by salification of the (R, S) -1- (1-methoxycarbonyl) - indanyl-amine by the acid (R) - (-) - 4-hydroxydinaphto [2,1- d: 1 ', 2' -f] [1,3,2] dioxaphosphepin-4-oxide in n-propanol as in preparation 3 stage 1. The precipitate obtained after resting at room temperature is the salt of the (R) enantiomer which is filtered . The filtrate left overnight makes it possible to recover a second precipitate which consists of the salt of the enantiomer (S) which is also filtered.

Each precipitate is treated separately in methanol with an excess of hydrochloric acid to displace the binaphthyl phosphoric acid which is recovered, the filtrates are evaporated to obtain the respective hydrochlorides of the (R) and (S) enantiomers:

- enantiomer (R) Yd = 53.3% [α] ²⁰ _D = + 36.4 ° (MeOH)

- enantiomer (S) Yield = 41.3% [α] ²⁰ _D = - 35.6 ° (MeOH) which, by treatment in an alkaline medium and extraction with ethyl acetate allow the two enantiomers to be obtained in form basic.

Preparation 4

stage 1: (1R) -1- (1-methoxycarbonyl) -1,2,3,4-tetrahydro naphthyl-amine (IV. a; (B) = -CH ₂ -CH ₂ -, * = R)

The compound is obtained by reaction of the corresponding racemic compound with acid (R) - (-) 4-hydroxydinaphto [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphosphepin-4- oxide in n-propanol then separation of the diastereoisomer salt and treatments as described in the 3-stage preparation procedure.

The enantiomer is obtained in the form of its hydrochloride (yield = 63%)

CCM: CH ₂ Cl ₂ / MeOH 98/2 Rf = 0.30 - stage 2: Methyl ester of the acid (1R) -1- (benzylo xy carbo ny l am i no) - 1 - (1, 2, 3, 4 - tetrahydronaphtyl) carboxylic (Pr.f; (B) = -CH ₂ -CH ₂ -, Z = CO-

O-CH ₂ -C ₆ H ₅ , * = R)

The compound is prepared according to the protocol of preparation 3 - stage 2 from the base of the compound obtained in the preceding stage - (Yield = 63%)

CMM: CH ₂ CCl ₂ / MeOH 98/2 Rf = 0.95

CH ₂ CCl ₂ / MeOH 95/5 Rf = 0.34

-stage 3: (1R) -1-carbamoyl-1- (benzyloxycarbonylamino-1,2,3,4- tetrahydrophthalene (Pr. g; (B) = -CH ₂ -CH ₂ -, Z = CO-O-CH ₂ -C ₆ H ₅ ,

* = R)

 The compound obtained in the preceding stage is hydrolyzed as described in preparation 3- stage 3 with lithium hydroxide then the acid obtained is treated according to the example described in preparation 1 - stage 2 - (Yield = 68%)

CCM: CH ₂ Cl ₂ / MeOH 95/5 Rf = 0.68

- stage 4: (1R) -1-aminomethyl-1- (benzyloxycarbonylamino) -

1,2,3,4-tetrahydronaphthalene (VII. B; (B) = -CH ₂ -CH ₂ -, 2 = CO-O- CH ₂ -C ₆ H ₅ , * = R)

 The compound is prepared according to the protocol of preparation 3 - stage 5 from the compound of the previous stage (Yield = 58%)

TLC: CH ₂ Cl ₂ / MeOH 95/5 Rf = 0.36 Preparation 5: [1- (4-benzyl) piperidyl] -4-oxo-butanoic acid.

(IX; W = OH, p = 2, R ₁ = -CO-R ₂ for R ₂ =

 In a reactor protected from humidity, a mixture of 5.0 g (28.5 mmol) of reflux is brought to reflux, with stirring for 5 hours.

4-benzylpiperidine, 2.85 g (2.85 mmol) of succinic anhydride and 4.3 g (42.35 mmol) of triethylamine in 200 ml of anhydrous tetrahydrofuran.

After cooling to 30-40 ° C., 200 ml of ethanol are added, extracted with 250 ml of an N / 5 solution of acid sulfate of potassium - dry then evaporate the organic phase to obtain 7.85 g (yield = 100%) of pure product.

CCM: CH ₂ Cl ₂ / MeOH 50/10 Rf = 0.53

NMR (CDCl ₃ ): δ = 9.9 (1H exchangeable); 7.4-6.95 (m 5H); 4.8-4.4 (d 1H); 4.1-3.7 (d 1H); 3.3-2.8 (t 1H); 2.7 (s1H); 2.7-2.3 (m 3H); 1.95-1.5 (m 3H); 1.5-0.8 (m 2H)

Preparation 6: [1- (4-p-chlorophenyl-4-hydroxy) - piperidyl] -butanoic acid. (IX); (W = OH, p = 2,

R ₁ = -CO-R ₂ for R ₂ =

 The compound is prepared as described in the preceding preparation from 4- (p-chlorophenyl) -4-hydroxypiperidine and succinic anhydride. (YId = 95%)

CCM. : CH ₂ Cl ₂ / MeOH 90/10 Rf = 0.50

NMR (CDCI ₃ ): δ = 7.65-7.15 (m 4H); 3.1-2.3 (m 5H including 1 exchangeable); 2, 3-2, 0 (m 4H); 2.0-1.2 (m 4H)

TOXICITY AND PHARMACOLOGICAL STUDIES

 The products of the invention, administered in solution or in suspension orally in the male rat show little toxicity.

Their "in vitro" pharmacological study consisted in determining their affinity for binding to the peripheral and central cholecystokinin receptors (CCK _A / CCK _B ) as well as to the gastrin receptors (gastrin).

 "In vivo" the biological effects of the compounds of the invention have been shown by their ability to inhibit the benzodiazepine withdrawal syndrome in rats and by their anxiolytic effect in rats in the so-called labyrinth test

"elevated + maze".

 "In vitro" tests

The nanomolar concentration capable of: - to inhibit 50% of the links of cholecystokinin labeled with iodine 125 ([125I] -CCK8 sulfated - supplier Amersham), on the one hand to the plasma membranes of rat pancreas to determine their affinity for the peripheral receptors CCK _A , on the other hand to the membranes of guinea pig brains to determine their affinity for central receptors CCK _B , and,

- to inhibit 50% of the bonds of gastrin labeled with iodine 125 ([1251] -gastrin) to the purified plasma membranes of the guinea pig funda mucosa.

The implementation of these tests initially consists in preparing the membranes from the various tissues previously presented. For this purpose, described techniques are used which are for rat plasma membranes that of Innis RB and Snyder SM (Eur. J. Pharmacol. 65, 124, 1980) for membranes of guinea pig brains that of Pelelaprat D. and collar. (Life Se. 37, 2483-2490, 1985) and for guinea pig fundus membranes that of Praissman M and Col. (J. Recept. Res., 3, 647-665, 1983).

Whatever the fabric used, the principle of the test is that described by INNIS RB and SNYDER. SM (already cited). It consists in preparing the membranes to obtain a homogeneous solution of cells in an incubation buffer prepared extemporaneously using bovine serum albumin, MgCl ₂ , bacitracin and Tris-HCl, then in incubating a solution of the test product. and of the specific labeled ligand considered in the cell solution. After determining the concentration of the unbound labeled ligand, the nanomolar IC ₅₀ (inhibitory concentration 50%) of the test products is calculated with the aid of appropriate software such as "Hofstee" for gastrin receptors, or that of Tallarida and Muray, (Springer-Verlag, New-York, 1981), for the cholecystokinin receptors.

The table below indicates the results obtained for the compounds of the invention compared to the compound PD-134,308 included in the tests by reference.

These results show that the products of the invention exhibit a significant affinity for the CCK _B and gastrin receptors, an affinity which is found to be preferential for the gastrin receptors. Furthermore, the compounds are practically devoid of affinity for the peripheral cholecystokinin receptors (CCK _A ).

In particular, the compounds of Examples 5 and 6 are respectively

3 and 45 times more active on gastrin receptors than the Parke-Davis 134.308 reference product.

In addition, in the case of examples 5 and 6, the ratio of the CI ₅₀ CCK _B / CI ₅₀ Gastrin is 11 and 3 respectively, which means that their affinity for the gastrin receptors is 11 and 3 times greater than the one at the receivers

CCK B 'which therefore makes it possible, moreover for activity on the central nervous system pertaining to these latter receptors, to obtain medicaments preferentially treating disorders dependent on the gastrin receptors, and conversely to the reference compound which is 20 times more affinity for CCK _B receptors than for gastrin.

"In vivo" tests.

a) - inhibition of benzodiazepine withdrawal syndrome. The principle of the test, carried out in rats, consists in determining the attenuation, by a test product administered intraperitoneally, of an acute syndrome induced by chlordiazepoxide and precipitated by flumazenil. The implementation is carried out according to a method derived from that described by R.BOISSE et al. (J. Pharmacol. Exp. Ther. -1986-239, 775-783) using a quote derived from that of GPRYAN et al (J. Pharmacol. Exp. Ther. -1983-239, 100-107).

- Operative protocol: we practice with male Sprague Dawley rats of approximately 180 grams which are distributed at the rate of 4 rats per cage. They receive unlimited food and water.

 Seventy-two hours before the test, the animals are weighed, marked and orally receive 450 mg / kg of chlordiazepoxide (solution of 2,520 g / 25 ml of distilled water). At a rate of 5 ml / kg of body weight.

Immediately after the force-feeding, each rat is placed in a cage with unlimited food and water. The animals are then in a state of respiratory distress and must not be handled for 2 days following this induction. They often present with diarrhea, hyper bloating (enlarged stomachs), hyperthermia, hypersensitivity to grasping and to noise, resulting in leaps and bounds.

 On the day of the test, the animals are weighed and then left to calm for approximately 1 hour 30 minutes before starting the actual experiment during which the products (flumazenil, lorazepam and test compounds) are administered intraperitoneally in a volume of 5 ml / kg in the form of solutions prepared in distilled water or in suspensions in an aqueous solution of hydroxypropylmethylcellulose at 0.2% (w / v) in water, lorazepam serving as active reference in this test;

- at t = -45 min: 4 rats per observation series are placed in the individual cages. After an acclimatization period of about 30 min, we start for 15 min. the rating prior to weaning. This rating concerns the behavioral modifications described by GP Ryan (already cited) - at t = 0 min: flumazenil (25 mg / kg) is injected ip, and either the vehicle (control batch) or the compound to be studied (treated batches) at doses of 0.3 and 3.0 mg / kg, then immediately after these treatments, the animals are again observed and scores for 15 minutes.

Expression of results: for each rat, the score by symptom as well as the total score corresponding to the rating before after weaning are reported. The results are grouped by treatment for each animal and for each symptom. We calculate the difference between the rating before and after weaning; the mean by symptom and the mean total score by group are then calculated from this difference. The analysis of the results between the control group and the different groups treated is made and makes it possible to calculate a% decrease for each group treated compared to the control group. The significant results obtained with the representative compounds of the invention are presented in the table which follows.

 b) - research of the anxiolytic effect.

The principle of the test, carried out in rats, consists, after administration of the products under test by the intraperitoneal route, in determining the behavior of animals placed in an anxiety-provoking situation in a labyrinth in the shape of a cross whose arms are lit or in the darkness (device called "+ maze"). The activity of the animal, its location in the lighted or dark parts make it possible to evaluate the possible anxiolytic effect of the test compound. - Operating protocol: we practice with male rats

Sprague Dawley of approximately 140 grams distributed at a rate of 5 rats per cage. They receive unlimited food and water. On the day of the test, the animals are brought into the room, which is fitted with black curtains at the windows and artificial lighting without neon lights above the apparatus where the experiment takes place, the cages containing the animals being kept at away from the device.

 The treatments are administered intraperitoneally 30 minutes before the test at a rate of 0.5 ml per 100 grams of rat, the compounds being either dissolved in distilled water, or when they are insoluble, suspended in an aqueous solution 0.2% hydroxypropyl methyl cellulose in distilled water.

The actual test then consists in placing the animal on the

"+ maze" facing an open arm then for 5 minutes to note:

 1 °) each passage in the open arms,

 2) each passage in the closed arms,

3) and, essentially in this study, the time spent on open arms;

 The measurement being made with a stopwatch at 1 / 100th of a minute, Expression of the results

In this study, the average and the standard error of the average time spent on open arms are calculated in batches. Statistical analysis of the results is carried out by analysis of variance, and expressed either as a percentage increase in the time spent on open arms compared to the batch of control animals, or by the ED50 which is the dose in mg / kg which increases the time spent on open arms by 50%. According to this protocol, the compound of the invention described in Example 9 shows an ED50 of 6.3 mg / kg. Furthermore, the results obtained with the other representative compounds of the invention tested at doses of 1.0 - 3.0 - 10.0 mg / kg are reported in the table below.

 ns: insignificant result; NT: not tested

By virtue of their properties, the compounds of the invention in the form of medicaments are suitable for the treatment of disorders of the central nervous system manifested during psychotic states, memory disorders and states of decline in cognitive faculties.

 They are useful for the treatment of states of dependence on drugs or drugs, for example during periods of withdrawal from benzodiazepines, alcohol, nicotine and cocaine. Also, they can act on eating disorders by normalizing satiety.

In addition, they make it possible to treat preventively or curatively effectively gastrointestinal disorders, in particular those caused by excessive secretion of gastric acidity. Among these disorders are cited gastritis, peptic ulcers, pancreatic inflammations, Zollinger-Ellison syndrome. The products of the invention are administered to humans by routes appropriate to the nature and severity of the condition to be treated and in therapeutic forms compatible with the intended route of administration.

The low toxicity of the products makes it possible to consider daily dosages of up to 1 g of product per day. However, in a more usual manner the current dosage will be between 10 and 500 mg / day which can be divided into several doses.

A pharmaceutical composition according to the invention comprises a sufficient therapeutic amount of 5 to 80 parts by weight of active principle, consisting of one or more compounds of formula (I), associated with 195 to 120 parts by weight of a pharmaceutically acceptable vehicle.

Different forms prepared from the products of the invention or from their salt are prepared by methods known per se.

 For example of these preparations, mention will be made of tablets, dragees, capsules, powders, solutions, suspensions, gels and suppositories and, to illustrate in a nonlimiting manner their manufacture, the tablets are given below.

 - Formula

 Active substance according to Example 5 5 to 80 mg

 Polyvinylpyrrolidone 2mg

Carboxymethyl starch 8 mg

 Magnesium stearate 3 mg

 Lactose 1/3

 Microcrystalline cellulose 2/3

 For one 200 mg tablet

- Manufacturing

 Dissolve polyvinylpyrrolidone at a concentration between 0.1 and 1.0% by weight in water, or in low molecular weight alcohol such as ethanol or a hydroalcoholic mixture.

Thoroughly mix the active substance, lactose, half the amount of crystalline cellulose and carboxymethyl starch used and then moisten this mixture with the polyvinylpyrrolidone solution obtained previously. Granulate the paste obtained on an oscillating granulator, then dry the granules in an oven or on a fluidized air bed.

Calibrate the dried granules on a sieve and add the magnesium stearate, the rest of microcrystalline cellulose and carboxymethyl starch. Mix thoroughly and then compress at a rate of 200.0 g per tablet.

Claims

1. α-methyl-R-tryptophyl-arylcycloalkylalkylamides of formula (I)

 in which,

(B) represents a methylene (-CH ₂ -) or ethylene (CH ₂ -CH ₂ -) group,

(C) represents a valence bond or a methylene group (-CH ₂ -),

 A is a valence bond or an aminocarbonyl group (NH-CO),

 p has the value 0, 1 or 2,

R ₁ represents a 1H-tetrazol-5-yl group or a carbonyl function -CO-R ₂ in which R ₂ is hydroxyl,

lower alkoxy, N-indolinyl or alternatively R ₂ represents a cycloalkylamine of formula (VIII),

in which R ₃ is hydrogen or a hydroxyl radical, oa for value O or 1 and R ₄ is hydrogen or a chlorine atom, * represents, established according to the rule of Cahn, Ingold and Prelog, the absolute configuration of the carbon in position 1 of the cycloalkyl block,

 and their optional addition salts with pharmaceutically acceptable bases.

2. α-methyl-R-tryptophyl-arylcycloalkylalkylamide according to claim 1 characterized in that A is aminocarbonyl (NH-CO), C is methylene (-CH ₂ -) pa for values 1 or 2,

3. α-methyl-R-tryptophyl-arylcycloalkylalkylamide according to claims 1 and 2 characterized in that (B) is methylene (-CH ₂ -),

4. α-methyl-R-tryptophyl-arylcycloalkylalkylamide according to claims 2 and 3 characterized in that R ₁ is a carbonyl function CO-R ₂ in which R ₂ is hydroxyl,

5. α-methyl-R-tryptophyl-arylcycloalkylalkylamide according to claims 1 to 4 characterized in that the carbon * is of absolute configuration R established according to the rule of Cahn, Ingold and Prelog,

6. 4 - [(1R) -1- [1- [N - [(2-adamantyloxy) carbonyl] -α- methyl-R-tryptophyl-aminomethyl] -indanyl] -amino] -4-oxo-butanoic acid and its addition salt with N-methyl-D-glucamine.

7. Process for the preparation of α-methyl-R-tryptophyl-arylcycloalkylalkylamide defined in claim 1 characterized in that it consists:

 A. To prepare a compound (I) in which,

A and (C) are a valence bond, pa for value O and R ₁ is a carbonyl radical -CO-R ₂ which corresponds to formula (Ia)

in which R ₂ is lower alkoxy,

to condense in tetrahydrofuran an intermediate (II. a)

in which R ₂ is lower alkoxy, with the 2-adamantyl chloroformate to obtain the corresponding compound Ia, and to prepare a compound (Ia) in which R ₂ is hydroxyl, to saponify in dioxane with lithium hydroxide a compound (Ia) in which R ₂ is lower alkoxy, then optionally salifying it with N-methyl-D-glucamine to obtain the corresponding addition salt,

B. To prepare a compound (I) in which,

A is aminocarbonyl (NH-CO), C is methylene (-CH ₂ -), p has the value 1 or 2 which corresponds to the formula (Ib).

to condense in tetrahydrofuran an intermediate (IV. b)

in which Z is an amino protecting group such as the benzyloxycarbonyl group which is preferred, with 2-adamantyl chloroformate to obtain an intermediate (Ill.b)

then removing the protective group Z by hydrogenolysis to obtain an intermediate (Il.b)

which is acylated with a reagent (IX) of formula W-OC- (CH ₂ ) pR ₁ in which W represents bromine, chlorine or a hydroxyl radical and R ₁ represents a group -CO-R ₂ such that mentioned for (I), except when R ₂ represents a hydroxyl, to obtain a corresponding compound (Ib) or,

which is acylated by the internal anhydride of a diacid such as succinic anhydride to obtain a corresponding compound (Ib) in which pa for value 2 and R ₁ is a radical -CO-R ₂ in which R ₂ is hydroxyl ,

which is optionally salified with N-methyl-D-glucamine to obtain the corresponding addition salt.

8. Medicament, intended for the treatment and prevention of gastric affections, characterized in that it comprises an α-methyl-R-tryptophyl-arylcycloalkylalkylamide (I) according to one of claims 1 to 6.

9. Medicament, intended for the treatment of disorders of the central nervous system, characterized in that it comprises an α-methyl-R-tryptophyl-arylcycloalkylalkylamide (I) according to one of claims 1 to 6.