CN1359373A

CN1359373A - 6[(aryl and heteroaryl)oxy] methyl] naphthalene-2-carboximidamide derivatives, preparation and therapeutic application thereof

Info

Publication number: CN1359373A
Application number: CN00809874A
Authority: CN
Inventors: C·阿尔库菲; P·贝勒维格; G·德拉克; C·拉塔姆; G·拉萨勒; S·马拉特; V·马丁; C·马森; G·麦科尔特
Original assignee: Sanofi Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1999-05-04
Filing date: 2000-04-25
Publication date: 2002-07-17
Also published as: ZA200108758B; EP1177169A1; YU78001A; BG106048A; NO20015387D0; JP2002543176A; PL356122A1; HUP0200893A2; NO20015387L; KR20020010634A; TR200103215T2; CA2371284A1; CZ20013959A3; AU4303700A; FR2793247B1; HUP0200893A3; WO2000066545A1; IS6121A; HK1042288A1; BR0010230A

Abstract

The invention concerns compounds of general formula (I) wherein: R1 represents either a hydrogen atom, or an amino group, or a C1-C4 alkyl group, or a C1-C6 alkoxycarbonyl group, or a -OH group; R2 represents either a C1-C6 alkyl group, or a phenyl or benzyl group, or a -CH2Q group, wherein Q is a heterocyclic group; R3 and R5 represent independently of each other for example either a hydrogen atom, or a C1-C4 alkyl group, or a -COOH group; R4 represents either a hydrogen atom, or a C1-C4 alkyl group, or a -(CH2)p-COOR8 group; Z represents either a -CH- group, or a nitrogen atom. The invention also concerns the methods of preparation and therapeutic use of said compounds.

Description

6- [ [ (aryl and heteroaryl) oxy ] methyl ] -naphthyl-2-carboximidamide derivatives, process for their preparation and their use in therapy

The object of the present invention are 6- [ [ (aryl or heteroaryl) oxy ] methyl ] -naphthyl-2-carboximidamide (carboximidamide) derivatives, their preparation and their use in therapy.

The compounds of the invention correspond to the general formula (I)

Wherein,

R₁to represent

A hydrogen atom, and a nitrogen atom,

or an amino group, or a salt thereof,

or C₁～C₄An alkyl group, a carboxyl group,

or C₁～C₆An alkoxycarbonyl group, a carbonyl group,

or an-OH group, or a group,can be in the form of tautomersThe form (a) of (b) exists,

R₂to represent

C₁～C₆An alkyl group which may be substituted with 1 to 3 fluorine atoms,

or a cyclohexyl-methyl group,

or 2, 3-dihydro-1, 4-benzodioxy (benzodiox) -7-ylmethyl,

or benzo-1, 3-dioxolan-6-ylmethyl,

or phenyl, benzyl or phenethyl, wherein the phenyl groups can be respectively and independently selected from 1 to 3-N (CH)₃)₂Trifluoromethoxy group, methylthio group, C₁～C₄Alkoxy, trifluoromethyl, amino, nitro, C₁～C₄Alkyl, halogen atom, -SO₂CH₃Hydroxy or-COOR₈or-OCH₂CO₂R₈Is substituted by radicals, where R₈Represents a hydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

or a group-CH₂Q, where Q is a heterocyclic group, which may be selected from the group consisting of-N (CH)₃)₂Trifluoromethoxy group, C₁～C₄Alkoxy, trifluoromethyl, amino, nitro, C₁～C₄Alkyl, halogen atom, -SO₂CH₃Hydroxy or-COOR₈or-OCH₂CO₂R₈Is substituted by radicals, where R₈Represents a hydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

R₃and R₅Independently of each other represent

A hydrogen atom or a fluorine atom, or a salt thereof,

or C₁～C₄An alkyl group, a carboxyl group,

or-COOH, or a group of-COOH,

or a hydroxyl group, or a mixture of hydroxyl groups,

or-N (CH)₃)₂，

or-Y-CH₂CO₂H, wherein Y represents an oxygen atom or a nitrogen atom,

R₄to represent

A hydrogen atom, and a nitrogen atom,

or C₁～C₄An alkyl group, a carboxyl group,

or- (CH)₂)_p-COOR₈Where p is equal to 0, 1 or 2, R₈Represents a hydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

x represents

-(CH₂)_mA group, where m is equal to 0, 1 or 2,

or-CR₆R₇-CH₂-or-CH₂-CR₆R₇A group, where R₆And R₇Each independently represents a hydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

or-NH-CO-or-CO-NH-groups,

or-NH-CH₂-、-CH₂-NH-、N(CH₂)-CH₂-、-CH₂-N(CH₃)-、-N(CH₂CH₃)-CH₂-or-CH₂-N(CH₂CH₃) The radical(s) is (are),

or

The radical W represents an oxygen atom or an NH groupGroup, Z represents

-a CH-group, in which,

or a nitrogen atom, or a mixture of nitrogen atoms,

and-A-B-C-represents

-a NH-CO-NH-group,

or an-NH-C (NH) -NH-group,

or- (CH)₂)_n-CO-NH groups, where n is equal to 0 or 1,

or- (CH)₂)_q-NR₈-SO₂-a group, where q is equal to 0, 1 or 2, and R₈As before, represents a hydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

or- (CH)₂)_q-NH-CO-group, where q is equal to 0 or 1,

or-CH₂-NH-CO-NH-groups.

Within the scope of the present invention, the following terms have the following meanings:

alkyl is a linear or branched saturated hydrocarbon-containing chain,

the heterocyclic group is a hydrocarbon chain containing 5 to 6 link rings and containing one or two oxygen, sulfur and nitrogen heteroatoms, the rings can be aromatic or non-aromatic, and are selected from pyridine, pyrimidine, thiazole, imidazole, pyrrole, oxazole, thiophene, furan, pyrazine and other groups or isomers of the groups.

In the context of the present invention, halogen atoms are preferably chlorine and fluorine.

The compounds of the present invention may include one or several asymmetric carbons. They may thus be in the form of enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures, form part of the present invention.

The compounds of the invention may be in the form of the free base or an addition salt with a pharmaceutically acceptable acid, which also forms part of the invention.

Preferred compounds within the scope of the present invention are those in which,

R₁to represent

A hydrogen atom, and a nitrogen atom,

or C₁～C₆An alkoxycarbonyl group, a carbonyl group,

or an-OH group, or a group,

R₂to represent

C which may be substituted by trifluoromethyl₁～C₆An alkyl group, a carboxyl group,

or a cyclohexyl-methyl group,

or 2, 3-dihydro-1, 4-benzodioxo-7-ylmethyl,

or benzo-1, 3-dioxolan-6-ylmethyl,

or phenyl, benzyl or phenethyl, wherein the phenyl groups can be 1-3 independently selected from-N (CH)₃)₂Trifluoromethoxy group, methylthio group, C₁～C₄Alkoxy, trifluoromethyl, hydrogen radical, nitro radical, C₁～C₄Alkyl, halogen atom, -SO₂CH₃Hydroxy or-COOR₈or-OCH₂CO₂R₈Is substituted by radicals, where R₈Represents a hydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

or-CH₂The group Q, where Q is a heterocyclic group, which may be selected from C₁～C₄Alkoxy, amino or-COOR₈Is substituted by radicals, where R₈Represents a hydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

R₃and R₅Independently of each other represent

A hydrogen atom, and a nitrogen atom,

or a-COOH group, or a group of-COOH,

or-CH₃The radical(s) is (are),

R₄to represent

A hydrogen atom, and a nitrogen atom,

or a-COOH group, or a group of-COOH,

x represents

-(CH₂)_mA group, where m is equal to 0 or 2,

or-CR₆R₇-CH₂A group, where R₆And R₇Each independently represents a hydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

or-NH-CO-or-NH-CH₂-a group of,

or-NH-CH₂-or-CH₂-N(CH₂CH₃) The radical(s) is (are),

z represents

-a CH-group, in which,

and-A-B-C-represents

-a NH-CO-NH-group,

or- (CH)₂)_n-CO-NH groups, where n is equal to 0 or 1,

or- (CH)₂)_q-NR₈-SO₂-a group, where q is equal to 0, 1 or 2, and R₈Represents a hydrogen atom, and is represented by,

or- (CH)₂)_q-NH-CO-group, where q is equal to 0 or 1,

or-CH₂-a NH-CO-NH-group,

or-CH₂-CO-NH groups.

According to the invention, the compounds of general formula (I) can be synthesized according to scheme 1. FIG. 1 schematically shows

Reacting a compound of formula (II) with a compound of formula (III) in the presence of a base such as potassium carbonate in an aprotic solvent, preferably acetonitrile or dimethylformamide, at a temperature of 20 to 80 ℃ to give a compound of formula (IV); r in the formula (II)₃And R₄As defined above (if R is₄Is a-COOH group, in fact in the form of an ester, until a compound of formula (VI) is obtained) and D represents a leaving group, such as a halogen or a sulfonate; r in the formula (III)₅X, Z, A and B are all as defined above (in fact when B is ultimately the group-CO-, it is-CO-during the synthesis₂-groups) and GP represent amine or carboxylic acid protecting groups, such as C₁～C₄Alkoxy or benzyloxy. In addition, the compound of the general formula (IV) can be prepared by Mitsunobu reaction of a compound of the general formula (II) in which D represents a hydroxyl group, with a compound of the general formula (III) condensed in the presence of diethyl azodicarboxylate or 1, 1' - (azodicarbonyl) dipiperidine and a trialkylphosphine or triarylphosphine, such as tri-n-butylphosphine or triphenylphosphine, in, for example, 1, 4-dioxane, tetrahydrofuran or toluene at a temperature of 0 to 60 ℃.

Deprotection of a compound of formula (IV) wherein A represents- (CH) to give a compound of general formula (V) under conditions known to those skilled in the art₂)_q-a group, where q may be 0, 1 or 2 and B represents a group-NR₈-, where R is₈Represents a hydrogen atom or C₁～C₄Alkyl Groups and GP represents amine protecting Groups such as tert-butyloxycarbonyl, trifluoroacetyl, trimethylsilylethoxycarbonyl or other various suitable protecting Groups as described in Protective Groups in Organic Synthesis, 2 nd edition, Wiley, NY, (1991) by T.Greene et al.

When referring to compounds of formula (IV) wherein A represents a group- (CH)₂)_n-, where n may be 0 or 1 and B represents a functional group-CO₂-, where GP represents a carboxylic acid protecting group, such as methyl, ethyl, tert-butyl or others, as is known to those skilled in the artKnown and described in Protective groups in organic Synthesis, 2 nd edition, Wiley, NY, (1991), Greene et al convert these ester compounds of the general formula (IV) in which A is a Group- (CH) to free carboxylic acids of the general formula (V) by conventional methods, such as saponification with hydroxide ions, hydrolysis with inOrganic or organic acids, or reaction of silyl Protective groups, such as trimethylsilylethoxycarbonyl, with fluoride ions₂) -, where n may be 0 or 1 and BH represents a functional group-CO₂H。

Then, in the presence of organic base such as triethylamine, N-methylmorpholine or N, N-diisopropylethylamine in a solvent such as dichloromethane or dimethylformamide at the temperature of 0-60 ℃, the A in the formula is represented by- (CH)₂)_q-a group (where q may equal 0, 1 or 2), BH representing-NHR₈And R is₈A compound of the formula (V) as defined above, and wherein R₂Formula R as defined above₂-SO₂Cl sulfonyl chloride to obtain a compound of a general formula (VI), wherein A represents- (CH)₂)_q-a group (where q may be equal to 0, 1 or 2), B represents-NR₈A group and C represents-SO₂-a group.

It is also possible to react A in the formula with a radical- (CH) under the conditions described above for the sulfonyl chloride₂)_q- (where q is equal to 0 or 1), BH representing an amino function

Or directly with R in the formula₂Formula R as defined above₂-N ═ C ═ O isocyanate reaction;

or with triphosgene or equivalent compound and then with R in the formula₂Formula R as defined above₂-NH₂Reaction of the amine to give a compound of the general formula (VI) in which A represents the group-NH-or-CH₂-NH-, B represents a group-CO-, and C represents a group-NH-.

In the formula, A represents a group- (CH)₂)_qAnd BH represents an amino function or a group-NHR₈A compound of the general formula (V) of (1),

or in the presence of an organic base with R in the formula₂Formula R as defined above₂-reaction of COCl acid chlorides, their corresponding mixed anhydrides or active esters;

or with R in the formula in a solvent such as dichloromethane, dimethylformamide or a mixture of the two, in the presence of a coupling agent such as N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide/1-hydroxybenzotriazole or [0- (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium (uronium) hexafluorophosphate or a peptide coupling agent known in the art, at a temperature of 0 to 25 ℃₂Formula R as defined above₂-CO₂H carboxylic acid to obtain the compound of the general formula (VI), wherein A represents- (CH)₂)_q-, where q is equal to 0 or 1, B represents a group-NH-, and C represents a group-CO-.

To obtain a compound in which A represents a group- (CH)₂)_n- (where n is equal to 0 or 1), B represents a group-CO-and C represents a group-NH-a compound of formula (VI) in which A represents a group- (CH)₂)_n- (where n is equal to 0 or 1), BH representing a group-CO₂H a compound of the general formula (V) and R in the formula₂Formula R as defined above₂-NH₂The amine is reacted under peptide coupling conditions as specified above.

In order to obtain a compound of formula (VI) in which A-B-C-represents a group-NH-C (NH) -NH-, A represents a group- (CH)₂)_q- (where q is equal to 0 or 1), BH represents an amine function, and R in the formula₂Formula R as defined above₂And reacting N-C-S isothiocyanate. The thiourea thus obtained can be converted to guanidine by alkylation with methyl iodide and substitution with an ammonia source, such as ammonium acetate or ammonium carbonate.

The compounds of the general formula (I) can subsequently be obtained from these compounds of the general formula (VI), for example by arranging the nitrile groups as amidino groups by the two processes A and B described below.

The method A comprises the following steps: the compound of the general formula (VI) dissolved in saturated hydrogen sulfide of a triethylamine/pyridine mixture (1: 9) is treated for 20 to 36 hours at normal temperature. The thioamides thus formed are alkylated by refluxing an excess of methyl iodide in acetone, for example in the presence of ammonium acetate or of the formula R₁-NH₂The resulting intermediate is heated under reflux in an alcohol such as methanol in the presence of a nitrogen source of a primary amine to give the compound of formula (I).

The method B comprises the following steps: the compound of formula (VI) is treated with hydroxylamine hydrochloride in an alcohol, preferably ethanol, in the presence of an organic base such as triethylamine at a temperature of 40 to 70 ℃. Under the pressure of 20-50 psi and the temperature of 20-60 ℃, in the alcohol such as methanol or ethanol, in the presence of active Raney nickel and a few equivalents of hydrochloric acid or acetic acid, the obtained hydroxyamidine (R in the formula)₁Compounds of the general formula (I) ═ OH) are hydrogenated to give compounds of the formula R₁A compound represented by the general formula (I) wherein is a hydrogen atom.

If desired R in the formula₁Is a group C₁～C₆The compound of the general formula (I) of alkoxycarbonyl is prepared by dissolving R in a solvent such as dichloromethane, tetrahydrofuran or acetonitrile in the presence of 1, 1, 3, 3-tetramethylguanidine, triethylamine or diisopropylethylamine at a temperature of 0-25 DEG C₁A compound of formula (I) ═ H is reacted with an alkyl chloroformate.

The compounds of formula (II) can be synthesized by methods known to those skilled in the art. By way of example, several synthetic methods for the compounds of the general formula (II) are given in schemes 2 and 3.

FIG. 2 is a schematic view of

According to scheme 2, the bromo ester compound of formula (VII) is treated with a cyanide source such as copper cyanide in dimethylformamide at 50-140 deg.C, or in a solvent such as triethylamine or tributylamine at 80-160 deg.C in palladium (0)) The catalyst, such as tetrakis (triphenylphosphine) palladium (0), is treated with trimethylsilyl cyanide in the presence of palladium (0), or zinc cyanide in dimethylformamide in the presence of palladium (0), such as tetrakis (triphenylphosphine) palladium (0), at 80 ℃ to give the nitrile of formula (VIII). The ester function can be reduced by a number of methods known in the art, for example by reaction with lithium borohydride in an aprotic solvent such as tetrahydrofuran at a temperature of 0 to 80 ℃. Treating the thus obtained compound of formula (IX) with a reagent such as phosphorus tribromide or sulfuryl chloride in a solvent such as dichloromethane or chloroform at a temperature of 0 to 60 ℃ to obtain a compound of formula (II) wherein R₄Represents a hydrogen atom, and D represents a halogen. The compounds of formula (IX) may also be converted into sulfonates, such as methanesulfonates, according to methods known to those skilled in the art.

If desired, to prepare R in the formula₄Represents a group-COOR₈(where R is₈Represents a hydrogen atom or a group C₁～C₄Alkyl), and D represents a hydroxyl function or a halogen atom, can be operated, for example, according to scheme 3, where the compound of formula (II) is R₄Represents the group-CO₂CH₂CH₃The compound of (1).

Schematic diagram 3

According to scheme 3, the ester derivatives of formula (VII) are first reduced to alcohol derivatives of formula (X) with, for example, lithium aluminum hydride in tetrahydrofuran at a temperature of-20 ℃ to-10 ℃. The hydroxy function of the compound of formula (X) is converted to the halogen atom (Hal) chlorine or bromine by reactions common in the art, such as with phosphorus tribromide or sulphuryl chloride under the conditions previously described. At a temperature of 0-25 ℃ in dichloromethane, a compound of formula (XI) is obtained in which the halogen atom is replaced by a cyanide source, preferably tetraethylammonium cyanide. By the reaction of a compound of the formula R₈Alcohols of-OH (R)₈Is represented by C₁～C₄Alkyl), the nitrile function of the compound of formula (XII) thus obtained is converted into an ester by treatment with, for example, 95% sulfuric acid under reflux.

The compound of the formula (XIII) is obtained, which is preferably reacted with zinc cyanide in dimethylformamide in the presence of tetrakis (triphenylphosphine) palladium (O). To give the derivatives of the formula (XIV)

Or into compounds of the general formula (II) in which D represents a bromine atom and R represents a bromine atom, by the action of N-bromosuccinimide in the presence of catalytic amounts of 2, 2' -aza-bis (2-methylpropanenitrile) or benzoyl peroxide at reflux in carbon tetrachloride₄Represents the group-CO₂CH₂CH₃；

Or converted by oxidation into glyoxylic acid derivatives of the general formula (XV) by means of selenium dioxide refluxed in pyridine. Selective reduction of a compound of formula (XV), preferably with sodium borohydride in tetrahydrofuran at low temperature, provides a compound of formula (II) wherein D represents a hydroxyl function and R₄Represents the group-CO₂CH₂CH₃。

The compounds of formula (III) may be prepared according to scheme 4. FIG. 4 is a schematic view of

The ketones of the general formula (XVII) are commercially available and can be prepared according to the methods described in the literature or according to known modifications.

By way of example, substituted tetralones of the general formula (XVII) in which Z represents a group-CH-are described in U.S. Pat. No. 4, 3,980,699 and in European patent application 0540051. Compounds of the general formula (XVII) in which Z represents a nitrogen atom, in which Z represents a radical-CH-and X represents-NH-CH-, are prepared according to EP-313295₂The compounds of the general formula (XVII) are prepared according to the modified method described in journal of the American chemical society (J.Amer.chem.Soc.)71, p.1901 (1949). The compounds of formula (XVIII) in which Z represents a group-CH-and X represents a group-NH-CO or-CONH-, are according to the chemistry described in FrancePrepared as described in the Association bulletin (Bull. Soc. Chim. Fr.)1, page 98 (1988). In which Z represents a group-CH₂-and X represent a group-CH₂-NH-or-CH₂The compounds of the general formula (XVII) which are N-alkyl can be prepared according to a variant of the Pictet-Gram method described in chem.Ber. 42, p 2943 (1909) and in Org.React 6, p 151 (1951). Compounds of the general formula (XXII) in which Z represents a nitrogen atom and X represents a group-NH-CO-, can be prepared by a modification of the process described in "chem.soc." (J.Chem.Soc.) Perkin Trans 1, p.353 (1991). Compounds of formula (XXII) wherein Z represents a group-CH-and X represents a group-CO-NH-may be prepared according to the methods described in the report on Chemicals (chem.pharm.Bull.), 16(3), page 455 (1968).

In addition, indanones are commercially available.

According to scheme 4, R can be₅The compounds of general formula (XVII) in which X and Z are as defined above, are subjected to the following reactions:

according to journal of the American society of chemistry 93, page 2897 (1971), the reductive amination is carried out directly with ammonium acetate and cyanoborohydride in methanol at ambient temperature:

or indirect reaction in two stages, under the usual conditions to give the oxime, which is then reduced with iron in acetic acid, or with lithium aluminium hydride, or by hydrogenation in the presence of palladium on carbon and acetic anhydride, to give the compound of the formula (XVIII). The compound of formula (XVIII) thus obtained is subsequently freed from methyl groups by reaction with 48% hydrobromic acid under reflux or, preferably, with boron tribromide in dichloromethane at low temperature (-70 to-20 ℃). The amine function of the resulting compound of the formula (XIX) may then be protected with an amine Protecting group, such as tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, trifluoroacetyl, or other Protecting Groups as described in Greene, organic Synthesis, Wiley, NY, 1991. Thus obtaining a compound of the general formula (III) wherein A represents- (CH)₂)_q-, where q is equal to 0, and B represents a group-NH-, GP represents a protecting group.

To obtain a compound in which A represents a group- (CH)₂)_q-, where q is equal to 1 and B represents a group-NH-, the starting ketone of the formula (XVII) is first converted into an enol ether of the formula (XX) by a Wittig reaction with (methoxymethyl) triphenylphosphine in tetrahydrofuran at a temperature of less than 0 ℃. The enol ether of formula (XX) is then hydrolyzed to the aldehyde of formula (XXI) in a refluxing mixture of water-tetrahydrofuran or water-dioxane with the aid of an organic acid such as formic acid or p-toluenesulfonic acid. In this case, the compound of the formula (XXI) is converted into the amine of the formula (XXII) under the conditions described above for the preparation of the compound of the formula (XVIII). The methyl group of the compound of formula (XXII) is then removed, preferably at low temperature, with boron tribromide in a solvent such as dichloromethane, and the amine functionality of the resulting compound of formula (XXIII) is protected as described above for the compound of formula (XIX) to give the compound of formula (III), wherein A represents- (CH)₂)_q-, where q is equal to 1, B represents the group-NH-, and GP is an amine protecting group as described above.

The compounds of formula (XXII) may also be prepared by reacting a compound of formula (XVII) with trimethylsilylcyanide in dichloromethane in the presence of titanium tetrachloride (IV) and then hydrogenating the resulting nitrile intermediate in a solvent such as methanol at a pressure of 10 to 50psi in the presence of platinum oxide or palladium on carbon.

The aldehydes of formula (XXI) may also be oxidized to carboxylic acid derivatives of formula (XXIV) by reaction with a suitable oxidizing agent known to those skilled in the art, such as sodium hypochlorite. The compound of formula (XXIV) thus obtained is then demethylated with boron tribromide at low temperature and the carboxylic acid function of the compound of formula (XXV) is esterified in a usual manner, for example by heating in methanol saturated with hydrogen chloride gas. Thus obtaining a compound of the general formula (III) wherein A represents- (CH)₂)_n-, where n is equal to 0 and B represents a group-CO₂And GP represents methyl.

To obtain a compound represented by the formula wherein A represents- (CH)₂)_n-, where n is equal to 1 and B represents a group-CO₂The compounds of formula (III) in which-and GP represent methyl groups can be prepared according to scheme 5.

FIG. 5 is a schematic view of

According to scheme 5, a compound of formula (XVII) can be reacted with the anion of methyl dimethylphosphorylacetate (obtained by deprotection with lithium trimethylsilylamide in tetrahydrofuran at a temperature of-50 to 20 ℃) to give an α, β -unsaturated ester of formula (XXVI). The compound of formula (XXVI) is then reduced to the compound of formula (XXVII) by catalytic hydrogenation, which is then demethylated with boron tribromide in dichloromethane at-70 ℃. To obtain a compound of the general formula (III) in which A represents- (CH)₂)_n-, where n is equal to 1 and B represents a group-CO₂-, and GP represents methyl.

The following examples are intended to illustrate the invention without limiting its scope. The structure of the resulting compound was confirmed by microanalysis, nuclear magnetic resonance spectroscopy (RMN), mass spectrometry and infrared spectroscopy (IR). The numbering of the exemplified compounds is with reference to the tables given at the end, which illustrate the chemical structure and physical properties of certain compounds of the invention.

Example 1: (32# Compound)

6- [ [ [8- [ [ [ (thiazol-4-yl) -methyl ] -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalene-2-carboximidamide hydrochloride

1.1.6-cyanonaphthalene-2-carboxylic acid methyl ester

To a suspension of 7.50g (28.29mmol) of methyl 6-bromo-naphthalene-2-carboxylate degassed and 2.01g (17.0mmol) of zinc cyanide in 20mL of dimethylformamide was added 2.28g (1.97mmol) of tetrakis (triphenylphosphine) palladium (0), and the mixture was heated at 80 ℃ under nitrogen for 16 hours. The reaction medium is evaporated to dryness and the residue is dissolved in 300mL of ethyl acetate and filtered. The filtrate was washed twice with water and then with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue is purified by flash chromatography on silica gel (chromatofoash) eluting with an ethyl acetate/toluene mixture (1: 9).

5.20g of white crystals were obtained.

Melting point: 163 ℃ C.

Yield: 84 percent.

1.2.6- (hydroxymethyl) -naphthalene-2-carbonitrile

To a solution of 10.0g (47.35mmol) of methyl 6-cyanonaphthalene-2-carboxylate in 160mL of tetrahydrofuran cooled to 0 ℃ under nitrogen was added 2.06g (94.7mmol) of lithium borohydride in small portions and then returned to ambient temperature over 4.5 hours. The reaction mixture was then heated at reflux for 2 hours, cooled to 0 ℃ and hydrolyzed by the slow addition of 100mL of 1N hydrochloric acid. The tetrahydrofuran was distilled off under reduced pressure and the product was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with an ethyl acetate/cyclohexane mixture (3: 7).

6.72g of product are obtained as a white solid.

Melting point: 129 ℃.

Yield: 78 percent.

1.3.6- (bromomethyl) -naphthalene-2-carbonitrile

To a solution of 20.0g (109.3mmol) of 6- (hydroxymethyl) naphthalene-2-carbonitrile dissolved in 600mL of dichloromethane cooled to 0 ℃ was added dropwise 4.1mL (43.7mmol) of phosphorus tribromide. The reaction medium is then stirred at 20 ℃ for 3 hours and then washed several times with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness.

21.10g of an off-white solid are obtained.

Melting point: 138-139 ℃.

Yield: 78 percent.

1.4.7-methoxy-1- (methoxymethylene) -1, 2, 3, 4-tetrahydronaphthalene

To a solution of 60.0g (175mmol) of (methoxymethyl) -triphenylphosphine (chrysolite) in 500mL of anhydrous tetrahydrofuran cooled to-50 ℃ under nitrogen was added 19.65g (175mmol) of potassium tert-butoxide, and stirring was continued at-40 ℃ for 30 minutes. At this point a solution of 22.0g (125mmol) of 7-methoxy-1-tetralone (tetralone) in 250mL of anhydrous tetrahydrofuran was added dropwise. The reaction medium is then stirred at 20 ℃ for 3 hours and then hydrolyzed by the slow addition of 500mL of water. The organic phase was decanted and the aqueous phase was extracted with ethyl acetate. The organic phase was decanted and the aqueous solution was extracted with ethyl acetate aqueous solution. The organic phases are combined and washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The resulting residue was triturated several times in cyclohexane and filtered to remove the precipitate. The filtrate was evaporated to dryness and the crude product was purified by flash chromatography on silica gel eluting with an ethyl acetate/cyclohexane mixture (5: 95).

25.94g of slurry were obtained and used as such in the next step.

1.5.7-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1-carbaldehyde

A solution of 25.50g (125mmol) of 7-methoxy-1- (methoxymethylene) -1, 2, 3, 4-tetrahydronaphthalene and 7.50g (39.43mmol) of p-toluenesulfonic acid monohydrate in 200mL of 1, 4-dioxane and 50mL of water was refluxed for 2 hours. The reaction medium is then evaporated under reduced pressure and the residue is dissolved in 250mL of ethyl acetate. The solution was washed twice with water, the organic phase was dried over sodium sulfate, filtered and evaporated to dryness.

24.1g of a pale yellow oil are obtained, which is used in the next step without further purification.

1.6.7-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1-carbaldehyde oxime

To a solution of 11.10g (160mmol) of hydroxylamine hydrochloride and 25mL (180mmol) of triethylamine in 100mL of absolute ethanol at ambient temperature was added 28.70g (150 mmol) of 7-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1-al dissolved in 20mL of ethanol. The mixture was then heated at reflux for 2 hours and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with 1M aqueous citric acid solution and then with saturated aqueous ammonium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness.

28.04g of product are obtained as a white solid.

Melting point: 147 ℃.

Yield: 93 percent.

1.7.7-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1-methanamine

To a solution of 10.0g (48.48mmol) of 7-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1-carboxaldoxime in 200mL of anhydrous tetrahydrofuran at ambient temperature was added 49mL (49mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran dropwise. The reaction medium is stirred at ambient temperature for 16 hours, and then hydrolysis is carried out by successively adding 1.9mL of water, 1.9mL of 1N sodium carbonate and then 5.6mL of water. Magnesium sulfate 50g was added, stirred for 5 minutes, and then filtered. The salt was washed with dichloromethane and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate, the solution was washed successively with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and evaporated to dryness.

8.99g of the product are obtained as a colorless oil.

Yield: 88 percent.

1.8.8- (aminomethyl) -5, 6, 7, 8-tetrahydronaphthalen-2-ol hydrobromide

To a solution of 9.50g (49.7mmol) of 7-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1-methanamine in 49mL of dichloromethane cooled to-78 deg.C was added 109mL (109mmol) of a 1M solution of boron tribromide in dichloromethane dropwise. The reaction medium is stirred at-78 ℃ for 30 minutes and then at ambient temperature for 30 minutes. 100mL of methanol was added dropwise at-78 ℃ for hydrolysis, followed by stirring at 20 ℃ for 1 hour. The medium was evaporated to dryness, then dissolved in toluene and evaporated again to dryness.

12.40g of an amorphous solid product having hygroscopicity was obtained.

Yield: 97 percent.

Melting point (hydrochloride salt): 181-183 ℃.

[ (7-hydroxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) -methyl ] -carbamic acid 1, 1-dimethylethyl ester

To a solution of 11.74g (45.50mmol) of 8- (aminomethyl) -5, 6, 7, 8-tetrahydronaphthalen-2-ol hydrobromide in 360mL of tetrahydrofuran at 20 ℃ with stirring was added 11.70g (53.67mmol) of di-tert-butyl dicarbonate. Then 12.7mL (91mmol) of triethylamine were added dropwise and stirred at 20 ℃ for 4 hours. At this point, the reaction medium is evaporated to dryness and the residue is dissolved in 300mL of ethyl acetate. The solution was washed with water, the organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The crude product was then purified by flash chromatography on a silica gel eluting with an ethyl acetate/cyclohexane mixture (1: 9).

8.15g of a gum-like product are obtained.

Yield: 68 percent.

1.10.[ [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -carbamic acid 1, 1-dimethylethyl ester

A solution of a mixture of 4.40g (17.8mmol)6- (bromomethyl) naphthalene-2-carbonitrile, 4.0g (14.4mmol) [ (7-hydroxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) -methyl ] -carbamic acid-1, 1-dimethylethyl ester and 3.20g (23.3mmol) potassium carbonate in 120mL acetonitrile was refluxed for 6 hours. The reaction medium is evaporated to dryness, the crude product is purified by flash chromatography on silica gel, eluting with a mixture of ethyl acetate/cyclohexane (1: 4).

5.60g of product are obtained as a white solid.

Melting point: 122 deg.C.

The yield thereof was found to be 87%.

1.11.6- [ [ [8- (aminomethyl) -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalene-2-carbonitrile hydrochloride

A solution of 4.70g (10.63mmol) [ [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -carbamic acid-1, 1-dimethylethyl ester in 100mL dichloromethane and 10mL 4N anhydrous hydrochloric acid in dioxane was stirred at 20 ℃ for 14 hours. The reaction medium is evaporated to dryness, the solid is triturated in ether, the liquid is removed and dried in vacuo.

3.80g of product are obtained as a white solid.

Melting point: 149-150 ℃.

Yield: 95 percent.

1.12. Thioacetic acid thiazol-4-yl methyl ester

A mixture of 3.50g (19.57mmol) of 4-chloromethylthiazole hydrochloride and 2.70g (19.57mmol) of potassium carbonate was stirred at 0 ℃ for 15 minutes. At this point 2.24g (19.57mmol) potassium thioacetate was added and stirring was continued at ambient temperature for 4 hours. The reaction medium is evaporated to dryness under reduced pressure and the residue is dissolved in diethyl ether. The solution was washed with ice water and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and then evaporated to dryness. The product was purified by flash chromatography on silica gel eluting with an ethyl acetate/cyclohexane mixture (3: 7) to give 2.35g of the expected product as an oil.

Yield: and 69 percent.

1.13. Thiazole-4-methanesulfonyl chloride hydrochloride

To a solution of 2.34g (13.53mmol) thiazol-4-ylmethyl thioacetate in 12mL acetic acid cooled to 0 deg.C was added 0.73mL (40.56mmol) of water, followed by 3.26mL (40.56mmol) of thionyl chloride dropwise, the temperature was allowed to rise to 20 deg.C, and then stirred at this temperature for 4 hours. The reaction medium is allowed to evaporate to dryness, the solid is triturated in ethyl acetate, then in ether and finally dried in vacuo.

1.95g of the expected product are obtained as a pale yellow solid.

Melting point: 170 deg.C.

Yield: 61 percent.

N- [ [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -thiazole-4-methanesulfonamide

Add 0.34g (1.45mmol) thiazole-4-methanesulfonyl chloride hydrochloride to a solution of 0.41g (1.20mmol)6- [ [ [3- (hydroxymethyl) -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalene-2-carbonitrile in 20mL dichloromethane cooled to 0 deg.C, followed by 0.44mL (3.30mmol) triethylamine and stir at ambient temperature for 16 h. The reaction medium is then diluted in 100mL of dichloromethane and the solution is washed with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and evaporated. The crude product was then purified by flash chromatography on silica gel eluting with a methanol/dichloromethane mixture (2: 98) containing a small amount of concentrated ammonia.

0.304g of white foam/gum-like product was obtained.

Yield: 50 percent.

N' -hydroxy-6- [ [ [8- [ [ [ (thiazol-4-ylmethyl) -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalen-2-carboximidamide

A solution of 0.30g (0.60mmol) of N- [ [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -thiazole-4-methanesulfonamide, 0.103g (1.49mmol) of hydroxylamine hydrochloride and 0.20mL (1.49mmol) of a mixture of triethylamine in 30mL of anhydrous ethanol was refluxed at elevated temperature for 8 hours. The reaction medium is then evaporated to dryness, the solid is triturated in water, the water is removed and then dried in vacuo.

0.319g of product is obtained as a white solid.

Melting point: at 140 ℃.

Yield: 99 percent.

1.16.6- [ [ [8- [ [ [ (thiazol-4-ylmethyl) -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalene-2-carboximidamide hydrochloride

A mixture of 0.31g (0.576mmol) of N' -hydroxy-6- [ [ [8- [ [ [ (thiazol-4-ylmethyl) -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] naphthalene-2-carboximidic acid amide in a solution of 30mL of methanol, 3mL of acetic acid and 11.8mL of anhydrous hydrochloric acid in isopropanol was hydrogenated in the presence of 0.25g of active Raney nickel under a pressure of 40psi in a Parr apparatus for 12 hours. At this point the reaction medium is filtered and the filtrate evaporated to dryness. The crude product is purified by reverse phase flash chromatography using C18, eluting with methanol in 0.001N aqueous hydrochloric acid in a gradient of 10-50%.

0.164g of product was obtained as a white solid.

Melting point: 135 ℃ is adopted.

Example 2: (17# Compound)

N- [7- [ [6- (aminoiminomethyl) -naphthalen-2-yl ] -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -3-methoxyphenylacetamide hydrochloride

2.1.7-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-amine

To a solution of 17.60g (99.89mmol) of 7-methoxy-1-tetralone and 77.0g (1mol) of anhydrous ammonium acetate in 500mL of methanol at ambient temperature was added 5.10g (81.16mmol) of sodium cyanoborohydride, followed by stirring at this temperature for 96 hours. The methanol was distilled off under reduced pressure and replaced by 400mL of diethyl ether. The mixture was cooled to 0 ℃ and then hydrolyzed by adding 6N hydrochloric acid until the pH was 1. The aqueous phase is washed with 100mL of ether in 3 portions and then separated, the pH being adjusted to 9 with concentrated sodium hydroxide. At this point the product was extracted with ether, the organic phase was dried over sodium sulphate, filtered and evaporated to dryness.

16.13g of a colorless oily product were obtained.

Yield: 93 percent

2.2 (7-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) carbamic acid 1, 1-dimethylethyl ester

16.0g (90.4mmol) of 7-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-amine are added in small portions to 300mL of hydrobromic acid (48%), and the mixture is refluxed for 15 hours at elevated temperature. The reaction medium is evaporated to dryness and the residue is dissolved in 250mL of tetrahydrofuran. 21.80g (100.0mmol) of di-tert-butyl dicarbonate are added and then 30mL (215.24mmol) of triethylamine are added dropwise and stirred at ambient temperature for 17 hours. Adjusting the pH value of the reaction medium to 5-6 by using acetic acid, and then extracting by using ethyl acetate. Washed with water, and the organic phase is then dried over sodium sulfate, filtered and evaporated to dryness. After recrystallization from ethanol, 21.07g of a white solid was obtained.

Melting point: 72-73 DEG C

Yield: 88 percent.

2.3[7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -carbamic acid 1, 1-dimethylethyl ester

A mixture of 11.50g (46.8mmol)6- (bromomethyl) -naphthalene-2-carbonitrile, 10.0g (38.02mmol) 1, 1-dimethylethyl (7-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) carbamate and 8.50g (61.51mmol) potassium carbonate in 300mL acetonitrile was refluxed at elevated temperature for 6 hours. The reaction mixture was then evaporated to dryness, eluting with ethyl acetate/cyclohexane (2: 8), and the crude product was purified by flash chromatography on silica gel.

14.13g of product are obtained as a white solid.

Melting point: 114-115 DEG C

Yield: 87 percent.

2.46- [ [ (8-amino-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -oxy ] -methyl ] -naphthalene-2-carbonitrile hydrochloride

A solution of 1.0g (2.33mmol) of [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] carbamic acid 1, 1-dimethylethyl ester in 80mL of dichloromethane cooled to 5 ℃ is bubbled with a stream of hydrochloric acid for 5 minutes, then stirred at ambient temperature for 5 hours. The reaction medium is then evaporated to dryness, the solid is triturated in ether, the liquid is removed and then dried in vacuo.

0.850g of product is obtained.

Melting point: 222-223 DEG C

Yield: 100 percent.

2.5N- [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -3-methoxyphenylacetamide

To a solution of 0.30g (1.81mmol) of 3-methoxyphenylacetic acid in 10mL of dichloromethane were added 0.66g (1.81mmol) of 6- [ [ 8-amino-5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalene-2-carbonitrile hydrochloride, 0.244g (1.81mmol) of 1-hydroxybenzotriazole, followed by 0.90mL (5.17mmol) of N, N-diisopropyl-N-ethylamine. The mixture was cooled to 0 ℃ and 0.38g (1.98mmol) of N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide were added. The temperature was allowed to rise back to ambient temperature and stirred for 14 hours. The reaction medium is then diluted in 150mL of ethyl acetate and the solution is washed with 1N aqueous citric acid (3X 50mL), water (50mL), saturated aqueous sodium bicarbonate (3X 50mL) and finally saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with a methanol/dichloromethane mixture (5: 95).

0.802g of product is obtained.

Melting point: 146 deg.C

Yield: 92 percent of

N- [7- [ [6- [ amino (hydroxyimino) -methyl ] -naphthalen-2-yl ] -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -3-methoxyphenylacetamide

A mixture of 0.793g (1.66mmol) of N- [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -3-methoxyphenylacetamide, 0.30g (4.31mmol) of hydroxylamine hydrochloride and 0.60mL (4.31mmol) of triethylamine in 50mL of anhydrous ethanol was heated under reflux for 6 hours. The reaction medium is then evaporated to dryness, the solid is triturated in 10mL of water, the water is removed and dried in vacuo. 0.768g of product is obtained as a white solid, yield: 90 percent.

2.7N- [7- [ [6- (aminoiminomethyl) naphthalen-2-yl ] methoxy ] -1, 2, 3, 4 tetrahydronaphthalen-1-yl ] -3-methoxyphenylacetamide hydrochloride

0.760g (1.49mmol) of N- [7- [ [6- [ amino (hydroxyimino) -methyl ] -naphthalen-2-yl ] methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -3-methoxyphenylacetamide is stirred in 15ml of 0.1N isopropanol hydrochloride solution for 10 minutes and then evaporated to dryness. At this point the hydrochloride was dissolved in 30mL of methanol and 3mL of acetic acid and the solution was placed in a Parr apparatus and hydrogenated in the presence of 0.50g of active Raney nickel at 40 deg.C and 40psi for 5 hours. The reaction mixture was filtered over celite and the filtrate was evaporated to dryness. The crude product is purified by C-18 reverse phase HPLC using a gradient elution with 0-100% acetonitrile in 0.001N aqueous hydrochloric acid for 180 minutes.

0.150g of product is obtained.

Melting point: 120 deg.C

Yield: 20 percent of

Example 3: (Compound No. 5)

6- [ [ [8- [ [ (pyridin-3-ylmethyl) -amino ] -carbonyl ] -amino ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] oxy ] -methyl ] naphthalen-2-carboximidamide hydrochloride

3.1.6- [ [ [8- [ [ (pyridin-3-ylmethyl) -amino ] -carbonyl ] -amino ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] oxy ] methyl ] -naphthalene-2-carbonitrile

0.73g (2.00mmol) of 6- [ [ (8-amino-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -oxy ] -methyl ] -naphthalene-2-carbonitrile hydrochloride in 20mL 1, 4-dioxane cooled to 5 ℃ was added 0.356g (1.20mmol) of bis (trichloromethyl) carbonate followed by 1.40mL (10mmol) of triethylamine. The mixture is stirred at ambient temperature for 30 minutes, and then 0.220g (2.03mmol) of 3-aminomethylpyridine are added to the isocyanate thus formed. The reaction mixture was stirred at 20 ℃ for 15 h, then 75mL of water was added and extracted with dichloromethane (3X 100 mL). The organic phase was collected, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with a methanol/dichloromethane mixture (5: 95).

0.707g of product was obtained.

Yield; 76 percent.

3.26- [ [ [8- [ [ (pyridin-3-ylmethyl) -amino ] -carbonyl ] -amino ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] naphthalen-2-carboximidamide hydrochloride

A mixture of 0.265g (3.81mmol) hydroxylamine hydrochloride, 0.707g (1.53mmol)6- [ [ [8- [ [ (pyridin-3-ylmethyl) -amino ] -carbonyl ] -amino ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] naphthalene-2-carbonitrile and 0.64mL (4.60mmol) triethylamine in 15mL anhydrous ethanol was heated at reflux for 5 hours. The reaction mixture was evaporated to dryness, the resulting solid was triturated in 10mL of water, water was removed and dried in vacuo. It was dissolved in 20mL of 0.1N isopropanol HCl solution and then evaporated to dryness. The hydrochloride salt was dissolved in 50mL of methanol/acetic acid (9: 1), and the solution was placed in a Parr apparatus and hydrogenated with 0.80g of active Raney nickel at 20 ℃ and 40psi for 13 hours. The reaction mixture was filtered and the filtrate was evaporated. Eluting with 20-100% gradient acetonitrile in 0.001N hydrochloric acid water solution, and purifying the product by reversed phase C18 flash chromatography.

0.315g of the product (dihydrochloride) is obtained as a white solid.

Melting point: 175 deg.C (decomposition).

Yield: 37 percent.

Example 4: (Compound No. 13)

6- [ [ [8- [ [ [ [ (3-methoxyphenyl) -methyl ] -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalene-2-carboximidamide hydrochloride

4.1.3-Methoxybenzenesulfonyl chloride

A mixture of 10.0g (49.7mmol) of 3-methoxybenzyl bromide, 6.30g (50.0mmol) of sodium sulfite and 0.16g (0.50mmol) of tetra-n-butylammonium bromide in 35mL of water is heated at 95 ℃ for 2 hours. Then stirred at room temperature overnight and the reaction mixture was evaporated to dryness. 10.5g of the resulting 16.5g of solid was suspended in 135mL of methylene chloride, and 20.1g (96.5mmol) of phosphorus pentachloride was added in small portions at ordinary temperature. The reaction mixture was stirred at this temperature for 1 hour and then evaporated to dryness. The residue was dissolved in ethyl acetate, and the solution was washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness.

6.95g of oily product are obtained.

Yield: 98 percent.

N- [ [7- (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -3-methoxybenzenesulphonamide

To a mixture of 0.644g (1.17mmol)6- [ [ [8- (aminomethyl) -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalene-2-carbonitrile hydrochloride and 0.68mL (4.90mmol) triethylamine in 50mL dichloromethane was added a solution of 0.60g (2.72mmol) 3-methoxybenzenesulfonyl chloride in 10mL dichloromethane and stirred at 20 ℃ for 3 hours. The reaction mixture was then evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed successively with 1M citric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The product was purified by flash chromatography on silica gel eluting with methanol/dichloromethane (2: 98).

0.382g of product is obtained in the form of a white foam.

Yield: 60 percent.

4.36- [ [ [8- [ [ [ [ (3-methoxyphenyl) -methyl ] -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] naphthalen-2-carboximidamide hydrochloride

A mixture of 0.382g (0.73mmol) of N- [ [7- (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -3-methoxybenzenesulphonamide, 0.13g (1.87mmol) of hydroxylamine hydrochloride and 0.28mL (2.0mmol) of triethylamine was heated to reflux for 6 hours. The reaction mixture was evaporated to dryness, the solid was triturated in 10mL water, water was removed and dried in vacuo. The product was dissolved in 10mL of 0.1N isopropanol hydrochloride solution and the solution was evaporated to dryness. This hydrochloride salt was dissolved in 20mL of methanol/acetic acid (9: 1), charged to a Parr apparatus, and hydrogenated in the presence of 0.25g of active Raney nickel at 45psi pressure and 20 ℃ for 5 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. Eluting with 30-50% acetonitrile solution in 0.01N hydrochloric acid water solution, and purifying the product by reversed phase flash chromatography. 0.18g of product is obtained as a white solid.

Melting point: 250 deg.C (decomposition).

Yield: and 43 percent.

Example 5: (31# Compound)

7- [ [6- (aminoiminomethyl) -naphthalen-2-yl ] -methoxy ] -N- (phenylmethyl) -1, 2, 3, 4-tetrahydronaphthalene-1-carboxamide hydrochloride

5.1.7-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1-carboxylic acid

To a two-phase solution of 3.88g (20.42mmol) of 7-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1-carbaldehyde in 50mL of dichloromethane and 10mL of water cooled to 5 ℃ was added a solution of 2.0g (20.60mmol) of sulfamic acid in 20mL of water. A solution of 6.9g (61.03mmol) of 80% sodium hypochlorite in 20mL of water is then added dropwise over 1 hour, the reaction medium is stirred for 30 minutes at 20 ℃ and then diluted in 50mL of dichloromethane. The organic phase was separated and washed with saturated aqueous sodium sulfite solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness.

3.04g of amorphous solid product was obtained.

Yield: 72 percent.

5.2.7-hydroxy-1, 2, 3, 4-tetrahydronaphthalene-1-carboxylic acid methyl ester

To a solution of 3.03g (14.71mmol) of 7-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1-carboxylic acid in 50mL of dichloromethane frozen to-70 ℃ was added dropwise 30mL (30mmol) of a 1M solution of boron tribromide in dichloromethane. The reaction medium is stirred at ambient temperature for 1 hour, then frozen to-78 ℃ and hydrolyzed with 5mL of methanol. The medium was evaporated to dryness and the residue was dissolved in 50mL of methanol. At this time, the solution was saturated with hydrogen chloride gas, and then heated under reflux for 2 hours. The medium is evaporated to dryness, the crude product is purified by flash chromatography on silica gel, eluting with a methanol/dichloromethane mixture (2: 98, then 5: 95).

2.10g of product are obtained.

Yield: 69 percent

5.3.7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalene-1-carboxylic acid methyl ester

A mixture of 2.80g (11.38mmol)6- (bromomethyl) -naphthalene-2-carbonitrile, 1.90g (9.21mmol) and 2.06g (14.90mmol) potassium carbonate in 50mL acetonitrile was heated at reflux for 3.5 h. The reaction mixture was then cooled to ambient temperature, filtered and the filtrate evaporated to dryness. The residue obtained is purified by flash chromatography on silica gel, eluting with an ethyl acetate/toluene mixture (1: 9).

2.40g of the expected product are obtained as a colorless oil.

Yield: 70 percent.

5.4.7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalene-1-carboxylic acid

To a solution of 2.39g (6.43mmol) of methyl 7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalene-1-carboxylate in 25mL of THF and 8mL of water cooled to 0 deg.C was added 3.88g (92.47mmol) of lithium hydroxide monohydrate, followed by stirring at ambient temperature for 24 hours. The tetrahydrofuran was evaporated under reduced pressure and the aqueous solution was washed with diethyl ether. The pH of the aqueous phase was then adjusted to 2 by addition of 1N hydrochloric acid. Extraction with ethyl acetate and drying of the organic phase over sodium sulfate, filtration and evaporation to dryness.

1.20g of the product was obtained as a colorless oil.

Yield: 52 percent.

5.5.7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -N- (phenylmethyl) -1, 2, 3, 4-tetrahydronaphthalene-1-carboxamide

To a solution of 0.50g (1.40mmol) of 7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalene-1-carboxylic acid in 10mL of dioxane and 2mL of dimethylformamide at 5 ℃ were added 0.16mL (1.46mmol) of benzylamine, 0.21g (1.55mmol) of 1-hydroxybenzotriazole, 0.50mL (2.87mmol) of N, N-diisopropyl-N-ethylamine and then 0.30g (1.56mmol) of N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide and stirred at ambient temperature for 14 h. The reaction mixture was then evaporated to dryness and the residue was dissolved in 200mL of dichloromethane. This solution was successively washed with a 1M aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with a methanol/dichloromethane mixture (5: 95).

0.44g of product is obtained as a white solid.

Melting point: 181 ℃ is adopted.

The yield thereof was found to be 70%.

5.6.7- [ [6- (aminoiminomethyl) -naphthalen-2-yl ] -methoxy ] -N- (phenylmethyl) -1, 2, 3, 4-tetrahydronaphthalene-1-carboxamide hydrochloride

A solution of 0.44g (0.985mmol) of 7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -N- (phenylmethyl) -1, 2, 3, 4-tetrahydronaphthalene-1-carboxamide, 0.171g (2.45mmol) of hydroxylamine hydrochloride and 0.34mL (2.45mmol) of triethylamine in 15mL of ethanol was heated at reflux for 8 h. The reaction medium is then evaporated to dryness, the solid obtained is triturated in 10mL of water, the water is removed and dried in vacuo. The hydroxyamidine is dissolved in 10mL of isopropanol hydrochloride and the solution is evaporated to dryness. This hydrochloride is dissolved in a mixture of 20mL of methanol and 2mL of acetic acid and the solution is hydrogenated in the presence of 0.40g of active Raney nickel at 20 ℃ and a pressure of 45psi for 14 hours in a Parr apparatus. The product was purified by reverse phase HPLC using C18, eluting with a gradient of 0-100% acetonitrile in 0.001N hydrochloric acid for 180 minutes.

0.194g of product are obtained as a white solid.

Melting point: 225 ℃ is adopted.

Yield: 40 percent.

Example 6: (34# Compound)

6- (Aminoiminomethyl) -alpha- [ [8- [ [ [ [ (3-methoxyphenyl) -methyl ] -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -naphthalene-2-acetic acid

6.1.6-bromonaphthalene-2-methanol

To a solution of 20.0g (75.44mmol) of methyl 6-bromonaphthalene-2-carboxylate in 325mL of tetrahydrofuran frozen to-20 ℃ was added 76mL (76.0mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran dropwise. The medium was stirred for 30 minutes at-20 ℃ and then hydrolyzed by slowly adding 3mL of water, 3mL of 15% sodium carbonate, and then 10mL of water. The mixture was stirred at ambient temperature for 1 hour, then 75g magnesium sulfate was added and filtered. The filtrate was evaporated to dryness to give 17.24g of the product as a white solid.

Melting point: at 154 ℃.

Yield: 96 percent.

6.2.2-bromo-6- (bromomethyl) -naphthalene

A solution of 17.23g (72.67mmol) of 6-bromonaphthalene-2-methanol in 500mL of dichloromethane was brominated at 0 ℃ with the aid of 2.8mL (29.1mmol) of phosphorus tribromide. The medium is stirred at ambient temperature for 16 hours and then hydrolyzed by addition of 10mL of methanol. This solution was washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness.

19.7g of product are obtained as a white solid.

Melting point: 127 ℃.

The yield thereof was found to be 90%.

6.3.6-Bromomaphthalene-2-acetonitrile

To a solution of 16.70g (55.67mmol) 2-bromo-6- (bromomethyl) -naphthalene in 400mL dichloromethane cooled to 0 deg.C was added 9.60g (61.0mmol) tetraethylammonium cyanide, which was then stirred at ambient temperature for 3 hours. The solution was washed twice with water, the organic phase was dried over sodium sulfate, filtered and evaporated to dryness.

13.62g of product are obtained as a pale yellow solid.

Melting point: 115 ℃ is carried out.

The yield thereof was found to be 99%.

6.4.6-Bromomaphthalene-2-acetic acid ethyl ester

80mL of concentrated sulfuric acid was added to a solution of 13.60g (55.26mmol) of 6-bromonaphthalene-2-acetonitrile in 140mL of ethanol at ambient temperature, followed by heating and refluxing for 2 hours. Most of the ethanol was distilled off under reduced pressure, and then the mixture was slowly poured onto 400g of crushed ice. Extraction with ethyl acetate was carried out, and the organic phase was then dried over sodium sulfate, filtered and evaporated to dryness.

15.70g of the expected product are obtained.

Yield: 97 percent.

6.5.6-Cyanonaphthalene-2-acetic acid ethyl ester

To a degassed suspension of 8.26g (28.19mmol) of ethyl 6-bromonaphthalene-2-acetate and 2.0g (17.03mmol) of zinc cyanide in 20mL of dimethylformamide was added 2.28g (1.97mmol) of tetrakis (triphenylphosphine) palladium (O), and the mixture was heated at 80 ℃ under nitrogen for 3 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in 250mL of ethyl acetate and filtered. The filtrate was washed 3 times with 100mL of water and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The residue was triturated in n-pentane and the resulting white precipitate was drained and dried in vacuo.

5.88g of product are obtained.

Melting point: and 65 ℃.

The yield thereof was found to be 87%

6.6. Alpha-bromo-6-cyanonaphthalene-2-acetic acid ethyl ester

To a mixture of 7.50g (31.35mmol) of ethyl 6-cyanonaphthalene-2-acetate and 8.37g (47.0mmol) of N-bromosuccinamide in 75mL of carbon tetrachloride was added 0.36g (2.19mmol) of 2, 2' -azobisisobutyronitrile, and the mixture was heated under reflux for 20 hours. The reaction medium is cooled to 5 ℃ and filtered. The filtrate was concentrated to 1/3, re-cooled to 5 ℃ and filtered again. The filtrate was evaporated to dryness, eluted with an ethyl acetate/cyclohexane mixture (1: 9) and the crude product was purified by flash chromatography on silica gel.

8.20g of oily product are obtained.

Yield: 82 percent.

6.7.6-cyano-alpha- [ [8- [ [ [ (1, 1-dimethylethoxy) -carbonyl ] -amino ] -methyl ] -5, 6, 7, 8- ] -tetrahydronaphthalen-2-yl ] -oxy ] -naphthalene-2-acetic acid ethyl ester

A mixture of 1.30g (4.09mmol) of ethyl α -bromo-6-cyanonaphthalene-2-acetate, 0.91g (3.28mmol) of 1, 1-dimethylethyl [ (7-hydroxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) -methyl ] carbamate and 1.10g (7.96mmol) of potassium carbonate in 20mL of acetonitrile is heated at reflux for 2 hours. The reaction medium is then evaporated to dryness, eluted with an ethyl acetate/toluene mixture (5: 95 and then 1: 9) and the residue is purified by flash chromatography on silica gel.

1.06g of product was obtained as a white foam.

Melting point: 78-80 ℃.

The yield thereof was found to be 63%.

6.8. Alpha- [ [8- (aminomethyl) -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -6-cyanonaphthalene-2-acetic acid ethyl ester hydrochloride

To a solution of 2.17g (4.22mmol) of ethyl 6-cyano- α - [ [8- [ [ [ (1, 1-dimethylethoxy) -carbonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -naphthalene-2-acetate in 40mL of dichloromethane was added 8mL of 4N dioxane hydrochloride solution and the mixture was stirred at 20 ℃ for 12 hours. The reaction medium is then evaporated to dryness, the solid is triturated in ether, the ether is removed and dried in vacuo.

1.85g of product are obtained.

Yield: 97 percent.

6.9.6-cyano- α - [ [8- [ [ [ [ (3-methoxyphenyl) -methyl ] -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -naphthalene-2-acetic acid ethyl ester

To a solution of 0.93g (2.06mmol) of ethyl α - [ [8- (aminomethyl) -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -6-cyanonaphthalene-2-acetate hydrochloride in 20mL of dichloromethane were added 0.86mL (6.17mmol) of triethylamine and 0.68g (3.33mmol) of 3-methoxybenzenesulfonyl chloride dissolved in 5mL of dichloromethane, and the mixture was stirred at 20 ℃ for 72 hours. The reaction medium is diluted in 100mL of dichloromethane and then washed with 1M citric acid and then with saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with methanol/dichloromethane (2: 98).

The product was obtained as an off-white foam.

Yield: 79 percent.

6.10.6- (Aminoiminomethyl) -alpha- [ [8- [ [ [ [ (3-methoxyphenyl) -methyl ] -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -naphthalene-2-acetic acid ethyl ester hydrochloride

In a solution of 0.967g (1.62mmol) of ethyl 6-cyano- α - [ [8- [ [ [ [ (3-methoxyphenyl) -methyl ] -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -naphthalene-2-acetate in 10mL of pyridine and 0.5mL of triethylamine, a stream of hydrogen sulfide was bubbled through for 30 minutes. The flask was then capped with a cork stopper and the solution was stirred at ambient temperature for 36 hours. The reaction medium is then evaporated to dryness and the residue is dissolved in 100mL of ethyl acetate. The solution was washed with 1M aqueous citric acid solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in 10mL of acetone, and 0.5mL (8.03mmol) of methyl iodide was added thereto, followed by heating under reflux for 5 hours. The medium is evaporated to dryness and dissolved in 10mL of methanol and heated at reflux in the presence of 0.50g (6.49mmol) of ammonium acetate for 13 hours. The reaction medium is evaporated to dryness and the product is purified by C18 reverse phase flash chromatography, eluting with a mixture of acetonitrile/0.01N hydrochloric acid (1: 1).

0.30g of product is obtained.

Yield: 29 percent.

6.11.6- (Aminoiminomethyl) -alpha- [ [8- [ [ [ [ (3-methoxyphenyl) -methyl ] -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -naphthalene-2-carboxylate

A solution of 0.30g (0.46mmol) of ethyl 6- (aminoiminomethyl) - α - [ [8- [ [ [ [ (3-methoxyphenyl) -methyl ] -sulfonyl ] -amino ] -methyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -naphthalene-2-acetate hydrochloride in 10mL of a 2N hydrochloric acid/tetrahydrofuran mixture (1: 2) was heated at reflux for 3 hours. The reaction medium is then evaporated to dryness, eluted with a mixture of acetonitrile/0.01N hydrochloric acid (2: 3) and the product is purified by C18 reverse phase flash chromatography.

Melting point: 180 ℃ is carried out.

Yield: 70 percent.

Example 7(23# Compound)

3- [ [ [ [ [ [ [7- [ (6-aminoiminomethyl) -naphthalen-2-yl ] -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -amino ] -sulfonyl ] -methyl ] benzoic acid hydrochloride

7.1.3- [ [ [ [ [ [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -amino ] -sulfonyl ] -methyl ] benzoic acid methyl ester

To a solution of 0.38g (1.00mmol) of 6- [ [ [8- (aminomethyl) -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalen-2-carbonitrile hydrochloride and 0.42mL (3.01mmol) of triethylamine in 10mL of dichloromethane cooled to 5 ℃ was added 0.350g (1.41mmol) of 3- [ (chlorosulfonyl) -methyl ] -benzoic acid methyl ester dissolved in 5mL of dichloromethane. The reaction medium is stirred at ambient temperature for 72 hours and then diluted in 100mL of dichloromethane. The solution was washed successively with a 1N aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and then a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and then evaporated to dryness. The product was purified by flash chromatography on silica gel eluting with a methanol/dichloromethane compound (2: 98).

0.479g of product is obtained in the form of a white foam.

Yield: 86 percent.

7.2.3- [ [ [ [ [7- (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -amino ] -sulfonyl ] -methyl ] -benzoic acid

A mixture of 0.47g (0.85mmol) of 3- [ [ [ [ [ [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -amino ] -sulfonyl ] -methyl ] -benzoic acid methyl ester and 0.07g (1.67mmol) of lithium hydroxide monohydrate in 10mL of tetrahydrofuran/water (1: 1) was stirred at ambient temperature for 3 hours. The tetrahydrofuran was distilled off under reduced pressure and the aqueous solution was acidified to pH1 with 1N hydrochloric acid. The product was extracted with ethyl acetate, the organic phase was dried over sodium sulfate, filtered and evaporated to dryness.

A white foamy product was obtained.

Yield: 100 percent.

7.3.3- [ [ [ [ [ [7- [ (6-Aminoiminomethyl) -cyanonaphthalen-2-yl ] -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -amino ] -sulfonyl ] -methyl ] -benzoic acid hydrochloride

A mixture of 0.47g (0.85mmol) of 3- [ [ [ [ [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -amino ] -sulfonyl ] -methyl ] -benzoic acid, 0.15g (2.16mmol) of hydroxylamine hydrochloride and 0.56mL (0.42mmol) of triethylamine in 10mL of anhydrous ethanol was heated to reflux. After 4 hours, the reaction medium is evaporated to dryness. The residue was dissolved in 20mL of a 0.1N isopropanol hydrochloride solution and then evaporated to dryness. This hydrochloride salt was hydrogenated in 20mL of a methanol/acetic acid mixture (9: 1) at 20 ℃ and 40psi pressure in the presence of 0.30g Raney nickel for 14 hours. The reaction medium is filtered and the filtrate is evaporated to dryness. The product is purified by C-18 reverse phase HPLC eluting over 180 minutes with a gradient of 0-100% acetonitrile in 0.001N hydrochloric acid.

0.167g of product was obtained as a white solid.

Melting point: 165 deg.C (decomposition).

Yield: 32 percent.

Example 8: (14# Compound)

6- [ [ [8- [ [ [ imino- [ [ (3-methoxyphenyl) -methyl ] -amino ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalen-2-carboximidic acid amide hydrochloride

8.1.1- (isothiocyanato) -3-methoxybenzene

2.3mL (30.17mmol) of thiophosgene is added dropwise to a mixture of 2.74g (20.0mmol) of 3-methoxybenzylamine and 6.0g (60.0mmol) of calcium carbonate in 20mL of water dissolved in 20mL of dichloromethane at ordinary temperature over 60 minutes. The organic phase is separated off after 2 hours, washed with water, dried over sodium sulfate, filtered and evaporated to dryness.

3.29g of oily product are obtained.

Yield: 92 percent.

N- [7- (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -N' - [ (3-methoxyphenyl) -methyl ] -thiourea

To a solution of 0.62g (1.70mmol) of 6- [ (8-amino-5, 6, 7, 8-tetrahydronaphthalen-2-yl) -oxy ] -methyl ] -naphthalene-2-carbonitrile hydrochloride and 0.50mL (3.59mmol) of triethylamine in 27mL of toluene were added 0.40g (2.23mmol) of 1- (isothiocyanate) -3-methoxybenzene, and the mixture was heated under reflux for 30 minutes. The reaction medium is allowed to return to ambient temperature and is then washed with a 1N hydrochloric acid solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The product was purified by flash chromatography on silica gel eluting with a methanol/dichloromethane (2: 98) mixture.

0.654g of product is obtained in the form of a white foam.

Yield: 71 percent.

8.3.6- [ [ [8- [ [ imino- [ [ (3-methoxyphenyl) -methyl ] -amino ] -5, 6, 7, 8-tetrahydronaphthalen-2-yl ] -oxy ] -methyl ] -naphthalene-2-carboximidic acid amide dihydrochloride

A solution of 0.654g (1.29mmol) of N- [7- (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -N' - [ (3-methoxyphenyl) -methyl ] -thiourea in 10mL of pyridine and 1mL of triethylamine is bubbled with a stream of hydrogen sulfide at 20 ℃ for 30 minutes. The reaction mixture was stirred at this temperature for 24 hours with a cork stopper. The reaction medium is then evaporated to dryness and the residue is dissolved in 100mL of ethyl acetate. This solution was washed with a 1M aqueous solution of citric acid and then with a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. This sulfamide was dissolved in 50mL of acetone, mixed with 10mL (160.63mmol) of methyl iodide and heated at reflux for 4 hours. The reaction medium was then evaporated to dryness to give 0.871g of a yellow powder. This product was dissolved in 50mL of methanol, 3.0g (38.92mmol) of ammonium acetate was added, and the mixture was heated under reflux for 3 hours. The reaction medium is then evaporated to dryness, eluted with a mixture of acetonitrile/0.01N hydrochloric acid (2: 3) and the product is purified by C18 reverse phase flash chromatography.

0.10g of product is obtained.

Melting point: at 220 ℃.

Yield: 14 percent.

Example 9: (24# Compound)

6- [ [ [8- [ [ [ (phenylmethyl) -sulfonyl ] -amino ] -methyl ] -bicyclo- [4.2.0] -oct-1, 3, 5-trien-3-yl ] -oxy ] -methyl ] -naphthalene-2-carboximidamide hydrochloride

9.1.3- (3-bromo-4-methoxybenzene) -propionitrile

2.16g (13.3mmol) of 3- (4-methoxyphenyl) -propionitrile in 13mL of acetic acid are brominated at ambient temperature by adding 0.678mL (13.3mmol) of bromine in the presence of 2.19g (26.6mmol) of anhydrous sodium acetate under the conditions described in tetrahedron 30, page 1053 (1974). After stirring for 2 hours, the reaction medium is poured into 150mL of water and extracted several times with diethyl ether. The organic phase was collected, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and evaporated to dryness.

3.085g of oily product were obtained.

Yield: 97 percent.

9.2.4-Methoxybicyclo- [4.2.0] -octa-1, 3, 5-triene-7-carbonitrile

50mg of iron (III) trichloride are added at-78 ℃ to a mixture of 14.5g (63.00mmol) of sodium in liquid ammonia, followed by 8.71g (36.3mmol) of 3- (3-bromo-4-methoxybenzene) -propionitrile, and the medium is stirred at-78 ℃ for 3 hours. The ammonia was distilled off, then sodium chloride was added, and then saturated aqueous ammonium chloride solution was slowly added. The medium is extracted with chloroform and the organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The product was purified by distillation under reduced pressure.

2.69g of oily product are obtained.

Yield: and 47 percent.

9.3.4-Methoxybicyclo [4.2.0] -oct-1, 3, 5-triene-7-methanamine

To a suspension of 0.45g (11.84mmol) of lithium aluminum hydride in 15mL of ether was added 1.50g (9.32mmol) of 4-methoxybicyclo [4.2.0] octa-1, 3, 5-triene-7-carbonitrile dissolved in 5mL of ether. The mixture was stirred at ambient temperature for 1 hour. Hydrolysis was then carried out with 1mL of water, 1mL of 1N sodium carbonate (soude), and then with 5mL of water. The organic phase was decanted and the aqueous phase was extracted again with ether. The organic phase was collected, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. 1.38g of oily product are obtained.

Yield: 91 percent.

9.4. [ (4-Hydroxybicyclo- [4.2.0] oct-1, 3, 5-trien-7-yl) -methyl ] carbamic acid 1, 1-dimethylethyl ester

To a solution of 1.52g (9.3mmol) of 4-methoxybicyclo [4.2.0] octa-1, 3, 5-trien-7-methanamine in 30mL of dichloromethane cooled to-78 deg.C was added dropwise 37.3mL (37.3mmol) of a 1M solution of boron tribromide in dichloromethane. After addition, the mixture was stirred at-10 ℃ for 1 hour, then cooled again to-78 ℃ and hydrolyzed with 20mL of methanol. The medium was allowed to warm to ambient temperature, then diluted with 50mL of methanol and evaporated to dryness. The residue was co-evaporated three times with benzene. The crude product was dissolved in 50mL of tetrahydrofuran, and 3.89mL (27.91mmol) of triethylamine and 2.0g (9.16mmol) of di-tert-butyl dicarbonate were added. The reaction medium is then stirred at ambient temperature for 14 hours and evaporated to dryness. The residue was dissolved in ethyl acetate, the solution was washed with a chilled 0.1N aqueous hydrochloric acid solution, a saturated aqueous sodium chloride solution, and then the organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The product was purified by flash chromatography on silica gel eluting with an ethyl acetate/cyclohexane mixture (1: 9).

1.21g of product are obtained.

Yield: 52 percent.

[ [ [ [4- [ (6-cyanonaphthalen-2-yl) -methoxy ] -bicyclo- [4.2.0] -oct-1, 3, 5-trien-7-yl ] -methyl ] -carbamic acid 1, 1-dimethylethyl ester

A mixture of 0.518g (2.08mmol) of [ (4-hydroxybicyclo- [4.2.0] -oct-1, 3, 5-trien-7-yl) -methyl ] -carbamic acid 1, 1-dimethylethyl ester, 0.614g (2.50mmol) of 6- (bromomethyl) naphthalene-2-carbonitrile and 0.465g (3.37mmol) of potassium carbonate in 25mL of acetonitrile is heated at 80 ℃ for 3 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. The solution was washed with cold 0.1N aqueous hydrochloric acid and then with saturated aqueous sodium chloride. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The product was purified by flash chromatography on silica gel eluting with an ethyl acetate/cyclohexane mixture (1: 4).

0.412g of product was obtained.

Yield: 48 percent.

9.6.6- [ [ [8- (aminomethyl) -bicyclo- [4.2.0] -oct-1, 3, 5-trien-3-yl ] -oxy ] -methyl ] -naphthalene-2-carbonitrile hydrochloride

To a solution of 0.412g (0.995mmol) [ [ [4- [ (6-cyanonaphthalen-2-yl) -methoxy ] -bicyclo- [4.2.0] -oct-1, 3, 5-trien-7-yl ] -methyl ] -carbamic acid-1, 1-dimethylethyl ester in 20mL of dioxane at 0 ℃ was added 1mL of a 4N dioxane hydrochloric acid solution, and the mixture was stirred at 0 ℃ for 10 hours. The liquid was removed from the precipitate, rinsed with dioxane and dried in vacuo.

0.244g of product was obtained.

Melting point: 170 deg.C.

Yield: 70 percent.

N- [ [4- [ (6-cyanonaphthalen-2-yl) -methoxy ] -bicyclo- [4.2.0] -oct-1, 3, 5-trien-7-yl ] -methyl ] -phenylmethanesulfonamide

To a solution of 0.244g (0.696mmol) of 6- [ [ [8- (aminomethyl) -bicyclo- [4.2.0] -octa-1, 3, 5-trien-3-yl ] -oxy ] -methyl ] naphthalene-2-carbonitrile hydrochloride and 0.211g (2.09mmol) triethylamine in 6mL of dichloromethane cooled to 5 ℃ was added 0.135g (0.71mmol) of a-toluenesulfonyl chloride. The solution was then stirred at 20 ℃ for 15 hours. The reaction medium is then evaporated to dryness and the residue is taken up in 100mL of ethyl acetate. This solution was washed with a 1N aqueous hydrochloric acid solution and then with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The product was purified by flash chromatography on silica gel eluting with a mixture of ethyl acetate/n-hexane (3: 7) and then 100% ethyl acetate.

0.20g of product is obtained.

Yield: 61 percent.

9.8.6- [ [ [8- [ [ [ (phenylmethyl) -sulfonyl ] -amino ] -methyl ] -bicyclo- [4.2.0] -oct-1, 3, 5-trien-3-yl ] -oxy ] -methyl ] -naphthalene-2-carboximidamide hydrochloride

A solution of 0.20g (0.42mmol) of N- [ [4- [ (6-cyanonaphthalen-2-yl) -methoxy ] -bicyclo- [4.2.0] -oct-1, 3, 5-trien-7-yl ] -methyl ] -phenylmethanesulfonamide in 8mL of a triethylamine/pyridine mixture (1: 9) was bubbled with hydrogen sulfide gas for 5 minutes at ambient temperature. At this point the container was stoppered and the solution was stirred at 20 ℃ for 48 hours. The reaction mixture was evaporated to dryness, the residue was dissolved in 5mL of acetone and heated at reflux in the presence of 0.656g (4.62mmol) of methyl iodide for 1 hour. The evaporation to dryness, the crude thioamide was dissolved in 5mL of methanol and heated at reflux in the presence of 0.065g (0.84mmol) of anhydrous ammonium acetate for 2 hours. The reaction medium is evaporated to dryness and the residue is dissolved in 10mL of 0.1N isopropanol hydrochloride solution and then evaporated to dryness. The product was purified by C-18 reverse phase HPLC over 180 minutes eluting with a gradient of 0-100% acetonitrile in 0.001N hydrochloric acid.

0.86g of product is obtained as a white solid.

Melting point: 125 ℃.

Yield: 39 percent.

Example 10: (57# Compound)

3- [ [ [ [ [ [ [7- [ [6- [ [ (ethoxycarbonyl) -amino ] -aminoiminomethyl ] -naphthalen-2-yl ] -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -amino ] -carbonyl ] -amino ] -methyl ] -benzoic acid methyl ester

To a suspension of 0.18g (0.335mmol) of methyl 3- [ [ [ [ [ [7- [ [6- (aminoiminomethyl) -naphthalen-2-yl ] -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -amino ] -carbonyl ] -amino ] -methyl ] benzoate in 15mL of tetrahydrofuran cooled to 0 ℃ was added 0.064mL (0.37mmol) of N, N-diisopropylethylamine followed by 0.034mL (0.35mmol) of ethyl chloroformate. The mixture was stirred at ambient temperature for 1 hour and the reaction mixture was diluted in 50mL of ethyl acetate. The solution was then washed with 0.1N aqueous hydrochloric acid, then with saturated aqueous sodium bicarbonate and finally with saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with a methanol/dichloromethane mixture (5: 95).

0.130g of product is obtained as a white solid.

Melting point: 118 deg.C (decomposition).

Yield: and 64 percent.

Example 11: (84# Compound)

3- [ [ [ [ [ [ [7- [ [6- [ amino- (hydroxyimino) -methyl ] -naphthalen-2-yl ] -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -amino ] -sulfonyl ] -methyl ] benzoic acid methyl ester hydrochloride

A solution of 0.50g (0.90mmol) of methyl 3- [ [ [ [ [7- [ (6-cyanonaphthalen-2-yl) -methoxy ] -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -methyl ] -amino ] -sulfonyl ] -methyl ] -benzoate (see example 7.1.), 0.154g (2.22mmol) of hydroxylamine hydrochloride and 0.31mL (2.22mmol) of triethylamine in 10mL of methanol was heated at reflux overnight. The reaction medium is evaporated to dryness and the residue is triturated in water. The solid was dewatered, rinsed with water and dried under vacuum at 40 ℃. The crude product was purified by flash chromatography on silica gel eluting with a methanol/dichloromethane mixture (5: 95) and then converted to the hydrochloride salt by means of 2N ethyl chloride solution.

0.23g of product is obtained as a white solid.

Melting point: 155 ℃.

Yield: 41 percent.

Watch (A)

All compounds are present as the hydrochloride salt except the indicated compound which is the dihydrochloride salt. In the table: - "dec" means that the compound decomposes at its melting point, - "tBu" means tert-butyl, i.e.1, 1-dimethylethyl, - "nBu" means straight-chain butyl, - "Et" means ethyl

The compounds of the invention, as subjects of pharmaceutical research, have proven their significance as substances with therapeutic activity.

The compounds of the invention were tested in particular for VII/VIIa coagulation factor inhibition.

Principle of Ki factor VIIa test

The purpose of this test was to measure the amidolytic activity of the factor VIIa/tissue factor complex on chromogenic substrates in the presence of various concentrations of the inhibitor to be tested. If a compound increases the Km value of factor VIIa for the substrate of the inhibitor, that is to say decreases the affinity of factor VIIa for its substrate, then this compound is a so-called competitive inhibitor for the inhibitor.

This amidolytic activity of factor VIIa tested at one concentration was measured kinetically (calculation speed), and the time-dependent cleavage of the substrate (both measured concentrations) was determined by means of a microspot counter which measures the release of p-nitroaniline at 405 nm. This compound was tested at 7 concentrations.

Ki was determined according to the Dixon method, in which the reciprocal velocity is plotted as a function of the compound concentration at each substrate (S1 and S2) concentration.

The intersection of the linear regression lines projected on the X-axis determines the inhibitor concentration corresponding to Ki.

Biological agent

The factor VIIa used is a recombinant human (produced in CHO cells)

Tissue factor is a human recombinant (produced in E.coli (E.coli)) corresponding to the extracellular soluble fraction (amino acids 1-219). The FVIIa factor/tissue factor complex was pre-formed by culturing factor VIIa and tissue factor in the presence of 5mM calcium chloride at a molar concentration ratio of 1/5, and the final concentration for FVIIa factor in the presence of 18.75nM tissue Factor (FT) was 3.75 nM.

Buffer TBSA: tromethamine (Tris)50mM, pH 7.5, sodium chloride 100mM, BSA 0.1%.

FVIIa factor/FT complex used in TBSA buffer +5mM calcium chloride is 3.75nM/18.75 nM.

The chromogenic substrate CBS-3447(HD-CHG-But-Arg-pNA) was used in concentrations of 0.66 and 2.64 mM.

The compound tested is a 1mM solution. The outline of the experiment was followed by the sequential administration of reagents (no culture; final concentration)

Compound (I)	Substrate	FVIIa/FT Complex
Compound (I)	Substrate	FVIIa/FT Complex	7 concentrations (+ control group)	S1＝0.66mMS2＝2.64mM	3.5nM/18.5nM
25μl	50μl	25 μ l (volume of each well)	7 concentrations (+ control group)	S1＝0.66mMS2＝2.64mM	3.5nM/18.5nM

The compounds of the invention preferably have Ki's of less than 1 μ M.

Another study of the compounds of the invention has been directed to anticoagulant activity.

Anticoagulant activity was measured on an arterial-venous shunt model.

Principle of testing

Tissue factor-dependent thrombosis in rats or guinea pigs was achieved by placing an arterio-venous shunt into which a section of cotton yarn impregnated with thromboplastin (tissue factor: TF) was inserted.

Operating procedure

Rats (Sprague Dawley) or guinea pigs (Hartley) with an average body weight of 300-350 g were anesthetized with sodium pentobarbital (60mg/kg ip). The femoral vein (rat) or right jugular vein (guinea pig) was cannulated for intravenous injection, and the left and right jugular veins were cannulated with 0.9% saline to make up the shunt. After 5 minutes of intravenous administration of the compounds (treatment group) or their solvents (control group), two cannulae were connected by a flexible plastic tube having an inner diameter of 3mm and a length of 6cm and containing cotton yarn impregnated with thromboplastin to form a shunt. Blood circulation was re-established for 5 minutes (rats) or 10 minutes (guinea pigs). At this point the shunt was removed and the cotton yarn associated with the thrombus was removed and weighed immediately.

Results show

The mean values (. + -. ESM) of thrombus weights were tested for different groups. The percentage of thrombus weight reduction for each treatment group relative to the control group was calculated as DA₅₀This is the dose of compound used to inhibit 50% of the thrombus weight in control animals.

DA of the Compound of the present invention₅₀Preferably less than 10 mg/kg.

The results of this physiological experiment show that the compounds of the invention have the property of inhibiting factor VII/VIIa.

Thus, they can be used to treat and prevent different forms of diseases involving factor VII/VIIa and the coagulation chain. They can therefore be used for the treatment of thrombosis of veins, arteries or coronary arteries, disseminated intravenous thrombosis, restenosis following angioplasty, prevention of reocclusion which is aggravated after thrombosis, arterial fibrillation, pulmonary embolism, edema, septic shock, tumor-induced hypercoagulability, treatment of bradycardia, inflammation, pulmonary fibrosis or prevention of unstable angina.

For this purpose, the compounds can be in various forms suitable for oral, parenteral, intravenous administration, such as tablets, pills, dragees, capsules, suspensions, drinkable solutions or injectable solutions, together with suitable excipients, in doses ranging from 0.1mg to 1g per day, to be taken in single or several portions.

It may also be in various forms suitable for transdermal and ocular (occulaire) administration.

Claims

1. A compound of formula (I) in racemic form or in the form of a pure enantiomer, or in the form of a mixture of enantiomers, or in the form of the free acid or free base, or in the form of a pharmaceutically acceptable addition salt:wherein: r₁Represents a hydrogen atom, and is represented by,

or an amino group, or a salt thereof,

or C₁～C₄An alkyl group, a carboxyl group,

or C₁～C₆An alkoxycarbonyl group, a carbonyl group,

or an-OH group, or a group,

the radicals may be in the form of tautomers

In the form of radicals R₂To represent

C₁～C₆An alkyl group which may be substituted with 1 to 3 fluorine atoms,

or a cyclohexyl-methyl group,

or 2, 3-dihydro-1, 4-benzodioxo-7-ylmethyl,

or benzo-1, 3-dioxolan-6-ylmethyl,

or phenyl, benzyl or phenethyl, wherein the phenyl groups can be respectively and independently selected from 1 to 3-N (CH)₃)₂Trifluoromethoxy group, methylthio group, C₁～C₄Alkoxy, trifluoromethyl, amino, nitro, C₁～C₄Alkyl, trifluoromethoxy, halogen, -SO₂CH₃Hydroxy or-COOR₈or-OCH₂CO₂R₈Wherein R is₈Represents a hydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

or-CH₂The group Q, where Q is a heterocyclic group, may be selected from the group consisting of-N (CH)₃)₂Trifluoromethoxy group, C₁～C₄Alkoxy, trifluoromethyl, amino, nitro, C₁～C₄Alkyl, trifluoromethoxy, halogen, -SO₂CH₃Hydroxy or-COOR₈or-OCH₂CO₂R₈Is substituted by radicals, where R₈Represents a hydrogen atom or C₁～C₄Alkyl radical, R₃And R₅Independently of each other represent

A hydrogen atom or a fluorine atom, or a salt thereof,

or C₁～C₄An alkyl group, a carboxyl group,

or-COOH, or a group of-COOH,

or a hydroxyl group, or a mixture of hydroxyl groups,

or-N (CH)₃)₂，

or-Y-CH₂CO₂H, where Y represents an oxygen atom or a nitrogen atom, R₄To represent

A hydrogen atom, and a nitrogen atom,

or C₁～C₄An alkyl group, a carboxyl group,

or- (CH)₂)_p-COOR₈Where p is equal to 0, 1 or 2, R₈Represents a hydrogen atom or C₁～C₄Alkyl, X represents

-(CH₂)_mA group, where m is equal to 0, 1 or 2,

or-NH-CO-or-CO-NH-groups,

or-NH-CH₂-、-CH₂-NH-、N(CH₂)-CH₂-、-CH₂-N(CH₃)-、-N(CH₂CH₃)-CH₂-or-CH₂-N(CH₂CH₃) A group, or

A group, wherein W represents an oxygen atom or an NH group, and Z represents

-a CH-group, in which,

or a nitrogen atom, and-A-B-C-represents

-a NH-CO-NH-group,

or an-NH-C (NH) -NH-group,

or- (CH)₂)_n-CO-NH groups, where n is equal to 0 or 1,

or- (CH)₂)_q-NH-CO-group, where q is equal to 0 or 1,

or-CH₂-NH-CO-NH-groups.

2. The device of claim 1A compound in racemic form or in the form of a pure enantiomer, or in the form of a mixture of enantiomers, or in the form of a free acid or a free base, or in the form of a pharmaceutically acceptable addition salt, characterized in that R is₁To represent

A hydrogen atom, and a nitrogen atom,

or C₁～C₄An alkoxycarbonyl group, a carbonyl group,

or-OH, R₂To represent

C₁～C₆Alkyl, which may be substituted with trifluoromethyl,

or a cyclohexyl-methyl group,

or 2, 3-dihydro-1, 4-benzodioxo-7-ylmethyl,

or benzo-1, 3-dioxolan-6-ylmethyl,

or phenyl, benzyl or phenethyl, each of which may be substituted by 1 to 3 substituents independently selected from the group consisting of-N (CH)₃)₂Trifluoromethoxy group, methylthio group, C₁～C₄Alkoxy, trifluoromethyl, amino, nitro, C₁～C₄Alkyl, trifluoromethoxy, halogen, -SO₂CH₃Hydroxy or-COOR₈or-OCH₂CO₂R₈Wherein R is₈Represents a hydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

or a group-CH₂Q, where Q is a heterocyclic group, which may be selected from C₁～C₄Alkoxy, amino or-COOR₈Wherein R is₈Represents a hydrogen atom or C₁～C₄Alkyl radical, R₃And R₅Independently of each other represent

A hydrogen atom, and a nitrogen atom,

or-COOH, or a group of-COOH,

or-CH₃，R₄To represent

A hydrogen atom, and a nitrogen atom,

or-COOH, X represents

-(CH₂)_mA group, where m is equal to 0 or 2,

or-CR₆R₇-CH₂A group, where R₆And R₇Each independently representHydrogen atom or C₁～C₄An alkyl group, a carboxyl group,

or-NH-CO-or-NH-CH₂-a group of,

or-NH-CH₂-or-CH₂-N(CH₂CH₃) The radical Z represents a-CH-group and-A-B-C-represents

-a NH-CO-NH-group,

or- (CH)₂)_n-a CO-NH-group, where n is equal to 0 or 1,

or- (CH)₂)_q-NH-CO-group, where q is equal to 0 or 1,

or-CH₂-a NH-CO-NH-group,

or-CH₂-CO-NH-groups.

3. A process for the preparation of a compound of formula (I) according to claim 1 or 2, characterized in that a compound of formula (II) is reacted with a compound of formula (III) in the presence of a base to give a compound of formula (IV),

wherein R is₃And R₄D represents a leaving group as defined in claim 1 or 2,

wherein R is₅X, Z, A and B are as defined in claim 1 or 2, and GP represents a protecting group for an amine or a carboxylic acid,deprotecting it to give a compound of formula (V)

And optionally reacting it with different reagents as follows to give compounds of general formula (VI):

in the formula (V), A represents- (CH)₂)_q-a group, where q may be 0,1 or 2, BH represents-NHR₈，R₈When defined as in claim 1, compounds of the formula (V) are reacted with compounds of the formula R₂-SO₂Sulfonyl chloride reaction of Cl, R₂As defined in claim 1, to give a compound of the general formula (VI) in which A represents- (CH)₂)_q-a group, where q may be equal to 0, 1 or 2, B represents-NR₈-, and C represents-SO₂-a group;

in the formula (V), A represents- (CH)₂)_qA group, where q may be equal to 0 or 1, BH represents an amine function, a compound of formula (V) with a compound of formula R₂-N ═ C ═ O isocyanate, or with triphosgene and then with the general formula R₂-NH₂Reaction of amines, R₂Is defined in claim 1, to give a compound of the general formula (VI) in which A represents-NH-or-CH₂-NH-group, B represents-CO-group and C represents-NH-group;

in the formula (V), A represents- (CH)₂)_q-a group, where q may be 0 or 1, BH represents an amine function, in the presence of an organic base, a compound of formula (V) with a compound of formula R₂-COCl acid chloride reaction, in which formula R₂Two cases as defined in claim 1; or a compound of the formula (V) with a compound of the formula R in the presence of a coupling agent₂-CO₂H carboxylic acid reaction of formula (I) wherein R₂Two cases as defined in claim 1; to obtain a compound of the general formula (VI) wherein A represents- (CH)₂)_q-, where q may be equal to 0 or 1, B represents an-NH-group and C represents a-CO-group;

in the formula (V), A represents- (CH)₂)_n-a group, where n may be equal to 0 or 1, BH representing-CO₂H, a compound of the formula (V) and a compound of the formula R₂-NH₂Reaction of amines, where R₂As defined in claim 1, to give a compound of the general formula (VI) in which A represents- (CH)₂)_n-a group, where n may be equal to 0 or 1, B represents a-CO-group and C represents a-NH-group;

in formula (V), A represents- (CH)₂)_q-a group, where q is equal to 0 or 1 and BH represents an amine function, orA compound of formula (V) and formula R₂Reaction of N ═ C ═ S isothiocyanate, where R is₂As defined in claim 1, to obtain a thiourea, and converting the thiourea thus obtained into a guanidine by alkylation with methyl iodide followed by substitution thereof with an ammonia source, to obtain a compound of the general formula (VI) wherein a-B-C represents an-NH-C (NH) -NH-group;

compounds of formula (VI) wherein R is formed by rearrangement of the nitrile function to the hydroxyamidine function₁A compound of formula (I) which is a hydroxyl group, which is then reduced to an amidine to give a compound of formula (I), which is optionally reacted with an alkyl chloroformate in the presence of a base to give R in the formula₁Is C₁～C₆Alkoxycarbonyl compounds of the general formula (I).

4. A medicament, characterized in that it comprises a compound according to claim 1 or 2.

5. A pharmaceutical composition comprising a compound according to claim 1 or 2 together with any pharmaceutically acceptable excipient.