HUP0200893A2 - 6-[[(aryl and heteroaryl)oxy]methyl]naphthalene -2-carboximidamide derivatives, preparation and therapeutic application thereof - Google Patents

Description

2/81

The invention relates to 6-{[(aryl- or heteroaryl)oxy]methyl}naphthalene-2-carboximidamide derivatives, their preparation and their medicinal use.

The compounds of the invention have a structure corresponding to the general formula (I), in which R1 represents a hydrogen atom, or an amino group, or an alkyl group having 1-4 carbon atoms, or a (1-6 carbon atoms) alkoxy)carbonyl group, or a hydroxyl group, the group of the general formula R1-NH-C(=NH)- may also exist in the H2N-C(=NRi) tautomeric form;

R2 meaning

a C1-6 alkyl group, which may be substituted with 1-3 fluorine atoms, or a cyclohexylmethyl group, or a 2,3-dihydro-1,4-benzodiox-7-ylmethyl group, or a 1,3-benzodioxolan-6-ylmethyl group, or a phenyl, benzyl or phenylethyl group, which is independently selected from the group -14(0¾) 2 group, the trifluoromethoxy group, the methylthio group, the C1-4 alkoxy group, the trifluoromethyl group, the amino group, the nitro group, the C1-4 alkyl group, the trifluoromethoxy group, the halogen atom, the -SO2CH3 group, the hydroxyl group and the group of the general formula -COOR ₈ and -OCH ₂ CO ₂ R8

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may be substituted with 1-3 groups, where Rg represents a hydrogen atom or a C1-4 alkyl group, or a group of the general formula -CH ₂ Q, where Q represents a heterocyclic group, which may be substituted with a group selected from the group -N(CH ₃ ) ₂ group, the trifluoromethoxy group, the C1-4 alkoxy group, the trifluoromethyl group, the amino group, the nitro group, the C1-4 alkyl group, the trifluoromethoxy group, the halogen atom, the -SO2CH3 group, the hydroxyl group and the groups of the general formula -COORg and -OCH2CO2R8, R3 and _R5 represent independently a hydrogen atom or a fluorine atom, or a C1-4 alkyl group, or a carboxyl group, or a hydroxyl group, or a -N(CH ₃ ) ₂ group, or a group of the general formula -Y-CH ₂ COOH, where Y represents an oxygen or nitrogen atom, _R4 represents a hydrogen atom, or a C1-C4 alkyl group, or a group of the general formula - (CH ₂ ) _p -COORg, where p is

is 0, 1 or 2, and Rg is hydrogen or C1-4 alkyl, X is — ( _CH2 ) ^m— , where m is 0, 1 or 2,

4/81 or a group of the general formula -CRgR ₇ -CH ₂ - or -CH2-CR6R7-, where R ₆ and R ₇ independently represent a hydrogen atom or an alkyl group having 1-4 carbon atoms, or a -NH-CO- or -CO-NH- group, or a -NH-CH ₂ -, -CH ₂ -NH-, -N (CH _{3 )} -CH _{2 -} , -CH 2 -N (CH _{3 )} -CH ₂ - or -CH ₂ -N (CH ₂ CH ₃ ) - group,

W or a group of the general formula -N (-C-CH3)-CH- ₂ , where W represents an oxygen atom or a -NH- group, Z represents

-CH- group, or nitrogen atom, and -A-B-C- means

-NH-CO-NH- group, or -NH-C(NH)-NH- group, or - (CH ₂ ) _n -CO-NH- group, where n is 0 or 1, or - (CH ₂ ) _q -NR ₈ -SO ₂ - group, where q is 0, 1 or 2, and Rs is hydrogen or an alkyl group having 1-4 carbon atoms, or - (CH ₂ ) q -NH-CO group, where q is 0 or 1, or -CH ₂ -NH-CO-NH- group.

In accordance with the invention, the following definitions have the following meanings:

- the alkyl group is a saturated, straight or branched hydrocarbon chain,

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- the heterocyclic group is a hydrocarbon chain having a 5- or 6-membered ring, and the ring contains 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms, this ring being aromatic or otherwise a group selected from pyridyl, pyrimidine, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, thienyl, furyl or pyrazine groups and their isomers.

In the context of the invention, the halogen atom is preferably a chlorine or fluorine atom.

The compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, they may exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and mixtures thereof, including racemic mixtures, are part of the invention.

The compounds of the invention may be prepared in the form of the free base or addition salts with pharmaceutically acceptable acids, which are also within the scope of the invention.

Preferred compounds of the invention are those in which

R1 represents a hydrogen atom, or a (C1-C6 alkoxy)carbonyl group or a hydroxyl group,

R ₂ meaning

a C1-C6 alkyl group, which may be substituted by a trifluoromethyl group, or a cyclohexylmethyl group, or a 2,3-dihydro-1,4-benzodiox-7-ylmethyl group,

6/81 or 1,3-benzodioxolan-6-ylmethyl group, or phenyl, benzyl or phenylethyl group, which may be substituted on the phenyl group by 1-3 groups independently selected from the group -N(CH ₃ ) ₂ , the group trifluoromethoxy, the group methylthio, the group alkoxy of 1-4 carbon atoms, the group trifluoromethyl, the group amino, the group nitro, the group alkyl of 1-4 carbon atoms, the group trifluoromethoxy, the group halogen, the group -SO2CH3, the group hydroxyl and the group of the general formula -COORg and -OCH ₂ CO ₂ R8, where R ₈ represents a hydrogen atom or a group alkyl of 1-4 carbon atoms, or a group of the general formula -CH ₂ Q, where Q represents a heterocyclic group, which may be substituted by a group alkoxy of 1-4 carbon atoms or an amino group or a group of the general formula -COORg, where R ₈ represents a hydrogen atom or a C1-C4 alkyl group, R ₃ and R ₅ independently represent a hydrogen atom, a carboxyl group, or a methyl group, R 4 represents a hydrogen atom or a carboxyl group,

X means

-(CH ₂ ) _m - a group of the general formula, where m is 0 or 2, or -CRgR7-CH ₂ - a group of the general formula, where Rg and R7 independently represent a hydrogen atom or an alkyl group having 1-4 carbon atoms,

7/81 or -NH-CO- or -NH-CH ₂ - group, or -NH-CH ₂ - or -CH ₂ -N(CH ₂ CH ₃ ) - group, Z is -CH- group, and -ABC- is

-NH-CO-NH- group, or - (CH ₂ ) _n -CO-NH- group, where n is 0 or 1, or - (CH ₂ ) _g -NR ₈ -SO ₂ - group, where q is 0, 1 or 2, and Rg is a hydrogen atom, or - (CH ₂ ) _q -NH-CO- group, where q is 0 or 1, or -CH ₂ -NH-CO-NH- group, or -CH ₂ -CO-NH- group.

The compounds of formula (I) according to the invention can be prepared as shown in Scheme 1.

A compound of formula (II), wherein R ₃ and R 4 are as defined above (if R ₄ is a carboxyl group, this group is present in ester form until the compound of formula (VI) is obtained), and D is a leaving group, for example a halogen atom or a sulfonic acid ester group, with a compound of formula (III), wherein R ₅ , X, Z, A and B are as defined above (if B is a -CO- group at the end, it is present in the form of a C0 ₂ — group during the synthesis) and GP is an amino or carboxylic acid protecting group, for example a C1-4 alkoxy or benzyloxy group, is reacted in the presence of a base, for example potassium carbonate, in an aprotic solvent, preferably acetonitrile or dimethylformamide, at a temperature between 20 and 80 °C.

8/81 to obtain a compound of formula (IV). Alternatively, this compound of formula (IV) can be prepared by the Mitsunobu reaction, in which a compound of formula (II), in which D is a hydroxyl group, is condensed with a compound of formula (III) in the presence of diethyl azodicarboxylate or 1,1'(azodicarbonyl)dipiperidine and a trialkyl or triarylphosphine, for example tri(n-butyl)phosphine or triphenylphosphine, in an aprotic solvent, for example 1,4-dioxane, tetrahydrofuran or toluene, at a temperature between 0°C and 60°C.

For compounds of formula (IV) wherein A is -(CH ₂ ) _q - where q is 0, 1 or 2 and B is -NR ₈ - where R ₈ is hydrogen or C 1-4 alkyl and GP is an amine protecting group such as tert-butyloxycarbonyl, trifluoroacyl or trimethylsilylethyloxycarbonyl or other suitable amine protecting groups as described, for example, by T. Greene in Protective Groups in Organic Synthesis (2nd Edition, Wiley, NY, 1991), the protecting group is removed under conditions known to those skilled in the art to give a compound of formula (V).

In the case where in the compound of formula (IV) A is a group of the general formula -(CH ₂ ) _n ^_ , where n is 0 or 1, and B is a group of the general formula -CO ₂ -, then GP is a carboxylic acid protecting group, for example a methyl, ethyl or tert-butyl group or a similar group as described by T. Greene in the manual Protective Groups in Organic Synthesis (2nd Edition, Wiley, NY, 1991). These are used in the ester of formula (IV)

9/81 compounds are converted into free acids of the general formula (V) by conventional methods, such as saponification with hydroxide ions, hydrolysis with inorganic or organic acids or reaction with fluoride ions in the case of silylated protecting groups, for example the trimethylsilylethyloxycarbonyl group, where A is a group of the general formula -(CH ₂ ) _n -, where n is 0 or 1, and BH is a -CO ₂ H group.

Compounds of formula (V) in which A is -(CH ₂ ) _q -, where q is 0, 1 or 2, and BH is -NHR ₈ -, where R _s is as defined above, can then be reacted with a sulfonyl chloride of formula R ₂ -SO ₂ C1, where R ₂ is as defined above, in the presence of an organic base such as triethylamine, N-methylmorpholine or N,N-diisopropylethylamine in a solvent such as dichloromethane or dimethylformamide at a temperature between 0 °C and 60 °C to give a compound of formula (VI) in which A is -(CH ₂ ) _q -, where q is 0, 1 or 2, B is -NR ₈ - and C is -SO ₂ -.

It is also possible to react the compound of formula (V), in which A is a group of the general formula -(CH ₂ ) _q -, where q is 0 or 1, and BH is an amino group, - directly with an isocyanate of the general formula R ₂ -N=C=O, where R ₂ is as defined above,

- or first reacted with triphosgene or its equivalent, then with an amine of the general formula R ₂ -NH ₂ under the conditions described above for the reaction with sulfonyl chloride

10/81, in which R ₂ is as above, thus obtaining a compound of general formula (VI) in which A is -NH- or CH ₂ -NH- group, B is -CO- group and C is -NH- group.

The compound of formula (V) wherein A is a group of the general formula (CH ₂ ) _q - and BH is an amino group or a group of the general formula -NHR ₈ ,

- an acid chloride of the general formula R ₂ -COC1, where R ₂ has the same meaning as above, can be reacted with its activated ester or mixed anhydride equivalent in the presence of an organic base,

- or with a carboxylic acid of the general formula R ₂ -CO ₂ H, where R ₂ is as above, in the presence of a coupling reagent, such as N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide/1-hydroxybenzotriazole or [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate or other known peptide coupling reagent, in a solvent, such as dichloromethane, dimethylformamide or a mixture of the two, at a temperature between 0 °C and 25 °C, to form a compound of the general formula (VI), where A is a group of the general formula -(CH ₂ ) _q -, where q is 0 or 1, B is a -NH- group and C is a -CO- group.

For the preparation of compounds of formula (VI) in which A is a group of the general formula -(CH ₂ ) _n - and n is 0 or 1, B is a group of the general formula -CO- and C is a group of the general formula -NH-, a compound of formula (V) in which A is a group of the general formula -(CH ₂ ) _n - where n is 0 or 1, BH is a group of the general formula -CO ₂ H, with an amine of the general formula R ₂ -NH ₂ is reacted with the following reaction:

11/81 are reacted under the peptide coupling conditions described above, in which R ₂ has the meaning given above.

To prepare compounds of formula (VI) containing -NH-C(NH)-NH- in place of -ABC-, a compound of formula (V) in which A is -(0Η ₂ ) ₃ - and q is 0 or 1 and BH is an amino group is reacted with an isothiocyanate of formula R.2N=C=S, where R ₂ is as defined above. The thiourea thus obtained is converted to guanidine by alkylation with methyl iodate, which is subjected to a substitution reaction with an ammonia source such as ammonium acetate or ammonium carbonate.

Compounds of formula (I) can then be prepared from compounds of formula (VI) by rearrangement of the nitrile group to an amidine group by process A) or B) described below.

Method A: The compound of formula (VI) is dissolved in a 1:9 (v/v) triethylamine:pyridine mixture saturated with hydrogen sulfide and kept at room temperature for 20-36 hours. The thioamide formed is alkylated with excess methyl iodide in acetone at reflux temperature, and the intermediate thus obtained is refluxed in an alcohol, e.g. methanol, in the presence of a nitrogen source, e.g. ammonium acetate or a primary amine of formula Rj-NH ₂ , to give the compound of formula (I).

Process B: the compound of general formula (VI) is reacted with hydroxylamine hydrochloride in the presence of an organic base, such as triethylamine.

12/81 in the presence of an alcohol, preferably ethanol, at a temperature between 40 °C and 70 °C. The formed hydroxyamidine, i.e. the compound of general formula (I) in which R1 represents a hydroxyl group, is hydrogenated in the presence of a Raney nickel catalyst activated in an alcohol, for example methanol or ethanol, and a few equivalents of hydrogen chloride or acetic acid at a temperature between 20 °C and 60 °C under a pressure of 137.8-344.5 kPa, thus obtaining a compound of general formula (I) containing a hydrogen atom in the position of _Rx .

To prepare a compound of formula (I) in which R _x is (C1-C6 alkoxy)carbonyl, a compound of formula (I) in which R _x is hydrogen is reacted with an alkyl chloroformate in a solvent such as dichloromethane, tetrahydrofuran or acetonitrile in the presence of a base such as 1,1,3,3-tetramethylguanidine, triethylamine or diisopropylethylamine at a temperature between 0°C and 25°C.

Compounds of formula (II) can be synthesized by methods known to those skilled in the art. Some methods suitable for the preparation of compounds of formula (II) are exemplified in Schemes 2 and 3.

According to Scheme 2, a bromoester of formula (VII) can be reacted with a cyanide source, such as copper cyanide in dimethylformamide at temperatures between 50 °C and 140 °C, or with trimethylsilyl cyanide in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) in a solvent, such as triethylamine or tributylamine at temperatures between 80 °C and 160 °C.

13/81 at a temperature between 13 and 81, or with zinc cyanide in dimethylformamide at 80 °C in the presence of palladium(0), such as tetrakis(triphenylphosphine)palladium(0), to form a nitrile of formula (VIII). The ester group may be reduced by one of a number of methods known in the art, such as with lithium borohydride in an aprotic solvent, such as tetrahydrofuran, at a temperature between 0 °C and 80 °C. The compound of formula (IX) thus formed may then be reacted with phosphorus tribromide or thionyl chloride in a solvent, such as dichloromethane or chloroform, at a temperature between 0 °C and 60 °C to give a compound of formula (II) wherein R ₄ is hydrogen and D is halogen. The compound of formula (IX) may also be converted to a sulfonic acid ester, such as methanesulfonate, by methods known in the art.

When it is desired to prepare a compound of formula (II) in which R ₄ is a group of the general formula -COOR ₈ , where R ₈ is a hydrogen atom or a C 1-4 alkyl group, and D is a hydroxyl group or a halogen atom, the reaction is carried out, for example, according to reaction scheme 3, where in the compound of formula (II) R ₄ is a -CO ₂ CH ₂ CH ₃ group.

According to Scheme 3, an ester derivative of the general formula (VII) is first reduced to an alcohol derivative of the general formula (X) by, for example, lithium aluminum hydride in tetrahydrofuran at a temperature of -20 °C to -10 °C. The hydroxyl group of the compound of the general formula (X) is reduced by reactions conventional in the art, such as with phosphorus tribromide or sulfonyl chloride.

14/81 under the conditions described above, the halogen atom is replaced by a bromine or chlorine atom. The halogen atom of the compound of general formula (XI) formed is replaced by a cyano group with a cyanide source, preferably tetraethylammonium cyanide in dichloromethane at a temperature between 0 °C and 25 °C. The cyano group of the compound of general formula (XII) thus obtained is converted into an ester group, for example with 95% sulfuric acid in an alcohol of general formula Rg-OH, where R ₈ is an alkyl group having 1-4 carbon atoms, by refluxing.

The compound of general formula (XIII) formed is then preferably reacted with zinc cyanide in dimethylformamide and in the presence of tetrakis(triphenylphosphine)palladium(0). The resulting derivative of general formula (XIV) is

- or by N-bromosuccinimide in the presence of a catalytic amount of 2,2'azobis(2-methylpropionitrile) or benzoyl peroxide in carbon tetrachloride under reflux to a compound of general formula (II) in which D represents a bromine atom and R ₄ represents a -CO ₂ CH ₂ CH ₃ group,

- or with selenium dioxide in pyridine, by boiling under reflux, to oxidize to a glyoxalic acid derivative of general formula (XV). The compound of general formula (XV) is preferably selectively reduced with sodium borohydride at low temperature in tetrahydrofuran, thus obtaining a compound of general formula (II) in which D is a hydroxyl group and R ₄ is a -COCH ₂ CH ₃ group.

Compounds of formula (III) can be prepared as shown in Scheme 4.

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Ketones of general formula (XVII) are commercially available or can be prepared by methods described in the literature or by modifications of known procedures.

For example, substituted tetralones of formula (XVII) in which Z is -CH- are described in U.S. Patent No. 3,980,699 and European Patent Application No. 0,540,051. Compounds of formula (XVII) in which Z is nitrogen can be prepared as described in European Patent Application No. EP313,295, and compounds of formula (XVII) in which Z is -CH- and X is -NH- _CH2 can be prepared by a modification of the procedure described in J. Amer. Chem. Soc. 71, 1901 (1949). Compounds of formula (XVIII) in which Z is CH- and X is -NH-CO- or -CONH- can be prepared as described in Bull. Soc. Chim. Fr., 1, 98 (1988). Compounds of formula (XVII) in which AZ is -CH ₂ - and X is -CH ₂ -NH- or -CH ₂ -N (alkyl)- can be prepared by the Pictet-Gram variation described in Chem. Bér. 42, 2943 (1909) and Org. React. 6, 151 (1951). Compounds of formula (XXII) in which Z is nitrogen and X is -NH-CO can be prepared by a modified version of the method described in J. Chem. Soc. Perkin Trans 1, 353 (1991). Compounds of formula (XXII) in which AZ is -CH- and X is -CO-NH- can be prepared by the method described in Chem. Pharm. Bull., 16(3), 455 (1968) using the procedure described in the literature.

16/81. In addition, indanones are commercially available.

According to Scheme 4, compounds of general formula (XVII) in which R ₅ , X and Z are as defined above,

- or directly by reductive amination reaction with ammonium acetate and cyanoborohydride in methanol at room temperature as described in J. Artier. Chem. Soc. 93, 2897 (1971), or

- indirectly, in two steps, by conversion to oxime in the usual manner, followed by hydrogenation with iron in acetic acid or with lithium aluminum hydride or in the presence of a palladium-on-carbon catalyst and acetic anhydride, to the compound of general formula (XVIII).

The compound of formula (XVIII) thus formed is then demethylated by refluxing with 48% hydrogen bromide or preferably with boron tribromide at low temperature (-70°C to -20°C) in dichloromethane. The amino group of the compound of formula (XIX) is protected with an amino protecting group, such as tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, trifluoroacetyl or the like, as described by Green in Protecting Groups in Organic Synthesis (Wiley, NY, 1991). In the compound of formula (III) thus obtained, A is a group of the formula -(CH ₂ ) _q -, where q is 0, B is a -NH- group and GP is a protecting group.

For the preparation of compounds of general formula (III) in which A is a group of general formula -(CH ₂ ) _q -, where q is 1, and B is a group -NH-, the general formula (XVII)

The starting ketone 17/81 is first converted to the enol ether of formula (XX) by a Wittig reaction with (methoxymethyl)triphenylphosphorane in tetrahydrofuran at a temperature below 0 °C. The enol ether of formula (XX) is then hydrolyzed to the aldehyde of formula (XXI) with an organic acid, such as formic acid or p-toluenesulfonic acid, in a water/tetrahydrofuran or water/dioxane mixture at reflux. The compound of formula (XXI) is then converted to the amine of formula (XXII) by the procedure described for the preparation of compounds of formula (XVIII). The compounds of formula (XXII) are then preferably demethylated with boron tribromide at low temperature in a solvent such as dichloromethane, and the amino group of the resulting compound of formula (XXIII) is protected in the same manner as described for compounds of formula (XIX) to give a compound of formula (III) in which A is -(CH ₂ ) q -, where q is 1, B is -NH-, and GP is an amino protecting group as described above.

Compounds of formula (XXII) can also be prepared by reacting compound of formula (XVII) with trimethylsilyl cyanide in the presence of titanium(IV) tetrachloride in dichloromethane, followed by hydrogenation of the nitrile intermediate at 68.9-344.5 kPa in a solvent such as methanol in the presence of platinum oxide or palladium on carbon catalyst.

Aldehydes of formula (XXI) can also be oxidized to carboxylic acid derivatives of formula (XXIV) using suitable oxidizing agents known to those skilled in the art, such as sodium chlorite.

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The compounds of formula (XXIV) formed are then demethylated with boron tribromide at low temperature and the carboxyl group of compound (XXV) is converted into an ester group by one of the conventional methods, for example by boiling in methanol saturated with hydrogen chloride gas. As a result of these reactions, a compound of formula (III) is obtained in which A is a group of the general formula -(CH ₂ ) _n ~ where n is 0, B is a group -CO ₂ - and GP is a methyl group.

For the preparation of compounds of formula (III) in which A is a group of the general formula -(CH ₂ ) _n -, where n is 1, B is a -CO ₂ - group and GP is a methyl group, the following reaction scheme can be used.

According to Scheme 5, the ketone of formula (XVII) can be reacted with methyl dimethylphosphonoacetate anion (obtained by deprotonation with lithium bis(trimethylsilyl)amide in tetrahydrofuran at -50 °C to 20 °C) to form the α,β-unsaturated ester of formula (XXVI). Compound (XXVI) is then reduced by catalytic hydrogenation to compound (XXVII), which is then demethylated with boron tribromide in dichloromethane at -70 °C to give compound (III) in which A is -(CH ₂ ) _n - where n is 1, B is -CO ₂ - and GP is methyl.

The following examples are intended to illustrate the invention without limiting it. The structures of the compounds prepared are confirmed by microanalysis results and NMR, mass and IR spectra.

19/81 is demonstrated. The number of compounds shown as examples refers to the table below, where the chemical structure and physical properties of some compounds of the invention are given. Example 1

6-[({[8-({[(Thiazol-4-1)methyl]sulfonyl}amino)methyl]-5,6,7,8tetrahydronaphthalen-2-yl}oxy)methyl]naphthalene-2-carboximidamide hydrochloride (Compound No. 32)

1.1. Methyl-(6-cyanonaphthalene-2-carboxylate)

To a degassed suspension of 7.50 g (28.29 mmol) of methyl (6-bromonaphthalene-2-carboxylate) and 2.01 g (17.0 mmol) of zinc cyanide in 20 ml of dimethylformamide was added 2.28 g (1.97 mmol) of tetrakis(triphenylphosphine)palladium(0) and the mixture was heated at 80 °C under nitrogen for 16 hours. The mixture was then evaporated to dryness and the residue was taken up in 300 ml 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 was purified by flash chromatography on silica gel, eluting with a 1:9 mixture of ethyl acetate and toluene. 5.20 g of white crystalline material were obtained. Melting point: 163 °C Yield: 84%

1.2. 6-(Hydroxymethyl)naphthalene-2-carbonitrile

To a solution of 10.0 g (47.35 mmol) of methyl-(6-cyanonaphthalene-2-carboxylate) in 160 ml of tetrahydrofuran and cooled to 0 °C, 2.06 g (94.7 mmol) of lithium borohydride were added in small amounts under nitrogen, and the mixture was left to warm to room temperature over 42 hours.

20/81 °C. Then it is boiled under reflux for 2 hours, cooled to 0 °C and hydrolyzed by slow addition of 100 ml of 1 N hydrochloric acid. The tetrahydrofuran is then evaporated under reduced pressure and the product is extracted with ethyl acetate. The organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The crude product is then purified by flash chromatography on silica gel, eluting with a 3:7 mixture of ethyl acetate and cyclohexane. 6.72 g of product are obtained as a white solid. Melting point: 129 °C Yield: 78 % 1.3. 6-(Bromomethyl)naphthalene-2-carbonitrile

To a solution of 20.0 g (109.3 mol) of 6-(hydroxymethyl)naphthalene-2-carbonitrile in 600 ml of dichloromethane cooled to 0 °C was added dropwise 4.1 ml (43.7 mol) of phosphorus tribromide. The reaction mixture was then stirred at 20 °C for 3 hours and then washed several times with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. 21.10 g of the product was obtained as an off-white solid. Melting point: 138-139 °C Yield: 78 % 1.4. 7-Methoxy-1-(methoxymethylene)-1,2,3,4-tetrahydronaphthalene

To a mixture of 60.0 g (175 mmol) of (methoxymethyl)triphenylphosphonium chloride and 500 ml of anhydrous tetrahydrofuran cooled to -50 °C was added 19.65 g (175 mmol) of potassium tert-butoxide under nitrogen, and the mixture was stirred at -40 °C for 30 minutes. Then 22.0 g (125

21/81 mmol) of 7-methoxy-l-tetralone in 250 ml of anhydrous tetrahydrofuran is added dropwise. The reaction mixture is stirred at 20 °C for 3 hours and then hydrolyzed by slow addition of 500 ml of water. After separation, the organic phase is separated and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue is triturated several times with cyclohexane and the precipitate is removed by filtration. The filtrate is evaporated to dryness and the crude product is purified by flash chromatography on silica gel, eluting with a 5:95 volume mixture of ethyl acetate and cyclohexane.

25.94 g of syrup is obtained, which is used in the next step.

1.5. 7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxaldehyde

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

24.1 g 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-carboxaldehyde oxime To a solution of 11.10 g (160 mmol) hydroxylamine hydrochloride and 25 ml (180 mmol) triethylamine in 100 ml absolute ethanol

22/81 at room temperature, a solution of 28.70 g (150 mmol) of 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxaldehyde in 20 ml of ethanol is added. The mixture is refluxed for 2 hours and then evaporated to dryness. The residue is taken up in ethyl acetate and the solution is washed with 1 molar 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. 28.04 g of product is obtained as a white solid. Melting point: 147 °C Yield: 93 % 1.7. 7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-methanamine

To a solution of 10.0 g (48.78 mmol) of 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxyaldehyde oxime in 200 ml of anhydrous tetrahydrofuran at room temperature, 49 ml (49 mmol) of a 1 molar solution of lithium aluminum hydride in tetrahydrofuran were added dropwise. The reaction mixture was then stirred for 16 hours at room temperature and then hydrolyzed by successive addition of 1.9 ml of water, 1.9 ml of 1N sodium hydroxide solution and finally 5.6 ml of water. The resulting mixture was stirred with 50 g of magnesium sulfate for 5 minutes and then filtered. The salts were rinsed with dichloromethane and the filtrate was evaporated to dryness. The residue is taken up in ethyl acetate and the solution is washed successively with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and finally saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. 8.99 g of product are obtained as a colorless oil.

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Yield: 88 %

1.8. 8-(Aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-ol hydrobromide To a solution of 9.50 g (49.7 mmol) of 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-methanamine in 49 ml of dichloromethane cooled to -78 °C, 109 ml (109 mmol) of a 1 molar solution of boron tribromide in dichloromethane was added dropwise. The reaction mixture was stirred for 30 minutes at -78 °C and then for 30 minutes at room temperature. It was then hydrolyzed by dropwise addition of 100 ml of methanol at -78 °C and stirred at 20 °C for 1 hour. The mixture was evaporated to dryness, the residue was taken up in toluene and evaporated to dryness again.

12.40 g of product are obtained in the form of a hygroscopic amorphous solid.

Melting point (hydrochloride): 181-183 °C Yield: 97 %

1.9. 1,1-Dimethylethyl-{[(7-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]carbamate} To a solution of 11.74 g (45.50 mmol) of 8-(aminomethyl)-5,6,7,8tetrahydronaphthalen-2-ol hydrobromide in 360 ml of tetrahydrofuran at 20 °C, 11.70 g (53.67 mmol) of di(tert-butyl)dicarbonate are added while stirring, then 12.7 ml (91 mmol) of triethylamine are added dropwise, and the mixture is stirred at 20 °C for 4 hours. It is then evaporated to dryness, and the residue is taken up in 300 ml of ethyl acetate. The solution is washed with water, and the organic phase is dried over sodium sulfate, filtered, and evaporated to dryness. The crude product is purified by flash chromatography on silica gel, eluting with a 1:9 mixture of ethyl acetate and cyclohexane.

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8.15 g of product are obtained as a gum. Yield: 68 %

1.10. 1,1-Dimethylethyl-[({7-[(6-cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)carbamate]

A mixture of 4.40 g (17.8 mmol) of 6-(bromomethyl)naphthalene-2-carbonitrile, 4.0 g (14.4 mmol) of 1,1-dimethylethyl-{[(7-hydroxy-1,2,3,4tetrahydronaphthalen-1-yl)methyl]carbamate}, 3.20 g (23.3 mmol) of potassium carbonate and 120 ml of acetonitrile was heated under reflux for 6 hours. It was then evaporated to dryness and the crude product was purified by flash chromatography on silica gel, eluting with a 1:4 mixture of ethyl acetate and cyclohexane. 5.60 g of product was obtained as a white solid. Melting point: 122 °C Yield: 87 % 1.11. 6-({[8-(Aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy Jmethyl)naphthalene-2-carbonitrile hydrochloride

A mixture of 4.70 g (10.63 mmol) of 1,1-dimethylethyl-[({7-[(6-cyanonaphthalen2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)carbamate], 100 ml of dichloromethane and 10 ml of 4N anhydrous dioxane solution was stirred for 14 hours at 20 °C. It was then evaporated to dryness and the solid residue was triturated with diethyl ether, filtered off with suction and dried in vacuo. 3.80 g of product was obtained as a white solid. Melting point: 149-150 °C Yield: 95 %

1.12. (Thiazol-4-ylmethyl)ethanethioate

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A mixture of 3.50 g (19.57 mmol) of 4-chloromethylthiazole hydrochloride and 2.70 g (19.57 mmol) of potassium carbonate is stirred for 15 minutes at 0 °C. Then 2.24 g (19.57 mmol) of potassium thioacetate are added and stirring is continued for 4 hours at room temperature. The mixture is then evaporated to dryness under reduced pressure and the residue is taken up in diethyl ether. The solution is washed with ice-cold water and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The product is purified by flash chromatography on silica gel, eluting with a 3:7 mixture of ethyl acetate and cyclohexane. 2.35 g of the expected product is obtained as an oil. Yield: 69 % 1.13. Thiazole-4-methanesulfonyl chloride hydrochloride

To a solution of 2.34 g (13.53 mmol) of thiazol-4-ylmethylethanethioate in 12 ml of acetic acid and cooled to 0 °C, 0.73 ml (40.56 mmol) of water are added, then 3.26 ml (40.56 mmol) of thionyl chloride are added dropwise, the temperature is allowed to rise to 20 °C and the mixture is stirred at this temperature for 4 hours. It is then evaporated to dryness and the remaining solid is triturated with ethyl acetate and then with diethyl ether and finally dried in vacuo. 1.95 g of the expected product are obtained as a pale yellow solid. Melting point: 170 °C Yield: 61 % 1.14. N— ({7—[(6-Cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)thiazole-4-methanesulfonamide

26/81

To a solution of 0.41 g (1.20 mmol) of 6-({[8-(aminomethyl)-5,6,7,8tetrahydronaphthalen-2-yl]oxy}methoxy)naphthalene-2-carbonitrile in 20 ml of dichloromethane and cooled to 0 °C, 0.34 g (1.45 mmol) of thiazole-4-methanesulfonyl chloride hydrochloride and then 0.44 ml (3.30 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 16 hours. It was then diluted with 100 ml of dichloromethane and the solution was washed with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel, eluting with a 2:98 mixture of methanol and dichloromethane and a trace of concentrated aqueous ammonia. 0.304 g of product was obtained as a foam/white gum. Yield: 50 % 1.15. N'-Hydroxy-6-({[8-({[(thiazol-4-ylmethyl)sulfonyl]amino}methyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}methyl)naphthalene-2-carboximidamide

A mixture of 0.30 g (0.60 mmol) of N-({7-[(6-cyanonaphthalen-2-yl)methoxy]1,2,3,4-tetrahydronaphthalen-1-yl}methyl)thiazole-4-methanesulfonamide, 0.103 g (1.49 mmol) of hydroxylamine hydrochloride, 0.20 ml (1.49 mmol) of triethylamine and 30 ml of absolute ethanol is heated under reflux for 8 hours. It is then evaporated to dryness and the solid is triturated with water, filtered off with suction and dried in vacuo.

0.319 g of product is obtained as a white solid. Melting point: 140 °C

Yield: 99 %

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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 0.31 g (0.576 mmol) of N'-hydroxy-6-({[8-({[(thiazol-4-ylmethyl)sulfonyl]amino}methyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}methyl)naphthalene-2-carboximidamide, 30 ml of methanol, 3 ml of acetic acid and 11.8 ml of anhydrous isopropanol hydrogen chloride solution was hydrogenated in a Parr apparatus at a pressure of 275.60 kPa for 12 hours in the presence of 0.25 g of activated Raney nickel. The mixture was then filtered and the filtrate was evaporated to dryness. The crude product was purified by reverse-phase flash chromatography on C18 adsorbent, eluting with a gradient mixture of 10% to 50% methanol and n/1000 aqueous hydrochloric acid. 0.164 g of product was obtained as a white solid. Melting point: 135 °C Example 2

N-(7-{[6-(Aminoiminomethyl)naphthalen-2-yl]methoxy}-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxyphenylacetamide hydrochloride (Compound No. 17)

2.1. 7-Methoxy-1,2,3,4-tetrahydronaphthalen-1-amine

To a mixture of 17.60 g (99.89 mmol) of 7-methoxy-l-tetralone, 77.0 g (1 mol) of anhydrous ammonium acetate and 500 ml of methanol at room temperature, 5.10 g (81.16 mmol) of sodium cyanoborohydride were added and the mixture was stirred at room temperature for 96 hours. The methanol was then evaporated under reduced pressure and replaced with 400 ml of diethyl ether. The mixture was cooled to 0 °C and hydrolyzed by acidifying with 6N hydrochloric acid to pH 1. The aqueous phase was washed with 3 x

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It is washed with 100 ml of diethyl ether, then separated and the pH is adjusted to 9 with concentrated sodium hydroxide solution. The product is then extracted with diethyl ether, the organic phases are dried over sodium sulfate, filtered and then evaporated to dryness. 16.13 g of product is obtained as a colorless oil. Yield: 93%

2.2. 1,1-Dimethylethyl-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate]

To 300 ml of 48% hydrogen bromide solution, 16.0 g (90.4 mmol) of 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine are added in small amounts, and the mixture is refluxed for 15 hours. It is then evaporated to dryness and the residue is taken up in 250 ml of tetrahydrofuran. 21.80 g (100.0 mmol) of di(tert-butyl)dicarbonate are added to the solution, followed by 30 ml (215.24 mmol) of triethylamine dropwise, and the mixture is stirred at room temperature for 17 hours. The pH of the mixture is then adjusted to 5-6 with acetic acid and the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness. After recrystallization from ethanol, 21.07 g of a white solid are obtained. Melting point: 72-73 °C Yield: 88 %

2.3. 1,1-Dimethylethyl-({7-[(6-cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}carbamate) 11.50 g (46.8 mmol) 6-(bromomethyl)naphthalene-2-carbonitrile, 10.0 g (38.02 mmol) 1,1-dimethylethyl-[(7-methoxy-1,2,3,4

29/81 tetrahydronaphthalen-1-yl)carbamate], 8.50 g (61.51 mmol) potassium carbonate and 300 ml acetonitrile are heated under reflux for 6 hours. The mixture is then evaporated to dryness and the crude product is purified by flash chromatography on silica gel, eluting with a 2:8 mixture of ethyl acetate and cyclohexane. 14.13 g of product are obtained as a white solid. Melting point: 114-115 °C Yield: 87 % 2.4. 6-{[(8-Amino-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]methyl}naphthalene-2-carbonitrile hydrochloride

A solution of 1.0 g (2.33 mmol) of 1,1-dimethylethyl-({7-[(6-cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}carbamate) in 80 ml of dichloromethane cooled to 0 °C was bubbled with gaseous hydrogen chloride for 5 minutes, and the mixture was stirred at room temperature for 5 hours. It was then evaporated to dryness, and the solid was triturated with diethyl ether, filtered off with suction, and dried in vacuo. 0.850 g of product was obtained. Melting point: 222-223 °C Yield: 100 % 2.5. N-{7-[(6-Cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}-3-methoxyphenylacetamide

To a solution of 0.30 g (1.81 mmol) of 3-methoxyphenylacetic acid in 10 ml of dichloromethane was added 0.66 g (1.81 mmol) of 6-{[ (8-amino-5,6,7,8tetrahydronaphthalen-2-yl)oxy]methyl}naphthalene-2-carbonitrile hydrochloride, 0.244 g (1.81 mmol) of 1-hydroxybenzotriazole and 0.90 ml (5.17 mmol) of N,N-diisopropyl-N-ethylamine. The reaction mixture was stirred for 1 h at 100 °C for 1 h at 100 °C.

30/81 was cooled to 0 °C and 0.38 g (1.98 mmol) of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide was added. The mixture was allowed to warm to room temperature and then stirred for 14 hours. It was then diluted with 150 ml of ethyl acetate and the solution was washed with 3 x 50 ml of 1N citric acid solution, 50 ml of water, 3 x 50 ml of saturated aqueous sodium bicarbonate solution and finally 50 ml of 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 5:95 mixture of methanol and dichloromethane. 0.802 g of product was obtained. Melting point: 146 °C Yield: 92 %

2.6. N-[7-({6-[Amino(hydroxyimino)methyl]naphthalen-2-ylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]-3-methoxyphenylacetamide 0.793 g (1.66 mmol) N-{7-[(6-cyanonaphthalen-2-yl)methoxy]-

A mixture of 1,2,3,4-tetrahydronaphthalen-1-yl}-3-methoxyphenylacetamide, 0.30 g (4.31 mmol) hydroxylamine hydrochloride, 0.60 ml (4.31 mmol) triethylamine and 50 ml absolute ethanol was refluxed for 6 hours. It was then evaporated to dryness and the remaining solid was triturated with 10 ml water, filtered off with suction and dried in vacuo.

0.768 g of product is obtained as a white solid. Yield: 90 %

2.7. N-(7-{[6-(Aminoiminomethyl)naphthalen-2-yl]methoxy)-1,2,3,4-

-tetrahydronaphthalen-1-yl)-3-methoxyphenylacetanide hydrochloride

31/81

A mixture of 0.760 g (1.49 mmol) of N-[7-({6-[amino-(hydroxyimino)methyl]naphthalen-2-yl]methoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]-3-methoxyphenylacetamide and 15 ml of 0.1 N isopropanol hydrogen chloride solution was stirred for 10 minutes and then evaporated to dryness. This hydrochloride was then dissolved in 30 ml of methanol and the solution was charged into a Parr apparatus after addition of 3 ml of acetic acid and hydrogenated for 5 hours at 40 °C at a pressure of 275.60 kPa in the presence of 0.50 g of activated Raney nickel. The reaction mixture was then filtered through celite and the filtrate was evaporated to dryness. The crude product was purified by reverse phase HPLC on C18 adsorbent, eluting with a gradient mixture of acetonitrile and n/1000 hydrochloric acid from 0% to 100% over 180 minutes. 0.150 g of product was obtained. Melting point: 120 °C Yield: 20 % Example 3

6-({[8-({[(Pyridin-3-ylmethyl)amino]carbonyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}methyl)naphthalene-2-carboximidamide hydrochloride (Compound No. 5)

3.1. 6-({[8-({[(Pyridin-3-ylmethyl) amino]carbonyl}amino )-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}methyl)naphthalene-2-carbonitrile 0.73 g (2.00 mmol) of 6-{[(8-amino-5,6,7,8-tetrahydronaphthalen2-yl)oxy]methyl}naphthalene-2-carbonitrile hydrochloride prepared in 20 ml of 1,4-dioxane and cooled to 5 °C was added 0.356 g (1.20 mmol) of bis(trichloromethyl)carbonate, then 1.40 ml (10 mmol) of triethylamine. The mixture was stirred at room temperature for 30 minutes, then 0.220 g (2.03 mmol) of

32/81

3-aminomethylpyridine is added. The reaction mixture is stirred for 15 hours at 20 °C, then 75 ml of water is added and extracted with 3 x 100 ml of dichloromethane. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The crude product is purified by flash chromatography on silica gel, eluting with a 5:95 mixture of methanol and dichloromethane. 0.707 g of product is obtained.

Yield: 76 %

3.2. 6-({[8-({[(Pyridin-3-ylmethyl)amino]carbonyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}methyl)naphthalene-2-carboximidamide hydrochloride

A mixture of 0.265 g (3.81 mmol) of hydroxylamine hydrochloride, 0.707 g (1.53 mmol) of 6-({[8-({[(pyridin-3-ylmethyl)amino]carbonyl}amino)5,6,7,8-tetrahydronaphthalen-2-yl]oxy}methyl)naphthalene-2-carbonitrile, 0.64 ml (4.60 mmol) of triethylamine and 15 ml of absolute ethanol was heated under reflux for 5 hours. The reaction mixture was then evaporated to dryness and the remaining solid was triturated with 10 ml of water, filtered off with suction and dried in vacuo. The residue was taken up in 20 ml of 0.1 N isopropanol hydrochloric acid solution and evaporated to dryness. The hydrochloride was dissolved in 50 ml of a 9:1 methanol:acetic acid mixture and the solution was charged into a Parr apparatus. 0.80 g of activated Raney nickel was added and hydrogenated for 13 hours at 20 °C and 275.60 kPa. The reaction mixture was filtered and the filtrate was evaporated. The product was purified on C18 adsorbent with 0.001 N hydrochloric acid and 20% to 100%

33/81 is purified by reverse phase flash chromatography eluting with a gradient mixture of varying amounts of acetonitrile.

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

Melting point: 175 °C (decomposes) Yield: 37% Example 4

6-[({8-[({[(3-Methoxyphenyl)methyl]sulfonyl}amino)methyl]-5,6,7,8tetrahydronaphthalen-2-yl}oxy)methyl]naphthalene-2-carboximidamide hydrochloride (Compound No. 13)

4.1. 3-Methoxyphenylmethanesulfonyl chloride

A mixture of 10.0 g (49.7 mmol) of 3-methoxybenzyl bromide, 6.30 g (50.0 mmol) of sodium sulfite, 0.16 g (0.50 mmol) of tetra(n-butyl)ammonium bromide and 35 ml of water was heated at 95 °C for 2 hours. It was then stirred at room temperature overnight and then evaporated to dryness. 10.5 g of the remaining 16.5 g of material was suspended in 135 ml of dichloromethane and 20.1 g (96.5 mmol) of phosphorus pentachloride were added to the suspension in small portions at room temperature. The reaction mixture was stirred at this temperature for 1 hour and then evaporated to dryness. The residue was taken up in ethyl acetate and the solution was washed with water and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. 6.95 g of product is obtained as an oil. Yield: 98 %

4.2. N-({7-[(6-Cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)-3-methoxyphenylmethanesulfonamide

34/81

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

0.382 g of product is obtained as a white foam. Yield: 60 %

4.2. 6-[({8-[({[(3-Methoxyphenyl)methyl]sulfonyl}amino)methyl]5,6,7,8-tetrahydronphthalin-2-yl}oxy)methyl]naphthalene-2carboximidamide hydrochloride

A mixture of 0.382 g (0.73 mmol) of N-({7-[(6-cyanonaphthalen-2-yl)methoxy]1,2,3,4-tetrahydronaphthalen-1-yl}methyl)-3methoxyphenylmethanesulfonamide, 0.13 g (1.87 mol) of hydroxylamine hydrochloride and 0.28 ml (2.0 mmol) of triethylamine is refluxed for 6 hours. It is then evaporated to dryness and the remaining solid is triturated with 10 ml of water, filtered off with suction and dried in vacuo. The product is taken up in 10 ml of 0.1 N isopropanol hydrogen chloride solution and the solution is evaporated to dryness.

35/81 evaporated. The hydrochloride is dissolved in 20 ml of a 9:1 methanol:acetic acid mixture, poured into a Parr apparatus and hydrogenated for 5 hours at 20 °C in the presence of 0.25 g of activated Raney nickel under a pressure of 310.5 kPa. The reaction mixture is then filtered and the filtrate is evaporated to dryness. The product is purified by reverse phase flash chromatography, eluting with a gradient mixture of 30% to 50% acetonitrile and 0.01 N hydrochloric acid.

0.18 g of product is obtained as a white solid. Melting point: 250 °C (decomposes) Yield: 43% Example 5

7-{[6-(Aminoiminomethyl)naphthalen-2-yl]methoxy}-N-(phenylmethyl)1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (Compound No. 31)

5.1. 7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

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

3.04 g of product are obtained as an amorphous solid.

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Yield: 72 %

5.2. Methyl-(7-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylate)

To a solution of 3.03 g (14.71 mmol) of 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid in 50 ml of dichloromethane cooled to -70 °C was added dropwise 30 ml (30 mmol) of a 1 molar solution of boron tribromide in dichloromethane. The reaction mixture was then stirred for 1 hour at room temperature, then cooled to -78 °C and hydrolyzed with 5 ml of methanol. The mixture was evaporated to dryness and the residue was taken up in 50 ml of methanol. The solution was saturated with gaseous hydrogen chloride and then refluxed for 2 hours. It was then evaporated to dryness and the crude product was purified by flash chromatography on silica gel, eluting with a mixture of methanol and dichloromethane in a 2:98 volume ratio and then a 5:95 volume ratio. 2.10 g of product are obtained. Yield: 69 %

5.3. Methyl-{7-[(6-cyanonaphthalen-2-yl)methoxy]-1,2,3,4-

-tetrahydronaphthalene-l-carboxylate}

A mixture of 2.80 g (11.38 mmol) of 6-(bromomethyl)naphthalene-2-carbonitrile, 1.90 g (9.21 mmol) of [lacuna], 2.06 g (14.90 mmol) of potassium carbonate and 50 ml of acetonitrile was heated under reflux for 32 hours. It was then cooled to room temperature, filtered and the filtrate was evaporated to dryness. The residue was purified by flash chromatography on silica gel, eluting with a 1:9 mixture of ethyl acetate and toluene.

2.40 g of the expected product are obtained in the form of a colorless thick oil. Yield: 70 %

5.4. 7-[(6-Cyanonaphthalen-2-yl)methoxy]-1,2,3,4-

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-tetrahydronaphthalene-1-carboxylic acid

To a solution of 2.39 g (6.43 mmol) of methyl {7-[(6-cyanonaphthalen-2-yl)methoxy]1,2,3,4-tetrahydronaphthalene-1-carboxylate} in 25 ml of tetrahydrofuran and 8 ml of water, cooled to 0 °C, was added 3.88 g (92.47 mmol) of lithium hydroxide monohydrate, and the mixture was stirred at room temperature for 24 hours. The tetrahydrofuran was then evaporated under reduced pressure and the aqueous solution was washed with diethyl ether. The pH of the aqueous phase was adjusted to 2 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were dried over sodium sulfate, filtered, and evaporated to dryness. 1.20 g of the product was obtained as a colorless oil. Yield: 52 % 5.5. 7-[(6-Cyanonaphthalen-2-yl)methoxy]-N-(phenylmethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide To a solution of 0.50 g (1.40 mmol) of 7-[(6-cyanonaphthalen-2-yl)methoxy]-1,2,3,4tetrahydronaphthalene-1-carboxylic acid in 10 ml of dichloromethane and 2 ml of dimethylformamide at 5 °C, 0.16 ml (1.46 mmol) of benzylamine, 0.21 g (1.55 mmol) of 1-hydroxybenzotriazole, 0.50 ml (2.87 mmol) of N,N-diisopropyl-N-ethylamine and 0.30 g (1.56 mmol) of Ν'-(3-dimethylaminopropyl)-N-ethylcarbodiimide were added, and the mixture was stirred for 14 hours at room temperature. It is then evaporated to dryness and the residue is taken up in 200 ml of dichloromethane. The solution is washed successively with 1 molar aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The crude product

38/81 is purified by flash chromatography on two silica gels, eluting with a 5:95 mixture of methanol and dichloromethane. 0.44 g of the product is obtained as a white solid. Melting point: 181 °C Yield: 70 %

5.6. 7-{[6-(Aminomethyl)naphthalen-2-yl]methoxy}-N-(phenylmethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride A solution of 0.44 g (0.985 mmol) of 7-[(6-cyanonaphthalen-2-yl)methoxy]-N(phenylmethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide, 0.171 g (2.45 mmol) of hydroxylamine hydrochloride and 0.34 ml (2.45 mmol) of triethylamine in 15 ml of absolute ethanol is refluxed for 8 hours. It is then evaporated to dryness and the solid residue is triturated with 10 ml of water, filtered off with suction and dried in vacuo. The hydroxyamidine is dissolved in 10 ml of isopropanol-hydrochloride solution and the solution is evaporated to dryness. The hydrochloride is taken up in a mixture of 20 ml of methanol and 2 ml of acetic acid and the solution is hydrogenated in a Parr apparatus at 20 °C for 14 hours in the presence of 0.40 g of activated Raney nickel under a pressure of 310.5 kPa. It is then filtered and the filtrate is evaporated to dryness. The product is purified by reverse phase HPLC on C18 adsorbent, eluting with a gradient mixture of n/1000 hydrochloric acid and acetonitrile varying from 0 % to 100 % over 180 minutes. 0.194 g of product is obtained as a white solid. Melting point: 225 °C Yield: 40 %

Example 6

39/81

6-(Aminoiminomethyl)-α-({8-[({[(3-methoxyphenyl)methyl]sulfonyl}amino)methyl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)naphthalene-2-acetic acid (Compound No. 34) 6.1. 6-Bromonaphthalene-2-methanol

To a solution of 20.0 g (75.44 mmol) of methyl-(6-bromonaphthalene-2-carboxylate) in 325 ml of tetrahydrofuran and cooled to -20 °C, 76 ml (76.0 mmol) of a 1 molar solution of lithium aluminum hydride in tetrahydrofuran were added dropwise. The mixture was stirred for 30 min at -20 °C, then hydrolyzed by adding 3 ml of water, 3 ml of 15% sodium hydroxide solution and a further 10 ml of water. The reaction mixture was stirred at room temperature for 1 h and filtered after adding 75 g of magnesium sulfate. The filtrate was evaporated to dryness. 17.24 g of product was obtained as a white solid. Melting point: 154 °C Yield: 96 %

6.2. 2-Bromo-6-(bromomethyl)naphthalene

17.23 g (72.67 mmol) of 6-bromonaphthalene-2-methanol in a solution of 500 ml of dichloromethane is brominated at 0 °C with 2.8 ml (29.1 mmol) of phosphorus tribromide. The mixture is stirred at room temperature for 16 hours and then hydrolyzed by adding 10 ml of methanol. The solution is washed with water and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness.

19.7 g of product is obtained as a white solid. Melting point: 127 °C

Yield: 90 %

6.3. 6-Bromonaphthalene-2-acetonitrile

40/81

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

13.62 g of product is obtained as a pale yellow solid. Melting point: 115 °C Yield: 99 %

6.4. Ethyl-(6-bromonaphthalene-2-acetate)

To a solution of 13.60 g (55.26 mmol) of 6-bromonaphthalene-2-acetonitrile in 140 ml of ethanol at room temperature was added 80 ml of concentrated sulfuric acid and the mixture was refluxed for 2 hours. Then most of the ethanol was evaporated under reduced pressure and the residue was slowly poured onto 400 g of crushed ice. The mixture was extracted with ethyl acetate, the organic phase was dried over sodium sulfate and evaporated to dryness.

15.70 g of the expected product are obtained.

Yield: 97 %

6.5. Ethyl-(6-cyanonaphthalene-2-acetate)

To a degassed suspension of 8.26 g (28.19 mmol) of ethyl-(6-bromonaphthalene-2-acetate) and 2.0 g (17.03 mmol) of zinc cyanide in 20 ml of dimethylformamide was added 2.28 g (1.97 mmol) of tetrakis(triphenylphosphine)palladium(0) and the mixture was heated at 80 °C under nitrogen for 3 hours. It was then evaporated to dryness and the residue was taken up in 250 ml of ethyl acetate and filtered. The filtrate was washed three times with 100 ml of water and then with saturated

The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The residue is triturated with n-pentane, the white precipitate formed is filtered off with suction and dried in vacuo.

5.88 g of product are obtained.

Melting point: 65 °C Yield: 87 %

6.6 Ethyl-(α-bromo-6-cyanonaphthalene-2-acetate)

To a mixture of 7.50 g (31.35 mmol) of ethyl-(6-cyanonaphthalene-2-acetate), 8.37 g (47.0 mmol) of N-bromosuccinimide and 75 ml of carbon tetrachloride was added 0.36 g (2.19 mmol) of 2,2 ¹ -azobisisobutyronitrile and the mixture was refluxed for 20 hours. It was then cooled to 5 °C and filtered. The filtrate was evaporated to one third, then cooled again to 5 °C and filtered. The filtrate was evaporated to dryness and the crude product was purified by flash chromatography on silica gel, eluting with a 1:9 mixture of ethyl acetate and cyclohexane.

8.20 g of product is obtained as an oil. Yield: 82 %

6.7. Ethyl - ( 6-cyano-oc- { [ 8- ({ [ (1,1-dimethylethoxy)-

-carbonyl]amino]methyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}naphthalene-2-acetate)

A mixture of 1.30 g (4.09 mmol) of ethyl (Ot-bromo-6-cyanonaphthalene-2-acetate), 0.91 g (3.28 mmol) of 1,1-dimethylethyl-{[(7-hydroxy-1,2,3,4tetrahydronaphthalen-1-yl)methyl]carbamate], 1.10 g (7.96 mmol) of potassium carbonate and 20 ml of acetonitrile was heated under reflux for 2 hours. It was then evaporated to dryness and the residue

42/81 is purified by flash chromatography on silica gel, eluting with a 5:95 volume mixture of ethyl acetate and toluene.

1.06 g of product is obtained as a white foam. Melting point: 78-80 °C Yield: 63 %

6.8. Ethyl-(α-{[8-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-6-cyanonaphthalene-2-acetate) hydrochloride To a solution of 2.17 g (4.22 mmol) of ethyl-(6-cyano-α-{[8-({[(1,1dimethylethoxy)carbonyl]amino}methyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}naphthalene-2-acetate) in 40 ml of dichloromethane, 8 ml of 4N dioxane hydrogen chloride solution were added, and the mixture was stirred for 12 hours at 20 °C. Then, it was evaporated to dryness, and the solid residue was triturated with diethyl ether, filtered off with suction and dried in vacuo. 1.85 g of product was obtained. Yield: 97 %

6.9. Ethyl-[6-cyano-a-({8-[({[(3-methoxyphenyl)methyl]sulfonyl}amino)methyl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)naphthalene-2-acetate]

To a solution of 0.93 g (2.06 mmol) of ethyl (α-{[8-(aminomethyl)-5,6,7,8tetrahydronaphthalen-2-yl]oxy}-6-cyanonaphthalene-2-acetate] hydrochloride in 20 ml of dichloromethane were added 0.86 ml (6.17 mmol) of triethylamine and 0.68 g (3.33 mmol) of 3-methoxyphenylmethanesulfonyl chloride dissolved in 5 ml of dichloromethane, and the mixture was stirred for 72 hours at 20 °C. It was then diluted with 100 ml of dichloromethane and washed with 1 M aqueous citric acid solution and saturated aqueous sodium chloride solution. The organic phase was washed with sodium

43/81 is dried over sulfate, filtered and evaporated to dryness. The residue is purified by flash chromatography on silica gel, eluting with a 2:98 volume mixture of methanol and dichloromethane. The product is obtained as a grayish white foam. Yield: 79 %

6.10. Ethyl-6-(aminoiminomethyl)-α-({8-[({[(3-methoxyphenyl)methyl]sulfonyl}amino)methyl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)naphthalene-2-acetate] hydrochloride

Hydrogen sulfide gas was bubbled through a solution of 0.967 g (1.62 mmol) of ethyl-[6-cyano-α-({8-[({[(3methoxyphenyl)methyl]sulfonyl}amino)methyl]-5,6,7,8tetrahydronaphthalen-2-yl}oxy)naphthalene-2-acetate] in 10 ml of pyridine and 0.5 ml of triethylamine for 30 min. The round-bottomed flask was then stoppered and the solution was stirred at room temperature for 36 h and then evaporated to dryness. The residue was taken up in 100 ml of ethyl acetate, the solution was washed with 1 molar aqueous citric acid solution and then with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue is taken up in 10 ml of acetone, 0.5 ml (8.03 mmol) of methyl iodide is added and the mixture is refluxed for 5 hours. It is then evaporated to dryness and the residue is taken up in 10 ml of methanol and refluxed for 13 hours in the presence of 0.50 g (6.49 mmol) of ammonium acetate. The reaction mixture is then concentrated and the product is purified by reverse phase flash chromatography on C18 adsorbent, eluting with a 1:1 mixture of acetonitrile and 0.01 N hydrochloric acid. 0.30 g of product is obtained.

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Yield: 29 %

6.11. 6-(Aminoiminomethyl)-α-({8-[({[(3-methoxyphenyl)methyl]sulfonyl}amino)methyl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)naphthalene-2-acetic acid hydrochloride

A solution of 0.30 g (0.46 mmol) of ethyl-[6-(aminoiminomethyl)-α-({8-[({[(3methoxyphenyl)methyl]sulfonyl}amino)methyl]-5,6,7,8tetrahydronaphthalen-2-yl}oxy)naphthalene-2-acetate] hydrochloride in 10 ml of a 1:2 2N hydrochloric acid:tetrahydrofuran mixture was refluxed for 3 hours. It was then evaporated to dryness and the product was purified by reverse phase flash chromatography on C18 adsorbent, eluting with a 2:3 mixture of acetonitrile and 0.01N hydrochloric acid. 0.20 g of product was obtained as a white solid. Melting point: 180 °C Yield: 70 % Example 7

3-[({[(7-{[(6-Aminoiminomethyl)naphthalen-2-yl]methoxy)-1,2,3,4tetrahydronaphthalen-1-yl)methyl]amino)sulfonyl)methyl]benzoic acid hydrochloride (Compound No. 23)

7.1. Methyl 1-[3-({[({7-[(6-cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)amino]sulfonyl)methyl)benzoate] To a solution of 0.38 g (1.00 mmol) 6-({[8-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}methyl)naphthalene-2-carbonitrile hydrochloride and 0.42 ml (3.01 mmol) triethylamine in 10 ml dichloromethane and cooled to 5 °C, 0.350 g (1.41 mmol) methyl {3-[(chlorosulfonyl)methyl]benzoate} in 5 ml

45/81 in dichloromethane. The reaction mixture is stirred at room temperature for 72 hours and then diluted with 100 ml of dichloromethane. The solution is washed successively with 1N aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and finally saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The product is purified by flash chromatography on silica gel, eluting with a 2:98 (v/v) mixture of methanol and dichloromethane. 0.479 g of product is obtained as a white foam. Yield: 86 %

7.2. 3-({[({7-[(6-Cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]sulfonyl}methyl)benzoic acid

A solution of 0.47 g (0.85 mmol) of methyl-[3-({[({7-[(6-cyanonaphthalen-2yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl)methyl)amino]sulfonyl}methyl)benzoate] and 0.07 g (1.67 mmol) of lithium hydroxide monohydrate in 10 ml of a 1:1 tetrahydrofuran:water mixture was stirred at room temperature for 3 hours. The tetrahydrofuran was then evaporated under reduced pressure and the aqueous solution was acidified to pH 1 with 1N hydrochloric acid. The product was extracted with ethyl acetate and the organic phases were dried over sodium sulfate, filtered and evaporated to dryness.

The product is obtained as a white foam. Yield: 100 %

7.3. 3-[({[(7-{[6-(Aminoiminomethyl)cyanonaphthalen-2-yl]methoxy}-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}sulfonyl)-

46/81 methyl]benzoic acid

A mixture of 0.47 g (0.85 mmol) of 3-({[({7-[(6-cyanonaphthalen-2-yl)methoxy]1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]sulfonyl}methyl)benzoic acid, 0.15 g (2.16 mmol) of hydroxylamine hydrochloride, 0.56 ml (4.02 mmol) of triethylamine and 10 ml of absolute ethanol is refluxed for 4 hours. It is then evaporated to dryness, the residue is taken up in 20 ml of 0.1 N isopropanol hydrogen chloride solution and the solution is evaporated to dryness. The hydrochloride is hydrogenated for 14 hours at 275.60 kPa in 20 ml of a 9:1 methanol:acetic acid mixture in the presence of 0.30 g of Raney nickel, then filtered and the filtrate is evaporated to dryness. The product is purified by reverse-phase HPLC on C18 adsorbent, eluting with a gradient mixture of acetonitrile and n/1000 hydrochloric acid from 0% to 100% over 180 minutes.

0.167 g of product is obtained as a white solid. Melting point: 165 °C (decomposes) Yield: 32 %

Example 8

6-[({8-[(Imino{[(3-methoxyphenyl)methyl]amino}methyl)amino]-5,6,7,8 tetrahydronaphthalen-2-yl}oxy)methyl]naphthalene-2-carboximidamide hydrochloride (Compound No. 14)

8.1. 2.3 ml (30.17 mmol) of thiophosgene are added dropwise to a mixture of 2.74 g (20.0 mmol) of 3-methoxybenzylamine dissolved in 1 ml of dichloromethane and 6.0 g (60.0 mmol) of calcium carbonate dissolved in 20 ml of water over a period of 60 minutes. After 2 hours, the phases are separated.

47/81 to separate, the organic phase is separated, washed with water, dried over sodium sulfate, filtered, and the filtrate is evaporated to dryness.

3.29 g of product is obtained as an oil. Yield: 92 %

8.2. N-[7-(6-Cyanonaphthalen-2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl]-N'-[(3-methoxyphenyl)methyl]thiourea To a solution of 0.62 g (1.70 mmol) of 6-{[(8-amino-5,6,7,8-tetrahydronaphthalen2-yl)oxy]methylnaphthalene-2-carbonitrile hydrochloride and 0.50 ml (3.59 mmol) of triethylamine in 27 ml of toluene, 0.40 g (2.23 mmol) of 1-(isothiocyanato)-3-methoxybenzene is added and the mixture is refluxed for 30 minutes. The mixture is then allowed to cool to room temperature and washed with 1 N hydrochloric acid. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The product is purified by flash chromatography on silica gel, eluting with a 2:98 volume mixture of methanol and dichloromethane.

0.654 g of product is obtained as an off-white foam.

Yield: 71 %

8.3. 6-[({8-[(Imino{[(3-methoxyphenyl)methyl]aminojmethyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)methyl]naphthalene-2-carboximidamide dihydrochloride

Hydrogen sulfide gas was bubbled through a solution of 0.654 g (1.29 mmol) of N-[7-(6-cyanonaphthalen-2-yl)methoxy]1,2,3,4-tetrahydronaphthalen-1-yl]-N ¹ -[(3-methoxyphenyl)methyl]thiourea in 10 ml of pyridine and 1 ml of triethylamine at 20 °C for 30 min. The round-bottomed flask was stoppered and the reaction mixture was stirred at this temperature for 24 h.

48/81 at the temperature. It is then evaporated to dryness and the residue is taken up in 100 ml of ethyl acetate. The solution is washed with 1 molar 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 thioamide is taken up in 50 ml of acetone and, after adding 10 ml (160.63 mmol) of methyl iodide, it is refluxed for 4 hours. The reaction mixture is evaporated to dryness, at which point 0.871 g of a yellow powder remains. The product is taken up in 50 ml of methanol, 3.0 g (38.92 mmol) of ammonium acetate are added to the solution and the mixture is refluxed for 3 hours. It is then evaporated to dryness and the product is purified by reverse phase flash chromatography on C18 adsorbent, eluting with a 2:3 volume mixture of acetonitrile and 0.01 N hydrochloric acid. 0.10 g of product is obtained. Melting point: 220 °C Yield: 14 % Example 9

6-({[8-({[(Phenylmethyl)sulfonyl]amino}methyl)bicyclo[4.2.0]octa1,3,5-trien-3-yl]oxy}methyl)naphthalene-2-carboximidamide hydrochloride (Compound No. 24)

9.1. 3-(3-Bromo-4-methoxyphenyl)propanenitrile

Under the conditions described in Tetrahedron 3 0 , 1053 (1974), 2.16 g (13.3 mmol) of 3-(4-methoxyphenyl)propanenitrile in 13 ml of acetic acid in the presence of 2.19 g (26.6 mmol) of anhydrous sodium acetate were brominated with 0.687 ml (13.3 mmol) of bromine at room temperature. The mixture was stirred for 2 hours, then poured into 150 ml of water and extracted several times with diethyl ether. The organic phases were

49/81 are combined, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated to dryness.

3.085 g of product is obtained as an oil. Yield: 97 %

9.2. 4-Methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile

To a mixture of 14.5 g (63.00 mmol) of sodium and liquid ammonia cooled to -78 °C, 50 mg of iron (III) chloride and then 8.71 g (36.3 mmol) of 3-(3-bromo-4-methoxyphenyl)propanenitrile were added, and the mixture was stirred for 3 hours at -78 °C. The ammonia was then evaporated, sodium chloride was added to the residue, and then a saturated aqueous ammonium chloride solution was slowly added. The mixture was extracted with chloroform, the organic phases were dried over sodium sulfate, filtered, and evaporated to dryness. The product was purified by distillation under reduced pressure. 2.69 g of the product was obtained as an oil. Yield: 47 % 9.3. 4-Methoxybicyclo[4.2.0]octa-1,3,5-triene-7-methanamine

To a suspension of 0.45 g (11.84 mmol) of lithium aluminum hydride in 15 ml of diethyl ether was added a solution of 1.50 g (9.32 mmol) of 4methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile in 5 ml of diethyl ether. The mixture was stirred at room temperature for 1 hour and then hydrolyzed by adding 1 ml of water, 1 ml of 1N sodium hydroxide solution and a further 5 ml of water. After the phases had separated, the organic phase was separated and the aqueous phase was extracted again with diethyl ether. The combined organic phase was

The solids are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness.

1.38 g of product is obtained as an oil. Yield: 91 %

9.4. 1,1-Dimethylethyl-{[(4-hydroxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]carbamate}

To a solution of 1.52 g (9.3 mmol) of 4-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-methanamine in 30 ml of dichloromethane cooled to -78 °C was added dropwise 37.3 ml (37.3 mmol) of 1 molar boron tribromide solution in dichloromethane. After the addition was complete, the mixture was stirred at -10 °C for 1 hour, then cooled again to -78 °C and hydrolyzed with 20 ml of methanol. The mixture was allowed to warm to room temperature, then diluted with 50 ml of methanol and evaporated to dryness. Benzene was evaporated from the residue three times. The crude product is taken up in 50 ml of tetrahydrofuran, and 3.89 ml (27.91 mmol) of triethylamine and 2.0 g (9.16 mmol) of di(tert-butyl)dicarbonate are added to the solution. The reaction mixture is stirred at room temperature for 14 hours and then evaporated to dryness. The residue is taken up in ethyl acetate, the solution is washed with 0.1 N cold hydrochloric acid and saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered and evaporated to dryness. The product is purified by flash chromatography on silica gel, eluting with a 1:9 mixture of ethyl acetate and cyclohexane.

1.21 g of product is obtained. Yield: 52 %

9.5. 1,1-Dimethylethyl-[({4-[(6-cyanonaphthalen-2-yl)methoxy]bicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl)carbamate]

51/81

A mixture of 0.518 g (2.08 mmol) of 1,1-dimethylethyl-{[(4-hydroxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]carbamate}, 0.614 g (2.50 mmol) of 6-(bromomethyl)naphthalene-2-carbonitrile, 0.465 g (3.37 mmol) of potassium carbonate and 25 ml of acetonitrile is heated at 80 °C for 3 hours. It is then evaporated to dryness and the residue is taken up in ethyl acetate. The solution is washed with 0.1 N cold hydrochloric acid and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The product is purified by flash chromatography on silica gel, eluting with a 1:4 mixture of ethyl acetate and cyclohexane. 0.412 g of product is obtained. Yield: 48 % 9.6. 6-({[8-(Aminomethyl)bicyclo[4.2.0]octa-1,3,5-trien-3-yl]oxy}methyl)naphthalene-2-carbonitrile hydrochloride

To a solution of 0.412 g (0.995 mmol) of 1,1-dimethylethyl-[({4-[(6-cyanonaphthalen-2-yl)methoxy]bicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl)carbamate in 20 ml of dioxane and cooled to 0 °C, 1 ml of 4N hydrogen chloride solution in dioxane was added and the mixture was stirred at 0 °C for 10 hours. The precipitate was filtered off with suction, rinsed with dioxane and dried in vacuo. 0.244 g of product was obtained. Melting point: 170 °C Yield: 70 % 9.7. N-({4-[(6-Cyanonaphthalen-2-yl)methoxy]bicyclo[4.2.0]octa-

-1,3,5-trien-7-ylmethyl)phenylmethanesulfonamide

52/81

To a solution of 0.244 g (0.696 mmol) of 6-({[8-(aminomethyl)bicyclo[4.2.0]octa1,3,5-trien-3-yl]oxy}methyl)naphthalene-2-carbonitrile hydrochloride and 0.211 g (2.09 mmol) of triethylamine in 6 ml of dichloromethane and cooled to 5 °C was added 0.135 g (0.71 mmol) of α-toluenesulfonyl chloride. The solution was then stirred for 15 hours at 20 °C, then evaporated to dryness, and the residue was taken up in 100 ml of ethyl acetate. The solution was washed with 1 N hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The product was purified by flash chromatography on silica gel using a 3:7 mixture of ethyl acetate and n-hexane, then eluting with ethyl acetate. 0.20 g of product was obtained. Yield: 61 %

9.8. 6-({[8-({[(Phenylmethyl)sulfonyl]amino}methyl)bicyclo[4.2.0]octa-1,3,5-trien-3-yl]oxy}methyl)naphthalene-2-carboximidamide hydrochloride A solution of 0.20 g (0.42 mmol) of N-({4-[(6-cyanonaphthalen-2yl)methoxy]bicyclo[4.2.0]octa-1,3,5-trien-7yl}methyl)phenylmethanesulfonamide in 8 ml of a 1:9 (v/v) mixture of triethylamine:pyridine was bubbled with hydrogen sulfide gas for 5 min. The container was then stoppered and the solution was stirred at 20 °C for 48 h. Then it is evaporated to dryness, the residue is dissolved in 5 ml of acetone and refluxed for 1 hour in the presence of 0.656 g (4.62 mmol) of methyl iodide. The reaction mixture is evaporated to dryness and the crude thioamide is dissolved in 5 ml of methanol and refluxed for 2 hours in the presence of 0.065 g (0.84 mmol) of anhydrous ammonium acetate.

53/81. The reaction mixture is then evaporated to dryness, the residue is taken up in 0.1 N isopropanol-hydrogen chloride solution and then evaporated to dryness. The product is purified by reverse-phase HPLC on C18 adsorbent, eluting with a gradient mixture of n/1000 hydrochloric acid and acetonitrile varying from 0 % to 100 % over 180 minutes.

0.86 g of product is obtained as a white solid. Melting point: 125 °C Yield: 39% Example 10

Methyl-[3-({[({7-[(6-{[(ethoxycarbonyl)amino]aminoiminomethyl}naphthalen-2-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl]amino)carbonyl]amino]methyl)benzoate] (Compound No. 57) To a suspension of 0.18 g (0.335 mmol) of methyl-{3-[({[(7-{[6-(aminoiminomethyl)naphthalen-2-yl]methoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)amino]carbonyl)amino)methyl]benzoate) prepared in 15 ml of tetrahydrofuran and cooled to 0 °C, 0.064 ml (0.37 mmol) of N,N-diisopropylethylamine and then 0.034 ml (0.35 mmol) of ethyl chloroformate were added. The mixture was stirred at room temperature for 1 hour and then diluted with 50 ml of ethyl acetate. The solution was washed with 0.1 N hydrochloric acid, then with saturated aqueous sodium bicarbonate solution and finally with 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 5:95 (v/v) mixture of methanol and dichloromethane.

0.130 g of product is obtained as a white solid.

54/81

Melting point: 118 °C (decomposes) yield: 64% Example 11

Methyl (3-{[({[7-({6-[amino(hydroxyimino)methyl]naphthalen-2yl}methoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl)amino)sulfonyl]methyl]benzoate) hydrochloride (Compound No. 84) A solution of 0.50 g (0.90 mmol) methyl-[3-({[({7-[(6-cyanonaphthalen-2yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]sulfonyl}methyl)benzoate] (see Example 7.1), 0.154 g (2.22 mmol) hydroxylamine hydrochloride and 0.31 ml (2.22 mmol) triethylamine in 10 ml methanol was refluxed overnight. It was then evaporated to dryness and the residue was taken up in water. The solid is filtered off with suction, rinsed with water and dried under vacuum at 40 °C. The crude product is purified by flash chromatography on silica gel, eluting with a 5:95 mixture of methanol and dichloromethane, and the resulting product is converted into the hydrochloride with 2N hydrogen chloride in diethyl ether. 0.23 g of the product is obtained as a white solid. Melting point: 155 °C. Yield: 41 %

55/81

mp (°C) (HC1) * co 1 lD 134* ' 125-130 tC X 1 1 X L> 1 1 X ω 1 X 1 I o 1 1 r o 1 1 χ ⁴ u 1 o X z 1 i X z 1 1 O ⁴ CO 1 CQ 1 o Q 1 O V 1 X z 1 X z 1 t X z 1 1 χ ⁴ u 1 oof X X X C£ X X X X X X £' This is \—C the? X X X o Z rH CX] cn

Table

56/81

m.p. (°C) (HG1) co CXI + I 1 157 152-157* 125 176 X O 1 X CJ 1 1 X o 1 1 X u 1 1 X CJ 1 1 X u 1 X CM □r ω 1 χ ⁴ 1 χ ⁴ 1 CM X o 1 1 □*? o 1 1 CM χ ¹ u 1 o 1 o co 1 1 X z 1 1 X z 1 1 X z 1 1 O U 1 1 6 ⁴ ω 1 ffl 1 X z 1 1 o u 1 1 o o 1 1 o u 1 1 X z 1 1 X z 1 < 1 1 X z 1 1 X z 1 1 X T 1 X 1 1 CM X O 1 af* X X X X X X £ I X X X X X £ X X X X X X CM x i 8 \ i—z \\ o ' ^v ^c5 \_^ X ¹ o CM X CJ 1 £ X X to X X X 0 z un <0 r- co σ>

57/81

m. p. (°C ) (HC1) 105 120 O 1 LT) 250 220 CO 1 X u ΰ 1 9 1 X o 1 X o X 1 n? Q 1 1 U 1 3? U 1 3? Q 1 1 CXI X Q 1 o 1 CXJ o co 1 1 CXI o ω 1 X z 1 1 (X) O ω 1 X 2 1 CQ 1 r 1 X z 1 1 o D 1 1 X z 1 1. o=z I 1 1 X z X o 1 CXI X y 1 X Z 1 ir> X X X X X X X X X X X X X X X X X What? X o o /~c5 o /~c5 X X X X X X 0 Z o CXJ m sr

58/81

mp (°C) (HC1) 110 110 120 162 145 135 1 X o 1 1 X o 1 1 X o 1 1 X u 1 X (J 1 1 X o 1 X 1 (N OJ X O 1 1 (N X CJ 1 (N X 1 -(CH ₂ ) ₂ - -C(CH ₃ ) ₂ -CH ₂ - -(CH ₂ ) ₂ - o 1 o ¹ 10 1 1 o' to 1 1 O U * 1 X z 1 1 page 1 1 O ¹ to 1 co X Z ! X z 1 X z 1 1 O U t X z 1 1 X z 1 1 1 1 1 X z 1 1 1 X (J 1 address* X X X X X X CiT X X X X X X (Σ' X X X X X X X \— sT o o u X o cn X O 1 OJ X o 1 xT X X X X X X the m f—· co σ\ CM

59/81

mp (°C) (HC1) 125-130 208 165 125 209-212 > 260 04 1 X o 1 X u 1 1 X u 1 1 X O 1 1 X <J 1 X O 1 X 1 X^ u 1 1 X* o 1 χ ⁴ u 1 1 (XJ χ ¹ o 1 1 CXJ X* CJ 1 o 1 o u 1 1 X z 1 O ω 1 1 o ¹ ω 1 1 o o 1 1 X z 1 ffl 1 X z 1 Oh (J 1 1 X z 1 1 X z 1 1 X z 1 1 o o 1 x u 1 1 X z 1 1 X u 1 xυ 1 1 1 X z 1 the? X X X X X X oT X X X X X X £‘ X X X X X X ÍXJ x t (J O o \— the: X X X ' X X X 0 z CM CXJ CXI CXJ CXI m CXJ XO CXJ

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m. p. ( °C ) (HC1) lD «Τ f~1 184 * co 180 225 135 CO N 1 X o 1 1 X u 1 1 X D 1 1 X ω 1 X CJ 1 X o 1 1 X Ϋ X 1 X o 1 1 X ¹ u 1 1 CM £ o 1 ’(Yl a? u 1 1 CN u 1 1 n? o 1 a? u 1 u 1 o cn 1 ό o 1 1 CM o CO 1 1 O cn 1 1 X z 1 1 CM o co 1 C? CO I CQ 1 X x 1 1 X z 1 1 X z 1 1 X x 1 1 O D 1 1 X X 1 X X 1 1 cm X O 1 1 1 1 1 1 X o 1 1 <N X (J 1 X X X X X X X «3* CÚ X X X X X X X cr? X X X X X X X ¹ \ /— Z \\ zT d? Ό CM X o 1 x° O 1 Sn ω & X X X X X' X X X 0 X OJ X CM σι CM o co Art.

61/81

m.p. (°C) (HG1) 180 252 CM CD 1 CO 160 (Dec) 112 116 > 250. (Dec) + co eq 1 X u 1 1 X o X u 1 1 X CJ 1 X o 1 X o 1 1 X o 1 X u X 1 (XI exj X CJ 1 1 OJ x? o 1 d 1 CJ 1 1 1 X^ (J 1 -NH-CO- CXI CXI X O 1 u 1 CXI O U) 1 1 X 2 1 1 O CQ 1 1 o ¹ ω 1 1 X z 1 1 X z 1 ω 1 1 <\) O CO 1 Q I X Z 1 1 O U l 1 X z 1 1 X z 1 1 o υ 1 1 o u 1 X z 1 1 X z 1 1 X* o 1 1 X Z xυ 1 1 I CJ 1 1 X z 1 X z o 1 CXJ X o 1 in X X X X X X X X X cz X o' o X X X X X X X of I X I X X X X X CXI X x 8 o CQ o b CXI X ω x* o 1 □ CŰ c -ch ₂ ch ₂ cf ₃ X* 2 oT X X X ' X X X X X No. m tn m ω m cn X m σ\ CD o

62/81

m. p . ( °C) (HG1) 180 (Dec) 170* 205* (dec) 205 260 (Dec) 172 c< 1 X o 1 -CH- 1 X o 1 -CH- 1 X o 1 1 X U 1 X 1 x? o 1 χ ⁴ o -(CH ₂ ) ₂ I 0 II -N(—C-CH ₃ )-CH,- CXI χ ⁴ O 1 CXJ CN X L) 1 o -HN- 1 cT CO 1 -HN... -NH- -so ₂ - -HN- CQ 1 O o -HN- -CO- 1 O U 1 -NH- 1 O ω 1 rt -NH- 1 X o 1 -NH- -NH- -ch ₂ - -HN- U) QÍ X X X X X X oT X X X X X X (Σ X X X X X X CM Qi x Q I* ~ :Γ0Η QT /-Ηθ (Σ X X X X X X 0 X tXJ 43 XT lD 46

63/81

m. p . ( °C) (HG1) o CM 163 168-130 co 212 (Dec) 189 (Dec) 'T 03 -CH- -CH- -CH- -CH- -CH- -CH- 1 X ω 1 X -(CH ₂ ) ₂ - 1 x ¹ o 1 X ⁴ ω Ί -(CH ₂ ) ₂ - | -(ch ₂ ) ₂ - 1 (XI X CJ 1 χ ⁴ ω 1 O -NH- -NH- -NH- -NH- -NH- 1 X z 1 -NH- CQ -C(NH)- -CO- 1g 1 o u 1 1 o o 1 1 o o 1 1 Ο Q 1 -NH- CM X ω 1 -NH- -HN- -NH- -NH- -HN- 04 X X X X X X X X X X X X X X (X X X X X X X 0? /~€3 5 X < ⁸ o □4 X X X ' X X X X 0 z co CTi o lT) U) 52 LT) lT)

64/81

mp (°C) (HC1) 148 (Dec) 158 118 (base ) 129-132 CO 14 2 173 N -CH- -CH- -CH- ¹ -CH- 1 -CH- -CH- -CH- X -(CH ₂ ) ₂ - 1 X ⁴ o 1 CM χ ⁴ υ 1* -(CH ₂ ) ₂ - χ ¹ o χ ⁴ o 1 CM X U 1 Q -NH- -HN- -NH- 1 CM o CO -NH- -HN- -NH- GO 1 O o 1 1 O U 1 1 O u 1 -NH- -CO- 1 O o 1 1 o L) 1 -NH- -HN- 1 X z 1 1 CM X o 1 -NH- -NH- -NH- X X X X X X X X CC X X X X X X X cc? X X X X X X X the? 0. δ ω oh water u d ^J o X \^-p the; X X EtOCO ' X X X X 0 z 55 -----------------------------------------------------------------------------------------------------i 56 57 X lO o kO kD 62

65/81

m. p. (°C ) (HC1) 174 (Dec) 200 (Dec) 1__________ 179 ___(Dec) 156-158 (Dec) 170 170 175 CO 1 X u 1 1 X Q 1 X o 1 Xω 1 1 X ο I 1 X or 1 1 X or 1 X 1 CM rr? U 1 -(CH ₂ ) ₂ - 2? 1 ’ x? o 1 -(CH ₂ ) ₂ - ΓΜ x ⁴ 1 I CM χ ⁴ ω 1 o 1 X z 1 1 X z 1 1 X z 1 1 Ο ω I 1 X ζ 1 1 X ζ 1 ι X ζ 1 CQ 1 C 1 Oh oh 1 Oh oh X ζ 1 ό ω 1 1 or 1 1 or 1 1 X z 1 1 X z 1 X z 1 X υ 1 1 X ζ ▼ 1 X ζ 1 X ζ x X X X X CM ο ο 1 X X X CC X X X X X X X Regards X X X X X X X CM CÚ Lu c5 ^5 1 Λ ^ch j HjC CH, X X X ' X X X X the 2 and and G CD CD Ch UP

66/81

. m. p . (°C) (HG1) 172 168 149 (Dec) 180 (Dec.) 190 (Dec) 170 (Dec) 173 (Dec) N 1 X (J 1 1 X 1 1 X 1 X o 1 Xω 1 X o 1 X o 1 X 1 £o 1 1 £ u 1 3? U f 1 X ω 1 X Z 1 CM X υ 1 CXI X Q 1 1 Cxi X U 1 o 1 X z 1 1 X z 1 1 X z 1 1 X z 1 1 X z 1 1 X z 1 1 X z 1 CQ 1 o u 1 o γ 1 o o 1 o o 1 O o 1 o 1 1 o ω 1 1 X z 1 1 X z 1 1 X z 1 1 X z 1 1 X z 1 1 X Z ▼ 1 X z 1 the: X X X X X X X K X X X X X X X the X X X X X X X CN X X X is δ χ-^5— 8 VhHhÍ £ X X X - x X X X 0 Z o r-i CXJ ΓΏ LT) X0

67/81

m. p. ( °C ) (HC1) 175 (Dec) 172 (Dec) 200 τ 158 205 (Dec) co 1 X (j 1 1 X o 1 1 X υ 1 1 X υ 1 1 X or I 1 X υ 1 1 X Ο 1 X 1 CM CXJ X U 1 1 CXJ CXI X U 1 1 CXJ χ ⁴ u 1 ' 1 x ⁴ υ 1 1 CM CXJ X υ 1 CX) X υ 'cm χ ⁴ υ 1 u 1 X z 1 I X z I 1 X Z 1 X ζ X 2 1 X ζ 1 1 X Ζ 1 CQ 1 o υ 1 1 o u 1 1 o υ 1 I Ο υ 1 1 of υ 1 of υ 1 or 1 1 1 X z ▼ 1 X z 1 X z 1 ζ ▼ i Ζ 1 X ζ 1 X Z 1 iT, X X X X X X X X cc* X X X X X X X the? X X X X X X X <XI X \_£p P.S. 'Hello . 1—X \\ 8 X 8 ζ=> Ε-^-ϊ Λ X X X ’ X X X X 0 z £ co ex ο co X CM X co

68/81

mp (°C) (HC1) (Lf) 180 234* tO 1 X U 1 -CH- -CH- X o 1 -(CH ₂ ) ₂ - 1 ω 2 1 X u 1 O 1 (N o CO 1 1 O co 1 X z 1 CQ -NH- -NH- 1 o CJ 1 1 X ¹ u 1 1 X u 1 -NH- of X X X οΓ X X X X X X X a CC x o X o c5 üF -OH -OH X 0 X CD LT) CD kO co

Λ ο Ό •Η h Ο ο Μ 75 -Η η Η 75

4->

Ο a ο ω υ •Η 4J

Φ •Η

Φ g •Η 75 ι

4->

CQ

4.J

W

69/81

The compounds of the invention were subjected to pharmacological tests which showed that the compounds have therapeutic effects.

The compounds of the invention are particularly characterized by their inhibitory effect on the coagulation factor VII/VIIa.

The principle of the Vila Ki test

The purpose of this assay is to measure the amidolytic effect of the factor VIIa/tissue factor complex on a chromogenic substrate in the presence of various concentrations of the compound being tested for inhibitory activity. A compound is a competitive inhibitor if it increases the Km value of factor VIIa for its substrate, i.e., decreases the affinity of factor VIIa for its substrate.

This amidolytic activity of factor VIIa was tested at one concentration and measured kinetically (by calculating the rate) by determining the time course of cleavage of the substrate (tested at two concentrations) using a microplate reader that determines the release of para-nitroaniline based on the absorbance measured at 405 nm. The compound was tested at 7 concentrations.

Ki was determined using Dixon's method, where 1/rate was plotted as a function of compound concentration and for each substrate concentration (S1 and S2).

By projecting the intercept of the linear regression straight lines onto the x-axis, we obtain the inhibitory concentration corresponding to Ki.

70/81

Biological reagents

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

- Tissue factor corresponds to human recombinant (produced in E. coli) and the extracellular soluble part (amino acids 1-219). VIIaF/tissue factor complexes were pre-prepared by incubating factor VIIa and tissue factor at a molar concentration of 1:5 in the presence of 5 mM calcium chloride and using a final concentration of 3.75 nM VIIaF in the presence of 18.75 nM TF.

- TBSA buffer: Tris 50 mM, pH 7.5, sodium chloride 100 mM, BSA (bovine serum albumin) 0.1 %

- The VIIaF/TF complex was used at a concentration of 3.75 nM/18.75 nM in TBSA buffer in the presence of 5 mM calcium chloride

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

- The compounds were tested in a solution with a concentration of 1 mM

Description of the experiment

The reagents were placed in the following order (without incubation; final concentrations)

Compound Substrate VIIaF/TF complex 7 concentrations (+ control) S1 = 0.66 mM S2 = 2.64 mM 3.5nM/18.5nM 25 μΐ 50 μΐ 25 μΐ (volume/cavity)

The Ki values of the compounds of the invention are preferably less than 1 μΜ.

71/81

The antithrombotic activity of the compounds of the invention was also examined. The antithrombotic activity was determined in an arteriovenous shunt model.

Principle of the test

TF-dependent thrombus formation was induced in rats or guinea pigs by inserting an arteriovenous shunt containing a cotton thread impregnated with thromboplastin (Tissue Factor: TF).

Requirement

Rats (Sprague Dawley) or guinea pigs (Hartley), with an average body weight of 300-350 g, were anesthetized with 60 mg/kg sodium pentobarbital administered intraperitoneally. The femoral vein of the rat or the right jugular vein of the guinea pig were cannulated for intravenous injections, while the left jugular vein and the right carotid artery were cannulated using a catheter filled with physiological saline (0.9%) to form a shunt. Five minutes after intravenous administration of several doses of the compound (treated group) or its solvent (control group), the shunt was assembled by connecting the two catheters with a flexible plastic tube with an inner diameter of 3 mm and a length of 6 cm, containing a cotton thread impregnated with thromboplastin. Circulation was restored for 5 minutes in rats and 10 minutes in guinea pigs. The shunt was then removed and the cotton thread to which the thrombus was attached was collected and weighed immediately.

Expression of results

72/81

The mean thrombus weights in the different groups were determined. The % reduction in thrombus weight in each treated group compared to the control group was calculated to determine the AD ₅₀ value of the compound, which is the dose of the compound that inhibits thrombus formation by 50% compared to control animals.

The compounds of the invention preferably have an AD ₅₀ value of less than 10 mg/kg.

The results of these biological assays indicate that the compounds of the invention possess factor VII/Vila inhibitory properties.

Therefore, the compounds can be used for the treatment and prevention of various forms of pathologies involving factor VII/VIIa and the coagulation cascade. Thus, they can be used for the treatment of venous, arterial or coronary thrombosis, disseminated intravascular coagulation, restenosis following angioplasty, aggravated reocclusion following thrombosis, atrial fibrillation, pulmonary embolism, edema, septic shock, prevention of oncological hypercoagulability, post-cardiac bypass treatment, treatment of inflammation, pulmonary fibrosis or prevention of unstable angina.

For this purpose, these compounds can be administered in any form suitable for oral, parenteral or intravenous administration, such as tablets, hard gelatin capsules, sugar-coated tablets, soft gelatin capsules, suspensions, oral solutions or injectable solutions, in combination with suitable excipients and

73/81 : ··:·····.:..

They can be used in doses that allow the administration of 0.1 mg -1 g of active ingredient per day in one or more doses.

The compounds can also be formulated for transdermal and ocular administration.

Claims (5)

74/81 Patent claims: 1. Compounds of general formula (I) - in the formula R1 represents a hydrogen atom, or an amino group, or an alkyl group having 1-4 carbon atoms, or a (1-6 carbon atoms) alkoxy)carbonyl group, or a hydroxyl group, the group of general formula R1-NH-C(=NH)- may also exist in the _H2NC (=NRi)tautomeric form; R ₂ meaning a C1-6 alkyl group which may be substituted with 1-3 fluorine atoms, or a cyclohexylmethyl group, or a 2,3-dihydro-1,4-benzodiox-7-ylmethyl group, or a 1,3-benzodioxolan-6-ylmethyl group, or a phenyl, benzyl or phenylethyl group, which may be substituted on the phenyl group by 1-3 groups independently selected from the group -N(CH ₃ ) ₂ group, the trifluoromethoxy group, the methylthio group, the C1-4 alkoxy group, the trifluoromethyl group, the amino group, the nitro group, the C1-4 alkyl group, the trifluoromethoxy group, the halogen atom, the -SO ₂ CH ₃ group, the hydroxyl group and the group of the general formula -COOR ₈ and -OCH ₂ CO ₂ R ₈ , where R ₈ is a hydrogen atom or a C1-4 alkyl group, or -CH ₂ Q general formula a group of the formula, where Q is a heterocyclic group, which is the group -N(CH ₃ ) ₂ , the 75/81 may be substituted by a group selected from the group consisting of trifluoromethoxy, C1-4 alkoxy, trifluoromethyl, amino, nitro, C1-4 alkyl, trifluoromethoxy, halogen, -SO2CH3, hydroxyl and -COOR ₈ and -OCH ₂ CO ₂ R8, where Rg is hydrogen or C1-4 alkyl, Ra and R ₅ are independently hydrogen or fluorine, or C1-4 alkyl, or carboxyl, or hydroxyl, or -N(CH ₃ ) ₂ , or -Y-CH ₂ COOH, where Y is oxygen or nitrogen, R ₄ is hydrogen or C1-4 alkyl, or -(CH ₂ ) _P -COOR ₈ , where p is 0, 1 or 2, and R ₈ represents a hydrogen atom or a C 1-4 alkyl group, X represents -(CH ₂ ) _m - a group of general formula, where m is 0, 1 or 2, or -CRgR7-CH ₂ - or -CLh-CRgR? ^- a group of general formula, where R ₆ and R ₇ independently represent a hydrogen atom or an alkyl group having 1-4 carbon atoms, or a -NH-CO- or -CO-NH- group, 76/81 or -NH-CH ₂ - or -CH ₂ -NH-, -N (CH ₃ ) -CH ₂ -, -CH ₂ -N (CH ₃ ) -, -N (CH ₂ CH ₃ ) -CH ₂ - or -CH ₂ -N(CH ₂ CH ₃ ) - group, or -N[-C(=W)-CH ₃ ]-CH ₂ - group, where W represents an oxygen atom or a -NH- group, Z represents -CH- group or nitrogen atom, and -A-B-C- means -NH-CO-NH- group, or -NH-C(NH)-NH- group, or -(CH ₂ ) _n -CO-NH- group, where n is 0 or 1, or -(CH ₂ ) _q -NR ₈ -SO ₂ - group, where q is 0, 1 or 2, and R ₈ is hydrogen or an alkyl group having 1 to 4 carbon atoms, or -(CH ₂ ) _q -NH-CO group, where q is 0 or 1, or -CH ₂ -NH-CO-NH- group in the form of a racemate or pure enantiomers or a mixture of enantiomers or in the form of a free acid or base or pharmaceutically acceptable addition salts. 2. Compounds according to claim 1 - in the formula R 1 represents a hydrogen atom, or a (C 1-6 alkoxy)carbonyl group, or a hydroxyl group, R ₂ meaning 77/81 a C1-6 alkyl group, which may be substituted by a trifluoromethyl group, or a cyclohexylmethyl group, or a 2,3-dihydro-1,4-benzodiox-7-ylmethyl group, or a 1,3-benzodioxolan-6-ylmethyl group, or a phenyl, benzyl or phenylethyl group, which may be substituted on the phenyl group by 1-3 groups independently selected from the group -N(CH ₃ ) ₂ group, the trifluoromethoxy group, the methylthio group, the C1-4 alkoxy group, the trifluoromethyl group, the amino group, the nitro group, the C1-4 alkyl group, the trifluoromethoxy group, the halogen atom, the -SO ₂ CH ₃ group, the hydroxyl group and the group of the general formula -COORg and -OCH ₂ CO ₂ R8, where Rg represents a hydrogen atom or a C1-4 alkyl group, or a group of the general formula -CH ₂ Q, where Q represents a heterocyclic group which may be substituted with a C1-4 alkoxy group or an amino group or a group of the general formula -COOR ₈ , where R ₈ represents a hydrogen atom or a C1-4 alkyl group, R ₃ and R ₅ independently represent a hydrogen atom, a carboxyl group, or a methyl group, R 4 represents a hydrogen atom or a carboxyl group, X means 78/81 -(CH ₂ ) _m - a group of the general formula, where m is 0 or 2, or -CRgR7-CH ₂ - a group of the general formula, where Rg and R7 independently represent a hydrogen atom or an alkyl group having 1-4 carbon atoms, or a -NH-CO- or -NH-CH ₂ - group, or a -NH-CH ₂ - or -CH ₂ -N (CH ₂ CH ₃ ) - group, Z is a -CH- group, and -ABC- is a -NH-CO-NH- group, or a group of the general formula - (CH ₂ ) _n -CO-NH-, where n is 0 or 1, or a group of the general formula - (CH ₂ ) _q -NR ₈ -SO ₂ -, where q is 0, 1 or 2, and Rg is a hydrogen atom, or a group of the general formula - (CH ₂ ) _q -NH-CO-, where q is 0 or 1, or a -CH ₂ -NH-CO-NH- group or a -CH ₂ -CO-NH- group in the form of a racemate or pure enantiomers or a mixture of enantiomers or in the form of a free acid or base or pharmaceutically acceptable addition salts. 3. A process for the preparation of compounds of general formula (I) according to claim 1 or 2, characterized in that a compound of general formula (II), wherein R ₃ and R ₄ are as defined in claim 1 or 2, and D is a leaving group, is reacted in the presence of a base with a compound of general formula (III), wherein R ₅ , X, Z, A and B are as defined in claim 1 or 2, and GP is a 79/81 amino or carboxylic acid protecting group, thus obtaining a compound of general formula (IV), from which the protecting group is removed, and the resulting compound of general formula (V) is - reacting with a sulfonyl chloride of the general formula R ₂ -SO ₂ C1, in which R ₂ is as defined in claim 1, so that from a compound of the general formula (V) in which A is a group of the general formula —(CH ₂ ) _q —, where q is 0, 1 or 2, and BH is a group of the general formula —NHR _S , where R ₈ is as defined in claim 1, a compound of the general formula (VI) is obtained in which A is a group of the general formula —(CH ₂ ) _q —, where q is 0, 1 or 2, B is a group of the general formula —NR ₈ , and C is a group of the general formula —SO ₂ —, - reacting with an isocyanate of the general formula R ₂ -N=C=O, or first with triphosgene and then with an amine of the general formula R ₂ -NH ₂ , where R ₂ is as defined in claim 1 in both cases, so that from a compound of the general formula (V) in which A is a group of the general formula -(CH ₂ ) _q -, where q is 0 or 1, and BH is an amino group, a compound of the general formula (VI) is obtained in which A is a -NH- or -CH ₂ -NH- group, B is a -CO- group and C is a -NH group, - reacting with an acid chloride of the general formula R ₂ -COC1 in the presence of a base, or with a carboxylic acid of the general formula R ₂ -CO ₂ H in the presence of a coupling reagent, where R ₂ is as defined in claim 1 in both cases, thus from a compound of the general formula (V) in which A is a group of the general formula -(CH ₂ ) _q and BH is an amino group, 80/81 A compound of general formula (VI) is obtained, in which A is a group of general formula (CH ₂ ) _q -, where q is 0 or 1, B is a -NH- group and C is a -CO- group, - reacting with an amine of the general formula R ₂ -NH ₂ , where R ₂ is as defined in claim 1, so that from a compound of the general formula (V) in which A is a group of the general formula -(CH ₂ ) _n - where n is 0 or 1, and BH is a -CO ₂ H group, a compound of the general formula (VI) is obtained in which A is a group of the general formula -(CH ₂ ) _n - where n is 0 or 1, B is a -CO- group and C is a -NH group, - reacting with an isothiocyanate of the general formula R ₂ N=C=S, where R ₂ is as defined in claim 1, so that from a compound of the general formula (V) in which A is a group of the general formula -(CH ₂ ) _q -, where q is 0 or 1, and BH is an amino group, a thiourea is obtained, which is alkylated with methyl iodide to guanidine, and which is then converted with an ammonia source into a compound of the general formula (VI) in which -ABC- is a group -NH-C(NH)-NH-, the nitrile group of which compound of the general formula (VI) is rearranged into a hydroxylamidine group, then a compound of the general formula (I) is obtained in which R _x is a hydroxyl group, and which is then converted by reduction into a compound of the general formula (I) containing an amidine group, which is optionally reacted with an alkyl chloroformate in the presence of a base, so that R _x is replaced by (1-6) A compound of general formula (I) containing a (-)-(C1-alkoxy)carbonyl group is obtained. 81/81 4. A medicament comprising a compound according to claim 1 or 2. 5. A pharmaceutical composition comprising a compound according to claim 1 or 2 in combination with any pharmaceutically acceptable excipient. Instead of the notifier, the Authorized