WO2002062785A1 - Benzimidazole derivatives, method for their production and use thereof as tryptase inhibitors - Google Patents

Abstract

The invention relates to carboxamide-substituted benzimidazole derivatives of the general formula (I), in which the groups X, R?1, R2, R3 and R4¿ are defined as per the claims and the description, to methods for their production and to the use of said carboxamide-substituted benzimidazole derivatives as medicaments, in particular as medicaments with a tryptase-inhibiting action.

Description

 BENZIMIDAZOLE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND USE THEREOF AS TRYPTASE INHIBITORS

The invention relates to benzimidazoldenvate of the formula (I)

wherein the radicals X, R1, R ² , R3 and R ⁴ can have the meanings given in the claims and in the description, processes for their preparation and the use of benzimidazoldenvates as medicaments, in particular as medicaments with tryptase-inhibiting activity.

Background of the Invention

Benzimidazoldenvate are known from the prior art as active ingredients with valuable pharmaceutical properties. Thus, in addition to other bicyclic heterocycles, international patent application WO 98/37075 also discloses benzimidazoles which, owing to their thrombin-inhibiting action, can be used effectively to prevent and treat venous and arterial thrombotic diseases.

In contrast to the use of benzimidazoldenvates described above and already known in the prior art, the object of the present invention is to provide new tryptase inhibitors which, owing to their tryptase-inhibiting properties, can be used to prevent and treat inflammatory and / or allergic diseases , Detailed description of the invention

Surprisingly, it was found that benzimidazoldenvate of the formula (I), in which the radicals R ¹ , R ² , R ³ and R ^{4 can have} the meanings given below, have a tryptase-inhibiting action and can be used according to the invention for the prevention and treatment of diseases in which tryptase inhibitors can have a therapeutic benefit.

The present invention thus relates to benzimidazoldenvate of the formula (I)

wherein

R ^{1 is} a residue selected from the group C- | -C <| 2-alkyl, C2-C- | 2-alkenyl and

C2-C | 2-alkynyl, which may be mono-, di- or triple by one or more of the radicals hydroxy, C- | -C4 alkoxy, CF3, phenoxy, COOH,

Halogen, -CO (C-ι -C _π 2-alkoxy), -CO-NR ⁵ R ⁶ , -NR ⁵ R ⁶ or C- | -C- | 2-Alkoxy-phenoxy may be substituted, or

Phenyl-C-C-12-alky ¹ . which may be one, two or three times by one or more of the radicals hydroxy, C- | -C- | 2-alkoxy, carboxy, halogen,

C- | -Ci2-Alkoxycarbonyl or CF3 may be substituted, or one directly or via a C- | -C- | 2-alkylene bridge linked 5- or 6-membered, saturated or unsaturated heterocycle, which may contain one or two heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, and de optionally by C-ι -C <i2- Alkyl or benzyl may be substituted; R ^{2 represents} -C (= NH) NH ₂ or -CH2-NH2; R ^{3 represents} a hydrogen atom or a C- | -C- | 2-alkyl group which is optionally selected one or two times by one or two radicals selected from the group -COOH, -COO-Ci ^ alkyl, furanyl, benzofuranyl,

Thiophenyl, benzothiophenyl, anthracenyl, phenyl, pyridyl and naphthyl can be substituted, the aromatic and heteroaromatic substituents mentioned in turn being in each case one, two or three times by one or more of the radicals selected from the group C1-C-12-alkyl, C - | -Ci2-alkoxy, halogen,

-NH2, -NH (C- | -C- | 2-alkyl), -N (C- | -Ci2-alkyl) 2, NO ₂ , hydroxy, -CF ₃ , -NHCO-C- | -Cι ₂ - alkyl, - COOH, -COO (C ₁ -C ₁₂ alkyl), -CONH ₂ , -CONHfC-iC ^ alkyl), -CON (C- | -C ₁₂ - alkyl) 2, -CONH (Cι-Ci2 -alkyl) -COO (C- | -C- | 2-alkyl) and phenyl-C- | -Ci2-alkyl may be substituted; X represents> C = O,> CH2 or -CH ₂ CH ₂ -;

R ^{4 is} a radical of the formula (A)

means; W represents N or CH;

A in the case of n = 0, for NR ⁶ , and in the case of n = 1 for O, CHR ⁶ or NR ⁶ ; R ⁵ and R ⁶ each independently represent a hydrogen atom or a group of the formula

-B- (CO) _m -, where

B for a C- | -C-i 2-alkyl-, Cß-Cs-cycloalkyl-, phenyl-, naphthyl or a

Fluorenyl group or a 5- or 6-membered nitrogen, oxygen and / or sulfur-containing heterocyclic group, the group B optionally being selected by one or more radicals from the group halogen, halo-C 1 -C 2 -alkyl, halo-C 1 -C-12-alkoxy, -OH, -C-C-12-alkyl, C- | -Ci 2-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, -CO-OH, -CO-OC- | -C- | 2-alkyl, -NO2, pyrrolidin-1-yl, piperidin-1-yl, -NH2,

-NH-C-ι-C-12-alkyl, -NH-phenyl, -NH-pyridyl, -N (Cι-Cι ₂ -alkyl) ₂ and -

C (= NH) NH2 can be substituted, and m represents 0 or 1, or R5 and RÖ together with the linked nitrogen atom form a 5- to 8-membered heterocycle which is selected from the group consisting of halogen, halo-C- | -Ci2-alkyl, -OH, -C- | -C <| 2-alkyl,

phenoxy,

Benzyloxy, -CO-O-C- | -C- | 2-alkyl, -NO2, phenyl, pyrrolidin-1-yl, piperidin-1-yl,

-NH ₂ , -NH-C-ι-C-12-alkyl, -NH-pyridyl, -N (C ₁ -C- | ₂ -a "<yl) 2 ^and -C (= NH) NH _{2 may be} substituted can, n is 0 or 1; optionally in the form of their tautomers, their racemates, their enantiomers, their

Diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

Unless otherwise defined, branched and unbranched alkyl groups with 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, particularly preferably with 1 to 6 carbon atoms, in particular with 1 to 6, are alkyl groups (also insofar as they are part of other radicals, in particular alkoxy) 4 carbon atoms considered. For example, the following are mentioned: methyl, ethyl, propyl, butyl, pentyl, hexyl etc. Unless otherwise stated, the abovementioned designations propyl, butyl, pentyl or hexyl encompass all of the possible isomeric forms. For example, the term propyl includes the two isomeric residues n-propyl and iso-propyl, the term butyl n-butyl, iso-butyl, sec. Butyl and tert-butyl, the term pentyl, iso-pentyl, neopentyl etc.

If necessary, common abbreviations such as Me for methyl, Et for ethyl etc. are used to denote the alkyl radicals mentioned above.

Haloalkyl groups (also insofar as they are part of other radicals, in particular haloalkoxy) are, unless otherwise defined, branched and unbranched Haloalkyl groups with 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, particularly preferably with 1 to 3 carbon atoms, which are substituted by at least one halogen atom, in particular fluorine atom, are considered. Fluorinated radicals of the formula are preferred

- (CH ₂ ) _p - (CF ₂ ) _q -Y where p is 0 or an integer from 1 to 4, q is an integer from 1 to 4, and Y is hydrogen or fluorine.

Examples include: trifluoromethyl, trifluoromethoxy, difluoromethoxy, perfluoroethyl, perfluoropropyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoroethoxy, 1, 1, 1-trifluoroprop-2-yl, etc.

Alkenyl groups (also insofar as they are part of other radicals) are branched and unbranched alkenyl groups with 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, in particular 2 to 4 carbon atoms, insofar as they have at least one double bond, for example also alkyl groups mentioned above, insofar as they have at least one double bond, such as vinyl (provided that no volatile enamines or enol ethers are formed), propenyl, isopropenyl, butenyl, pentenyl, hexenyl.

Alkynyl groups (also insofar as they are part of other radicals) are alkynyl groups with 2 to 12 carbon atoms, preferably 2 to 6

Carbon atoms, in particular 2 to 4 carbon atoms, insofar as they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl.

Halogen is generally referred to as fluorine, chlorine, bromine or iodine. The term "5- or 6-membered nitrogen, oxygen and / or sulfur-containing heterocyclic group" as used with respect to radical B generally stands for an aromatic or saturated radical with 5 or 6 ring atoms, at least one ring atom is a heteroatom selected from the group N, O and S, which can optionally be condensed with a further ring system.

The term "5- to 8-membered heterocycle" as used for the group, the R 5 and R ⁶ together with the enclosed nitrogen atom is usually a saturated nitrogen-containing radical having from 5 to 8 ring atoms, optionally containing one or can have several heteroatoms selected from the group N, O and S.

Examples of particular heterocyclic groups are acridinyl, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazulenyl, azabenzanthracenyl, azabenzanthrenyl, azachrysenyl, azacyclazinyl, azaindolyl, azanaphthacenyl,

Azanaphthalenyl, Azaprenyl, Azatriphenylenyl, Azepinyl, Azinoindolyl, Azinopyrrolyl, Benzacridinyl, Benzazapinyl, Benzofuryl, Benzonaphthyridinyl, Benzopyranonyl, Benzopyranyl, Benzopyronyl, Benzoquinolinyl, Benzoquinolizyl, Benzothiepinyl, Benzothieylinyl, Benzothiepinyl Chromonopyranyl, coumarinyl, coumaronyl, decahydroquinolinyl, Decahydrochinolonyl, Diazaanthracenyl, Diazaphenanthrenyl, Dibenzazapinyl, dibenzofuranyl, Dibenzothiphenyl, Dichromylenyl, dihydrofuranyl, Dihydroisocumarinyl, dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl, Dihydropyridonyl, Dihydropyronyl, dihydrothiopyranyl, Diprylenyl, Dioxanthylenyl, Oenantholactamyl, Flavanyl, Flavonyl, Fluoranyl, Fluoresceinyl, furandionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl, furopyranyl, furopyronyl, heteroazulenyl, hexahydropyrazinoisoquinolinyl, hydrofuranyl, hydrofuranonyl, hydroindolyl, hydropyranyl, Hydropyridinyl, hydropyrrolyl, hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, indolizidinyl, indolizinyl, indolonyl, isatinyl, isatogenyl, isobenzofurandionyl, isobenzfuranyl, isochromanyl, isoflavonyl, isoindolinyl, isoindolobolazol Isoquinolinyl, Isochinuclidinyl, lactamyl, Lactonyl, maleimidyl, Monoazabenzonaphthenyl, naphthalenyl, Naphthimidazopyridindionyl, Naphthindolizinedionyl, Naphthodihydropyranyl, Naphthofuranyl, naphthyridinyl, oxepinyl, oxindolyl, Oxolenyl, Perhydroazolopyridinyl, perhydroindolyl, Phenanthrachinonyl, Phthalideisoquinolinyl, phthalimidyl, Phthalonyl, piperidinyl, piperidonyl, prolinyl, Parazinyl, Pyranoazinyl, Pyranoazolyl, Pyranopyrandionyl, Pyranopyridinyl, Pyranochinolinyl, Pyranopyrazinyl, pyranyl, Pyrazolopyridinyl, Pyridinethionyl, Pyridinonaphthalenyl, Pyridinopyridinyl, pyridinyl, Pyridocolinyl, pyridoindolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrrolyl, Pyridochinolinyl, pyronyl, Pyrrocolinyl, pyrrolidinyl, pyrrolizidinyl, pyrrolizinyl, Pyrrolodioazinyl,

Pyrrolonyl, Pyrrolopyrmidinyl, Pyrrolochinolonyl, pyrrolyl, Chinacridonyl, quinolinyl, Chinolizidinyl, quinolizinyl, quinolonyl, quinuclidinyl, rhodamine, Spirocumaranyl, succinimidyl, Sulpholanyl, Sulpholenyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydropyridinyl, Tetrahydrothiapyranyl, tetrahydrothiophenyl, Tetrahydrothipyranonyl, Tetrahydrothipyranyl, Tetronyl, Thiaphenyl, Thiachromanyl, Thiadecalinyl, thianaphthenyl, Thiapyranyl, Thiapyronyl, thiazolopyridinyl, thienopyridinyl, Thienopyrrolyl, Thienothiophenyl, thiepinyl, Thiochromenyl, Thiocumarinyl, thiopyranyl, Triazaanthracenyl, Triazinoindolyl, triazolopyridinyl, tropanyl, xanthenyl, Xanthonyl, Xanthydrolyl, adeninyl, Alloxanyl, Alloxazinyl, anthranilyl, Azabenzanthrenyl, Azabenzonaphthenyl, azanaphthacenyl,

Azaphenoxazinyl, azapurinyl, azinyl, azoloazinyl, azolyl, barbituric acid, benzazinyl, benzimidazolethionyl, benzimidazolonyl, benzisothiazolyl, benzisoxazolyl, benzocinnolinyl, benzodiazocinyl, benzodioxolanyl; Benzodioxolyl, Benzopyridazinyl, Benzothiazepinyl, benzothiazinyl, benzothiazolyl, benzoxazinyl, Benzoxazolinonyl, benzoxazolyl, cinnolinyl, Depsidinyl, Diazaphenanthrenyl, diazepinyl, diazinyl, Dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzothiazinyl, dihydrooxazolyl, dihydropyridazinyl, dihydropyrimidinyl, dihydrothiazinyl, dioxanyl, Dioxenyl, dioxepinyl, Dioxinonyl, dioxolanyl, Dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl, dithiolanyl, dithiolenyl, dithiolyl, flavinyl, furopyrimidinyl, glycocyamidinyl, guaninyl, hexahydropyrazinoisoquinolinyl, hexahydropyridazinyl, hydantoinyl,

Hydroimidazolyl, hydroparazinyl, hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl, Imidazolinyl, imidazolyl, imidazoquinazolinyl, imidazothiazolyl, indazolebenzopyrazolyl, indoxazenyl, inosinyl, isoalloxazinyl, isothiazolyl, isoxazolidinyl, isoxazolinonyl, isoxazolinyl, isoxazolonyl. Isoxazolyl, Lumazinyl, Methylthyminyl, Methyluracilyl, morpholinyl, Naphthimidazolyl, Oroticyl, Oxathianyl, Oxathiolanyl, Oxazinonyl, oxazolidinonyl, oxazolidinyl, Oxazolidonyl, Oxazolinonyl, oxazolinyl, Oxazolonyl, Oxazolopyrimidinyl, oxazolyl, Perhydrocinnolinyl, Perhydropyrroloazinyl, Perhydropyrrolothiazinyl, Perhydrothiazinonyl, perimidinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, Phenoxazonyl, phthalazinyl, Piperazindionyl, Piperazinodionyl, Polyquinoxalinyl, pteridinyl, Pterinyl, purinyl, pyrazinyl, pyrazolidinyl, Pyrazolidonyl, Pyrazolinonyl, Parazolinyl, Pyrazolobenzodiazepinyl, pyrazolonyl, pyrazolopyrimidinyl, Pyrazolotriazinyl, pyrazolyl, pyridazinyl, Pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, Pyrimidinethionyl, Pyrimidinyl, pyrimidionyl, pyrimidoazepinyl, pyrimidopteridinyl, pyrrolobenzodiazepinyl, pyrrolodiazinyl, pyrrolopyrimidinyl, quinazolidinyl, quinazolinonyl, quinazolinyl, quinoxalinyl, sultamyl, sultinyl, sultonyl, tetrahydrooxazolyl, tetrah ydropyrazinyl, tetrahydropyridazinyl, Tetrahydroquinoxalinyl, Tetrahydrothiazolyl, Thiazepinyl, thiazinyl, Thiazolidinonyl, thiazolidinyl, Thiazolinonyl, thiazolinyl, Thiazolobenzimidazolyl, thiazolyl, thienopyrimidinyl, Thiazolidinonyl, thyminyl, Triazolopyrimidinyl, uracilyl, xanthinyl, Xylitolyl, Azabenzonapththenyl, Benzofuroxanyl, Benzothiadiazinyl,

Benzotriazepinonyl, Benzotriazolyl, Benzoxadiazinyl, Dioxadiazinyl, Dithiadazolyl, Dithiazolyl, Furazanyl, Furoxanyl, Hydrotriazolyl, Hydroxytrizinyl, Oxadiazinyl, Oxadiazolyl, Oxathiazinonylyl, Titrazolyl, Tetraazylylidyl, Pentazolylidyl, Tetrazylylidylylazylidyl, Tetrazolylidylylazidylylidonyl, Tetrazolylidylylidonyl, Pentazolylidylylidonyl, Tetradylylidylylidonyl Thiadiazolyl, thiadioxazinyl, thiathazinyl, thiatriazolyl, thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl, triazolinedionyl, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl, triphenodithiazinyl, trithiadialanyzepinyl, trithiolioxlinyl or trithiolioxane.

As particularly preferred 5-, 6- or 7-membered, saturated or unsaturated heterocycles which contain nitrogen, oxygen or sulfur as heteroatoms Unless otherwise described in the definitions, furan, tetrahydrofuran, tetrahydrofuranone, γ-butylrolactone, α-pyran, γ-pyran, dioxolane, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolane, dithiolane, pyrrole, pyrrole, pyrrole, pyrrole, Pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine,

Piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepane, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole, pyrazolidine, where the heterocycle can be substituted as indicated in the definitions.

Compounds of formula (I) in which X is> C = O, W is N and A is NR ⁶ are preferred.

m is preferably 0 and n is preferably 1.

R5 is preferably naphthyl, in particular naphth-2-yl, pyridyl, in particular pyrid-2-yl or pyrid-3-yl or a phenyl group optionally substituted by one or two halogen atoms, in particular selected from the formula

wherein i represents a fluorine, chlorine, bromine or iodine atom, and

L ² and L ³ each independently represent a hydrogen, fluorine or chlorine atom.

According to the invention, preference is given to compounds of the formula (I) in which R 1 is a C 1 -C 6 -alkyl group, in particular methyl, ethyl, propyl or butyl, which may be one, two or three times through one or more of the hydroxyl, C- | - radicals C4-alkoxy, CF3, phenoxy, COOH, halogen, -CO (C-ι-C4-alkoxy), -CO-NR ⁵ R ⁶ , -NR ⁵ R ⁶ or C- | -C -alkoxy-phenoxy may be substituted.

Also preferred are compounds of the formula (I) in which R ^{4 is} a radical of the formula (A), A is NR ⁶ ,

R ^{5 is} a C- _| -C4 alkyl, phenyl, naphthyl, fluorenyl, pyridyl, pyrrolidinyl or

Benzyl group means, these groups in each case optionally selected from the group halogen, -OH, halo-C <ι-C4-alkyl, halo-C- | by one, two or three radicals -C4-alkoxy, C- | -C4-alkyl, Cι-C4-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, -CO-OH, -CO-O-C- | -C4-alkyl, -NO2,

Pyridyl, pyrrolidin-1-yl, piperidin-1-yl, -NH2, -NH-C- | -C4-alkyl, may be substituted, and

R6 represents a hydrogen atom or a C 1 -C 4 alkyl group.

The compounds of the formula (I) in which R ^{1 is} methyl, ethyl or propyl are particularly preferred; and

R ^{4 is} a radical of the formula (A1)

means; X represents> C = O;

R ^{5 is} a hydrogen atom or a C -] - C4-alkyl, C- | -C4-alkanoyl, phenyl,

Naphthyl, fluorenyl, anthracenyl, pyridyl, pyrrolidinyl, benzyl group, these groups in each case optionally by one or more radicals, preferably one or two radicals selected from the group halogen, halo -CC ₄ -alkyl, halo -Cι-C ₄ -alkoxy, -OH, C- | -C 4 alkyl,

C- | -C4-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, -CO-OC- | -C4-alkyl, -NO2, pyridyl, pyrrolidin-1-yl, piperidin-1-yl, -NH2, NH-C | -C4-alkyl, -N (-C -C4-alkyl) ₂ and -C (= NH) NH2 may be substituted, and R ^{6 represents} a hydrogen atom or a C- | -C4-alkyl group.

Also preferred are benzimidazole derivatives of the general formula (I), in which

R ¹ C- | -C4-alkyl, which is optionally one, two or three times by one or more of the radicals hydroxy, C- | -C4-Alkoxy, CF3, phenoxy, COOH, halogen, -CO (-C -C4-alkoxy or -C-C4-alkoxy-phenoxy may be substituted, R ² -C (= NH) NH ₂ or -CH2-NH2 means;

R ^{3 is} methyl, -CH ₂ -COOH, -CH2-COO- CjC ^ alkyl, naphthylmethyl, benzyl or

Pyridylmethyl, which is substituted on the respective aromatic and heteroaromatic ring by a radical selected from the group Ci -Cß-alkyl, -NH2, -NH (C- | -C4-alkyl) and -N (C- | -C4-alkyl) 2 R ^{4 can be} a radical of the formula (A) in which A is NR ⁶ ; X> C = O;

R ^{5 is} methyl, ethyl, propyl, butyl, phenyl, naphthyl, pyridyl or benzyl, which is optionally selected from the group halogen, trifluoromethyl, trifluoromethoxy, methyl, -OH, methoxy, -NO2, phenyl, naphthyl, pyrrolidine by one or two radicals -1-yl, -NH2, -NH-methyl, -N (methyl) ₂ , -NH-ethyl,

-N (ethyl) 2 and -C (= NH) NH2 may be substituted,

R6 is hydrogen, methyl, ethyl, propyl or butyl, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

Benzimidazole derivatives of the formula (I) are particularly preferred in which R ¹ denotes methyl, ethyl, propyl or butyl, preferably methyl; R ^{2 is} -C (= NH) NH ₂ or -CH ₂ -NH ₂ , preferably -C (= NH) NH ₂ ; R ^{3 is} methyl, -CH ₂ -COOH, -CH ₂ -COO-ethyl, naphthylmethyl, benzyl or

Is pyridylmethyl, R ^{4 is} a radical of the formula (A1); X> C = O;

R ^{5 is} phenyl, naphthyl, pyridyl or benzyl, which is optionally selected from the group consisting of fluorine, chlorine, bromine, iodine and one or two radicals,

Trifluoromethyl, methyl, -OH, methoxy and phenyl can be substituted, R ^{6 is} hydrogen or methyl, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

Benzimidazole derivatives of the formula (I) in which R is methyl; R ² -C (= NH) NH ₂ ;

R ^{3 is} methyl, -CH ₂ -COOH, -CH ₂ -COO-ethyl, naphthylmethyl, benzyl or pyridylmethyl; R ^{4 is} a radical of the formula (A1); X> C = O;

R ^{5 is} phenyl, naphthyl, pyridyl or benzyl, which may optionally be substituted by one or two radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, -OH, methoxy and phenyl,

R6 is hydrogen or methyl, optionally in the form of their tautomers, their racemates or theirs

Enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts. Of particular importance according to the invention are benzimidazole derivatives of the formula (I) in which

R ^{1 is} methyl; R ² -C (= NH) NH ₂ ;

R ^{3 is} methyl, -CH2-COOH, -CH2-COO-ethyl, benzyl, naphth-1-ylmethyl or pyrid-

4-ylmethyl;

R ^{4 is} a radical of the formula (A1); X> C = O; mean, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

The compounds of the formulas (IA) and (IB) are particularly preferred

wherein each R ^{3 is} hydrogen, -CH ₂ -COOH, -CH ₂ -COO-ethyl, methyl, butyl, benzyl,

Pyridylmethyl or naphthalinylmethyl means, where the aromatic groups can each be substituted by Ci-Cß-alkyl, -NO2, -NH2, -NH-C- | -C4-alkyl, or N (C -] - C4-alkyl) 2; R ^{5 is} a C- _| -C4-alkyl-, C- _| -C4 alkanoyl, phenyl, pyridyl, benzoyl or

Pyridylcarbonyl group means, these groups in each case optionally by one or more, preferably one, two or three, in particular one or two radicals selected from the group halogen, -OH, -C -] - C4-alkyl, C- | -C4-alkoxy , Phenyl, naphthyl, phenoxy, benzyl, benzyloxy,

-CO-OC- | -C ₄ -alkyl, -NO ₂ , phenyl, -NH ₂ , -NH-C- | -C ₄ -alkyl and -N (C- | -C4-alkyl) 2 may be substituted, and

R ^{6 represents} a hydrogen atom or a methyl group, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

In addition to the abovementioned compounds of the general formula (I), the present invention furthermore relates to compounds which, owing to a functionality which can be split off in vivo, are only converted by the organism into the therapeutically active compounds of the general formula (I) after they have been taken by the patient. Such compounds are called prodrugs. A further aspect of the present invention accordingly targets prodrugs of the formula (II)

wherein

X, R ^, R ³ and R ^{4 have} the meanings given above and R ^{7 is} hydroxy, -COO-C- | -C- | 2-alkyl, -COO-C ^< | -C- | 2-haloalkyl, -CO -Phenyl, -CO-pyridyl, -COO-phenyl or -COO-Ci-Cs-alkyl-phenyl, where in the above-mentioned groups the phenyl ring is in each case represented by C 1 -C 4 -alkyl, -C-C4-alkoxy, OH, halogen, -NH2, C -C4-alkyl-NH, di- (C _π -C4 alkyl) N or

CF3 can be substituted means, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

Preferred prodrugs of the formula (II) are those in which

R ⁷ hydroxy, -COO-C- _| -C6-alkyl, -COO-C- | -C6-haloalkyl, -CO-phenyl, -CO-pyridyl,

-COO-phenyl or -COO-Cι-C6-alkyl-phenyl, where in the above-mentioned group the phenyl ring in each case by C-ι-C4-alkyl, C- | -C4 alkoxy,

OH, halogen or CF3 may be substituted, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

Prodrugs of the general formula (II), in which

R ⁷ hydroxy, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 2,2,2-

Trichloroethoxycarbonyl, butyloxycarbonyl, benzoyl, benzyloxycarbonyl or nicotinoyl means, optionally in the form of their tautomers, their racemates, their enantiomers, their

Diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

The present invention further aims at the use of the compounds of the general formula (I) defined above and on the prodrugs of the general formula (II) for the manufacture of a medicament for the treatment of diseases in which tryptase inhibitors can have a therapeutic benefit. According to the invention, preference is given to the use of compounds of the general formula (I) mentioned above for the preparation of a medicament for the prevention and / or treatment of inflammatory and / or allergic Diseases. The use of the compounds of the general formula (I) mentioned at the outset is particularly preferred for the production of a medicament for the prevention and / or treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis, allergic gastrointestinal diseases, Crohn's disease , Ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis. Also of interest is the use of the compounds of the general formula (I) mentioned at the outset for the production of a medicament for the prevention and / or treatment of diseases with remodeling processes in the respiratory tract and the lung parenchyma, such as chronic (obstructive) bronchitis and interstitial

Lung diseases such as idiopathic pulmonary fibrosis, fibrosing alveolitis, sarcoidosis and histiocytosis X and other fibrosing diseases such as scarring, collagenosis such as lupus erythematosus and scleroderma as well as arteriosclerosis, psoriasis and neoplasia.

The synthesis of the substituted benzimidazole derivatives of the formula (I) and that of the prodrugs of the general formula (II) can be carried out via different synthetic approaches. Possible approaches based on and using conventional chemical synthesis methods are shown below as examples. Scheme 1 shows a possible procedure for building up the basic benzimidazole body of the compounds according to the invention.

Scheme 1:

Starting from the 2-halogeno-5-nitro-anilines (1), an aminolysis to the diaminonitrobenzenes (2) according to scheme 1 (stage i) can be carried out first. The aminolysis of

Compounds (1) with the primary amines RI-NH2 are carried out in suitable organic solvents such as, for example, dimethyl sulfoxide, N, N-

Dimethylformamide, N-methylpyrrolidone, acetone or optionally also in water or alcohols at room temperature or in a temperature range of 30-80 ° C, preferably 40-50 ° C.

The reaction of the compounds (2) with p-cyanophenylpropionic acid leads to

Presence of dehydrating reagents for the nitro-benzimidazoles (3, stage ii). The reaction is optionally carried out in a solvent or solvent mixture such as acetic acid, methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane. Suitable dehydrating agents are, for example, isobutyl chloroformate, tetraethyl orthocarboxylate, triethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, phosphorus oxychloride, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, 1-2-1-dihydrochloride EEDQ), 1, 2-dihydro-2 - / - propyloxy-quinoline-1-carboxylic acid - / - propyl ester (IIDQ),

N.N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2- (1 H-benzotriazol-1-yl) - 1, 1, 3, 3-tetramethyluronium tetrafluoroborate, 2- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy-benzotriazole, N.N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride. If appropriate, the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine may prove expedient. The reaction is usually carried out at temperatures between 0 and 150 ° C., preferably at temperatures between 20 and 120 ° C. The nitrobenzimidazole derivatives (3) obtainable according to the procedure described above can be reductively converted into the aminobenzimidazoles (4) (stage iii, scheme 1). The nitro group is reduced to the compounds (3), for example, by catalytic hydrogenations in organic solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, optionally also in a mixture with dimethylformamide, ethyl acetate, dioxane or acetic acid, at elevated hydrogen pressure or at normal pressure at temperatures between 0-50 ° C, preferably at 20-40 ° C. Common hydrogenation catalysts are suitable as catalysts. Palladium and Raney nickel are preferred. Palladium is preferably used in accordance with the invention. Palladium on carbon (5%) is particularly preferred as catalyst. An alternative procedure for reducing the nitro compounds (3) provides for the use of reducing agents such as Na ₂ S ₂ O or SnCl2. This reaction takes place in protic, water-miscible organic solvents such as short-chain alcohols (methanol, ethanol, isopropanol) or in a mixture of the abovementioned solvents with water, optionally with acetic acid, dimethylformamide or ethyl acetate. The reaction is usually carried out at elevated temperature, preferably under reflux of the particular solvent or solvent mixture. After complete conversion of the starting compounds (3) is worked up in the usual way. The compounds (4) can be purified, for example, by crystallization from nonpolar organic solvents, such as diethyl ether or petroleum ether, optionally in a mixture with ethyl acetate.

Starting from the benzimidazoles (4) obtainable according to scheme 1, the compounds (5) are formed according to scheme 2 by reaction with the compounds R -Nu, where Nu for a nucleofugal leaving group such as chlorine, bromine, iodine, methanesulfonate, methyl triflate, p -Toluenesulfonate etc. stands. Alternatively, the compounds (5) can be obtained from the compounds (4) in the sense of reductive amination by reaction with appropriately substituted ketones or aldehydes under reductive conditions.

Scheme 2:

The reaction of compounds (4) with R ³ -Nu according to stage iv can be carried out as follows. A compound (4) is dissolved in a polar solvent, such as dimethylformamide, dimethylactamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide and particularly preferably anhydrous, optionally absolute dimethylformamide. A base and the corresponding alkylating agent R ³ -Nu are added to the solution thus obtained. Suitable bases are the alkali or alkaline earth carbonates of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. Furthermore, the alkali or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium, calcium, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide can be used in alcohols or water. The reaction mixture is stirred for 0.5-8h, preferably 1-4h at elevated temperature, preferably at 50-120 ° C, especially under reflux of the solvent used. After conversion is complete, the mixture is worked up in the customary manner and the crude product obtained is purified by crystallization or chromatography on silica gel.

If the compounds (5) are obtained from the compounds (4) by reductive amination, the procedure is as follows. In a suitable solvent such as dichloromethane, dichloroethane, methanol, ethanol, tetrahydrofuran or toluene, the compound (4) is dissolved and between 0-60 ° C, preferably at 20-40 ° C with the corresponding carbonyl compound in the presence of an acid, preferably one Carboxylic acid, particularly preferably a short-chain carboxylic acid, most preferably acetic acid. A suitable reducing agent is then added. Come as a reducing agent According to the invention, Na [HB (OAc) 3], Na [BH ₃ CN], NaBH ₄ , Pd / CH _{2 are} preferred, Na [HB (OAc) 3J is preferred. After the usual work-up, the product is purified by crystallization or chromatography on silica gel.

As can be seen from Scheme 3, compounds (5) can be used for

Acylation (stage va) or alkylation (stage vb) the intermediates of the general formula (III), in which n is 1, are obtained.

R ¹ va

Scheme 3: The reaction of the compounds (5) with the chloroacetic acid to the intermediates of the general formula (III) can be carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclimidodimodylcarbodidoxynodimodiodoxynodimodiodoxynodimodiodoxynodimodiodimodioxydimodiodimodiodimodiodimodiodimodiodimodiodimodiodimodiocarbodiodimodiocarbodi, N'-dicyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2- (1 H-benzothazol-1-yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate, 2- (1 H-benzotriazol-1-yl) -1 , 1, 3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy-benzotriazole, N.N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine Temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, are carried out. Alternatively, the intermediates of the general formula (III) can also be used

Standard procedures by reaction with alkylation reagents R ⁴ -CH ₂ X ¹ (with X ¹ : halide, mesylate, tosylate, etc.) or activated carboxylic acid derivatives R ⁴ -COX ²

(With X ² : halide, alkoxy, etc.) can be obtained in the abovementioned solvents or solvent mixtures in the presence of bases such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine.

The compounds (IIIA) can be reacted with the amines according to stage vi to give the intermediates (III). The compound (IIIA) is dissolved in a polar solvent, such as dimethylformamide, dimethylactamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide and particularly preferably anhydrous, optionally absolute dimethylformamide. A base and the corresponding amine are added to the solution thus obtained. As the base come the alkali or

Alkaline earth carbonates of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. The reaction mixture is stirred for 0.5-8h, preferably 1-4h at elevated temperature, preferably at 50-120 ° C, especially under reflux of the solvent used. After complete sales, the usual way worked up and the crude product obtained purified by crystallization or chromatography on silica gel.

As can be seen from Scheme 4, the intermediates of the general can be obtained from the compounds (5) by reaction with the corresponding isocyanates

Formula (III) in which R ^{6 is} hydrogen and 0 is obtained. The connections of the

Formula (III), in which R ^{6 is} different from hydrogen, can be obtained by alkylation with an alkylating reagent R ⁶ -X ³ (with X ³ : halide, mesylate, tosylate, etc.) or by reductive amination according to the methods described in Scheme 2 receive.

R ¹

Scheme 4:

According to stage vii in scheme 5, the compounds of the formula (I) according to the invention are accessible from the intermediates (III). R ¹

Scheme 5 The preparation of the compounds of the general formula (I) according to the invention in which R ^{2 is} —C (= NH) NH2 can be carried out in different ways.

A compound of general formula (I) is obtained, for example, by treating a compound of general formula (III) with an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol, optionally in a mixture with another organic solvent such as chloroform, nitrobenzene or toluene in the presence of an acid such as hydrochloric acid or by reacting an appropriate amide with a thalkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between -10 and 50 ° C, but preferably at 0-20 ° C and below Aminolysis with, for example, alcoholic ammonia solution. Alternatively, the compounds of the general formula (I) can be obtained by reacting a compound of the general formula (III) with sulfur nucleophiles such as, for example, hydrogen sulfide, ammonium or sodium sulfide, sodium hydrogen sulfide, Carbon disulfide, thioacetamide or bistrimethylsilylthioether, optionally in the presence of bases such as triethylamine, ammonia, sodium hydride or sodium alcoholate in solvents such as methanol, ethanol, water, tetrahydrofuran, pyridine, dimethylformamide or 1,3-dimethyl-imidazolidin-2-one at 20-100 ° C and subsequent treatment with a suitable methylating agent such as methyl iodide or dimethyl sulfate in a solvent such as acetonitrile or acetone at temperatures between -10 and 50 ° C, but preferably at 0-20 ° C and subsequent treatment with ammonia, ammonium carbonate or ammonium chloride in a suitable alcohol , such as methanol, ethanol, isopropanol etc. at temperatures between -10 and 50 ° C, but preferably at 0-20 ° C.

Furthermore, the compounds of the general formula (I) according to the invention are obtainable by treating a compound of the general formula (IM) with lithium hexamethyldisilazide in a suitable organic solvent, e.g. Tetrahydrofuran at temperatures between -20 and 50 ° C, but preferably at 0-20 ° C and subsequent hydrolysis with dilute hydrochloric acid at 0-5 ° C. Another alternative approach to compounds of general formula (I) is by treating a compound of general formula (III) with ammonium chloride and trimethylaluminum in a suitable organic solvent such as e.g. Toluene at temperatures between 20 and 150 ° C, but preferably at 110 ° C.

Compounds of the general formula (I) in which R ² denotes -CH2-NH2 can be obtained from the intermediates (III), for example by catalytic hydrogenation on Raney nickel. These reactions are preferably carried out in protic organic solvents such as short-chain alcohols (methanol, ethanol or isopropanol) at temperatures between 10-40 ° C, preferably at 20-30 ° C under normal pressure. A compound of general formula (II) is obtained, for example, by treating a compound of general formula (III) (Scheme 3, step vii) with hydroxylamine in the presence of carbonates or alcoholates of the alkali or alkaline earth metals in solvents such as methanol, ethanol, n -Propanol or isopropanol, optionally in a mixture with dioxane or tetrahydrofuran. The alcoholates can be prepared from the respective alkali metals or metal hydrides and the corresponding alcohol. The reaction is preferably carried out at 20-100 ° C., particularly preferably at the boiling point of the solvent used. Compounds of the general formula (II) are alternatively obtainable by treating a compound of the general formula (III) with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a Trialkyloxonium salt such as T ethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between -10 and 50 ° C, but preferably at 0-20 ° C and subsequent

Treatment with hydroxylamine in the presence of bases in a suitable alcohol, such as methanol, ethanol, isopropanol etc. at temperatures between -10 and 50 ° C, but preferably at 0-20 ° C.

A compound of the general formula (I) can be obtained, for example, from

Treatment of a compound of general formula (II), (Scheme 3, stage viii) with hydrogen in the presence of hydrogenation catalysts such as Raney nickel or rhodium / aluminum oxide in water or methanol, optionally with the addition of acids such as hydrochloric acid or methanesulfonic acid or by treatment with hydrogen in Presence of palladium / carbon in acetic acid / acetic anhydride at 20-50 ^β C and 1-5 bar hydrogen pressure, preferably at room temperature and normal pressure.

The acyl or alkoxycarbonyl prodrugs (II) of the compound having the general formula (I) are obtained by reacting the compounds of the general formula (I) with the corresponding acid chlorides in the presence of bases such as, for example Triethylamine, N-methylmorpholine, diethylisopropylamine or DBU in a suitable solvent such as methylene chloride, chloroform, tetrahydrofuran, acetonitrile, dimethylformamide or dimethyl sulfoxide.

According to their central importance for the synthesis of the compounds of the general formula (I) according to the invention and for the synthesis of the prodrugs of the general formula (II), a further aspect of the present invention aims at the intermediates of the general formula (IM)

wherein the radicals X, R1, R3 and R4 have the meanings given above.

The compounds of the formula (III) are valuable intermediates for the preparation of the benzimidazole derivatives of the general formula (I) according to the invention and of the prodrugs of the general formula (II) according to the invention.

Because of their pharmacological properties, the compounds according to the invention can be used as medicaments, in particular as medicaments with tryptase-inhibiting activity. Can be used wherever tryptase inhibitors can have therapeutic benefits.

According to the invention, preference is given to using compounds of the general formula (I) for the manufacture of a medicament for the prevention and / or treatment of inflammatory and / or allergic diseases. The use of the compounds of the general formula (I) mentioned at the outset is particularly preferred for the preparation of a medicament for the prevention and / or treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, Urticaria, allergic otitis, allergic gastrointestinal diseases, Crohn's disease, ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis.

Also of interest is the use of the compounds of the general formula (I) mentioned at the outset for the production of a medicament for the prevention and / or treatment of fibrosis such as pulmonary fibrosis, fibrosing alveolitis and scarring, of collagenoses such as lupus erythematosus and scleroderma, and of arteriosclerosis, psoriasis and neoplasia ,

Exemplary procedures for producing the compounds according to the invention are described in more detail below. The following synthesis examples serve only for a more detailed explanation, without restricting the subject matter of the invention to the same.

Example 1: N-f2-r2- (4-amidinophenvl) -ethvlM-methvl-benzimidazole-5-vlVN- [naphth-1-ylmethyl] -2- (4-phenylamino-piperid-1-yl) -acetamide, dihydrochloride

a) N ¹ -Methyl-1, 2-diamino-4-nitrobenzene

2-fluoro-5-nitro-aniline (15.0 g, 160 mmol) becomes 40% aqueous in 480 mL

Methylamine solution taken up, 2.5 days at room temperature and 2 h at 40-

50 ° C stirred. It is diluted with water, the solid is filtered off, washed with water and dried.

Yield: 26 g (97%); Mp: 171-173 ° C.

b 2-r2- (4-cvanophenvπ-ethyl-1-methyl-5-nitro-benzimidazole N ¹ -methyl-1,2-diamino-4-nitrobenzene (8.3 g, 49.6 mmol) and p-cyano phenyl-propionic acid (9.6 g, 55 mmol) are taken up in 90 mL of POCl 3, and 1, 5 hours under reflux. After cooling, the excess POCI _3, with

Ice water decomposes. It is made alkaline with NH3 with stirring / cooling and stirred at room temperature for 1 h. The solid is filtered off, washed with water and recrystallized from DMF. Yield: 11.7 g (76.4%); Mp: 202-204 ° C.

c) 5-Amino-2-f2- (4-cvanophenyl) -ethyll-1-methyl-benzimidazole 2- [2- (4-cyanophenyl) -ethyl] -1-methyl-5-nitro-benzimidazole (5.5 g, 18 mmol) in 150 mL THF and 75 mL methanol in the presence of 1.0 g 5% Pd / C Room temperature and normal pressure hydrogenated. The catalyst is filtered off, the filtrate is not completely evaporated to dryness, diluted with 100 mL acetonitrile and concentrated to a residual volume of 30 mL. The crystal slurry is cooled and filtered. The crystals are washed with cold acetonitrile and ether. Yield: 4.7 g (94%); Mp: 187-192 ° C.

d 2-r2- (4-Cvanophenvπ-ethyl-1-methyl-5-naphth-1 -ylmethylamino-benzimidazole 1.0 g (3.6 mmol) of 5-amino-2- [2- (4-cyanophenyl) -ethyl] -1 -methyl-benzimidazole and 1-naphthylaldehyde (0.33 mL, 3.6 mmol) are mixed with 0.22 mL acetic acid in 25 mL dichloromethane at room temperature and while stirring with Na [HB (OAc) ₃ ]. The mixture is stirred for 1 h at room temperature, overlaid with water, carefully acidified with concentrated aqueous hydrochloric acid and then made alkaline with 4N NaOH solution. The organic phase is separated off, dried and concentrated. The product is chromatographed on silica gel and optionally crystallized from diethyl ether. Yield: 0.8 g (67 %); Mp: 112-114 ° C.

e) N 2-f2- (4-cvanophenyl) -ethyl1-1 -methyl-benzimidazol-5-yl! -N- (naphth-1 -ylmethvO- 2-chloroacetamide

A mixture of 4.0 g (9.6 mmol) of 2- [2- (4-cyanophenyl) ethyl] -1-methyl-5-naphth-1-ylmethylamino-benzimidazole and 1.1 mL (10.0 mmol) of N-methylmorpholine in 80 ml of dichloromethane were cooled to 10 ° C. A solution of 0.8 mL (10.0 mmol) of chloroacetyl chloride in 15 ml of dichloromethane was added dropwise to the solution within 15 minutes. The mixture was then stirred at room temperature for 30 min. It is washed with water and dilute potassium carbonate solution, dried and concentrated. The product is chromatographed on silica gel. Yield: 4.1 g, 87%. fi N- {2-r2- (4-cvanophenyl) ethyll-1-methylbenzimidazol-5-yl -N- (naphth-1-ylmethvH- 2- (4-phenylamino-piperid-1-vπ-acetamide)

A solution of 2.1 g (4.3 mmol) of N- {2- [2- (4-cyanophenyl) ethyl] -1-methyl-benzimidazol-5-yl} -N- (naphth-1-ylmethyl) -2 -chloroacetamide, 1.5 g (6.0 mmol) 4- phenylamino-1-piperidine, 2.2 mL N-methylmorpholine in 15 mL dimethylformamide are stirred at 70-80 ° C for 8 hours. It is then poured onto ice, extracted with ethyl acetate and washed with water, dried and distilled off. The product is chromatographed on silica gel. Yield: 2.0 g (73%).

g) N- (2-r2- (4-amidinophenvπ-ethyl-1-methyl-benzimidazol-5-yl) -N-fnaphth-1-yl-methyll-2- (4-phenylamino-piperid-1-yl) -acetamide.dihydrochloride N- {2- [2- (4-cyanophenyl) ethyl] -1-methyl-benzimidazol-5-yl} -N-methyl- [3- (4-cyano-phenyl) propionamide] ( 1.3 g, 2.9 mmol) is taken up in 50 ml of a cooled ethanolic HCl solution saturated at 0 ° C. The mixture is stirred until the starting material has completely dissolved and then kept overnight at 0-5 ° C. The ethanol is at a maximum of 40 ° C. and the residue was taken up in 40 ml of an ethanolic ammonia solution saturated at 0 ° C. The mixture was stirred for 2 hours at room temperature, for 3 hours at 50-60 °, and a further 10 ml of saturated ammonia solution were added, for 2 hours boiled under reflux and kept at room temperature overnight, the precipitated inorganic salts are filtered off, the filtrate is concentrated and the residue is chromatographed on silica gel: yield: 1.0 g (62%), 1 H-NMR (250 MHz, CD3OD): δ = 8.21 -6.55 (19H, aryl-H), 5.52 (2H, s, naphth.-CH2-N), 3.87 (2H, CH2-CO), 4.74 (3H, s, N-CH3), 3.24 (4H, aryl- CH2CH2-), 3.63, 2.36-1.64 (9H, m, pip.CH2; CH). Example 2: N- {2- [2- (4-amidinophenyl) ethyl] -1-methylbenzimidazol-5-yl} -N- [naphth-1-ylmethyl] -2- {4- [N-methyl -N- (3-hydroxypropyl) amino] piperid-1-yl} acetamide, trihydrochloride

a) N- (2-r2- (4-Cvanophenyl) -ethyll-1-methyl-benzimidazol-5-ylVN- (naphth-1 -ylmethvO- 2- (4-rN-methyl-N- (3-hvdroxypropyl) -amino1-piperid-1-yl) -acetamide The synthesis succeeds starting from N- {2- [2- (4-cyanophenyl) ethyl] -1-methyl-benzimidazol-5-yl} obtainable according to Example 1, stage e. -N- (naphth-1-ylmethyl) -2-chloroacetamide, 4- [N-methyl-N- (3-hydroxypropyl) amino] -1-piperidine and potassium carbonate analogously to that described in Example 1, stage f Procedure: Yield: 92%.

b) N- {2-r2- (4-amidinophenv0-ethyl-1-methyl-benzimidazol-5-yl) -Nf naphth-1 -ylmethyl-1-2- (4-fN-methyl-N- (3- hvdroxypropyl) -amino1-piperid-1-yl) -acetamide, trihydrochloride The synthesis of the title compound is carried out as described for example 1 step g starting from N- {2- [2- (4-cyanophenyl) ethyl] -1-methyl- benzimidazol-5-yl} -N- (naphth-1-ylmethyl) -2- {4- [N-methyl-N- (3-hydroxypropyl) amino] piperid-1-yl} - acetamide. Yield: 37%.

¹ H NMR (250 MHz, DMSO-d6): δ = 9.38; 9.16 (4H, 2s, NH ₂ -C = N ⁺ H ₂ ), 8.19-6.66 (14H, m, aryl / naphthyl-H), 5.36 (2H, s, naphth.-CH ₂ -N), 3.63 (3H , s, NCH ₃ ), 3.43 (2H, t, J = 6.5Hz, OCH ₂ -), 3.32 (2H, s, CH ₂ C = O), 3.13 (4H, s, aryl-CH ₂ CH ₂ ), 2.93, 2:56 (3H, N- CH _3), 2:17 to 1:39 (14H, m, pip. CH _2, CH, OH). Example 3: N- (2-r2- (4-Amidinoρhenyl) -ethvn-1 -methyl-benzimidazol-5-ylVN- (4-tert-butylphenylmethyl) -2-r4-f2-pyridylamino) -piperid-1-vn acetamide. dihydrochloride

a) 2-r2- (4-Cvanophenvh-ethyl1-1-methyl-5- (4-tert-butylphenylmethvπ-amino-benzimizazole

The reductive amination succeeds starting from 5-amino-2- [2- (4-cyanophenyl) ethyl] -1-methyl-benzimidazole and 4-tert-butyl-benzaldehyde obtainable according to Example 1, stage c analogously to that in Example 1 , Step d described procedure. Yield: 60%

b) N- {2-r2- (4-Cvanophenvπ-ethvn-1-methyl-benzimidazol-5-yl) -N- (4-tert-butylphenyl-methvO-2-chloro-acetamide

Analogously to Example 1, stage e, 2- [2- (4-cyanophenyl) ethyl] -1-methyl-5- (4-tert-butylphenylmethyl) amino-benzimidazole was reacted with chloroacetyl chloride. The purification was carried out chromatographically on silica gel. Yield: 100%.

c) N- {2-r2- (4-Cvanophenvπ-ethyl1-1-methyl-benzimidazol-5-yl N-f4-tert-butylphenyl-methyl) -2-f4- (2-pyridylamino) -piperid-1- yll-acetamide

N- {2- [2- (4-cyanophenyl) ethyl] -1-methyl-benzimidazol-5-yl} -N- (4-tert-butylphenyl-methyl) -2-chloroacetamide was prepared according to Example 1, Stage f implemented with 4- (2-pyridyl) amino piperidine. The chromatographic purification was carried out on silica gel. Yield: 56% d) N-f2-f2- (4-Amidinoρhenyl) -ethvn-1-methyl-benzimidazol-5-yl> -N- (4-tert-butyl-phenylmethylV2-r4- (2-pyridylaminoVpiperid-1-vfl-acetamide , dihydrochloride

Analogously to Example 1, stage g, N- {2- [2- (4-cyanophenyl) ethyl] -1-methylbenzimidazol-5-yl} -N- (4-tert-butylphenylmethyl) -2- [4- (2-pyridylamino) piperid-1-yl] acetamide converted to the title compound. The purification was carried out chromatographically on silica gel.

Yield: 53%.

¹ H-NMR (250 MHz, CD ₃ OD): δ = 7.89-6.45 (15H, m, aryl / pyridyl-H), 4.93 (2H, s, aryl-CH ₂ -N), 3.74 (3H, s, N-CH ₃ ), 3.64, 3.26 (4H, m, aryl-CH ₂ CH ₂ ), 2.45-1.62 (11 H, m, pip.-CH ₂ , CH, CH ₂ C = O), 1.25 [9H, s, C (CH ₃ ) ₃ ].

Example 4: N- (2-r2- (4-Arnidinophenyl) -ethyl1-1 -methyl-benzimidazol-5-yll-N- (methyl) -2- [4- (2-chlorophenylamino) -piperid-1-yl ] -acetamide dihydrochloride

a ^ N- {2-r2- (4-Cvanophenvπ-ethvn-1-methyl-benzimidazol-5-ylHrifluoroacetamide 27.6 g (100.0 mmol) 5-amino-2- [2- (4-cyanophenyl) -ethyl] -1 trifluoroacetic anhydride (15.0 ml) is added dropwise in 270 ml of pyridine at 5-20, the mixture is stirred at room temperature for 15 minutes and diluted with water. The solid is filtered off and washed with water. The crystals are heated with 300 mL ethyl acetate dissolved, dried and not evaporated to dryness, cooled, the precipitated solid filtered off and washed with diethyl ether. Yield: 32.2 g (86%), mp: 225-228 ° C. b) 2-f2- (4-cvanophenyl) -ethyll-1-methyl-5-methylamino-benzimidazole 11.2 g (30.0 mmol) of N- {2- [2- (4-cyanophenyl) -ethyl] -1-methyl- benzimidazol-5-yl} - trifluoroacetamide, 10.5 g (76.0 mmol) potassium carbonate and 2.0 mL methyl iodide are stirred in 80 mL dimethyl sulfoxide for 3 hours at 40-50 ° C. The mixture is then diluted with 100 ml of ethyl acetate, poured onto water and extracted. The organic phase is washed again with water, dried and concentrated. The residue is chromatographed on silica gel. The methylated trifluoroacetamide is taken up in MeOH, with 10 mL conc. aqueous ammonia solution and stirred at 30-40 ° C for 4 h. The methanol is distilled off, the residue is taken up in 75 ml of ethyl acetate, washed with water, dried and concentrated. The product is crystallized from diethyl ether. Yield: 6.5 g (75%); Mp: 155-158 ° C.

c) N-f2-r2- (4-CvanophenylVethvn-1 -methyl-benzimidazol-5-yl ^' -N-methyl-2-chloroacetamide)

According to Example 1, stage e, 2- [2- (4-cyanophenyl) ethyl] -1-methyl-5-methylamino-benzimidazole are reacted with chloroacetyl chloride. The purification was carried out chromatographically on silica gel. Yield: 68%.

d N- (2-f2- (4-Cvanophenvn-ethvn-1-methyl-benzimidazol-5-yl> -N- (methvn-2-f4-f2-chlorophenyl) amino-piperid-1-vn-acetamide as in the example 1, stage f was N- {2- [2- (4-cyanophenyl) ethyl] -1-methyl-benzimizazol-5-yl} -N-methyl-2-chloroacetamide with 4- (2- Chlorophenyl) amino-1-piperidine and purified by column chromatography on silica gel. Yield: 86%. e) N 2-r2- (4-amidinophenvn-ethyl-1-methyl-benzimidazol-5-ylVN-methyl-2-f4-f2-chlorophenvπamino-piperid-1-yl-acetamide, dihydrochloride

N- {2- [2- (4-cyanophenyl) ethyl] -1-methyl-benzimidazol-5-yl} -N- (methyl) -2- [4- (2-chlorophenyl) amino-piperide- 1-yl] -acetamide was reacted analogously to Example 1, stage g to the title compound. The residue was chromatographed on silica gel. Yield: 1.1 g (73%).

¹ H-NMR (250 MHz, DMSO-d6): δ = 9.40, 9.05 (4H, 2s, NH ₂ -C = N ⁺ H ₂ ), 7.90-6.52 (11 H, m, aryl-H), 4.76 ( 1 H, d, J = 8.0 Hz, NH-CH), 3.81 (3H, N-CH ₃ ), 3.31 (4H, s, aryl-CH ₂ CH ₂ -), 2.80 (2H, s, CH ₂ C = O), 3.22 (3H, s, N-CH ₃ ), 3.35, 2.86-1.38 (9H, m, pip.-CH ₂ , CH).

Example 5: N- {2- [2- (4-amidinophenyl) ethyl] -1-methyl-benzimidazol-5-yl} -N- (naphth-1-ylmethyl) -N'-benzylurea, hydrochloride

a) 1 - (2-r2- (4-Cvanophenyl) -ethvn-1 -methyl-benzimidazol-5-yl) -1 -maphth-1 -ylmethvh-

3-benzylurea

1.37 g (3.3 mmol) of 2- [2- (4-cyanophenyl) ethyl] -1-methyl-5-naphth-1-ylmethylamino-benzimidazole, obtainable from example, stage d, were dissolved in 20 mL dichloromethane at room temperature became 0.40 g (3.0 mmol) of benzyl isocyanate was added dropwise to the solution. The mixture was then stirred at 50 ° C. for 6 h and left to stand overnight.

The solution was evaporated in vacuo on a rotary evaporator and purified by column chromatography on silica gel. Yield: 1.28 g (71%). b) 1 -f2-r2- (4-amidinophenvO-ethvπ-1-methyl-benzimidazol-5-yl) -1 - (naphth-1-yl-methyl) -3-benzylurea, hydrochloride

1.25 g (2.27 mmol) 1- {2- [2- (4-cyanophenyl) ethyl] -1-methyl-benzimidazol-5-yl} -1-

(Naphth-1-methyl) -3-benzylurea was converted to amidine according to Example 1, stage g. The purification was carried out by column chromatography on silica gel.

Yield: 1.23 g (67%).

¹ H-NMR (250 MHz, CD ₃ OD): δ = 8.33-6.85 (19H, m, aryl-H), 5.40 (2H, s, naphth.-

CH ₂ -N), 4.34 (2H, s, aryl-CH ₂ -N), 3.63 (3H, s, NCH ₃ ), 3.19 (4H, s, aryl-CH ₂ CH ₂ -).

In analogy to the examples described above, the following tables summarize further compounds of the general formula (I) synthesized according to the invention.

Table 1 :

Table 2:

Table 3:

Example 84: Nf 2-.2- (4-Aminobenzvl.-Ethvl] -1-methyl-benzimidazole-5-vl) -N-methyl-2- [4- (2-chloro-4-fluorophenylamino) piperide- 1-yl] -acetamide. ditrifluoroacetate

Stage a) 2-f2- (4-aminobenzvπ-ethvn-1-methyl-5-methylamino-benzimidazole) 2- [2- (4-cyanophenyl) ethyl] -1-methyl-5-methylamino synthesized according to Example 4 stage b -benzimidazole (4.9 g, 17 mmol) is hydrogenated in 100 ml of methanol and 25 ml of tetrahydrofuran in the presence of 1 g of Raney nickel and 4 ml of saturated alcoholic ammonia solution at room temperature and normal pressure for 10 hours Shaken at 30-40 ° C. and 5 bar, the mother liquor is distilled off and the residue is chromatographed on silica gel. Yield: 3.4 g (69%).

Step b) 2-r2- (4- (tert-Butyloxycarbonylamino) benzyl) -ethvn-1-methyl-5-methylamino-benzimidazole

2- [2- (4-aminobenzyl) ethyl] -1-methyl-5-methylamino-benzimidazole (3.4 g, 11, 6 mmol) are dissolved in 50 mL dichloromethane and cooled to 5 ° C. A solution of 2.5 g (11.5 mmol) of di-tert-butyldicarbonate in 10 ml of dichloromethane is added dropwise within 30 min. The mixture is stirred at about 5 ° C. for 2 hours and then at room temperature for 2 hours. The compounds were purified by column chromatography on silica gel. Yield: 3.0 g (66%).

Step c) N- {2-r2- (4- (tert-Butyloxycarbonylamino) benzvD-ethvπ-1-methyl-benzimidazol-5-yl) -N-methyl-2-chloroacetamide

According to Example 1, stage e, 2- [2- (4- (tert-butyloxycarbonylamino) benzyl) ethyl] -1-methyl-5-methylamino-benzimidazole (2.1 g, 5.3 mmol) are reacted with chloroacetyl chloride. The purification was carried out chromatographically on silica gel. Yield: 2.5 g (100%). Step d) N- (2-f2- (4- (aminobenzyl) -ethvn-1-methyl-benzimidazol-5-ylVN-methyl-2-f4- (2-chloro-4-fluorophenylamino) -piperid-1-yl acetamide, ditrifluoroacetate 1.2 g (3.5 mmol) 4- (2-chloro-4-fluorophenylamino) -1 -piperidine were mixed with 1.3 g (2.7 mmol) N- {2- [2- (4th - (tert-Butyloxycarbonylamino) benzyl) -ethyl] -1-methyl-benzimidazol-5-yl} -N-methyl-2-chloroacetamide and 2.8 g of potassium carbonate in 15 mL of dimethylformamide within 3 hours at 80-90 ° C The protective group was then cleaved off with trifluoroacetic acid and the title compound was purified by column chromatography on silica gel. Yield: 1.5 g (84%).

¹ H-NMR (250 MHz, CD ₃ OD): δ = 7.95-6.61 (m, 10 H, aryl-H), 4.09 (s, 2H, Ph-CH ₂ -N), 3.94-3.50 and 3.18-2.93 (m, 5H, piperidine), 3.82 (s, 3H, imidazole ~ CH ₃ ), 3.42 (t, 2H, J = 67 Hz, CH ₂ -PI-1), 3.38 (s, 3H, N-CH ₃ ) , 3.23 (t, 2H, J = 8.2 Hz, CH ₂ -Ph), 2.41-2.07 (, 2H, CH ₂ -piperidine), 1.97-1.68 (m, 2H, CH ₂ -piperidine).

Analogously to Example 84 described above, Table 4 below summarizes further compounds of the general formula (I) synthesized according to the invention.

Table 4:

In analogy to the examples described above, Table 5 below summarizes further compounds of the general formula (I) synthesized according to the invention.

Table 5:

The compounds according to the invention are notable for their tryptase-inhibiting activity. Said ability to inhibit tryptase was tested according to the test description below. The determination is carried out in Tris HCl buffer (100 mM), which additionally contains calcium (5 mM) and heparin (100 mg / ml), at pH 7.4. The standard used is rh beta tryptase, which can be purchased, for example, from Promega. Np-Tosyl-Gly-Pro-Lys-para-nitroaniline serves as the substrate in a concentration of 0.6 mM. The substrate is digested by tryptase to produce p-nitroaniline, which can be measured at 405 nm. An incubation time of 5 minutes and an incubation temperature of 37 ° C. are usually selected. As enzyme activity 0.91 U / ml are used. The determination is carried out in an auto analyzer (Cobas Bio) from Hofmann LaRoche. The potential inhibitory substances are used in concentrations of 10 μM in the screening, the inhibition of tryptase being stated in percent. If the inhibition is over 70%, the IC _{50 is} determined (concentration at which 50% of the enzyme activity is inhibited). After preincubation of the potential inhibitor substances for 5 minutes, the substrate is added to start the reaction, the formation of p-nitroaniline being taken as a measure of the enzyme activity after 5 minutes after testing the linearity.

Table 6 below contains the results of the in vitro test; it mean:

+++ IC50: 0.0005 - 0.0030 μM,

++: IC50: 0.0040 - 0.0300 µM

+: IC50: 0.0310-1.0000 μM

Table 6:

The tryptase inhibitors according to the invention can be administered orally, transdermally, by inhalation or parenterally. The compounds according to the invention are present here as active constituents in customary dosage forms, for example in compositions which essentially consist of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, coated tablets, capsules, wafers, powders, solutions, suspensions, emulsions , Syrups, suppositories, transdermal systems etc. An effective dose of the compounds according to the invention is between 1 and 100, preferably between 1 and 50, particularly preferably between 5-30 mg / dose in the case of oral use, and between 0.001 and. In the case of intravenous or intramuscular use 50, preferably between 0.1 and 10 mg / dose. Solutions which contain 0.01 to 1.0, preferably 0.1 to 0.5% active ingredient are suitable for inhalation. The use of powders is preferred for inhalation application. It is also possible to use the compounds according to the invention as Infusion solution, preferably in a physiological saline or nutrient solution.

The compounds according to the invention can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active compounds. Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Corresponding tablets can be obtained, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Correspondingly, coated tablets can be produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core can also consist of several layers in order to achieve a depot effect or to avoid incompatibilities. Likewise, the coated tablet to achieve a depot effect can consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.

Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. You can also suspending aids or thickening agents such as sodium carboxymethyl cellulose, wetting agents, for example

Condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates. Injection solutions are prepared in a customary manner, for example with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and are filled into injection bottles or ampoules.

The capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatin capsules.

Suitable suppositories can be produced, for example, by mixing them with carriers, such as neutral fats or polyethylene glycol or its derivatives.

A therapeutically effective daily dose is between 1 and 800 mg, preferably 10-300 mg per adult.

The following examples illustrate the present invention without, however, restricting its scope:

Pharmaceutical formulation examples

A) tablets per tablet

Active ingredient 100 mg milk sugar 140 mg

Corn starch 240 mg

Polyvinylpyrrolidone 15 mg magnesium stearate 5 mq

500 mg

The finely ground active ingredient, milk sugar and part of the corn starch are mixed together. The mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of a suitable shape and size.

B) tablets per tablet

Active ingredient 80 mg

Corn starch 190 mg

Milk sugar 55 mg

Microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg

Sodium carboxymethyl starch 23 mg

Magnesium stearate 2 mq

400 mg

The finely ground active ingredient, part of the corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the rest of the corn starch and water to form a granulate, which is dried and sieved. The sodium carboxymethyl starch and the magnesium stearate are added, and the mixture is mixed and pressed into tablets of a suitable size.

C) Dragees per dragee

Active ingredient 5 mg

Corn starch 41.5 mg milk sugar 30 mg

Polyvinyl pyrrolidone 3 mg

Magnesium stearate 0.5 mα

80 mg

The active ingredient, corn starch, milk sugar and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is pressed through a sieve with a 1 mm mesh size, dried at approx. 45 ° C and then the granules are passed through the same sieve. After adding magnesium stearate The active ingredient, corn starch, milk sugar and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is pressed through a sieve with a 1 mm mesh size, dried at approx. 45 ° C and then the granules are passed through the same sieve. After admixing magnesium stearate, domed dragee cores with a

6 mm diameter pressed. The dragee cores thus produced are coated in a known manner with a layer consisting essentially of sugar and talc. The finished coated tablets are polished with wax.

D) capsules per capsule

Active ingredient 50 mg

Corn starch 268.5 mg

Magnesium stearate 1.5 mg

320 mg

The substance and corn starch are mixed and moistened with water. The moist mass is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is filled into size 1 hard gelatin capsules.

E) Ampoule solution

Active ingredient 50 mg

Sodium chloride 50 mg

Aqua per inj. 5 ml

The active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5 to 6.5, and sodium chloride is added as the isotonic agent, the solution obtained is filtered pyrogen-free and the filtrate is filled into ampoules under aseptic conditions, which are then sterilized and sealed , The ampoules contain 5 mg, 25 mg and 50 mg of active ingredient.

F) suppositories Active ingredient 50 mg

Adeps solidus 1650 mα

1700 mg

The hard fat is melted. The milled active substance is homogeneously dispersed at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

Claims

claims

1. Compounds of formula (I)

wherein

R ^{1 is} a radical selected from the group CjC ^ alkyl, C2-C ^ 2-al enyl and C2-Ci2-alkynyl, which is optionally one, two or three times by one or more of the radicals hydroxy, C ^ -C ^ Alkoxy, CF3, phenoxy, COOH, halogen, -CO (C- | -Ci2-alkoxy), -CO-NR ⁵ R ⁶ , -NR ⁵ R ⁶ or Cι -C <| 2-alkoxy-phenoxy may be substituted, or

Phenyl-C- | -C-i2- ^a 'kyl, which optionally one, two or three times by one or more of the radicals hydroxy, C- | -C- | 2-alkoxy, carboxy, halogen, C- | -Ci2-alkoxycarbonyl or CF3 may be substituted, or one directly or via a C- | C- | 2-alkylene bridge linked 5- or 6-membered, saturated or unsaturated heterocycle which may contain one or two heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur and which may be substituted by C- | -C- | 2-alkyl or benzyl may be substituted; R ^{2 represents} -C (= NH) NH ₂ or -CH ₂ -NH ₂ ;

R ^{3 is} a hydrogen atom or a C- | Means —C12-alkyl group, which is optionally selected one or two times by one or two radicals selected from the group —COOH, —COO-C- | _6-alkyl, furanyl, benzofuranyl,

Thiophenyl, benzothiophenyl, anthracenyl, phenyl, pyridyl and naphthyl may be substituted, the aromatic and heteroaromatic substituents mentioned being in turn one, two or three times by one or more of the radicals selected from the group C1-C12-

Alkyl, -C-C i2 alkoxy, halogen, -Cι-C <| 2- ^{a |} kyl-halogen, -NH2, -NH (C- | -C- | 2-alkyl), -N (C _π -Ci2-alkyl) 2, NO ₂ , hydroxy, -CF3, -NHCO-C- | -C <| 2-alkyl, -COOH,

-COO (C ₁ -C ₁₂ alkyl), -CONH ₂ , -CONH (C- | -Ci2-alkyl), -CON (C ₁ -C ₁ 2-alkyl) ₂ ,

-CONH (-C-Ci2-alkyl) -COO (-C-Ci2-alkyl) and phenyl-C <| -C- | 2-alkyl may be substituted;

X represents> C = O,> CH2 or -CH2CH2-;

R4 is a radical of the formula (A)

means;

W represents N or CH;

A in the case of n = 0, for NR ⁶ , and in the case of n = 1 for O, CHR ⁶ or NR ⁶ ;

R ⁵ and R ⁶ each independently represent a hydrogen atom or a group of the formula

-B- (CO) _m -, where

B for a C- | -Ci2-alkyl-, Cs-Cß-cycloalkyl-, phenyl-, naphthyl or a

Fluorenyl group or a 5- or 6-membered nitrogen, oxygen and / or sulfur-containing heterocyclic group, the group B in each case optionally being selected by one or more radicals from the group halogen, halo-C <| -C- | 2- Alkyl, halo-C- | -C- | 2-alkoxy, -OH, CjC ^ alkyl,

C- | -C- | 2-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, -CO-O-H,

-CO-O-C <| -Ci2-alkyl, -NÜ2, pyrrolidin-1-yl, piperidin-1-yl, -NH2,

-NH-Cι-C-12-alkyl, -NH-phenyl, -NH-pyridyl, -N (C- | -Ci2-alkyl) 2 and

-C (= NH) NH2 can be substituted, and m represents 0 or 1, or

R ⁵ and R ⁶ together with the linked nitrogen atom form a 5- to 8-membered heterocycle, which is selected by a radical selected from the group halogen, halo-CjC ^ alkyl, -OH, -CjC ^ alkyl, Ci-C ^ - lkoxy, phenoxy, Benzyloxy, -CO-OC- | -Ci2-alkyl, -NO2, phenyl, pyrrolidin-1-yl, piperidin-1-yl,

-NH ₂ , -NH-Cι-Ci2-a'kyl, -NH-pyridyl, -N (C ^< | -Ci2-alkyl) 2 and -C (= NH) NH2 may be substituted, n is 0 or 1; optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

2. Compounds of formula (I) according to claim 1, wherein R ² , R3 ₍ R4 _| R5 _unc ( _{n have} the meaning given in claim 1, and X is> C = O, W is N, and A is NR ⁶ ,

3. Compounds of formula (I) according to claim 1 or 2, wherein R ² , R _ R4 R5 and n have the meaning given in claim 1, and

R ^{1 represents} a C ¹ -C 6 -alkyl group which may be mono-, di- or triple by one or more of the radicals hydroxy, C <] -C4-alkoxy, CF3,

Phenoxy, COOH, halogen, -CO (-C -C4-alkoxy), -CO-NR ⁵ R6, -NR5R6 or C- | -C4-alkoxy-phenoxy can be substituted.

4. Compounds of formula (I) according to any one of claims 1 to 3, wherein R ¹ , R ² , and R ^{3 have} the meaning given, and R ^ is a radical of formula (A), wherein n is 1.

5. Compounds of formula (I) according to any one of claims 1 to 4, wherein R ² , R ³ and R4 have the meaning given, and R ^{1 is} methyl, ethyl, propyl or butyl.

6. Compounds of formula (I) according to one of claims 5 to 5, wherein R1, R ² and R ^{3 have} the meaning given in claim 1, 2, 3 or 4, and R ^ denotes a radical of formula (A),

A NR ⁶ means

R ^{5 represents} a C 1 -C 4 -alkyl, phenyl, naphthyl, pyridyl or benzyl group, these groups each optionally being selected from the group halogen, -OH, halo-C- | -C4-alkyl, halo -Cι-C4-alkoxy, C < _| -C4-alkyl, Cj-C4-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy,

-CO-OH, -CO-OC- | -C4-alkyl, -NO2, pyridyl, pyrrolidin-1-yl, piperidin-1-yl, -NH2, -NH-Cj -C4-alkyl, may be substituted, and R ^{6 represents} a hydrogen atom or a C- | -C4 alkyl group.

7. Compounds of formula (I) according to any one of claims 1 to 6, wherein R ² and R ^{3 have} the meaning given, and

R ^{1 is} methyl, ethyl or propyl; R ^ is a radical of the formula (A1)

means;

R ^{5 is} a hydrogen atom or a C 1 -C 4 alkyl, C 1 -C 4 alkanoyl, phenyl,

Naphthyl, pyridyl, benzyl, benzoyl or pyridylcarbonyl group, these groups each optionally being selected from the group halogen, halo -CC ₄ -alkyl, -OH, by one, two or three radicals,

C- | -C4 alkyl, C- | -C4-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy,

-CO-OC- | -C4-alkyl, -NO2, pyrrolidin-1 -yl, piperidin-1-yl, -NH2, -NH-C <ι-C4-alkyl, -N (C- | -C4-alkyl) 2 and -C (= NH) NH2 may be substituted, and

R ^{6 represents} a hydrogen atom or a C <] - C4-alkyl group.

8. Compounds of the formula (IA)

wherein

R ^{3 is} hydrogen, methyl, butyl, -CH ₂ -COOH, -CH ₂ -COO-ethyl, benzyl,

Pyridylmethyl or naphthylmethyl means, the aromatic and heteroaromatic π groups each by C-i-Cß-alkyl, -NO2, -NH2, -NH-

C- | -C4-alkyl, or -N (C- | -C4-alkyl) 2 may be substituted;

R5 is a C 1 -C 4 alkyl, C 1 -C 4 alkanoyl, phenyl, pyridyl, benzoyl or

Pyridylcarbonyl group, these groups each optionally being selected from the group halogen, -OH, -C <] - C4-alkyl, C <ι-C4-alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, in each case by one or more radicals,

-CO-OC- | -C4-alkyl, -NO ₂ , -NH ₂ , -NH-C -C4-alkyl and -N (C-ι-C4-alkyl) ₂ may be substituted, and

R6 represents a hydrogen atom or a methyl group, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

9. Compounds of the formula (IB)

wherein R ^{3 is} hydrogen, methyl, butyl, -CH ₂ -COOH, -CH ₂ -COO-ethyl, benzyl,

Pyridylmethyl or naphthylmethyl means, where the aromatic and heteroaromatic groups each by C-i -Cß-alkyl, -NO2, -NH2, -NH-

C 1 -C 4 -alkyl, or -N (C 1 -C 4 -alkyl) 2 may be substituted;

R ^{5 is} a C- | -C4-alkyl-, -C-C4-alkanoyl, phenyl, pyridyl, benzyl (BIIM1297),

Naphthyl (BIIM1301), benzoyl or pyridylcarbonyl group, (what about the substances in which R5 and R6 form a piperidine ring (BIIM1364) and have a cyclohexyl ring on N (BIIM1365 and BIIM1382 and BIIM1386, all mentioned as examples), these being Groups each optionally by one or more radicals selected from the group halogen, -OH, -C -C4 alkyl, C <| -C4 alkoxy, phenyl, naphthyl, phenoxy, benzyl, benzyloxy, -CO-OC- | -C -alkyl, -NO ₂ , -NH ₂ , -NH-C ^< | -C4-alkyl and -N (C- | -C4-alkyl) ₂ may be substituted, and R ^{6 represents} a hydrogen atom or a methyl group, optionally in Form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

10. Compounds of formula (I) according to any one of the preceding claims for use as a medicament

1 1. Prodrugs of Formula (II)

wherein

X, Rl, R ³ and R ^{4 have} the meanings given above, and R ^{7 is} hydroxy, -COO-Ci-C ^ alkyl, -COO-Cι-C ^< | 2-haloalkyl, -CO-phenyl, -CO- Pyridyl, -COO-phenyl or -COO-Ci-Cg-alkyl-phenyl, the phenyl ring in the abovementioned groups being in each case by C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, OH, halogen, -NH2, Ci-C ^ alkyl-NH, which may be substituted by di- (C- | -C4-alkyl) N or CF3, means

optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

12. prodrugs of the general formula (II) according to claim 11, wherein X, R ¹ , R ³ and

R ^{4 have} the meanings given above, and

R ^{7 is} hydroxy, -COO-C- | -C6-alkyl, -COO-Ci-Cß-haloalkyl, -CO-phenyl, -CO-pyridyl,

-COO-phenyl or -COO-Ci-Cß-Alkyl-Phβnyl, where in the above group the phenyl ring can each be substituted by C- | -C4-alkyl, Cι-C4-Al oxy, OH, halogen or CF3, means, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

13. prodrugs of the general formula (II) according to claim 1 1 or 12, wherein R1, R ³ and R ^{4 have} the meanings given above and R ⁷ hydroxy, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 2,2,2-

Trichloroethoxycarbonyl, Butyloxycarbonyl, Benzoyl, Benzyloxycarbonyl or Nicotinoyl means, if here is the PD that we really did, then it should also: Isobutyloxycarbonyl (BIIM1465), 4-methoxyphenoxycarbonyl (BIIM1468), Isopropyloxycarbonyl (BIIM146970, 4-fluorobenzoyl ) optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts.

14. Compounds of formula (III)

wherein the radicals X, R ¹ , R ³ and R ^{4 have} the meanings given in claims 1 to 9.

15. Use of compounds of general formula (I), (IA) or (IB) according to any one of claims 1 to 9 for the manufacture of a medicament for the prevention and / or treatment of diseases in which tryptase inhibitors can have a therapeutic benefit.

16. Use of prodrugs of the general formula (II) according to one of claims 1 1, 12 or 13 for the manufacture of a medicament for the prevention and / or treatment of diseases in which tryptase inhibitors can have a therapeutic benefit.

17. Pharmaceutical composition characterized by a content of one or more compounds according to one of claims 1 to 13.

18. Process for the preparation of compounds of the general formula (I)

in which the radicals X, R1, R ² , R ³ and R ⁴ can have the meanings given in Claims 1 to 9, characterized in that a compound of the general formula (III)

in which the radicals X, R1, R ³ and R ⁴ can have the meanings given in claims 1 to 9, is converted directly into the compounds of the general formula (I).