JP2003519129A - Benzimidazoles, their preparation and use as pharmaceutical compositions - Google Patents

Abstract

(57) The present invention provides a novel benzimidazole of the general formula (I) (wherein R _{a to} R _b are as indicated in claim 1) having effective properties, Tautomers, stereoisomers, mixtures thereof, prodrugs, derivatives thereof having negatively charged groups instead of carboxy groups under physiological conditions, or salts, especially inorganic acids or inorganic bases or organic acids or organic bases And a physiologically acceptable salt. The compounds of general formula (I) in which R _c is not an amidino group are effective intermediate products which produce amidino compounds of general formula (I) having effective pharmacological properties, in particular antithrombotic activity. [Chemical 1]

Description

Detailed Description of the Invention

  The present invention has the following general formula having effective characteristics.

[0001]

[Chemical 8]

[0002] Having benzimidazole, its tautomers, stereoisomers, mixtures thereof, pro
A drug, which has a negatively charged group instead of a carboxy group under physiological conditions
Physiology with derivatives, or salts thereof, especially inorganic acids or inorganic bases or organic acids or organic bases
Pharmaceutically acceptable salts.   R_aIs a straight chain C_1-3-Alkyl group, C in the 1-position_1-3-Even if substituted with an alkyl group
Good pyrrolidinocarbonyl group or 2,5-dihydropyrrolocarbonyl group or cyano-C _1-4 -Substituted by amino groups, which are mono-substituted by alkyl groups, and / or R_c
Is a cyano group or C at the 5-position_1-3-1,2,4-O substituted with an alkyl or phenyl group
A oxadiazol-3-yl group, wherein the phenyl substituent is a fluorine atom, chlorine
Atom or bromine atom, or C_1-3-Of the above general formula I optionally substituted with an alkyl group
The compound is an intermediate product useful for preparing other compounds of general formula I, R_cBut
A compound of the above general formula I, which is one of the following amidino groups, tautomers and stereoisomers thereof
, Its mixtures, prodrugs, negatively charged instead of the carboxy group under physiological conditions
A physiologically permissible derivative thereof, or a salt thereof, particularly an inorganic salt or an organic salt.
Acceptable salts, or their stereoisomers, have effective pharmacological properties, especially antithrombotic activity
.

The present application therefore relates to the novel compounds of formula I above, the process for their preparation, the pharmaceutical compositions containing the pharmacologically active compounds, the process for their preparation and their use. In the above general formula, R _a is _a pyrrolidinocarbonyl group or _a hydrogen atom which may be partially or entirely substituted with a fluorine atom, and which may be substituted with a C _1-3 -alkyl group at the 1-position. , 5-Dihydropyrrolocarbonyl group and carboxy-C _1-4 -alkyl group, cyano-C _1-4 -alkyl group or tetrazolyl-C _1-4-
N- (carboxy-C _1-3 -alkylaminocarbonyl) amino, which is mono-substituted with an alkyl group, or is an amino group, or one or both amino nitrogen atoms of which may be substituted with a C _1-3 -alkyl group. Group, carboxy-C _1-3 -alkoxy group, N- (carboxy-C _1-3 -alkyl) amino group, N- (C _1-3 -alkyl) -N- (carboxy-C _1-3 -alkyl) Amino group, N- (carboxy-C _1-3 -alkylsulfonyl) amino group, N- (C _1-3 -alkyl) -N- (carboxy-C _1-3 -alkylsulfonyl) amino group or tetrazolyl-C _{1 -3} - C substituted at the terminal with an alkyl group _1-3 - is substituted with an alkyl group, a linear C _1-3 - alkyl group, R _b is C _1-3 - alkyl group, R _c is an amidino group, a cyano group or 5-position C _1-3 - it is substituted with an alkyl group or a phenyl group 1,2,4-oxadiazol-3-yl group, wherein the phenyl substituents It may be substituted with an alkyl group - a fluorine atom, a chlorine atom or a bromine atom or a C _1-3.

[0004]   The carboxy group described in the above group definition can be converted to a carboxy group in vivo.
Or a group that is negatively charged under physiological conditions, The amino group and imino group described in the definition of the above group are substituted with a group that can be cleaved in vivo.
It may have been done. Such groups are described, for example, in International Application No. 98/46576 and N.M.N.
ielson et al., International Journal of Pharmaceutics39, 75-85 (1987)
Has been done.   A group that can be converted to a carboxy group in vivo is, for example, a hydroxymethyl group or an alkyl group.
A carboxylic group esterified with Cole, wherein the alcohol moiety is preferably
Is C_1-6-Alkanol, Phenyl-C_1-3-Alkanol, C_3-9-Cycloalkanol
And C_5-8-Cycloalkanol is 1 or 2 C_1-3-Further substituted with alkyl groups
May be C_5-8-Cycloalkanol, where the methylene group at the 3 or 4 position is an acid
Elementary atom or C_1-3-Alkyl group, Phenyl-C_1-3-Alkyl group, Phenyl-C_1-3-Al
Coxycarbonyl group or C_2-6-Imino group optionally substituted by alkanoyl group
And the cycloalkanol moiety is 1 or 2 C_1-3-Further substituted with alkyl groups
May be C_4-7-Cycloalkenol, C_3-5-Alkenol, Phenyl-C _3-5 -Arkenol, C_3-5-Alkynol or phenyl-C_3-5-Alkynol, but
, The bond to the oxygen atom does not start with a carbon atom having a double or triple bond, C_{3 -8} -Cycloalkyl-C_1-3-Alkanols, bicycloa with 8 to 10 carbon atoms
Lucanol, wherein the bicycloalkyl moiety is 1 or 2 C_1-3-Update with alkyl group
Optionally substituted with 1,3-dihydro-3-oxo-1-isobenzofuranol or
The following formula R_d-CO-O- (R_eCR_f) -OH (In the formula, R_dIs C_1-8-Alkyl group, C_5-7-Cycloalkyl group, phenyl group or phenyl group
Le-C_1-3-Is an alkyl group,

R _e is a hydrogen atom, a C _1-3 -alkyl group, a C _5-7 -cycloalkyl group or a phenyl group, and R _f is a hydrogen atom or a C _1-3 -alkyl group. ) Means an alcohol having, group which is negatively charged under physiological conditions, tetrazol-5-yl group, phenylcarbonylamino group, trifluoromethyl carbonyl amino carbonyl group, C _{1 -6} - alkylsulfonylamino group , Phenylsulfonylamino group, benzylsulfonylamino group, trifluoromethylsulfonylamino group, C _1-6 -alkylsulfonylaminocarbonyl group, phenylsulfonylaminocarbonyl group, benzylsulfonylaminocarbonyl group or perfluoro-C _1-6 -alkylsulfonyl Means a group such as an aminocarbonyl group,

The group capable of being cleaved from an imino group or an amino group in vivo is, for example, a hydroxy group, an acyl group, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, or a C _1-3 -alkyl group or C _{1 -3-} benzoyl group which may be mono- or di-substituted by an alkoxy group, wherein the substituents may be the same or different, pyridinoyl group or C _1-16 -alkanoyl group, for example, formyl group, acetyl group, Propionyl group, butanoyl group, pentanoyl group or hexanoyl group, 3,3,3-trichloropropionyl group or allyloxycarbonyl group, C _1-16 -alkoxycarbonyl group or C _1-16 -alkylcarbonyloxy group, wherein hydrogen Atoms may be wholly or partially substituted with a fluorine atom or a chlorine atom, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxy group. Rubonyl group, isopropoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group, pentoxycarbonyl group, hexoxycarbonyl group, octyloxycarbonyl group, nonyloxycarbonyl group, decyloxycarbonyl group, undecyloxycarbonyl group, dodecyl Oxycarbonyl group, hexadecyloxycarbonyl group, methylcarbonyloxy group, ethylcarbonyloxy group, 2,2,2-trichloroethylcarbonyloxy group, propylcarbonyloxy group, isopropylcarbonyloxy group, butylcarbonyloxy group,

Tert-butylcarbonyloxy group, pentylcarbonyloxy group, hexylcarbonyloxy group, octylcarbonyloxy group, nonylcarbonyloxy group, decylcarbonyloxy group, undecylcarbonyloxy group, dodecylcarbonyloxy group or hexadecylcarbonyloxy group Group, phenyl-C _1-6 -alkoxycarbonyl group, for example, benzyloxycarbonyl group, phenylethoxycarbonyl group or phenylpropoxycarbonyl group, 3-aminopropionyl group, wherein the amino group is a C _1-6 -alkyl group or C _3-7 -cycloalkyl group may be mono- or di-substituted, the substituents may be the same or different, C _1-3 -alkylsulfonyl-C _2-4 -alkoxycarbonyl group, C _{1- 3} - alkoxy -C _2-4 - alkoxy -C _2-4 - alkoxycarbonyl group _{R d -CO-O- (R d} CR f) -O-CO group, C _1-6 - alkyl _{-CO-NH- (R g CR h} ) -O-CO or C _1-6 - alkyl -CO- O- (R _g CR _h )-(R _g CR _h ) -OCO group, wherein R _{d to} R _f are as defined above, R _g and R _h may be the same or different, and Means an atom or a C ₁₃ alkyl group.

Further, saturated alkyl moieties and saturated alkoxy moieties having more than two carbon atoms as defined above include branched chain isomers thereof, such as the isopropyl group, tert.
-Butyl group, isobutyl group, etc. are included. Preferred compounds of general formula I above are those wherein R _b and R _c are as defined above and R _a is as defined above, wherein one substituent is a straight chain C _1-3 -alkyl. Basis or
It is a 2,5-dihydropyrrolocarbonyl group optionally substituted with a C _1-3 -alkyl group, R _a is _a pyrrolidinocarbonyl group at the 1-position and _a methoxy group, a dimethylamino group or a tolyl group at the 2-position ethoxy moiety. Ethoxycarbonylmethyl group substituted with a group, carboxymethyl group, C _3-4 -alkoxycarbonylmethyl group, cyclohexyloxycarbonylmethyl group, 3- (C _2-3 -alkoxycarbonyl) propyl group or tetrazolylmethyl group An ethyl group substituted with an amino group substituted with, R _b is a methyl group, and R _c is substituted with a benzoyl group, a methylbenzoyl group, a fluorobenzoyl group or a trifluoromethylbenzoyl group Is an amidino group,

R _a is an ethyl group substituted with a pyrrolidinocarbonyl group substituted at the 2-position with a methyl group at the 1-position and an amino group substituted with a carboxymethyl group or an ethoxycarbonylmethyl group, R _b is a methyl group, R _c is an amidino group, or R _a is substituted at the 1-position with a pyrrolidinocarbonyl group and a carboxymethyl group, a C _3-4 -alkoxycarbonylmethyl group or a tetrazolylmethyl group. Amino group, or tetrazolyl group, carboxymethoxy group, ethoxycarbonylmethoxy group, ethoxycarbonylmethylamino group, N- (2-carboxyethyl) -N-methylamino group, N
-[2- (C _1-3 -alkoxycarbonyl) ethyl] -N-methylamino group, N- (carboxymethylaminocarbonyl) -N-methylamino group, N- (C _1-3 -alkoxycarbonylmethylaminocarbonyl ) -N-Methylamino group, N- (carboxymethylsulfonyl) -N-
A methylamino group or an N- (C _1-3 -alkoxycarbonylmethylsulfonyl) -N-methylamino group-substituted alkyl group, an ethyl group, R _b is a methyl group, and R is _A compound in which _c is an amidino group, a tautomer, an isomer or a salt thereof.

Particularly preferred compounds of the above general formula I are (1) 2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5-
[1- (n-butyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl
] Benzimidazole or (2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazol-5-ylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] except benzimidazole It is a compound of the above general formula I, or a tautomer, isomer or salt thereof.

Particularly preferred compounds of the above general formula I are those wherein R _a is _a 2,5-dihydrocarbonyl group optionally substituted with a methyl group at the 1-position and a C _2-4 -alkoxy moiety is a methoxy group, dimethylamino Group, a C _1-4 -alkoxycarbonyl-C _1-4 -alkyl group mono-substituted at the terminal with a phenyl group or a tolyl group,
A carboxy-C _1-4 -alkyl group, a cyclohexyloxycarbonyl-C _1-4 -alkyl group or a tetrazolyl-C _1-4 -alkyl group which may be substituted with an amino group, or one or both amino nitrogen atoms C _1-3 -Alkyl group-substituted N- (carboxy-C _1-3 -alkylaminocarbonyl) amino group or N- (C _1-3 -alkoxycarbonyl-C _1-3 -alkylaminocarbonyl ) Amino group, carboxy-C _1-3 -alkoxy group, C _1-3 -alkoxycarbonyl-C _1-3 -alkoxy group, N- (C _1-3 -alkyl) -N
-(Carboxy-C _1-3 -alkyl) amino group, N- (C _1-3 -alkyl) -N- (C _1-3 -alkoxycarbonyl-C _1-3 -alkyl) amino group, N- ( C _1-3 - alkyl) -N- (carboxy -C _1-3 - alkylsulfonyl) amino group or a N- (C _1-3 - alkyl) -N- (C _1-3 - alkoxycarbonyl -C _1-3 -Alkylsulfonyl) amino group or a tetrazolyl-C _1-3 -alkyl group, which is terminally substituted with a C _1-3 -alkyl group, which is an ethyl group, R _b is a methyl group, and R _c Is a benzoyl group, a methylbenzoyl group, a fluorobenzoyl group or an amidino group optionally substituted with a trifluoromethylbenzoyl group,

R _a is _a pyrrolidinocarbonyl group at the 1-position and an ethoxycarbonylmethyl group, a carboxymethyl group, a propyloxycarbonylmethyl group, or an isopropyl group in which the ethoxy moiety at the 2-position is substituted with a methoxy group, a dimethylamino group or a tolyl group. An oxycarbonylmethyl group, an isobutyloxycarbonylmethyl group, a cyclohexyloxycarbonylmethyl group, a 3- (C _2-3 -alkoxycarbonyl) propyl group or a tetrazolylmethyl group, which is an ethyl group, R _b is A methyl group, R _c is an amidino group substituted with a benzoyl group, a methylbenzoyl group, a fluorobenzoyl group or a trifluoromethylbenzoyl group, R _a is substituted with a methyl group at the 2-position and a 2-position Pyrrolidinocarbonyl group and carboxymethyl group or ethoxycarbonyl group An ethyl group substituted with a chloro group, an ethyl group, R _b is a methyl group, and R _c is an amidino group, or

R _a is an amino group substituted at the 1-position with a pyrrolidinocarbonyl group and a carboxymethyl group or a C _3-4 -alkoxycarbonylmethyl group, or a tetrazolyl group, a carboxymethoxy group, an ethoxycarbonylmethoxy group, an ethoxycarbonyl group. Methylamino group, N- (2-carboxyethyl) -N-methylamino group, N
-[2- (C _1-3 -alkoxycarbonyl) ethyl] -N-methylamino group, N- (carboxymethylaminocarbonyl) -N-methylamino group, N- (C _1-3 -alkoxycarbonylmethylaminocarbonyl ) -N-Methylamino group, N- (carboxymethylsulfonyl) -N
An ethyl group substituted with a methylamino group or an N- (C _1-3 -alkoxycarbonylmethylsulfonyl) -N-methylamino group, R _b is a methyl group, and R _c is an amidino group A compound, its tautomer, isomer or salt.

Examples of particularly preferred compounds include the following compounds, isomers or salts thereof. (1) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole, (2) 2 -[4- (N-Phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5-
[1- (Ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole, (3) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl]- 1-methyl-5- [1- (isobutyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl
) Ethyl] benzimidazole, (4) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1 -(Pyrrolidinocarbonyl
) Ethyl] benzimidazole, (5) (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1-[(R, S) -1- Methyl-pyrrolidinocarbonyl] ethyl] benzimidazole, (6) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (2,5-dihydropyrrolocarbonyl ) Ethyl] benzimidazole or (7) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (cyclohexyloxycarbonylmethylamino) -1- ( 2,5-Dihydropyrrolocarbonyl) ethyl] benzimidazole.

According to the invention, the compounds of general formula I are obtained by known methods, for example: a) R _c is substituted with a cyano group or a C _1-3 -alkyl group or a phenyl group at the 5-position 1
Is a 2,2,4-oxadiazol-3-yl group, wherein the phenyl substituent is a fluorine atom, a chlorine atom or a bromine atom, or a general formula I which may be substituted with a C _1-3 -alkyl group. In order to prepare the compound of the following general formula which may be formed as a reaction mixture

[0016]

[Chemical 9]

(Wherein R _a and R _b are as defined above, R _c ′ is a cyano group or 1,2,2 substituted with a C _1-3 -alkyl group or a phenyl group at the 5-position.
A 4-oxadiazol-3-yl group, wherein the phenyl substituent is a fluorine atom,
It may be substituted with a chlorine atom or a bromine atom, or a C _1-3 -alkyl group, Z ₁ and Z ₂ may be the same or different, an amino group, a hydroxy group or 1 to 6 carbon atoms.
Is a mercapto group which may be substituted with an alkyl group having, Z ₁ and Z ₂ are both an oxygen atom or a sulfur atom, an imino group which may be substituted with an alkyl group having 1 to 3 carbon atoms, It is also an alkylenedioxy group or an alkylenedithio group having 2 or 3 carbon atoms. ) Is cyclized. The cyclization is carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide or tetralin, or a compound of the general formula II. In an excess of the acylating agent used to prepare the, for example, the corresponding nitrile, anhydride, acid halide, ester or amide, for example at a temperature of 0 to 250 ° C., preferably the boiling temperature of the reaction mixture. And optionally a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, N, N-dicyclohexyl. A base in the presence or optionally of a carbodiimide, eg If it is conveniently carried out in the presence of potassium ethoxide or potassium tert- butoxide. However, the cyclization can be carried out without solvent and / or condensing agent. b) In order to prepare the compound of the general formula I in which R _c is an amidino group, the following general formula which may be formed as a reaction mixture is used.

[0018]

[Chemical 10]

(Wherein R _a and R _b are as defined above, Z ₄ is an alkoxy group or an aralkoxy group, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group or a benzyloxy group. Or a compound having an alkylthio group or an aralkylthio group such as a methylthio group, an ethylthio group, an n-propylthio group or a benzylthio group.) Is reacted with ammonia or a salt thereof. The reaction is conveniently carried out in methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at a temperature of 0 to 150 ° C., preferably 0 to 80 ° C. with ammonia or one of its salts, eg ammonium carbonate or ammonium acetate. Done. Compounds of general formula III are prepared by reacting, for example, the corresponding cyano compound with the corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid. The amide and a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at a temperature of 0 to 50 ° C, preferably 20 ° C, or the corresponding nitrile and hydrogen sulfide. And are conveniently obtained by reacting in the presence of a base such as triethylamine in a solvent such as pyridine or dimethylformamide and alkylating the thioamide formed with the corresponding alkyl or aralkyl halide. c) to prepare compounds of general formula I in which R _a has a carboxy group and R _c is as defined above, the following general formula

[0020]

[Chemical 11]

Where R _b and R _c are as defined above and R _a 'means R _a as shown above, where R _a is hydrolyzed, treated with acid or base. , Having a group capable of being converted to a carboxy group by thermal decomposition or hydrogenolysis.) By hydrolysis, treatment with an acid or base, thermal decomposition or hydrogenolysis of R _a of the general formula I Convert to compound. A group that can be converted to a carboxy group is, for example, a carboxyl group protected with a protecting group, such as a functional derivative thereof, which is conveniently converted to a carboxyl group by hydrolysis, such as an unsubstituted or substituted amide thereof, Esters, thioesters, trimethylsilyl esters, orthoesters or iminoesters, their esters with tertiary alcohols which are conveniently converted to carboxyl groups by treatment with acid or thermal decomposition, for example tert-butyl ester, or by hydrogenolysis It may also be its ester with aralkanol, which is conveniently converted to a carboxyl group, such as the benzyl ester.

The hydrolysis may be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. Water, water / methanol, water / ethanol, in the presence
Water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water
/ Conveniently carried out in a suitable solvent such as dioxane at a temperature of 10 to 120 ° C., for example room temperature to a boiling temperature of the reaction mixture. When the compound of the formula IV has, for example, a tert-butyl group or a tert-butyloxycarbonyl group, it is treated with trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid. Acid, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at a temperature of -10 to 120 ° C, for example 0 to 60.
At a temperature of ° C or thermally, optionally methylene chloride, chloroform, benzene,
In an inert solvent such as toluene, tetrahydrofuran or dioxane, preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably the boiling temperature of the solvent used, e.g. It can be cut by treating it at a temperature of 40 to 120 ° C.

When the compound of formula IV has, for example, a benzyloxy group or a benzyloxycarbonyl group, it is subjected to hydrogenolysis in the presence of a hydrogenation catalyst such as palladium / charcoal in the presence of methanol, ethanol, ethanol / In a suitable solvent such as water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably 0-50 ° C.
Can be cleaved at a hydrogen pressure of 1 to 5 bar at a temperature of, for example, room temperature. d) In order to prepare a compound of the general formula I in which R _c is an amidino group substituted with an in vivo cleavable group,

[0024]

[Chemical 12]

(Wherein R _a and R _b are as defined above), a compound of the following general formula Z ₅ -R ₉ (VII) (wherein R ₉ is defined in claims 1 to 5) One of the in vivo cleavable groups described, Z ₅ being a halogen atom, for example chlorine, bromine or iodine, or a nucleofugal leaving group such as a p-nitrophenyl group. .). The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic base or a tertiary organic base, preferably at 20 ° C. It is carried out at the boiling temperature of the solvent used. In compounds of general formula VII where Z ₅ is a nucleofugal leaving group, the reaction is preferably methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone /
It is carried out in a solvent such as water, dimethylformamide or dimethylsulfoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert-butoxide or N-ethyldiisopropylamine, at a temperature of 0-60 ° C. e) to prepare compounds of general formula I in which R _c is one of the above amidino groups, the following general formula

[0026]

[Chemical 13]

Where R _a and R _b are as defined above and R _c ″ is 1,2,4-oxa substituted at the 5-position with a C _1-3 -alkyl group or a phenyl group. A diazol-3-yl group, wherein the phenyl substituent may be substituted with a fluorine atom, a chlorine atom or a bromine atom, or a C _1-3 -alkyl group. The compound thus obtained is hydrolyzed, if necessary, The catalytic hydrogenation is preferably methanol, ethanol, ethanol / water, glacial acetic acid, ethanol / glacial acetic acid, ethyl acetate, dioxane or It is carried out in the presence of a hydrogenation catalyst such as palladium on charcoal in a suitable solvent such as dimethylformamide, preferably at a temperature of 0 to 50 ° C., for example at room temperature and a hydrogen pressure of 1 to 5 bar. Hydrolysis that can be carried out is hydrochloric acid, sulfuric acid, phosphoric acid, Acid, trichloroacetic acid, trifluoroacetic acid or the presence or lithium hydroxide, such acids as mixtures thereof,
Temperature in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane -10 to 120 ° C. , Conveniently at room temperature to the boiling temperature of the reaction mixture. f) R _a is an amino-C _1-3 -alkyl group, wherein the amino group is carboxy-C _1-4-.
To prepare compounds of general formula I which are mono-substituted with an alkyl group or a tetrazolyl-C _1-4 -alkyl group, the compounds of the general formula

[0028]

[Chemical 14]

[0029] (wherein, R _b and R _c are as defined above, R _a "is amino -C _1-3 -. Alkyl group) following general formula to a compound having a R _a" '- Z ₇ (X) (wherein R _a "'is a carboxy-C _1-4 -alkyl group or a tetrazolyl-C _1-4 -alkyl group, and Z ₇ is a halogen atom or a sulfonate group, for example, chlorine. Atom, bromine atom or iodine atom, or a nucleofugal leaving group such as p-nitrophenyl group.) Alkylation is performed with methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl. In a solvent such as formamide or acetone, optionally in the presence of a reaction promoter such as sodium or potassium iodide, preferably in the presence of a base such as sodium carbonate or potassium carbonate, or N-ethyldiisopropionate. In the presence of a tertiary organic base, such as lopyramine or N-methylmorpholine, which can simultaneously act as a solvent, or optionally in the presence of silver carbonate or silver oxide, a temperature of -30 to 100 ° C, preferably Conveniently done at a temperature of -10 to 80 ° C.

If, according to the invention, _a compound of general formula I in which R _a has a carboxy group is obtained, it can subsequently be converted by esterification into the corresponding compound in which R _a has an esterified carboxy group, And / or when R _a provides a compound of general formula I having an esterified carboxy group,
Subsequently, when R _a by a transesterification reaction can be converted to the corresponding compounds having other esterified carboxy group, and / or R _a is a compound of the general formula I are obtained having a cyano group, subsequently , R _a can be converted to a corresponding compound having _a tetrazolyl group.

Subsequent esterification is carried out with the corresponding alcohol, usually in a solvent or mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, preferably in excess of the alcohol used. , Optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, such as isobutyl chloroformate, thionyl chloride, trimethylchlorosilane,
Hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentachloride, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldi Imidazole or N, N'-
Presence of a base such as potassium carbonate, N-ethyldiisopropylamine or N, N-dimethylaminopyridine, optionally in the presence of thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine / diethylazodicarboxylate. Below, conveniently at a temperature of 0-150 ° C, preferably at a temperature of 0-80 ° C,
Or a corresponding halide and a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction promoter such as sodium iodide or potassium iodide, preferably sodium carbonate. Or in the presence of a base such as potassium carbonate or in the presence of a tertiary organic base such as N-ethyldiisopropylamine or N-methylmorpholine which can simultaneously act as a solvent, or optionally silver carbonate or silver oxide. At a temperature of -30 to 100 ° C, preferably -10 to 80 ° C.

The subsequent transesterification reaction is carried out with the corresponding alcohol, conveniently in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, preferably in excess. Use in alcohol, conveniently in the presence of acid such as hydrochloric acid or like 2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo [3.3.3] undecane In the presence of such a compound at a temperature of 0 to 150 ° C, preferably at a temperature of 0 to 80 ° C. Subsequent conversion of the cyano group to the tetrazolyl group is preferably 80-150 ° C, preferably 120-130 ° C in a solvent such as benzene, toluene or dimethylformamide.
It is carried out at a temperature of ° C. The required triazo acid is conveniently liberated from the alkali metal azide, eg sodium azide, during the reaction in the presence of a weak acid such as ammonium chloride. The reaction can also be carried out with other salts or derivatives of triazo acid, preferably azidoaluminum or azidotributyltin, the tetrazole compound thus optionally obtained from the salt contained in the reaction mixture from 2N hydrochloric acid or 2N sulfuric acid. It is liberated by acidifying with a dilute acid such as.

In the above reaction, existing reactive groups such as carboxy, amino or alkylamino groups can be protected during the reaction with conventional protecting groups which are cleaved again after the reaction. For example, a protecting group for a carboxy group can be a trimethylsilyl group, a methyl group, an ethyl group, a tert-butyl group, a benzyl group or a tetrahydropyranyl group,
Amino group or alkylamino group protecting group is acetyl group, trifluoroacetyl group, benzoyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, benzyl group, methoxybenzyl group or 2,4-dimethoxybenzyl group. The protecting group for the amino group may be a phthalyl group. The protecting groups used are optionally subsequently followed, for example by hydrolysis, in an aqueous solvent,
For example, water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or an alkali such as lithium hydroxide, sodium hydroxide or potassium hydroxide. Cleavage can be carried out in the presence of a metal base or by ether cleavage, for example in the presence of iodotrimethylsilane, at a temperature of 0-100 ° C, preferably at a temperature of 10-50 ° C.

However, benzyl, methoxybenzyl or benzyloxycarbonyl groups can be hydrolyzed, for example, with hydrogen in the presence of a catalyst such as palladium / charcoal with methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide. / Cleavage in a solvent such as acetone or glacial acetic acid, optionally further with an acid such as hydrochloric acid at a temperature of 0-50 ° C, preferably at room temperature at a hydrogen pressure of 1-7 bar, preferably 3-5 bar. . The methoxybenzyl group is 0 to 0 in a solvent such as methylene chloride, acetonitrile or acetonitrile / water in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate.
It is also possible to cut at a temperature of 50 ° C., preferably room temperature. However, the 2,4-dimethoxybenzyl group is preferably cleaved in the presence of anisole in trifluoroacetic acid. The tert-butyl group or tert-butyloxycarbonyl group is cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally with a solvent such as methylene chloride, dioxane or ether. The phthalyl group is preferably at a temperature of 20-50 ° C. in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine. Disconnect with.

The allyloxycarbonyl group is a catalytic amount of tetrakis (triphenylphosphine).
0 to 1 with palladium (O), preferably in a solvent such as tetrahydrofuran, preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone.
By treatment under inert gas at a temperature of 00 ° C., preferably room temperature, or with a catalytic amount of tris (triphenylphosphine) rhodium (I) chloride in a solvent such as aqueous ethanol, optionally 1,4-diazabicyclo. [2.2.2] Cleavage by treatment in the presence of a base such as octane at a temperature of 20-70 ° C. The compounds of the general formulas II to X used as starting materials, some of which are known from the literature, are obtained by methods known from the literature, the preparation of which is described in the examples. The chemistry of compounds of general formula II is described, for example, by Jack Robinson, J. Chem. Soc. 1941 , 7
44, the chemistry of benzimidazoles is described by Katritzky & Rees, Comprehensiv.
e Heterocyclic Chemistry, Oxford, Pergamon Press, 1984; Schaumann, Hetar
ene III, Methoden der organischen Chemie (Houben-Weyl), 4th edit., Thiem
e, Stuttgart 1993.

Thus, for example, compounds of general formula II are obtained by acylating the corresponding o-diamino compounds with the corresponding reactive acyl derivatives, compounds of general formula III, IV, VI, VIII or IX being , The corresponding substituted compounds are cyclized according to step a) and, if necessary, the cyano compounds thus obtained are converted into the desired starting compounds using known methods. Furthermore, the compounds of general formula I obtained can be resolved into their enantiomers and / or diastereomers. Thus, for example, the resulting compound of general formula I present as a racemate is
Known method (Allinger NL & Eliel EL, "Topics in Stereochemistry",
See Vol. 6, Wiley Interscience, 1971. Compounds of general formula I, which can be separated into their optical antipodes with) and have at least two asymmetric carbon atoms, are physicochemical using known methods, for example by chromatography and / or fractional crystallization. The diastereomers can be resolved based on the difference, and if the compounds are obtained in racemic form, they can be subsequently resolved into the enantiomers as described above.

The enantiomer is preferably a column separation by a chiral phase or recrystallization from an optically active solvent or a salt or derivative, for example, an optically active substance which forms an ester or an amide with a racemate, particularly an acid or an activated derivative thereof. Or a diastereomeric mixture of salts or derivatives thus obtained by reacting with an alcohol, for example:
Separated by separation on the basis of solubility differences, the free enantiomers can be released from the pure diastereomeric salt or derivative by the action of the appropriate drug. Conventional optically active acids are, for example, the D or L form of tartaric acid or dibenzoyltartaric acid, di-o-tolyl tartaric acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. The optically active alcohol may be, for example, (+) or (−)-methanol, and the optically active acyl group of the amide may be, for example, (+)-or (−)-menthyloxycarbonyl. Furthermore, the compounds of formula I can be converted into their salts, especially for pharmaceutical use, into physiologically acceptable salts with inorganic or organic acids. Acids which can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Furthermore, if the novel compounds of formula I have a carboxy group, then, if desired, subsequently with salts with inorganic or organic bases, especially physiologically acceptable salts for pharmaceutical use. Can be converted to. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine or triethanolamine. As mentioned above, the novel compounds of general formula I or their salts possess valuable properties. Thus, compounds of general formula I in which R _c is a cyano group are useful intermediate products for preparing other compounds of general formula I, in which general formula I in which R _c is one of the amidino groups described above. , Its tautomers, stereoisomers or physiologically acceptable salts are effective pharmacological properties, particularly preferably affecting thrombin or factor Xa, for example, inhibitory action against thrombin or factor Xa. , Has an antithrombotic effect based on the effect of prolonging aPTT time or an inhibitory effect on related serine proteases such as trypsin, urokinase factor VIIa, factor IX, factor XI or factor XII. For example, the following compound: A = 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole Dihydrochloride, B = (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1-[(R, S) -2-methyl-pyrroli Dinocarbonyl] ethyl] benzimidazole dihydrochloride or C = (2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (2,5-dihydro The effect of prolonging the aPTT time was investigated for pyrrolocarbonyl) ethyl] benzimidazole dihydrochloride as follows.

Materials: Plasma, human citrated blood, PTT reagent, Boehringer Mannheim (524298), calcium solution (0.025 mol / l), Behring Werke, Marburg (ORH 056/57) , Diethyl barbituric acid acetate buffer, Behringberge, Marburg
(ORWH 60/61), Biomatic B10 Coagulometer, Desaga, Wiesloch. Method: aPTT time was determined using a Biotic B10 Coagulometer manufactured by Messrs. Desaga. The test substances were placed in the tubes specified by the manufacturer with 0.1 ml of human citrated plasma and 0.1 ml of PTT reagent. The mixture was incubated at 37 ° C for 3 minutes. The coagulation reaction was initiated by adding 0.1 ml of calcium solution. The time from the addition of the calcium solution to the coagulation of the mixture is measured with the device. 0.1 ml DB
The mixture containing A buffer was used as a control. According to the definition, a dose-activity curve was used to determine the effective concentration of the substance, ie the concentration at which the aPTT time was doubled compared to the control. The following table shows the results.

[0040]

[Table 1]

The compounds prepared according to the present invention are well tolerated because no toxic side effects could be detected at therapeutic doses. Furthermore, the corresponding prodrugs, eg the compounds of Examples 1 (6), 2, 3 (2) and 3 (5), have good oral absorption. From the viewpoint of pharmacological properties, the novel compounds or physiologically acceptable salts thereof are used for the prevention and treatment of venous or arterial thrombosis, for example, for the treatment of deep leg venous thrombosis, bypass surgery or angioplasty (PT). (C) A) Suitable for post-reocclusion or peripheral arterial embolism, for example, prevention of pulmonary embolism, disseminated intravascular coagulation, coronary thrombosis, stroke or shunt occlusion. Further, the compounds of the present invention may be used in thrombolytic therapy, e.g., antithrombotic support in rt-PA or streptokinase, prevention of long-term restenosis after PT (C) A, metastasis and clot-dependent tumors or fibrin-dependent. It is suitable for preventing the growth of inflammatory bumps, for example for treating pulmonary fibrosis. The dose required to obtain such effects is about 0.1-30 mg by the intravenous route.
/ kg, preferably 0.3-10 mg / kg, 0.1-50 mg / kg by oral route, preferably 0.3-30
mg / kg, in each case administered 1 to 4 times daily. for that purpose,
A compound of formula I prepared according to the invention is optionally combined with other active substances in one or more conventional inert carriers and / or diluents such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, With a fatty substance such as polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or hard fat or suitable mixtures thereof. Prescribed plain or coated tablets, capsules,
Conventional galenical formulations such as powders, suspensions or suppositories can be prepared. The following example illustrates the invention.

[0042] Example 1 (R) -2- [4- [N- (4-Methylphenylcarbonyl) amidino] phenylaminomethyl] -1
-Methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl)D Chill] benzimidazole a. (R) -5- (4-chloro-3-nitrophenyl) -5-methylimidazolidine-2,4-dione   10.0 g (4.45 mmol) of (R) -5- (4-chlorophenyl) -5-methylimidazolidine
-2,4-dione is added batchwise to 50 ml fuming nitric acid at -25 to -35 ° C. -25 to -20 ℃
After 45 minutes, pour the reaction mixture into ice water. The crystalline product is suction filtered and filtered with water.
Wash and dry. Yield: 10.5 g (100% of theory) Melting point: 173-178 ℃ R_f Value: 0.30 (silica gel; cyclohexane / ethyl acetate = 1: 1)b. (R) -2-amino-2- (4-chloro-3-nitrophenyl) propionic acid   10.5 g (0.044 mol) of (R) -5- (4-chloro-3-nitrophenyl) -5-methylimidazo
Reflux lysine-2,4-dione in 200 ml dioxane and 700 ml 6N hydrochloric acid for 5 days.
. The solution is concentrated by evaporation, the residue is taken up in water and extracted with ethyl acetate. The water phase
It is concentrated by evaporation, mixed with toluene and evaporated to dryness. Triturate the residue with ether and absorb
Filter and dry. Yield: 6.8 g (63% of theory) R_f Value: 0.24 (reverse phase RP8, 5% saline / methanol = 1: 1)

[0043] c. (R) -2-tert-butyloxycarbonylamino-2- (4-chloro-3-nitrophenyl) Propionic acid   72.5 g (0.296 mol) of (R) -2-amino-2- (4-chloro-3-nitrophenyl) propio
Dissolve the acid in 850 ml of dioxane and 200 ml of water and add 108.7 ml (0.78 mol) of tricarboxylic acid.
Add ethylamine and 136 g (0.623 mol) of di-tert-butyl dicarbonate
After that, the mixture is stirred at room temperature for 18 hours. After adding 800 ml of 1N sodium hydroxide solution,
The solution is stirred for 30 minutes and then extracted 3 times with 500 ml ether. Aqueous phase 1N salt
Adjust to pH 7 with acid and then to pH 4 with 5% citric acid. 4 with 500 ml ethyl acetate
After extraction twice, the combined organic phases are washed with water, dried and suctioned with magnesium sulphate.
Filter and concentrate by evaporation. Yield: 86.8 g (85% of theory) R_f Value: 0.3 (silica gel; methylene chloride / methanol = 4: 1 + 1% ammonia) C₁₄H₁₇ClN₂O₆ (344.7) Mass spectrum: (M-H)^- = 343

[0044] d. (R) -2-tert-butyloxycarbonylamino-2- (4-methylamino-3-nitrof
Phenyl) propionic acid
  96 g (0.278 mol) of (R) -2-tert-butyloxycarbonylamino-2- (4-chloro-
Add 3-nitrophenyl) propionic acid and 440 ml of methylamine solution (40% aqueous solution).
Heat at 90 ° C in a pressure vessel for 7 hours. After cooling, add glacial acetic acid to the reaction solution.
Is adjusted to pH 3.5, cooled with ice and extracted with ethyl acetate. Evaporate the solvent and leave
The remaining residue is washed with ether and dried. Yield: 70 g (74% of theory) R_f Value: 0.30 (silica gel; methylene chloride / ethanol = 19: 1 + 1% glacial acetic acid) C₁₅H_{twenty one}N₃O₆ (339.3) Mass spectrum: (M-H)^- = 338 e. (R) -2- (4-methylamino-3-nitrophenyl) -2-tert-butyloxycarbonyl Amino-1-pyrrolidinopropanone   50 g (0.147 mol) of (R) -2-tert-butyloxycarbonylamino-2- (4-methyl
Amino-3-nitrophenyl) propionic acid dissolved in 275 ml dimethylformamide
47.5 g (0.147 mol) of O- (benzotriazol-1-yl) -N, N, N ', N'-tetrame
Cyluronium tetrafluoroborate, 24.5 g (0.334 mol) of pyrrolidine and
After adding 30 ml (0.273 mol) of N-methylmorpholine, the mixture was allowed to stand at room temperature for 2 hours.
Stir for a while. The solution is poured into ice water and acidified with citric acid (pH 5-6). occured
The precipitate is suction filtered, washed with water and dried. Yield: 45.5 g (79% of theory) R_f Value: 0.6 (silica gel; petroleum ether / ethyl acetate = 1: 1)

[0045] f. (R) -2- (4-Methylamino-3-aminophenyl) -2-tert-butyloxycarbonyl Amino-1-pyrrolidinopropanone   25.5 g (65 mmol) of (R) -2- (4-methylamino-3-nitrophenyl) -2-tert-butane
Add tyloxycarbonylamino-1-pyrrolidinopropanone to 650 ml of methanol.
After dissolution and addition of 4.0 g palladium / activated carbon (20%), the mixture was stirred at room temperature for 2 times.
Hydrogenate for hours. Then the catalyst is filtered off and concentrated by evaporation. Yield: 21.4 g (91% of theory) R_f Value: 0.31 (silica gel; ethyl acetate + 1% ammonia) g. (R) -2- [4-methylamino-3- (4-cyanophenylaminomethylcarbonylamino ) Phenyl] -2-tert-butyloxycarbonylamino-1-pyrrolidinopropanone   (R) -2- (4-methylamino-3-aminophenyl) -2-tert- in dimethylformamide
Butyloxycarbonylamino-1-pyrrolidinopropanone, O- (benzotriazol
(L-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 4-shi
Prepared from anophenylglycine and N-methylmorpholine as in Example 1e.
It was Yield: 100% of theory R_f Value: 0.47 (silica gel; ethyl acetate)

[0046] h. (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (N-tert-butyloxy Cycarbonylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole   47.7 g (0.042 mol) of (R) -2- [4-methylamino-3- (4-cyanophenylaminometh
Cylcarbonylamino) phenyl] -2-tert-butyloxycarbonylamino-1-pi
Reflux lolidinopropanone in 300 ml glacial acetic acid for 2 hours. Reaction mixture in ice water
Add and adjust to pH 8 with concentrated ammonia. The precipitate formed is filtered off, washed with water and dried.
It Yield: 46 g (100% of theory) R_f Value: 0.3 (silica gel; ethyl acetate + 1% ammonia) i. (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-amino-1- (pyrrolidi Nocarbonyl) ethyl] benzimidazole   25.1 g (50 mmol) of (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- [
1- (N-tert-butyloxycarbonylamino) -1- (pyrrolidinocarbonyl) ethyl]
Dissolve benzimidazole in 500 ml of 6N hydrochloric acid at 35 ° C and stir at this temperature for 1 hour.
To do. The solution is mixed with ice, made alkaline with ammonia and extracted with ethyl acetate.
To do. The combined organic extracts are dried and concentrated by evaporation. Yield: 17.8 g (88% of theory) R_f Value: 0.5 (silica gel; methylene chloride / ethanol = 4: 1 + 1% ammonia)

[0047] k. (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5- (1-ethoxycarbonyl Methylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole   4.2 g (10.44 mmol) of (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5
Add 100 ml of-[1-amino-1- (pyrrolidinocarbonyl) ethyl] benzimidazole.
Dissolve in cetone, add 2.3 g (16.65 mmol) potassium carbonate and 2.25 ml (20.2 mm).
Mol) bromine ethyl acetate. The suspension is heated to 60 ° C. for 5 hours. Cool down
After that, the reaction mixture was stirred in 400 ml of ice water, the precipitate formed was filtered off, washed with water and dried.
To do. The crude product is chromatographed on silica gel with methylene chloride / ethane.
Elute with the nols (19: 1 and 9: 1). Identical fractions are combined and concentrated by evaporation. Yield: 3.1 g (61% of theory) R_f Value: 0.4 (silica gel; ethyl acetate / ethanol = 9: 1) l. (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (1-ethoxycarboxyl
Bonylethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole salt
Acid salt   6.8 g (13.8 mmol) of (R) -2- (4-cyanophenylaminomethyl) -1-methyl-5-
[1-Ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benz
Dissolve imidazole in 400 ml of saturated ethanolic hydrochloric acid and stir at room temperature for 23 hours.
The solvent was evaporated and the residue was dissolved in 200 ml absolute ethanol to give 20 g (0.21 mol)
Combine with ammonium carbonate. After 20 hours at room temperature, add 100 ml of ethanol,
After further stirring for 10 hours at room temperature, the mixture is filtered and evaporated and stirred. 20 residues
Dissolve in 0 ml acetone, filter off, wash with ether and dry. Yield: 7.6 g (100% of theory) R_f Value: 0.61 (reverse phase RP8; 5% sodium chloride solution / methanol = 3: 2) C₂₇H₃₆N₇O₃ × HCl (505.64 / 542.09) Mass spectrum: (M + H)⁺ = 506

M. (R) -2- [4- [N- (4-methylphenylcarbonyl) amidino] phenylaminomethyl
] -1-methyl-5- [1- (ethoxycarbonylmethyl) -1- (pyrrolidinopyridine carbonylation) ethyl] benzimidazole 25 ml of methylene chloride 0.7 g of (1.2 mmol) (R) -2 A suspension of-(4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole dihydrochloride in 4.0 ml (28 mmol ) And 0.8 g (3.0 mmol) 4-nitrophenyl 4-methylbenzoate and heated to 50 ° C. for 3.5 hours, at which time a clear solution results.
After cooling, wash with sodium bicarbonate solution, brine and water, dry over magnesium sulfate and concentrate by evaporation. The crude product is purified by silica gel, eluting with ethyl acetate / ethanol (50: 1 and 9: 1). Identical fractions are combined, concentrated by evaporation, triturated with ether, suction filtered and dried. Yield: 0.5 g (66% of theory) R _f value: 0.50 (silica gel; ethyl acetate / ethanol = 9: 1) C ₃₅ H ₄₁ N ₇ O ₄ (623.75) Mass spectrum: (M + H) ⁺ = 624 (M + Na) ⁺ = 646 (MH) ^- = 622

The following compounds are obtained as in Example 1. (1) (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (isopropyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole acetate Yield: 69% of theory R _f value: 0.2 (silica gel; methylene chloride / ethanol = 7: 3 + 1% glacial acetic acid) C ₂₈ H ₃₇ N ₇ O ₃ × CH ₃ COOH (519.65 / 579.70) Mass spectrum: (M + H) ⁺ = 520 (MH) ^- = 518 (2) (R) -2- [4- [N- (4-fluorophenylcarbonyl) amidino] phenylaminomethyl] -1-methyl-5- [1- ( Ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole Yield: 40% of theory R _f value: 0.4 (silica gel; ethyl acetate / ethanol = 9: 1 + 1% ammonia) C ₃₄ H ₃₈ FN ₇ O ₄ (627.72) Mass spectrum: (M + H) ⁺ = 628 (M + Na) ⁺ = 650 (MH) ^- = 626

(3) (R) -2- [4- [N- (4-trifluoromethylphenylcarbonyl) amidino] phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino)- 1- (Pyrrolidinocarbonyl) ethyl] benzimidazole Yield: 47% of theory R _f value: 0.53 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 0.9: 0.
1) C ₃₅ H ₃₈ F ₃ N ₇ O ₄ (677.73) Mass spectrum: (M + H) ⁺ = 678 (M + Na) ⁺ = 700 (MH) ^- = 676 (4) (R) -2- [ 4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (tetrazol-5-ylmethylamino) -1- (pyrrolidinocarbonyl) ethyl
] Benzimidazole (5) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole dihydrochloride Salt yield: 94% of theory R _f value: 0.2 (reverse phase RP8; 5% saline / methanol = 2: 3) C ₂₇ H ₃₃ N ₇ O ₃ × 2 HCl (503.6 / 576.51) Mass spectrum: (M + H) ⁺ = 504 (M-H + HCl) ^- = 538/540 (Cl)

(6) 2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5-
[1- (Ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole Yield: 71% of theory R _f value: 0.3 (silica gel; ethyl acetate / ethanol = 9: 1) C ₃₄ H ₃₇ N ₇ O ₄ (607.72) Mass spectrum: (M + H) ⁺ = 608 (M + Na) ⁺ = 630 (MH) ^- = 606 (7) (R) -2- (4-amidinophenylamino Methyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1-[(R, S) -1-methylpyrrolidinocarbonyl] ethyl] benzimidazole dihydrochloride (mixture of diastereomers) Yield : 88% of theory R _f value: 0.3 (reverse phase RP8; 5% saline / methanol = 3: 2) C ₂₈ H ₃₇ N ₇ O ₃ × 2 HCl (519.65 / 592.56) Mass spectrum: (M + H ) ⁺ = 520 (M + Cl) ^- = 554/6 (Cl)

(8) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (3-ethoxycarbonylpropylamino) -1- (pyrrolidino Carbonyl) ethyl] benzimidazole Yield: 19% of theory R _f value: 0.44 (silica gel; methylene chloride / methanol = 4: 1 + 1% glacial acetic acid) C ₃₆ H ₄₃ N ₇ O ₄ (637.79) mass spectrum: ( M + H) ⁺ = 638 (MH) ^- = 636 (9) (R) -2- [4- (Nn-hexyloxycarbonylamidino) phenylaminomethyl]
-1-Methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole Yield: 70% of theory R _f value: 0.37 (silica gel; ethyl acetate / ethanol = 9: 1) C ₃₅ H ₄₉ N ₇ O ₅ (647.82) Mass spectrum: (M + Na) ⁺ = 670 (MH) ^- = 646

Example 2 (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5-
Of 0.3 g (0.53 mmol) in [1-(n- butyloxycarbonyl-methylamino) -1- (pyrrolidinocarbonyl) ethyl le] benzimidazole 5 ml of n- butanol (R) -2- [4- ( 0.1 g of a solution of N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
(0.46 mmol) 2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo [
3.3.3] Mix with undecane and stir at room temperature for 1 hour. The reaction mixture was purified by silica gel, ethyl acetate / ethanol / concentrated ammonia (50: 0.95: 0.05 and 20: 0.95: 0.
Elute with 05). Identical fractions are combined and concentrated by evaporation. Yield: 0.19 g (57% of theory) R _f value: 0.45 (silica gel; ethyl acetate / ethanol = 9: 1 + 1% ammonia) C ₃₆ H ₄₃ N ₇ O ₄ (637.78) Mass spectrum: (M + H ) ⁺ = 638 (M + Na) ⁺ = 660 (MH) ^- = 636

The following compounds are obtained as in Example 2. (1) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (isobutyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl
) Ethyl] benzimidazole Yield: 16% of theory R _f value: 0.48 (silica gel; ethyl acetate / ethanol = 9: 1 + 1% ammonia) C ₃₆ H ₄₃ N ₇ O ₄ (637.78) Mass spectrum: (M + H) ⁺ = 638 (M + Na) ⁺ = 660 (MH) ^- = 636 (2) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [ 1- (2-Methoxyethyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole Yield: 43% of theory R _f value: 0.31 (silica gel; ethyl acetate / ethanol = 9: 1 + 1% Ammonia) C ₃₅ H ₄₁ N ₇ O ₅ (639.76) Mass spectrum: (M + H) ⁺ = 640 (MH) ^- = 638

(3) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (2-dimethylaminoethyloxycarbonylmethylamino) -1- (Pyrrolidinocarbonyl) ethyl] benzimidazole Yield: 23% of theory R _f value: 0.26 (silica gel; methylene chloride / methanol / ammonia = 9: 0.9: 0.1
) C ₃₆ H ₄₄ N ₈ O ₄ (652.8) Mass spectrum: (M + H) ⁺ = 651 (MH) ^- = 653

(4) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (2- (2-methylphenyl) ethyloxycarbonylmethylamino ) -1- (Pyrrolidinocarbonyl) ethyl] benzimidazole Yield: 23% of theory R _f value: 0.52 (silica gel; ethyl acetate / ethanol / ammonia = 9: 0.95: 0.05)
C ₄₁ H ₄₅ N ₇ O ₄ (699.86) Mass spectrum: (M + H) ⁺ = 700 (M + Na) ⁺ = 722 (MH) ^- = 698 (5) (R) -2- [4- (N -Phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (cyclohexyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole Yield: 34% of theory R _f value: 0.49 (Silica gel; ethyl acetate / ethanol = 9: 1 + 1% ammonia) C ₃₈ H ₄₇ N ₇ O ₄ (663.83) Mass spectrum: (M + H) ⁺ = 664 (M + Na) ⁺ = 686 (MH) ^- = 662

[0057] Example 3 (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5-
[1- (isopropyloxycarbonylmethylamino) -1- (2,5-dihydropyrrolocar
Bonyl) ethyl] benzimidazole   2.1 ml concentrated sulfuric acid was added to 0.5 g (0.82 mmol) of (R) in 12.3 ml isopropanol.
-2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1-
(Ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl]
Add dropwise to benzimidazole. After 4 hours at 85 ° C, the solution was cooled and 250 ml of
Pour into ice water. Adjust the pH to 8.5 by adding concentrated ammonia. Occur
The precipitate formed is suction filtered, dried, purified on silica gel and washed with methylene chloride + 2% methanol.
Elute with tanol + 0.01% ammonia. Combine the same fractions, evaporate and concentrate,
The residue is triturated with ether, filtered off and dried. Yield: 0.19 g (37% of theory) R_f Value: 0.46 (silica gel; ethyl acetate / ethanol = 9: 1 + 1% ammonia) C₃₅H₃₉N₇O_Four (621.75) Mass spectrum: (M + H)⁺  = 622                  (M + Na)⁺ = 644                  (M-H)^-  = 620

The following compounds are obtained as in Example 3. (1) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1- (2,5- Dihydropyrrolocarbonyl) ethyl] benzimidazole Yield: 33% of theory R _f value: 0.46 (silica gel; ethyl acetate / ethanol = 9: 1 + 1% ammonia) C ₃₅ H ₃₉ N ₇ O ₄ (621.75) Mass spectrum: (M + H) ⁺ = 622 (M + Na) ⁺ = 644 (MH) ^- = 620 (2) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl- 5- [1- (n-propyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl
) Ethyl] benzimidazole Yield: 36% of theory R _f value: 0.45 (silica gel; ethyl acetate / ethanol = 9: 1 + 1% ammonia) C ₃₅ H ₄₁ N ₇ O ₄ (623.76) Mass spectrum: (M + H) ⁺ = 624 (M + Na) ⁺ = 646 (MH) ^- = 622

(3) (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (n-butyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benz Imidazole dihydrochloride Yield: 8% of theory R _f value: 0.44 (silica gel; methylene chloride / methanol = 4: 1 + 1% ammonia) C ₂₉ H ₃₉ N ₇ O ₃ × 2 HCl (533.69 / 606.6) mass spectrum : (M + H) ⁺ = 534 (MH) ^- = 532 (4) (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) ) -1- (Pyrrolidinocarbonyl) ethyl] benzimidazole sulfate Yield: 7% of theory R _f value: 0.36 (silica gel; methylene chloride / methanol = 4: 1 + 1% ammonia) C ₂₈ H ₃₇ N ₇ O ₃ × H ₂ SO ₄ (519.65 / 617.7) Mass spectrum: (M + H) ⁺ = 520

(5) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (cyclohexyloxycarbonylmethylamino) -1- (2,5 -Dihydropyrrolocarbonyl) ethyl] benzimidazole Yield: 22% of theory R _f value: 0.60 (silica gel; ethyl acetate / ethanol = 9: 1 + 1% ammonia) C ₃₈ H ₄₃ N ₇ O ₄ (661.81) mass spectrum : (M + H) ⁺ = 662 (M + Na) ⁺ = 684 (MH) ^- = 660 (6) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl -5- [1- (3- (isopropyloxycarbonyl) propylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole (7) (R) -2- [4- (N-phenylcarbonylamidino) phenylamino Methyl] -1-methyl-5- [1- (3- (n-propyloxycarbonyl) propylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole

[0061] Example 4 (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazole-5-y
Lumethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole a. 4- (5-Methyl-1,2,4-oxadiazol-3-yl) phenylaminoethylacetate
Out   4- (5-methyl-1,2,4-oxadiazole-3- in N-ethyldiisopropylamine
Prepared as in Example 1k from yl) aniline and ethyl bromoacetate. Yield: 78% of theory R_f Value: 0.60 (silica gel; ethyl acetate / petroleum ether = 1: 1) b. 4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl-N-tert-butyloxy
Cycarbonylaminoethyl acetate   4- (5-methyl-1,2,4-oxadiazol-3-yl) phenylaminoe in dioxane
Tyl acetate and di-tert-butyl dicarbonate / N-ethyl diisopropyl acetate
Prepared as in Example 1c from Min. Yield: 63% of theory R_f Value: 0.48 (silica gel; ethyl acetate / cyclohexane = 1: 2)

[0062] c. 4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl-N-tert-butyloxy
Cycarbonylaminoacetic acid   3.5 g (9.7 mmol) 4- in 10 ml tetrahydrofuran and 4 ml methanol
(5-Methyl-1,2,4-oxadiazol-3-yl) phenyl-N-tert-butyloxycal
Bonyl aminoethyl acetate was added to 9.7 ml of 1N sodium hydroxide solution (9.7 millimolar).
And stirred at room temperature for 3 hours. Evaporate the reaction mixture to half its volume
, Mix with water. The pH value was adjusted to 4-5 by adding glacial acetic acid and the resulting precipitate
The lord is filtered off, washed with water and dried. Yield: 2.8 g (87% of theory) R_f Value: 0.5 (reverse phase RP8; 5% saline / methanol = 1: 3) d. (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl-N-tert-butyl
Luoxycarbonyl-aminomethyl] -1-methyl-5- [2-tert-butyloxycarboni Luamino-1- (pyrrolidinocarbonyl) ethyl] benzimidazole   (R) -2- (4-Methylamino-3-aminophenyl) -2-tert-buth in tetrahydrofuran
Tyloxycarbonylamino-1-pyrrolidinopropanone, 4- (5-methyl-1,2,4-o-
(Xadiazol-3-yl) phenyl-N-tert-butyloxycarbonylaminoacetic acid
And carbonyldiimidazole were prepared in the same manner as in Example 1g / h, followed by ice
Treat with acetic acid. Yield: 47% of theory R_f Value: 0.46 (silica gel; ethyl acetate)

[0063] e. (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenylaminomethyi
] -Methyl-5- [1-amino-1- (pyrrolidinocarbonyl) ethyl] benzimidazo Le   (R) -2- [4- (5-Methyl-1,2,4-oxadiazol-3-yl) phenyl-N-tert-butyl
Luoxycarbonylaminomethyl] -1-methyl-5- [2-tert-butyloxycarboni
Lu-amino-1- (pyrrolidinocarbonyl) ethyl] benzimidazole and 6N hydrochloric acid
Were prepared as in Example 1i. Yield: 91% of theory R_f Value: 0.44 (silica gel; methylene chloride / methanol / ammonia = 9: 0.9: 0.1) f. (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenylaminomethyl
] -1-Methyl-5- [1-cyanomethylamino-1- (pyrrolidinocarbonyl) ethyl] benThe Imidazole   (R) -2- [4- (5-Methyl-1,2,4-oxadiazol-3-yl) phenyla in acetone
Minomethyl] -1-methyl-5- [1-amino-1- (pyrrolidinocarbonyl) ethyl] benzii
Same as Example 1k from midazole and bromoacetonitrile / potassium carbonate
Prepare. Yield: 72% of theory R_f Value: 0.54 (silica gel; ethyl acetate / ethanol = 9: 1 + 1% ammonia) C₂₇H₃₀N₈O₂ (498.59) Mass spectrum: (M + H)⁺  = 499                  (M-H)^-  = 497                  (M + Na)⁺ = 521

G. (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenylaminomethyl
] -1-methyl-5- [1- (tetrazol-5-yl methyl) -1- (pyrrolidinopyridine carbonylation
) Ethyl] benzimidazole 1.1 g of (2.2 mmol) (R) -2- [4- ( -3- 5- methyl-1,2,4-oxadiazol-yl)
Phenylaminomethyl] -1-methyl-5- [1-cyanomethylamino-1- (pyrrolidinocarbonyl) ethyl] benzimidazole was suspended in 20 ml toluene and 60 ml dioxane to give 2.2 g (6.6 mmol). Combine with tributyltin azide. 1 reaction mixture
Heat to 30 ° C for 6 hours. After evaporation of the solvent, the residue was triturated with petroleum ether,
Filter, wash with petroleum ether and dry. The crude product is purified by silica gel, eluting with methylene chloride / methanol 20: 1 and 9: 1. Identical fractions are combined and concentrated by evaporation. Yield: 0.7 g (59% of theory) R _f value: 0.33 (silica gel; methylene chloride: methanol = 9: 1) C ₂₇ H ₃₁ N ₁₁ O ₂ (541.6) Mass spectrum: (MH) ^- = 540 (M + Na) ⁺ = 564

[0065] h. (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazole-5- Ilmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole   In ethanol / glacial acetic acid (R) -2- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl
Phenylaminomethyl] -1-methyl-5- [1- (tetrazol-5-ylmethylamino) -1- (
Pyrrolidinocarbonyl) ethyl] benzimidazole and hydrogen / palladium (20% /
Activated carbon) in the same manner as in Example 1h. Yield: 63% of theory R_f Value: 0.35 (reverse phase RP8; 5% saline / methanol = 4: 3) C_{twenty five}H₃₁N₁₁O (501.6) Mass spectrum: (M + H)⁺ = 502                  (M-H)^- = 500

[0066] Example 5 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyl Luoxymethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole acetate a. Methyl 2- (4-chlorophenyl) -3-hydroxy-2-methylpropionate   35 ml of a 1.6 molar solution of n-butyllithium / hexane (61 mmol) in 20 ml of tet
To a solution of 8.1 ml diisopropylamine (85 mmol) in lahydrofuran at -78 ° C.
Drop it. Then 10.0 g (50 mmol) of methyl in 30 ml of tetrahydrofuran.
 A solution of 2- (4-chlorophenyl) -propionate is added dropwise at -78 ° C. Gas hol
Mulaldehyde is piped into the reaction mixture for 30 minutes at -20 ° C. Add 5% citric acid and glacial acetic acid
After addition, the mixture is extracted with ethyl acetate. The organic phase is 1N sulfuric acid, water, sodium bicarbonate.
Wash with saturated ammonium solution and brine, dry over magnesium sulfate. The crude product is
Purified by Rica gel, cyclohexane / ethyl acetate (19: 1; 9: 1; 4: 1; 1: 1 and
Elute with 0: 1). Identical fractions are combined and concentrated by evaporation. Yield: 9.7 g of yellow oil (84% of theory) R_f Value: 0.25 (silica gel; petroleum ether / ethyl acetate = 4: 1)

B. 2- (4-Chlorophenyl) -3-hydroxy-2-methylpropionate Methyl 2- (4-chlorophenyl) -3-hydroxy -2-methylpropionate in ethanol and from sodium hydroxide solution Prepare as in Example 8. Yield: 83% of theory R _f value: 0.55 (silica gel; ethyl acetate / cyclohexane = 2: 1 + 1% glacial acetic acid) c. 2- (4-chloro-3-nitrophenyl) -2-methyl-3- Prepared as in Example 1a from 2- (4-chlorophenyl) -3-hydroxy-2-methylpropionic acid nitrooxypropionic acid and nitric acid. Yield: 90% of theory Melting point: 129-132 ° C C ₁₀ H ₉ ClN ₂ O ₇ (304.64) d. 2- (4-chloro-3-nitrophenyl) -2-methyl-3-hydroxypropionic acid in dioxane Prepared as in Example 1i from 2- (4-chloro-3-nitrophenyl) -3-nitrooxy-2-methylpropionic acid and 6N hydrochloric acid. Yield: 98% of theory C ₁₀ H ₁₀ ClNO ₅ (259.65) Mass spectrum: (MH) ^- = 258/60 (Cl) (2M-H) ^- = 517/9 (Cl ₂ ).

[0068] e. 2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-hydroxy Propionic acid   2- (4-chloro-3-nitrophenyl) -3-hydroxy-2-methylpropionic acid and N-
Prepared as in Example 1e from methylbenzylamine. Yield: 81% of theory C₁₈H₂₀ClN₂O_Five (344.37) Mass spectrum: M⁺ = 344 f. 2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-hydroxy -1-pyrrolidin-1-yl-propan-1-one   2- [4- (N-benzylmethylamino) -3-nitrophenyl] -3-hydroxy-2-methyl
Prepared as in Example 1e from propionic acid and pyrrolidine. Yield: 96% of theory C_{twenty two}H₂₇N₃O_Four (397.48) Mass spectrum: M⁺     = 398                 (M + Na)⁺ = 420

[0069] g. 2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-ethoxycarbox Rubonylmethyloxy-1-pyrrolidinopropan-1-one   8.0 g (20 mmol) of 2- [4- (N-benzylmethylamido) in 50 ml of methylene chloride
No) -3-Nitrophenyl] -2-methyl-3-hydroxy-1-pyrrolidinopropan-1-one
And a solution of 5 ml (48 mmol) of ethyl diazoacetate in 2.0 ml of boron trifluoride-diene
Mix with chill ether complex (16 mmol) at room temperature and reflux for 14 hours. After cooling
The reaction solution is put into ice water and stirred, and the organic phase is separated. Aqueous phase with methylene chloride 3 times
The extracted and combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation.
To do. The residue was dissolved in ethyl acetate and purified on silica gel, first with petroleum ether.
Tell, then with petroleum ether / ethyl acetate (1: 1). Combine the same fractions,
Evaporate and concentrate. Yield: 2.5 g (26% of theory) R_f Value: 0.6 (silica gel; ethyl acetate) C₂₆H₃₃N₃O₆ (483.57) Mass spectrum: (M + H)⁺ = 484

[0070] h. 2- (4-methylamino-3-aminophenyl) -2-methyl-3-ethoxycarbonylmethy Luoxy-1-pyrrolidinopropan-1-one   2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-ethoxymeth
Tyloxy-1-pyrrolidin-1-ylpropan-1-one and hydrogen / palladium / activated carbon
From Example 1f. Yield: 81% of theory R_f Value: 0.40 (silica gel; methylene chloride / ethanol = 19: 1) i. 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyl
(Tyroxymethyl) -1- (pyrrolidinocarbonyl) ethylbenzimidazole   2- (4-methylamino-3-aminophenyl) -2-methyl-3-ethoxycarbonylmethyl
Luoxy-1-pyrrolidinopropan-1-one, 4-cyanophenylglycine / O- (benzo
Triazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluorobore
Is prepared in the same manner as in Example 1g / h, and subsequently treated with glacial acetic acid. Yield: 77% of theory R_f Value: 0.40 (silica gel; methylene chloride / ethanol = 19: 1) C₂₈H₃₃N_FiveO_Four (503.61) Mass spectrum: (M + H)⁺  = 504                  (M + Na)⁺ = 526

[0071] k. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonyl
Methyloxymethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole vinegar
Acid salt   2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarboxyl) in ethanol
Lubonylmethyloxymethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
Prepare as in Example 1l from sol and hydrochloric acid / ammonium carbonate. Yield: 64% of theory R_f Value: 0.25 (silica gel; methylene chloride / ethanol = 4: 1 + 1% glacial acetic acid) C₂₈H₃₆N₆O_Four× CH₃COOH (520.63 / 580.69) Mass spectrum: (M + H)⁺ = 521

[0072] Example 6 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (1H-tetrazol-5-yl -Methyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride a. 2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-methanesul Honyloxy-1-pyrrolidinopropan-1-one   1.2 g (3.0 mmol) of 2- [4- (N-benzylmethyi) in 20 ml of tetrahydrofuran.
Lumino) -3-nitrophenyl] -2-methyl-3-hydroxy-1-pyrrolidinopropane-1
The solution of -one is combined with 1.3 ml (9.3 mmol) triethylamine at room temperature. Next
To this, 0.27 ml (3.5 mmol) of methanesulfonyl chloride is added dropwise at 2-5 ° C. room temperature
After 2 hours at, the precipitate formed is suction filtered and the filtrate is concentrated by evaporation. Purify the crude product
Without reacting. Yield: 1.4 g (98% of theory) b. 2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-cyano-1-
Pyrrolidin-propan-1-one   8.2 g (17 mmol) of 2- [4- (N-benzylmethanoyl) in 125 ml of dimethylformamide.
Cylamino) -3-nitrophenyl] -2-methyl-3-methanesulfonyloxy-1-pyrroli
A solution of dinopropan-1-one was mixed with 1.8 g (27 mmol) potassium cyanide.
, Heat to 100 ℃ for 2 hours. After cooling, the reaction solution was put in ice water and stirred,
Extract 3 times with ethyl acetate. The combined organic phases are washed with brine, sodium sulfate
Dry on. The crude product was dissolved in methylene chloride, purified by silica gel and
Elute first with methylene chloride and then with methylene chloride / ethanol (50: 1 and 25: 1).
Identical fractions are combined and concentrated by evaporation. Yield: 5.0 g (72% of theory) R_f Value: 0.45 (silica gel; methylene chloride / ethanol = 19: 1) C_{twenty three}H₂₆N_FourO₃ (406.49) Mass spectrum: M⁺     = 406                 (M + Na)⁺ = 429

[0073] c. 2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3- (1H-tetra Zol-5-yl) -1-pyrrolidinopropan-1-one   2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-cyano-1-pi
Similar to Example 4g from loridinopropan-1-one and tributyltin azide.
Prepare. Yield: 37% of theory R_f Value: 0.55 (silica gel; methylene chloride / ethanol = 9: 1) C_{twenty three}H₂₇N₇O₃ (449.52) Mass spectrum: (M + Na)⁺ = 472                  (M-H)^-  = 448 d. 2- [4- (N-methylamino) -3-aminophenyl] -2-methyl-3- (1H-tetrazole-5 -Yl) -1-pyrrolidinopropan-1-one   2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3- (1H-tetra
From zol-5-yl) -1-pyrrolidinopropan-1-one and hydrogen / palladium / activated carbon
Prepare as in Example 1f. Yield: 48% of theory R_f Value: 0.3 (silica gel; methylene chloride / ethanol = 9: 1) C₁₆H_{twenty three}N₇O (329.41) Mass spectrum: (M + H)⁺ = 330                  (M-H)^- = 328

[0074] e. 2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (1H-tetrazole-5-y
Lumethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole   2- [4- (N-methylamino) -3-aminophenyl] -2-methyl-3- (1H-tetrazole-5-
Yl) -1-pyrrolidinopropan-1-one, 4-cyanophenylglycine / O- (benzoto
Lyazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate
Is prepared in the same manner as in Example 1g / h, and subsequently treated with glacial acetic acid. Yield: 17% of theory R_f Value: 0.25 (silica gel; methylene chloride / ethanol = 9: 1) C_{twenty five}H₂₇N₉O (469.55) Mass spectrum: (M-H)^- = 468 f. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (1H-tetrazole-5-
Ilmethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride   2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (1H-tetra in ethanol
Zol-5-yl-methyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
And hydrochloric acid / ammonium carbonate as in Example 1l. Yield: 25% of theory R_f Value: 0.35 (reverse phase RP8; 5% saline / methanol = 1: 1) C_{twenty five}H₃₀N_TenO × HCl (486.58 / 523.05) Mass spectrum: (M + H)⁺ = 487

[0075] Example 7 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyl
Luminomethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole diacetic acid
salt a. 2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-azido-1-
Pyrrolidinopropan-1-one   2- [4- (N-benzylmethylamino) -3-nitrophenyl]-in dimethylformamide
2-Methyl-3-methanesulfonyloxy-1-pyrrolidinopropan-1-one and azide
Prepare from sodium as in Example 6b. Yield: 100% of theory R_f Value: 0.75 (silica gel; ethyl acetate / petroleum ether = 1: 1) C_{twenty two}H₂₆N₆O₃ (422.49) Mass spectrum: M⁺ = 422 b. 2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-amino-1-
Pyrrolidinopropan-1-one   24.75 g (59 mmol) of 2- [4- (in 250 ml of tetrahydrofuran and 1.8 ml of water
N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-azido-1-pyrrolidino
Chamber a solution of propan-1-one and 15.7 g (60 mmol) of triphenylphosphine.
Stir at temperature for 60 hours. After evaporating the solvent, the residue is purified by silica gel,
Methylene chloride first, then methylene chloride / ethanol (50: 1, 9: 1, 8: 2 and 7: 3)
Elute with. Identical fractions are combined and concentrated by evaporation. Yield: 21.7 g (93% of theory) R_f Value: 0.25 (reverse phase RP8; 5% saline / methanol = 2: 3) C_{twenty two}H₂₈N_FourO₃ (396.49) Mass spectrum: (M + H)⁺ = 397

[0076] c. 2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-tert-butyl
Luoxycarbonylamino-1-pyrrolidinopropan-1-one   2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3 in dioxane
-Amino-1-pyrrolidinopropan-1-one and di-tert-butyl dicarbonate / N-E
Prepared as in Example 1c from tildiisopropylamine. Yield: 98% of theory R_f Value: 0.55 (silica gel; methylene chloride / ethanol = 19: 1) C₂₇H₃₆N_FiveO_Four (496.61) Mass spectrum: M⁺      = 496                 (M + Na)⁺  = 519                 (M-H)^-   = 495 d. 2- [4- (N-methylamino) -3-aminophenyl] -2-methyl-3-tert-butyloxy
Carbonylamino-1-pyrrolidinopropan-1-one   2- [4- (N-benzylmethylamino) -3-nitrophenyl] -2-methyl-3-tert-butyl
Oxycarbonylamino-1-pyrrolidinopropan-1-one and hydrogen / palladium / activity
Prepared as in Example 1f from charcoal. Yield: 23% of theory R_f Value: 0.4 (silica gel; methylene chloride / ethanol = 19: 1) C₂₀H₃₂N_FourO₃ (376.5) Mass spectrum: (M + Na)⁺ = 399                  (M-H)^-  = 375

[0077] e. 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (tert-butyloxycal Bonylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole   2- [4- (N-methylamino) -3-aminophenyl] -2-methyl-3- (tert-butyloxy
Carbonylamino) -1-pyrrolidinopropan-1-one, 4-cyanophenylglycine /
Prepared from carbonyldiimidazole as in Example 1g / h, followed by ice vinegar
Treat with acid. Yield: 58% of theory R_f Value: 0.5 (aluminum oxide; methylene chloride / ethanol = 19: 1) C₂₉H₃₆N₆O₃ (516.65) Mass spectrum: M⁺      = 516                 (M + Na)⁺  = 539 f. 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1-aminomethyl-1- (pyrroli Dinocarbonyl) ethyl] benzimidazole   2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (tert-butyl in dioxane
Luoxycarbonylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl] benzii
Prepared as in Example 1i from imidazole and 6N hydrochloric acid. Yield: 82% of theory R_f Value: 0.25 (silica gel; methylene chloride / ethanol = 9: 1)

[0078] g. 2- (4-cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethyl
Cylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole   2- (4-Cyanophenylamino-methyl) -1-methyl-5- [1-aminomethyl in acetone
-1- (Pyrrolidinocarbonyl) ethyl] benzimidazole and bromoethyl acetate /
Prepared as in Example 1k from potassium carbonate. Yield: 25% of theory R_f Value: 0.6 (silica gel; methylene chloride / ethanol = 9: 1) C₂₈H₃₄N₆O₃ (502.62) Mass spectrum: (M + H)⁺  = 503                  (M + Na)⁺ = 525                  (M-H)^-  = 501 h. 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonyl
Methylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
Acetate   2- (4-Cyanophenylaminomethyl) -1-methyl-5- [1- (ethoxycarboxyl) in ethanol
Lubonylmethylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole
Prepared as in Example 1l from sol and hydrochloric acid / ammonium carbonate. Yield: 66% of theory R_f Value: 0.35 (silica gel; methylene chloride / ethanol = 4: 1 + 1% glacial acetic acid) C₂₈H₃₇N₇O₃× 2 CH₃COOH (519.65 / 639.76) Mass spectrum: (M + H)⁺ = 520

The following compounds are obtained as in Example 7. (1) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N- (2-ethoxycarbonylethyl) -N-methylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl] Benzimidazole (2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylsulfonyl) -N-methylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl
] Benzimidazole (3) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-ethoxycarbonylmethylaminocarbonyl-N-methylaminomethyl) -1- (2,5-dihydro Pyrrolocarbonyl) ethyl] benzimidazole hydrochloride Yield: 55% of theory R _f value: 0.4 (reverse phase RP8; 5% saline / methanol = 1: 1) C ₃₀ H ₃₈ N ₈ O ₄ × HCl (574.36 / 610.81) Mass spectrum: (M + H) ⁺ = 575 (MH) ^- = 573 (M + Cl) ^- = 609/611 (Cl)

[0080] Example 8 (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethyl
Mino) -1-[(R, S) -2-methylpyrrolidinocarbonyl] ethyl] benzimidazole
Hydrochloride (mixture of diastereomers)   500 mg (0.84 mmol) of (R) -2- (4-amidinophenylaminomethyl) in 4 ml of water.
) -1-Methyl-5- [1- (ethoxycarbonylmethylamino) -1-[(R, S) -2-methylpyrro
Lysinocarbonyl] ethyl] benzimidazole dihydrochloride (mixture of diastereomers
Compound) is mixed with 2.7 ml of 1N sodium hydroxide solution and stirred at room temperature for 45 minutes. So
The pH value of the solution in 1 is adjusted to 3.5 by adding 1N hydrochloric acid. Add toluene
The solution is evaporated down by adding and the residue is mixed with a little methanol.
. After filtering off the undissolved inorganic material, the filtrate is concentrated by evaporation and triturated with ether.
The solid formed is filtered off and dried. Yield: 480 mg (100% of theory) R_f Value: 0.5 (reverse phase RP8; 5% saline / methanol = 1: 1) C₂₆H₃₃N₇O₃× 2 HCl (491.6 / 564.51) Mass spectrum: (M + H)⁺  = 492                  (M + Na)⁺ = 514

The following compounds are obtained as in Example 8. (1) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylaminomethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole dihydrochloride Yield: 70 theoretical % R _f value: 0.45 (reverse phase RP8; 5% saline / methanol = 1: 1) C ₂₆ H ₃₃ N ₇ O ₃ × 2 HCl (491.6 / 564.51) Mass spectrum: (M + H) ⁺ = 492 ( 2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole dihydrochloride Yield: Theoretical 100% R _f value of: 0.5 (reverse phase RP8; 5% saline / methanol = 1: 1) C ₂₅ H ₂₉ N ₇ O ₃ × 2 HCl (475.55 / 548.46) mass spectrum: (M + H) ⁺ = 476 (MH) ^- = 474 (3) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (carboxymethylamino) -1- (pyrroli Gino carbonyl) ethyl] benzimidazole yield: 67% R _f value of theory: 0.46 (silica Gel; 5% methylene chloride / methanol / concentrated ammonia = 4: 0.9
: 0.1) C ₃₂ H ₃₅ N ₇ O ₄ (581.67) Mass spectrum: (M + H) ⁺ = 582 (MH) ^- = 580 (M + Na) ⁺ = 604

(4) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethyloxymethyl) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole hydrochloride Yield: Theoretical 45% R _f value for: 0.4 (reverse phase RP8; 5% saline / methanol = 1: 1) C ₂₆ H ₃₂ N ₆ O ₄ × HCl (492.58 / 529.03) Mass spectrum: (M + H) ⁺ = 493 (MH) ^- = 491 (5) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N- (2-carboxyethyl) -N-methylaminomethyl) -1- (pyrroli (Dinocarbonyl) ethyl] benzimidazole (6) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylsulfonyl-N-methylaminomethyl) -1- (pyrrolidinocarbonyl ) Ethyl] benzimidazole (7) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (N-carboxymethylaminocarbonyl) -N-methylaminomethyl) -1- (2,5 -Dihydropyrrolocarb (Nil)
Ethyl] benzimidazole hydrochloride Yield: 15% of theory R _f value: 0.5 (reverse phase RP8; 5% saline / methanol = 1: 1) C ₂₈ H ₃₄ N ₈ O ₄ × HCl (546.62 / 583.09) mass Spectrum: (M + H) ⁺ = 547 (MH) ^- = 545 (M + Cl) ^- = 581/583 (Cl)

Example 9 Dry ampoule containing 75 mg of active substance / 10 ml Composition: Active substance 75.0 mg Mannitol 50.0 mg Water for injection total 10.0 ml Preparation: The active substance and mannitol are dissolved in water. After filling the solution, it is lyophilized. The product is dissolved in water for injection to make a ready-to-use solution.

Example 10 Dry ampoule containing 35 mg active substance / 2 ml Composition: Active substance 35.0 mg Mannitol 100.0 mg Water for injection Total 2.0 ml Preparation: The active substance and mannitol are dissolved in water. After packing the solution, it is lyophilized.
The product is dissolved in water for injection to make a ready-to-use solution.

Example 11 Tablets containing 50 mg of active substance Composition: (1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg Preparation: Mix (1), (2) and (3) together and granulate with aqueous solution of (4). Add (5) to the dried particulate material. Tablets from this mixture are biplanar, bilaterally faced, and scored on one side. Tablet diameter: 9 mm

Example 12 Tablets containing 350 mg of active substance Preparation: (1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Corn starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg (1), (2) and (3) are mixed together and granulated with the aqueous solution of (4). Add (5) to the dried particulate material. Tablets from this mixture are biplanar, bilaterally faced, and scored on one side. Tablet diameter: 12 mm

Example 13 Capsules containing 50 mg of active substance Composition: (1) Active substance 50.0 mg (2) Dried corn starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg Preparation: Mill (1) with (3). This grind is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is filled into size 3 hard gelatin capsules in a capsule filling machine.

Example 14 Capsules containing 350 mg of active substance Composition: (1) Active substance 350.0 mg (2) Dry corn starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg Preparation: Mill (1) with (3). This grind is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is filled into size 0 hard gelatin capsules in a capsule filling machine.

Example 15 Suppositories Containing 100 mg of Active Substance One suppository contains the following ingredients: Active substance 100.0 mg Polyethylene glycol (MW 1500) 600.0 mg Polyethylene glycol (MW 6000) 460.0 mg Polyethylene sorbitan Monostearate 840.0 mg 2000.0 mg Method: Polyethylene glycol is melted with polyethylene sorbitan monostearate. At 40 ° C. the powdered active substance is evenly dispersed in the melt. 38 ° C
Cool and pour into slightly chilled suppository molds.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 43/00 111 A61P 43/00 111 C07D 403/06 C07D 403/06 403/12 403/12 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, G, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Howell Norbert Germany 88433 Schemmerhoven Malderweg 12 (72) Inventor Priebke Heninck Germany 88447 Waldhausen Birkenhalder Strasse 11 (72) Inventor Naru Herbert Germany Republic of Japan 88441 Mittelbibelach Ulrica-Nisch-Strasse 8 (72) Inventor Stassen-Yean-Marie Germany 88442 Bad Buchau Gottlieb-Gunant-Strasse 25 (72) Inventor Wienen Wolfgang Germany 88400 Biberach Kirschen Lach 27 F term (reference) 4C063 AA01 BB04 BB09 CC26 CC47 DD03 DD04 EE01 4C086 AA01 AA03 AA04 BC39 BC62 GA07 MA01 MA04 NA14 ZA54 ZA59 ZC20

Claims (10)

[Claims] 1. A benzimidazole having the following general formula, its tautomer,
Stereoisomers, mixtures thereof, prodrugs, derivatives thereof having negatively charged groups instead of carboxy groups under physiological conditions, or salts. [Chemical 1] (In the formula, R _a may have a hydrogen atom substituted with a fluorine atom in whole or in part, 1
Position C _1-3 -pyrrolidinocarbonyl group optionally substituted with an alkyl group or 2,5-dihydropyrrolocarbonyl group and carboxy-C _1-4 -alkyl group, cyano-C _1-4 -alkyl group or Tetrazolyl-C _1-4-
N- (carboxy-C _1-3 -alkylaminocarbonyl) amino, which is mono-substituted with an alkyl group, or is an amino group, or one or both amino nitrogen atoms of which may be substituted with a C _1-3 -alkyl group. Group, carboxy-C _1-3 -alkoxy group, N- (carboxy-C _1-3 -alkyl) amino group, N- (C _1-3 -alkyl) -N- (carboxy-C _1-3 -alkyl) Amino group, N- (carboxy-C _1-3 -alkylsulfonyl) amino group, N- (C _1-3 -alkyl) -N- (carboxy-C _1-3 -alkylsulfonyl) amino group or tetrazolyl-C _{1 -3} - C substituted at the terminal with an alkyl group _1-3 - is substituted with an alkyl group, a linear C _1-3 - alkyl group, R _b is C _1-3 - alkyl group, R _c is an amidino group, a cyano group or 5-position C _1-3 - it is substituted with an alkyl group or a phenyl group 1,2,4-oxadiazol-3-yl group, wherein the phenyl substituents It may be substituted with an alkyl group - a fluorine atom, a chlorine atom or a bromine atom or a C _1-3. ) 2. R _b and R _c are as defined in claim 1 and R _a is as defined above, wherein one substituent is a straight chain C _1-3 -alkyl group or
A 1,5-dihydropyrrolocarbonyl group which may be substituted with a C _1-3 -alkyl group, R _a is _a pyrrolidinocarbonyl group at the 1-position and _a methoxy group, a dimethylamino group or a tolyl group at the 2-position ethoxy moiety. Ethoxycarbonylmethyl group substituted with a group, carboxymethyl group, C _3-4 -alkoxycarbonylmethyl group, cyclohexyloxycarbonylmethyl group, 3- (C _2-3 -alkoxycarbonyl) propyl group or tetrazolylmethyl group An ethyl group substituted with an amino group substituted with, R _b is a methyl group, and R _c is substituted with a benzoyl group, a methylbenzoyl group, a fluorobenzoyl group or a trifluoromethylbenzoyl group an amidino group, pyrrolidinocarbonyl group R _a is substituted with a methyl group at the 2-position to the 1-position and carboxymethyl group or ethoxy Is substituted with an amino group which is substituted with a carbonyl methyl group, an ethyl group, R _b is a methyl group, R _c is an amidino group, or R _a is pyrrolidinocarbonyl group and carboxy # 1 A methyl group, an amino group substituted by a C _3-4- -alkoxycarbonylmethyl group or a tetrazolylmethyl group, or a tetrazolyl group, a carboxymethoxy group, an ethoxycarbonylmethoxy group, an ethoxycarbonylmethylamino group, N- (2- Carboxyethyl) -N-methylamino group, N
-[2- (C _1-3 -alkoxycarbonyl) ethyl] -N-methylamino group, N- (carboxymethylaminocarbonyl) -N-methylamino group, N- (C _1-3 -alkoxycarbonylmethylaminocarbonyl ) -N-Methylamino group, N- (carboxymethylsulfonyl) -N-
A methylamino group or an N- (C _1-3 -alkoxycarbonylmethylsulfonyl) -N-methylamino group-substituted alkyl group, an ethyl group, R _b is a methyl group, and R is The benzimidazole of the general formula I, a tautomer, isomer or salt thereof according to claim 1, wherein _c is an amidino group. 3. (1) 2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (n-butyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl ) Ethyl] benzimidazole or (2) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (tetrazol-5-ylmethylamino) -1- (pyrrolidinocarbonyl) ethyl] benzimidazole The benzimidazole of the general formula I as defined in claim 1, except for: tautomers, isomers or salts thereof. 4. A 2,5-dihydrocarbonyl group in which R _a is optionally substituted with a methyl group at the 1-position and a C _2-4- -alkoxy moiety is a methoxy group, a dimethylamino group, a phenyl group or a tolyl group at the end. A mono-substituted C _1-4 -alkoxycarbonyl-C _1-4 -alkyl group,
A carboxy-C _1-4 -alkyl group, a cyclohexyloxycarbonyl-C _1-4 -alkyl group or a tetrazolyl-C _1-4 -alkyl group which may be substituted with an amino group, or one or both amino nitrogen atoms C _1-3 -Alkyl group-substituted N- (carboxy-C _1-3 -alkylaminocarbonyl) amino group or N- (C _1-3 -alkoxycarbonyl-C _1-3 -alkylaminocarbonyl ) Amino group, carboxy-C _1-3 -alkoxy group, C _1-3 -alkoxycarbonyl-C _1-3 -alkoxy group, N- (C _1-3 -alkyl) -N
-(Carboxy-C _1-3 -alkyl) amino group, N- (C _1-3 -alkyl) -N- (C _1-3 -alkoxycarbonyl-C _1-3 -alkyl) amino group, N- ( C _1-3 - alkyl) -N- (carboxy -C _1-3 - alkylsulfonyl) amino group or a N- (C _1-3 - alkyl) -N- (C _1-3 - alkoxycarbonyl -C _1-3 -Alkylsulfonyl) amino group or a tetrazolyl-C _1-3 -alkyl group, which is terminally substituted with a C _1-3 -alkyl group, which is an ethyl group, R _b is a methyl group, and R _c Is a benzoyl group, a methylbenzoyl group, a fluorobenzoyl group or an amidino group which may be substituted with a trifluoromethylbenzoyl group, R _a is _a pyrrolidinocarbonyl group or a methoxy group at the 1-position, a dimethylamino group or a tolyl group. 2-position substituted ethoxycarbonylmethyl group, carboxymethyl group, propyloxycarbonylmethyl group Ru,
Isopropyloxycarbonylmethyl group, isobutyloxycarbonylmethyl group, cyclohexyloxycarbonylmethyl group, 3- (C _2-3 -alkoxycarbonyl)
It is an ethyl group substituted with a propyl group or a tetrazolylmethyl group, R _b is a methyl group, and R _c is substituted with a benzoyl group, a methylbenzoyl group, a fluorobenzoyl group or a trifluoromethylbenzoyl group. Is an amidino group, R _a is a pyrrolidinocarbonyl group substituted at the 1-position with _a methyl group at the 2-position, and an ethyl group substituted with an amino group substituted with a carboxymethyl group or an ethoxycarbonylmethyl group. Wherein R _b is a methyl group, R _c is an amidino group, or R _a is amino substituted at the 1-position with a pyrrolidinocarbonyl group and a carboxymethyl group or a C _3-4 -alkoxycarbonylmethyl group. Group, or tetrazolyl group, carboxymethoxy group, ethoxycarbonylmethoxy group, ethoxycarbonylmethylamino group, N- (2-carboxyl group Ethyl) -N- methylamino group, N
-[2- (C _1-3 -alkoxycarbonyl) ethyl] -N-methylamino group, N- (carboxymethylaminocarbonyl) -N-methylamino group, N- (C _1-3 -alkoxycarbonylmethylaminocarbonyl ) -N-Methylamino group, N- (carboxymethylsulfonyl) -N
An ethyl group substituted with a methylamino group or an N- (C _1-3 -alkoxycarbonylmethylsulfonyl) -N-methylamino group, R _b is a methyl group, and R _c is an amidino group A benzimidazole of general formula I according to claim 1 or a tautomer, isomer or salt thereof. 5. (1) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (
Ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl]
Benzimidazole, (2) 2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5-
[1- (Ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole, (3) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl]- 1-methyl-5- [1- (isobutyloxycarbonylmethylamino) -1- (pyrrolidinocarbonyl
) Ethyl] benzimidazole, (4) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (n-propyloxycarbonylmethylamino) -1 -(Pyrrolidinocarbonyl
) Ethyl] benzimidazole, (5) (R) -2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1-[(R, S) -1- Methylpyrrolidinocarbonyl] ethyl] benzimidazole, (6) 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (carboxymethylamino) -1- (2,5-dihydropyrrolocarbonyl) Ethyl] benzimidazole or (7) (R) -2- [4- (N-phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1- (cyclohexyloxycarbonylmethylamino) -1- (2 The benzimidazole of the general formula I according to claim 1 which is 5,5-dihydropyrrolocarbonyl) ethyl] benzimidazole, an isomer or salt thereof. 6. R _c is one of the amidino groups according to claims 1-5,
A physiologically acceptable salt of the compound according to any one of claims 1 to 6. 7. A compound according to any one of claims 1 to 5 wherein R _c is one of the amidino groups according to claims 1 to 5 or optionally a salt according to claim 6. A pharmaceutical composition comprising one or more inert carriers and / or diluents. 8. R _c for preparing a pharmaceutical composition having an action of prolonging thrombosis time, an action of inhibiting thrombus or an inhibitory action on a related serine protease is one of the amidino groups according to claims 1 to 5. The compound according to any one of claims 1 to 5,
Or the use of the salt according to claim 6. 9. The method for preparing the pharmaceutical composition according to claim 7, wherein R _c is 1
To the compound according to any one of claims 1 to 5, which is one of the amidino groups according to claim 5, or the salt according to claim 6, in one or more inert carriers and / or diluents in a non-chemical manner. The above-mentioned preparation method, characterized in that the preparation is carried out by a conventional method. 10. A method for preparing a compound according to claims 1 to 6, wherein a) R _c is substituted with a cyano group or a C _1-3 -alkyl group or a phenyl group at the 5-position.
, 4-oxadiazol-3-yl group, wherein the phenyl substituent is a fluorine atom,
General formula I optionally substituted with chlorine or bromine, or C _1-3 -alkyl groups
In order to prepare the compound of formula (I), a compound represented by the following general formula, which may be formed as a reaction mixture, (In the formula, R _a and R _b are as defined in claims 1 to 5, and R _c ′ is a cyano group or 1,2 substituted with a C _1-3 -alkyl group or a phenyl group at the 5-position. ,
A 4-oxadiazol-3-yl group, wherein the phenyl substituent is a fluorine atom,
It may be substituted with a chlorine atom or a bromine atom, or a C _1-3 -alkyl group, Z ₁ and Z ₂ may be the same or different, an amino group, a hydroxy group or 1 to 6 carbon atoms.
Is a mercapto group which may be substituted with an alkyl group having, Z ₁ and Z ₂ are both an oxygen atom or a sulfur atom, an imino group which may be substituted with an alkyl group having 1 to 3 carbon atoms, It is also an alkylenedioxy group or an alkylenedithio group having 2 or 3 carbon atoms. ), And b) to prepare a compound of general formula I in which R _c is an amidino group, a compound of the following general formula, which may be formed as a reaction mixture, (Wherein R _a and R _b are as defined in claims 1 to 5 and Z ₄ is an alkoxy group, an aralkoxy group, an alkylthio group or an aralkylthio group.) And ammonia or a salt thereof. In order to prepare a compound of general formula I wherein c) R _a has a carboxy group and R _c is as defined in claims 1-5, the following general formula (In the formula, R _b and R _c are as defined in claims 1 to 5, R _a 'means R _a shown in claims 1 to 5, wherein R _a is hydrolyzed, treatment with acid or base hydrolysis of a compound having a.) a group capable of converting into carboxy group by thermolysis or hydrogenolysis, treatment with an acid or a base, the R _a is a carboxy group by thermolysis or hydrogenolysis In order to prepare a compound of the general formula I, wherein d is amidino group in which R _c is substituted with an in vivo cleavable group, the compound of the general formula I (Wherein R _a and R _b are as defined in claims 1 to 5) and a compound having the following general formula Z ₅ -R ₉ (VII) (wherein R ₉ is defined in claims 1 to 5) is a kind of acyl group group capable of cleaving in vivo as described in, Z ₅ is a nucleofugal leaving group.) is reacted with a compound having, e) R _c is claims 1-5 In order to prepare a compound of general formula I which is one of the amidino groups described in (In the formula, R _a and R _b are as defined in claims 1 to 5, and R _c "is 1,2,4-substituted at the 5-position with a C _1-3 -alkyl group or a phenyl group. An oxadiazol-3-yl group, wherein the phenyl substituent may be substituted with a fluorine atom, a chlorine atom or a bromine atom, or a C _1-3 -alkyl group. And, if necessary, hydrolyzing the compound thus obtained, f) R _a is an amino-C _1-3 -alkyl group, wherein the amino group is carboxy-C _{1- 4-}
In order to prepare compounds of general formula I which are mono-substituted with an alkyl group or a tetrazolyl-C _1-4 -alkyl group, the following general formula (Wherein, the R _b and R _c are as defined in claims 1 to 5, R _a "Amino -C _1-3 -. Alkyl group) compound of the following general formula R _a with"' -Z ₇ (X) (In the formula, R _a "'is a carboxy-C _1-4 -alkyl group or a tetrazolyl-C _1-4 -alkyl group, and Z ₇ is a nucleofugal leaving group.) alkylated with a compound having, subsequently, corresponding if desired, a compound of the general formula I R _a obtained in this way have a carboxy group, which by esterification R _a has the esterified carboxy group And / or a compound of the general formula I in which R _a thus has an esterified carboxy group is converted to a corresponding compound in which R _a has another esterified carboxy group by a transesterification reaction. Converting to a compound, and / or R _a thus obtained has a cyano group in general Converting the compound of formula I with triazo acid to the corresponding compound wherein R _a has a tetrazolyl group, and / or cleaving the protecting group used during the reaction to protect the reactive group, and /
Or resolving the compound of general formula I thus obtained into its stereoisomers,
And / or a compound of general formula I thus obtained, in which its salts, especially for pharmaceutical use,
The above method, which comprises converting an inorganic acid or an inorganic base, an organic acid or an organic base and a physiologically acceptable salt thereof.