JP2002502844A - 5-membered heterocyclic fused benzo derivatives, their preparation and their use as pharmaceuticals - Google Patents

Abstract

(57) [Summary] The present invention provides a compound represented by the general formula (I): (Wherein R _{a to} R _c , A, Ar, X and Y have the meanings as defined in claim 1), and their tautomers and stereoisomers It relates to salts with the bodies, mixtures and inorganic or organic acids or bases, in particular their physiologically compatible salts, which have beneficial properties. R _c is equivalent to a valuable intermediate products in the preparation of the remaining compounds of the compounds of the above general formula is a cyano group (I) is formula (I), R _c is one of the amidino group of the following Certain compounds of the above general formula (I), and their tautomers and stereoisomers, have valuable pharmacological properties, especially antithrombotic activity.

Description

DETAILED DESCRIPTION OF THE INVENTION

(Disclosure of the Invention)

[0002]

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Novel 5-membered heterocyclic fused benzo derivatives, their tautomers, stereoisomers, mixtures thereof and their salts with inorganic or organic acids or bases, especially their physiologically acceptable salts ( These have beneficial properties). Compounds of the above general formula I in which R _c represents a cyano group are useful intermediates for the preparation of other compounds of the general formula I and compounds of the above general formula I in which R _c represents one of the following amidino groups: , And their tautomers and stereoisomers have valuable pharmacological properties, especially antithrombotic activity. The present application thus relates to the novel compounds of the above general formula I and to their preparation, to pharmaceutical compositions comprising pharmacologically active compounds and to their use. In the above general formula, A represents an oxygen atom or a sulfur atom; a carbonyl group, a sulfinyl group or a sulfonyl group; an imino group optionally substituted by a C _1-3 -alkyl group, or a carboxy-C _1- group if necessary. ₃ - alkyl group or a C _1-3 - alkoxy carbonylation Le -C _1-3 - represents a mono- or di-optionally substituted methylene group by an alkyl group, Ar is a fluorine atom each optionally, a chlorine atom or bromine atom, trifluoromethyl group, C _1-3 - alkyl group or a C _1-3 - alkoxy group by an optionally substituted phenylene group or a naphthylene group, each optionally C _1-3 in the carbon skeleton - by alkyl groups Optionally represents a thienylene group, a thiazolylene group, a pyridinylene group, a pyrimidinylene group, a pyrazinylene group or a pyridazinylene group,

X represents a nitrogen atom or a —R ₁ C = group (where R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a C _1-3 -alkyl group or a C _1-3- Represents an alkoxy group), Y represents an oxygen atom or a sulfur atom or a -R ₂ N- group, wherein R ₂ is a hydrogen atom or a C _1-5 -alkyl group, a C _1-3 -alkyl group (This is optionally substituted by a phenyl group which may be substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group), a C _1-5 -alkyl group (this is a carboxy group, a C _1-3- alkoxycarbonyl group, carboxy -C _1-3 - alkoxycarbonyl group, C _1-3 - alkoxycarbonyl -C _1-3 - alkoxide aryloxycarbonyl group, carboxy -C _1-3 - alkyl - amino group or a C _{1- 3-}
Substituted by an alkoxycarbonyl-C _1-3 -alkylaminocarbonyl group, or an nC _2-4 -alkyl group (which is terminated by a di- (C _1-3 -alkyl) -amino group, a pyrrolidino group, a piperidino Group, morpholino group, piperazino group or NC _1-3 -alkyl-piperazino group, and the cyclic group may be further substituted with one or two C _1-3 -alkyl groups.) Represents)

R _a represents a hydrogen atom or a C _1-3 -alkyl group, R _b represents an R ₃ -CO-C _3-5 -cycloalkylene group, an R ₃ -SO ₂ -NR ₄ group, an R ₃ -CO -NR ₄ groups, R ₅ NR ₆ -CO
Group, R ₅ NR ₆ -SO ₂ -group or R ₅ NR ₆ -CO-C _3-5 -cycloalkylene group, wherein R ₃ is a C _1-6 -alkyl group or C _5-7- Cycloalkyl, C _1-3 -alkyl (including C _5-7 -cycloalkyl, phenyl, C _1-3 -alkylamino, di- (C _1-3 -alkyl) -amino, carboxy -C _1-3 - alkylamino group, C _1-3 - alkoxycarbonylamino group, which is substituted by phenyl sulfonylamino group or Te Torazoriru group), C _1-3 - alkyl group (which carboxy group, C _{1 -3} -alkoxycarbonyl group, carboxy-C _1-3 -alkoxy group or C _1-3 -alkoxy-carbonyl-C _1-3 -alkoxy group),

A C _1-3 -alkyl group, which is replaced by an imidazolyl group or a benzimidazolyl group, wherein the imidazole part of said group is one or two C _1-3 -alkyl groups or carboxy-C _{1- 3} -alkyl group or C _1-3 -alkoxycarbonyl-C _1-3 -alkyl group), if necessary, C _1-3 -alkyl group, C _1-3 -alkoxy group, trifluoromethyl Or a phenyl group which may be mono- or disubstituted by a carboxy group or a C _1-3 -alkoxycarbonyl group (the substituents may be the same or different), 3 or Represents a phenyl group substituted by four methyl groups, a naphthyl group, a pyridinyl group, a pyrazolyl group, a quinolyl group, or an isoquinolyl group, each of which may be optionally substituted by a C _1-3 -alkyl group. ,

R ₄ is a hydrogen atom, a C _1-5 -alkyl group or a C _5-7 -cycloalkyl group, a C _1-5 -alkyl group, which is substituted by a carboxy group or a C _1-5 -alkoxycarbonyl group A 2- or 3-position alkoxy moiety may be further substituted with a hydroxy group), a C _1-3 -alkyl group (this is an aminocarbonyl group, a hydroxyaminocarbonyl group, a C _1-3 -alkyl Substituted by an amino-carbonyl group, a di- (C _1-3 -alkyl) -aminocarbonyl group or a C _5-7 -alkylene-iminocarbonyl group, and the C _6-7 -alkyleneimino moiety is further substituted at the 4-position. A di- (C _1-3 -alkyl) -amino group, which may be substituted by a phenyl-optionally substituted C _1-3 -alkyl group, which is a carboxy-C _1-3 - alkoxy - carbonyl group, C _1-3 - alkoxy Aryloxycarbonyl
-C _1-3 -alkoxycarbonyl group, carboxy-C _1-3 -alkylaminocarbonyl group, N- (C _1-3 -alkyl) -carboxy-C _1-3 -alkyl-aminocarbonyl group, C _1-3 - alkoxycarbonyl -C _1-3 - alkylaminocarbonyl group, N-(C _1-3 - alkyl) -C _{1 -3} - alkoxycarbonyl -C _1-3 - alkylaminocarbonyl group, Moruhorinokaru Boniru group or 4- (Substituted by a (C _1-3 -alkyl) -piperazinocarbonyl group),

C _1-3 -alkyl groups, which are carboxy-C _1-3 -alkylaminocarbonyl groups, N- (
C _1-3 -alkyl) -carboxy-C _1-3 -alkyl-aminocarbonyl group, C _1-3 -alkoxycarbonyl-C _1-3 -alkylaminocarbonyl group or N- (C _1-3 -alkyl) -C _1-3 -alkoxycarbonyl-C _1-3 -alkylamino-carbonyl groups, which are further substituted by carboxy groups or C _1-3 -alkoxycarbonyl groups at the carbon atoms of the alkylamino moiety A C _1-3 -alkyl group, which is substituted by a di- (C _1-3 -alkyl) -aminocarbonyl group, wherein the alkyl moiety further comprises a di- (C _{1 A 3} -alkyl) -amino group, a C _1-3 -alkyl group (this is a 4- (morpholinocarbonyl-C _1-3 -alkyl) -piperazinocarbonyl group, an N- ( C _1-3 -alkyl) -pyrrolidinyl group or N- (C _1-3 -alkyl) -piperidinyl group) Or an nC _2-4 -alkyl group, which is substituted at the end by a di- (C _1-3 -alkyl) -amino group, a C _5-7 -alkylenimino group or a morpholino group;

R ₅ is a C _1-5 -alkyl group or a C _5-7 -cycloalkyl group, a phenyl-C _1-3 -alkyl group (this is a carboxy group or a C _1-3 -alkoxycarbonyl group in the alkyl portion thereof) NC _2-4 -alkyl group (this is a hydroxy group, C _1-3 -alkylamino group or di- (C _1-3 -alkyl) at the 2-, 3- or 4-position) -Substituted by an amino group), mono- or disubstituted by a C _1-3 -alkyl group, a C _1-3 -alkoxy group, a trifluoromethyl group, a carboxy group or a C _1-3 -alkoxycarbonyl group as required. Optionally substituted phenyl groups (these substituents may be the same or different), a phenyl group substituted by three or four methyl groups, a naphthyl group, a pyridinyl group, a quinolyl group Group or isoquinolyl group,

R ₆ represents a C _1-5 -alkyl group or a C _1-3 -alkyl group which may be substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group, if necessary _1-3 - alkylaminocarbonyl group, di - (C _1-3 - alkyl) - aminocarbonyl group, carboxy -C _1-3 - alkylamino Bruno carbonyl group or a C _1-3 - alkyloxycarbonyl -C _1-3 - Substituted by an alkylaminocarbonyl group), or an nC _2-4 -alkyl group (which is a hydroxy, C _1-3 -alkylamino or di- (C _{1- 3} - alkyl) - represents an amino group substituted by), or represents a group one hydrogen atom of R ₅ or R _6, whereas, another one of these groups are shown for the R ₅ and R ₆ R ₅ and R ₆ together with the nitrogen atom between them, if necessary Or two C _{1 -3} - may be substituted by an alkyl group a pyrrolidino group or a piperidino group (This is further carboxy -C _1-3 - alkyl group or a C _1-3 - alkoxy -C _1-3 - Which may be substituted by an alkyl group, or to which a benzene ring may be fused via two adjacent carbon atoms))

R _b represents an amino group, a C _1-3 -alkylamino group or a C _5-7 -cycloalkyl-amino group (these are phenylaminocarbonyl group, N-phenyl-C _1-3- Alkylaminocarbonyl group, phenylsulfonylamino-C _1-3 -alkylcarbonyl group, C _1-3 -alkyloxy-carbonyl-C _1-3 -alkyl group, N- (C _3-5 -cycloalkyl) -C _{1 -3} -alkylamino-carbonyl group, N- (hydroxycarbonyl-C _1-3 -alkyl) -aminocarbonyl group, N- (C _1-3 -alkoxycarbonyl-C _1-3 -alkyl) -aminocarbonyl- A C _3-5 -cycloalkylamino group), a piperidino group substituted at the 4-position with a di- (C _1-3 -alkyl) -amino group, a C _1-3 -alkyl at the 4-position A piperazino group substituted by a group,

A C _2-4 -alkylsulfonyl group, which is di- (C _1-3 -alkyl at the 2-, 3- or 4-position
) -Amino group), 4-oxo-3,4-dihydro-phthalazinyl-1-yl group or 4-oxo-2,3-diazaspiro [5.5] undec-1-ene (ene ) -1-yl group, methyl group substituted by C _5-7 -cycloalkyleneimino-carbonyl group (the methyl group is a carboxy-C _1-3 -alkyl group or C _1-3 -alkoxy-C _1-3 -Alkyl group), a C _3-5 -cycloalkyl group or a carbonyl group or methyl group substituted by a C _3-5 -alkyl group (the cycloalkyl portion of which is further substituted with a C _1-3 -alkyl group, It may be substituted by a carboxy-C _1-3 -alkyl group or a C _1-3 -alkoxy-carbonyl-C _1-3 -alkyl group, and the methyl part thereof is a C _1-3 -alkoxy group or a C _1- alkoxy group. Substituted by a ₄ -alkylamino group), C _5-7 -cycloalkyl-N- (carboxy-C _1-3 -alkoxy)- Iminomethylene group or C _5-7 - cycloalkyl-N-(C _1-3 - alkoxycarbonyl -C _1-3 - alkoxy) - alkyl - C _1-3 iminomethylene group (these further cycloalkyl moiety May be replaced by

A phosphinyl group (this is a C _1-6 -alkyl or C _5-7 -cycloalkyl group and a hydroxy group, a C _1-3 -alkoxy group, a carboxy-C _1-3 -alkoxy group or a C _1-3 -Alkoxycarbonyl-C _1-3 -alkoxy group), piperidino group (in the 2-position, a methylene group is substituted by a carbonyl group or a sulfonyl group), if necessary, a C _1-5 -alkyl group A mono- or di-substituted tetrazolyl group optionally substituted by a C _1-3 -alkyl group, a C _1-3 -alkoxy group, a trifluoromethyl group, a carboxy group or a C _1-3 -alkoxycarbonyl group An optionally substituted phenyl or phenylsulfonyl group (these substituents may be the same or different), a sulfoimidyl group (which is a C _{5-7 -cyclo} at the sulfur atom) Substituted with an alkyl group, and further at the position of the nitrogen atom, a C _2-4 -alkanoyl group, carboxy-C _1-3 -alkyl group, C _1-3 -alkoxycarbonyl-C _1-3 -alkyl group, carboxy- C _2-4-
Alkanoyl group or C _1-3 -alkoxycarbonyl-C _2-4 -alkanoyl group).

The position 1 carboxy -C _1-3 - alkyl group or a C _1-3 - alkoxycarbonyl -C _1-3 - imidazolyl group substituted by A alkyl group (which may further C _1-5 - by alkyl groups optionally substituted), C _1-3 - alkoxycarbonyl -C _1-3 - alkyl group (which in the alkyl moiety C _5-7 - is substituted by a cycloalkyl amino carbonyl group), C _{1- A 3} -alkyl group, which may be a 1-imidazolyl group, the imidazolyl part of which may be further substituted by one or two C _1-3 -alkyl groups, or carboxy-C _1-3 at the 2-position. - alkyl or C _1-3 - alkoxycarbonyl -C _1-3 - optionally substituted by an alkyl group - substituted by substituted 1-benzimidazolyl group by an alkyl group), or a C _1-3 necessary Represents a good furanyl-1-pyrazolyl group,

R _c represents a cyano group or an amidino group (which is a hydroxy group, one or two C _1-3 -alkyl groups, one or two C _1-8 -alkoxycarbonyl groups or Which may be substituted by a cleavable group).

BEST MODE FOR CARRYING OUT THE INVENTION In particular, A, X, Y and R _{a to} R _d are as defined above, provided that Ar represents a 1,4-phenylene group, R ₃ is a pyrazolyl group or respectively C _1-3 - naphthyl group substituted by an alkyl group, Pi lysinyl group, a pyrazolyl group, does not represent a quinolyl group or an isoquinolyl group, and C as required is R _{b 1-3} - alkyl Compounds are preferred, provided that they do not represent a furanyl-1-pyrazolyl group which may be substituted by a group. The term "a group capable of being cleaved in vivo from an imino or amino group" includes, for example,
Hydroxy group, an acyl group, for example, benzoyl or pyridinoyl group or a C _{1 -16} - alkanoyl group such as formyl group, acetyl group, propionyl group, butanoyl group, pentanoyl group or hexanoyl group, an allyloxycarbonyl group, C _{1- 16} -alkoxycarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl , Nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl, phenyl-C _1-6 -alkoxycarbonyl, examples For example, benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl, C _1-3 -alkylsulfonyl-C _2-4 -alkoxycarbonyl, C _1-3 -alkoxy-C _2-4 -alkoxy-C _2-4 -alkoxycarbonyl group or R ₇ CO-O- (R ₈ CR ₉ ) -O-CO group

[0017] (wherein, R ₇ is C _1-8 - alkyl group, C _5-7 - cycloalkyl, phenyl or phenyl -C _1-3 - represents an alkyl group, R ₈ is a hydrogen atom, C ₁ Represents a _-3 -alkyl group, a C _5-7 -cycloalkyl group or a phenyl group, and R ₉ represents a hydrogen atom or a C _1-3 -alkyl group). Further, the saturated alkyl and alkoxy moieties described above that contain more than two carbon atoms also include their branched isomers, for example, isopropyl, tert. Butyl, isobutyl, and the like. The preferred compounds of the present invention have the general formula

[0018]

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Wherein A, X, Y and R _a -R _c are as defined above, especially where A is optionally a carboxy-C _1-3 -alkyl group or C _1-3 - alkoxycarbonyl alkylsulfonyl -C _1-3 - alkyl methylene group optionally substituted by a group, or represents a carbonyl group or an imino group, wherein X is a nitrogen atom or -R ₁ C = group (wherein, R ₁ is hydrogen An atom, a fluorine atom, a chlorine atom or a bromine atom, a C _1-3 -alkyl group or a C _1-3 -alkoxy group), and Y represents an oxygen atom or a sulfur atom or a —R ₂ N— group Wherein R ₂ is a hydrogen atom or a C _1-5 -alkyl group, a benzyl group (which may be substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group at the phenyl moiety), C _{1 -5} - alkyl groups (which carboxy group or a C _1-3 - is replaced by an alkoxycarbonyl group That), C _1-3 - alkyl group (which carboxy -C _1-3 - alkoxycarbonyl group, carboxy -C _1-3 - alkylaminocarbonyl group or a C _1-3 - alkoxycarbonyl -C _1-3 - Represents an alkylaminocarbonyl group) or an nC _2-4 -alkyl group (which is substituted at the terminal by a di- (C _1-3 -alkyl) -amino group or a morpholino group)

R _a represents _a hydrogen atom or a methyl group, R _b represents an R ₃ -CO-C _3-5 -cycloalkylene group, an R ₃ -SO ₂ -NR ₄ group, an R ₃ -CO-NR ₄ group, R ₅ NR ₆ -CO
A group, R ₅ NR ₆ -SO ₂ group or R ₅ NR ₆ -CO-C _3-5 -cycloalkylene group, wherein R ₃ is a C _1-4 -alkyl group, a cyclopentyl group, a cyclohexyl group or Benzyl group, C _1-3 -alkyl group (this is a tetrazolyl group, carboxy group, C _1-3 -alkoxycarbonyl group, carboxy-C _1-3 -alkoxy group, C _1-3 -alkoxycarbonyl-C _1-3 -Alkoxy group, carboxy-C _1-3 -alkylamino group, substituted by C _1-3 -alkoxycarbonylamino group), methyl group, methoxy group, trifluoromethyl group, carboxy group or methoxycarbonyl group as required A phenyl group which may be mono- or disubstituted by these (these substituents may be the same or different); a phenyl group substituted by three or four methyl groups; an alkyl group - C _1-3 by Represents may be substitution 5-pyrazolyl group, a naphthyl group, a pyridinyl group, a quinolyl group or an isoquinolyl group,

R ₄ is a hydrogen atom, a C _1-5 -alkyl group or a C _5-7 -cycloalkyl group, a C _1-5 -alkyl group, which is substituted by a carboxy group or a C _1-5 -alkoxycarbonyl group And the alkoxy moiety at the 2- or 3-position may be further substituted with a hydroxy group), a C _1-3 -alkyl group (this is an aminocarbonyl group, a hydroxyaminocarbonyl group or a piperidinocarbonyl group). Substituted, the piperidino moiety may be further substituted at the 4-position by a dimethylamino group), a C _1-3 -alkyl group (this is a carboxy-C _1-3 -alkylaminocarbonyl group, N- (
C _1-3 -alkyl) -carboxy-C _1-3 -alkyl-aminocarbonyl group, C _1-3 -alkoxycarbonyl-C _1-3 -alkylaminocarbonyl group, N- (C _1-3 -alkyl) -C _1-3 -alkoxycarbonyl-C _1-3 -alkylaminocarbonyl group, morpholinocarbonyl group or 4- (C _1-3 -alkyl) -piperazinocarbonyl group),

A C _1-3 -alkyl group, which is a carboxy-C _1-3 -alkylaminocarbonyl group, N- (
C _1-3 -alkyl) -carboxy-C _1-3 -alkyl-aminocarbonyl group, C _1-3 -alkoxycarbonyl-C _1-3 -alkylaminocarbonyl group or N- (C _1-3 -alkyl) -C _1-3 -alkoxycarbonyl-C _1-3 -alkylamino-carbonyl groups, which are further substituted by carboxy groups or C _1-3 -alkoxycarbonyl groups at the carbon atoms of the alkylamino moiety A C _1-3 -alkyl group, which is substituted at its alkyl portion by a di- (C _1-3 -alkyl) -aminocarbonyl group, and the alkyl portion is further substituted at the 2- or 3-position. -(C _1-3 -alkyl) -amino group, which may be substituted by a C _1-3 -alkyl group, which is 4- (morpholinocarbonyl-C _1-3-
Alkyl) -piperazinocarbonyl group or N- (C _1-3 -alkyl) -pyrrolidinyl group, or nC _2-3 -alkyl group (which is di- (C _1-3- Alkyl) -amino group, substituted by a C _5-7 -alkylenimino group or a morpholino group)

R ₅ is a C _1-5 -alkyl group or a C _5-7 -cycloalkyl group, a phenyl-C _1-3 -alkyl group (the alkyl part of which is a carboxy group or a C _1-3 -alkoxycarbonyl group Represents a phenyl group, a naphthyl group, a pyridinyl group, a quinolyl group or an isoquinolyl group, and R ₆ may be substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group as required. C _1-5 -alkyl group, C _1-3 -alkyl group (this is a C _1-3 -alkylaminocarbonyl group, di- (C _1-3 -alkyl) -aminocarbonyl group, carboxy-C _{A 1-3} -alkylaminocarbonyl group or a C _1-3 -alkyloxycarbonyl-C _1-3 -alkylaminocarbonyl group, an nC _2-3 -alkyl group (this is the 2- or 3-position With a C _1-3 -alkylamino group or di - (C _{1 -3} - alkyl) - represents is substituted) by an amino group, or one of the radicals R ₅ or R ₆ represents a hydrogen atom, whereas, another one of these groups wherein R ₅ and Has the meaning indicated for R ₆ , or R ₅ and R ₆ together with the nitrogen atom therebetween are optionally C _1-3 -alkyl, carboxy-C _1-3 -alkyl or C _A pyrrolidino group or piperidino group optionally substituted by a _1-3- alkoxy-C _1-3 -alkyl group (to which a benzene ring may be further condensed via two adjacent carbon atoms). Represents) or

When R _b is a nitrogen atom, a phenylaminocarbonyl group, an N-phenyl-methylaminocarbonyl group, a phenylsulfonylaminomethylcarbonyl group, a hydroxycarbonyl-methylaminocarbonyl group or a C _1-3 -alkyloxycarbonylmethylamino An amino group, a methylamino group, a cyclopentylamino group or a cyclohexylamino group substituted by a carbonyl group, a piperidino group substituted by a di- (C _1-3 -alkyl) -amino group at the 4-position, a C _1- A piperazino group substituted by a ₃ -alkyl group, a C _2-3 -alkylsulfonyl group, which is substituted at the 2- or 3-position by a di- (C _1-3 -alkyl) -amino group, 4- Oxo-3,4-dihydro-phthalazinyl-1-yl group or 4-oxo-2,3-diazaspiro [5.5] undec-1-en-1-yl group, cyclopentyl group, cyclo Cyclohexyl group or a C _3-5 - alkyl-substituted carbonyl group or a methyl group by group (methyl moiety thereof C _1-3 - alkoxy or C _1-4 - is optionally substituted with an alkylamino group, or its cycloalkyl The moiety may be further substituted by a methyl, carboxymethyl or C _1-3 -alkoxycarbonylmethyl group),

A cyclohexyl-N- (carboxymethoxy) -iminomethylene group or cyclohexyl
Le-N- (C_1-3-Alkoxycarbonylmethoxy) -iminomethylene groups (these may be further substituted by a methyl group at the cyclohexyl moiety), phosphinyl groups (which are_3-6-Alkyl and hydroxy groups, C_1-3-Alkoxy
Group, carboxymethoxy group or C_1-3-Substituted by an alkoxycarbonylmethoxy group), a piperidino group (in the 2-position, a methylene group is replaced by a carbonyl group or a sulfonyl group).
Has been replaced), C if necessary_1-5-A tetrazolyl group optionally substituted by an alkyl group, a phenyl group or phenylsulfur optionally substituted by a methyl group
Honyl group, sulfoimidyl group (which is substituted by cyclohexyl group at the sulfur atom)
And C at the position of the nitrogen atom_2-4-Alkanoyl group, carboxymethyl group, C _1-3 -Alkoxycarbonylmethyl group, carboxy-C_2-3-Alkanoyl group or C_1-3 -Alkoxycarbonyl-C_2-3-May be substituted by an alkanoyl group),

The first place in the carboxymethyl group or a C _1-3 - alkoxycarbonyl methyl group by replacement has been imidazolyl group (which is more C _1-5 - may be substituted by an alkyl group), C _1-3 - alkoxycarbonyl -C _1-3 - alkyl group (which C _5-7 in the alkyl moiety - is substituted by a cycloalkyl amino carbonyl group), C _1-3 - alkyl group (which 1-imidazolyl group ( The imidazolyl moiety may be further substituted by one or two C _1-3 -alkyl groups) or at position 2 a carboxy-C _1-3 -alkyl group or C _1-3 -alkoxycarbonyl- C _1-3 - substituted by substituted 1-benzimidazolyl group by an alkyl group), or optionally by C _1-3 - represents optionally substituted 5-furanyl-1-pyrazolyl group by an alkyl group, And R _c is a cyano group Or an amidino group (which may be substituted by one or two C _1-3 -alkyl groups, one or two C _1-8 -alkoxycarbonyl groups or hydroxy groups), Compounds of Ia, their tautomers, stereoisomers and salts.

Particularly preferred compounds of the general formula I are those in which A represents a methylene group or an imino group, X is a nitrogen atom or a -R ₁ C = group, wherein R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom or Represents a bromine atom or a methyl group), Y represents an oxygen atom or a sulfur atom or a -R ₂ N- group, wherein R ₂ is a hydrogen atom, a methyl group, a benzyl group, a 4-carboxybenzyl group or Four-
A methoxycarbonylbenzyl group, a C _1-3 -alkyl group (which is substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group), a methyl group (which is a carboxymethylaminocarbonyl group or a C _1-3 -alkoxy group) Substituted with a carbonylmethylaminocarbonyl group) or an nC _2-3 -alkyl group (which is substituted at the terminal with a morpholino group)

R _a represents _a hydrogen atom, R _b represents an R ₃ -CO- (1,1-cyclopropylene) group, an R ₃ -SO ₂ -NR ₄ group, an R ₃ -CO-NR ₄ group, an R ₅ NR ₆ -C
O group, R ₅ NR ₆ -SO ₂ group or R ₅ NR ₆ -CO-C _3-5- (1,1-cyclopropylene) group, wherein R ₃ is a C _1-3 -alkyl group , cyclopentyl or cyclohexyl group, a methyl group (this tetrazolyl group, carboxymethoxy group, C _1-3 - alkoxy carbonyl methoxy, carboxy -C _1-3 - alkylamino group, C _1-3 - by alkoxy carbonyl amino group Substituted), phenyl, naphthyl, pyridinyl, 1-methyl-5-pyrazolyl, quinolyl or isoquinolyl;

R ₄ is hydrogen, C _1-3 -alkyl or cyclopentyl, C _1-5 -alkyl (substituted by carboxy or C _1-3 -alkoxycarbonyl), methyl (This is substituted by a 4-dimethylamino-piperidinocarbonyl group, a morpholinocarbonyl group, a 4-methylpiperazino group or a 4-morpholinocarbonylmethyl-piperazinocarbonyl group), a C _1-3 -alkyl group (which is Carboxy-methylaminocarbonyl group, N- (C _1-3 -alkyl) -carboxymethyl-aminocarbonyl group, C _1-3 -alkoxycarbonylmethylaminocarbonyl group or N- (C _1-3 -alkyl) -C _{1 -3} - alkoxy substituted by carbonyl methylation aminocarbonyl group), C _1-3 - alkyl group (which di - (C _1-3 - alkyl) - substituted by aminocarbonyl group Ri, alkyl moieties of the di in another 2-position or 3-position - (C _1-3 - alkyl) - substituted by amino group), C _1-3 - alkyl group (which carboxymethyl aminocarbonyl group or a C ₁ Substituted by an _-3 -alkoxycarbonylmethyl-aminocarbonyl group, the methyl group of the methylamino portion of which is further substituted by an aminocarbonylmethyl group, an nC _2-3 -alkyl group (which is di-terminal at the terminal). (C _1-3 - alkyl) - amino group, a has been replaced) by a pyrrolidino group or a morpholino group, R ₅ is C _1-5 - alkyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a naphthyl group, pyridinyl A quinolyl group or an isoquinolyl group;

R ₆ is a C _1-5 -alkyl group, a C _1-3 -alkyl group optionally substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group (this is a C _1-3 -alkyl group) Substituted by an alkylaminocarbonyl group, a carboxymethylaminocarbonyl group or a C _1-3 -alkyloxycarbonylmethylaminocarbonyl group), or R ₅ and R ₆ together with the nitrogen atom between them Represents a pyrrolidino group or a pyrrolidino group substituted with a carboxymethyl group or a C _1-3 -alkoxymethyl group (to which a benzene ring is fused via two adjacent carbon atoms) or R _b is N - pyrrolidinocarbonyl - methylamino group, phenylsulfonyl group, 4-OH Kiso-2,3-diazaspiro [5.5] undec-1-en-1-yl group or a C _3-5 - Arukirute Torazoriru group, cyclohexyl Carbonyl group (which methyl group, a carboxymethyl group or a C _1-3 - alkoxy substituted by ethoxycarbonylmethyl group), cyclohexyl-N-(carboxymethoxy) - iminomethylene group or cyclohexyl-N-(C _1-3 -Alkoxycarbonylmethoxy) -iminomethylene group (which is further substituted by a methyl group in a cyclohexyl moiety), phosphinyl group (which is substituted by a C _3-6 -alkyl group and a C _1-3 -alkoxymethoxy group) A) sulfoimidyl group which is substituted at the sulfur atom by a cyclohexyl group and further substituted at the nitrogen atom by a _C2-4 -alkanoyl group, or 3-methyl-5. A compound, a tautomer, a stereoisomer and a salt thereof, which represents-(furan-2-yl) -1-pyrazolyl group and R _c represents an amidino group.

The most particularly preferred compounds of the general formula I are those in which A represents a methylene group, X represents a nitrogen atom or a —HC = group, Y represents an oxygen or sulfur atom or a —R ₂ N— group; Wherein R ₂ represents a hydrogen atom, a methyl group, a benzyl group or a C _1-3 -alkoxycarbonylmethyl group) Ra represents _a hydrogen atom, R _b represents an R ₅ NR ₆ -SO ₂ group, R ₅ NR ₆ represents (1,1-cyclopropylene) group, - -CO group, R ₃ -SO ₂ -NR ₄ group, R ₃ -CO-NR ₄ group, or _{R 5 NR 6 -CO-C 3-} 5

(Wherein R ₃ is a cyclopentyl group, a cyclohexyl group, a phenyl group, a naphthyl group,
1-methyl-5-pyrazolyl group, quinolyl group or isoquinolyl group or methyl group (this is carboxymethylamino group, C _1-3 -alkoxycarbonyl-methylamino group, carboxymethoxy group, C _1-3 -alkoxycarbonylmethoxy group Or R ₄ is a hydrogen atom or a carboxy group, a C _1-3 -alkoxycarbonyl group, a morpholino carbonyl group, a 4-dimethyl-amino-piperidinocarbonyl group, a 4-methyl -Piperazinocarbonyl group, 4-morpholinocarbonylmethyl-piperazinocarbonyl group, carboxymethylaminocarbonyl group, N-methyl-carboxymethylaminocarbonyl group, C _1-3 -alkoxycarbonylmethylaminocarbonyl group, N-methyl -C _{1 -3} - alkoxycarbonylmethyl amino group, N- (C _1-3 - alkyl) -N- (2-
Dimethylamino-ethyl) -aminocarbonyl group, N- (1-carboxy-2-aminocarbonyl-ethyl) -aminocarbonyl group or N- (1-C _1-3 -alkoxycarbonyl-2-aminocarbonyl-ethyl)- Represents a methyl group or a cyclopentyl group substituted by an aminocarbonyl group,

R ₅ represents a C _1-5 -alkyl group, a phenyl group or a pyridyl group; R ₆ represents a C _1-5 -alkyl group, which is substituted at the terminal by a carboxy group or a C _1-3 -alkoxycarbonyl group Substituted with a methylaminocarbonyl group, a carboxymethylaminocarbonyl group or a C _1-3 -alkoxycarbonylmethylaminocarbonyl group, or a C substituted with a dimethylamino group at the 2- or 3-position. _{Represents a 1-3} -alkyl group, or R ₅ together with R ₆ and the nitrogen atom between them is a 1-methyl-5-pyrazolyl group, optionally substituted by a C _1-3 -alkoxycarbonyl group A pyrrolidino group or a pyrrolidino group (to which a benzene ring is fused via two adjacent carbon atoms) or

R _b is N-pyrrolidinocarbonyl-methylamino group, phenylsulfonyl group, 4-oxo-2,3-diaza-spiro [5.5] undec-1-en-1-yl group or C _3-5 -Alkyltetrazolyl group, cyclohexylcarbonyl group (substituted at the 1-position with a methyl group, carboxymethyl group or C _1-3 -alkoxycarbonyl-methyl group), cyclohexyl-N- (carboxymethoxy) -imino A methylene group or a cyclohexyl-N- (C _1-3 -alkoxycarbonylmethoxy) -imino methylene group, which is further substituted by a methyl group at the cyclohexyl moiety, or a phosphinyl group, which is a C _3-6 -alkyl group and C _1-3 - alkoxy substituted by carboxy methoxy group), represents, and R _c represents an amidino group, a compound, in particular

A represents a methylene group, X represents a nitrogen atom or a —HC = group, Y represents an oxygen atom or a sulfur atom or a —R ₂ N— group (where R ₂ is a hydrogen atom, a methyl group, a benzyl group R _a represents _a hydrogen atom, R _b represents an R _5a NR _6a -SO ₂ group, wherein R _5a represents a C _1-3 -alkyl group or a C _1-3 -alkoxycarbonylmethyl group; Or R _6a represents a C _1-5 -alkyl group, which is substituted at the terminal by a carboxy group or a C _1-3 -alkoxycarbonyl group, or dimethylamino at the 2- or 3-position R _5a together with R _6a and the nitrogen atom between them, and optionally a pyrrolidino group optionally substituted by a C _1-3 -alkoxycarbonyl group or Pyrrolidino group (
Wherein the benzene ring is fused via two adjacent carbon atoms)), or

R _3a —SO ₂ —NR _4a group, wherein R _3a represents a cyclopentyl group, a cyclohexyl group, a phenyl group, a naphthyl group, a quinolyl group or an isoquinolyl group, and R _4a represents a hydrogen atom or a methyl group (This is a carboxy group, C _1-3 -alkoxycarbonyl group, morpholinocarbonyl group, 4-dimethylamino-piperidinocarbonyl group, 4
-Methyl-piperazinocarbonyl group, 4-morpholinocarbonylmethyl-piperazinocarbonyl group, carboxymethylaminocarbonyl group, N-methyl-carboxymethylaminocarbonyl group, C _1-3 -alkoxycarbonylmethyl-aminocarbonyl group, N -Methyl-C _1-3 -alkoxycarbonylmethyl-aminocarbonyl group, N- (C _1-3 -alkyl) -N- (2-dimethylamino-ethyl) -aminocarbonyl group, N- (1-carboxy-2 -Aminocarbonyl-ethyl) -aminocarbonyl group or N- (1-C _1-3 -alkoxycarbonyl-2-aminocarbonyl-ethyl) -aminocarbonyl group)) or

R _5b NR _6b -CO group, wherein R _5b represents a C _3-5 -alkyl group, phenyl group or pyridyl group, and R _6b represents a C _1-5 -alkyl group or C _1-3 An alkyl group, which is substituted by a carboxy group, a C _1-3 -alkoxycarbonyl group, a methylaminocarbonyl group, a carboxymethylaminocarbonyl group or a C _1-3 -alkoxycarbonylmethylaminocarbonyl group; Also substituted at position 3 by a dimethylamino group), or

R _3b —CO—NR _4b group (wherein R _3b represents a phenyl group and R _4b represents a C _1-3 -alkyl group, which is substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group Or R _3b is substituted by a methyl group (which is substituted by a carboxymethylamino group, a C _1-3 -alkoxycarbonylmethylamino group, a carboxymethoxy group, a C _1-3 -alkoxycarbonylmethoxy or tetrazolyl group) R _4b represents a cyclopentyl group), or an R _5c NR _6c -CO-C _3-5- (1,1-cyclopropylene) group, wherein R _5c represents R _6c and Together with the nitrogen atom between them, a 1-methyl-5-pyrazolyl group, a pyrrolidino group optionally substituted by a C _1-3 -alkoxycarbonyl group or a pyrrolidino group (to which Condensed through two adjacent carbon atoms It represents a represents), or

R _b is N-pyrrolidinocarbonyl-methylamino group, phenylsulfonyl group, 4-oxo-2,3-diaza-spiro [5.5] undec-1-en-1-yl group or C _3-5 -Alkyltetrazolyl group, cyclohexylcarbonyl group (substituted at the 1-position with a methyl group, carboxymethyl group or C _1-3 -alkoxycarbonyl-methyl group), cyclohexyl-N- (carboxymethoxy) -imino A methylene group or a cyclohexyl-N- (C _1-3 -alkoxycarbonylmethoxy) -iminomethylene group (which is further substituted by a cyclohexyl moiety with a methyl group), a phosphinyl group (which is a C _3-6 -alkyl group) and C _1-3 - alkoxy substituted by methoxy group), represents, and R _c represents an amidino group, a compound of general formula I, are the tautomers, stereoisomers and salts thereof

The following compounds are examples of particularly preferred compounds. (a) 4-[(5- (N-carboxymethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine, (b) 4- ((5- (N-carboxymethylaminoacetyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine, (c) 4-[(5 -(N- (2-dimethylamino-ethyl) -benzenesulfonylamino) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzamidine, (d) 4-[(5- (N -(2-diethylamino-ethyl) -benzenesulfonylamino) -1- (carboxymethylaminocarbonyl) -methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine, (e) 4-[(5 -Pyrrolidinosulfonyl-1-methyl-1H-benzimidazol-2-yl)-
(F) 4-[(5- (N-cyclopentyl-methanesulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine, (g) 4- ((5- (N-cyclopentyl-3-carboxypropionylamino) -1-methyl-1
(H-benzimidazol-2-yl) -methyl] -benzamidine, (h) 4-[(5-pyrrolidinocarbonylcyclopropyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine And (i) 4-[(5- (N-carboxymethyl-quinolin-8-yl-sulfonylamino-benzothiazol-2-yl) -methyl] -benzamidine and salts thereof.

According to the present invention, the compounds of general formula I are obtained using known methods, for example the following methods. a) R _c represents a cyano group, and X is To prepare the compounds of general formula I represents a nitrogen atom, the reaction mixture also may formula is generated in necessary

[0042]

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Wherein R _a , R _b , A, Ar and Y are as defined above, and Z ₁ and Z ₂ (which may be the same or different) Represents an amino group, a hydroxy group or a mercapto group optionally substituted by an alkyl group having 1 to 6 carbon atoms, or Z ₁ and Z ₂ together represent an oxygen atom or a sulfur atom, Represents an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy group or an alkylenedithio group having 2 or 3 carbon atoms, respectively. Method. The cyclization can be carried out in a solvent or a mixture of solvents, for example, ethanol, isopropanol,
Excess acylating agent used in glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or to prepare compounds of general formula II, for example In the corresponding nitrile, acid anhydride, acid halide, ester or amide, for example at a temperature of 0 to 250 ° C., preferably at the boiling temperature of the reaction mixture, if necessary with condensing agents such as phosphorus oxychloride, thionyl chloride. , In the presence of sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or, if necessary, also in the presence of a base such as potassium ethoxide or potassium tert.butoxide. Is performed appropriately. However, the cyclization may be performed without using solvents and / or condensing agents.

However, if necessary, in the presence of a carboxylic acid of the general formula HOCO-A-Ar-CN (III), wherein A and Ar are as defined above, the corresponding o-nitro compound is It is particularly advantageous to carry out the reaction by preparing a compound of general formula II in the reaction mixture by acylating the corresponding amino compound formed in the reaction mixture by reduction. b) R _b represents an R ₃ —SO ₂ —NR ₄ group, an R ₃ —CO—NR ₄ group or an (R ₅ NR ₆ ) CO—NR ₄ group, and R _c represents a cyano group; To prepare the compound, the general formula

[0045]

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[0046] _{(wherein, R a, R 4, A} , Ar, X and Y are as defined above) the formula R ₁₀ a compound of - W - OH (V) (wherein, R ₁₀ Has the meaning previously indicated for R _{3 to} R ₆ , and W represents a carbonyl group or a sulfonyl group), or a reactive derivative thereof. The reaction of the acids of the general formula V is optionally carried out in a solvent or a mixture of solvents, for example methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally with a dehydrating agent, for example isobutylchloroform. Mate, tetraethyl orthocarbonate,
Trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydride Roxysuccinimide, N, N'-dicyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium-tetrafluoroborate, 2 -(1H-benzotriazol-1-yl)-
1,1,3,3-tetramethyluronium-tetrafluoroborate / 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride For example, pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine is added, and the reaction is suitably performed at a temperature of 0 to 150 ° C, preferably at a temperature of 0 to 100 ° C.

The reaction of the corresponding reactive compound of the general formula V, for example its ester, imidazolide or halide, in a solvent such as methylene chloride or ether, and preferably in a tertiary organic base such as triethylamine, N-ethyl It is preferably carried out in the presence of -diisopropylamine or N-methyl-morpholine at a temperature of 0 to 150 ° C, preferably at a temperature of 50 to 100 ° C. For c) R _b represents R ₃ -SO ₂ -NR ₄ group, and R _c to prepare compounds of general formula I represents cyano group, the general formula

[0048]

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Wherein R _a , R ₃ , A, Ar, X and Y are as defined above, with a compound of the general formula R ₄ —Z ₃ (VII) wherein R ₄ is And Z ₃ is a nucleophilic group, for example, a halogen atom, for example, a chlorine atom, a bromine atom or an iodine atom, or a sulfonate group, for example, a trifluoromethane-sulfonyloxy group, methane. A sulfonyloxy group or a p-toluenesulfonyloxy group). The reaction is carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, if necessary with an inorganic or tertiary organic base such as sodium hydride,
It is preferably carried out in the presence of potassium carbonate, potassium tert. Butoxide or N-ethyl-diisopropylamine at a temperature of from 20 ° C. to the boiling temperature of the solvent used, preferably from 0 to 60 ° C. d) wherein R _{b comprises} an alkylated phosphinyl group and a sulfoimidyl group
To prepare compounds of the general formula I, which represent one of the groups mentioned for R _b and R _c represents a cyano group,

[0050]

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[0051] _{(wherein, R a, R 3, A} , Ar, X and Y are as hereinbefore defined and R _b 'are previously described for R _b containing a phosphinyl group and Hoimi Doyle group A compound of the general formula Z ₄ -R ₁₁ (IX), wherein Z ₄ is a nucleophilic group, for example a halogen atom, for example a chlorine, bromine or iodine atom And R ₁₁ represents one of the alkyl moieties described in the definition of the alkylated phosphinyl group and the sulphoimidoyl group described above for the group R _b ). The reaction is carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, if necessary with an inorganic or tertiary organic base such as sodium hydride,
It is preferably carried out in the presence of potassium carbonate, potassium tert. Butoxide or N-ethyl-diisopropylamine at a temperature of from 20 ° C. to the boiling temperature of the solvent used, preferably from 0 to 60 ° C. For e) R _b to prepare compounds of general formula I representing one of the groups previously described for R _b containing acylated sul Hoimi Doyle group, the general formula

[0052]

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Wherein R _a , R _c , A, Ar, X and Y are as defined above, and R _b "is a group described above for R _b including a sulfoimidyl group A compound of the general formula HO-R ₁₂ (XI) wherein R ₁₂ is an acyl moiety as defined in the definition of the acylated sulfoimidyl group given above for the group R _b Or a reactive derivative thereof. The reaction of the acid of the general formula XI may be carried out, if necessary, with a solvent or a mixture of solvents, for example, methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran. In benzene / tetrahydrofuran or dioxane, if necessary with dehydrating agents such as isobutyl chloroformate, tetraethyl orthocarbonate,
Trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydride Roxysuccinimide, N, N'-dicyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium-tetrafluoroborate, 2 -(1H-benzotriazol-1-yl)-
1,1,3,3-tetramethyluronium-tetrafluoroborate / 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride For example, pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine is added, and the reaction is suitably performed at a temperature of 0 to 150 ° C, preferably at a temperature of 0 to 100 ° C.

The corresponding reactive compound of general formula XI, for example its ester, imidazolide or
The reaction of the halide is carried out in a solvent, for example methylene chloride or ether, and preferably
Is preferably carried out in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at a temperature of 0 to 150 ° C, preferably at a temperature of 50 to 100 ° C. f) R_bIs R_FiveNR₆-CO group, R_FiveNR₆-SO_TwoGroup, R_FiveNR₆-CO-C_3-5-Cycloalkylene group or R _Five NR₆-CO-NR_FourRepresents a group, and R_cTo prepare a compound of general formula I, wherein represents a cyano group,

[0055]

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Wherein R _a , A, Ar, X and Y are as defined above, and U is HO-CO-C _3-5 -cycloalkylene, HO-CO or HO-SO ₂ Or a reactive derivative thereof with an amine of the general formula (R ₅ NR ₆ ) —H (XIII), wherein R ₅ and R ₆ are as defined above. .

The reaction of the acid of the general formula XII may optionally be carried out in a solvent or a mixture of solvents, for example in methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally with a dehydrating agent, for example , Isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N '-Dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-Dicyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluro Nium-tetraf Ruboroborate, 2- (1H-benzotriazol-1-yl
) In the presence of -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride If necessary, a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine is added, and the reaction is carried out at a temperature of 0 to 150 ° C, preferably 0 to 100 ° C.

The reaction of the corresponding reactive compound of the general formula XII, for example its ester, imidazolide or halide, is carried out in a solvent, for example methylene chloride or ether, and preferably also a tertiary organic base, for example triethylamine, N- It is preferably carried out in the presence of ethyl-diisopropylamine or N-methyl-morpholine at a temperature of 0 to 150 ° C, preferably at a temperature of 50 to 100 ° C. g) R _b is R ₃ -CO-C _3-5 - represents a cycloalkylene group, and for R _c to prepare compounds of one general formula I represents cyano group, the general formula

[0059]

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Wherein R _a , A, Ar, X and Y are as defined above, and R _b ′ ″ represents an R ₃ — (HCOH) —C _3-5 -cycloalkylene group A) oxidizing the compound in a solvent such as ether, tetrahydrofuran, methylene chloride, glacial acetic acid or acetonitrile, such as manganese dioxide, potassium permanganate, potassium dichromate, dimethylsulfoxide / chloride. It is preferably carried out in the presence of oxalyl or dimethylsulfoxide / dicyclohexylcarbodiimide at a temperature of 0 to 50 ° C., preferably at a temperature of 15 to 25 ° C. h) R _b is one of the radicals mentioned above for R _b Which represents a compound of general formula I comprising a methyl group attached to an adjacent bicyclic moiety optionally substituted by an optionally substituted amino group,

[0061]

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Wherein R _a , R _c , A, Ar, X and Y are as defined above, and R _b "" represents one of the groups described above for R _b , ketone general formula H of which is coupled to the adjacent bicyclic moiety through a carbonyl group) - R ₁₃ (XVI) (wherein, R ₁₃ is amino group which may optionally be substituted, for example, If R _b is attached to the adjacent bicyclic moiety via a methyl group which may be optionally substituted by an amino group, represents an amino group as described above for R _b ) Method for reducing amination with The reductive amination is carried out in the presence of a solvent such as methanol, methanol / water, diethyl ether, tetrahydrofuran or dioxane, in the presence of a reducing agent such as a complex metal hydride, such as sodium borohydride, lithium borohydride Or with sodium cyanoborohydride, preferably at a pH of 6-7, or with catalytically activated hydrogen, for example with hydrogen in the presence of palladium, at a temperature of 0-50 ° C., preferably 15-15 ° C. Performed at a temperature of 30 ° C. i) R _b represents a single previously R _b a phenyl group which may optionally be substituted as described for, and in order to prepare compounds of general formula I in which R _c represents a cyano group, the general formula

[0063]

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Wherein R _a , A, Ar, X and Y are as defined above, and V represents a trifluoromethanesulfonyloxy group, a bromine atom or an iodine atom. ₁₄ -Z ₅ (XVIII) wherein R ₁₄ represents one of the optionally substituted phenyl groups described above for R _b , and Z ₅ represents a boric acid group or a tri- ( C _1-3 -alkyl) -tin group). The reaction is carried out in a solvent such as toluene / water, dimethoxyethane or dimethylformamide with a phosphine such as bis (triphenyl-phosphine) -palladium (II) chloride or tetrakis- (triphenyl-phosphine) -palladium (0). Temperature in the presence of a base in the presence, for example, sodium carbonate, at a temperature of 20-100 ° C., preferably 4 ° C.
It is preferably carried out at a temperature of 0 to 80 ° C. j) R _c represents an amidino group, which is optionally present in the reaction mixture to prepare a compound of general formula I which may be substituted by one or two C _1-3 -alkyl groups. General formula that may be generated

[0065]

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Wherein R _a , R _b , A, Ar, X and Y are as defined above, and Z ₆ is an alkoxy or aralkoxy group, such as a methoxy, ethoxy, n- propoxy, isopropoxy or benzyloxy group or an alkylthio group or an aralkylthio group, for example, methylthio group, ethylthio group, n- propylthio compound of the general formula represents a group or benzylthio _{group) H - R 15 NR 16 (} XX) (Wherein, R ₁₅ and R ₁₆ may be the same or different)
Represents a hydrogen atom or a C _1-3 -alkyl group, respectively) or a salt thereof. The reaction is carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at a temperature of 0-150 ° C., preferably at a temperature of 0-80 ° C., an amine of the general formula XX or the corresponding acid addition salt, for example , Ammonium carbonate or ammonium acetate. Compounds of general formula XIX can be prepared, for example, by reacting the corresponding cyano compound with a corresponding alcohol, for example methanol, ethanol, n-propanol, in the presence of an acid such as hydrochloric acid.
By reacting with isopropanol or benzyl alcohol, or the corresponding amide in a solvent such as methylene chloride, tetrahydrofuran or dioxane at a temperature of 0 to 50 ° C., preferably at 20 ° C., a trialkyloxonium salt, for example triethyloxonium By reacting with tetrafluoroborate or by reacting the corresponding nitrile with a base such as triethylamine in a suitable solvent such as pyridine or dimethylformamide in the presence of a suitable base such as triethylamine, and subsequently obtaining the corresponding thioamide It is obtained by alkylation with an alkyl halide or aralkyl halide. k) To prepare compounds of general formula I, wherein R _c represents an amidino group substituted by a hydroxy group,

[0067]

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Wherein R _a , R _b , A, Ar, X and Y are as defined above, with hydroxylamine or a salt thereof. The reaction is carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran, tetrahydrofuran / water, dioxane or dioxane / water at a temperature of 0 to 150 ° C., preferably at a temperature of 0 to 80 ° C. It is performed in l) R _b contains a carboxy group and R _c is as defined above, or R _b is as defined above, and R _c is a hydroxy group or one or two To prepare a compound of general formula I, which represents an amidino group optionally substituted by a C _1-3 -alkyl group of the general formula

[0069]

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Wherein R _a , A, Ar, X and Y are as defined above, and R _b ""'and R _c ' have the meanings indicated above for R _b and R _c With the proviso that _Rb contains a group that can be converted to a carboxy group by hydrolysis, treatment with an acid or base, thermal decomposition or hydrogenolysis, and _Rc is as defined above. Or an amidino group in which R _c is optionally substituted by a hydroxy group or one or two C _1-3 -alkyl groups by hydrolysis, treatment with an acid or base, thermal decomposition or hydrogenolysis. Represents a group that can be converted and R _b is as defined above)
A compound of general formula I wherein R _b contains a carboxy group and R _c is as defined above, by hydrolysis, treatment with acid or base, thermal decomposition or hydrogenolysis, or R _b is as defined above, and R _c represents an amidino group optionally substituted by a hydroxy group or one or two C _1-3 -alkyl groups) . Examples of groups that can be converted into carboxy groups are, for example, carboxyl groups protected by protecting groups, such as functional derivatives thereof, such as unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or iminoesters (These are suitably converted to carboxyl groups by hydrolysis), their esters with tertiary alcohols, such as tert. Butyl esters (these are appropriately converted to carboxyl groups by treatment with acid or thermal decomposition) And their esters with aralkanol, such as benzyl esters, which are suitably converted to carboxyl groups by hydrogenolysis. The hydrolysis is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or a mixture thereof, or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. In a suitable solvent, for example, water, water / methanol, water / ethanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at a temperature of -10 to 120 ° C., eg ambient temperature to the reaction mixture It is suitably carried out at a temperature of the boiling temperature.

For example, if the compound of formula XXII contains a tert.butyl group or a tert.butyloxycarbonyl group, this may also optionally be an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or Treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid in dioxane preferably at a temperature of -10 to 120 ° C, for example at a temperature of 0 to 60 ° C. Optionally or optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, preferably in a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid,
Cleavage by heat, preferably in the presence of phosphoric acid or polyphosphoric acid, at the boiling temperature of the solvent used, for example at a temperature of 40 to 120 ° C. For example, if the compound of formula XXII contains, for example, a benzyloxy group or a benzyloxycarbonyl group, these may also be in the presence of a hydrogenation catalyst such as palladium / charcoal in a suitable solvent such as methanol, ethanol, ethanol / In water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably from 0 to 50
Cleavage by hydrogenolysis at a temperature of 0 C, for example at ambient temperature and a hydrogen pressure of 1 to 5 bar. m) to prepare compounds of the general formula I in which R _c represents an amidino group, which is substituted by one or two C _1-8 -alkoxycarbonyl groups or groups which can be cleaved in vivo. , General formula

[0072]

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[0073] _{(wherein, R a, R b, A} , Ar, X and Y are as hereinbefore defined and R _c "represents an amidino group) with a compound of general formula Z ₇ - R ₁₇ (XXIV) (wherein, R ₁₇ represents a C _1-8 -alkoxycarbonyl group or an acyl group of one of the aforementioned groups that can be cleaved in vivo, and Z ₇ is a nucleophilic group, for example, a halogen atom, For example, a chlorine atom, a bromine atom or an iodine atom, or a nitrophenyl group) in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide. If necessary in the presence of an inorganic base or a tertiary organic base, preferably at 20 ° C.
It is preferably carried out at the temperature of the boiling temperature of the solvent used.

When Z ₃ is a compound of the general formula XXIV, which represents a nucleophilic group, the reaction is carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulfoxide, if necessary with a base, for example It is preferably carried out at a temperature of 0 to 60 ° C. in the presence of sodium hydride, potassium carbonate, potassium tert. Butoxide or N-ethyl-diisopropylamine. If, according to the invention, a compound of the general formula I is obtained in which R _c represents an amidino group, this is reacted with a haloacetic acid derivative, which is subsequently substituted by one or two methyl groups by hydrolysis and decarboxylation. And if R _c represents a hydroxyamidino group, the compound of general formula I is obtained, which may be converted to the corresponding amidino compound by catalytic hydrogenation, And / or if a compound of the general formula I is obtained in which R _b contains a carboxy group, this can be converted to the corresponding ester by esterification and / or of the general formula I in which R _b contains an O-alkyl-phosphinyl group. If the compound is obtained, this is can be converted into a phosphinyl compound corresponding by ether cleavage, and / or a compound of general formula I R _b contains a halogen atom is obtained The case, which can be converted to dehalogenation compound corresponding by dehalogenation, and / or if R _b are compounds of formula I containing a quinolyl group is obtained, which tetrahydroquinolyl corresponding by catalytic hydrogenation It may be converted to a compound.

The subsequent alkylation is optionally carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, optionally in the presence of a promoter such as sodium iodide or potassium iodide.
Also preferably in the presence of a base, for example sodium carbonate or potassium carbonate, or in the presence of a tertiary organic base, for example N-ethyl-diisopropylamine or N-methyl-morpholine, which can simultaneously be used as solvent. The reaction is suitably carried out at a temperature of -30 to 100 ° C, preferably -10 to 80 ° C, or in the presence of silver carbonate or silver oxide as required. The subsequent hydrolysis is carried out in the presence of an acid, for example hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or a mixture thereof, or of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. It is suitably carried out in the presence of a suitable solvent, for example water, water / methanol, water / ethanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane, and the subsequent decarboxylation is carried out with said acid. A temperature of -10 to 120 ° C, in the presence of
For example, it is carried out at a temperature between ambient temperature and the boiling temperature of the reaction mixture.

The subsequent esterification is carried out in a suitable solvent or mixture of solvents using the corresponding alcohol, for example in methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, preferably in the excess In alcohol, optionally in the presence of an acid, for example hydrochloric acid, or in the presence of a dehydrating agent, for example, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid , Phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole, triphenyl Phosphine / carbon tetrachloride or In the presence of phenylphosphine / diethylazodicarboxylate, if necessary, in the presence of a base, for example, potassium carbonate, N-ethyl-diisopropylamine or N, N-dimethylamino-pyridine, suitably at a temperature of 0 to 150 ° C. In a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, preferably at a temperature of from 0 to 80 ° C. or with the corresponding halide, if necessary a reaction accelerator, for example sodium iodide Or in the presence of potassium iodide, preferably in the presence of a base, such as sodium carbonate or potassium carbonate, or a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, In the presence of, or, if necessary, silver carbonate or Presence at -30 to 100 ° C. of the temperature of the silver oxide is preferably carried out at a temperature of -10 to 80 ° C..

The subsequent dehalogenation and catalytic hydrogenation are carried out using hydrogen, in the presence of a catalyst, for example palladium / charcoal or platinum, in the presence of a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or ice. If necessary, an acid such as hydrochloric acid is added in acetic acid at a temperature of 0 to 50 ° C., preferably at an ambient temperature.
It is carried out at a hydrogen pressure of 7 bar, preferably 3 to 5 bar. Subsequent ether cleavage can be carried out using, for example, iodotrimethylsilane, bromotrimethylsilane or chloromethylsilane / sodium iodide in a solvent such as methylene chloride, chloroform or acetonitrile from 0 ° C. to the boiling temperature of the reaction mixture, preferably 20 ° C. It is performed at a temperature of 6060 ° C.

In the above reaction, the reactive groups present, for example, hydroxy, carboxy, amino, alkylamino or imino groups, are reacted during the reaction by the usual protecting groups, which are cleaved again after the reaction. May be protected. For example, the protecting group for the hydroxy group may be a trimethylsilyl group, an acetyl group, a benzoyl group, a tert.butyl group, a trityl group, a benzyl group or a tetrahydropyranyl group, and the protecting group for the carboxyl group may be a trimethylsilyl group, a methyl group, It may be an ethyl group, a tert.butyl group, a benzyl group or a tetrahydropyranyl group, and the protecting group for the amino group, the alkylamino group or the imino group is an acetyl group, a trifluoroacetyl group, a benzoyl group, an ethoxycarbonyl group, tert.-butoxycarbonyl group, benzyloxycarbonyl group, benzyl group, methoxybenzyl group or 2,4-
It may be a dimethoxybenzyl group and also a phthalyl group for the amino group.

[0079] Any subsequent cleavage of the protecting group used can be, for example, an aqueous solvent such as water,
Acid in isopropanol / water, tetrahydrofuran / water or dioxane / water,
For example, by hydrolysis in the presence of trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or in the presence of, for example, iodotrimethylsilane. By ether cleavage, the reaction is carried out at a temperature of 0 to 100 ° C, preferably at a temperature of 10 to 50 ° C. However, benzyl, methoxybenzyl or benzyloxycarbonyl groups can be converted by hydrogenolysis, for example in the presence of a catalyst such as palladium / charcoal, to a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone. Or use of hydrogen in glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at a temperature of 0 to 50 ° C., preferably at room temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar. And can be cleaved. Also, the methoxybenzyl group may be cleaved in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at a temperature of 0-50 ° C, preferably at ambient temperature, in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate.

However, it is preferred that the 2,4-dimethoxybenzyl group is cleaved in trifluoroacetic acid in the presence of anisole. The tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, if necessary, using a solvent, for example methylene chloride, dioxane or ether. The phthalyl group is a hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in the presence of a solvent, such as
Preferably, it is cleaved in isopropanol, toluene / water or dioxane at a temperature of 20-50 ° C.

The allyloxycarbonyl group is preferably reacted with a solvent such as tetrahydrofuran, preferably in the presence of an excess of base, for example morpholine or 1,3-dimedone, from 0 to
If necessary, by treatment with a catalytic amount of tetrax- (triphenylphosphine) -palladium (O) at a temperature of 100 ° C., preferably at ambient temperature, under an atmosphere of inert gas, or in a solvent such as aqueous ethanol. Cleaved by treatment with a catalytic amount of tris- (triphenylphosphine) -rhodium (I) -chloride at a temperature of 20-70 ° C in the presence of a base such as 1,4-diazabicyclo [2.2.2] octane. You. The compounds of the general formulas II to XXIV used as starting materials (some of which are known from the literature) can be obtained by methods known from the literature and their preparation is described in the examples.

The chemistry of compounds of general formula III is described, for example, by Jack Robinson, J. Chem. Soc. 1941,
744 and the chemistry of benzimidazole is described by Katritzky and Rees in Compreh.
hensive Heterocyclic Chemistry, Oxford, Pergamon Press, 1984, which describes the chemistry of benzothiazole and benzoxazole by
III, Methoden der organischen Chemie (Houben-Weyl), Vol. 4, Verlag Thieme
, Stuttgart 1993, Chemistry by Mustafa
of Heterocyclic Compounds, Vol. 29, New York, Wiley 1974,
The chemistry of sulfoximid was described by Johnson in Accounts in Chemical Research 6, 341 (197
3), and the chemistry of phosphinic acid is described by Regitz in Phosphor-Verbindungen 1 and 2, Methoden der organischen Chemie (Houben-Weil), Volume 12, Verlag Thiem
e, Stuttgart 1993, and the chemistry of boric acid is described in Pure and A by Sieckus.
pplied Chemistry 66, 2155 (1994).

Thus, for example, a compound of general formula II can be obtained by converting the corresponding o-diamino compound to a compound of general formula II
The compounds of general formulas IV, XV, VIII, X, XII, XIV and XVII are obtained by acylation with the corresponding reactive derivatives of the compounds of the formula I, cyclizing the corresponding substituted compounds, optionally followed by a phenyl moiety Reduction, acylation,
Amidation and / or halogenation; a compound of general formula VI obtained by sulfonylation of a compound of general formula IV; a compound of general formula XIX, XXI, XXII and XXIII is suitable by one of the above methods Is obtained. Furthermore, the compounds of general formula I obtained may be resolved into their enantiomers and / or diastereomers. Thus, for example, the resulting compounds of the general formula I which occur in racemic form can be prepared in a manner known per se ("Topics in Stereoche by Allinger NL and Eliel EL").
mistry ", Vol. 6, Wiley Interscience, 1971), and compounds of general formula I having at least two asymmetric carbon atoms are known per se. May be separated into their diastereomers on the basis of their physical-chemical differences, for example by chromatography and / or fractional crystallization, if they occur in racemic form May be subsequently separated into their enantiomers as described above.

The enantiomer separation may be by column separation with a chiral phase or recrystallization with an optically active solvent, or by reaction with an optically active substance, in particular an acid and its activated derivative or alcohol, which is a racemate and a salt or derivative, for example, Preferably, this is carried out by separating the diastereomeric salt mixtures or derivatives thus obtained, for example on the basis of their different solubilities, while the free enantiomers are formed by a suitable agent Can be released from pure diastereomeric salts or derivatives. Particularly common optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Including. The optically active alcohol may be, for example, (+)-menthol or (-)-menthol, and the optically active acyl group in the amide is, for example, a (+)-or (-)-menthyloxycarbonyl group. There may be.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular their physiologically acceptable salts with inorganic or organic acids for pharmaceutical use. Examples of acids suitable for this purpose include hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, succinic, lactic, citric, tartaric or maleic acid. In addition, the novel compounds of the formula I thus obtained can, if they contain a carboxyl group, be subsequently treated, if desired, with salts with inorganic or organic bases, more particularly with
For pharmaceutical use, they may be converted into their physiologically acceptable salts. Examples of suitable bases include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. As already mentioned above, the novel compounds of the general formula I and their salts have valuable properties. Thus, compounds of general formula I wherein R _c represents a cyano group are useful intermediate products for preparing other compounds of general formula I, and compounds wherein R _c represents one of the above amidino groups The compounds of the formula I, and their tautomers, stereoisomers and physiologically acceptable salts, have valuable pharmacological properties, in particular antithrombotic effects, which are activities affecting thrombin or factor Xa, for example A thrombin inhibitory activity or a factor Xa inhibitory activity,
Preferably, it is based on the aPTT time prolonging activity and the inhibitory effect on related serine proteases such as trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.

For example, the following compound A = 4-[(5- (N-carboxymethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -methyl Benzoamidine hydrochloride, B = 4-[(5- (N-carboxymethylaminoacetyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine Hydrochloride, C = 4-[(5- (N- (2-dimethylamino-ethyl) -benzenesulfonylamino) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine dihydrochloride D = 4-[(5- (N- (2-diethylamino-ethyl) -benzenesulfonylamino) -1- (carboxymethylaminocarbonylmethyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine Dihydrochloride, E = 4-[(5-pyrrolidinosulfonyl-1-methyl-1H-benzimidazol-2-yl)
-Methyl] -benzoamidine hydrochloride, F = 4-[(5- (N-cyclopentyl-methanesulfonylamino) -1-methyl-1H-benzoimidazol-2-yl) -methyl] -benzoamidine hydrochloride, G = 4-[(5- (N-cyclopentyl-3-carboxypropionylamino) -1-methyl-
1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride, H = 4-[(5- (1-pyrrolidinocarbonylcyclopropyl) -1-methyl-1H-benzimidazol-2-yl)- Methyl] -benzamidine hydrochloride and I = 4-[(5- (N-carboxymethyl-quinolin-8-yl-sulfonylamino) -benzothiazol-2-yl) -methyl] -benzamidine hydrochloride are shown below. Thus their effect on extending aPTT time was investigated.

Materials:-from plasma, human citrated blood-PTT reagent, Boehringer Mannheim (524298),-calcium solution (0.025 mol / l), Boehringer Berge, Marburg (OR
H 056/57),-diethyl barbiturate acetate buffer, Boehringer Berge, Marburg (ORWH 60/61),-Biomatic B10 coagulometer, Desaga, Vieslotch. Method: aTTP time is measured with a Biomatic B10 core globometer manufactured by Desaga. The test substance was placed in a test tube specified by the manufacturer together 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 started by adding 0.1 ml of calcium solution. The time required for the mixture to solidify from the addition of the calcium solution is measured using the device. The mixture to which 0.1 ml of DBA buffer was added was used as a control. The effective concentration of the substance whose aPTT time was twice that of the control was determined by a dose / activity curve. The table below contains the results obtained.

[0088]

[Table 1]

The compounds prepared according to the present invention were well tolerated. This is because toxic side effects cannot be observed at therapeutic dosages. In view of their pharmacological properties, the novel compounds and their physiologically acceptable salts are useful for the prevention and treatment of venous and arterial thrombosis, such as the treatment of deep leg vein thrombosis, bypass surgery or angioplasty (PT (PT) C) It is suitable for reocclusion after A) and for prevention of obstruction in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prevention of coronary thrombosis, prevention of stroke, and prevention of shunt obstruction. In addition, the compounds of the invention may be used, for example, for anti-thrombotic support in the treatment of thrombosis with rt-PA or streptokinase, prevention of prolonged restenosis after PT (C) A, metastasis and growth of clot-dependent tumors and fibrin-dependent Suitable for the prevention of sexual inflammatory processes.

The dosage required to obtain the corresponding activity is suitably 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg, by the intravenous route, 1 to 4 times a day. According to the oral route, it is 0.1 to 50 mg / kg, preferably 0.3 to 30 mg / kg. For this purpose, the compounds of the formula I prepared according to the invention, optionally together with other active substances, may contain one or more customary inert carriers and / or diluents, for example corn starch, lactose, glucose, Microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol,
Water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, fatty substances such as carboxymethylcellulose or hard fats or suitable mixtures thereof with conventional galenic preparations, for example simple or coated tablets, capsules, powders , Suspensions or suppositories. The following examples are intended to more fully illustrate the present invention.

Example 1 Example 1 4-[(5-benzenesulfonylamino-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride a. 4-[(5-nitro -1H-benzimidazol-2-yl) -methyl] -benzonitrile 4-nitro-o-phenylenediamine 3.1 g (0.02 mol) and 4-cyanophenylacetic acid 3.7
g (0.023 mol) are refluxed in 30 ml of phosphorus oxychloride for 2 hours. After cooling, the mixture is neutralized with concentrated ammonia and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with methylene chloride / methanol (50: 1). The desired fraction is concentrated by evaporation, the residue is triturated with ethyl acetate / ether, filtered off with suction and dried.
Yield: 2.1 g (38% of theory), R _f value: 0.25 (silica gel; methylene chloride / methanol _{= 19: 1) C 15 H} 10 N 4 O 2 (278.3) Mass spectrum: M ⁺ = 278

B. 4-[(5-nitro-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and 4-[(6-nitro-1-methyl-1H-benzimidazole- 2-yl) -methyl ] -benzonitrile 4-[(5-nitro-1H-benzimidazol-2-yl) -methyl] -benzonitrile 1.4
g (5.0 mmol), potassium carbonate x ₂ H2O 2.6 g (15 mmol) and methyl iodide
0.84 g (6.0 mmol) is dissolved in 60 ml of acetone and stirred at ambient temperature for 1 hour. The solvent is evaporated off, the residue is mixed with water, the precipitated product is filtered off with suction and dried. Yield: 1.1 g (75% of theory), _Rf value: 0.2 (silica gel; methylene chloride / methanol = 19: 1) c. 4-[(5-amino-1-methyl-1H-benzimidazole-2- Yl) -methyl] -benzonitrile 1.1 g (37.6 mmol) of 4-[(5-nitro-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and 4-[(6-nitro 1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile in methanol 30 ml and methylene chloride 40
Dissolve in ml and hydrogenate at ambient temperature for 60 minutes after addition of 0.2 g palladium on activated carbon (10%). Then the catalyst is filtered off and the filtrate is concentrated by evaporation. The residue is chromatographed on silica gel, methylene chloride / methanol (30: 1).
Elute with Yield: 0.3 g (30% of theory), R _f value: 0.4 (silica gel; methylene chloride / methanol _{= 9: 1) C 16 H} 14 N 4 (262.3) Mass spectrum: M ⁺ = 262

. [0093] d 4 - [(5-benzenesulfonylamino-1-methyl -1H- benzoimidazol-2 b le) - methyl - benzonitrile 4 - [(5-amino-1-methyl -1H- benzimidazole 300 mg (11.4 mmol) of 2--2-yl) -methyl] -benzonitrile and 200 mg (11.4 mmol) of benzenesulfonic acid chloride are stirred in 10 ml of pyridine at ambient temperature for 1 hour. Then 1 ml of water is added and the mixture is concentrated by distillation. The residue is combined with water and ethyl acetate and stirred at ambient temperature for 1 hour, during which time the material slowly crystallizes. The ethyl acetate is evaporated off and the crystalline residue is filtered off with suction. Yield: 380 mg (83% of theory), _Rf value: 0.5 (silica gel; methylene chloride / methanol = 9: 1) e. 4-[(5-benzenesulfonylamino-1-methyl-1H-benzimidazole-2) - b le) - methyl] - Benzoamijin hydrochloride 4 - [(5-benzenesulfonylamino-1-methyl -1H- benzimidazol-2-yl)
-Methyl] -benzonitrile (430 mg, 1.07 mmol) is dissolved in saturated ethanolic hydrochloric acid (30 ml) and stirred at ambient temperature for 5 hours. The solvent is distilled off, the residue is dissolved in 30 ml of absolute ethanol and combined with 1.0 g (10.7 mmol) of ammonium carbonate. After 60 hours at ambient temperature, the mixture is evaporated to dryness. The residue is chromatographed on silica gel, eluting with methylene chloride / methanol (5: 1). Evaporate the corresponding fractions, triturate with ether and filter with suction. Yield: 170 mg (29% of theory), R _f value: 0.2 (silica gel; methylene chloride / methanol _{= 5: 1) C 22 H} 21 N 5 O 2 S x HCl (419.50 / 455.96) Mass spectrum: (M + H) ⁺ = 420

Example 2 4-[(5-benzenesulfonylamino-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In the same manner as in Example 1e, 4-[(5-benzene Prepared from sulfonylamino-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 59% of theory, C ₂₁ H ₁₉ N ₅ O ₂ S × HCl (405.48 / 441.95) Mass spectrum: (M + H) ⁺ = 406

Example 3 4-[(6-benzenesulfonylamino-4-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In ethanol, as in Example 1e, Prepared from (6-benzenesulfonylamino-4-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 38% of _{theory, C 22 H 21 N 5 O} 2 S x HCl (419.50 / 455.96) Mass ^{spectrum: (M + H) + =} 420

Example 4 4-[(6-benzenesulfonylamino-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In ethanol, as in Example 1e, Prepared from (6-benzenesulfonylamino-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 23% of theory, R _f value: 0.25 (silica gel; methylene chloride / methanol = 5: 1) C ₂₂ H ₂₁ N ₅ O ₂ S x HCl (419.50 / 455.96) Mass spectrum: (M + H) ⁺ = 420

[0097] Example 5 4 - [(5-benzenesulfonylamino -1-n-propyl -1H- benzimidazol-2-b le) - methyl] - Benzoamijin in the same manner as hydrochloride Example 1e in ethanol 4-[(5-benzenesulfonylamino-1-n-
Propyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid /
Prepared from ammonium carbonate. Yield: 43% of theory, C ₂₄ H ₂₅ N ₅ O ₂ S x HCl (447.55 / 484.02) Mass spectrum: (M + H) ⁺ = 448 Example 6 4-[(6-benzenesulfonylamino-1 -n- propyl -1H- benzoimidazol-2-b le) - methyl] - Benzoamijin hydrochloride example 1e and similarly in ethanol 4 - [(amino -1-n-6- benzenesulfonyl
Propyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid /
Prepared from ammonium carbonate. Yield: 39% of _{theory, C 24 H 25 N 5 O} 2 S x HCl (447.55 / 484.02) Mass ^{spectrum: (M + H) + =} 448

Example 7 4-[(5-phenylaminosulfonyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride a. 4-phenylaminosulfonyl-2-nitro-chlorobenzene Prepared from aniline and 4-chlorine-3-nitro-benzenesulfonic acid chloride in pyridine as in Example 1d. Yield: 97% of theory, _Rf value: 0.5 (silica gel; methylene chloride / ethanol = 19: 1)

B. 4-Phenylaminosulfonyl-2-nitro-N-methyl-aniline 4-phenylaminosulfonyl-2-nitro-chlorobenzene 6.0 g (0.019 mol) and 40 ml of a methylamine solution (40% in water) are bombarded. Heat to 130 ° C for 2 hours. The contents are diluted with water and neutralized with hydrochloric acid. The precipitated product is filtered off with suction,
dry. Yield: 5.0 g (86% of theory), _Rf value: 0.45 (silica gel; methylene chloride / ethanol = 19: 1) c. 4-phenylaminosulfonyl-2-amino-N-methyl-aniline 4-phenylamino 5.0 g (0.016 mol) of sulfonyl-2-nitro-N-methyl-aniline
Is dissolved in 300 ml of ethyl acetate and 30 ml of methanol and hydrogenated at 60 ° C. with hydrogen after addition of 1.0 g of Raney nickel. The catalyst is removed by suction filtration and methanolic hydrochloric acid 40
Add ml and evaporate the solution. The residue is crystallized from ether / ethyl acetate, filtered off with suction and dried. Yield: 5.0 g (89% of theory), _Rf value: 0.41 (silica gel; methylene chloride / ethanol = 9: 1)

. [0100] d 4 - [(5-phenyl-aminosulfonyl-1-methyl -1H- benzoimidazol-2 b le) - methyl] - in the same manner as benzonitrile Example 1a in phosphorus oxychloride 4-phenyl Prepared from aminosulfonyl-2-amino-N-methyl-aniline hydrochloride and 4-cyano-phenylacetic acid. Yield:. 36% of theory e 4 - [(5-phenyl-aminosulfonyl-1-methyl -1H- benzoimidazol-2 b le) - methyl] - Benzoamijin ethanol in the same manner as hydrochloride Example 1e Prepared from 4-[(5-phenylaminosulfonyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 11% of _{theory, C 22 H 21 N 5 O} 2 S x HCl (419.5 / 456.0) Mass ^{spectrum: (M + H) + =} 420

Example 8 4-[(5-benzenesulfonylamino-1-ethyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In ethanol, as in Example 1e, 4- [ Prepared from (5-benzenesulfonylamino-1-ethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 35% of theory, C ₂₃ H ₂₃ N ₅ O ₂ S x HCl (433.53 / 469.99) Mass spectrum: (M + H) ⁺ = 434 Example 9 4-[(5- (N-methyl- benzenesulfonylamino) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and similarly in ethanol 4 - [(5-(N-methyl - benzenesulfonylamino ) -1-Methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 27% of theory, C ₂₃ H ₂₃ N ₅ O ₂ S x HCl (433.53 / 469.99) Mass spectrum: (M + H) ⁺ = 434

[0102] Example 10 4 - [(5-benzenesulfonylamino-1-ethoxycarbonylmethyl--1H- Benzoimi imidazole-2-yl) - methyl] - Benzoamijin hydrochloride Example 1e and 4 in ethanol in the same manner Prepared from-[(5-benzenesulfonylamino-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 68% of _{theory, C 25 H 25 N 5 O} 4 S x HCl (491.58 / 528.05) Mass ^{spectrum: (M + H) + =} 492

Example 11 4-[(5-benzenesulfonylamino-1-carboxymethyl-1H-benzimidazol- 2-yl) -methyl] -benzamidine 4-[(5-benzenesulfonylamino-1-ethoxycarbonyl 200 mg (0.379 mmol) of methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride are dissolved in 10 ml of ethanol and stirred at 40 ° C. for 90 minutes after addition of 1 ml of 2N sodium hydroxide solution. The solvent is distilled off, the residue is diluted with 20 ml of water and acidified with glacial acetic acid.
The precipitated product is filtered off with suction and dried. Yield: 160 mg (91% of _{theory), C 23 H 21 N 5} O 4 S (463.53) Mass ^{spectrum: (M + H) + =} 464

Example 12 4-[(5- (N-ethoxycarbonylmethyl-benzenesulfonylamino) -1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride a. 4- [ (5-(N-ethoxycarbonylmethyl - benzenesulfonylamino) -1-methylation)-1H-benzimidazol-2-yl] - methyl] - 4 with potassium carbonate / acetone in the same manner as benzonitrile example 1b Prepared from-[(5-benzenesulfonylamino-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and ethyl bromoacetate. Yield: 99% of theory, R _f value:. 0.3 (silica gel; methylene chloride / methanol = 9: 1) b 4 - [(5-(N-ethoxycarbonylmethyl - benzenesulfonylamino) -1-methylation -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (N-ethoxycarbonylmethyl-benzenesulfonylamino) -1-methyl- 1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 41% of _{theory, C 24 H 23 N 5 O} 4 S x HCl (505.62 / 542.06) Mass ^{spectrum: (M + H) + =} 506 (3M + 2H) ++ = 758.8

Example 13 4-[(5- (N-carboxymethyl-benzenesulfonylamino) -1-methyl-1H- benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (N-ethoxycarbonylmethyl-benzenesulfonylamino) -1-methyl-
0.6 g (1.1 mmol) of 1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride and 0.22 g (5.5 mmol) of sodium hydroxide are stirred for 2 hours at ambient temperature in 15 ml of water and 10 ml of ethanol. The mixture is diluted with water and adjusted to pH 4 with hydrochloric acid. The solvent is concentrated by evaporation, the residue is triturated with ether, suction filtered and
dry. Yield: 0.3 g (53% of _{theory), C 24 H 23 N 5} O 4 S x HCl (477.54 / 514.00) Mass ^{spectrum: (M + H) + =} 478

[0106] Example 14 4 - [(5-(N-benzyl - methanesulfonylamino) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin hydrochloride a 4 -. [(5 -Methanesulfonylamino-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile 4-[(5-amino-1-methyl-1H-benzimidazole) in pyridine in the same manner as in Example 1d. -2-yl) -methyl] -benzonitrile and methanesulfonic acid chloride. Yield: 62% of theory, _Rf value: 0.6 (silica gel; methylene chloride / methanol = 9: 1)

. [0107] b 4 - [(5-(N-benzyl - methanesulfonylamino) -1-methyl -1H- Benzoimida 2-yl) - methyl] - In in the same manner as benzonitrile Example 1b in acetone 4-[(5-methanesulfonylamino-1-methyl
-1H-benzimidazol-2-yl) -methyl] -benzonitrile, benzyl chloride and potassium carbonate. Yield: 79% of theory, _Rf value: 0.7 (silica gel; methylene chloride / methanol = 9: 1) c. 4-[(5- (N-benzyl-methanesulfonylamino) -1-methyl-1H- Benzoimida-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and 4 in ethanol in the same manner - [(5-(N-benzyl - methanesulfonylamino) -1-methyl -1H- benzimidazole - 2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 54% of _{theory, C 24 H 25 N 5 O} 2 S x HCl (447.55 / 484.01) Mass ^{spectrum: (M + H) + =} 448

Example 15 4-[(5- (N- (Naphthalen-1-yl-methyl) -methanesulfonylamino) -1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride in ethanol 4 in the same manner as salt example 1e - [(5- (N- (naphthalen-1-yl - methyl)
-Methanesulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl
Prepared from -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 11% of _{theory, C 28 H 27 N 5 O} 2 S x HCl (497.62 / 534.08) Mass ^{spectrum: (M + H) + =} 498

[0109] Example 16 4 - [(5- (naphthalen-1-yl - sulfonylamino) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin In analogy to the hydrochloride Example 1e Prepared from 4-[(5- (naphthalen-1-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 66% of theory, C ₂₆ H ₂₃ N ₅ O ₂ S x HCl (469.57 / 506.03) Mass spectrum: (M + H) ⁺ = 470 Example 17 4-[(5- (naphthalene-2- yl - sulfonylamino) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5- (naphthalen-2-yl - Prepared from sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 74% of theory, C ₂₆ H ₂₃ N ₅ O ₂ S x HCl (469.57 / 506.03) Mass spectrum: (M + H) ⁺ = 470

Example 18 4-[(5-Benzylsulfonylamino-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride Prepared from (5-benzylsulfonylamino-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 68% of _{theory, C 23 H 23 N 5 O} 2 S x HCl (433.53 / 469.99) Mass ^{spectrum: (M + H) + =} 434

Example 19 4-[(5- (quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol- 2-yl) -methyl] -benzamidine hydrochloride In the same manner as in Example 1e. Prepared from 4-[(5- (quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 65% of theory, C ₂₅ H ₂₂ N ₆ O ₂ S x HCl (470.55 / 507.01) Mass spectrum: (M + H) ⁺ = 471 Example 20 4-[(5- (3,5- Bis-trifluoromethylphenylsulfonylamino) -1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (3, 5-bis-trifluoromethylphenylsulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 63% of _{theory, C 24 H 19 F 6 N} 5 O 2 S x HCl (555.51 / 591.97) Mass ^{spectrum: (M + H) + =} 556

[0112] Example 21 4 - [(5- (2,5-dimethoxyphenyl sulfonylamino) -1-methyl -1H- Benzoimida 2-yl) - methyl] - Benzoamijin In analogy to the hydrochloride Example 1e Prepared from 4-[(5- (2,5-dimethoxyphenylsulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 83% of _{theory, C 24 H 25 N 5 O} 4 S x HCl (479.55 / 516.01) Mass ^{spectrum: (M + H) + =} 480

Example 22 4-[(5- (2,3,5,6-tetramethylphenylsulfonylamino) -1-methyl-1H- benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (2,3,5,6-tetramethylphenylsulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile in ethanol as in Example 1e And hydrochloric acid / ammonium carbonate. Yield: 17% of theory, C ₂₆ H ₂₉ N ₅ O ₂ S x HCl (475.61 / 512.08) Mass spectrum: (M + H) ⁺ = 476 Example 23 4-[(5-phenylsulfonylaminoacetylamino) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5-phenyl sulfonylamino acetate Chiruamino-1-methyl - 1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 65% of _{theory, C 24 H 24 N 6 O} 3 S x HCl (476.56 / 513.03) Mass ^{spectrum: (M + H) + =} 477

Example 24 4-[(5- (N-methyl-naphthalen-1-yl-aminocarbonyl) -1-methyl-1H- benzimidazol-2-yl) -methyl] -benzamidine hydrochloride a. 4-Chloro-3-nitro-benzoic acid chloride 20.1 g (0.1 mol) of 4-chloro-3-nitro-benzoic acid, 11 ml of thionyl chloride and 1 drop of dimethylformamide are mixed together and refluxed for 2 hours. The thionyl chloride is removed by evaporation. Yield: 21.9 g (100% of theory)

B. To a solution of 2.8 g (0.02 mol) of 1-naphthylamine and 2.0 g (0.02 mol) of triethylamine in 50 ml of 4-chloro-3-nitro-N- (naphthalen-1-yl) -benzamide tetrahydrofuran At −20 ° C., a solution of 4.4 g (0.02 mol) of 4-chloro-3-nitro-benzoic chloride in 20 ml of tetrahydrofuran is added dropwise. The solution is stirred at ambient temperature for 30 minutes. The solvent is then evaporated off and the residue is chromatographed on silica gel, eluting with methylene chloride. The desired fraction is concentrated by evaporation, triturated with ether, filtered off with suction and dried. Yield: 5.9 g (90% of theory) c. 4-Chloro-3-nitro-N-methyl-N- (naphthalen-1-yl) -benzamide 4-chloro-3-nitro-N- (naphthalene-1 Dissolve 3.2 g (0.01 mol) of -yl) -benzamide and 1.1 g (0.01 mol) of potassium tert.-butoxide in 50 ml of dimethylsulfoxide and stir at ambient temperature for 30 minutes. Then 1 ml of methyl iodide is added to it and the mixture is stirred at ambient temperature for a further 3 hours. Pour the solution into saturated sodium chloride solution and extract with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with methylene chloride. Yield: 3.2 g (94% of theory), melting point: 118-120 ° C

D. 4 -Methylamino-3-nitro-N-methyl-N- (naphthalen-1-yl) -benzamide 4-chloro-3-nitro-N-methyl-N- (naphthalen-1-yl) -Benzoamide 3.0 g (8.8
3 mmol) and 30 ml of a methylamine solution (40% in water) are heated to 130 ° C. in a bomb for 14 hours. After cooling, the solution is poured into water, the residue is filtered off with suction, chromatographed on silica gel and eluted with methylene chloride. Yield: 2.9 g (98% of theory), _Rf value: 0.3 (silica gel; methylene chloride / ethanol = 50: 1) e. 4-methylamino-3-amino-N-methyl-N- (naphthalene-1) -Yl) -benzamide 4-methylamino-3-nitro-N-methyl-N- (naphthalen-1-yl) -benzoamide2.9
g (8.6 mmol) was dissolved in 100 ml of methanol, and 0.5 g of palladium / activated carbon (20%
) Is hydrogenated at ambient temperature for 2 hours. Then the catalyst is filtered off and the filtrate is concentrated by evaporation. Yield: 2.6 g (98% of theory), _Rf value: 0.15 (silica gel; methylene chloride / ethanol = 50: 1)

. [0117] f 4 - [(5-(N-methyl - naphthalen-1-yl - amino carbonyl) -1-methyl -1H- Baie emission zone imidazol-2-yl) - methyl] - benzonitrile 4-Cyano 483 mg (3.0 mmol) of phenylacetic acid and carbonyldiimidazole 48
6 mg (3.0 mmol) is dissolved in 20 ml of tetrahydrofuran and stirred at 50 ° C. for 1 hour. Then 916 mg of 5- (naphthalen-1-yl-methylaminocarbonyl) -2-methylamino-aniline are added thereto and stirring is continued at 50 ° C. for a further 3 hours. The solvent is concentrated by evaporation, the residue is combined with 30 ml of glacial acetic acid and refluxed for 1 hour. After evaporation of the solvent, the filtrate is chromatographed on silica gel, methylene chloride / ethanol 99: 1.
, 98: 1 and 97: 1. The desired fraction is concentrated by evaporation and the residue is acetone /
Triturate with ether, filter with suction and dry. Yield: 970 mg (75% of theory), melting point:. 266-268 ℃ g 4 - [(5-(N-methyl - naphthalen-1-yl - amino carbonyl) -1-methyl -1H- base down zone imidazole 2-yl) -methyl] -benzamidine hydrochloride in ethanol in the same manner as in Example 1e, and 4-((5- (N-methyl-naphthalen-1-yl-aminocarbonyl) -1-methyl-1H- Benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 82% of _{theory, C 28 H 25 N 5 O} x HCl (447.55 / 484.01) Mass spectrum: M ⁺ = 447

Example 25 4-[(5-Phenylmethylaminocarbonyl-1-methyl-1H-benzimidazol-2- yl) -methyl] -benzamidine hydrochloride In ethanol, as in Example 1e, Prepared from [(5-phenylmethylaminocarbonyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 95.5% of theory, C ₂₄ H ₂₃ N ₅ O x HCl (397.49 / 433.96) Mass spectrum: M ⁺ = 397 Example 26 4-[(5- (N-phenyl-n-butylaminocarbonyl) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5-(N-phenyl--n- Buchiruaminoka carbonyl) 1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 95% of theory, C ₂₇ H ₂₉ N ₅ O x HCl (439.57 / 476.03) Mass spectrum: (M + H) ⁺ = 440

Example 27 4-[(4-benzenesulfonylamino-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride Prepared from (4-benzenesulfonylamino-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 63% of _{theory, C 22 H 21 N 5 O} 2 S x HCl (419.50 / 455.96) Mass ^{spectrum: (M + H) + =} 420

Example 28 4-[(5- (N-methylaminocarbonyl-N-phenyl-aminocarbonyl) -1-methyl-1 H-benzimidazol-2-yl) -methyl] -benzamidine-mesylate 4 -[(5- (N-methylaminocarbonyl-N-phenyl-aminocarbonyl) -1-methyl
-1H-benzimidazol-2-yl) -methyl] -benzonitrile 700 mg (1.6 mmol), hydroxylamine hydrochloride 222 mg (3.2 mmol) and sodium carbonate 170 mg (1.6 mmol) in 100 ml methanol and 4 ml water for 16 hours. Bring to reflux. After the addition of 150 mg of methanesulfonic acid and 500 mg of Raney nickel, the mixture is hydrogenated at ambient temperature with 5 atm of hydrogen. The catalyst is filtered off, the residue is concentrated by evaporation,
Chromatography on silica gel, eluting with methylene chloride / ethanol (8: 2). Yield: 680 mg (77% of _{theory), C 26 H 26 N 6} O 2 x CH 3 SO 3 H (454.54 / 550.64) Mass ^{spectrum: (M + H) + =} 455

Example 29 4-[(6- (Naphthalen-2-yl-sulfonylamino) -1-ethoxycarbonylmethyl-1 H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride Example 1e 4-[(6- (Naphthalen-2-yl-sulfonylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol Prepared from Yield: 63% of theory, C ₂₉ H ₂₇ N ₅ O ₄ S x HCl (541.64 / 578.1) Mass spectrum: (M + H) ⁺ = 542

[0122] Example 30 4 - [(4- (naphthalen-2-yl - sulfonylamino) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin In analogy to the hydrochloride Example 1e Prepared from 4-[(4- (naphthalen-2-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 66% of theory, C ₂₆ H ₂₃ N ₅ O ₂ S x HCl (469.57 / 506.03) Mass spectrum: (M + H) ⁺ = 470 Example 31 4-[(5- (N- (2 - morpholino - ethyl) - quinolin-8-yl - sulfonylamino) -1-methylation -1H- benzimidazol-2-yl) - methyl] - Benzoamijin dihydrochloride example 1e and 4 in ethanol in the same manner -[(5- (N- (2-morpholino-ethyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / carbonic acid Prepared from ammonium. Yield: 66% of _{theory, C 31 H 33 N 7 O} 3 S x 2 HCl (583.72 / 656.63) Mass ^{spectrum: (M + H) + =} 584

[0123] Example 32 4 - [(5- (N- (2- morpholino - ethyl) - quinolin-8-yl - amino) -1-methyl -1H- Ben zo-imidazol-2-yl) - methyl] - Benzoamidine hydrochloride 4-[(5- (N- (2-morpholino-ethyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazole- in ethanol as in Example 1e. 2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 96% of _{theory, C 31 H 31 N 7 O} 4 S x HCl (597.70 / 634.17) Mass ^{spectrum: (M + H) + =} 598

[0124] Example 33 4 - [(5- (N- (3- ethoxycarbonyl -n- propyl) - quinolin-8-yl - Suruhonirua amino) -1-methyl -1H- benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5- (N- (3- ethoxycarbonyl -n- propyl) - quinolin-8-yl) - sulfonylamino) -1 -Methyl-1H-benzimidazol-2-yl] -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 58% of _{theory, C 31 H 32 N 6 O} 4 S x HCl (584.71 / 621.17) Mass ^{spectrum: (M + H) + =} 585 Example 34 4 - [(5-(N-ethoxycarbonyl Methyl-quinolin-8-yl-sulfonylamino) -1- methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine hydrochloride in ethanol as in Example 1e in 4-[(5- ( N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino-1-methyl-1H-benzimidazol-2-yl)-
Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 68% of _{theory, C 29 H 28 N 6 O} 4 S x HCl (556.65 / 593.12) Mass ^{spectrum: (M + H) + =} 557 (M + Na) + = 579 (M + 2H) + ⁺ = 279

Example 35 4-[(5- (N-ethoxycarbonylmethyl-benzoylamino) -1-methyl-1H- benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In the same manner as in Example 1e. Prepared from 4-[(5- (N-ethoxycarbonylmethyl-benzoylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 47% of _{theory, C 27 H 27 N 5 O} 3 x HCl (469.55 / 506.0) Mass ^{spectrum: (M + H) + =} 470

Example 36 4-[(5- (N- (3-ethoxycarbonyl) -phenylsulfonylamino) -1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (N- (3-ethoxycarbonyl) -phenylsulfonylamino-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid in ethanol as in 1e / was prepared from ammonium carbonate. yield: 24% of _{theory, C 25 H 25 N 5 O} 4 S x HCl (491.6 / 528.0) mass ^{spectrum: (M + H) + =} 492 example 37 4 - [(. 5-(N-methyl - pyridin-3-yl aminocarbonyl) -1-methyl -1H- Benzoimi imidazole-2-yl) - methyl] - the same as Benzoamijin hydrochloride example 1e to ethanol 4- [ (5- (N-methyl-pyridin-3-ylaminocarbonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / carbonic acid Was prepared from Moniumu yield. 49% of _{theory, C 23 H 22 N 6 O} x HCl (398.48 / 434.94) Mass ^{spectrum: (M + H) + =} 399

[0127] Example 38 4 - [(5-(N-methyl - pyridin-2-yl aminocarbonyl) -1-methyl -1H- Benzoimi imidazole-2-yl) - methyl] - Benzoamijin hydrochloride Example 1e 4-[(5- (N-methyl-pyridin-2-yl-aminocarbonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid in ethanol / Ammonium carbonate. Yield: 49% of theory, C ₂₃ H ₂₂ N ₆ O x HCl (398.48 / 434.94) Mass spectrum: (M + H) ⁺ = 399

Example 39 4-[(5- (N-phenyl-N-ethoxycarbonylmethyl-aminocarbonyl) -1-methyl -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (N-phenyl-N-ethoxycarbonylmethyl-aminocarbonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid in ethanol as in 1e / Ammonium carbonate. Yield: 65% of theory, C ₂₇ H ₂₇ N ₅ O ₃ x HCl (469.55 / 506.02) Mass spectrum: (M + H) ⁺ = 470 Example 40 4-[(5- (N-phenyl-N - (2-dimethylamino-ethyl) - - aminocarbonyl) -1-methylation -1H- benzimidazol-2-yl) - methyl] - Benzoamijin dihydrochloride example 1e and similarly in ethanol 4- [ Prepared from (5- (N-phenyl-N- (2-dimethylamino-ethyl) -aminocarbonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate . Yield: 24% of _{theory, C 27 H 30 N 6 O} x 2 HCl (454.59 / 527.50) Mass ^{spectrum: (M + H) + =} 455

Example 41 4-[(5- (N-Carboxymethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (N-carboxymethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] in ethanol / water as in Example 13 -Prepared from benzamidine hydrochloride and sodium hydroxide. Yield: 56% of _{theory, C 27 H 24 N 6 O} 4 S x HCl (528.60 / 565.05) Mass ^{spectrum: (M + H) + =} 529 (M + Na) + = 551

Example 42 4-[(5- (N- (3-carboxy-n-propyl) -quinolin-8-yl-sulfonylamino) -1- methyl-1H-benzimidazol-2-yl) -methyl ] -Benzoamidine hydrochloride 4-[(5- (N- (3-carboxy-n-propyl) -quinolin-8-yl-sulfonylamino) -1-methyl- 1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 46% of theory, C ₂₉ H ₂₈ N ₆ O ₄ S x HCl (556.65 / 593.10) Mass spectrum: (M + H) ⁺ = 557 (M + Na) ⁺ = 579 Example 43 4- [ (5- (N- (2- morpholino - ethyl) - quinolin-8-yl - sulfonylamino) -1-methylation -1H- benzimidazol-2-yl) - carbonyl] - Benzoamijin dihydrochloride example 1e 4-((5- (N- (2-morpholino-ethyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -carbonyl in ethanol -Benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 37% of _{theory, C 31 H 31 N 7 O} 4 S x 2 HCl (597.7 / 670.62) Mass ^{spectrum: (M + H) + =} 598

Example 44 4-[(5- (N- (3-dimethylamino-n-propyl) -quinolin-8-yl-sulfonylamino ) -1-methyl-1H-benzimidazol-2-yl)- Methyl] -benzamidine dihydrochloride 4-[(5- (N- (3-dimethylamino-n-propyl) -quinolin-8-yl-sulfonylamino) -1-in ethanol in the same manner as in Example 1e. Methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 78% of _{theory, C 30 H 33 N 7 O} 2 S x 2 HCl (555.71 / 663.07) Mass ^{spectrum: (M + H) + =} 556 (M + 2H) ++ = 278.8 Example 45 4 -[(5- (N- (2-dimethylamino-ethyl) -quinolin-8-yl-sulfonylamino) -1- methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride 4-[(5- (N- (2-dimethylamino-ethyl)-] in ethanol in the same manner as in Example 1e
Quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl)
-Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 81% of _{theory, C 29 H 31 N 7 O} 2 S x 2HCl (541.68 / 612.59) Mass ^{spectrum: (M + H) + =} 542

[0132] Example 46 4 - [(5-(N-Benzoyl -N- carboxymethyl - amino) -1-methyl -1H- Benzoimida 2-yl) - methyl] - Benzoamijin hydrochloride Example 13 Similarly, 4-[(5- (N-benzoyl-N-ethoxycarbonylmethyl-amino) -1-methyl-1H-benzimidazol-2-yl) -methyl] in ethanol / water
-Prepared from benzamidine hydrochloride and sodium hydroxide. Yield: 98% of theory, C ₂₅ H ₂₃ N ₅ O ₃ x HCl (441.50 / 447.95) Mass spectrum: (M + H) ⁺ = 442 (M + Na) ⁺ = 464

[0133] Example 47 4 - [(5- (3-carboxyphenyl sulfonylamino) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - in analogy to Benzoamijin hydrochloride Example 13 Prepared from 4-[(5- (3-ethoxycarbonylphenylsulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide in ethanol / water. Yield: 82% of theory, C ₂₃ H ₂₁ N ₅ O ₄ S x HCl (463.50 / 499.95) Mass spectrum: (M + H) ⁺ = 464 Example 48 4-[(5- (N-phenyl- N- carboxymethyl - aminocarbonyl) -1-methyl -1H- Ben zo-imidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 13 in the same manner as 4 ethanol / water - [(5-(N -Phenyl-N-ethoxycarbonylmethyl-aminocarbonyl) -1-methyl-1H-benzimidazol-2-yl)-
Methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 68% of theory, C ₂₅ H ₂₃ N ₅ O ₃ (441.50 / 477.95) Mass spectrum: (M + H) ⁺ = 442

[0134] Example 49 4 - [(5-benzenesulfonylamino -1-n-propyl -1H- benzimidazol-2-b le) - methyl] - Benzoamijin in the same manner as hydrochloride Example 1e in ethanol 4-[(5-benzenesulfonylamino-1-n-
Propyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid /
Prepared from ammonium carbonate. Yield: 62% of _{theory, C 25 H 27 N 5 O} 2 S x HCl (461.58 / 498.04) The mass ^{spectrum: (M + H) + =} 462

[0135] Example 50 4 - [(5-(N-ethoxycarbonylmethyl - benzenesulfonylamino) -1-n-propyl Le -1H- benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride Example 4-[(5- (N-ethoxycarbonylmethyl-benzenesulfonylamino) -1-n-propyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid in ethanol as in 1e / Ammonium carbonate. Yield: 45% of theory, C ₂₉ H ₃₃ N ₅ O ₄ S x HCl (547.68 / 584.14) Mass spectrum: (M + H) ⁺ = 548 Example 51 4-[(5- (N-methyl- benzenesulfonylamino) -1-n-propyl -1H- Benzoimida-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and similarly in ethanol 4 - [(5-(N-methyl - benzene Prepared from sulfonylamino) -1-n-propyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 45% of _{theory, C 26 H 29 N 5 O} 2 S x HCl (475.62 / 512.08) Mass ^{spectrum: (M + H) + =} 476

[0136] Example 52 4 - [(5-(N-carboxymethyl - benzenesulfonylamino) -1-n-propyl -1H- Baie emission zone imidazol-2-yl) - methyl] - Benzoamijin hydrochloride Example 4-[(5- (N-ethoxycarbonylmethyl-benzenesulfonylamino) -1-n-propyl-1H-benzimidazol-2-yl)-in ethanol / water in the same manner as 13
Methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 62% of theory, C ₂₇ H ₂₉ N ₅ O ₄ S x HCl (519.63 / 556.08) Mass spectrum: (M + H) ⁺ = 520

Example 53 4-[(5- (N-phenyl-N- (3-ethoxycarbonyl-n-propyl) -aminocarbonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -Benzoamidine hydrochloride 4-[(5- (N-phenyl-N- (3-ethoxycarbonyl-n-propyl) -aminocarbonyl) -1-methyl-1H-benzo in ethanol as in Example 1e Imidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 70% of theory, C ₂₉ H ₃₁ N ₅ O ₃ x HCl (497.61 / 534.07) Mass spectrum: (M + H) ⁺ = 498 Example 54 4-[(5-((N-pyridine- 3-yl - carbonyl) -N- methyl - amino) -1-methyl -1H- Ben zo-imidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and 4 in ethanol in the same manner - [( Prepared from 5-((N-pyridin-3-yl-carbonyl) -N-methyl-amino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate . Yield: 54% of _{theory, C 23 H 22 N 6 O} x HCl (398.5 / 434.95) Mass spectrum: M ⁺ = 398

[0138] Example 55 4 - [(5 - ((N-pyridin-4-yl - carbonyl) -N- methyl - amino) -1-methyl -1H- Ben zo-imidazol-2-yl) - methyl] - Benzoamidine hydrochloride 4-[(5-((N-pyridin-4-yl-carbonyl) -N-methyl-amino) -1-methyl-1H-benzimidazole-ethanol in ethanol as in Example 1e. Prepared from 2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 53% of _{theory, C 23 H 22 N 6 O} x HCl (398.5 / 434.95) Mass ^{spectrum: (M + H) + =} 399

Example 56 4-[(5- (pyridin-3-yl-sulfonylamino) -1-methyl-1H-benzimidazol- 2-yl) -methyl] -benzamidine hydrochloride In the same manner as in Example 1e. Prepared from 4-[(5- (pyridin-3-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 48% of theory, C ₂₁ H ₂₀ N ₆ O ₂ S x HCl (420.5 / 456.95) Mass spectrum: (M + H) ⁺ = 421 Example 57 4-[(5- (N-ethoxycarbonyl) methyl - benzenesulfonylamino) -1-ethoxycarbonylmethyl -1H- benzimidazol-2-yl) - methyl] - Benzoamijin salt salt example 1e and 4 in ethanol in the same manner - [(5-(N- Prepared from ethoxycarbonylmethyl-benzenesulfonylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 64.5% of _{theory, C 29 H 31 N 5 O} 6 S x HCl (577.67 / 614.14) Mass ^{spectrum: (M + H) + =} 578

Example 58 4-[(5- (N- (2-dimethylamino-ethyl) -benzenesulfonylamino) -1-ethoxycarbonylmethyl -1H-benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride example 1e and 4 in ethanol in the same manner - [(5- (N- (2- dimethylamino - ethyl) -
Benzenesulfonylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 11.1% of _{theory, C 28 H 32 N 6 O} 4 S x 2 HCl (548.68 / 621.6) Mass ^{spectrum: (M + H) + =} 549 (M + 2H) ++ = 275.1

[0141] Example 59 4 - [(6-benzenesulfonylamino-amino-1-ethoxycarbonylmethyl--1H- Benzoimi imidazole-2-yl) - methyl] - Benzoamijin hydrochloride Example 1e and 4 in ethanol in the same manner Prepared from-[(6-benzenesulfonylamino-1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 90% of theory, C ₂₅ H ₂₅ N ₅ O ₄ S x HCl (491.58 / 528.05) Mass spectrum: (M + H) ⁺ = 492 Example 60 4-[(5- (3-ethoxycarbonyl) -n- propylamino) -1-ethoxycarbonyl-methylation -1H- benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and 4 in ethanol in the same manner - [(5- (3- Prepared from ethoxycarbonyl-n-propylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 41.7% of theory, C ₂₅ H ₃₁ N ₅ O ₄ x HCl (465.56 / 502.03) Mass spectrum: (M + H) ⁺ = 466

[0142] Example 61 4 - [(5- (ethoxycarbonylmethyl-amino) -1-ethoxycarbonylmethyl -1H- Baie emission zone imidazol-2-yl) - methyl] - Benzoamijin In analogy to the hydrochloride Example 1e Prepared from 4-[(5- (ethoxycarbonylmethylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 56.4% of _{theory, C 23 H 27 N 5 O} 4 x HCl (437.51 / 473.98) Mass ^{spectrum: (M + H) + =} 438 Example 62 4 - [(5-(N-methyl - piperidine -1-yl-carbonylamino) -1-methyl-1H- benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (N-methyl -Piperidin-1-yl-carbonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 55% of _{theory, C 23 H 28 N 6 O} x HCl (404.52 / 440.98) Mass spectrum: M ⁺ = 404

[0143] Example 63 4 - [(5-(N-methyl-2,3-dihydro-indol-1-yl - carbonyl amino) -1-methylation -1H- benzimidazol-2-yl) - methyl] - Benzoamidine hydrochloride 4-[(5- (N-methyl-2,3-dihydroindole-1-yl-carbonylamino) -1-methyl-1H-benzimidazole in ethanol as in Example 1e -2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 78% of _{theory, C 26 H 26 N 6 O} x HCl (438.54 / 475.00) Mass spectrum: M ⁺ = 438

Example 64 4-[(5- (N- (3-ethoxycarbonyl-n-propyl) -benzenesulfonylamino) -1- ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -methyl Benzoa spermidine hydrochloride example 1e and 4 in ethanol in the same manner - [(5- (N- (3- ethoxycarbonyl -n- propyl) - benzenesulfonylamino) -1-ethoxycarbonyl - methyl -1H- benzimidazole -2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 59.5% of theory, C ₃₁ H ₃₅ N ₅ O ₆ S x HCl (605.9 / 641.4) Mass spectrum: (M + H) ⁺ = 606 Example 65 4-[(6- (N-methyl- Benzenesulfonylamino) -1-ethoxycarbonylmethyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(6- (N-methyl-benzene) in ethanol in the same manner as in Example 1e. Sulfonylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 45% of theory, C ₂₆ H ₂₇ N ₅ O ₄ S x HCl (505.61 / 542.07) Mass spectrum: (M + H) ⁺ = 506

Example 66 4-[(5-benzenesulfonylamino-1- (3-ethoxycarbonyl) -n-propyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride Example 1e Similarly, in ethanol, 4-[(5-benzenesulfonylamino-1- (3
-Ethoxycarbonyl) -n-propyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 58% of theory, C ₂₇ H ₂₉ N ₅ O ₄ S x HCl (519.6 / 556.1) Mass spectrum: (M + H) ⁺ = 520

Example 67 4-[(5-benzenesulfonylamino-1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In ethanol, as in Example 1e, 4- [ Prepared from (5-benzenesulfonylamino-1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 63% of theory, C ₂₈ H ₂₅ N ₅ O ₂ S x HCl (495.6 / 532.1) Mass spectrum: (M + H) ⁺ = 496 Example 68 4-[(5-benzenesulfonylamino-1 - (2-morpholino - ethyl)-1H-Benzoimida-2-yl) - methyl] - Benzoamijin dihydrochloride example 1e and in ethanol 4 in the same manner - [(5-benzenesulfonylamino-1- ( Two
-Morpholino-ethyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 96% of theory, C ₂₇ H ₃₀ N ₆ O ₃ S × 2 HCl (518.65 / 591.56) Mass spectrum: (M + H) ⁺ = 519

[0147] Example 69 4 - [(5-benzenesulfonylamino-1- (2-dimethylamino - ethyl)-1H-benzoyl imidazole-2-yl) - methyl] - Similar to Benzoamijin dihydrochloride Example 1e And in ethanol with 4-[(5-benzenesulfonylamino-1- (2
-Dimethylamino-ethyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 38% of _{theory, C 25 H 28 N 6 O} 2 S x 2 HCl (476.6 / 549.56) Mass ^{Spectrum: (M + H) + =} 477

[0148] Example 70 4 - [(5-(N-ethoxycarbonylmethyl - benzenesulfonylamino) -1- (3-ethoxy aryloxycarbonyl -n- propyl)-1H-benzimidazol-2-yl) - methyl] - Benzoa spermidine hydrochloride example 1e and ethanol 4 in the same manner - [(5-(N-ethoxycarbonylmethyl - benzenesulfonylamino) -1- (3-ethoxycarbonyl -n- propyl)-1H-benzoimidazole -2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 61% of theory, C ₃₁ H ₃₅ N ₅ O ₆ S x HCl (605.7 / 642.2) Mass spectrum: (M + H) ⁺ = 606 Example 71 4-[(5- (N-ethoxycarbonyl) Methyl-benzenesulfonylamino) -1-benzyl- 1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride -Benzenesulfonylamino) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 43% of _{theory, C 32 H 31 N 5 O} 4 S x HCl (581.7 / 618.2) Mass ^{spectrum: (M + H) + =} 582

Example 72 4-[(5- (N- (N'-phenyl-methylaminocarbonyl) -methylamino) -1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride in ethanol 4 in the same manner as salt example 1e - [(5- (N- (N'- phenyl - methylaminocarbonyl) - methylamino) -1-methyl -1H- benzimidazol-2-yl) - methyl -Benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 43% of theory, C ₂₅ H ₂₆ N ₆ O x HCl (426.52 / 462.98) Mass spectrum: (M + H) ⁺ = 427

[0150] Example 73 4 - [(5- (N- (ethoxycarbonylmethyl-amino-acetyl) - quinolin-8-yl - sul Honiruamino) -1-methyl -1H- benzimidazol-2-yl) - methyl] - Benzoami hydrochloride example 1e and similarly in ethanol 4 - [(5- (N- (ethoxycarbonylmethyl aminocarbonyl) - quinolin-8-yl - sulfonylamino) -1-methyl -1H- benzonitrile and was prepared from hydrochloric acid / ammonium carbonate. yield:. 80% of _{theory, C 31 H 31 N 7 O} 5 S x HCl (613.70 / 650.16) mass ^{spectrum: (M + H) + =} 614 example 74 4- [ (5- (N- (4-dimethylaminopiperidinocarbonylmethyl) -quinolin-8-yl- sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine dihydrochloride 4-[(5- (N- (4-dimethylaminopiperidinocarbonylmethyl) -quinoline-8] in ethanol in the same manner as in Example 1e -Yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate 78% of theory, C ₃₄ H ₃₈ N ₈ O ₃ S x 2 HCl (638.8 / 711.73) Mass spectrum: (M + H) ⁺ = 639.

[0151] Example 75 4 - [(5-(N-ethoxycarbonylmethyl - benzenesulfonylamino) -1- (2-Moruho Reno - ethyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin dihydrochloride example 1e and 4 in ethanol in the same manner - [(5-(N-ethoxycarbonylmethyl - benzenesulfonylamino) -1- (2-morpholino - ethyl)-1H-benzonitrile and hydrochloric acid / ammonium carbonate Yield: 68% of theory, C ₃₁ H ₃₆ N ₆ O ₅ S × 2 HCl (604.7 / 677.66) Mass spectrum: (M + H) ⁺ = 605 Example 76 4-[(5- (N- aminocarbonyl-methyl - benzenesulfonylamino) -1- (3-ethoxycarbonyl -n- propyl)-1H-benzimidazol-2-yl) - methyl] - Benzoami hydrochloride example 1e and ethanol in the same manner 4-((5- (N-aminocarbonylmethyl-benzenesulfonylamino) -1- (3-ethoxycarbonyl-n-propyl) Propyl)-1H-Benzoni was prepared tolyl and hydrochloric acid / ammonium carbonate. Yield:. 49% of _{theory, C 29 H 32 N 6 O} 5 S x HCl (576.7 / 613.1) Mass spectrum: (M + H) ⁺ = 577

Example 77 4-[(5- (N-aminocarbonylmethyl-benzenesulfonylamino) -1-benzyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride As in Example 1e Prepared from 4-[(5- (N-aminocarbonylmethyl-benzenesulfonylamino) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol did. Yield: 61% of _{theory, C 30 H 28 N 6 O} 3 S x HCl (552.7 / 588.2) Mass ^{spectrum: (M + H) + =} 553

[0153] Example 78 4 - [(5-(N-aminocarbonyl-methyl - benzenesulfonylamino) -1- (2-Moruhori Bruno - ethyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin dihydrochloride example 1e and in ethanol 4 in the same manner - [(5-(N-aminocarbonyl-methyl - base emissions Zen sulfonylamino) -1- (2-morpholino - ethyl)-1H-benzonitrile and hydrochloric acid / . was prepared from ammonium carbonate. yield: 78% of _{theory, C 29 H 33 N 7 O} 4 S x HCl (575.7 / 648.6) mass ^{spectrum: (M + H) + =} 576 example 79 4 - [(5 - (N-carboxymethyl - benzenesulfonylamino) -1- (2-morpholino - an ethyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin dihydrochloride example 13 in analogy ethanol / 4- (5-N- (ethoxycarbonylmethyl-benzenesulfonylamino) -1- (2-morpholino-ethyl) -1H-benzimidazole in water . 2-yl] - methyl] - Benzoamijin was prepared from the dihydrochloride salt and sodium hydroxide. Yield: 87% of _{theory, C 29 H 32 N 6 O} 5 S x 2 HCl (576.7 / 649.62) Mass spectrum : (M + H) ⁺ = 577

[0154] Example 80 4 - [(5-(N-ethoxycarbonylmethyl - benzenesulfonylamino-1- (2-dimethylcarbamoyl arylamino - ethyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin two in ethanol 4 in the same manner as hydrochloride example 1e - [(5-(N-ethoxycarbonylmethyl - benzenesulfonylamino) -1- (2-dimethylamino - ethyl)-1H-benzimidazol-2-yl) - methyl] - was prepared from benzonitrile and hydrochloric acid / ammonium carbonate. yield:. 60% of _{theory, C 29 H 34 N 6 O} 4 S x 2 HCl (562.7 / 635.66) mass spectrum: (M + H) ⁺ = 563 (M + 2H) ⁺⁺ = 282

[0155] Example 81 4 - same as Benzoamijin hydrochloride Example 13 - [(5-(N-carboxymethyl - benzenesulfonylamino) -1-benzyl -1H- Ben zo-imidazol-2-yl) - methyl] From 4-[(5- (N-ethoxycarbonylmethyl-benzenesulfonylamino) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide in ethanol / water Prepared. Yield: 84% of theory, C ₃₀ H ₂₇ N ₅ O ₄ S x HCl (553.65 / 590.11) Mass spectrum: (M + H) ⁺ = 554 Example 82 4-[(5- (N- (carboxy) methylamino-acetyl) - quinolin-8-yl - Suruhonirua amino) -1-methyl -1H- benzimidazol-2-yl) - methyl] - in analogy to Benzoamijin hydrochloride example 13 is made in ethanol / water 4 ((5- (N- (ethoxycarbonylmethylaminoacetyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride and hydroxylated Prepared from sodium. Yield: 74% of theory, C ₂₉ H ₂₇ N ₇ O ₅ S × HCl (585.65 / 622.11) Mass spectrum: (M + H) ⁺ = 586 (M + Na) ⁺ = 608

Example 83 4-[(5- (N-Carboxymethyl-benzenesulfonylamino) -1- (2-dimethylamino- ethyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine Hydrochloride 4-[(5- (N-ethoxycarbonylmethyl-benzenesulfonylamino) -1- (2-dimethylamino-ethyl) -1H-benzimidazol-2-yl in ethanol / water in the same manner as in Example 13. ) -Methyl] -benzamidine dihydrochloride and sodium hydroxide. Yield: 62% of theory, C ₂₇ H ₃₀ N ₆ O ₄ S × 2 HCl (534.65 / 607.56) Mass spectrum: (M + H) ⁺ = 535

[0157] Example 84 4 - [(5- (N- (4- methyl-piperazino-carbonyl-methyl) - quinolin-8-yl - sulfonyl arylamino) -1-methyl -1H- benzimidazol-2-yl) - Methyl] -benzamidine dihydrochloride 4-[(5- (N- (4-methyl-piperazinocarbonylmethyl) -quinolin-8-yl-sulfonylamino) -1 in ethanol in the same manner as in Example 1e. -Methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 86% of theory, C ₃₂ H ₃₄ N ₈ O ₃ S x 2 HCl (610.74 / 683.67) Mass spectrum: (M + H) ⁺ = 611 Example 85 4-[(5- (N- ( N '- (2-dimethylaminoethyl) - ethylaminocarbonyl methyl) - key Norin 8-yl - sulfonylamino) -1-methyl -1H- benzimidazol-2-yl) - methyl] - Benzoamijin dihydrochloride 5- (N- (N ′-(2-dimethylaminoethyl) -ethylaminocarbonylmethyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1 in ethanol as in Example 1e
H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 95% of _{theory, C 33 H 38 N 8 O} 3 S x 2 HCl (626.79 / 699.71) Mass ^{spectrum: (M + H) + =} 627

[0158] Example 86 4 - [(5 - [(1-ethoxycarbonyl-2-aminocarbonyl - ethylamino) - carbonyl Rumechiru] - quinolin-8-yl - sulfonylamino) -1-methyl -1H- benzoimidazol 2- (2-yl) -methyl] -benzamidine hydrochloride in ethanol in the same manner as in Example 1e. ] -Quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 63% of theory, C ₃₃ H ₃₄ N ₈ O ₆ S x HCl (670.75 / 707.21) Mass spectrum: (M + H) ⁺ = 671 Example 87 4-[(5- (N- (4 -(2-morpholino-2-oxo-ethyl) -piperazinocarbonylmethyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine Hydrochloride In ethanol in the same manner as in Example 1e, 4-[(5- (N- (4- (2-morpholino-2-oxo-
Ethyl) -piperazinocarbonylmethyl) -quinolin-8-yl-sulfonylamino) -1-
Methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 81% of theory, C ₃₇ H ₄₁ N ₉ O ₅ S × 2 HCl (723.87 / 796.79) Mass spectrum: (M + H) ⁺ = 724

Example 88 4-[(5- (N- (2-dimethylamino-ethyl) -benzenesulfonylamino) -1-ethoxycarbonylmethyl -1H-benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride example 1e and 4 in ethanol in the same manner - [(5- (N- (2- dimethylamino - ethyl) -
Benzenesulfonylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 84% of _{theory, C 29 H 34 N 6 O} 4 S x 2 HCl (562.71 / 635.63) Mass ^{spectrum: (M + H) + =} 563

Example 89 4-[(5- (N- (2-dimethylamino-ethyl) -quinolin-8-yl-sulfonylamino-1- ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl ) - Benzoa spermidine dihydrochloride example 1e and 4 in ethanol in the same manner - [(5- (N- (2- dimethylamino - ethyl) -
Prepared from quinolin-8-yl-sulfonylamino) -1-ethoxycarbonyl-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 86% of theory, C ₃₂ H ₃₅ N ₇ O ₄ S × 2 HCl (613.75 / 686.68) Mass spectrum: (M + H) ⁺ = 614 Example 90 4-[(5- (N-amino carbonyl-methyl - benzenesulfonylamino) -1- (2-dimethylamino - ethyl)-1H-benzimidazol-2-yl) - methyl] - the same as Benzoamijin disalt salt example 1e to ethanol 4- Prepared from [(5- (N-aminocarbonylmethyl-benzenesulfonylamino) -1- (2-dimethylamino-ethyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate did. Yield: 83% of theory, C ₂₇ H ₃₁ N ₇ O ₃ S × 2 HCl (533.7 / 606.56) Mass spectrum: (M + H) ⁺ = 534

[0161] Example 91 4 - [(5-(N-(2-dimethylamino-ethyl) - - benzenesulfonylamino-1- (2-Moruho Reno - ethyl)-1H-benzimidazol-2-yl) - methyl ] - Benzoamijin trihydrochloride example 1e and 4 in ethanol in the same manner as - [(5- (N- (2- dimethylamino - ethyl) -
(Benzenesulfonylamino) -1- (2-morpholino-ethyl) -1H-benzimidazole
-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate.
Yield: 76% of _{theory, C 31 H 39 N 7 O} 3 S x 3 HCl (589.8 / 699.18) Mass ^{spectrum: (M + H) + =} 590 (M + 2H) ++ = 295.8 Example 92 4 - [(5-(N-(2-dimethylamino-ethyl) - - benzenesulfonylamino) -1- (3-ethoxy alkoxycarbonyl -n- propyl)-1H-benzimidazol-2-yl) - methyl] - benzo Amidine dihydrochloride 4-[(5- (N- (2-dimethylamino-ethyl)-
Prepared from benzenesulfonylamino) -1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 70% of _{theory, C 31 H 38 N 6 O} 4 S x 2 HCl (590.7 / 663.62) Mass ^{spectrum: (M + H) + =} 591

Example 93 4-[(5- (N- (2-dimethylamino-ethyl) -benzenesulfonylamino) -1-benzyl -1H-benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride in ethanol 4 in the same manner as salt example 1e - [(5- (N- (2- dimethylamino - ethyl) -
Prepared from benzenesulfonylamino) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 55% of _{theory, C 32 H 34 N 6 O} 2 S x 2 HCl (566.7 / 639.62) Mass ^{spectrum: (M + H) + =} 567

[0163] Example 94 4 - [(5-(N - [(1-carboxy-2-aminocarbonyl - ethylamino) - carbonyl methyltransferase] - quinolin-8-yl - sulfonylamino) -1-methyl -1H -Benzimidazol- 2-yl) -methyl] -benzamidine hydrochloride In ethanol / water, 4-[(5- (N-[(1-ethoxycarbonyl-2-aminocarbonyl- Ethylamino) -carbonylmethyl] -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine hydrochloride and sodium hydroxide. Yield: 55% of theory, C ₃₁ H ₃₀ N ₈ O ₆ S x HCl (642.70 / 679.16) Mass spectrum: (M + H) ⁺ = 643 Example 95 4-[(5- (N- (2 -Dimethylamino-ethyl) -n-butanesulfonylamino) -1-ethoxycarbonylmethyl -1H-benzimidazol-2-yl) -methyl] -benzoamidine dihydrochloride 4-ethanol in ethanol as in Example 1e ((5- (N- (2-dimethylamino-ethyl)-
n-butanesulfonylamino) -1-ethoxycarbonylmethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 77% of theory, C ₂₇ H ₃₈ N ₆ O ₄ S × 2 HCl (542.72 / 615.64) Mass spectrum: (M + H) ⁺ = 543

Example 96 4-[(5- (N-methoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1- methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (N-methoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) in methanol in the same manner as in Example 1e
-Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 67% of theory, C ₂₈ H ₂₆ N ₆ O ₄ S x HCl (542.63 / 579.09) Mass spectrum: (M + H) ⁺ = 543 (M + 2H) ⁺⁺ = 272 (M + H + Na) ²⁺ = 283

Example 97 4-[(5- (N-methoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1- methyl-1H-benzimidazol-2-yl) -methyl] -N'-methoxy carbonyl - Ben Zoamijin 4 - [(5-(N-methoxycarbonylmethyl - quinolin-8-yl - sulfonylamino) -1
-Methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 0.7 g (1.2 mmol) and potassium carbonate 0.66 g (4.8 mmol) in 5 ml of water and acetone 20
After addition of 0.12 g (1.3 mmol) of methyl chloroformate, the mixture is stirred at ambient temperature for 30 minutes. The solvent is evaporated off and the residue is chromatographed on silica gel, eluting with methylene chloride / methanol 40: 1. The desired fraction is concentrated by evaporation, the residue is triturated with ether and suction filtered. Yield: 0.26 g (36% of _{theory), C 30 H 28 N 6} O 6 S (600.66) Mass ^{spectrum: (M + H) + =} 601 (M + Na) + = 623

Example 98 4-[(5- (N- (2-dimethylamino-ethyl) -quinolin-8-yl-sulfonylamino) -1- carboxymethyl-1H-benzimidazol-2-yl) -methyl ] - Benzoamijin salt salt example 13 was prepared in analogy to 4 in ethanol / water - [(5- (N- (2- dimethylamino - ethyl) - quinolin-8-yl - sulfoamino) -1-ethoxycarbonylmethyl [1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 60% of _{theory, C 30 H 31 N 7 O} 4 S x HCl (585.67 / 622.13) Mass ^{spectrum: (M + H) + =} 586

[0167] Example 99 4 - [(5-(N-(2-dimethylamino-ethyl) - - benzenesulfonylamino) -1- (ethoxy aryloxycarbonyl methylaminocarbonyl methyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin dihydrochloride example 1e and in ethanol 4 in the same manner - [(5- (N- (2- dimethylamino - ethyl) -
Benzenesulfonylamino-1- (ethoxycarbonylmethyl-aminocarbonylmethyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 85% of theory, C ₃₁ H ₃₇ N ₇ O ₅ S × 2 HCl (619.76 / 692.68) Mass spectrum: (M + H) ⁺ = 620 (M + 2H) ⁺⁺ = 310.8

[0168] Example 100 4 - [(5- (N- (3- dimethylaminopropyl -n- propyl) - benzenesulfonylamino) -1-benzyl -1H- benzimidazol-2-yl) - methyl] - benzo Amidine dihydrochloride 4-[(5- (N- (3-dimethylamino-n-propyl) -benzenesulfonylamino) -1-benzyl-1H-benzimidazole-2-ethanol in ethanol in the same manner as in Example 1e. Yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 83% of _{theory, C 33 H 36 N 6 O} 2 S x 2 HCl (580.8 / 653.7) Mass ^{spectrum: (M + H) + =} 581 (M + 2H) ++ = 291

[0169] Example 101 4 - [(5-(N-(2-dimethylamino-ethyl) - - benzenesulfonylamino) -1- (carboxymethyl aminocarbonyl-methyl)-1H-benzimidazol-2-yl) - Methyl] -benzoamidine dihydrochloride 4-[(5- (N- (2-dimethylamino-ethyl) -benzenesulfonylamino) -1- (ethoxycarbonylmethyl-amino) in ethanol / water in the same manner as in Example 13. Carbonylmethyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride and sodium hydroxide. Yield: 94% of theory, C ₂₉ H ₃₃ N ₇ O ₅ S x 2 HCl (591.71 / 664.64) Mass spectrum: (M + H) ⁺ = 592 Example 102 4-[(5- (N- ( 2-methyl - propyl butyloxycarbonylmethyl) - quinolin-8-yl - sul Honiruamino) -1-methyl -1H- benzimidazol-2-yl) - and Benzoamijin example 97 - methyl] -N'- methoxyethanol carbonyl Similarly, in acetone / water, 4-[(5- (N- (2-methyl-propyloxycarbonylmethyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -Methyl] -benzamidine hydrochloride and methyl chloroformate. Yield: 25% of _{theory, C 33 H 34 N 6 O} 6 S (642.74) Mass ^{spectrum: (M + H) + =} 643 (M + Na) + = 665

Example 103 4-[(5- (N-ethoxycarbonylmethyl-isoquinolin-5-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (N-ethoxycarbonylmethyl-isoquinolin-5-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -ethanol in ethanol in the same manner as in Example 1e Prepared from benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 98% of theory, C ₂₉ H ₂₈ N ₆ O ₄ S x HCl (556.65 / 593.11) Mass spectrum: (M + H) ⁺ = 557 Example 104 4-[(5- (isoquinoline-5- yl - sulfonylamino) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and 4 in ethanol in the same manner - [(5- (isoquinolin-5 Yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 48% of theory, C ₂₅ H ₂₂ N ₆ O ₂ S x HCl (470.55 / 507.02) Mass spectrum: (M + H) ⁺ = 471

Example 105 4-[(5- (N- (2-Pyrrolidino-ethyl) -benzenesulfonylamino-1-benzyl-1H -benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride 4-[(5- (N- (2-pyrrolidino-ethyl) -benzenesulfonylamino) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -methyl in ethanol as in Example 1e
Prepared from benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 53% of theory, C ₃₄ H ₃₆ N ₆ O ₂ S × 2 HCl (592.8 / 665.7) Mass spectrum: (M + H) ⁺ = 593 (M + 2H) ⁺⁺ = 297

[0172] Example 106 4 - [(5-(N-(2-pyrrolidino-ethyl) - - benzenesulfonylamino-1- (3-Etokishika carbonyl -n- propyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamiji down dihydrochloride example 1e and in ethanol 4 in the same manner - [(5-(N-(2-pyrrolidino-ethyl) - - benzenesulfonylamino) -1- (3-ethoxycarbonyl -n- propyl)-1H-Benzonito was prepared from Lil and hydrochloric acid / ammonium carbonate. yield:. 33% of _{theory, C 33 H 40 N 6 O} 4 S x 2 HCl (616.8 / 689.7) mass spectrum: (M + H) ⁺ = 617 (M + 2H) ⁺⁺ = 309 Example 107 4-[(5- (N- (3-piperidino-n-propyl) -benzenesulfonylamino) -1-benzyl -1H-benzimidazole-2- Yl) -Methyl] -benzamidine dihydrochloride 4-[(5- (N- (3-piperidino-n-propyl)-
Prepared from benzenesulfonylamino) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 56% of theory, C ₃₆ H ₄₀ N ₆ O ₂ S × 2 HCl (620.8 / 693.7) Mass spectrum: (M + H) ⁺ = 621

[0173] Example 108 4 - [(5-benzenesulfonylamino-1- (2-ethoxycarbonyl - ethyl)-1H-ben zo-imidazol-2-yl) - methyl] - Benzoamijin same as hydrochloride Example 1e And in ethanol with 4-[(5-benzenesulfonylamino-1- (2
-Ethoxycarbonyl-ethyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 67% of theory, C ₂₆ H ₂₇ N ₅ O ₄ S x HCl (505.60 / 542.06) Mass spectrum: (M + H) ⁺ = 506

[0174] Example 109 4 - [(5-(N-carboxymethyl - isoquinolin-5-yl - sulfonylamino) -1-methylation -1H- benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride In the same manner as in Example 13, 4-[(5- (N-ethoxycarbonylmethyl-isoquinolin-5-yl-sulfonylamino) -1-methyl-1H-benzimidazole-
2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 90% of theory, C ₂₇ H ₂₄ N ₆ O ₄ S x HCl (528.60 / 565.06) Mass spectrum: (M + H) ⁺ = 529 Example 110 4-[(5- (N- (3 - dimethylaminopropyl -n- propyl) - benzenesulfonyl) -1- (3-ethoxycarbonyl -n- propyl)-1H-benzimidazol-2-yl) - methyl] - similar to the base Nzoamijin dihydrochloride example 1e 4-((5- (N- (3-dimethylamino-n-propyl) -benzenesulfonylamino) -1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazole-2- Yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield 78 percent of _{theory, C 32 H 40 N 6 O} 4 S x 2 HCl (604.8 / 677.7) Mass ^{spectrum: (M + H) + =} 605

[0175] Example 111 4 - [(5-(N-(3-piperidino -n- propyl) - benzenesulfonyl) -1- (3-ethoxy alkoxycarbonyl -n- propyl)-1H-benzo imidazol-2 -Yl) -methyl] -benzamidine dihydrochloride 4-[(5- (N- (3-piperidino-n-propyl)-
Prepared from benzenesulfonylamino) -1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 72% of theory, C ₃₅ H ₄₄ N ₆ O ₄ S × 2 HCl (644.8 / 717.7) Mass spectrum: (M + H) ⁺ = 645 Example 112 4-[(5- (N- ( 3-dimethylaminopropyl -n- propyl) - benzenesulfonyl) -1- (3-carboxy -n- propyl)-1H-benzimidazol-2-yl) - methyl] - similar to Benzoami dihydrochloride example 13 4-[(5- (N- (3-dimethylamino-n-propyl) -benzenesulfonylamino) -1- (3-ethoxycarbonyl-n-propyl) -1H
-Benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride and sodium hydroxide. Yield: 79% of _{theory, C 30 H 36 N 6 O} 4 S x 2 HCl (576.7 / 649.6) Mass ^{spectrum: (M + H) + =} 577

[0176] Example 113 4 - [(5-(N-(3-piperidino -n- propyl) - benzenesulfonyl) -1- (3-Cal Bokishi - propyl)-1H-benzimidazol-2-yl) -Methyl] -benzamidine dihydrochloride 4-[(5- (N- (3-piperidino-n-propyl) -benzenesulfonylamino) -1- (3-ethoxy) in ethanol / water as in Example 13 Carbonyl-propyl) -1H-benzoimidazol-2-yl) -methyl] -benzamidine dihydrochloride and sodium hydroxide. Yield: 64% of _{theory, C 33 H 40 N 6 O} 4 S x 2 HCl (616.8 / 689.7) Mass ^{spectrum: (M + H) + =} 617

[0177] Example 114 4 - [(5-(N-(2-dimethylamino-ethyl) - - benzenesulfonylamino) -1- (4-meth alkoxycarbonyl - benzyl)-1H-benzimidazol-2-yl) - methyl] - Benzoa spermidine dihydrochloride example 1e and in ethanol 4 in the same manner - [(5-(N-(2-dimethylamino - ethyl - benzene sulfonylamino) -1- (4-methoxycarbonyl - benzyl ) -1H-Benzimidazol-2-yl) -methyl) -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 78% of theory, C ₃₄ H ₃₆ N ₆ O ₄ S × 2 HCl (624.8 / 697.7) Mass spectrum: (M + H) ⁺ = 625 Example 115 4-[(5- (N- ( 2-dimethylamino-ethyl) - - benzenesulfonylamino-1- (2-ethoxy aryloxycarbonyl - ethyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamiji down dihydrochloride example 1e and ethanol in the same manner In 4-[(5- (N- (2-dimethylamino-ethyl)-
Prepared from benzenesulfonylamino) -1- (2-ethoxycarbonyl-ethyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 84% of _{theory, C 30 H 36 N 6 O} 4 S x 2 HCl (576.73 / 651.65) Mass ^{spectrum: (M + H) + =} 577

Example 116 4-[(5- (N- (3-dimethylamino-n-propyl) -benzenesulfonylamino) -1- (2- ethoxycarbonyl-ethyl) -1H-benzimidazol-2-yl ) -Methyl ] -benzamidine dihydrochloride 4-[(5- (N- (3-dimethylamino-n-propyl) -benzenesulfonylamino) -1- (2- Ethoxycarbonylethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate Yield: 81% of theory, C ₃₁ H ₃₈ N ₆ O ₄ S × 2 HCl ( 590.75 / 663.67) Mass spectrum: (M + H) ⁺ = 591 (M + 2H) ⁺⁺ = 296. Example 117 4-[(5- (N- (2-dimethylamino-ethyl) -benzenesulfonylamino)- 1- (2-Cal Bokishi - ethyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin disalt salt example 13 was prepared in analogy to 4 in ethanol / water - [(5-(N- (2-Dimethi Amino-ethyl) -benzenesulfonylamino) -1- (2-ethoxycarbonyl-ethyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride and sodium hydroxide. 92% of _{theory, C 28 H 32 N 6 O} 4 S x 2 HCl (548.67 / 621.59) mass ^{spectrum: (M + H) + =} 549

Example 118 4-[(5- (N- (3-dimethylamino-n-propyl) -benzenesulfonylamino) -1- (2- carboxy-ethyl) -1H-benzimidazol-2-yl) -Methyl] -benzamidine dihydrochloride 4-[(5- (N- (3-dimethylamino-n-propyl) -benzenesulfonylamino) -1- (2- Ethoxycarbonylethyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride and sodium hydroxide. Yield: 42% of theory, C ₂₉ H ₃₄ N ₆ O ₄ S × 2 HCl (548.67 / 621.59) Mass spectrum: (M + H) ⁺ = 549

[0180] Example 119 4 - [(5-(N-phenyl--N-(3- carboxy -n- propyl) - aminocarbonyl) -1-methylation -1H- benzimidazol-2-yl) - methyl] -Benzoamidine hydrochloride 4-[(5- (N-phenyl-N- (3-ethoxycarbonyl-n-propyl) -aminocarbonyl) -1-methyl-1H-) in ethanol / water in the same manner as in Example 13. Benzimidazole-
2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 78% of theory, C ₂₇ H ₂₇ N ₅ O ₃ x HCl (469.55 / 506.02) Mass spectrum: (M + H) ⁺ = 470 Example 120 4-[(5- (N- (3- dimethylamino -n- propyl) - methanesulfonyl-amino-1- (2-ethoxy alkoxycarbonyl - ethyl)-1H-benzimidazol-2-yl) - methyl] - Benzoami dihydrochloride example 1e and ethanol in the same manner In 4-[(5- (N- (3-dimethylamino-n-propyl) -methanesulfonylamino) -1- (2-ethoxycarbonylethyl-1H-benzimidazol-2-yl) -methyl]- Prepared from benzonitrile and hydrochloric acid / ammonium carbonate Yield: 90% of theory, C ₂₆ H ₃₆ N ₆ O ₄ S × 2 HCl (528.68 / 601.61) Mass spectrum: (M + H) ⁺ = 529

[0181] Example 121 4 - [(5-(N-(2-dimethylamino-ethyl) - - methanesulfonylamino) -1- (2-ethoxy aryloxycarbonyl - ethyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamiji down dihydrochloride example 1e and in ethanol 4 in the same manner - [(5- (N- (2- dimethylamino - ethyl) -
(Methanesulfonylamino) -1- (2-ethoxycarbonyl-ethyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 94% of theory, C ₂₅ H ₃₄ N ₆ O ₄ S × 2 HCl (514.65 / 587.57) Mass spectrum: (M + H) ⁺ = 515 Example 122 4-[(5- (2-dimethyl amino - ethylamino sulfonyl) -1-benzyl -1H- benzoyl imidazole-2-yl) - methyl] - Benzoamijin dihydrochloride example 1e and 4 in ethanol in the same manner - [(5- (2-dimethylamino -Ethylaminosulfonyl) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 84% of _{theory, C 26 H 30 N 6 O} 2 S x 2 HCl (490.6 / 563.6) Mass ^{spectrum: (M + H) + =} 491

Example 123 4-[(5- (N-methyloxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -N'- isobutyloxy Cal Boniru - Benzoamijin example 97 in the same manner as 4 acetone / water - [(5-(N-methyl-oxycarbonyl-methyl - quinolin-8-yl - sulfonylamino) -1-methyl -1H- benzimidazole -2-
Yl) -methyl] -benzamidine hydrochloride and isobutyl chloroformate. Yield: 41% of _{theory, C 33 H 34 N 6 O} 6 S (642.75) Mass ^{spectrum: (M + H) + =} 643 (M + Na) + = 665

[0183] Example 124 4 - [(5-(N-(3- dimethylaminopropyl -n- propyl) - methanesulfonyl-amino) -1- (2-mosquito Rubokishi - ethyl)-1H-benzimidazol-2-yl ) -Methyl] -benzamidine dihydrochloride 4-[(5- (N- (3-dimethylamino-n-propyl) -methanesulfonylamino) -1- (2 -Ethoxycarbonylethyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride and sodium hydroxide. Yield: 63% of theory, C ₂₄ H ₃₂ N ₆ O ₄ S x 2 HCl (500.62 / 573.54) Mass spectrum: (M + H) ⁺ = 501 Example 125 4-[(5- (N- ( 2-dimethylamino-ethyl) - - methanesulfonylamino) -1- (2-carboxyethyl - ethyl)) - 1H-benzimidazol-2-yl] - methyl] - in analogy to Benzoamijin disalts salt example 13 4-((5- (N- (2-dimethylamino-ethyl) -methanesulfonylamino) -1- (2-ethoxycarbonyl-ethyl) -1H-benzimidazol-2-yl) -methyl in ethanol / water ] -Benzamidine dihydrochloride and sodium hydroxide. Yield: 72% of _{theory, C 23 H 30 N 6 O} 4 S x 2 HCl (486.6 / 559.52) Mass ^{spectrum: (M + H) + =} 487

Example 126 4-[(5- (N-ethyloxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -N′- Cyclohexyloxycarbonyl -benzamidine In acetone / water as in Example 97, 4-[(5- (N-ethyloxycarbonylmethyl-quinolin-8-yl-sulfonylamino-1-methyl-1H-benzimidazole-2) - yl) - methyl] - Benzoamijin hydrochloride and cyclohexyl chloroformate and formate or al preparation yield. 61% of _{theory, C 36 H 38 N 6 O} 6 S (682.81) mass spectrum: (M + H) ⁺ = 683 (M + Na) ⁺ = 705

Example 127 4-[(5- (N-Ethyloxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -N'- benzyloxy carboxymethyl sulfonyl - Benzoamijin example 97 in the same manner as 4 acetone / water - [(5-(N-ethyloxycarbonylmethyl - quinolin-8-yl - sulfonylamino) -1-methyl -1H- benzimidazole -2-
Yl) -methyl] -benzamidine hydrochloride and benzyl chloroformate. Yield: 65% of theory, C ₃₇ H ₃₄ N ₆ O ₆ S (690.79) Mass spectrum: (M + H) ⁺ = 691 (M + Na) ⁺ = 713 Example 128 4-[(5- ( 4-dimethylamino - piperidino)-1H-benzimidazol-2-yl) - methylation] - Benzoamijin dihydrochloride example 1e and 4 in ethanol in the same manner - [(5- (4-dimethylamino - piperidino ) -1H-Benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 100% of _{theory, C 22 H 28 N 6 x} 2 HCl (376.51 / 449.42) Mass ^{spectrum: (M + H) + =} 377

Example 129 4-[(5- (4-Dimethylamino-piperidino) -1- (2-ethoxycarbonyl-ethyl) -1H -benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride 4-[(5- (4-dimethylamino-piperidino) in ethanol in the same manner as in Example 1e
-1- (2-ethoxycarbonyl-ethyl) -1H-benzimidazol-2-yl) -methyl]
Prepared from -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 100% of theory, C ₂₇ H ₃₆ N ₆ O ₂ x 2 HCl (476.63 / 549.56) Mass spectrum: (M + H) ⁺ = 477 Example 130 4-[(5- (N- (2 - dimethylamino - ethyl) - methanesulfonyl-amino) -1- (3-ethoxy aryloxycarbonyl methylaminocarbonyl -n- propyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin dihydrochloride example 1e 4-((5- (N- (2-dimethylamino-ethyl)-
(Methanesulfonylamino) -1- (3-ethoxycarbonylmethylaminocarbonyl-n-
Propyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 98% of _{theory, C 28 H 39 N 7 O} 5 S x 2 HCl (585.74 / 658.67) Mass ^{spectrum: (M + H) + =} 586

[0187] Example 131 4 - [(5-(N-(2-dimethylamino-ethyl) - - methanesulfonylamino) -1- (3-ethoxy aryloxycarbonyl -n- propyl)-1H-benzoimidazol-2 yl) - methyl] - Benzoa spermidine dihydrochloride example 1e and in ethanol 4 in the same manner - [(5- (N- (2- dimethylamino - ethyl) -
Prepared from methanesulfonylamino) -1- (3-ethoxycarbonyl-n-propyl) -1H-benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 94% of theory, C ₂₆ H ₃₆ N ₆ O ₄ S × 2 HCl (528.69 / 601.62) Mass spectrum: (M + H) ⁺ = 529

Example 132 4-[(5- (N-Ethyloxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -N′- ethyl oxy carbonylation Le - Benzoamijin example 97 in the same manner as 4 acetone / water - [(5- (N- (2- ethyloxy carbonylation Rumechiru - quinolin-8-yl - sulfonylamino) -1-methyl Prepared from -1H-benzimidazol-2-yl) -methyl) -benzamidine hydrochloride and ethyl chloroformate. Yield: 63% of theory, C ₃₂ H ₃₂ N ₆ O ₆ S (628.71) Mass spectrum: (M + H) ⁺ = 629 Example 133 4-[(5- (N-methyl-piperidinocarbonyl) (Amino) -1- (3-ethoxycarbonyl-n- propyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-((5- ( Prepared from N-methyl-piperidinocarbonylamino) -1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 21% of theory, C ₂₈ H ₃₆ N ₆ O ₃ x HCl (504.64 / 541.11) Mass spectrum: (M + H) ⁺ = 505 (M + 2H) ⁺⁺ = 253

Example 134 4-[(5- (N-Carboxymethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H -benzimidazol-2-yl) -methyl] -N'-ethyloxy carbonyl - Benzoa spermidine example 13 in the same manner as 4 ethanol / water - [(5-(N-ethoxycarbonylmethyl - quinolin-8-yl - sulfonylamino) -1-methyl -1H- benzimidazol-2-yl ) -Methyl] -N'-ethyloxycarbonyl-benzamidine hydrochloride and sodium hydroxide. Yield: 70% of theory, C ₃₀ H ₂₈ N ₆ O ₆ S (600.66) Mass spectrum: (M + H) ⁺ = 601 (MH) ⁻ = 599 (M + Na) ⁺ = 623 Example 135 4 -[(5- (N-methyl-piperidinocarbonylamino) -1- (3-carboxy-n-propyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride Example 13 Similarly, in ethanol / water, 4-[(5- (N-methyl-piperidinocarbonylamino) -1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazole-
2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 63% of _{theory, C 26 H 32 N 6 O} 3 x HCl (476.59 / 513.05) Mass ^{spectrum: (M + H) + =} 477

[0190] Example 136 4 - [(5-(N-(2-diethylamino-ethyl) - - benzenesulfonylamino) -1- (ethoxy aryloxycarbonyl methylaminocarbonyl methyl)-1H-benzimidazol-2-yl) - Methyl] -benzamidine dihydrochloride 4-[(5- (N- (2-diethylamino-ethyl)-
Benzenesulfonylamino) -1- (ethoxycarbonylmethylaminocarbonylmethyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 76% of _{theory, C 33 H 41 N 7 O} 5 S x 2HCl (647.81 / 720.74) Mass ^{spectrum: (M + H) + =} 648 (M + 2H) ++ = 324.8 Example 137 4- [(5-(N-(2-dimethylamino - ethyl) -N- ethyl - aminosulfonyl) -1- (3-ethoxy carboxylate -n- propyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamidine dihydrochloride 4-[(5- (N- (2-dimethylamino-ethyl)-
N-ethyl-aminosulfonyl) -1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 64% of theory, C ₂₇ H ₃₈ N ₆ O ₄ S × 2 HCl (542.7 / 615.6) Mass spectrum: (M + H) ⁺ = 543

[0191] Example 138 4 - [(5-(N-(2-dimethylamino-ethyl) - - aminosulfonyl) -1- (3-Etokishikaru Boniru -n- propyl -1H- benzimidazol-2-yl) - Methyl) -benzamidine dihydrochloride 4-[(5- (N- (2-dimethylamino-ethyl)-
Aminosulfonyl) -1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 93% of theory, C ₂₅ H ₃₄ N ₆ O ₄ S x 2 HCl (514.7 / 587.6) Mass spectrum: (M + H) ⁺ = 515 Example 139 4-[(5- (N- ( 2-diethylamino-ethyl) - - benzenesulfonylamino) -1- (carboxymethyl aminocarbonyl-methyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin dihydrochloride example 13 in analogy ethanol / 4-((5- (N- (2-diethylamino-ethyl) -benzenesulfonylamino) -1- (ethoxycarbonylmethyl-aminocarbonylmethyl) -1H-benzimidazol-2-yl) -methyl] -benzo in water Prepared from amidine dihydrochloride and sodium hydroxide. Yield: 78% of theory, C ₃₁ H ₃₇ N ₇ O ₅ S × 2 HCl (619.76 / 692.69) Mass spectrum: (M + H) ⁺ = 620 (M + 2H) ⁺⁺ = 311 (M + H + Na) ⁺⁺ = 322

[0192] Example 140 4 - [(5-(N-(2-dimethylamino-ethyl) - - ethylamino sulfonyl) -1- (3-carboxypropyl -n- propyl)-1H-benzimidazol-2-yl ) -Methyl] -benzamidine dihydrochloride 4-[(5- (N- (2-dimethylamino-ethyl) -ethylaminosulfonyl) -1- (3-ethoxy) in ethanol / water in the same manner as in Example 13. Carbonyl-n-propyl) -1H-benzoimidazol-2-yl) -methyl] -benzamidine dihydrochloride and sodium hydroxide. Yield: 86% of theory, C ₂₅ H ₃₄ N ₆ O ₄ S x 2 HCl (514.7 / 587.6) Mass spectrum: (M + H) ⁺ = 515 Example 141 4-[(5- (N- ( ethoxycarbonylmethyl aminocarbonylmethyl) - phenyl - amino carbonyl) -1-methyl -1H- benzimidazol-2-yl) - methyl] - Benzoami hydrochloride example 1 was prepared in analogy to 4 in ethanol - [( Prepared from 5- (N- (ethoxycarbonylmethylaminocarbonylmethyl) -phenylaminocarbonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 88% of theory, C ₂₈ H ₃₀ N ₆ O ₄ x HCl (514.6 / 551.05) Mass spectrum: (M + H) ⁺ = 515

[0193] Example 142 4 - [(5- (N- (carboxymethyl aminocarbonyl-methyl) phenylamino carbonylation Le) -1-methyl -1H- benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride 4-[(5- (N- (ethoxycarbonylmethylaminocarbonylmethyl) -phenylaminocarbonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl in ethanol / water in the same manner as in Example 13. ] -Benzamidine hydrochloride and sodium hydroxide. Yield: 33% of _{theory, C 27 H 26 N 6 O} 4 x HCl (498.55 / 535.13) Mass ^{spectrum: (M + H) + =} 499

[0194] Example 143 4 - [(5- (2-dimethylamino - ethylamino) -l- (3-carboxy -n- propyl)-1H-benzimidazol-2-yl) - methyl] - benzo Amidine dihydrochloride 4-[(5- (2-Dimethylamino-ethylaminosulfonyl) -1- (3-ethoxycarboxy-n-propyl) -1H-benzimidazolone in ethanol / water as in Example 13. Ru-2-yl) -methyl] -benzamidine dihydrochloride and sodium hydroxide. Yield: 75% of _{theory, C 23 H 30 N 6 O} 4 S x 2 HCl (486.6 / 559.5) Mass ^{spectrum: (M + H) + =} 487 Example 144 4 - [(5- (N- ( 1-methyl - piperidin-2-yl - methyl) - benzenesulfonylamino) - l- (ethoxycarbonylmethyl aminocarbonyl methyl)-1H-benzimidazol-2-yl) - methyl] -. Benzoamijin dihydrochloride a 4 - [(5-benzenesulfonylamino-1- (methyl ethoxycarbonylamino mosquito Rubonirumechiru)-1H-benzimidazol-2-yl) - methyl] - benzonitrile 4 - [(5-benzenesulfonylamino-1-carboxymethyl -1H-benzimidazol-2-yl) -methyl] -benzonitrile 2.7 g (6.1 mmol), glycine-ethyl ester hydrochloride 0.85 g (6.1 mmol) and triethylamine 1.5 g (15 mmol) were dissolved in dimethylformamide 80 ml. , O- (benzotriazol-1-yl) -N, N, N ', N
After addition of 2.4 g (7.5 mmol) of '-tetramethyluronium tetrafluoroborate, the mixture is stirred at ambient temperature for 16 hours. The solvent is evaporated off and the residue is chromatographed on silica gel, eluting with methylene chloride / ethanol 99: 1 and 98: 2. The desired fraction is concentrated by evaporation, the residue is triturated with ether, filtered off with suction and dried. Yield: 1.9 g (59% of theory), mp: 166-168 ° C

. [0195] b 4 - [(5-(N-(1-methyl - piperidin-2-yl - methyl) - benzenesulfonyl amino) -1- (ethoxycarbonyl methylaminocarbonyl methyl)-1H-benzoimidazol over 2-yl) - methyl] - in the same manner as benzonitrile example 1b in acetone 4 - [(5-benzenesulfonylamino-1- (e-butoxycarbonyl-methyl-aminocarbonyl-methyl)-1H-benzo imidazol-2 -Yl) -methyl] -benzonitrile, 2- (chloromethyl) -N-methyl-piperidine and potassium carbonate. Yield: 38% of theory, C ₃₄ H ₃₈ N ₆ O ₅ S (642.79) Mass spectrum: (M + H) ⁺ = 643 c. 4-[(5- (N- (1-methyl-piperidine- 2-yl - methyl) - benzenesulfonyl amino) -1- (ethoxycarbonyl methylaminocarbonyl methyl)-1H-benzo imidazole-2-yl) - methyl] - in analogy to the Benzoamijin dihydrochloride example 1e 4-((5- (N- (1-methyl-piperidin-2-yl-methyl) -benzenesulfonylamino) -1- (ethoxycarbonylmethylaminocarbonylmethyl) -1H-benzimidazole-2 in ethanol -Yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 100% of theory, C ₃₄ H ₄₁ N ₇ O ₅ S × 2 HCl (659.82 / 732.75) Mass spectrum: (M + H) ⁺ = 660 (M + 2H) ⁺⁺ = 330.7

Example 145 4-[(5- (N- (N'-ethoxycarbonylmethyl-N'-methyl-aminocarbonylmethyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzo imidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5- (N- (N'- ethoxycarbonylmethyl -N'- methyl - aminocarbonyl-methyl) -Quinolin-8-yl-sulfonylamino) -1
-Methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 52% of theory, C ₃₂ H ₃₃ N ₇ O ₅ S x HCl (627.73 / 664.19) Mass spectrum: (M + H) ⁺ = 628 Example 146 4-[(5- (N-methyl- piperidinocarbonyl amino) -1-benzyl -1H- Benzoimida-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and similarly in ethanol 4 - [(5-(N-methyl - pin Peridinocarbamino) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 57% of theory, C ₂₉ H ₃₂ N ₆ O x HCl (480.62 / 517.08) Mass spectrum: (M + H) ⁺ = 481

[0197] Example 147 4 - [(5- (N- (N'- carboxymethyl -N'- methyl - aminocarbonyl-methyl) - reluctant emission-8-yl - sulfonylamino) -1-methyl -1H- benzo imidazol-2-yl) - methylation] - Benzoamijin hydrochloride example 13 in the same manner as 4 ethanol / water - [(5- (N- (N'- ethoxycarbonylmethyl -N'- methyl - aminocarbonyl Methyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine hydrochloride and sodium hydroxide. Yield: 69% of _{theory, C 30 H 29 N 7 O} 5 S x HCl (599.67 / 636.13) Mass ^{spectrum: (M + H) + =} 600

Example 148 4-[(5- (N-ethoxycarbonylmethylaminocarbonylmethyl-quinolin-8-yl -sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -N '- cyclo hexyl oxycarbonyl - Benzoamijin example 97 in the same manner as 4 tetrahydrofuran / water - [(5-(N-ethoxycarbonylmethyl-aminocarbonyl-methyl - quinolin-8-yl - sulfonylamino) -1- main Tyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine hydrochloride and cyclohexyl chloroformate. Yield: 48% of theory, C ₃₈ H ₄₁ N ₇ O ₇ S (739.86) Mass spectrum: (M + H) ⁺ = 740 (M + 2H) ⁺⁺ = 370.8 (M + H + Na) ⁺⁺ = 381.6 Example 149 4-[(5- (N-ethoxycarbonylmethylaminocarbonylmethyl-quinolin-8-yl -sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -methyl ' - base emissions benzyloxycarbonyl - Benzoamijin example 97 in the same manner as 4 tetrahydrofuran / water - [(5-(N-ethoxycarbonylmethyl-aminocarbonyl-methyl - quinolin-8-yl - sulfonylamino) -1- methylation -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride and benzyl chloroformate. Yield: 38% of theory, C ₃₉ H ₃₇ N ₇ O ₇ S (747.85) Mass spectrum: (M + H) ⁺ = 748 (M + Na) ⁺ = 770 (M + H + Na) ⁺⁺ = 385.2

Example 150 4-[(5- (N- (1-methyl-piperidin-2-yl-methyl) -benzenesulfonylamino-1- (carboxymethylaminocarbonylmethyl) -1H-benzimidazole-2- yl) - methyl] - Benzoamijin dihydrochloride example 13 was prepared in analogy to in ethanol 4 - [(5- (N- (1- methyl - piperidin-2-y le - methyl) - benzenesulfonylamino) - . 1- (ethoxycarbonylmethyl aminocarbonyl methyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin was prepared from the dihydrochloride salt and sodium hydroxide. yield: 83% of theory, C ₃₂ H ₃₇ N ₇ O ₅ S x 2 HCl (631.77 / 704.7) Mass spectrum: (M + H) ⁺ = 632 (M + 2H) ⁺⁺ = 316.8 Example 151 4-[(5- (2-dimethylamino-ethyl) - aminocarbonyl) -1- (ethoxycarbonyl methylaminocarbonyl methyl)-1H-benzimidazol-2-yl] - methyl] - base Nzoa Dihydrochloride Example 1e and in ethanol 4 in the same manner - [(5- (2-dimethylamino-ethyl) - - amino carbonyl) -1- (ethoxycarbonyl methylaminocarbonyl methyl)-1H-benzimidazole - 2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 95% of theory, C ₂₆ H ₃₃ N ₇ O ₄ × 2 HCl (507.61 / 580.54) Mass spectrum: (M + H) ⁺ = 508

Example 152 4-[(5- (N- (2-Dimethylamino-ethyl) -ethylaminosulfonyl) -1-methyl-1H -benzimidazol-2-yl) -methyl] -benzoamidine dihydrochloride in ethanol 4 in the same manner as salt example 1e - [(5- (N- (2- dimethylamino - ethyl) -
Ethylaminosulfonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl]-
Prepared from benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 82% of _{theory, C 22 H 30 N 6 O} 2 S x 2 HCl (442.6 / 515.5) Mass ^{spectrum: (M + H) + =} 443 Example 153 4 - [(5-cyclohexyl-carbonylamino - 1- (3-ethoxycarbonyl-n-propyl ) -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride a. 4-cyclohexylcarbonylamino-2-nitro-fluorobenzene 4-fluoro-3- 15.6 g (0.1 mol) of nitro-aniline and 17.9 g (0.11 mol) of cyclohexylcarboxylic acid chloride are dissolved in 250 ml of tetrahydrofuran and, after addition of 12.1 g (0.12 mol) of triethylamine, the mixture is stirred at ambient temperature for 3 hours. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation. Yield: 17.1 g (64% of theory), _Rf value: 0.2 (silica gel; methylene chloride / petroleum ether = 9: 1)

B. Tert.butyl 4- [4- (cyclohexylcarbonylamino) -2-nitro-phenyl- amino] butyrate 4-cyclohexylcarbonylamino-2-nitro-fluoro in dimethylsulfoxide as in Example 7b Prepared from benzene, tert.butylaminobutyrate and potassium carbonate. Yield: 49% of theory, _Rf value: 0.3 (silica gel; methylene chloride / methanol = 50: 1) c. Tert.butyl 4- [4- (cyclohexylcarbonylamino) -2-amino- phenylamino] butyrate Prepared from tert.butyl 4-[(4- (cyclohexylcarbonylamino) -2-nitro-phenylamino] butyrate and palladium / activated carbon / hydrogen in methanol in the same manner as in Example 7c. 94%, _Rf value: 0.5 (silica gel; methylene chloride / methanol = 9: 1)

. [0203] d 4 - [(5-cyclohexyl-carbonylamino-1-(3-tert-butyloxy carbonylation Le -n- propyl)-1H-benzimidazol-2-yl.) - methyl] - benzonitrile 4- 0.65 g (4.0 mmol) of cyanophenylacetic acid and 0.65 g (4.0 mmol) of N, N'-carbonyldiimidazole are dissolved in 50 ml of tetrahydrofuran and refluxed for 30 minutes. After addition of 1.3 g (3.5 mmol) of tert.butyl 4- [4- (cyclohexylcarbonylamino) -2-amino-phenylamino] butyrate, the mixture is refluxed for a further 3 hours. The solvent is concentrated by evaporation and the residue is refluxed for 1 hour with 30 ml of glacial acetic acid. Then it is evaporated down i. Vac., The residue is poured into water, made basic with ammonia and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with methylene chloride / methanol 50: 1. The desired fractions are combined and concentrated by evaporation. Yield: 0.9 g (52% of theory), _Rf value: 0.4 (silica gel; methylene chloride / methanol = 9: 1) e. 4-[(5-cyclohexylcarbonylamino-1- (3-ethoxycarbonyl-n) - propyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5-cyclohexylcarbonyl amino -1- (3-tert. (Butyloxycarbonyl-n-propyl) -1H-benzimidazole-2
-Yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 95% of _{theory, C 28 H 35 N 5 O} 3 x HCl (489.62 / 526.08) Mass ^{spectrum: (M + H) + =} 490

Example 154 4-[(5-Cyclohexylcarbonylamino-1- (4-ethoxycarbonyl-n-butyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride Example 1e Similarly, 4-[(5-cyclohexylcarbonylamino-1- (4-ethoxycarbonyl-n-butyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol Prepared from Yield: 79% of theory, C ₂₉ H ₃₇ N ₅ O ₃ x HCl (503.64 / 540.11) Mass spectrum: (M + H) ⁺ = 504 Example 155 4-[(5-cyclohexylcarbonylamino-1- (3-carboxy -n- propyl)-1H-Baie emission zone imidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 13 in the same manner as 4 ethanol / water - [(5-cyclohexyl-carbonylamino - 1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazol-2-yl)
-Methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 100% of theory, C ₂₆ H ₃₁ N ₅ O ₃ x HCl (461.57 / 498.03) Mass spectrum: (M + H) ⁺ = 462

[0204] Example 156 4 - [(5-cyclohexyl-carbonylamino-1- (4-carboxy -n- butyl)-1H-ben zo-imidazol-2-yl) - methyl] - Benzoamijin hydrochloride Example 13 Similarly, 4-[(5-cyclohexylcarbonylamino-1- (4-ethoxycarbonyl-n-butyl) -1H-benzimidazol-2-yl) -methyl] -benzoamidine hydrochloride and ethanol in ethanol / water Prepared from sodium. Yield: 98% of theory, C ₂₇ H ₃₃ N ₅ O ₃ x HCl (475.59 / 512.05) Mass spectrum: (M + H) ⁺ = 476

[0205] Example 157 4 - [(5-cyclohexylmethyl-amino-1- (3-ethoxycarbonyl--n- flop propyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride Example 4-[(5-Cyclohexylmethylaminocarbonyl-1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid in ethanol in the same manner as 1e / Ammonium carbonate. Yield: 67% of theory, C ₂₉ H ₃₇ N ₅ O ₃ x HCl (503.66 / 540.12) Mass spectrum: (M + H) ⁺ = 504 Example 158 4-[(5- (N-cyclohexyl-methyl) (Aminocarbonyl) -1- (3-ethoxycarbonyl- n-propyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In ethanol in the same manner as in Example 1e, 4-[(5- (N-cyclohexylmethylaminocarbonyl) -1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazole-2
-Yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 64% of theory, C ₂₉ H ₃₇ N ₅ O ₃ x HCl (503.66 / 540.12) Mass spectrum: (M + H) ⁺ = 504

Example 159 4-[(5- (N-methyl-cyclohexylcarbonylamino) -1- (3-ethoxycarbonyl- n-propyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine in the same manner as the hydrochloride example 1e in ethanol 4 - [(5-(N-methyl - cyclohexyl Cal Boniruamino) -1- (3-ethoxycarbonyl -n- propyl)-1H-benzoimidazole
-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate.
Yield: 74% of theory, C ₂₉ H ₃₇ N ₅ O ₃ x HCl (503.65 / 540.11) Mass spectrum: (M + H) ⁺ = 504

Example 160 4-[(5- (N-methyl-cyclohexylcarbonylamino) -1- (4-ethoxycarbonyl- n-butyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine Hydrochloride 4-[(5- (N-methyl-cyclohexylcarbonylamino) -1- (4-ethoxycarbonyl-n-butyl) -1H-benzimidazole-2-ethanol in ethanol in the same manner as in Example 1e.
Yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 87% of theory, C ₃₀ H ₃₉ N ₅ O ₃ x HCl (517.68 / 554.15) Mass spectrum: (M + H) ⁺ = 518 Example 161 4-[(5- (N-methyl-cyclohexyl) carbonylamino) -1- (3-carboxy -n- propyl)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 13 in the same manner as 4 ethanol / water - [(5 -(N-methyl-cyclohexylcarbonylamino) -1- (3-ethoxycarbonyl-n-propyl) -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide . Yield: 44% of _{theory, C 27 H 33 N 5 O} 3 x HCl (475.59 / 512.06) Mass ^{spectrum: (M + H) + =} 476

[0208] Example 162 4 - [(5-(N-methyl - cyclohexyl carbonylamino) -1- (4-carboxy -n- butyl Le)-1H-benzimidazol-2-yl) - methyl] - Benzoamijin Hydrochloride 4-[(5- (N-methyl-cyclohexylcarbonylamino) -1- (4-ethoxycarbonyl-n-butyl) -1H-benzimidazol-2-yl in ethanol / water in the same manner as in Example 13. ) -Methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 47% of theory, C ₂₈ H ₃₅ N ₅ O ₃ x HCl (489.62 / 526.08) Mass spectrum: (M + H) ⁺ = 490

[0209] Example 163 4 - [(5- (N- (3- ethoxycarbonyl -n- propyl) - ethylamino) -l- methylation -1H- benzimidazol-2-yl) - methyl] - benzo Amidine hydrochloride 4-[(5- (N- (3-ethoxycarbonyl-n-propyl) -ethylaminosulfonyl) -1-methyl-1H-benzimidazol-2-yl in ethanol in the same manner as in Example 1e. ) -Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 61% of _{theory, C 24 H 31 N 5 O} 4 S x HCl (485.6 / 522.1) Mass ^{spectrum: (M + H) + =} 486 Example 164 4 - [(5- (N- (4 - ethoxycarbonyl -n- butyl) - ethylamino) -l- methylation -1H- benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and 4 in ethanol in the same manner - [( Prepared from 5- (N- (4-ethoxycarbonyl-n-butyl) -ethylaminosulfonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 63% of theory, C ₂₅ H ₃₃ N ₅ O ₄ S x HCl (499.6 / 536.1) Mass spectrum: (M + H) ⁺ = 500

Example 165 4-[(5- (N- (3-carboxy-n-propyl) -ethylaminosulfonyl) -1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4 in ethanol in the same manner as salt example 13 - [(5- (N- (3- ethoxycarbonyl -n- propyl) - ethylamino sulfonyl) -1-methyl -1H- benzimidazol-2-yl) - Methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 66% of _{theory, C 22 H 27 N 5 O} 4 S x HCl (457.6 / 494.1) Mass ^{spectrum: (M + H) + =} 458

[0211] Example 166 4 - [(5- (N- (4- carboxy -n- butyl) - ethylamino sulfonyl) -1-methyl -1H- Baie emission zone imidazol-2-yl) - methyl] - benzo Amidine hydrochloride 4-[(5- (N- (4-ethoxycarbonyl-n-butyl) -ethylaminosulfonyl) -1-methyl-1H-benzimidazol-2-yl in ethanol in the same manner as in Example 13. ) -Methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 66% of theory, C ₂₃ H ₂₉ N ₅ O ₄ S x HCl (471.6 / 508.1) Mass spectrum: (M + H) ⁺ = 472 Example 167 4-[(5- (N- (2 -Ethoxycarbonyl-ethyl) -ethylaminosulfonyl) -1-methyl -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In ethanol, as in Example 1e, 4-((5- ( N- (2-ethoxycarbonyl-ethyl) -ethylaminosulfonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 18% of _{theory, C 23 H 29 N 5 O} 4 S x HCl (471.6 / 508.1) Mass ^{spectrum: (M + H) + =} 472

Example 168 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl) -sulfonylamino) -1- methyl-1H-benzimidazol-2-yl] -amino] -benzamidine hydrochloride Salt a. 2-Methylamino-5 -nitro-aniline 12.5 g (0.079 mol) of 2-fluoro-5-nitroaniline and 100 ml of methylamine (40% in water) are stirred at ambient temperature for 48 hours. The precipitated product is diluted with water, filtered off with suction, washed and dried. Yield: 12.0 g (91% of theory), _Rf value: 0.5 (silica gel; ethyl acetate / petroleum ether = 6: 4)

B. 5-Nitro-1-methyl-benzimidazol-2-one 2-methylamino-5-nitro-aniline 3.4 g (0.02 mol) and N, N'-carbonyldiimidazole 3.9 g (0.024 mol) Is dissolved in 100 ml of tetrahydrofuran and refluxed for 2 hours. The solvent is concentrated by evaporation, the residue is mixed with water, the precipitated product is filtered off with suction and dried. Yield: 3.1 g (86% of _{theory), C 8 H 7 N 3} O 3 x HCl (193.17) Mass spectrum:. M ⁺ = 193 c 5--Nitro-2 chloro-1-methyl - benzimidazole pentachloride 2.1 g (0.01 mol) of phosphorus is dissolved in 2.5 ml of phosphorus oxychloride, and after addition of 1.9 g (0.01 mol) of 5-nitro-1-methyl-benzimidazol-2-one, the mixture is added to 12 ml.
Stir at 5 ° C for 2 hours. The solvent is evaporated off, the residue is poured into ice-water and neutralized with ammonia. The precipitate formed is suction filtered and dried. Yield: 1.6 g (76% of theory), _Rf value: 0.66 (silica gel; ethyl acetate / petroleum ether = 4: 1)

. [0214] d 4-[5-Nitro-1-methyl -1H- benzimidazol-2-yl] - amino - Benzoni tolyl 5-nitro-2-chloro-1-methyl - benzimidazole 1.5 g (7.1 mmol) And 4-
2.1 g (17.5 mmol) of aminobenzonitrile are melted at 150 ° C. for 2 hours. The reaction mixture is cooled and diluted with ethyl acetate. The precipitate is filtered off with suction and dried. Yield: 2.0 g (95% of theory), _Rf value: 0.6 (silica gel; ethyl acetate / ethanol / ammonia-90: 10: 1) e. 4- [5-amino-1-methyl-1H-benzimidazole 2-yl] - amino - Benzoni tolyl example 1c and Similarly in dimethylformamide 4- [5-nitro-1-methyl -1H- benzimidazol-2-yl] - amino - benzonitrile and palladium / activated carbon / Hydrogen. Yield: 55% of theory, _Rf value: 0.5 (silica gel; ethyl acetate / ethanol / ammonia = 90: 10: 1)

. [0215] f 4 - [(5- (quinoline-8-yl - sulfonylamino) -1-methyl -1H- benzo imidazole 2-yl) - amino] - in the same manner as benzonitrile Example 1d Prepared from 4- [5-amino-1-methyl-1H-benzimidazol-2-yl] -amino-benzonitrile and 8-quinolinesulfonic acid chloride in pyridine. Yield: 91% of theory, _Rf value: 0.6 (silica gel; ethyl acetate / ethanol / ammonia = 90: 10: 1) g. 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl) -Sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -amino] -benzonitrile 4-[(5- (quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazole- 1.0 g (2.2 mmol) of 2-yl) -amino] -benzonitrile and 0.8 of cesium carbonate
g (2.5 mmol) are dissolved in 15 ml of dimethylformamide and, after addition of 0.4 g (2.5 mmol) of ethyl bromoacetate, stirred for 30 minutes at ambient temperature. The solvent is concentrated by evaporation, the residue is taken up in water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. Yield: 0.8 g (70% of theory), _Rf value: 0.7 (silica gel; ethyl acetate / ethanol / ammonia = 90: 10: 1) h. 4-[(5- (N-ethoxycarbonylmethyl-quinoline- 8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -amino] -benzamidine hydrochloride 4-[(5- (N-ethoxycarbonyl) in ethanol in the same manner as in Example 1e. Methyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl)
-Amino] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 86% of theory, C ₂₈ H ₂₇ N ₇ O ₄ S x HCl (557.64 / 594.11) Mass spectrum: (M + H) ⁺ = 558

Example 169 4-[(5- (N-Carboxymethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H -benzimidazol-2-yl) -amino] -benzamidine hydrochloride 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) in ethanol in the same manner as in Example 13.
-Amino] -benzamidine hydrochloride and sodium hydroxide. Yield: 78% of theory, C ₂₆ H ₂₃ N ₇ O ₄ S x HCl (529.52 / 565.98) Mass spectrum: (M + H) ⁺ = 530 Example 170 4-[(5- (N-carboxymethyl - quinolin-8-yl - sulfonylamino) -1-methyl-1H - benzoimidazol-2-yl) - methyl]-N'-tert-butyloxycarbonyl -. 4 in ethanol in the same manner as Ben Zoamijin example 13 -[(5- (N-ethoxycarbonylmethylquinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -N'-tert.butyloxycarbonyl-benzoamidine and Prepared from sodium hydroxide. Yield 64% of _{theory, C 32 H 32 N 6 O} 6 S (628.71) Mass ^{spectrum: (M + H) + =} 629

[0217] Example 171 4 - [(5- (4-methyl - piperazino)-1H-benzimidazol-2-yl) - methyl] - in a manner similar to Ben Zoamijin dihydrochloride Example 1e in ethanol 4- Prepared from [(5- (4-methyl-piperazino) -1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 72% of _{theory, C 20 H 24 N 6 x} 2 HCl (348.46 / 421.39) Mass ^{spectrum: (M + H) + =} 349 Example 172 4 - [(5- (N- (5- ethoxy carbonyl -n- pentyl) - ethylamino) -l- methylation -1H- benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and 4 in ethanol in the same manner - [(5- Prepared from (N- (5-ethoxycarbonyl-n-pentyl) ethylaminosulfonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 60% of _{theory, C 26 H 35 N 5 O} 4 S x HCl (513.7 / 550.1) Mass ^{spectrum: (M + H) + =} 514

[0218] Example 173 4 - [(5-pyrrolidinosulfonyl-1-methyl -1H- benzimidazol-2-yl) - methylation] - the same as Benzoamijin hydrochloride Example 1e to ethanol 4- ((5-pyrrolidinosulfonyl-1-methyl
-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 43% of _{theory, C 20 H 23 N 5 O} 2 S x HCl (397.5 / 434.0) Mass ^{spectrum: (M + H) + =} 398

Example 174 4-[(5- (quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol- 2-yl) -amino] -benzamidine hydrochloride In the same manner as in Example 1e. Prepared from 4-[(5- (quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -amino] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 90% of _{theory, C 24 H 21 N 7 O} 2 S x 2HCl (471.54 / 544.48) Mass ^{spectrum: (M + H) + =} 472 Example 175 4 - [(5- (N- (3 -Ethoxycarbonyl-n-propyl) -phenylaminosulfonyl) -1- methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In ethanol, as in Example 1e, 4-((5 -(N- (3-ethoxycarbonyl-n-propyl) -phenylaminosulfonyl) -1-methyl-1H-benzimidazol-2-yl)
-Amino] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 41% of _{theory, C 28 H 31 N 5 O} 4 S x HCl (533.7 / 570.1) Mass ^{spectrum: (M + H) + =} 534

Example 176 4-[(5- (N- (4-ethoxycarbonyl-n-butyl) -isobutylaminosulfonyl) -1- methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine Hydrochloride 4-[(5- (N- (4-ethoxycarbonyl-n-butyl) -isobutylaminosulfonyl) -1-methyl-1H-benzimidazol-2-yl) in ethanol in the same manner as in Example 1e
-Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 41% of theory, C ₂₇ H ₃₇ N ₅ O ₄ S x HCl (527.7 / 564.2) Mass spectrum: (M + H) ⁺ = 528

[0221] Example 177 4 - [(5- (2-dimethylamino - ethyl sulfonyl) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - In analogy to the Benzoamijin dihydrochloride Example 1e Prepared from 4-[(5- (2-dimethylamino-ethylsulfonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 78% of _{theory, C 20 H 25 N 5 O} 2 S x HCl (399.52 / 472.44) Mass ^{spectrum: (M + H) + =} 400 Example 178 4 - [(5- (2-ethoxycarbonyl - pyrrolidinosulfonyl) -1-methyl -1H- benzoyl imidazole-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5- (2-ethoxycarbonyl - pylori Dinosulfonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 64% of theory, C ₂₃ H ₂₇ N ₅ O ₄ S x HCl (469.6 / 506.0) Mass spectrum: (M + H) ⁺ = 470

[0222] Example 179 4 - [(5- (4-oxo-3,4-dihydro - phthalazin-1-yl) -1-methyl -1H- Benzoimi imidazole-2-yl) - methyl] - Benzoamijin hydrochloride in ethanol 4 in the same manner as salt example 1e - [(5- (4-oxo-3,4-dihydro - phthalazin-1-yl) -1-methyl -1H- benzimidazol-2-yl) - methyl ] -Benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 90% of _{theory, C 24 H 20 N 6 O} x HCl (408.5 / 444.9) Mass ^{spectrum: (M + H) + =} 409

[0223] Example 180 4 - [(5- (2-carboxy - pyrrolidinosulfonyl) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin in the same manner as the hydrochloride salt EXAMPLE 13 Prepared from 4-[(5- (2-ethoxycarbonyl-pyrrolidinosulfonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide in ethanol. Yield: 85% of theory, C ₂₁ H ₂₃ N ₅ O ₄ S × HCl (441.5 / 477.96) Mass spectrum: (M + H) ⁺ = 442 Example 181 4-[(5-benzylaminocarbonyl-1 -Methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5-benzylaminocarbonyl-1-methyl-1H-benzimidazol-2) in ethanol as in Example 1e. -Yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 72% of _{theory, C 24 H 23 N 5 O} x HCl (397.49 / 470.42) Mass ^{spectrum: (M + H) + =} 398

[0224] Example 182 4 - [(5-pyrrolidinosulfonyl-1-methyl -1H- benzimidazol-2-yl) - (ethoxy butoxycarbonyl) methyl] -. Benzoamijin hydrochloride a methyl 2- (4 1.7 g (0.01 mol) of -cyanophenyl) -tert.butylmalonate methyl 4-cyanophenyl acetate in tetrahydrofuran 30
Dissolve in 0.4 ml, add 0.48 g (0.01 mol) of sodium hydride (60% in oil) in several portions and stir at 60 ° C for 15 minutes. Then tert.butyl bromoacetate 1.5
ml (0.01 mol) are added dropwise at ambient temperature. The reaction mixture is refluxed for 5 hours, cooled, poured into water and extracted with methylene chloride. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (4: 1). Yield: 1.5 g (52% of theory), _Rf value: 0.7 (silica gel; petroleum ether / ethyl acetate = 7: 3)

B. Mono-tert.butyl 2- (4-cyanophenyl) -malonate methyl 1.5 g (5.2 mmol) of 2- (4-cyanophenyl) -tert.butylmalonate and 0.6 g of sodium hydroxide (15 g) (Mmol) in 25 ml of ethanol and 5 ml of water at ambient temperature for 2 hours. Then the mixture is acidified with hydrochloric acid and concentrated by evaporation. The residue is extracted with methylene chloride and water, the combined organic extracts are dried and evaporated. The crude product is chromatographed on silica gel, eluting with methylene chloride + 1-5% ethanol. Yield: 950 mg (67% of theory), _Rf value: 0.40 (silica gel; methylene chloride / ethanol = 19: 1) c. 4-[(5-pyrrolidinosulfonyl-1-methyl-1H-benzimidazole-2) -Yl)-( tert.butoxycarbonylmethyl) methyl] -benzonitrile Mono-tert.butyl 2- (4-cyanophenyl ) in N, N'-carbonyldiimidazole / tetrahydrofuran and glacial acetic acid as in Example 24f ) -Malonate and 4-pyrrolidinosulfonyl-2-amino-N-methylaniline. Yield: 47% of theory, _Rf value: 0.6 (silica gel; methylene chloride / ethanol = 19: 1) d. 4-[(5-pyrrolidinosulfonyl-1-methyl-1H-benzimidazol-2-yl) )-( Ethoxycarbonylmethyl) methyl] -benzamidine hydrochloride 4-[(5-pyrrolidinosulfonyl-1- methyl) in ethanol in the same manner as in Example 1e
-1H-benzimidazol-2-yl)-(tert.butoxycarbonylmethyl) methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 63% of _{theory, C 24 H 29 N 5 O} 4 S x HCl (483.6 / 520.1) Mass ^{spectrum: (M + H) + =} 484

Example 183 4-[(5- (N- (2-ethoxycarbonyl-ethyl) -quinolin-8-yl-sulfonylamino ) -1-methyl-1H-benzimidazol-2-yl) -methyl] -Benzoamidine hydrochloride 4-[(5- (N- (2-ethoxycarbonyl-ethyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzo in ethanol as in Example 1e Imidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 92% of _{theory, C 30 H 30 N 6 O} 4 S x HCl (570.68 / 607.14) Mass ^{spectrum: (M + H) + =} 571 Example 184 4 - [(5- (N- (2 -Ethoxycarbonyl-ethyl) -quinolin-8-yl-sulfonylamino ) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride in ethanol as in Example 13 ((5- (N- (2-ethoxycarbonyl-ethyl) -quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine hydrochloride and hydroxylated Prepared from sodium. Yield: 67% of theory, C ₂₈ H ₂₆ N ₆ O ₄ S x HCl (542.63 / 585.09) Mass spectrum: (M + H) ⁺ = 543

Example 185 4-[(5-Cyclohexylcarbonyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In ethanol in the same manner as in Example 1e, 4-[( 5-cyclohexylcarbonyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 95% of theory, C ₂₃ H ₂₆ N ₄ O x HCl (374.49 / 410.95) Mass spectrum: (M + H) ⁺ = 375 Example 186 4-[(5- (α-ethoxycarbonyl) benzyl aminocarbonyl-1-methyl -1H- Ben zo-imidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and 4 in ethanol in the same manner - [(5-(alpha-ethoxycarbonyl) benzyl aminocarbonyl 1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 69% of theory, C ₂₇ H ₂₇ N ₅ O ₃ x HCl (469.55 / 506.01) Mass spectrum: (M + H) ⁺ = 470

[0228] Example 187 4 - [(5-(alpha-carboxy) benzyl aminocarbonyl-1-methyl -1H- Benzoimida 2-yl) - methyl] - Benzoamijin 4 in the same manner as the hydrochloride salt EXAMPLE 13 Prepared from-[(5- (α-ethoxycarbonyl) benzylaminocarbonyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 91% of theory, C ₂₅ H ₂₃ N ₅ O ₃ x HCl (441.5 / 477.96) Mass spectrum: (M + H) ⁺ = 442

[0229] Example 188 4 - [(5-pyrrolidinosulfonyl-1-methyl -1H- benzimidazol-2-yl) - (Cal Bokishimechiru) methyl] - Benzoamijin hydrochloride Example 13 in analogy to ethanol With 4-[(5-pyrrolidinosulfonyl-1-methyl
[1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl) methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 76% of _{theory, C 22 H 25 N 5 O} 4 S x HCl (455.5 / 491.96) Mass ^{spectrum: (M + H) + =} 456 Example 189 4 - [(5-cyclohexyl-- (alpha- n- propylamino) methyl -1-methyl -1H- Benzoimi imidazole-2-yl) - methyl] - Benzoamijin dihydrochloride a 4-(cyclohexylcarbonyl) -. chlorobenzene chlorobenzene 80 ml (0.78 mol) and aluminum chloride 30 g ( (0.22 mol), 24 ml (0.18 mol) of cyclohexanecarboxylic acid chloride is added dropwise at 15-20 ° C. After 1 hour at ambient temperature, the reaction mixture is brought to 50 ° C. for 5 hours.
Heat to After cooling, the mixture is decomposed with ice water / concentrated hydrochloric acid and the aqueous phase is extracted with methylene chloride. The combined organic extracts are dried and evaporated. The residue is distilled under high vacuum (2 mm, 105-115 ° C.). The desired fraction is combined with water, the precipitate formed is suction filtered and dried. Yield: 6.6 g (16% of _{theory), C 13 H 15 ClO (} 222.72) Mass spectrum: M ⁺ = 222

B. 4- (cyclohexylcarbonyl) -2-nitro-chlorobenzene fuming nitric acid in 50 ml of nitric acid at -25 ° C., 6.4 g of 4- (cyclohexylcarbonyl) -chlorobenzene
(28.8 mmol) are added in several portions. The solution is stirred at -25 ° C for 10 minutes and then poured into ice water. The precipitated product is filtered off with suction, washed with water and dried. Yield: 7.3 g (95% of theory), _Rf value: 0.2 (silica gel, petroleum ether / methylene chloride = 2: 1) c. 4- (cyclohexylcarbonyl) -2-nitro-N-methyl-aniline Prepared from 4- (cyclohexylcarbonyl) -2-nitro-chlorobenzene and methylamine solution as in 7b. Yield: 96.5% of _{theory, C 14 H 18 N 2 O} 3 (262.31) Mass spectrum: M ⁺ = 262

D. 4- (cyclohexylcarbonyl) -2-amino- N-methyl-aniline 2.6 g (0.01 mol) of 4- (cyclohexylcarbonyl) -2-nitro-N-methyl-aniline was added to 100 ml of ethyl acetate and 30 ml of methanol. And, after addition of 0.5 g of Raney nickel, hydrogenate with hydrogen at ambient temperature. Then the catalyst is filtered off and the filtrate is concentrated by evaporation. Yield: 2.2 g (100% of theory), _Rf value: 0.55 (silica gel; methylene chloride / ethanol = 19: 1) e. 4-[(5-cyclohexylcarbonyl-1-methyl-1H-benzimidazole-2) - b le) - methyl] - tetrahydrofuran in the same manner as benzonitrile example 24f, and with glacial acetic acid 4- (cyclohexylcarbonyl) -2-amino -N- methyl - aniline, 4-cyanophenyl acetate and N, N Prepared from '-carbonyldiimidazole. Yield: 74% of theory, _Rf value: 0.3 (silica gel; methylene chloride / ethanol = 50: 1)

F. 4-[(5-cyclohexyl- (α-n-propylamino) methyl-1-methyl-1H- benzimidazol-2-yl) -methyl] -benzonitrile and 4-[(5-cyclohexyl -( Hydroxy) methyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile 4-[(5-cyclohexylcarbonyl-1H-benzimidazol-2-yl) -methyl]
-Dissolve 715 mg (2.0 mmol) of benzonitrile, 1.0 ml of n-propylamine and 1.0 g of sodium acetate in 30 ml of methanol, 2 ml of water and 2 ml of glacial acetic acid and divide into 1.5 g (39.6 mmol) of sodium borohydride in several portions. Match. After 1 hour at ambient temperature, the mixture is poured into water and extracted with ethyl acetate. The combined organic extracts are washed with a saline solution and dried over sodium sulfate. After evaporation of the solvent in vacuo, the residue is chromatographed on silica gel, eluting with methylene chloride + 1% ethanol.
Yield: 100 mg (12% of theory), _Rf value: 0.1 and 0.4 (silica gel; methylene chloride / ethanol = 19: 1) g. 4-[(5-cyclohexyl- (α-n-propylamino) methyl- 1-methyl-1H- benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride 4-[(5-cyclohexyl- (α-n-propylamino) methyl- 1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 100% of theory, C ₂₆ H ₃₅ N ₅ × 2 HCl (417.61 / 490.54) Mass spectrum: (M + H) ⁺ = 418

Example 190 4-[(5- (Cyclohexyl- (methoxy) methyl) -1-methyl-1H-benzimidazol- 2-yl) -methyl] -benzamidine hydrochloride Methanol was prepared in the same manner as in Example 1e. Prepared from 4-[(5- (cyclohexyl- (hydroxy) methyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 75% of theory, C ₂₄ H ₃₀ N ₄ O x HCl (390.54 / 427.0) Mass spectrum: (M + H) ⁺ = 391

[0234] Example 191 4 - [(5- (4-oxo-2,3-diaza - spiro [5.5] undec-1-en-1-yl) -1-methylation -1H- benzoimidazol-2 Yl) -methyl] -benzamidine hydrochloride a. [1- (4-Chloro-benzoyl) -cyclohexyl] -acetic acid 4- (4-chlorophenyl) -4-oxo-butyric acid 8.4 g (0.04 mol) in tetrahydrofuran
Dissolve in 300 ml and combine with 5.8 g (0.12 mol) of sodium hydride (50% in oil) in several portions and reflux for 90 minutes. After addition of 8.9 ml (0.06 mol) of 1,5-diiodopentane, the reaction mixture is refluxed for a further 3 hours. After cooling, the reaction mixture is stirred in ice water, the tetrahydrofuran is distilled off and the residue is extracted with methylene chloride. The aqueous phase is acidified with hydrochloric acid and extracted with methylene chloride. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with methylene chloride + ethanol (1-2%). Yield: 6.2 g (55% of theory)

B. [1- (4-Chloro-3-nitro-benzoyl) -cyclohexyl] -acetic acid From [1- (4-chloro-benzoyl) -cyclohexyl] -acetic acid and fuming nitric acid in the same manner as in Example 189b. Prepared. Yield: 96% of theory. C. [1- (4-N-methylamino-3-nitro-benzoyl) -cyclohexyl] -acetic acid [1- (4-chloro-benzoyl) -acetic acid in the same manner as in Example 7b. [Cyclohexyl] -acetic acid and methylamine solution. Yield: 93% of theory d. 4-[(5- (4-oxo-2,3-diaza-spiro [5.5] undec-1-en-1-yl) -3- nitro-N-methylaniline 2.5 ml of hydrazine hydrate was gradually added dropwise to 25 ml of glacial acetic acid, and then [1- (4-
2.4 g (7.5 mmol) of N-methylamino-3-nitro-benzoyl) -cyclohexyl] -acetic acid are added. The reaction mixture is refluxed for 3 hours, then cooled and diluted with water.
The precipitate formed is suction filtered and dried. Yield: 2.0 g (85% of theory)

E. 4-[(5- (4-oxo-2,3-diaza-spiro [5.5] undec-1-en-1-yl) -3- amino-N-methylaniline Same as in Example 1c 4-((5- (4-oxo-2,3-diaza-spiro [5.5] undec-1-en-1-yl) -3-nitro-N-methylaniline and palladium in dimethylformamide / Activated carbon / hydrogen Yield: 80% of theory f. 4-[(5- (4-oxo-2,3-diaza-spiro [5.5] undec-1-en-1-yl)- 1- Methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile Tetrahydrofuran, 4-((5- (4-oxo-2,
Prepared from 3-diaza-spiro [5.5] undec-1-en-1-yl) -3-amino-N-methylaniline, 4-cyanophenylacetic acid and N, N'-carbonyldiimidazole. Yield: 49% of theory, _Rf value: 0.4 (silica gel; methylene chloride / ethanol = 19: 1) g. 4-[(5- (4-oxo-2,3-diaza-spiro [5.5] undece) 1-en-1-yl) -1- methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In ethanol, as in Example 1e, 4-[(5- (4- Oxo-2,3-diaza-spiro [
5.5] Undec-1-en-1-yl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 70% of _{theory, C 25 H 28 N 6 O} x HCl (428.5 / 465.0) Mass ^{spectrum: (M + H) + =} 429

Example 192 4-[(5- (1-Ethoxycarbonylmethyl-cyclohexane-1-yl-carbonyl) -1- methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride a . methyl [1- (4-methyl-amino-3-nitro - benzoyl) - cyclohexyl] - acetate Tate [1- (4-methyl-amino-3-nitro - benzoyl) - cyclohexyl] - acetic 4.9 g (0.
015 mol) in 100 ml of tetrahydrofuran and after addition of 2.4 g (0.015 mol) of N, N'-carbonyldiimidazole the mixture is refluxed for 15 minutes. After concentration of the solution and addition of 30 ml of methanol, the mixture is refluxed for 3 hours. Distill off the solvent,
The residue is chromatographed on silica gel, methylene chloride + methanol
(1-5%). The desired fractions are combined and concentrated by evaporation. Yield:. 2.4 g (48% of theory) b-methyl [1- (4-methylamino-3-amino - benzoyl) - cyclohexyl] - methyl in methanol in the same manner as acetate Tate Example 1c [1- ( Prepared from 4-methylamino-3-nitro-benzoyl) -cyclohexyl] -acetate and palladium / activated carbon / hydrogen. Yield: 96% of theory

C. 4-[(5- (1-ethoxycarbonylmethyl-cyclohexane-1-yl-carbonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile Example 24f Prepared similarly from methyl [1- (4-methylamino-3-amino-benzoyl) -cyclohexyl] -acetate, 4-cyanophenylacetic acid and N, N'-carbonyldiimidazole in tetrahydrofuran / glacial acetic acid. Yield: 66% of theory, _Rf value: 0.5 (silica gel; methylene chloride / ethanol = 50: 1) d. 4-[(5- (1-ethoxycarbonylmethyl-cyclohexane-1-yl-carbonyl) - 1-Methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (1-ethoxycarbonylmethyl-cyclohexane-1-yl- )- ethanol in the same manner as in Example 1e. Carbonyl) -1-methyl-1H-benzimidazol-2-yl)
-Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 55% of _{theory, C 27 H 32 N 4 O} 3 x HCl (460.6 / 497.0) Mass ^{spectrum: (M + H) + =} 461

Example 193 4-[(5- (n-Pentyl-O-ethyl-phosphinyl) -1-methyl-1H-benzimidazol- 2-yl) -methyl] -benzamidine hydrochloride a.Dichloro- ( 104.8 ml (1.2 mol) of phosphorus trichloride are added dropwise at ambient temperature to a suspension of 53.3 g (0.4 mol) of aluminum chloride in 40 ml (0.39 mol) of 4-chlorophenyl) -phosphinechlorobenzene. The reaction mixture is refluxed for 3 hours. Then, within 30 minutes, 37.2 ml (0.4 mol) of phosphorus oxychloride are added dropwise at 83 ° C. After 12 hours at ambient temperature, the residue is stirred with petroleum ether and decanted. Combine the organic extracts under high vacuum at 57-61 ° C and 0.048-0.0
Distill at 35 mbar. Yield: 45.6 g (55% of theory) b. 14.9 ml (0.184 mol) of pyridine and ethanol 10.50 in 50 ml of diethyl (4-chlorophenyl) -phosphonate tetrahydrofuran.
8 ml (0.184 mol) of the solution was cooled within 1 hour while cooling with tetrahydrofuran.
A solution of 17.9 g (0.083 mol) of dichloro- (4-chlorophenyl) -phosphine in 20 ml is added dropwise. The suspension is stirred at ambient temperature for 72 hours, filtered by suction and concentrated by evaporation. The residue is distilled at 80-83 ° C. and 0.19 mbar. Yield: 11.7 g (61% of theory), _Rf value: 0.4 (silica gel; methylene chloride / ethanol = 50: 1)

C. 3.5 g (15 mmol) of ethyl (4-chlorophenyl) -n-pentyl-phosphinate diethyl (4-chlorophenyl) -phosphonate and 3 ml (24.7 mmol) of n-pentyl bromide are stirred at 150 ° C. for 90 minutes. Heat to The cooled clear solution is chromatographed on silica gel, eluting with cyclohexane / ethyl acetate (7: 3-1: 1). Yield: 2.7 g (66% of _{theory), C 13 H 20 ClO 2} P (274.74) Mass spectrum:. M ⁺ = 274 d of ethyl (4-chloro-3-nitro - phenyl)-n-pentyl - phosphinate embodiment Prepared similarly as in Example 189b from ethyl (4-chlorophenyl) -n-pentyl-phosphinate and fuming nitric acid. Yield: 56% of theory,

E. Ethyl (4-methylamino-3-nitro-phenyl) -n-pentyl-phosphinate Ethyl (4-chloro-3-nitro-phenyl) -n-pentyl-phosphinate and analogously to Example 7b Prepared from methylamine solution. Yield: 100% of theory. F. Ethyl (4-methylamino-3-amino-phenyl) -n-pentyl-phosphinate Ethyl (4-methylamino-3-nitro- Prepared from (phenyl) -n-pentyl-phosphinate and palladium / activated carbon / hydrogen. Yield:. 100% g of theory 4 - [(5-(n-pentyl -O- ethyl - phosphinyl) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - benzonitrile [ Prepared similarly as in Example 24f from ethyl (4-methylamino-3-amino-phenyl) -n-pentyl-phosphinate, 4-cyanophenylacetic acid and N, N′-carbonyldiimidazole in tetrahydrofuran and glacial acetic acid. Yield:. 43.7% h of theory 4 - [(5-(n-pentyl -O- ethyl - phosphinyl) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin hydrochloride in the same manner as in the salt example 1e in ethanol 4 - [(5-(n-pentyl -O- ethyl - phosphinyl) -1-methyl -1H- benzimidazol-2-yl) - methyl] - benzonitrile and hydrochloric acid / Ammonium carbonate. Yield: 78% of _{theory, C 23 H 31 N 4 O} 2 P x HCl (426.51 / 462.97) Mass ^{spectrum: (M + H) + =} 427

Example 194 4-[(5- (N- (2-dimethylamino-ethyl) -benzenesulfonylamino-1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride 4-[(5- (N- (2-dimethylamino-ethyl)-] in ethanol in the same manner as in Example 1e
Benzenesulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 83% of theory, C ₂₆ H ₃₀ N ₆ O ₂ S × 2 HCl (490.64 / 563.57) Mass spectrum: (M + H) ⁺ = 491 Example 195 4-[(5- (n-pentyl) -Phosphinyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (n-pentyl-O-ethyl-phosphinyl) -1-in 5 ml of methylene chloride. Methyl-
To a solution of 100 mg (0.2 mmol) of 1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride is added 1.8 ml (14 mmol) of trimethylsilyl bromide. After addition of 20 ml of methylene chloride, the reaction mixture is stirred for 6 days at ambient temperature. After evaporation of the solvent, the residue is triturated with water / 2N hydrochloric acid. The solid formed is filtered off with suction, the filtrate is concentrated by evaporation, mixed several times with ethanol and concentrated by evaporation. The residue is triturated with methanol / acetone, filtered off with suction and dried. Yield: 70 mg (74% of _{theory), C 21 H 27 N 4} O 2 P x HCl (398.45 / 434.91) Mass ^{spectrum: (M + H) + =} 399

[0243] Example 196 4 - [(5-(n-pentyl -O- ethoxycarbonylmethyl - phosphinyl) -1-methyl -1H- benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride a [. (5- (n-pentyl-phosphinyl) -1-methyl-1H-benzimidazol-2-yl ) -methyl] -benzonitrile 4-[(5- (n-pentyl-O-ethyl-phosphinyl) -1- 0.6 g (1.5 mmol) of methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile was dissolved in 45 ml of methylene chloride, combined with 2 ml (15.4 mmol) of trimethylbromosilane and added at ambient temperature.
Stir for 2 hours. After evaporation of the solvent, the residue is combined with ice water and adjusted to pH 6 with sodium acetate. After 2 hours, the precipitate formed is suction filtered and dried. Yield: 0.37 g (66% of theory), _Rf value: 0.35 (reverse phase, 5% sodium chloride solution / methanol = 1: 2)

B. 4-[(5-n-pentyl-O-ethoxycarbonylmethyl-phosphinyl) -1-methyl- 1H-benzimidazol-2-yl] -methyl] -benzonitrile dimethylformamide in 7 ml ((5- (n-pentyl-phosphinyl) -1-methyl-1
To a solution of 370 mg (0.97 mmol) of H-benzimidazol-2-yl) -methyl] -benzonitrile was added 170 mg (1.2 mmol) of potassium carbonate and ethyl bromoacetate 13
0 mg (1.2 mmol) are added. Heating the reaction mixture to 50 ° C. for 20 minutes,
Cool, then pour into ice water and extract with ethyl acetate. The organic extract is washed with citric acid and sodium carbonate solution, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel, eluting with ethyl acetate / ethanol (25: 1 and 10: 1). Yield: 0.4 g (88% of theory), _Rf value: 0.4 (silica gel; methylene chloride / ethanol = 50: 1) c. 4-[(5- (n-pentyl-O-ethoxycarbonylmethyl-phosphinyl) 1-methyl -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5-n-pentyl-O-ethoxycarbonylmethyl-phosphinyl) in ethanol as in Example 1e -1-methyl-1H-benzimidazol-2-yl] -methyl]-
Prepared from benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 76% of theory, C ₂₅ H ₃₃ N ₄ O ₄ P x HCl (484.55 / 521.01) Mass spectrum: (M + H) ⁺ = 485

[0245] Example 197 4 - [(5-(n-pentyl -O- carboxymethyl - phosphinyl) -1-methyl -1H- benzoyl imidazole-2-yl) - methyl] - Benzoamijin hydrochloride Example 13 Similarly, 4-[(5- (n-pentyl-O-ethoxycarbonylmethyl-phosphinyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] in ethanol
-Prepared from benzamidine hydrochloride and sodium hydroxide. Yield: 74% of _{theory, C 23 H 29 N 4 O} 4 P x HCl (456.49 / 492.95) Mass ^{spectrum: (M + H) + =} 457 Example 198 4 - [(5- (1-Carboxymethyl -Cyclohexan-1-yl-carbonyl) -1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine To a solution of 160 mg (4 mmol) of sodium hydroxide in 5 ml of water and 20 ml of ethanol, ((5- (1-ethoxycarbonylmethyl-cyclohexane-1-yl-carbonyl) -1
-Methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 400mg
(0.8 mmol) is added. After 2 hours at ambient temperature, the solution is evaporated, the residue is dissolved in water and acidified with glacial acetic acid. The precipitate is filtered off with suction and dried. Yield: 250 mg (72% of _{theory), C 25 H 28 N 4} O 3 (432.5) Mass ^{spectrum: (M + H) + =} 433

[0246] Example 199 4 - [(5- (2-oxo - piperidin-1-yl) -1-methyl -1H- benzoimidazol-2 b le) - methyl] - Benzoamijin hydrochloride a 4-. Fluoro-3-nitro-N- (5-bromobutyloxy) -aniline After addition of 3 ml of triethylamine at ambient temperature to a solution of 3.7 g (0.024 mol) of 4-fluoro-3-nitro-aniline in 100 ml of tetrahydrofuran, -4.8 g (0.024 mol) of bromovaleric chloride are added dropwise. The mixture is then stirred at ambient temperature for 2 hours and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with methylene chloride. The desired fractions are combined and evaporated. Yield: 7.0 g (92% of theory), _Rf value: 0.6 (silica gel; petroleum ether / ethyl acetate = 3: 7)

B. To a suspension of 1.0 g (21.9 mmol) of sodium hydride (50% in oil) in 200 ml of 4- (2-oxo-piperidin-1-yl) -2-nitro-fluorobenzenetetrahydrofuran At ambient temperature, a solution of 7.0 g (21.9 mmol) of 4-fluoro-3-nitro-N- (5-bromobutyloxy) -aniline in 50 ml of tetrahydrofuran is added dropwise. After 30 minutes, pour it into ice water, distill off tetrahydrofuran,
The aqueous phase is extracted with methylene chloride. The combined organic extracts are dried and evaporated.
The residue is chromatographed on silica gel, petroleum ether / ethyl acetate
Elute at (7: 3). Yield: 4.1 g (79% of theory), _Rf value: 0.4 (silica gel; petroleum ether / ethyl acetate = 3: 7) c. 4- (2-oxo-piperidin-1-yl) -2-nitro- N-Methyl-aniline Prepared from 4- (2-oxo-piperidin-1-yl) -2-nitro-fluorobenzene and aqueous methylamine as in Example 7b. Yield: 92% of theory, _Rf value: 0.35 (silica gel; petroleum ether / ethyl acetate = 1: 9) d. 4- (2-oxo-piperidin-1-yl) -2-amino-N-methyl -Aniline Prepared from 4- (2-oxo-piperidin-1-yl) -2-nitro-N-methyl-aniline and palladium / activated carbon / hydrogen in methanol as in Example 1c. Yield: 97% of theory, _Rf value: 0.25 (silica gel; methylene chloride / ethanol = 19: 1)

E. 4-[(5- (2-oxo-piperidin-1-yl) -1-methyl-1H-benzimidazol-2 -yl) -methyl] -benzonitrile Tetrahydrofuran as in Example 24f Prepared from 4- (2-oxo-piperidin-1-yl) -2-amino-N-methyl-aniline, 4-cyanophenylacetic acid and N, N'-carbonyldiimidazole / glacial acetic acid. Yield: 35% of theory, R _f value: 0.23 (silica gel, methylene chloride / ethanol = 19: 1) f. 4-[(5- (2-oxo-piperidin-1-yl) -1-methyl- 1H-benzimidazol- 2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (2-oxo) piperidin-1-yl-1 in ethanol in the same manner as in Example 1e.
-Methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 87% of theory, C ₂₁ H ₂₃ N ₅ O x HCl (361.5 / 397.9) Mass spectrum: (M + H) ⁺ = 362

Example 200 4-[(5- (n-butane-sultam-2-yl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride As in Example 1e 4-((5- (n-butane-sultam-2-yl) -1-
Methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 77% of _{theory, C 20 H 23 N 5 O} 2 S x HCl (397.5 / 434.0) Mass ^{spectrum: (M + H) + =} 398

[0250] Example 201 4 - [(5-(N-cyclohexyl - methanesulfonylamino) -1-methyl -1H- Benzoimi imidazole-2-yl) - methyl] - Benzoamijin hydrochloride Example 1e and similarly Prepared from 4-[(5-N-cyclohexyl-methanesulfonylamino) -1-methyl-1H-benzimidazol-2-yl] -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 52% of _{theory, C 23 H 29 N 5 O} 2 S x HCl (439.59 / 476.06) Mass ^{spectrum: (M + H) + =} 440 Example 202 4 - [(5- (1-methyl - cyclohexane-1-yl - carbonyl) -1-methyl -1H- benzoyl imidazole-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5- (1-methyl -Cyclohexane-1-yl-carbonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 63% of theory, C ₂₄ H ₂₈ N ₄ O x HCl (388.5 / 425.0) Mass spectrum: (M + H) ⁺ = 389

Example 203 4-[(5- (1-Isobutyl-tetrazol-5-yl) -1-methyl-1H-benzimidazol- 2-yl) -methyl] -benzamidine hydrochloride a. 4-chloro 3-Nitro-benzoic acid-isobutylamide Prepared from 4-chloro-3-nitro-benzoyl chloride, isobutylamine and triethylamine in tetrahydrofuran analogously to Example 24b. Yield: 88% of theory,

B. 10.3 g (0.04 mol) of 4-[(5- (1-isobutyl-tetrazol-5-yl) -2-nitro-chlorobenzene 4-chloro-3-nitro-benzoic acid-isobutyramide was methylene chloride Dissolve in 200 ml, combine with 2.6 g (0.04 mol) of sodium azide, then add 6.7 ml (0.04 mol) of trifluoromethanesulfonic anhydride dropwise at 0 ° C. Then bring the reaction to ambient temperature. Stir for 40 h, combine with 5% sodium carbonate solution, separate, dry and evaporate the organic phase, chromatograph the residue on silica gel, eluting with methylene chloride + ethanol (0-1%). Yield: 3.6 g (32% of theory), C ₁₁ H ₁₂ ClN ₅ O ₂ (281.7) Mass spectrum: M ⁺ = 281 c. 4-[(5- (1- isobutyl - tetrazol-5-yl) -2-nitro -N- methyl - in analogy to the aniline in example 7b 4 - [(5- (1-isobutyl-- tetrazol-5-yl) -2-nitro
-Prepared from chlorobenzene and methylamine solutions. Yield: 100% of theory, R _f value: 0.3 (silica gel; methylene chloride / ethanol = 50: 1)

D. 4-[(5- (1-Isobutyl-tetrazol-5-yl) -2-amino-N-methyl-aniline In methanol as in Example 24e, 4-[(5- (1 -Isobutyl-tetrazole-5
-Yl) -2-nitro-N-methyl-aniline and palladium / activated carbon / hydrogen. Yield: 100% of theory, R _f value: 0.3 (silica gel; methylene chloride / ethanol = 19: 1) e. 4-[(5- (1-isobutyl-tetrazol-5-yl-1-methyl-1H) - benzo imidazole-2-yl) - methyl] - tetrahydrofuran in the same manner as benzonitrile example 24f, in glacial acetic acid 4 - [(5- (1-Isobuchi Le - tetrazol-5-yl) -2- Prepared from amino-N-methyl-aniline, 4-cyanophenylacetic acid and N, N′-carbonyldiimidazole Yield: 86% of theory, R _f value: 0.4 (silica gel; methylene chloride / ethanol = 19: . 1) f 4 - [(5- (1-isobutyl-- tetrazol-5-yl-1-methyl -1H- benzo imidazole-2-yl) - methyl] - Benzoamijin in analogy to the hydrochloride example 1e In ethanol with 4-[(5- (1-isobutyl-tetrazole-5-
Yl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 44% of _{theory, C 21 H 24 N 8 x} HCl (388.5 / 425.0) Mass ^{spectrum: (M + H) + =} 389

[0254] Example 204 4 - [(5-phenyl-1-methyl -1H- benzimidazol-2-yl) - methyl] - Benzoa spermidine hydrochloride a 2-nitro-4-phenyl -N- methyl -. Acetanilide Dissolve 3.0 g (11.7 mmol) of 2-nitro-4-phenylacetanilide in 70 ml of dimethylformamide and combine in several portions with 576 mg (12 mmol) of sodium hydride (50% in oil) at ambient temperature. After 30 minutes at 65 ° C., the reaction mixture is cooled to ambient temperature, combined with 3 ml of methyl iodide and stirred for 30 minutes. The mixture is stirred in a saturated sodium chloride solution and extracted with ethyl acetate. The combined organic extracts are washed with water, dried and evaporated. The residue is chromatographed on silica gel, eluting with methylene chloride + ethanol (0-5%). The desired fractions are combined and evaporated. Yield: 3.2 g (100% of theory), _Rf value: 0.43 (silica gel; methylene chloride / ethanol = 19: 1)

B. 2-Nitro-4-phenyl-N-methyl-aniline 3.2 g (11.7 mmol) of 2-nitro-4-phenyl-N-methyl-acetanilide are refluxed in 99 ml of half-concentrated hydrochloric acid for 7 hours. The solution is cooled and extracted with methylene chloride.
The organic phase is washed with water, washed with sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel, eluting with methylene chloride. The desired fractions are combined and evaporated. Yield: 2.0 g (75% of theory), _Rf value: 0.8 (silica gel; methylene chloride)

C. 2-Amino-4-phenyl-N-methyl-aniline Prepared from 2-nitro-4-phenyl-N-methyl- aniline and palladium / activated carbon / hydrogen in methanol as in Example 1c. did. Yield: 91% of theory, _Rf value: 0.4 (silica gel; methylene chloride / ethanol = 19: 1) d. 4-[(5-phenyl-1-methyl-1H-benzimidazol-2-yl)- methyl] - preparation aniline, 4-cyanophenyl acetate and N, N'- carbonyldiimidazole imidazole - in the same manner as Ben Zonitoriru example 24f in tetrahydrofuran and glacial acetic acid 2-amino-4-phenyl -N- methyl did. Yield:. 100% e of theory 4 - [(5-phenyl-1-methyl -1H- benzimidazol-2-yl) - methyl] - 4 in the same manner as Ben Zoamijin hydrochloride Example 1e in ethanol Prepared from-[(5-phenyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 60% of _{theory, C 22 H 2 ON 4 x} HCl (340.4 / 376.9) Mass ^{spectrum: (M + H) + =} 341

Example 205 4-[(5-((1-Methyl-cyclohexane-1-yl) -ethoxycarbonylmethyloxyimino- methylene) -1-methyl-1H-benzimidazol-2-yl) -methyl] - benzo amidine hydrochloride a 4 -. [(5 - ((1-methyl - cyclohexane-1-yl) - methyl ethoxycarbonyl O Kishiimino - methylene) -1-methyl -1H- benzimidazol-2-yl) - methyl ] - base Nzonitoriru 4 - [(5- (1-methyl - cyclohexane-1-yl - carbonyl) -1-methyl -1H- benzimidazol-2-yl) - methyl] - in the same manner as benzonitrile (example 194 750 mg (2 mmol) and 645 mg (3 mmol) of carboxymethoxyamine
Are refluxed for 2 hours in 10 ml of methanol and 1 ml of water. The solvent is distilled off, the residue is chromatographed on silica gel, methylene chloride + ethanol (5-1
0%). The desired fractions are combined and evaporated. Yield: 450 mg (54% of theory), _Rf value: 0.5 (silica gel; methylene chloride / ethanol = 9: 1)

. [0258] b 4 - [(5 - ((1-methyl - cyclohexane-1-yl) - methyl ethoxycarbonyl O Kishiimino - methylene) -1-methyl -1H- benzimidazol-2-yl) - methyl] - in ethanol 4 in the same manner as the base Nzoamijin hydrochloride example 1e - [(5 - ((1-methyl - cyclohexane-1-yl) - ethoxycarbonylmethyl oxyimino - methylene) -1-methyl -1H- benzimidazole -2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 41% of theory, C ₂₈ H ₃₅ N ₅ O ₃ x HCl (489.6 / 526.1) Mass spectrum: (M + H) ⁺ = 490 Example 206 4-[(5- (N-cyclopentyl-methane) sulfonylamino) -1-methyl -1H- Benzoimi imidazole-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and similarly in ethanol 4 - [(5-(N-cyclopentyl - Metansuru Honiruamino) - 1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 65% of _{theory, C 22 H 27 N 5 O} 2 S x HCl (425.56 / 462.02) Mass ^{spectrum: (M + H) + =} 426

[0259] Example 207 4 - [(5- (N- (2- ethoxycarbonyl-ethyl) - - isobutyl aminocarbonyl) -1-methylation -1H- benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride in ethanol 4 in the same manner as salt example 1e - [(5- (N- (2- ethoxycarbonyl-ethyl) - - isobutyl aminocarbonyl) -1-methyl -1H- benzimidazol-2-yl) - methyl] Prepared from -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 54% of theory, C ₂₆ H ₃₃ N ₅ O ₃ x HCl (463.59 / 500.06) Mass spectrum: (M + H) ⁺ = 464 Example 208 4-[(5- (N- (2- (Carboxy-ethyl) -isobutylaminocarbonyl) -1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine In ethanol, as in Example 198, 4-[(5- (N- (2 -Ethoxycarbonyl-ethyl) -isobutylaminocarbonyl-1-methyl-1H-benzimidazol-2-yl)-
Methyl] -benzamidine hydrochloride and sodium hydroxide. Yield 72% of _{theory, C 24 H 29 N 5 O} 3 (435.5) Mass ^{spectrum: (M + H) + =} 436

[0260] Example 209 4 - [(5-tert-butyl-1- methyl -1H- benzimidazol-2-yl.) - methylation] - Benzoamijin hydrochloride Example 1e and 4 in ethanol in the same manner Prepared from-[(5-tert.butylcarbonyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 50% of theory, C ₂₁ H ₂₄ N ₄ O x HCl (348.5 / 384.9) Mass spectrum: (M + H) ⁺ = 349

[0261] Example 210 4 - [(5- (1-methyl - cyclopentane-l-yl - carbonyl) -1-methyl -1H- benzoyl imidazole-2-yl) - methyl] - Benzoamijin hydrochloride Example 4-[(5- (1-Methyl-cyclopentan-1-yl-carbonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid in ethanol as in 1e / Ammonium carbonate. Yield: 55% of theory, C ₂₃ H ₂₆ N ₄ O x HCl (374.5 / 411.0) Mass spectrum: (M + H) ⁺ = 375 Example 211 4-[(5- (S-cyclohexyl-sulhuimi) Doyle) -1-methyl -1H- benzo imidazole-2-yl) - methyl] -. Benzoamijin hydrochloride a 1-chloro-4-cyclohexane sulfanyl-2-nitrobenzene 4-chloro-3-nitroaniline 16.4 g (0.095 Mol) are suspended in 150 ml of hydrochloric acid (12%) and combined with a solution of 6.55 g (0.095 mol) of sodium nitrite in 12 ml of water at 2-5 ° C. The reaction mixture is added dropwise to a suspension of 11.6 ml (0.095 mol) of cyclohexylmercaptan in 175 ml of sodium hydroxide solution (15%), combined with 10 g of copper powder,
Then heat to 80 ° C. for 1 hour. After cooling to ambient temperature, the mixture is extracted with methylene chloride, the organic extracts are washed with hydrochloric acid and water, dried and evaporated.
The residue is chromatographed on aluminum oxide, eluting with cyclohexane / ethyl acetate (9: 1 and 4: 1). The desired fractions are combined and concentrated by evaporation.
Yield: 15.7 g (61% of theory), _Rf value: 0.3 (aluminum oxide, petroleum ether)

B. 1-Chloro-4 -cyclohexanesulfinyl-2-nitrobenzene 11.6 g (0.043 mol) of 1-chloro-4-cyclohexanesulfanyl-2-nitrobenzene was dissolved in 200 ml of acetic anhydride, and 4.4 g of perhydrol (10 ° C.) was dissolved. 0.038 mol). The solution is stirred at ambient temperature for 48 hours and concentrated by evaporation. The residue is combined with ice and ammonia and extracted with ethyl acetate. The organic extract is washed with a sodium chloride solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with cyclohexane / ethyl acetate 7: 3 and 1: 2. Yield: 6.7 g (54% of theory), _Rf value: 0.9 (silica gel; cyclohexane / ethyl acetate = 2: 1) c. 1-chloro-4-cyclohexylsulfoimidyl-2-nitrobenzene 1-chloro-4 Dissolve 8.4 g (0.029 mol) of -cyclohexanesulfinyl-2-nitrobenzene, 24.8 g (0.086 mol) of ethyl O-mesitylene-sulfonyl-acetohydroxamate and 28.6 g (0.15 mol) of p-toluenesulfonic acid in 160 ml of dimethylformamide. Stir at ambient temperature for 90 hours. Then the mixture is diluted with ice water and combined with sodium carbonate. After extraction with ethyl acetate, the combined organic phases are washed with sodium chloride, dried and evaporated. The residue is chromatographed on silica gel, eluting with methylene chloride / ethanol (50: 1 and 30: 1). The desired fractions are combined and concentrated by evaporation. Yield: 7.1 g (81% of theory), _Rf value: 0.3 (silica gel; cyclohexane / ethyl acetate = 2: 1)

D. 1-Chloro-4-cyclohexylsulfoimidyl- 2-nitrobenzene in 10 ml of 1-chloro-4 -cyclohexyl-N-tert.butoxycarbonyl-sulfoimidyl- 2-nitrobenzenetetrahydrofuran
To a solution of 3.1 g (0.01 mol) of nitrobenzene is added dropwise at 5 ° C. a solution of 1.4 g (0.012 mol) of potassium tert. Butoxide in 5 ml of tetrahydrofuran. After 20 minutes, a solution of 4.4 g (0.02 mol) of di-tert.butyl dicarbonate in 30 ml of tetrahydrofuran is added. After 3 hours at ambient temperature, the mixture is stirred with ammonium chloride solution and extracted with ethyl acetate. The organic extract is washed with water and sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel, ethyl acetate / cyclohexane (9: 1 and 4: 1).
Elute with Yield: 2.7 g (65% of theory), _Rf value: 0.5 (silica gel; petroleum ether / ethyl acetate = 4: 1)

E. 1-Methylamino-4-cyclohexyl-N-tert.butoxycarbonyl-sulfimidoyl- 2-nitrobenzene 1-chloro-4-cyclohexyl-N-tert.butoxycarbonyl as in Example 7b -Sulfimidoyl-2-nitrobenzene and methylamine solution. Yield: 92% of theory, R _f value: 0.6 (silica gel; cyclohexane / ethyl acetate = 1: 1) f. 1-Methylamino-2-amino-4-cyclohexyl-N-tert.butoxycarbonyl- sulhuimi Doyl-benzene 1-methylamino-4-cyclohexyl-N-te in methanol as in Example 1c
rt. butoxycarbonyl-sulfoimidyl-2-nitrobenzene and palladium / activated carbon / hydrogen. The crude product is reacted further without purification. g. 4-[(5- (cyclohexyl-N-tert.butoxycarbonyl-sulfoimidyl) -1 -methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile Tetrahydrofuran in the same manner as in Example 24f. Prepared from 1-methylamino-2-amino-4-cyclohexyl-N-tert. Butoxycarbonyl-sulfoimidyl-benzene, 4-cyanophenylacetic acid and N, N'-carbonyldiimidazole in glacial acetic acid. Yield: 40.6% of theory, R _f value: 0.5 (silica gel; ethyl acetate)

. [0265] h 4 - [(5- (cyclohexyl - sul Hoimi Doyle) -1-methyl -1H- benzo imidazole-2-yl) - methyl] - benzonitrile 4 - [(5- (cyclohexyl -N -tert.butoxycarbonyl-sulfoimidyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile (1.3 g, 2.6 mmol) was dissolved in dioxane (15 ml), and 6N hydrochloric acid (10 ml) was added. The mixture is stirred at ambient temperature for 8 hours. The solution is diluted with ice, combined with ammonia and extracted with ethyl acetate. The organic phase is washed with water and sodium chloride solution, dried and concentrated by evaporation. Yield: 1.0 g (98% of theory), _Rf value: 0.65 (silica gel; methylene chloride / ethanol = 9: 1) i. 4-[(5- (cyclohexyl-sulfimidoyl) -1-methyl-1H - benzo imidazole-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5- (cyclohexyl - Suruhoimido yl) -1-methyl -1H- benzimidazole - 2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 90% of _{theory, C 22 H 27 N 5 OS} x HCl (409.56 / 446.02) Mass ^{spectrum: (M + H) + =} 410

[0266] Example 212 4 - [(5-(N-ethoxycarbonylmethyl - cyclohexylsulfanyl Hoimi Doyle) -1-methylation -1H- benzimidazol-2-yl) - (ethoxycarbonylmethyl) - methylene] - benzo amidine hydrochloride a 4 -. [(5-(N-ethoxycarbonylmethyl - cyclohexylsulfanyl Hoimi Doyle) -1 - methyl -1H- benzoimidazol-2-yl) - (ethoxycarbonylmethyl) - methylene emissions] - benzonitrile and 4 - [(5- (cyclohexyl - sul Hoimi Doyle) -1-methyl -1H- benzimidazol-2-yl) - (ethoxycarbonylmethyl) methylene] - Ben Zonitoriru 4 - [(5- (cyclohexylsulfanyl Hoimi Doyle ) -1-Methyl-1H-benzimidazole
2-yl) -methyl] -benzonitrile 0.7 g (1.78 mmol) and potassium carbonate 1 g (
7.25 mmol) was dissolved in 100 ml of acetone, and 0.45 ml (4.0%) of ethyl bromoacetate was dissolved.
(Mmol) is added and the mixture is refluxed for 95 hours. The precipitate formed is filtered off with suction, the mother liquor is concentrated by evaporation and the residue is chromatographed on silica gel, eluting with ethyl acetate / ethanol (1: 0 and 9: 1). Yield: 4-[(5- (N-ethoxycarbonylmethyl-cyclohexylsulfoimidyl)
-1-methyl -1H- benzimidazol-2-yl) - (ethoxycarbonylmethyl) methylene] - 20% of the benzonitrile 0.2 g _{(theory), C 30 H 36 N 4} O 5 S (564), mass spectrum : M ⁺ = 564 and 0.2 g of 4-[(5- (cyclohexylsulfimidoyl) -1-methyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl) methylene] -benzonitrile (theoretical 20 _{%), C 26 H 30 N} 5 O 3 S (478.6), mass spectrum: M ⁺ = 478

. [0267] b 4 - [(5-(N-ethoxycarbonylmethyl - cyclohexylsulfanyl Hoimi Doyle) -1 - methyl -1H- benzoimidazol-2-yl) - (ethoxycarbonylmethyl) - methylene emissions] - Benzoamijin Hydrochloride 4-[(5- (N-ethoxycarbonylmethyl-cyclohexylsulfoimidyl) -1-methyl-1H-benzimidazol-2-yl)-(
Ethoxycarbonylmethyl) methylene] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 31% of _{theory, C 30 H 39 N 5 O} 5 S x HCl (581.75 / 618.21) Mass ^{spectrum: (M + H) + =} 582

Example 213 4-[(5- (Cyclohexyl-sulfimidoyl) -1-methyl-1H-benzimidazol- 2-yl)-(ethoxycarbonylmethyl) methylene] -benzamidine hydrochloride Example 1e Similarly prepared from 4-[(5- (cyclohexyl-sulfoimidyl) -1-methyl-1H-benzimidazol-2-yl)-(ethoxycarbonylmethyl) methylene] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol did. Yield: 70% of theory, C ₂₆ H ₃₃ N ₅ O ₃ S × HCl (495.66 / 532.12) Mass spectrum: (M + H) ⁺ = 496 Example 214 4-[(5- (N-cyclopentyl- 3-methoxycarbonyl-propionylamino) -1-methylation -1H- benzimidazol-2-yl) - methyl! - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5-(N-cyclopentyl 3-Methoxycarbonylpropionylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 81% of theory, C ₂₆ H ₃₁ N ₅ O ₃ x HCl (461.57 / 498.04) Mass spectrum: (M + H) ⁺ = 462 (M + 2H) ⁺⁺ = 231.7 (M + H + Na ) ⁺⁺ = 242.8

[0269] Example 215 4 - [(5- (N-acetyl - cyclohexylsulfanyl Hoimi Doyle) -1-methyl -1H- benzoyl imidazole-2-yl) - methyl] - Benzoamijin hydrochloride 4 - [(5- (N-acetyl-cyclohexylsulfoimidyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride (150 mg, 0.29 mmol) was suspended in glacial acetic acid (5 ml), and acetic anhydride (3 ml) was added. After addition, stir at 40 ° C. for 75 minutes. The reaction mixture is concentrated by evaporation at 70 ° C., the residue is triturated with ether, filtered off with suction,
dry. Yield: 150 mg (100% of _{theory), C 24 H 29 N 5} O 2 S x HCl (451.6 / 488.06) Mass ^{spectrum: (M + H) + =} 452

Example 216 4-[(5- (N- (3-carboxypropionyl) -cyclohexylsulfoimidyl) -1- methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4 -[(5- (cyclohexylsulfoimidyl) -1-methyl-1H-benzimidazole
210 mg (0.4 mmol) of 2--2-yl) -methyl] -benzamidine hydrochloride are dissolved in 5 ml of glacial acetic acid, and after addition of 61 mg (0.6 mmol) of succinic anhydride, the mixture is stirred at 70 ° C for 1 hour. The glacial acetic acid is distilled off, the residue is triturated with ether and acetone, suction filtered and dried. Yield: 200 mg (86% of _{theory), C 26 H 31 N 5} O 4 S x HCl (509.64 / 546.1) Mass ^{spectrum: (M + H) + =} 510

Example 217 4-[(5-phenylsulfonyl-1-methyl-1H-benzimidazol-2-yl) -methyl ] -benzamidine hydrochloride a. 4-benzenesulfonyl-phenylamine Same as in Example 1c Prepared from 4-nitrodiphenylsulfone and hydrogen / palladium / activated carbon in methylene chloride / methanol. Yield: 99% of theory, R _f value: 0.6 (silica gel; methylene chloride / ethanol = 19: 1) b. N- (4-benzenesulfonyl-phenyl) -methanesulfonamide Pyridine as in Example 1d Prepared from 4-benzenesulfonyl-phenylamine and methanesulfonic acid chloride. Yield: 81% of theory, _Rf value: 0.45 (silica gel; methylene chloride / ethanol = 19: 1)

C. N- (4-benzenesulfonyl-2-nitro-phenyl) -methanesulfonamide Prepared from N- (4-benzenesulfonyl-phenyl) -methanesulfonamide and fuming nitric acid as in Example 189b. . Yield: 90% of theory, _Rf value: 0.62 (silica gel; methylene chloride / ethanol = 19: 1) d. N- (4-benzenesulfonyl-2-nitro-phenyl) -N-methyl-methanesulfone in the same manner as bromide example 204a in dimethylformamide N-(4-benzenesulfonyl -
Prepared from 2-nitro-phenyl) -methanesulfonamide, methyl iodide and sodium hydride. Yield: 50% of theory, R _f value: 0.63 (silica gel; ethyl acetate) e. (4-benzenesulfonyl-2-nitro-phenyl) -N-methylamine N- (4-benzenesulfonyl-2-nitro) 7.2 g (19.4 mmol) of -phenyl) -N-methyl-methanesulfonamide are heated to 130 ° C. in 70 ml of concentrated sulfuric acid for 15 minutes. Then the mixture is poured into ice-water, the precipitate formed is suction filtered, washed with water and dried. Yield: 5.5 g (97% of theory), _Rf value: 0.73 (silica gel; ethyl acetate / petroleum ether = 3: 1)

F. (4-benzenesulfonyl-2-amino-phenyl) -N-methylamine (4-benzenesulfonyl-methanol) in methylene chloride / methanol as in Example 1c.
Prepared from 2-nitro-phenyl) -methyl-amine and palladium / activated carbon / hydrogen. Yield: 100% of theory g. 4- (5-benzenesulfonyl-1-methyl-1H-benzimidazol-2-yl-methyl ) -benzonitrile In tetrahydrofuran / glacial acetic acid as in Example 24f Prepared from 4-benzenesulfonyl-2-amino-phenyl) -methyl-amine, 4-cyanophenylacetic acid and N, N'-carbonyldiimidazole. Yield: 80% of theory, _Rf value: 0.54 (silica gel; methylene chloride / ethanol = 19: 1) h. 4- (5-benzenesulfonyl-1-methyl-1H-benzimidazol-2-yl-methyl) ) -Benzoamidine hydrochloride 4- (5-benzenesulfonyl-1-methyl- 1H-) in ethanol as in Example 1e.
Prepared from benzimidazol-2-yl-methyl) -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 57% of _{theory, C 22 H 20 N 4 O} 2 S x HCl (404.5 / 441.0) Mass ^{spectrum: (M + H) + =} 405

[0274] Example 218 4 - [(5-(N-cyclopentyl-N-(2-ethoxycarbonyl - ethylsulfonyl) - amino-1-methyl -1H- benzimidazol-2-yl) - methyl] - benzo Amidine hydrochloride a.Cyclopentyl- (4-fluoro-3-nitro-phenyl) -aminecyclopentanone 6.7 g (0.08 mol), 4-fluoro-3-nitro-aniline 12.5 g (0
.08 mol) and 30 ml (0.1 mol) of titanium-IV-isopropoxide are stirred at 40 ° C. for 30 minutes and at ambient temperature for 1 hour. After addition of 150 ml of ethanol, the reaction mixture is stirred for 30 minutes and then combined with 2.4 g (0.066 mol) of sodium borohydride in several portions. After 4 hours, the reaction mixture is poured into ice water and combined with ethyl acetate. After filtration, the organic phase is separated off, dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (9: 1). Combine the desired fractions and concentrate by evaporation. Yield: 8.8 g (49% of theory), _Rf value: 0.68 (silica gel; petroleum ether / ethyl acetate = 4: 1)

B. N-cyclopentyl- (4-methylamino-2 -nitro-phenyl) -amine From a solution of cyclopentyl- (4-fluoro-3-nitrophenyl) -amine and methylamine as in Example 168a. Prepared. Yield: 100% of theory, R _f value:. 0.44 (silica gel; methylene chloride) c Methyl 3- [cyclopentyl - (4-methylamino-3-nitro - phenyl) - sulfa carbamoyl] - and propionate Example 1d Prepared similarly from cyclopentyl- (4-methylamino-2-nitro-phenyl) -amine and methylchlorosulfonyl-propionate in pyridine. Yield: 36% of theory, R _f value:. 0.45 (silica gel; methylene chloride / ethanol 50: 1) d methyl 3- [cyclopentyl - (3-amino-4-methylamino-phenyl) - - sulfa carbamoyl] - Propionate Prepared from methyl 3- [cyclopentyl- (4-methylamino-3-nitro-phenyl) -sulfamoyl] -propionate and palladium / activated carbon / hydrogen in methylene chloride / methanol in the same manner as in Example 1c. Yield: 100% of theory, R _f value: 0.52 (silica gel; methylene chloride / ethanol 50: 1)

E. 4-[(5- (N-cyclopentyl-N- (2-ethoxycarbonyl-ethylsulfonyl) -amino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile Methyl 3-[(3-amino) in tetrahydrofuran / glacial acetic acid in the same manner as in Example 24f
-4-Methylamino-phenyl) -cyclopentyl-sulfamoyl] -propionate, 4-cyanophenylacetic acid and N, N'-carbonyldiimidazole. Yield: 72% of theory, R _f value: 0.41 (silica gel; methylene chloride / ethanol = 50: 1) f. 4-[(5- (N-cyclopentyl-N- (2-ethoxycarbonyl-ethylsulfonyl)) - amino) -1-methyl -1H- benzimidazol-2-yl) - methyl] - Benzoamijin salt salt example 1e and similarly in ethanol 4 - [(5-(N-cyclopentyl--N- ( 2-ethoxycarbonyl-ethylsulfonyl) -amino) -1-methyl-1H-benzimidazole-2-
Yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 76% of theory, C ₂₆ H ₃₃ N ₅ O ₄ S x HCl (511.66 / 548.12) Mass spectrum: (M + H) ⁺ = 512

Example 219 4-[(5- (1-Methoxycarbonylmethyl-4-isobutyl-imidazol-5-yl) -1- methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride Salt a. To a suspension of 66.7 g (0.5 mol) of aluminum chloride in 300 ml of 1- (4-chlorophenyl) -4-methyl- pentan -1-one chlorobenzene was added 56 g (0.42 mol) of isocaproic chloride in 20 ml of chlorobenzene. ) Is added dropwise. The solution is stirred at 50 ° C. for 3 hours and then concentrated by evaporation. The residue is carefully poured into ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried, concentrated by evaporation and the residue obtained is chromatographed on silica gel, eluting with petroleum ether / methylene chloride (2: 8). Yield: 72.5 g (83% of theory), _Rf value: 0.6 (silica gel; methylene chloride)

B. 2-Bromo-1- (4-chloro-phenyl) -4-methyl- pentan -1-one 55 g (0.344 mol) of bromine were added in 300 ml of dioxane and 300 ml of methylene chloride until decolorization started. Add dropwise to a solution of 72.5 g (0.344 mol) of-(4-chlorophenyl) -4-methyl-pentan-1-one. After 10 minutes at ambient temperature, the solvent is evaporated off. Yield: 99 g (100% of theory), _Rf value: 0.76 (silica gel; methylene chloride) c. 5- (4-chloro-phenyl) -4-isobutyl-1H-imidazole 2-bromo-1- (4- 38 g of chloro-phenyl) -4-methyl-pentan-1-one (0.43 mol)
Is heated to 160 ° C. in 400 ml of formamide for 10 hours. After 12 hours at ambient temperature, the mixture is diluted with water and combined with ammonia. The precipitate formed is filtered off and washed with water and ether. Yield: 19 g (66% of theory), _Rf value: 0.5 (silica gel; methylene chloride / methanol = 9: 1)

. [0279] d ethyl [5- (4-chloro - phenyl) -4-isobutyl - imidazol-1-yl] - A Seteto 5- (4-chloro - phenyl) -4-isobutyl--1H- imidazole 19 g (0.085 Is dissolved in 500 ml of acetone and the mixture is refluxed for 16 hours after addition of 41.5 g (0.3 mol) of potassium carbonate and 16.7 g (0.13 mol) of ethyl bromoacetate. Then it is filtered to remove insolubles and the mother liquor is concentrated by evaporation. The residue is chromatographed on silica gel, eluting with methylene chloride / methanol (80: 1). The desired fractions are combined and concentrated by evaporation. Yield: 5.4 g (20% of theory), _Rf value: 0.54 (silica gel; methylene chloride / methanol = 9: 1) e. [5- (4-chloro-phenyl) -4-isobutyl-imidazole-1- Yl] -ethyl acetate [5- (4-chloro-phenyl) -4-isobutyl-imidazol-1-yl] -acetate (4.8 g, 0.015 mol) was dissolved in ethanol (15 ml) and water (40 ml). After addition of g (0.05 mol), it is stirred for 2 hours at ambient temperature. The alcohol is distilled off, the residue is diluted with water and adjusted to pH 5 with hydrochloric acid. The precipitate formed is filtered off, washed with water and dried. Yield: 3.9 g (89% of theory), _Rf value: 0.38 (silica gel; methylene chloride / methanol = 5: 1)

F. [5- (4-Chloro-3-nitro-phenyl) -4-isobutyl-imidazol-1-yl] -acetic acid [5- (4-chloro-phenyl) -acetic acid in the same manner as in Example 189b. 4-isobutyl-imidazol-1-yl] -acetic acid and fuming nitric acid. Yield: 75% of theory, _Rf value: 0.4 (silica gel; methylene chloride / methanol = 5: 1) g. [4-isobutyl-5- (4-methylamino-3-nitro-phenyl) -imidazole- 1- yl-acetic acid Prepared from [5- (4-chloro-3-nitro-phenyl) -4-isobutyl-imidazol-1-yl] -acetic acid and methylamine solution (40%) as in Example 7b. . Yield: 99% of theory, _Rf value: 0.42 (reverse phase, RP18, methanol / 5% sodium chloride solution = 6: 4) h. Ethyl [4-isobutyl-5- (4-methylamino-3- nitro - phenyl) - imidazole-1-yl] - acetate absolute ethanol 100ml saturated with hydrochloric acid gas, [4-isobutyl-5- (4-Mechiruami Roh-3-nitro - phenyl) - imidazol-1-yl] After addition of 3.6 g (0.011 mol) of acetic acid, stir at ambient temperature for 3 hours. The solution is concentrated by evaporation in vacuo, the residue is dissolved in water, made basic with ammonia and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. Yield: 2.9 g (73% of theory), _Rf value: 0.64 (silica gel; methylene chloride / methanol = 9: 1)

I. 4-[(5- (1-Methoxycarbonylmethyl-4-isobutyl-imidazol-5-yl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile In the same manner as in 24f, tetrahydrofuran / glacial acetic acid [4-isobutyl-5- (4
-Methylamino-3-nitro-phenyl) -imidazol-1-yl] -acetic acid, N, N'-carbonyldiimidazole and 4-cyanophenylacetic acid. Yield: 37% of theory, _Rf value: 0.67 (silica gel; methylene chloride / methanol = 9: 1) k. 4-[(5- (1-methoxycarbonylmethyl-4-isobutyl-imidazol-5-yl) ) -1-Methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride In methanol in the same manner as in Example 1e, 4-[(5- (1-methoxycarbonylmethyl-4
-Isobutyl-imidazol-5-yl) -1-methyl-1H-benzimidazol-2-yl)-
Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 29% of _{theory, C 26 H 30 N 6 O} 2 x HCl (458.57 / 495.038) Mass ^{spectrum: (M + H) + =} 459 (M + 2H) ++ = 230

Example 220 4-[(5- (N-Cyclopentyl-tetrazol-5-yl- methylcarbonylamino ) -1- methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (N-cyclopentyl-tetrazol-5-yl-methylcarbonylamino) -1-methyl-1H-benzimidazol-2-yl) in ethanol as in Example 1e
-Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 63% of theory, C ₂₄ H ₂₇ N ₉ O x HCl (457.55 / 494.01) Mass spectrum: (M + H) ⁺ = 458 Example 221 4-[(5- (N-cyclohexyl-methanesulfonyl) amino) -1-methyl -1H- Benzoimi imidazole-2-yl) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(5-(N-cyclohexyl - Metansuru Honiruamino) -1 -Methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 89% of _{theory, C 23 H 29 N 5 O} 2 S x HCl (439.59 / 476.06) Mass ^{spectrum: (M + H) + =} 440

[0283] Example 222 4 - [(5-(N-cyclopentyl-3- carboxymethyl propionylamino) -1-methyl -1H- Baie emission zone imidazol-2-yl) - methyl] - Benzoamijin hydrochloride Example 13 4-[(5- (N-cyclopentyl-3-ethoxycarbonylpropionylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine hydrochloride and water in ethanol Prepared from sodium oxide. Yield: 52% of theory, C ₂₅ H ₂₉ N ₅ O x HCl (447.55 / 484.02) Mass spectrum: (M + H) ⁺ = 448 (M + Na) ⁺ = 470 (M + H + Na) ⁺ = 235.6 eXAMPLE 223 4 - [(5-(N-phenyl-- methylaminocarbonyl) -1,7-dimethyl -1H- Benzoimida-2-yl) - methyl] - Benzoamijin in analogy to the hydrochloride example 1e Prepared from 4-[(5- (N-phenyl-methylaminocarbonyl) -1,7-dimethyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol . Yield: 56% of _{theory, C 25 H 25 N 5 O} x HCl (411.5 / 448.0) Mass spectrum: M ⁺ = 411

Example 224 4-[(5- (N-Cyclopentyl-ethoxycarbonylmethyloxyacetylamino) -1 -methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride Example 1e Similarly, 4-[(5- (N-cyclopentyl-ethoxycarbonylmethyloxyacetylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol Prepared from Yield: 68% of theory, C ₂₇ H ₃₃ N ₅ O ₄ x HCl (491.60 / 528.07) Mass spectrum: M ⁺ = 492 (M + 2H) ⁺⁺ = 246.6 (M + H + Na) ⁺⁺ = 235.6

Example 225 4-[(5- (N-cyclopentyl-carboxymethyloxyacetylamino) -1-methyl- 1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride As in Example 13. 4-((5- (N-cyclopentyl-ethoxycarbonylmethyloxyacetylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine hydrochloride and sodium hydroxide in ethanol Prepared from Yield: 98% of theory, C ₂₅ H ₂₉ N ₅ O ₄ x HCl (463.55 / 500.02) Mass spectrum: (M + H) ⁺ = 464 (M + 2H) ⁺⁺ = 232.7 (M + H + Na ) ⁺⁺ = 243.7 example 226 4 - [(5- (2,3-dihydro-indol-1-yl - sulphonyl) -1-methyl -1H- Benzoimi imidazole-2-yl) - methyl] - Benzoamijin hydrochloride 4-[(5- (2,3-dihydroindole-1-yl-sulfonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoni) in ethanol as in Example 1e Prepared from tolyl and hydrochloric acid / ammonium carbonate. Yield: 32% of _{theory, C 24 H 23 N 5 O} 2 S x HCl (445.545 / 482.00) Mass ^{spectrum: (M + H) + =} 446

[0286] Example 227 4 - [(5- (1,3-dihydro - isoindol-2-yl - sulphonyl) -1-methyl -1H- Baie emission zone imidazol-2-yl) - methyl] - Benzoamijin Hydrochloride 4-((5- (1,3-dihydro-isoindole) in ethanol as in Example 1e
2-yl-sulfonyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 32% of _{theory, C 24 H 23 N 5 O} 2 S x HCl (445.545 / 482.00) Mass ^{spectrum: (M + H) + =} 446

[0287] Example 228 4 - [[5- (1- (N- ethoxycarbonylmethyl - methylaminocarbonyl) - Shikuropu propane-1-yl) -1-methyl -1H- benzimidazol-2-yl] - methyl ! - Benzoa spermidine hydrochloride a diethyl 2-acetylamino-2-. (4-cyano - benzyl) - malonate sodium 3g was dissolved in ethanol 100 ml, then diethyl acetamide malonate 27.7 g (0.127 mol) in dioxane 200ml and Combine with a solution of 6.4 g (0.04 mol) of potassium iodide. Then 4-cyanobenzyl bromide 2 in 200 ml of dioxane
5 g (0.127 mol) of the solution are added dropwise and the reaction mixture is refluxed for 3 hours. After 12 hours at ambient temperature, it is filtered, the filtrate is concentrated by evaporation, the residue is crystallized from petroleum ether and filtered off with suction. Yield: 41.1 g (97% of theory), _Rf value: 0.62 (silica gel; methyl ethyl ketone / xylene = 1: 1) Melting point: 177-178 ° C

B. Diethyl 2-amino -3- (4-cyano-phenyl) -propionate 2-acetylamino-2- (4-cyano-benzyl) -malonate (40 g, 0.12 mol) was added to glacial acetic acid (110 ml) and concentrated hydrochloric acid. Dissolve in 50 ml and 135 ml of water and reflux for 8 hours. The solution is concentrated by evaporation in vacuo, the residue is crystallized from isopropanol / ether,
Filter with suction and dry. Yield: 18.6 g (68% of theory), _Rf value: 0.37 (silica gel; methyl ethyl ketone / xylene = 1: 1) c. 4- (5-oxo-2-trifluoromethyl-4,5-dihydro-oxazole 4-yl) methylation - benzonitrile 2-amino-3- (4-cyano-phenyl) - - a 5.7g propionic acid (2.5 mmol) was dissolved in trifluoroacetic anhydride 26.3 g (12.5 mmol), refluxed for 24 hours Let it. The solution is then concentrated by evaporation in vacuo and the residue is chromatographed on silica gel, eluting with methylene chloride. The desired fractions are combined and concentrated by evaporation.
Yield: 3.6 g (53% of theory), _Rf value: 0.71 (silica gel; methyl ethyl ketone / xylene = 1: 1)

D. 4- (2-oxo-propionic acid) -benzonitrile 3.5 g of 4- (5-oxo-2-trifluoromethyl-4,5-dihydro-oxazol-4-yl) methyl-benzonitrile 0.013 mol) in 20 ml of 70% trifluoroacetic acid,
Stir for 24 hours at ambient temperature. The solid formed is filtered off with suction, washed with water and dried.
Yield: 1.8 g (75% of theory), _Rf value: 0.2 (silica gel; methylene chloride / ethanol = 9: 1) e. 1- (4-chloro-3-nitrophenyl) -cyclopropanecarboxylic acid fuming nitric acid 350 ml are combined with 50.0 g (0.21 mol) of 1- (4-chloro-phenyl) -cyclopropanecarbonic acid in several portions at -25 to -30 ° C. After all of it has been added, the mixture is stirred at -25 ° C for a further 15 minutes and then poured onto ice. The precipitated material is filtered off with suction, washed with water and dried. Yield: 58.5 g (95% of theory), _Rf value: 0.43 (silica gel; methylene chloride / methanol = 9.5: 0.5)

F. 1- (4-Methylamino-3 -nitro-phenyl) -cyclopropanecarboxylic acid 20.0 g (0.083 mol) of 1- (4-chloro-3-nitrophenyl) -cyclopropanecarboxylic acid was added to a glass cylinder. In 180 ° C. with 100 ml of methylamine solution (40%) for 5 hours in water. The solution is concentrated by evaporation in vacuo, the residue is taken up in water and acidified with glacial acetic acid. The precipitated material is filtered off with suction, washed with water and dried. Yield: 16.9 g (93% of theory), _Rf value: 0.59 (silica gel; methylene chloride / methanol = 9: 1)

G. 1- (3-Amino- 4-methylamino-phenyl) -cyclopropanecarboxylic acid 3.2 g of 1- (4-methylamino-3-nitro-phenyl) -cyclopropanecarboxylic acid (13.
(5 mmol) are dissolved in 120 ml of ethanol and hydrogenated with hydrogen for 90 minutes after addition of 0.5 g of palladium on activated carbon. The catalyst is filtered off and the solution is evaporated. Yield: 2.8 g (100% of theory), _Rf value: 0.41 (silica gel; methylene chloride / methanol = 9: 1) h. 4-[(5- (1-carboxy-cyclopropan-1-yl)- 1-methyl -1H- Benzoimida 2-yl) - methyl] - benzonitrile and 4 - [(6- (1-carboxy - Shikuropu propane-1-yl) -1-methyl-2-oxo-1,2 -Dihydroquinoxalin-3-yl) -methyl ] -benzonitrile 4- (2-oxo-propionic acid) -benzonitrile 2.6 g (13.5 mmol) and 1- (3-amino-4-methylamino-phenyl) -cyclo 2.8 g (13.5 mmol) of propanecarboxylic acid are placed in 100 ml of ethanol and refluxed for 5 hours under a stream of nitrogen. The reaction mixture is stirred for 72 hours at ambient temperature, then half of the solvent is distilled off. The precipitated material is filtered off with suction and dried. Yield: 4-[(5- (1-carboxy-cyclopropan-1-yl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile, 1.3 g (28% of theory) , R _f value: 0.43 (silica gel; methylene chloride / ethanol _{= 9: 1) C 20 H} 17 N 3 O 2 (331.38) mass spectrum: M ⁺ = 331 the filtrate was evaporated and combined with ether. The precipitate formed is suction filtered and dried. Yield: 4-[(6- (1-carboxy-cyclopropan-1-yl) -1-methyl-2-oxo-1,2-
Dihydroquinoxalin-3-yl) -methyl] -benzonitrile, 1.0 g (21% of theory)
), R _f value: 0.50 (silica gel; methylene chloride / ethanol = 9: 1) C ₂₁ H ₁₇ N ₃ O ₃ (359.38) Mass spectrum: M ⁺ = 359

. [0292] i 4 - [[5- (1- (N- ethoxycarbonylmethyl - methylaminocarbonyl) - consequent Ropuropan-1-yl) -1-methyl -1H- benzimidazol-2-yl] - methyl] - Ben Zonitoriru 4 - [(5- (1-carboxy - cyclopropyl) -1-methyl -1H- benzoimidazol-2
Yl) -methyl] -benzonitrile 0.5 g (1.5 mmol) in dimethylformamide 5m
l-O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate 0.48 g (1.5 mmol), N-methylmorpholine 0.46 ml and sarcosine ethyl After the addition of 0.3 g of ester hydrochloride, the mixture is brought to ambient temperature for 20 minutes.
Stir for hours. The suspension is diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with sodium hydrogen carbonate solution and sodium chloride solution, dried,
Concentrate by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate / 1% ammonia. The desired fractions are combined and concentrated by evaporation. Yield: 370 mg (58% of theory), _Rf value: 0.61 (silica gel; methylene chloride / ethanol = 9: 1) k. 4-[[[5- (1- (N-ethoxycarbonylmethyl-methylaminocarbonyl)] - Sik Ropuropan-1-yl) -1-methyl -1H- benzimidazol-2-yl] - methyl] - Ben Zoamijin hydrochloride example 1e and 4 in ethanol in the same manner - [[5- (1- ( N-ethoxycarbonylmethyl-methylaminocarbonyl) -cyclopropan-1-yl) -1-methyl-1H-benzimidazol-2-yl] -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 93% of theory, C ₂₅ H ₂₉ N ₅ O ₃ x HCl (447.55 / 484.02) Mass spectrum: (M + H) ⁺ = 448

Example 229 4-[(5- (1- (pyrrolidin-1-yl-carbonyl) -cyclopropan-1-yl) -1-methyl -1H-benzimidazol-2-yl) -methyl] -methyl Benzoamidine hydrochloride 4-[(5- (1- (pyrrolidin-1-yl-carbonyl) -cyclopropan-1-yl) -1-methyl-1H-benzimidazole in ethanol as in Example 1e -2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 96% of theory, C ₂₄ H ₂₇ N ₅ O x HCl (401.52 / 437.99) Mass spectrum: (M + H) ⁺ = 402 Example 230 4-[(5- (1- (N-carboxy methyl - methylaminocarbonyl) - cyclopropane-1-yl) -1-methyl -1H- benzimidazol-2-yl) - methyl] - Benzoamijin hydrochloride example 13 in the same manner as 4 in ethanol - [( 5- (1- (N-ethoxycarbonylmethyl-methylaminocarbonyl) -cyclopropan-1-yl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine hydrochloride and hydroxyl Prepared from sodium solution. Yield: 86% of theory, C ₂₃ H ₂₅ N ₅ O ₃ x HCl (419.49 / 455.96) Mass spectrum: (M + H) ⁺ = 420 (M + Na) ⁺ = 442

Example 231 4-[(5- (pyrrolidin-1-yl-carbonyl- (ethoxycarbonylmethyl) -methylene ) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride Salt a. 2- (4-chloro-phenyl) -1-pyrrolidin-1-yl-ethanone p-chlorophenylacetic acid, pyrrolidine, O- (benzotriazol-1-yl) in dimethylformamide as in Example 230i Prepared from -N, N, N ', N'-tetramethyluronium tetrafluoroborate and N-methylmorpholine. Yield: 75% of theory, _Rf value: 0.5 (silica gel; methylene chloride / ethanol 19: 1)

B. 16.8 g of ethyl 3- (4-chloro-phenyl) -4-oxo-4-pyrrolidin-1-yl-butyrate 2- (4-chloro-phenyl) -1-pyrrolidin-1-yl-ethanone (0.075 mol) is dissolved in 175 ml of dimethyl sulfoxide and, after addition of 8.9 g (0.08 mol) of potassium tert. Butoxide, stirred for 15 minutes at ambient temperature. 18.1 ml of ethyl iodoacetate (0.
(085 mol), the reaction mixture is stirred at ambient temperature for 45 hours. Pour the solution into ice water and extract with ethyl acetate. The combined organic extracts are washed with a sodium chloride solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting initially with petroleum ether and later with petroleum ether / ethyl acetate (8: 2 and 1: 1). The desired fractions are combined and concentrated by evaporation. Yield: 11.0 g (48% of theory), _Rf value: 0.73 (silica gel; ethyl acetate / petroleum ether = 7: 3) c. Ethyl 3- (4-chloro-3-nitro-phenyl) -4-oxo 4-pyrrolidin-1-yl - Bed Chireto and ethyl 3- (4-chloro-2-nitro - phenyl) -4-oxo-4-pyrrolidin-1 - yl - the butyrate fuming nitric acid 40 ml, ethyl 3- (4 7.8 g (0.025 mol) of -chloro-phenyl) -4-oxo-4-pyrrolidin-1-yl-butyrate are added in several portions at -30 ° C. The solution-
Stir at 30 ° C. for 15 minutes, then pour into ice water. The supernatant water is decanted off and the residue is taken up in ethyl acetate and sodium hydrogen carbonate solution and extracted. The combined organic extracts are dried and concentrated by evaporation. Yield: 7.9 g (89% of theory), ethyl 3- (4-chloro-3-nitro-phenyl) -4-oxo-4-pyrrolidin-1-yl as a mixture of isomers in a ratio of 1: 9 -Butyrate and ethyl 3- (4-chloro-2-nitro-phenyl) -4-oxo-4-pyrrolidin-1-yl-butyrate, R _f value: 0.68 (silica gel; methylene chloride / ethanol = 19: 1)

D. Ethyl 3- (4-methylamino-3-nitro-phenyl) -4-oxo-4-pyrrolidin-1- yl-butyrate ethyl 3- (4-chloro-3-nitro-phenyl) -4 7.9 g of 23-oxo-4-pyrrolidin-1-yl-butyrate and ethyl 3- (4-chloro-2-nitro-phenyl) -4-oxo-4-pyrrolidin-1-yl-butyrate (mixture of isomers) Mmol) in 65 ml of ethanol and, after addition of 5 ml of methylamine, the mixture is stirred for 8 hours in a pressure vessel for 1 hour.
Heat to 0 ° C. After cooling to ambient temperature and addition of 5 g of silica gel, the mixture is evaporated to dryness. The residue is chromatographed on silica gel, eluting initially with petroleum ether and later with petroleum ether / ethyl acetate (9: 1). Yield: 330 mg (3.6% of theory), R _f value:. 0.58 (silica gel; methylene chloride / ethanol _{= 19: 1) C 17 H} 23 N 3 O 5 (349.4) Mass spectrum: M ⁺ = 349 e ethyl 3 -(4-methylamino-3-amino-phenyl) -4-oxo-4-pyrrolidin-1- yl-butyrate ethyl 3- (4-methylamino-3-nitro-phenyl) -4-oxo-4-pyrrolidine 300 mg (8.6 mmol) of 1-yl-butyrate are dissolved in 60 ml of ethyl acetate and 10 ml of methanol and, after addition of 600 mg of Raney nickel, the mixture is hydrogenated with hydrogen at ambient temperature for 2.5 hours. The catalyst is filtered off and the filtrate is evaporated. Yield: 260 mg (94% of theory), _Rf value: 0.28 (silica gel; methylene chloride / ethanol = 19: 1)

. [0297] f 4 - [(5- (pyrrolidin-1-yl - carbonyl - (ethoxycarbonylmethyl) - methylcarbamoyl Ren) -1-methyl -1H- benzimidazol-2-yl) - methyl] - benzonitrile and 4 - [(5- (pyrrolidin-1-yl - carbonyl - (ethoxycarbonylmethyl) - methylene) -1-methyl-2-oxo-1,2-dihydro-quinoxaline-3-yl) - methyl] - Benzonito Lil ethyl 260 mg (0.81 mmol) of 3- (3-amino-4-methylamino-phenyl) -4-cyclopentyl-4-oxo-butyrate and 189 mg (1.0 mmol) of 3- (4-cyano-phenyl) -2-oxo-propionic acid ) Is refluxed for 1 hour in 10 ml of ethanol. The reaction solution is combined with 5 g of silica gel, evaporated and dried. The residue is chromatographed on silica gel, eluting initially with petroleum ether and later with petroleum ether / ethyl acetate 9: 1 and 8: 2. The desired fractions are combined and concentrated by evaporation. Yield: 4-[(5- (pyrrolidin-1-yl-carbonyl- (ethoxycarbonylmethyl) methylene) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile, 100 m
g (28% of theory), R _f value: 0.28 (silica gel; methylene chloride / ethanol = 19: 1) C ₂₆ H ₂₈ N ₄ O ₃ (444.5) Mass spectrum: M ⁺ = 444 and 4-[(5 -(Pyrrolidin-1-yl-carbonyl- (ethoxycarbonylmethyl) methylene)
1-methyl-2-oxo-1,2-dihydro-quinoxaline-3-yl) - methyl] - 52% Benzonito Lil, 200 mg (theoretical _{value), C 27 H 28 N 4} O 4 (472.5) Mass spectrum: . M ⁺ = 472 g 4 - [(5- (pyrrolidin-1-yl - carbonyl - (ethoxycarbonylmethyl) - methylcarbamoyl Ren) -1-methyl -1H- benzimidazol-2-yl) - methyl] - Benzoamijin ethyl in ethanol in the same manner as hydrochloride example 1e 3- [3- (4-cyano - benzyl) -1-methyl-2-oxo-1,2-dihydro - quinoxalin-6-yl] -4-cyclopentyl Prepared from 4-oxo-butyrate and hydrochloric acid / ammonium carbonate. Yield: 21% of theory, C ₂₆ H ₃₁ N ₅ O ₃ x HCl (461.6 / 498.05) Mass spectrum: (M + H) ⁺ = 462

Example 232 4-[(5- (1- (pyridin-2-yl-carbonyl) -cyclopropan-1-yl) -1-methyl-1 H-benzimidazol-2-yl) -methyl] - Benzoamijin hydrochloride a. [1- (4-chlorophenyl) - cyclopropane-l-yl] - to a solution of methanone tetrahydrofuran 200ml solution of 2-bromopyridine 19.6 g (0.124 mol), - pyridin-2-yl A solution of 85 ml (0.141 mol) of n-butyllithium (15% in hexane) is added dropwise at -45 ° C. After 1 hour at -45 ° C., a solution of 21.2 g (0.119 mol) of 1- (4-chloro-phenyl) -1-cyclopropanecarbonitrile in 50 ml of tetrahydrofuran is added dropwise. After heating to ambient temperature, the mixture is poured into ice-water, adjusted to pH 5 with formic acid and extracted with ethyl acetate. The organic extract is washed with a sodium chloride solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (19: 1). The desired fractions are combined and concentrated by evaporation. Yield: 7.2 g (23% of theory), _Rf value: 0.71 (silica gel; methylene chloride / ethanol = 19: 1)

B. [1- (4-Chloro-3-nitro-phenyl) -cyclopropan-1-yl] -pyridin-2- yl-methane [1- (4-chlorophenyl) -Cyclopropan-1-yl] -pyridin-2-yl-methanone and fuming nitric acid. Yield: 28% of theory, _Rf value: 0.73 (silica gel; petroleum ether / ethyl acetate = 1: 1) c. [1- (4-Methylamino-3-nitro-phenyl) -cyclopropane-1- yl] - pyrimidin-2-yl - analogously to methanone example 231d was in isopropanol with [1- (4-chloro-3-nitro --phenyl) - cyclopropane-1-yl] - pyridin-2-yl -Prepared from methanone and methylamine. Yield: 60% of theory. D. 4- [5- (1-hydroxy-pyridin-2-yl-methyl) -cyclopropan-1-yl] -1 -methyl-1H-benzimidazol-2-yl) Methyl] -benzonitrile [1- (4-methylamino-3-) in ethanol in the same manner as in Example 231f and Example 1c.
Prepared from nitro-phenyl) -cyclopropan-1-yl] -pyridin-2-yl-methanone, hydrogen / palladium / activated carbon and 3- (4-cyano-phenyl) -2-oxo-propionic acid. Yield: 10% of _{theory, C 25 H 22 N 4 O} (394.5) Mass spectrum: M ⁺ = 394

. [0300] e 4 - [(5- (l- (pyridin-2-yl - carbonyl) - cyclopropane-1-yl) -1-methylation -1H- benzimidazol-2-yl) - methyl] - Benzonitrile 4- [5- (1-hydroxy-pyridin-2-yl-methyl) -cyclopropan-1-yl] -1-
415 mg (1.0 mmol) of methyl-1H-benzimidazol-2-yl) methyl] -benzonitrile are dissolved in 50 ml of methylene chloride and, after addition of 2.5 g of manganese dioxide, stirred at ambient temperature for 16 hours. The precipitate is filtered off and the mother liquor is concentrated by evaporation. The residue is chromatographed on silica gel, eluting initially with methylene chloride and later with methylene chloride / ethanol (50: 1 and 25: 1). The desired fractions are combined and concentrated by evaporation. Yield: 285 mg (69% of theory), _Rf value: 0.63 (silica gel; methylene chloride / ethanol = 19: 1) f. 4-[(5- (1- (pyridin-2-yl-carbonyl) cyclopropane) -1-yl-1-methyl -1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4- [5- (1- (pyridin-2-yl) in ethanol in the same manner as in Example 1e. -Carbonyl
) -Cyclopropan-1-yl) -1-methyl-1H-benzimidazol-2-yl) -methyl]
Prepared from -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 41% of theory, C ₂₅ H ₂₃ N ₅ O (409.5 / 445.96) Mass spectrum: (M + H) ⁺ = 410

[0301] Example 233 4 - [(5-benzenesulfonylamino - benzoxazol-2-yl) - methyl] - in a manner similar to Ben Zoamijin hydrochloride a 4-benzenesulfonylamino-2-nitrophenol in Example 1d. Prepared from 4-hydroxy-3-nitro-aniline and benzenesulfonic acid chloride in pyridine. Yield: 45% of theory, R _f value: 0.47 (silica gel; methylene chloride / ethanol = 19: 1) b. 4-benzenesulfonylamino-2-amino-phenol 4 in methanol as in Example 1c. Prepared from -benzenesulfonylamino-2-nitrophenol, palladium / activated carbon and hydrogen. Yield: 80% of theory, R _f value: 0.26 (silica gel; methylene chloride / ethanol = 19: 1)

C. 4-[(5-benzenesulfonylamino-benzoxazol-2-yl) -methyl] -benzonitrile 4-benzenesulfonylamino-2-amino-phenol in tetrahydrofuran and sulfolane as in Example 24f And N, N'-carbonyldiimidazole. Yield: 9.8% of theory, R _f value: 0.38 (silica gel; methylene chloride / ethanol = 19: 1) d. 4-[(5-benzenesulfonylamino-benzoxazol-2-yl) -methyl] -benzo Amidine hydrochloride Prepared from 4-[(5-benzenesulfonylamino-benzoxazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol as in Example 1e. Yield: 56% of theory, C ₂₁ H ₁₈ N ₄ O ₃ S x HCl (406.5 / 442.9) Mass spectrum: (M + H) ⁺ = 407 (M + Na) ⁺ = 439 (2 M + H) ⁺ = 813

[0303] Example 234 4 - [(5-(N-ethoxycarbonylmethyl - quinolin-8-yl - sulfonylamino) - Baie Nzochiazoru-2-yl) - methyl] -. Benzoamijin hydrochloride a 4-nitro - 2- (4-cyanophenylmethylcarbonylamino) -fluorobenzene 4-cyanophenylacetic acid (7.0 g, 44.8 mmol) was dissolved in methylene chloride (200 ml) and dimethylformamide (4 drops). Bring to reflux. The solvent is evaporated down i. Vac., The residue is dissolved in 20 ml of chlorobenzene and refluxed with 7.0 g (44.8 mmol) of 2-fluoro-5-nitro-aniline for 15 minutes. The solution is cooled, the precipitated material is filtered off with suction and dried. Yield: 10.9 g (81.5% of theory), _Rf value: 0.18 (silica gel; ethyl acetate / petroleum ether = 3: 7) b. 4- (5-nitro-benzothiazol-2-yl) -methyl-benzo Nitrile 4-nitro-2- (4-cyanophenyl-methylcarbonylamino) -fluorobenzene 1
0.9 g (36.5 mmol), 7.6 g of 2,4-bis- (4-methoxyphenyl) -1,3-dithio-2,4-diphosphetane-2,4-disulfide and 300 ml of toluene are refluxed for 18 hours. The solvent is distilled off, the residue is chromatographed on silica gel and extracted with methylene chloride. The desired fractions are combined and concentrated by evaporation. Yield: 8.2 g (76% of theory), _Rf value: 0.44 (silica gel; ethyl acetate / petroleum ether = 3: 7)

C. 4- (5-Amino-benzothiazol-2-yl) -methyl -benzonitrile 8.8 g (29.8 mimol) of 4- (5-nitro-benzothiazol-2-ylmethyl) -benzonitrile in pyridine Dissolve in 300 ml and at 50 ° C sodium dithionite 15.4 g and water 60
and heat to 95 ° C. for 1 hour. The pyridine is distilled off, the residue is combined with ice water, the precipitated product is filtered off with suction and dried. Yield: 6.9 g (87% of theory) Melting point: 178-180 ° C. R _f value: 0.2 (silica gel; ethyl acetate / petroleum ether = 1: 1) d. 4-[(5- (quinolin-8-yl) -Sulfonylamino) -benzothiazol-2-yl) -methyl] -benzonitrile 4- (5-amino-benzothiazol-2-yl) -methyl-benzonitrile and quinoline in pyridine as in Example 1d Prepared from 8-sulfonyl chloride. Yield: 77% of theory, _Rf value: 0.25 (silica gel; ethyl acetate / petroleum ether / ammonia = 1: 1: 0.01)

E. 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -benzothiazol-2-yl) -methyl] -benzonitrile hydrochloride 4-[(5- ( Quinolin-8-yl-sulfonylamino) -benzothiazol-2-yl) -methyl] -benzonitrile 3.8 g (8.3 mmol), potassium carbonate 5.7 g (41.6 mmol), ethyl bromoacetate 2.3 ml (20.8 mmol) and 1,8-diazabicyclo [5
.4.0.] Dissolve 1.4 ml (9.2 mmol) of undec-7-ene in 200 ml of acetone and reflux for 1 hour. The insolubles are filtered off and the mother liquor is concentrated by evaporation. The residue was chromatographed on silica gel, ethyl acetate / petroleum ether (1: 9, 2: 8 and 3: 8).
Elute in 7). The desired fractions are combined and concentrated by evaporation. Yield: 1.3 g (29% of theory), _Rf value: 0.45 (silica gel; ethyl acetate / petroleum ether / ammonia = 1: 1: 0.01) f. 4-[(5- (N-ethoxycarbonylmethyl-quinoline) -8-yl-sulfonylamino) -benzothiazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (N-ethoxycarbonylmethyl-quinoline-8) in ethanol as in Example 1e. -Yl-sulfonylamino) -benzothiazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 59% of _{theory, C 28 H 25 N 5 O} 4 S 2 x HCl (559.67 / 596.13) Mass ^{spectrum: (M + H) + =} 560

[0306] Example 235 4 - [(5-(N-carboxymethyl - quinolin-8-yl - sulfonylamino) - Benzochia-2-yl) - methyl] - Benzoamijin in the same manner as the hydrochloride salt EXAMPLE 13 Prepared from 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -benzothiazol-2-yl) -methyl] -benzoamidine hydrochloride and sodium hydroxide in ethanol. Yield: 88% of theory, C ₂₆ H ₂₁ N ₅ O ₄ S x HCl (531.62 / 568.08) Mass spectrum: (M + H) ⁺ = 532 (M + Na) ⁺ = 554 Example 236 4- [ (5- (2-methylphenyl) - benzothiazol-2-yl) - methyl] - Benzoamiji down hydrochloride a 4 -. [(5- (2-methylphenyl) - benzothiazol-2-yl) - methyl] - Benzoni tolyl nitrogen atmosphere at 4 - [(5-bromo - benzothiazol-2-yl) - methyl] - benzonitrile 1.3 g (3.95 mmol) and bis (triphenylphosphine) - palladium (
II) 1.3 g (1.1 mmol) of -chloride are stirred at 40 ° C. in 40 ml of toluene for 15 minutes. Then 1.3 g (12.3 mmol) of sodium carbonate in 5.6 ml of water and 5 ml of methanol
0.84 g (6.1 mmol) of o-tolylboric acid are added. The reaction mixture is refluxed for 10 hours. After cooling, the reaction solution is diluted with ethyl acetate and extracted with water. The combined organic extracts are washed with a sodium chloride solution and dried. The residue is chromatographed on silica gel, eluting with ethyl acetate / petroleum ether 5:95, 10:95 and 15:85. The desired fractions are combined and concentrated by evaporation. Yield: 0.55 g (41% of theory), _Rf value: 0.51 (silica gel; ethyl acetate / petroleum ether = 3: 7) b. 4-[(5- (2-methylphenyl) -benzothiazole-2- yl) - methyl] - Benzoa spermidine hydrochloride example 1e and in ethanol 4 in the same manner - [(5- (2-methylphenyl) - benzothiazol-2-yl) - methyl] - benzonitrile and hydrochloric acid / carbonate Prepared from ammonium. Yield: 58% of _{theory, C 22 H 19 N 3 S} x HCl (357.48 / 393.94) Mass ^{spectrum: (M + H) + =} 358

[0307] Example 237 4 - [(5- (quinoline-8-yl - sulfonylamino) - indol-2-yl) - methyl] -. Baie Nzoamijin hydrochloride a 1-methyl-2-tributyltin -1H- indole To a solution of 10.0 g (76.2 mmol) of N-methylindole in 100 ml of tetrahydrofuran is added 30.5 ml (75 mmol) of n-butyllithium (2.5 mol in hexane) dropwise at 0-5 ° C. under a nitrogen atmosphere. . After 2 hours at 0 ° C., the reaction mixture is
Cool to 0 ° C. and add dropwise 24.4 g (75 mmol) of tributyltin chloride. The reaction mixture is heated to ambient temperature overnight and extracted with an ethyl acetate / sodium chloride solution. The combined organic extracts are dried and concentrated by evaporation. The residue is distilled at 196-200 ° C. in vacuo at 9 mbar. Yield: 20.9 g (65.3% of theory), _Rf value: 0.48 (aluminum oxide, petroleum ether) C ₂₁ H ₃₅ NSn (420.219) Mass spectrum: M ⁺ = 417/19/21 (Sn)

B. 4- (1-Methyl-1H-indol-2-yl) -methyl-benzonitrile 1-methyl-2-tributyltin-1H-indole 12.9 g (30.7 mmol), 4- (bromomethyl)- 5.7 g (29.2 mmol) of benzonitrile and 0.34 g of bis- (triphenylphosphine) -palladium-dichloride are refluxed for 2 hours in 90 ml of tetrahydrofuran under a nitrogen atmosphere. After cooling, the mixture is diluted with ethyl acetate and a 15% potassium fluoride solution and stirred overnight at ambient temperature. The precipitate formed is suction filtered and washed with ethyl acetate. The organic phase is washed with sodium chloride solution, dried and
Concentrate by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate / petroleum ether (5:95). The desired fractions are combined and concentrated by evaporation. Yield: 5.9 g (81.4% of theory), _Rf value: 0.41 (silica gel; ethyl acetate / petroleum ether = 3: 7)

C. 4- (1-Methyl-5-nitro-1H-indol-2-yl) -methyl-benzonitrile 4- (1-methyl-1H-indol-2-yl) -methyl-benzonitrile6.9 g (28 mmol) in 50 ml of concentrated sulfuric acid. At 2 ° C., 2.9 g (28 mmol) of potassium nitrate are added in several portions, after which the temperature rises to 10 ° C. After 30 minutes at 2 ° C., the mixture is poured onto ice, the precipitated product is filtered off with suction, washed with ice-water, dried and recrystallized from acetone. Yield: 5.2 g (63.7% of theory), _Rf value: 0.17 (silica gel; ethyl acetate / petroleum ether = 3: 7) d. 4- (1-methyl-5-amino-1H-indol-2-yl) ) -Methyl-benzonitrile 4- (1-methyl-5-nitro-1) in methylene chloride / methanol analogously to Example 1c.
Prepared from H-indol-2-yl) -methyl-benzonitrile, palladium / activated carbon and hydrogen. Yield: 90% of theory, R _f value: 0.34 (silica gel; ethyl acetate / petroleum ether = 5: 5)

E. 4-[(5- (quinolin-8-yl-sulfonylamino) -1-methyl-indol-2-yl ) -methyl] -benzonitrile 4- (1- Methyl-5-amino-1H-indol-2-yl) -methyl-
Prepared from benzonitrile and quinoline-8-sulfonic acid chloride. Yield: 51% of theory, _Rf value: 0.49 (silica gel; methylene chloride / ethanol = 19: 1) f. 4-[(5- (quinolin-8-yl-sulfonylamino) -1-methyl-indole 2- (yl ) -methyl] -benzamidine hydrochloride 4-[(5- (quinolin-8-yl-sulfonylamino) -1-methyl-indol-2-yl) in ethanol as in Example 1e -Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 30% of theory, R _f value: 0.24 (silica gel; methylene chloride / ethanol / glacial acetic acid = 4: 1: 0.01) C ₂₆ H ₂₃ N ₄ O ₂ S x HCl (469.57 / 506.03) Mass spectrum: (M + H) ⁺ = 470

Example 238 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1- methyl-indol-2-yl) -methyl] -benzamidine hydrochloride Example 1e 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1-methyl-indol-2-yl) -methyl] -benzonitrile and hydrochloric acid / carbonic acid in ethanol Prepared from ammonium. Yield: 71% of theory, R _f value: 0.26 (silica gel; methylene chloride / ethanol / glacial acetic acid = 4: 1: 0.01) C ₃₀ H ₂₉ N ₅ O ₄ S × HCl (555.66 / 592.12) Mass spectrum: (M + H) ⁺ = 556 (M + 2H) ⁺⁺ = 278.8 (M + Na + H) ⁺⁺ = 289.8 Example 239 4-[(5- (N-carboxymethyl-quinolin-8-yl-sulfonyl) amino) -1-methyl - Lee Ndoru-2-yl) - methyl] - Benzoamijin hydrochloride example 13 in the same manner as in ethanol 4 - [(5-(N-ethoxycarbonylmethyl - quinolin-8-yl -Sulfonylamino) -1-methyl-indol-2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 23% of theory, R _f value: 0.14 (silica gel; methylene chloride / ethanol / glacial acetic acid = 4: 1: 0.01) C ₂₈ H ₂₅ N ₅ O ₄ S x HCl (527.61 / 564.07) Mass spectrum: (M + H) ⁺ = 528 (M + Na) ⁺ = 550

[0312] Example 240 4 - [(5-benzenesulfonylamino-1-methyl - indol-2-yl) - methyl] - base Nzoamijin hydrochloride Example 1e and in ethanol 4 in the same manner - [(5- Benzenesulfonylamino-1-methyl-indol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 20% of theory, R _f value: 0.26 (silica gel; methylene chloride / ethanol / glacial acetic acid = 4: 1: 0.01) C ₂₃ H ₂₂ N ₄ O ₂ S x HCl (418.52 / 454.98) Mass spectrum: (M + H) ⁺ = 419 Example 241 4-[(5- (N- (ethoxycarbonylmethylaminocarbonylmethyl) -quinolin-8- yl-sulfonylamino) -1-methyl-indol-2-yl)- methyl] - Benzoamiji down hydrochloride example 1e and in ethanol 4 in the same manner - [(5- (N- (ethoxycarbonylmethyl aminocarbonylmethyl) - quinolin-8-yl - sulfonylamino-1-methyl - in Dole 2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate Yield: 52% of theory, R _f value: 0.22 (silica gel; methylene chloride / ethanol = 4: 1) C ₃₂ H ₃₂ N ₆ O ₅ S x HCl (612.71 / 649.17) Mass spectrum: (M + H) ⁺ = 613.

Example 242 4-[(5-n-propanesulfonylamino-1-methyl-indol-2-yl) -methyl] -benzamidine hydrochloride In ethanol as in Example 1e, 4-[(( 5-n-propanesulfonylamino-1-
Methyl-indol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 71% of theory, R _f value: 0.21 (silica gel; methylene chloride / ethanol = 4: 1) C ₂₀ H ₂₄ N ₄ O ₂ S x HCl (384.51 / 420.97) Mass spectrum: (M + H) ⁺ = 385 Example 243 4-[(5- (N-ethoxycarbonylmethyl-n-propanesulfonylamino) -1-methyl- indol-2-yl) -methyl] -benzamidine hydrochloride As in Example 1e. In ethanol, 4-[(5- (N-ethoxycarbonylmethyl-n
-Propanesulfonylamino-1-methyl-indol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 66% of theory, R _f value: 0.52 (silica gel; methylene chloride / ethanol = 4: 1) C ₂₄ H ₃₀ N ₄ O ₄ S x HCl (470.60 / 507.06) Mass spectrum: (M + H) ⁺ = 471

[0314] Example 244 4 - [(5-(N-carboxymethyl-aminocarbonyl-methyl - quinolin-8-yl - sulfo Niruamino) -1-methyl - indol-2-yl) - methyl] - Benzoamijin hydrochloride [ 4-[(5- (N-ethoxycarbonylmethylaminocarbonylmethyl-quinolin-8-yl-sulfonylamino-1-methyl-indol-2-yl) -methyl] -benzo in ethanol as in Example 13 was prepared from amidine hydrochloride and the sodium hydroxide yields:. 93% of _{theory, C 30 H 28 N 6 O} 5 S x HCl (584.66 / 621.12) mass ^{spectrum: (M + H) + =} 585

[0315] Example 245 4 - [(5-(N-carboxymethyl -n- propane sulfonylamino) -1-methyl - indole-2-yl) - methyl] - in analogy to Benzoamijin hydrochloride Example 13 In ethanol, 4-[(5- (N-ethoxycarbonylmethyl-n
-Propanesulfonylamino) -1-methyl-indol-2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 86% of theory, R _f value: 0.17 (silica gel; methylene chloride / ethanol = 4: 1) C ₂₂ H ₂₆ N ₄ O ₄ S x HCl (442.54 / 479.60) Mass spectrum: (M + H) ^{+ = 443 (M + Na)} + = 465 example 246 4 - [(5-(N-ethoxycarbonylmethyl -n- butane sulfonylamino) -1-methyl - Lee Ndoru-2-yl) - methyl] - benzo Amidine hydrochloride 4-[(5- (N-ethoxycarbonylmethyl-n
-Butanesulfonylamino) -1-methyl-indol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 71% of theory, R _f value: 0.25 (silica gel; methylene chloride / ethanol = 4: 1) C ₂₅ H ₃₂ N ₄ O ₄ S x HCl (484.62 / 521.08) Mass spectrum: (M + H) ⁺ = 485

Example 247 4-[(5- (N-carboxymethyl-n-butanesulfonylamino) -1-methyl-indol- 2-yl) -methyl] -benzamidine hydrochloride In the same manner as in Example 13 4-((5- (N-ethoxycarbonylmethyl-n
-Butanesulfonylamino) -1-methyl-indol-2-yl) -methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 68% of theory, R _f value: 0.25 (silica gel; methylene chloride / ethanol = 4: 1) C ₂₃ H ₂₈ N ₄ O ₄ S x HCl (456.57 / 493.03) Mass spectrum: (M + H) ⁺ = 457 (M + Na) ⁺ = 479 Example 248 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1- methyl-indol-2-yl) -methyl] -N '-(methoxycarbonyl) benzamidine 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1-methyl-indole-2 in tetrahydrofuran analogously to Example 97. -Yl) -methyl] -benzamidine hydrochloride, methyl chloroformate and potassium carbonate. Yield: 85% of _{theory, C 32 H 31 N 5 O} 6 S (613.70) Mass ^{spectrum: (M + H) + =} 614 (M + Na) + = 636

Example 249 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1- methyl-indol-2-yl) -methyl] -N ′-(2-methane sulfonyl - Echiruokishika carbonyl) Benzoamijin 4 - [(5-(N-ethoxycarbonylmethyl - quinolin-8-yl - sulfonylamino) -1
-Methyl-indol-2-yl) -methyl] -benzamidine hydrochloride 300 mg (0.5 mmol), 2- (methylsulfonyl) -ethyl-4-nitrophenyl carbonate 170 mg (0.6 mg)
Mmol) and 210 mg (1.5 mmol) of potassium carbonate are stirred at ambient temperature in 30 ml of tetrahydrofuran for 5 hours. Then the reaction mixture is filtered and the mother liquor is concentrated by evaporation. The residue is taken up in methylene chloride and washed with sodium hydrogen carbonate solution.
The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on aluminum oxide, eluting with methylene chloride / ethanol (99: 1). Yield: 150 mg (43% of _{theory), C 34 H 35 N 5} O 8 S 2 (705.81) Mass ^{spectrum: (M + H) + =} 706 (M + Na) + = 728

[0318] Example 250 4 - [(5-(N-ethoxycarbonylmethyl - quinolin-8-yl - sulfonylamino-1-methylation - indol-2-yl) - methyl] -N, N-dimethyl-benzo amidine 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1
450 mg (0.76 mmol) of -methyl-indol-2-yl) -methyl] -benzamidine are suspended in 15 ml of tetrahydrofuran and combined at 5 ° C. with 0.11 ml (1.0 mmol) of 2-bromoethyl chloroformate. After 10 minutes, the mixture is extracted with ethyl acetate and sodium chloride solution, the combined organic extracts are dried and concentrated by evaporation. The residue is taken up in 10 ml of tetrahydrofuran and stirred with 5 ml of dimethylamine at ambient temperature for 18 hours. After evaporation of the solvent, the residue is chromatographed on aluminum oxide, eluting with methylene chloride + 1-2% ethyl acetate. Yield: 150 mg (34% of _{theory), C 32 H 33 N 5} O 4 S (583.71) Mass ^{spectrum: (M + H) + =} 584

Example 251 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -1- methyl-indol-2-yl) -methyl]-(methylcarbonyloxy- (methyl ) methylcarbamoyl alkyleneoxy carbonyl) -. Benzoamijin a carboxylic acid - (1-chloroethyl-4-nitrophenyl) - ester of methylene chloride 300ml and pyridine 7.2 g (91 mmol) in p- nitrophenol 1
To 2.6 g (90 mmol) of the solution, 14.2 g (99 mmol) of 1-chloroethyl chloroformate are added dropwise at -10 ° C. The solution is stirred at ambient temperature for 72 hours, then extracted with water and 0.5% sodium hydroxide solution. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on aluminum oxide, eluting with methylene chloride. The combined fractions are concentrated by evaporation, triturated with petroleum ether and suction filtered. Yield: 7.3 g (33% of theory), _Rf value: 0.58 (silica gel; ethyl acetate / petroleum ether = 3: 7)

B. 7.2 g (29.3 mmol) of 1- (4-nitro-phenoxycarbonyloxy) -ethylacetatecarboxylate- (1-chloroethyl-4-nitrophenyl) -ester and 10.9 g of mercury (II) acetate ( (34.2 mmol) at ambient temperature in 200 ml of glacial acetic acid for 16 hours. Then the mixture is evaporated to dryness, the residue is chromatographed on silica gel and extracted with methylene chloride. Yield: 4.2 g (53% of theory), _Rf value: 0.48 (silica gel; methylene chloride) c. 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl) -sulfonylamino ) -1 - methyl - indol-2-yl] - methyl] -N- (methyl carbonyloxy - (methylation) - methylene - oxycarbonyl) - Benzoamijin 4 - [(5-(N-ethoxycarbonylmethyl - quinolin-8 Yl) -sulfonylamino)-
1-methyl-indol-2-yl] -methyl] -benzamidine hydrochloride 300 mg (0.5 mmol), methylene chloride 25 ml, 1- (4-nitro-phenoxycarbonyloxy) -ethyl acetate 150 mg (0.55 mmol) and N- 0.18 ml (1 mmol) of ethyldiisopropylamine are stirred at ambient temperature for 18 hours. The solvent is distilled off and the residue is chromatographed on aluminum oxide, methylene chloride / ethanol (99: 1).
Elute with The desired fractions are combined and concentrated by evaporation. Yield: 220 mg (65% of _{theory), C 35 H 35 N 5} O 8 S (685.76) Mass ^{spectrum: (M + H) + =} 686 (M + Na) + = 708

[0321] Example 252 4 - [(5-(N-hydroxyamino carbonyl methyl - quinolin-8-yl - Suruhonirua amino) -1-methyl - indol-2-yl) - methyl] -N- hydroxy-benzo amidine 4-[(5- (N-ethoxycarbonylmethyl-quinolin-8-yl) -sulfonylamino-1
540 mg (1 mmol) of -methyl-indol-2-yl) -methyl] -benzonitrile are refluxed for 5 hours with 278 mg (4 mmol) of hydroxylamine hydrochloride, 205 mg (4 mmol) of sodium carbonate, 14 ml of methanol and 2 ml of water. The solvent is distilled off and the residue is chromatographed on silica gel, methylene chloride / 1 to 1
Elute with 5% ethanol. The desired fractions are combined and concentrated by evaporation. Yield: 250 mg (44.6% of _{theory), C 28 H 26 N 6} O 5 S (558.61) Mass ^{spectrum: (M + H) + =} 559 (M + Na) + = 581

Example 253 4-[(5- (N-isopropyloxycarbonylmethyl-quinolin-8-yl-sulfonylamino ) -1-methyl-indol-2-yl) -methyl] -benzamidine hydrochloride 4- ((5- (N-carboxymethyl-quinolin-8-yl) -sulfonylamino) -1-methyl
-Indol-2-yl) -methyl] -benzamidine hydrochloride (420 mg, 0.75 mmol) is dissolved in 10 ml of isopropanol and refluxed. Then hydrogen chloride gas is introduced for 30 minutes. The reaction mixture is concentrated by evaporation, the residue is triturated with ether,
Wash with acetone. Yield: 450 mg (100% of _{theory), C 31 H 31 N 5} O 4 S x HCl (569.70 / 606.16) Mass ^{spectrum: (M + H) + =} 570

[0323] EXAMPLE 254 4 - [(5- (N- (2- hydroxyethyl butyloxycarbonylmethyl) - quinolin-8-yl) - scan Ruhoniruamino) -1-methyl - indol-2-yl) - methyl] - in the same manner as Benzoamijin hydrochloride example 253 4 - [(5-(N-carboxymethyl-8-yl - sulfo Niruamino) -1-methyl - indol-2-yl) - methyl] - Benzoamijin hydrochloride Prepared from ethylene glycol monobenzyl ether and hydrogen chloride gas. Yield: 11% of _{theory, C 30 H 29 N 5 O} 5 S x HCl (571.66 / 608.12) Mass ^{spectrum: (M + H) + =} 572 Example 255 4 - [(5-(N-carboxymethyl - quinolin-8-yl - sulfonylamino) -1-methyl - Lee Ndoru-2-yl) - methyl] -N- hydroxy-benzo amidine 4 - [(5-(N-carboxymethyl - quinolin-8-yl - sulphonyl Reflux 260 mg (0.5 mmol) of amino-1-methyl-indole-2-yl) -methyl] -benzonitrile with 14 ml of methanol, 139 mg of hydroxylamine hydrochloride, 105 mg of sodium carbonate and 1 ml of water for 24 hours. The residue is mixed with water, acidified with hydrochloric acid, the precipitated material is filtered off with suction and dried The crude product is chromatographed on silica gel, eluting with methylene chloride / 6-30% ethanol. The desired fractions are combined and concentrated by evaporation Yield: 180 mg (theory _{67%), C 28 H 25 N 5} O 5 S (543.61) Mass ^{spectrum: (M + H) + =} 544 (M + Na) + = 566

[0324] Example 256 4 - [(5-(N-ethoxycarbonylmethyl - quinolin-8-yl - sulfonylamino-1-methylation - indol-2-yl) - methyl) -N, N-bis - ( n- octyloxy carbonyl) - 4 in tetrahydrofuran in the same manner as base Nzoamijin example 97 - [(5-(N-ethoxycarbonylmethyl - quinolin-8-yl - sulfonylamino) -1-methyl - indol-2 Yl) -methyl] -benzamidine hydrochloride, n-octyl chloroformate and potassium carbonate. Yield: 19% of theory, C ₄₈ H ₆₁ N ₅ O ₈ S (868.11) Mass spectrum: (M) ⁺ = 868 Example 257 4-[(5- (N-ethoxycarbonylmethyl-quinoline-8- Yl-sulfonylamino) -1- methyl-indol-2-yl) -methyl] -N- (n-octyloxycarbonyl) -benzamidine In tetrahydrofuran, 4-((5- (N -Ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino-1-methyl-indol-2-yl) -methyl] -benzamidine hydrochloride, n-octyl chloroformate and potassium carbonate. 16% of theory, C ₃₉ H ₄₅ N ₅ O ₆ S (711.89) Mass spectrum: (M + H) ⁺ = 712 (M + H + Na) ⁺⁺ = 367.7

Example 258 4-[(5- (Methoxycarbonylmethyloxymethyl) carbonyl-N-cyclopentyl -amino-1-methyl-indol-2-yl) -methyl] -benzamidine hydrochloride As in Example 1e Prepared from 4-[(5- (methoxycarbonylmethyloxymethyl) carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in methanol. Yield: 49% of theory, C ₂₇ H ₃₂ N ₄ O ₄ x HCl (476.58 / 513.04) Mass spectrum: (M + H) ⁺ = 477 (M + 2H) ⁺⁺ = 239 (M + H + Na ) ⁺⁺ = 250

Example 259 4-[(5- (Ethoxycarbonylmethylamino) carbonyl-N-cyclopentylamino- 1-methyl-indol-2-yl) -methyl] -benzamidine hydrochloride In the same manner as in Example 1e. Prepared from 4-[(5- (ethoxycarbonylmethylamino) carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol. Yield: 79% of _{theory, C 27 H 33 N 5 O} 3 x HCl (475.6 / 512.06) Mass ^{spectrum: (M + H) + =} 476 (M + H + Na) ++ = 250 Example 260 4 - [(5- (carboxymethyl amino) carbonyl -N- cyclopentylamino-1-methylation - indol-2-yl) - methyl] - Benzoamijin hydrochloride example 13 in the same manner as 4 in ethanol - [( 5- (ethoxycarbonylmethylamino) carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl) -methyl] -benzoamidine hydrochloride and sodium hydroxide. Yield: 79 percent of _{theory, C 25 H 29 N 5 O} 3 x HCl (447.54 / 484.0) Mass ^{spectrum: (M + H) + =} 448 (M + Na) + = 470 (M + H + Na) ⁺⁺ = 235.6

Example 261 4-[(5- (Carboxymethyloxymethyl) carbonyl-N-cyclopentylamino-1 -methyl-indol-2-yl) -methyl] -benzamidine hydrochloride In the same manner as in Example 13. Prepared from 4-[(5- (ethoxycarbonylmethyloxymethyl) carbonyl-N-cyclopentylamino-1-methyl-indol-2-yl) -methyl] -benzoamidine hydrochloride and sodium hydroxide in ethanol. Yield: 43% of theory, C ₂₆ H ₃₀ N ₄ O ₄ x HCl (462.55 / 499.01) Mass spectrum: (M + H) ⁺ = 463 (M + 2H) ⁺⁺ = 232 (M + H + Na ) ⁺⁺ = 243

Example 262 4-[(6- (Quinolin-8-yl) -sulfonylamino-3-methyl-benzofuran-2-yl) -methyl] -benzamidine hydrochloride a. 3-Methyl-2-tributyltin - benzofuran example 237a and to 3-methylbenzofuran was prepared in the same manner as the n- butyl lithium and tributyltin chloride in tetrahydrofuran. Yield: 100% of theory, R _f value: 0.73 (silica gel; petroleum ether) C ₂₁ H ₃₄ OSn (421.19) Mass spectrum: M ⁺ = 422 b. 4- (3-methyl-benzofuran-2-yl) Methyl-benzonitrile 3-methyl-2-tributyltin in tetrahydrofuran as in Example 237b
Prepared from benzofuran, 4- (bromomethyl) -benzonitrile and bis (triphenylphosphine) -palladium (II) -chloride. Yield: 49% of theory, R _f value: 0.57 (silica gel; petroleum ether / ethyl acetate = 4: 1)

C. 4- (3-Methyl-6-nitro -benzofuran-2-yl) methyl-benzonitrile 4.3 g (17.4 mmol) of 4- (3-methyl-benzofuran-2-yl) methyl-benzonitrile Is dissolved in 50 ml of methylene chloride and mixed at -50 ° C. with a solution of 9.0 g (34.8 mmol) of tin (IV) chloride in 22 g (34.8 mmol) of fuming nitric acid within 30 minutes. After 2 hours at -50 ° C, the mixture is extracted with methylene chloride and water. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluted with methylene chloride, the desired fractions are combined and concentrated by evaporation. Yield: 2.5 g (49% of theory), _Rf value: 0.79 (silica gel; methylene chloride) d. 4- (3-methyl-6-amino-benzofuran-2-yl) methyl-benzonitrile Example 189d Similarly, in methanol / methylene chloride, 4- (3-methyl-6-nitro
-Benzofuran-2-yl) methyl-benzonitrile and Raney nickel / hydrogen. Yield: 64% of theory, R _f value: 0.25 (silica gel; methylene chloride)

. [0330] e 4 - [(6- (quinolin-8-yl - sulfonylamino) -3-methyl - benzofuran-2 b le) - methyl] - 4 in pyridine in the same way as benzonitrile Example 1d Prepared from-(3-methyl-6-amino-benzofuran-2-yl) methyl-benzonitrile and quinoline-8-sulfonic acid chloride. Yield: 17% of theory, R _f value: 0.66 (silica gel; methylene chloride / ethanol = 95: 5) f. 4-[(6- (quinolin-8-yl-sulfonylamino) -3-methyl-benzofuran 2-b Le) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(6- (quinolin-8-yl - sulfonylamino) -3-methyl - benzofuran-2-yl ) -Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 59% of _{theory, C 26 H 22 N 4 O} 3 S x HCl (470.56 / 507.03) Mass ^{spectrum: (M + H) + =} 471

Example 263 4-[(6- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -3- methyl-benzofuran-2-yl) -methyl] -benzoamidine hydrochloride Example 1e 4-[(6- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -3-methyl-benzofuran-2-yl) -methyl] in ethanol in the same manner as
Prepared from -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 41% of _{theory, C 30 H 28 N 4 O} 5 S x HCl (556.65 / 593.12) Mass ^{spectrum: (M + H) + =} 557 (M + 2H) ++ = 279 (M + H + Na) ⁺⁺ = 290 example 264 4 - [(6- (N-carboxymethyl - quinolin-8-yl - sulfonylamino) -3-methyl - base Nzofuran-2-yl) - methyl] - Benzoamijin hydrochloride 4-[(6- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino-3-methyl-benzofuran-2-yl) -methyl] -methyl in ethanol in the same manner as in Example 13.
Prepared from benzamidine hydrochloride and sodium hydroxide. Yield: 83% of theory, C ₂₈ H ₂₄ N ₄ O ₅ S x HCl (528.6 / 565.06) Mass spectrum: (M + H) ⁺ = 529 (M + Na) ⁺ = 551 (M + H + Na ) ⁺⁺ = 276

Example 265 4-[(6- (quinolin-8-yl-sulfonylamino) -3-bromo-benzofuran-2-yl) -methyl] -benzamidine hydrochloride a. 4- (benzofuran-2- Il) Methyl-benzonitrile 2-coumaranone (10.4 g, 77.3 mmol) was dissolved in xylene (200 ml), and 4-cyano-benzyl-triphenylphosphonium chloride (32 g, 77.3 mmol) and potassium-t
After addition of 8.7 g (77.3 mmol) of ert. butoxide, the mixture is refluxed for 3 hours under a nitrogen atmosphere. The solvent is distilled off, the residue is taken up in ethyl acetate, combined with silica gel and concentrated by evaporation. It is then chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (8: 2). Combine the desired fractions and concentrate by evaporation. Yield: 17.0 _g (94% of theory), _Rf value: 0.5 (silica gel; petroleum ether / ethyl acetate = 4: 1)

B. 4- (3-Bromo -benzofuran-2-yl) methyl-benzonitrile 1.2 g of 4- (benzofuran-2-yl) methyl-benzonitrile in 25 ml of methylene chloride (
(5 mmol) is added dropwise at 2 ° C. a solution of 0.8 g (5 mmol) of bromine in 5 ml of carbon tetrachloride. The solution is stirred at 2 ° C. for 90 minutes, the precipitate formed is suction filtered, washed with a little methylene chloride and dried. Yield: 1.1 g (70% of theory), _Rf value: 0.57 (silica gel; petroleum ether / ethyl acetate = 4: 1) c. 4- (3-bromo-6-nitro-benzofuran-2-yl) methyl - in the same manner as benzonitrile example 262c in methylene chloride 4- (3-bromo - benzofuran-2-yl)
Prepared from methyl-benzonitrile and tin (IV) chloride / fuming nitric acid. Yield: 30% of theory, R _f value: 0.71 (silica gel; methylene chloride)

D. 4- (6-Amino-3-bromo-benzofuran-2-yl) methyl-benzonitrile 4- (3-bromo-6-nitro) in methylene chloride / methanol analogously to Example 189d.
-Benzofuran-2-yl) methyl-benzonitrile and Raney nickel / hydrogen. Yield: 59% of theory, R _f value:. 0.25 (silica gel; methylene chloride) e 4 - [(6- (quinolin-8-yl - sulfonylamino) -3-bromo - benzofuran-2-b le) -Methyl] -benzonitrile Prepared as in Example 1d from 4- (6-amino-3-bromo-benzofuran-2-yl) methyl-benzonitrile and quinoline-8-sulfonic acid chloride in pyridine. Yield: 93% of theory, R _f value: 0.7 (silica gel; methylene chloride / ethanol = 95: 5) f. 4-[(6- (quinolin-8-yl-sulfonylamino) -3-bromo-benzofuran 2-b Le) - methyl] - Benzoamijin hydrochloride example 1e and in ethanol 4 in the same manner - [(6- (quinolin-8-yl - sulfonylamino) -3-bromo - benzofuran-2-yl ) -Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 42% of theory, C ₂₅ H ₁₉ BrN ₄ O ₃ S × HCl (535.44 / 571.9) Mass spectrum: (M + H) ⁺ = 535/5 (Cl)

Example 266 4-[(6- (1,2,3,4-tetrahydroquinolin-8-yl-sulfonylamino) -3-bromo- benzofuran-2-yl) -methyl] -benzoamidine and 4 - [(6- (1,2,3,4 Tetorahi Dorokinorin 8-yl - sulfonylamino) - benzofuran-2-yl) - methyl] - Ben Zoamijin 4 - [(6- (quinolin-8-yl - Sulfonylamino) -3-bromo-benzofuran-2-yl
0.18 g (0.336 mmol) of) -methyl] -benzamidine hydrochloride are dissolved in 10 ml of methanol and hydrogenated with hydrogen for 60 minutes after addition of 200 mg of palladium on activated carbon. The catalyst is filtered off and the solvent is concentrated by evaporation. The residue is chromatographed on silica gel, methylene chloride / ethanol / glacial acetic acid 95: 5: 0.1 and 90: 1.
Elute at 0: 0.1. The desired fractions are combined and concentrated by evaporation. Yield: 30 mg (18% of _{theory), C 25 H 23 BrN 4} O 3 S (539.47) Mass ^{spectrum: (M2 + H) + =} 539/41 (Br) C 25 H 24 N 4 O 3 (460.57) Mass spectrum: (M1 + H) ⁺ = 461 (as a 1: 1 mixture)

Example 267 4-[(6- (N-ethoxycarbonylmethyl-quinolin-8-yl) -sulfonylamino) -3- bromo-benzofuran-2-yl] -methyl] -benzamidine hydrochloride a. 4-[(6- (N-ethoxycarbonylmethyl-quinolin-8-yl) -sulfonylamino- 3-bromo-benzofuran-2-yl) -methyl] -benzonitrile 4-[(6- (quinolin-8 -yl 1.0 g (2 mmol) of yl-sulfonylamino) -3-bromo-benzofuran-2-yl] -methyl] -benzonitrile in 20 ml of anhydrous tetrahydrofuran
And, after addition of 100 mg (2 mmol) of sodium hydride (50% in oil), stir for 20 minutes at ambient temperature. Then 0.22 ml (2 mmol) of ethyl bromoacetate
Is added under a nitrogen atmosphere. The reaction mixture is refluxed for 6 hours, cooled, diluted with ethyl acetate and washed with sodium chloride solution. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (90:10 and 75:25). The desired fractions are combined and concentrated by evaporation. Yield: 420 mg (35% of theory), _Rf value: 0.55 (silica gel; petroleum ether / ethyl acetate = 1: 1) b. 4-[(6- (N-ethoxycarbonylmethyl-quinolin-8-yl- Sulfonylamino) -3-bromo-benzofuran-2-yl) -methyl] -benzamidine hydrochloride 4-[(6- (N-ethoxycarbonylmethyl-quinolin-8-yl) in ethanol in the same manner as in Example 1e. -Sulfonylamino) -3-bromo-benzofuran-2-yl) -methyl]
Prepared from -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 43% of _{theory, C 29 H 25 BrN 4 O} 5 S x HCl (621.53 / 658.0) Mass ^{spectrum: (M + H) + =} 621/23 (Br)

Example 268 4-[(6- (N-carboxymethyl-quinolin-8-yl-sulfonylamino) -3-ethoxy- benzofuran-2-yl) -methyl] -benzamidine hydrochloride Example 13 Similarly, in ethanol, 4-[(6- (N-ethoxycarbonylmethyl-quinolin-8-yl-sulfonylamino) -3-bromo-benzofuran-2-yl) -methyl]
-Prepared from benzamidine hydrochloride and sodium hydroxide. Yield: 90% of _{theory, C 29 H 26 N 4 O} 6 S x HCl (558.63 / 595.09) Mass ^{spectrum: (M + H) + =} 559 (M + Na) + = 581.6

Example 269 4-[(5- (2-ethoxycarbonyl-ethyl-benzimidazol-1-yl) methyl-1- methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine hydrochloride a. Ethyl 3- (1H-benzimidazol-2-yl) -propionate Suspension of 10 g (52.5 mmol) of 2-benzoimidazole-propionic acid refluxing hydrogen chloride gas in 250 ml of absolute ethanol for 1 hour. Introduce into the liquid. The mixture is then concentrated by evaporation, the residue is dissolved in water and made alkaline with concentrated ammonia. Then it is extracted with ethyl acetate and the combined organic extracts are washed with water, dried and concentrated by evaporation. Yield: 10.2 g (89% of theory)

. [0339] b Ethyl 3- [1- (4-chloro-3-nitro - benzyl)-1H-benzimidazol-2-y le] - propionate Example 231b and ethyl dimethyl sulfoxide in the same manner as 3- ( Prepared from 1H-benzimidazol-2-yl) -propionate, 4-chloro-3-nitro-benzyl ester methanesulfonate and potassium tert. Butoxide. Yield: 75% of theory, _Rf value: 0.54 (silica gel; methylene chloride / ethanol = 19: 1) c. N-methyl-3- [1- (4-methylamino-3-nitro-benzyl)- 1H- benzo imidazole-2-yl] - propionamide example 7b and ethyl at 80 ° C. in the same manner 3- [1- (4-chloro-3-nitro - benzyl)-1H-
Benzimidazol-2-yl] -propionate and methylamine solution. Yield: 99% of theory, R _f value: 0.21 (silica gel; methylene chloride / ethanol = 19: 1)

. [0340] d 3- [1- (4-methylamino-3-nitro - benzyl)-1H-benzimidazol-2-y le] - propionic acid N- methyl-3- [1- (4-methylamino- 4.5 g (12.2 mmol) of 3-nitro-benzyl) -1H-benzimidazol-2-yl] -propionamide are stirred in 100 ml of half-concentrated hydrochloric acid at 100 ° C. for 3 hours. The mixture is then cooled and the precipitated product is filtered off with suction, washed with water and dried. Yield: 4.1 g (95% of theory), _Rf value: 0.12 (silica gel; methylene chloride / ethanol = 19: 1) e. Ethyl 3- [1- (4-methylamino-3-nitrobenzyl) -1H - benzimidazol - 2-yl] - in propionate ethanol 3- [1- (4-methylamino-3-nitro - benzyl)-1H-benzimidazol-2-yl] - was prepared from propionic acid and hydrochloric acid gas. Yield: 93% of theory, R _f value: 0.33 (silica gel; methylene chloride / ethanol = 19: 1)

F. Ethyl 3- [1- (3-amino-4-methylamino-benzyl) -1H-benzimidazol- 2-yl] -propionate Similar to Example 1c, (1- (4-methylamino-
Prepared from 3-nitro-benzyl) -1H-benzimidazol-2-yl] -propionate and palladium / activated carbon. Yield: 100% of theory g. 4-[(5- (2-ethoxycarbonyl-ethyl-benzimidazol-1-yl) methyl -1-methyl-1H-benzimidazol-2-yl) -methyl] -methyl Benzonitrile Ethyl 3- [1- (3-amino-4-methylamino-benzyl) -1H-benzimidazol-2-yl] -propionate, 4-cyanoate in tetrahydrofuran and glacial acetic acid as in Example 24f Prepared from -phenylacetic acid and N, N'-carbonyldiimidazole.
Yield: 100% of theory h. 4-[(5- (2-ethoxycarbonyl-ethyl-benzimidazol-1-yl) methyl -1-methyl-1H-benzimidazol-2-yl) -methyl] -methyl Benzoamidine hydrochloride 4-[(5- (2-ethoxycarbonyl-ethyl-
(Benzimidazol-1-yl) methyl-1-methyl-1H-benzimidazol-2-yl)-
Methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 58% of _{theory, C 29 H 30 N 6 O} 2 x HCl (494.6 / 531.07) Mass ^{spectrum: (M + H) + =} 495 (M + 2H) ++ = 248 (2M + H) + = 989

Example 270 4-[(5- (2-Carboxy-ethyl-benzimidazol-1-yl) methyl-1-methyl-1H -benzimidazol-2-yl) -methyl] -benzamidine hydrochloride 4-[(5- (2-ethoxycarbonyl-ethyl-ethyl) in ethanol in the same manner as in Example 13.
(Benzimidazol-1-yl) methyl-1-methyl-1H-benzimidazol-2-yl)-
Methyl] -benzamidine hydrochloride and sodium hydroxide. Yield: 78% of theory, C ₂₇ H ₂₆ N ₆ O ₂ x HCl (466.55 / 503.01) Mass spectrum: (M + H) ⁺ = 467 (M + Na) ⁺ = 489

Example 271 4-[(5-Imidazol-1-yl-methyl) -1-methyl-1H-benzimidazol-2-yl ] -methyl] -benzamidine hydrochloride Ethanol was prepared in the same manner as in Example 1e. In the 4-[(5-imidazol-1-yl-methyl-1-
Methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 52% of _{theory, C 20 H 20 N 6 x} HCl (344.4 / 380.9) Mass ^{spectrum: (M + H) + =} 345 (M + 2H) ++ = 173 Example 272 4 - [(5 -(2-Ethyl-4-methyl-imidazol-1-yl-methyl) -1-methyl-1H- benzimidazol-2-yl) -methyl] -benzamidine dihydrochloride in ethanol as in Example 1e From 4-[(5- (2-ethyl-4-methyl-imidazol-1-yl-methyl) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate Prepared. Yield: 30% of theory, C ₂₃ H ₂₆ N ₆ × 2 HCl (386.5 / 459.42) Mass spectrum: (M + H) ⁺ = 387 (M + 2H) ⁺⁺ = 194

Example 273 4-[[5- (1-Methyl-pyrazol-5-yl-carbonyl-cyclopropan-1-yl) -1- methyl-1H-benzimidazol-2-yl] -methyl] -methyl Benzoamidine hydrochloride 4-[[5- (1-Methyl-pyrazol-5-yl-)-ethanol in the same manner as in Example 1e.
Carbonyl-cyclopropan-1-yl) -1-methyl-1H-benzimidazol-2-yl] -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 14% of theory, C ₂₄ H ₂₄ N ₆ O x HCl (412.5 / 448.96) Mass spectrum: (M + H) ⁺ = 413 Example 274 4-[[5- (3-methyl-5- (furan-2-yl) - pyrazol-1-yl) -1-methyl -1H- Ben zo-imidazol-2-yl] - methyl] - Benzoamijin in the same manner as hydrochloride example 1e in ethanol 4- [ (5- (3-methyl-5- (furan-2-yl)-
Pyrazol-1-yl) -1-methyl-1H-benzimidazol-2-yl] -methyl] -benzonitrile and hydrochloric acid / ammonium carbonate. Yield: 84% of _{theory, C 24 H 22 N 6 O} x HCl (410.48 / 446.94) Mass ^{spectrum: (M + H) + =} 411

Example 275 Dry ampoule containing 75 mg of active substance per 10 ml Composition: 75.0 mg of active substance 50.0 mg of water for injection Add up to 10.0 ml of water Preparation: Active substance and mannitol are dissolved in water. After decanting, the solution is lyophilized. The product is dissolved in water for injection to prepare a working solution for use. Example 276 Dry ampoule containing 35 mg of active substance per 2 ml Composition: 35.0 mg of active substance 100.0 mg of water for injection Add up to 2.0 ml of water Preparation: Active substance and mannitol are dissolved in water. After decanting, the solution is lyophilized. The product is dissolved in water for injection to prepare a working solution for use.

Example 277 Tablet composition containing 50 mg of active substance : (1) 50.0 mg of active substance (2) 98.0 mg of lactose (3) 50.0 mg of corn starch (4) 15.0 mg of polyvinylpyrrolidone (5) 2.0 mg of magnesium stearate 215.0 mg Preparation: (1), (2) and (3) are mixed together and granulated with the aqueous solution of (4). Add (5) to the dried granules. Tablets are compressed from this mixture, these are two sides engraved on both sides, with a split notch on one side. Tablet diameter: 9 mm.

Example 278 Tablet composition containing 350 mg of active substance (1) 350.0 mg of active substance (2) 136.0 mg of lactose (3) 80.0 mg of corn starch (4) 30.0 mg of polyvinylpyrrolidone (5) 4.0 mg of magnesium stearate 600.0 mg Preparation: (1), (2) and (3) are mixed together and granulated with the aqueous solution of (4). Add (5) to the dried granules. Tablets are compressed from this mixture, these are two sides engraved on both sides, with a split notch on one side. Tablet diameter: 12 mm.

Example 279 Capsule composition containing 50 mg of active substance : (1) 50.0 mg of active substance (2) 58.0 mg of dried corn starch (3) 50.0 mg of powdered lactose (4) 2.0 mg 160.0 mg of magnesium stearate Preparation: (1 ) With (3). (2) and (
Add to the mixture of 4). This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.

Example 280 Capsule composition containing 350 mg of active substance : (1) Active substance 350.0 mg (2) Dried corn starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg Preparation: (1 ) With (3). (2) and (
Add to the mixture of 4). The powder mixture is packed into size 0 hard gelatin capsules in a capsule filling machine.

Example 281 Suppository 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 Preparation: Melt polyethylene glycol with polyethylene sorbitan monostearate. At 40 ° C., the ground active substance is homogeneously dispersed in the melt. 38
Cool to ° C. and pour into slightly cooled suppository molds.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4184 A61K 31/4184 4H050 31/423 31/423 31/428 31/428 31/4439 31/4439 31/454 31/454 31/4709 31/4709 31/4725 31/4725 31/496 31/496 31/502 31/502 31/5377 31/5377 A61P 7/02 A61P 7/02 9/10 9/10 103 103 C07D 209/14 C07D 209/14 263/56 263/56 277/66 277/66 307/81 307/81 401/04 401/04 401/12 401/12 401/14 401/14 403/04 403 / 04 403/06 403/06 403/08 403/08 403/12 403/12 403/14 403/14 405/12 405/12 405/14 405/14 417/12 417/12 C07F 9/32 C07F 9 / 32 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF , BJ, F, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, 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, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Mime Gerhard Doi Federal Republic Day 88400 Biberach Schölichweg 8 (72) Inventor Priebke Henning Germany Day 88447 Werthausen Birkenhalder Strasse 11 (72) Inventor Bindel Klaus Federal Republic of Germany Day 65187 Wiesbaden Bipricher Allee 15 ( 72) Inventor Stersen-Jan-Marie, Germany Day 884447 Werthausen, Berglübenweg 11 (72) Inventor Wienen Wolfgang, Germany Day 88400 Biberach Kirschenweg 27 (72) Inventor, Zimmermann Reinel Germany Day 88441 Mittel Biberach Laurenbühlstrasse 17 F term (reference) 4C037 PA09 QA03 QA04 QA07 4C056 AA01 AB01 AC02 AD03 AE03 CA11 CA12 CA19 CA21 CA24 CA25 4C063 AA01 BB08 BB09 CC26 CC52 CC62 CC76 CC94 A144C 01 AA02 AA03 AA04 BC39 GA07 MA01 MA04 ZA54 ZC20 4C204 BB01 BB09 CB03 DB29 DB30 DB31 EB01 EB02 FB01 FB02 GB02 GB03 GB20 GB22 GB32 4H050 AA01 AA03 AB20 AB23

Claims (13)

[Claims] 1. A compound of the general formula 5 membered heterocyclic fused benzo derivatives, tautomers, stereoisomers, mixtures and salts thereof. (Wherein A is an oxygen atom or a sulfur atom; a carbonyl group, a sulfinyl group or a sulfonyl group; an imino group optionally substituted by a C _1-3 -alkyl group or a carboxy-C _1-3 -Alkyl group or a C _1-3 -alkoxy-carbonyl-C _1-3 represents a methylene group which may be monosubstituted or disubstituted by an alkyl group, Ar represents a fluorine atom, a chlorine atom or a bromine atom, respectively, if necessary. trifluoromethyl group, C _1-3 - alkyl group or a C _1-3 - alkoxy group by an optionally substituted phenylene group or a naphthylene group, each optionally C _1-3 in the carbon skeleton - is substituted by an alkyl group unprotected Chi enylene group, thiazolylene group, pyridinylene group, a pyrimidinylene group, pyrazinylene group or pyridazinylene group, X is a nitrogen atom or -R ₁ C = group (wherein , R ₁ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a C _1-3 -alkyl group or a C _1-3 -alkoxy group), and Y represents an oxygen atom, a sulfur atom or- represents R ₂ N-group, (wherein, R ₂ is a hydrogen atom or a C _1-5 - alkyl group, C _1-3 - by alkoxycarbonyl group - alkyl group (which carboxy group or a C _1-3 necessary A C _1-5 -alkyl group (substituted by an optionally substituted phenyl group), a carboxy group, a C _1-3 -alkoxycarbonyl group, a carboxy-C _1-3 -alkoxycarbonyl group, a C _{1 -3} -alkoxycarbonyl-C _1-3 -alkoxycarbonyl group, carboxy-C _1-3 -alkyl-aminocarbonyl group or C _1-3-
Substituted by an alkoxycarbonyl-C _1-3 -alkylaminocarbonyl group, or an nC _2-4 -alkyl group (which is terminated by a di- (C _1-3 -alkyl) -amino group, a pyrrolidino group, a piperidino Group, morpholino group, piperazino group or NC _1-3 -alkyl-piperazino group, and the cyclic group may be further substituted by one or two C _1-3 -alkyl groups.) R _a represents _a hydrogen atom or a C _1-3 -alkyl group, R _b is an R ₃ -CO-C _3-5 -cycloalkylene group, an R ₃ -SO ₂ -NR ₄ group, an R ₃ -CO -NR ₄ groups, R ₅ NR ₆ -CO
Group, R ₅ NR ₆ -SO ₂ -group or R ₅ NR ₆ -CO-C _3-5 -cycloalkylene group, wherein R ₃ is a C _1-6 -alkyl group or C _5-7- Cycloalkyl, C _1-3 -alkyl (including C _5-7 -cycloalkyl, phenyl, C _1-3 -alkylamino, di- (C _1-3 -alkyl) -amino, carboxy -C _1-3 - alkylamino group, C _1-3 - alkoxycarbonylamino group, which is substituted by phenyl sulfonylamino group or Te Torazoriru group), C _1-3 - alkyl group (which carboxy group, C _{1 A -3} -alkoxycarbonyl group, a carboxy-C _1-3 -alkoxy group or a C _1-3 -alkoxy-carbonyl-C _1-3 -alkoxy group, a C _1-3 -alkyl group (this is are replacement by imidazolyl or benzimidazolyl group, the imidazole moiety of the groups one or two C _1-3 - Al Group or carboxy -C _1-3 - alkyl or C _1-3 - alkoxycarbonyl -C _1-3 - may be substituted by an alkyl group), C _1-3 necessary - alkyl, C _{1- A} phenyl group which may be mono- or disubstituted by a ₃ -alkoxy group, a trifluoromethyl group, a carboxy group or a C _1-3 -alkoxycarbonyl group (the substituents may be the same or different; A phenyl group substituted by three or four methyl groups, a naphthyl group, a pyridinyl group, a pyrazolyl group, a quinolyl group, each of which may be optionally substituted by a C _1-3 -alkyl group. Represents an isoquinolyl group, and R ₄ represents a hydrogen atom, a C _1-5 -alkyl group or a C _5-7 -cycloalkyl group, a C _1-5 -alkyl group (this is a carboxy group or a C _1-5 -alkoxycarbonyl group). Has been replaced, The 2- or 3-position alkoxy moiety may be further substituted by a hydroxy group, a C _1-3 -alkyl group (this is an aminocarbonyl group, a hydroxyaminocarbonyl group, a C _1-3 -alkylamino-carbonyl Group, a di- (C _1-3 -alkyl) -aminocarbonyl group or a C _5-7 -alkylene-iminocarbonyl group, and the C _6-7 -alkyleneimino moiety further has a di- ( C _1-3 - alkyl) - optionally substituted by amino group), which may be phenyl-substituted necessary C _1-3 - alkyl group (which carboxy -C _1-3 alkyl moiety - alkoxy - Carbonyl group, C _1-3 -alkoxycarbonyl
-C _1-3 -alkoxycarbonyl group, carboxy-C _1-3 -alkylaminocarbonyl group, N- (C _1-3 -alkyl) -carboxy-C _1-3 -alkyl-aminocarbonyl group, C _1-3 - alkoxycarbonyl -C _1-3 - alkylaminocarbonyl group, N-(C _1-3 - alkyl) -C _{1 -3} - alkoxycarbonyl -C _1-3 - alkylaminocarbonyl group, Moruhorinokaru Boniru group or 4- (Substituted by (C _1-3 -alkyl) -piperazinocarbonyl group), C _1-3 -alkyl group (this is a carboxy-C _1-3 -alkylaminocarbonyl group, N- (
C _1-3 -alkyl) -carboxy-C _1-3 -alkyl-aminocarbonyl group, C _1-3 -alkoxycarbonyl-C _1-3 -alkylaminocarbonyl group or N- (C _1-3 -alkyl) -C _1-3 -alkoxycarbonyl-C _1-3 -alkylamino-carbonyl groups, which are further substituted by carboxy groups or C _1-3 -alkoxycarbonyl groups at the carbon atoms of the alkylamino moiety A C _1-3 -alkyl group, which is substituted by a di- (C _1-3 -alkyl) -aminocarbonyl group, wherein the alkyl moiety further comprises a di- (C _{1 A 3} -alkyl) -amino group, a C _1-3 -alkyl group (this is a 4- (morpholinocarbonyl-C _1-3 -alkyl) -piperazinocarbonyl group, an N- ( C _1-3 -alkyl) -pyrrolidinyl group or N- (C _1-3 -alkyl) -piperidinyl group) Or nC _2-4 - alkyl groups (which di at the end - (C _1-3 - alkyl) - amino group, C _5-7 - which is substituted by Al Kiren'imino group or morpholino group) represents, R ₅ Is a C _1-5 -alkyl group or a C _5-7 -cycloalkyl group, a phenyl-C _1-3 -alkyl group, which is substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group in the alkyl part. NC _2-4 -alkyl group, which is substituted at the 2-, 3- or 4-position by a hydroxy, C _1-3 -alkylamino or di- (C _1-3 -alkyl) -amino group If necessary, mono- or disubstituted by a C _1-3 -alkyl group, a C _1-3 -alkoxy group, a trifluoromethyl group, a carboxy group or a C _1-3 -alkoxycarbonyl group. Phenyl groups (these substituents may be the same or different), 3 Properly the four phenyl group substituted by a methyl group, a naphthyl group, a pyridinyl group, a quinolyl group or an isoquinolyl group, R ₆ is a carboxy group or a C _1-3 necessary - be substituted by an alkoxycarbonyl group A C _1-5 -alkyl group, a C _1-3 -alkyl group (which is a C _1-3 -alkylaminocarbonyl group, a di- (C _1-3 -alkyl) -aminocarbonyl group, a carboxy -C _1-3 -alkylaminocarbonyl group or C _1-3 -alkyloxycarbonyl-C _1-3 -alkylaminocarbonyl group, or nC _2-4 -alkyl group (this is the 2-position Substituted at the 3- or 4-position by a hydroxy group, a C _1-3 -alkylamino group or a di- (C _1-3 -alkyl) -amino group), or one of the radicals R ₅ or R ₆ One represents a hydrogen atom, while another one of these groups Have the meanings given for R ₅ and R _6, or R ₅ and R ₆ are C _{1 -3} necessary together with the nitrogen atom of one or two among them - is substituted by an alkyl group A pyrrolidino or piperidino group (which may be further substituted by a carboxy-C _1-3 -alkyl group or a C _1-3 -alkoxy-C _1-3 -alkyl group, or Benzene ring may be condensed through two adjacent carbon atoms) or R _b is an amino group, a C _1-3 -alkylamino group or a C _5-7 -cycloalkyl-amino group Is a phenylaminocarbonyl group, an N-phenyl-C _1-3 -alkylaminocarbonyl group, a phenylsulfonylamino-C _1-3 -alkylcarbonyl group, a C _1-3 -alkyloxy-carbonyl-C ₁ at the position of the nitrogen atom. _-3 -alkyl group, N- (C _3-5 -cycloalkyl) -C _1-3 -alkylamino-ca Rubonyl group, N- (hydroxycarbonyl-C _1-3 -alkyl) -aminocarbonyl group, N- (C _1-3 -alkoxycarbonyl-C _1-3 -alkyl) -aminocarbonyl-C _3-5 -cyclo May be substituted with an alkylamino group), a piperidino group substituted at the 4-position with a di- (C _1-3 -alkyl) -amino group, a piperazino substituted at the 4-position with a C _1-3 -alkyl group A C _2-4 -alkylsulfonyl group (this is a di- (C _1-3 -alkyl
) -Amino group), 4-oxo-3,4-dihydro-phthalazinyl-1-yl group or 4-oxo-2,3-diazaspiro [5.5] undec-1-en-1-yl group A methyl group substituted by a C _5-7 -cycloalkyleneimino-carbonyl group (the methyl group is substituted by a carboxy-C _1-3 -alkyl group or a C _1-3 -alkoxy-C _1-3 -alkyl group) and has), C _3-5 - cycloalkyl group or a C _3-5 - alkyl-substituted carbonyl group or a methyl group by group (the cycloalkyl moiety is further C _1-3 - alkyl group, a carboxy -C _1-3 -Alkyl group or C _1-3 -alkoxy-carbonyl-C _1-3 -alkyl group, and the methyl portion thereof may be substituted by a C _1-3 -alkoxy group or a C _1-4 -alkylamino group. is substituted), C _5-7 - cycloalkyl -N- (carboxy -C _1-3 - alkoxy) - Iminomechire Group or C _5-7 - cycloalkyl-N-(C _1-3 - alkoxycarbonyl -C _1-3 - alkoxy) - substituted alkyl group - C _1-3 iminomethylene group (these further cycloalkyl moiety Phosphinyl group (which may be a C _1-6 -alkyl group or a C _5-7 -cycloalkyl group and a hydroxy group, a C _1-3 -alkoxy group, a carboxy-C _1-3 -alkoxy group or C _1-3 - alkoxycarbonyl -C _1-3 - substituted by an alkoxy group), piperidino group (the 2-position, methylene group is replaced by a carbonyl group or a sulfonyl group), C necessary _{1- A} tetrazolyl group which may be substituted by a ₅ -alkyl group, if necessary, a C _1-3 -alkyl group, a C _1-3 -alkoxy group, a trifluoromethyl group, a carboxy group or a C _1-3 -alkoxycarbonyl group; May be substituted or disubstituted A phenyl group or a phenylsulfonyl group (these substituents may be the same or different), a sulfoimidyl group (which is substituted by a C _5-7 -cycloalkyl group at the sulfur atom) And further at the position of the nitrogen atom a C _2-4 -alkanoyl group, carboxy-C _1-3 -alkyl group, C _1-3 -alkoxycarbonyl-C _1-3 -alkyl group, carboxy-C _2-4 -
Alkanoyl group or C _1-3 -alkoxycarbonyl-C _2-4 -alkanoyl group), carboxy-C _1-3 -alkyl group or C _1-3 -alkoxycarbonyl-C at the 1-position An imidazolyl group substituted by a _1-3- alkyl group (which may be further substituted by a C _1-5 -alkyl group), a C _1-3 -alkoxycarbonyl-C _1-3 -alkyl group (this C _5-7 in the alkyl moiety - is substituted by a cycloalkyl amino carbonyl group), C _1-3 - alkyl group (which 1-imidazolyl group (the imidazolyl moiety may further one or two C _{1 -3} - the alkyl may be substituted by a group), or a carboxy -C _1-3 in 2-position - alkyl or C _1-3 - alkoxycarbonyl -C _1-3 - substituted by alkyl group 1- Substituted by a benzimidazolyl group), or Alkyl group by represents an furanyl-1-pyrazolyl group which may be substituted, and R _c is cyano group or an amidino group (which hydroxy groups, one or two C _1-3 - C _1-3 by - Alkyl group, one or two C _1-8 -alkoxycarbonyl groups or a group which can be cleaved in vivo). ) 2. A, X, Y and R _{a to} R _d are as defined in claim 1, provided that Ar represents a 1,4-phenylene group, R ₃ represents a pyrazolyl group or each C _1-3 - optionally substituted by alkyl group - naphthyl group substituted by an alkyl group, Pi lysinyl group, a pyrazolyl group, does not represent a quinolyl group or an isoquinolyl group, and C _1-3 the required R _b 5. A 5-membered heterocyclic fused benzo derivative of the general formula I according to claim 1, provided that it does not represent a good furanyl-1-pyrazolyl group, their tautomers, stereoisomers and mixtures. And salt. 3. A compound of the general formula Wherein A, X, Y and R _{a to} R _c are as defined above in claim 1), their tautomers, stereoisomers Bodies, mixtures and salts thereof. 4. A is optionally carboxy-C_1-3-Alkyl group or C_1-3-Alkoxycarbonyl-C_1-3-A methylene group which may be substituted by an alkyl group, or carbonyl
X represents a nitrogen atom or -R₁C = group (where R₁Is hydrogen, fluorine, chlorine or bromine, C_1-3-Alkyl group or C_1-3-Represents an alkoxy group), and Y is an oxygen atom or a sulfur atom or -R_TwoRepresents an N-group, wherein R_TwoIs a hydrogen atom or C_1-5-Alkyl group, benzyl group (this is a carboxy group or C_1-3-Optionally substituted by an alkoxycarbonyl group), C_1-5-Alkyl groups, which are carboxy groups or C_1-3-By alkoxycarbonyl group
Has been replaced), C_1-3-Alkyl group (this is carboxy-C_1-3-Alkoxycarbonyl group, carboxy-C_1-3-Alkylaminocarbonyl group or C_1-3-Alkoxycarbonyl-C_1-3-Substituted by an alkylaminocarbonyl group), or n-C_2-4-Alkyl group (which is di- (C_1-3-Alkyl) -amino group or morpholine
R)_aRepresents a hydrogen atom or a methyl group; R_bIs R_Three-CO-C_3-5-Cycloalkylene group, R_Three-SO_Two-NR_FourGroup, R_Three-CO-NR_FourGroup, R_FiveNR₆-CO
Group, R_FiveNR₆-SO_TwoGroup or R_FiveNR₆-CO-C_3-5-Represents a cycloalkylene group, wherein R_ThreeIs C_1-4-Alkyl group, cyclopentyl group, cyclohexyl group or benzyl group, C_1-3-Alkyl groups (which are tetrazolyl, carboxy, C_1-3-Alkoxyka
Rubonyl group, carboxy-C_1-3-Alkoxy group, C_1-3-Alkoxycarbonyl-C_1-3 -Alkoxy group, carboxy-C_1-3-Alkylamino group, C_1-3-Alkoxycarboni
A methyl group, a methoxy group, a trifluoromethyl group, a carboxy group or
A phenyl group which may be mono- or disubstituted by a methoxycarbonyl group (this
These substituents may be the same or different), 3 or 4
A phenyl group substituted by a methyl group of_1-3-A 5-pyrazolyl group, a naphthyl group, a pyridinyl group, a quinolyl group or a 5-pyrazolyl group which may be substituted by an alkyl group;
Represents an isoquinolyl group; R_FourIs a hydrogen atom, C_1-5-Alkyl group or C_5-7-Cycloalkyl group, C_1-5-Alkyl groups, which are carboxy groups or C_1-5-By alkoxycarbonyl group
And the 2- or 3-position alkoxy moiety is further substituted with a hydroxy group.
May be substituted), C_1-3-Alkyl groups, which are substituted by aminocarbonyl, hydroxyaminocarbonyl or piperidinocarbonyl groups, the piperidino portion of which is further
May be substituted by a dimethylamino group at the 4-position), C_1-3-Alkyl group (this is carboxy-C_1-3-Alkylaminocarbonyl group, N- (
C_1-3-Alkyl) -carboxy-C_1-3-Alkyl-aminocarbonyl group, C_1-3-Alkoxycarbonyl-C_1-3-Alkylaminocarbonyl group, N- (C_1-3-Alkyl) -C_1-3-Alkoxycarbonyl-C_1-3-Alkylaminocarbonyl group, morpholinocarboni
Group or 4- (C_1-3-Alkyl) -piperazinocarbonyl group), C_1-3-Alkyl group (this is carboxy-C_1-3-Alkylaminocarbonyl group, N- (
C_1-3-Alkyl) -carboxy-C_1-3-Alkyl-aminocarbonyl group, C_1-3-Alkoxycarbonyl-C_1-3-Alkylaminocarbonyl group or N- (C_1-3-Alkyl) -C_1-3 -Alkoxycarbonyl-C_1-3-Alkylamino-carbonyl group
These further include a carboxy group or C at the carbon atom of the alkylamino moiety._1-3 -Substituted by an alkoxycarbonyl group), C_1-3-Alkyl group, which is di- (C_1-3-Alkyl) -aminocar
Substituted at the 2- or 3-position with a di- (C_1-3-Alkyl) -amino group), C_1-3-Alkyl group, whose alkyl moiety is 4- (morpholinocarbonyl-C_1-3-
Alkyl) -piperazinocarbonyl group or N- (C_1-3-Alkyl) -pyrrolidinyl group
Substituted) or n-C_2-3-Alkyl group (which is di- (C_1-3-Alkyl) -amino group, C_5-7-Alkyleneimino or morpholino), R_FiveIs C_1-5-Alkyl group or C_5-7-Cycloalkyl group, phenyl-C_1-3-Alkyl group, which is a carboxy group or C_1-3 -May be substituted by an alkoxycarbonyl group), a phenyl group, a naphthyl group, a pyridinyl group, a quinolyl group or an isoquinolyl group
Then R₆Is optionally a carboxy group or C_1-3-C optionally substituted by an alkoxycarbonyl group_1-5-Alkyl group, C_1-3-Alkyl group, which is an alkyl moiety with C_1-3-Alkylaminocarbonyl
Group, di- (C_1-3-Alkyl) -aminocarbonyl group, carboxy-C_1-3-Alkylaminocarbonyl group or C_1-3-Alkyloxycarbonyl-C_1-3-Alkylaminocarbonyl), n-C_2-3-Alkyl group (this is C at the 2 or 3 position_1-3-Alkylamino group or di- (C_{1 -3} -Alkyl) -amino group) or a group R_FiveOr R₆One represents a hydrogen atom, while another one of these groups is_FivePassing
And R₆Has the meaning indicated for or R_FiveAnd R₆Together with the nitrogen atom between them if necessary_1-3-Alkyl group, carboxy-C_1-3-Alkyl group or C_1-3-Alkoxy-C_1-3-A pyrrolidino group or a piperidino group which may be substituted by an alkyl group, which has two benzene rings.
Which may be condensed via adjacent carbon atoms) or R_bIs a nitrogen atom at the position of phenylaminocarbonyl, N-phenyl-methylaminocarbonyl, phenylsulfonylaminomethylcarbonyl, hydroxy
Rubonylmethyl-aminocarbonyl group or C_1-3-Alkyloxycarbonylmethyl
Amino group, methylamino group, cyclopentene substituted by aminocarbonyl group
Or cyclohexylamino group, di- (C_1-3-Alkyl) -amino group, piperidino group substituted at the 4-position_1-3-A piperazino group substituted by an alkyl group, C_2-3-Alkylsulfonyl group (this is di- (C_1-3-Alkyl) -ami
4-oxo-3,4-dihydro-phthalazinyl-1-yl group or 4-oxo-2,3-diazaspi
B [5.5] undec-1-en-1-yl group, cyclopentyl group, cyclohexyl group or C_3-5-A carbonyl group or a methyl group substituted by an alkyl group (the methyl_1-3-Alkoxy group or C_1-4-Al
Substituted with a killamino group, and the cycloalkyl moiety is further substituted with methyl.
Group, carboxymethyl group or C_1-3-Alkoxycarbonylmethyl group), cyclohexyl-N- (carboxymethoxy) -iminomethylene group or cyclohexyl
Le-N- (C_1-3-Alkoxycarbonylmethoxy) -iminomethylene groups (these may be further substituted by a methyl group at the cyclohexyl moiety), phosphinyl groups (which are_3-6-Alkyl and hydroxy groups, C_1-3-Alkoxy
Group, carboxymethoxy group or C_1-3-Substituted by an alkoxycarbonylmethoxy group), a piperidino group (in the 2-position, a methylene group is replaced by a carbonyl group or a sulfonyl group).
Has been replaced), C if necessary_1-5-A tetrazolyl group optionally substituted by an alkyl group, a phenyl group or phenylsulfur optionally substituted by a methyl group
Honyl group, sulfoimidyl group (which is substituted by cyclohexyl group at the sulfur atom)
And C at the position of the nitrogen atom_2-4-Alkanoyl group, carboxymethyl group, C _1-3 -Alkoxycarbonylmethyl group, carboxy-C_2-3-Alkanoyl group or C_1-3 -Alkoxycarbonyl-C_2-3-Alkanoyl group), carboxymethyl group at the 1-position or C_1-3-An imidazolyl group replaced by an alkoxycarbonylmethyl group, which is_1-5-May be substituted by an alkyl group), C_1-3-Alkoxycarbonyl-C_1-3-Alkyl group, which is an alkyl moiety with C_{Five- 7} -Substituted by a cycloalkylaminocarbonyl group), C_1-3-Alkyl group, which is a 1-imidazolyl group (the imidazolyl moiety of which is one or two more C_1-3-Optionally substituted by an alkyl group) or at the 2-position carboxy-C_1-3-Alkyl group or C_1-3-Alkoxycarbonyl-C_1-31-benzimidazolyl group which is substituted by -alkyl group) or C_1-3-Furanyl-1-pyrazoli optionally substituted by alkyl group
And R_cIs a cyano group or an amidino group (this is one or two C_1-3-Alkyl group, one or two C_1-8-A 5-membered heterocyclic fused benzo derivative of the general formula Ia according to claim 2, which may be substituted with an alkoxycarbonyl group or a hydroxy group,
Isomers, stereoisomers and salts. 5. A represents a methylene group or an imino group, X represents a nitrogen atom or a —R ₁ C = group, wherein R ₁ represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom or a methyl group. Y represents an oxygen atom or a sulfur atom or a -R ₂ N- group, wherein R ₂ is a hydrogen atom, a methyl group, a benzyl group, a 4-carboxybenzyl group or a 4-methoxycarbonylbenzyl group, _{A 1-3} -alkyl group (which is substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group), a methyl group (which is a carboxymethylaminocarbonyl group or a C _1-3 -alkoxycarbonylmethylaminocarbonyl group) Substituted) or nC _2-3 -alkyl group (which is substituted at the terminal by a morpholino group) Ra represents _a hydrogen atom, R _b represents R ₃ -CO- (1,1 - cyclopropylene) group, R ₃ -SO ₂ -NR ₄ , R ₃ -CO-NR ₄ group, R ₅ NR ₆ -C
O group, R ₅ NR ₆ -SO ₂ group or R ₅ NR ₆ -CO-C _3-5- (1,1-cyclopropylene) group, wherein R ₃ is a C _1-3 -alkyl group , cyclopentyl or cyclohexyl group, a methyl group (this tetrazolyl group, carboxymethoxy group, C _1-3 - alkoxy carbonyl methoxy, carboxy -C _1-3 - alkylamino group, C _1-3 - by alkoxy carbonyl amino group Substituted), a phenyl group, a naphthyl group, a pyridinyl group, a 1-methyl-5-pyrazolyl group, a quinolyl group or an isoquinolyl group, wherein R ₄ is a hydrogen atom, a C _1-3 -alkyl group or a cyclopentyl group, A C _1-5 -alkyl group (which is substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group), a methyl group (which is a 4-dimethylamino-piperidinocarbonyl group, a morpholinocarbonyl group, Methyl piperazino group or 4-mo Substituted with a rufolinocarbonylmethyl-piperazinocarbonyl group), a C _1-3 -alkyl group (which is a carboxy-methylaminocarbonyl group, N- (C _1-3 -alkyl) -carboxymethylamino-carbonyl group, C _1-3 - alkoxycarbonylmethyl amino group or a N- (C _1-3 - alkyl) -C _1-3 - substituted by alkoxycarbonylamino methylation aminocarbonyl group), C _1-3 - alkyl Group, which is substituted by a di- (C _1-3 -alkyl) -aminocarbonyl group, wherein the alkyl moiety is further substituted at the 2- or 3-position by a di- (C _1-3 -alkyl) -amino group. and has), C _1-3 - alkyl group (which carboxymethyl aminocarbonyl group or a C _1-3 - alkoxycarbonyl - is optionally substituted with a methyl aminocarbonyl group, a methyl group of the methylol arylamino portion further Aminoka Bonirumechiru substituted by group), or nC _2-3 - alkyl group (which is a terminal di - (C _1-3 - alkyl) - amino group, a has been replaced) by a pyrrolidino group or a morpholino group, R ₅ represents a C _1-5 -alkyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a naphthyl group, a pyridinyl group, a quinolyl group or an isoquinolyl group, and R ₆ represents a carboxy group or a C _1-3 -alkoxycarbonyl group as required. optionally substituted C _1-5 by - alkyl group, C _1-3 - alkyl group (which C _1-3 - alkylaminocarbonyl group, a carboxymethyl aminocarbonyl group or a C _1-3 - alkyloxy - represents are replaced) by a carbonyl methylaminocarbonyl group, or R ₅ and R ₆ together with the nitrogen atom between them a carboxymethyl group or a C _1-3 - alkoxy - methyl groups Ri substituted pyrrolidino group or a pyrrolidino group represents a (which the benzene ring is further is fused via two adjacent carbon atoms)), or R _b is N- pyrrolidinocarbonyl - methylamino group, phenylsulfonyl group , 4-oxo-2,3-diazaspiro [5.5] undec-1-en-1-yl group or C _3-5 -alkyltetrazolyl group, cyclohexylcarbonyl group (this is a methyl group, a carboxymethyl group or a C _1- Substituted by a ₃ -alkoxycarbonylmethyl group), a cyclohexyl-N- (carboxymethoxy) -iminomethylene group or a cyclohexyl-N- (C _1-3 -alkoxycarbonylmethoxy) -iminomethylene group (which is further cyclohexyl substituted by methyl group moiety), the phosphinyl group (which C _3-6 - which is substituted by alkoxy methoxy - alkyl and C _1-3 , Sul Hoimi Doyle group (which is substituted by a cyclohexyl group in the position of the sulfur atom, more C _2-4 at the position of the nitrogen atom - substituted by alkanoyl group), or 3-methyl-5- (furan 2. A 5-membered fused heterocyclic benzo derivative of the general formula I according to claim 1, wherein R represents a 2-amino) -1-pyrazolyl group and R _c represents an amidino group; Isomers and salts. 6. A represents a methylene group, X represents a nitrogen atom or a —HC = group, and Y represents an oxygen atom or a sulfur atom or —R_TwoRepresents an N-group, wherein R_TwoIs a hydrogen atom, a methyl group, a benzyl group or C_1-3-Represents an alkoxycarbonylmethyl group) R_aRepresents a hydrogen atom, R_bIs R_FiveNR₆-SO_TwoGroup, R_FiveNR₆-CO group, R_Three-SO_Two-NR_FourGroup, R_Three-CO-NR_FourGroup or R_FiveNR₆-CO-C_{3- Five} -(1,1-cyclopropylene) group, wherein R_ThreeIs cyclopentyl, cyclohexyl, phenyl, naphthyl, 1-methyl
5-pyrazolyl group, quinolyl group or isoquinolyl group or methyl group (this is a carboxymethylamino group,_1-3-Alkoxycarbonyl-methylamino group, cal
Boxymethoxy group, C_1-3-Alkoxycarbonylmethoxy or tetrazolyl)), R_FourIs a hydrogen atom or a carboxy group, C_1-3-Alkoxycarbonyl group, morpholino carbonyl group, 4-dimethyl-amino-piperidinocarbonyl group, 4-methyl-piperazinocarbonyl group, 4-morpholinocarbonylmethyl-piperazinocarbonyl group, carboxymethylaminocarbonyl group, N- Methyl-carboxymethylaminocarbonyl group, C_1-3-Alkoxycarbonylmethyl-aminocarbonyl group, N-methyl-C _1-3 -Alkoxycarbonylmethylaminocarbonyl group, N- (C_1-3-Alkyl) -N- (2
-Dimethylamino-ethyl) -aminocarbonyl group, N- (1-carboxy-2-aminocar
Bonyl-ethyl) -aminocarbonyl group or N- (1-C_1-3-Alkoxycarbonyl-2-a
A methyl group or a cyclopentyl group substituted by a (minocarbonyl-ethyl) -aminocarbonyl group;_FiveIs C_1-5-Represents an alkyl group, a phenyl group or a pyridyl group, R₆Is C_1-5-Alkyl group (which is carboxy or C at the end_1-3-Alkoxy carb
Or a methylaminocarbonyl group, a carboxy group
Xymethylaminocarbonyl group or C_1-3-Substituted by an alkoxycarbonylmethylaminocarbonyl group, or by a dimethylamino group at the 2- or 3-position.
Replaced C_1-3-Represents an alkyl group, or R_FiveIs R₆And a 1-methyl-5-pyrazolyl group together with a nitrogen atom between them, optionally C_1-3A pyrrolidino group or a pyrrolidino group optionally substituted by an alkoxycarbonyl group, to which a benzene ring is fused via two adjacent carbon atoms;
) Or R_bIs N-pyrrolidinocarbonyl-methylamino group, phenylsulfonyl group, 4-oxo-2,3-diaza-spiro [5.5] undec-1-en-1-yl group or C_3-5-Alkyl
Tolazolyl, cyclohexylcarbonyl (this is a methyl, carboxymethyl or
Is C_1-3-Alkoxycarbonyl-methyl group), cyclohexyl-N- (carboxymethoxy) -iminomethylene group or cyclohexyl
Le-N- (C_1-3-Alkoxycarbonylmethoxy) -iminomethylene group (which is further substituted by a methyl group in the cyclohexyl moiety), phosphinyl group (which is_3-6-Alkyl group and C_1-3-By an alkoxymethoxy group
), And R_c5 represents an amidino group, 5 membered heterocyclic fused benzo derivatives of the general formula I according to claim 1,
Isomers, stereoisomers and salts. 7. A represents a methylene group, X represents a nitrogen atom or a —HC = group, Y represents an oxygen atom or a sulfur atom or a —R ₂ N— group (wherein R ₂ is a hydrogen atom, a methyl group , A benzyl group or a C _1-3 -alkoxycarbonylmethyl group), Ra represents _a hydrogen atom, R _b represents an R _5a NR _6a -SO ₂ group, wherein R _5a represents C _1-3 -Alkyl or phenyl, and R _6a is a C _1-5 -alkyl group which is substituted at the terminus by a carboxy or C _1-3 -alkoxycarbonyl group, or at the 2 or 3 position R _5a together with R _6a and the nitrogen atom between them, R _5a is optionally substituted by a C _1-3 -alkoxycarbonyl group. Group or pyrrolidino group (
A benzene ring is condensed through two adjacent carbon atoms), or R _3a —SO ₂ —NR _4a group, wherein R _3a is a cyclopentyl group, a cyclohexyl group, a phenyl group, Represents a naphthyl group, a quinolyl group or an isoquinolyl group, and R _4a is a hydrogen atom or a methyl group (this is a carboxy group, a C _1-3 -alkoxycarbonyl group, a morpholinocarbonyl group, a 4-dimethylamino-piperidinocarbonyl group) ,Four
-Methyl-piperazinocarbonyl group, 4-morpholinocarbonylmethyl-piperazinocarbonyl group, carboxymethylaminocarbonyl group, N-methyl-carboxymethylaminocarbonyl group, C _1-3 -alkoxycarbonylmethyl-aminocarbonyl group, N -Methyl-C _1-3 -alkoxycarbonylmethylaminocarbonyl group, N- (C _1-3-
Alkyl) -N- (2-dimethylamino-ethyl) -aminocarbonyl group, N- (1-carboxy-2-aminocarbonyl-ethyl) -aminocarbonyl group or N- (1-C _1-3 -alkoxycarbonyl -2-aminocarbonyl-ethyl) -aminocarbonyl group) or R _5b NR _6b -CO group, wherein R _5b is a C _3-5 -alkyl group, a phenyl group or a pyridyl group And R _6b represents a C _1-5 -alkyl group or a C _1-3 -alkyl group (this is a carboxy group, a C _1-3 -alkoxycarbonyl group, a methylaminocarbonyl group, a carboxymethylaminocarbonyl group or a C ₁ Substituted by a _-3 -alkoxycarbonylmethylaminocarbonyl group or substituted at the 2- or 3-position and also by a dimethylamino group), or an R _3b -CO-NR _4b group, wherein R _3b represents a phenyl group, and R _4b represents C _1-3 An alkyl group (which is substituted by a carboxy group or a C _1-3 -alkoxycarbonyl group), or R _3b represents a methyl group (which is a carboxymethylamino group, a C _1-3 -alkoxycarbonylmethylamino group) , A carboxymethoxy group, a C _1-3 -alkoxycarbonylmethoxy group or a tetrazolyl group), and R _4b represents a cyclopentyl group), or R _5c NR _6c -CO-C _3-5- (1,1-cyclopropylene) group, wherein R _5c is a 1-methyl-5-pyrazolyl group together with R _6c and a nitrogen atom therebetween, and optionally a C _1-3 -alkoxycarbonyl group Represents an optionally substituted pyrrolidino group or a pyrrolidino group (to which a benzene ring is condensed via two adjacent carbon atoms), or R _b is N-pyrrolidinocarbonyl-methyl Amino group, Nirusuruhoniru group, 4-OH Kiso-2,3-diaza - spiro [5.5] undec-1-en-1-yl group or a C _3-5 - alkyl tetrazolyl group, cyclohexyl group (which 1-position Substituted by a methyl group, a carboxymethyl group or a C _1-3 -alkoxycarbonyl-methyl group), a cyclohexyl-N- (carboxymethoxy) -iminomethylene group or a cyclohexyl-N- (C _1-3 -alkoxycarbonylmethoxy) ) -Iminomethylene group (which is further substituted by a methyl group in a cyclohexyl moiety), phosphinyl group (which is substituted by a C _3-6 -alkyl group and a C _1-3 -alkoxymethoxy group), And a 5-membered fused heterocyclic benzo derivative of the general formula I according to claim 1, wherein R _c represents an amidino group, tautomers, stereoisomers and salts thereof. 8. (a) 4-[(5- (N-carboxymethyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine, (b) 4-[(5- (N-carboxymethylaminoacetyl-quinolin-8-yl-sulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine, (c) 4-[(5- (N- (2-dimethylamino-ethyl) -benzenesulfonylamino) -1-benzyl-1H-benzimidazol-2-yl) -methyl] -benzamidine, (d) 4- [ (5- (N- (2-diethylamino-ethyl) -benzenesulfonylamino) -1- (carboxymethylaminocarbonyl) -methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine, (e) 4-[(5-pyrrolidino-sulfonyl-1-methyl-1H-benzimidazol-2-yl)
-Methyl] -benzoamidine, (f) 4-[(5- (N-cyclopentyl-methanesulfonylamino) -1-methyl-1H-benzimidazol-2-yl) -methyl] -benzoamidine, (g) 4 -[(5- (N-cyclopentyl-3-carboxypropionylamino) -1-methyl-1
(H-benzimidazol-2-yl) -methyl] -benzamidine, (h) 4-[(5-pyrrolidinocarbonylcyclopropyl-1-methyl-1H-benzimidazol-2-yl) -methyl] -benzamidine And (i) 4-[(5- (N-carboxymethyl-quinolin-8-yl-sulfonylamino-benzothiazol-2-yl) -methyl] -benzamidine. 5-membered heterocyclic fused benzo derivatives of I and salts thereof. 9. A physiologically acceptable salt of a compound according to claims 1 to 8, wherein R _c represents one of the amidino groups according to claims 1 to 8. 10. The method according to claim 1, wherein R _c represents one of the amidino groups according to claims 1 to 8, optionally together with one or more inert carriers and / or diluents.
A pharmaceutical composition comprising at least one compound according to any one of claims to 8, or a salt according to claim 9. 11. thrombin time increasing effect, for preparing a pharmaceutical composition having an inhibitory effect on thrombin inhibiting effect and release serine protease, one amidino group R _c is wherein the first term - Claim 8 Use of at least one compound according to claims 1 to 8 or a salt according to claim 9 representing the following. 12. The compound according to claim 1, wherein R _c represents one of the amidino groups according to claims 1 to 8, or at least one of the compounds according to claim 9
11. The method for preparing a pharmaceutical composition according to claim 10, wherein the salt according to claim 10 is mixed into one or more inert carriers and / or diluents by a non-chemical method. 13. A) R_cRepresents a cyano group and X represents a nitrogen atom.
The general formula which may be formed in the reaction mixture if necessary(Where R_a, R_b, A, Ar and Y are defined as in claims 1 to 8;₁And Z_Two(These may be the same or different)
Amino optionally substituted by an alkyl group having from 1 to 8 carbon atoms
Group, hydroxy group or mercapto group, or Z₁And Z_TwoAre together oxygen or sulfur atoms, and if necessary 1 to 3
An imino group which may be substituted by an alkyl group having a silicon atom,
Or an alkylenedioxy or alkylenedithio group having 3 carbon atoms.
B) R)_bIs R_Three-SO_Two-NR_FourGroup, R_Three-CO-NR_FourGroup or (R_FiveNR₆) CO-NR_FourRepresents a group, and R_cBut
To prepare compounds of the general formula I representing an ano group, a compound of the general formula(Where R_a, R_Four, A, Ar, X and Y are defined as in claims 1-8.
Of the general formula R_Ten− W−OH (V) (where R_TenIs R in the claims 1 to 8._Three~ R₆And W is a carbonyl group or a sulfonyl group), or an acyl derivative thereof, or c) R_bIs R_Three-SO_Two-NR_FourRepresents a group, and R_cPrepares a compound of the general formula I which represents a cyano group.
In order to produce, the general formula(Where R_a, R_Three, A, Ar, X and Y are defined as described in claims 1 to 8.
Of the general formula R_Four − Z_Three (VII) (wherein, R_FourIs defined as in claims 1 to 8, and Z_ThreeIs nuclear
Or d) R_bContains an alkylated phosphinyl group and a sulfoimidyl group
In the first to eighth ranges of R_bRepresents one of the groups described for_cIs cyano
To prepare compounds of the general formula I representing the group(Where R_a, R_Three, A, Ar, X and Y are defined as in claims 1-8.
Justified and R_b'Includes a phosphinyl group and a sulfoimidyl group;_bWhich represents one of the groups described for the compounds of the general formula Z_Four − R₁₁ (IX) (where Z_FourRepresents a nucleophilic group, and R₁₁Is a group represented by R in the claims 1 to 8_bOne of the alkyl moieties described in the definition of the alkylated phosphinyl and sulfimidoyl groups described for
Or e) R_bContains an acylated sulfoimidoyl group.
To R_bTo prepare compounds of the general formula I, which represent one of the groups described for(Where R_a, R_c, A, Ar, X and Y are defined as in claims 1-8.
Justified and R_b"Represents a sulfoimidoyl group._bWhich represents one of the groups described for the compounds of the general formula HO-R₁₂ (XI) (where R₁₂Is a group represented by R in the claims 1 to 8_bOr a reactive derivative thereof, or f) R_bIs R_FiveNR₆-CO group, R_FiveNR₆-SO_TwoGroup, R_FiveNR₆-CO-C_3-5-Cycloalkylene group or R _Five NR₆-CO-NR_FourRepresents a group, and R_cIn order to prepare a compound of the general formula I in which represents a cyano group, a compound of the general formula(Where R_a, A, Ar, X and Y are defined as in claims 1-8.
And U is HO-CO-C_3-5-Cycloalkylene, HO-CO or HO-SO_TwoOr a reactive derivative thereof represented by the general formula (R_FiveNR₆) − H (XIII) (where R_FiveAnd R₆Has the meaning given in claims 1 to 8), or g) R_bIs R_Three-CO-C_3-5-Represents a cycloalkylene group, and R_cIn order to prepare a compound of the general formula I in which represents a cyano group, a compound of the general formula(Where R_a, A, Ar, X and Y are defined as in claims 1-8.
And R_b'"Is R_Three-(HCOH) -C_3-5-Represents a cycloalkylene group) or h) R_bIs R in the claims 1 to 8._bRepresents one of the groups described for
It contains a methyl group attached to an adjacent bicyclic moiety, which is optionally substituted
To prepare compounds of the general formula I substituted with an optionally substituted amino group, a compound of the general formula(Where R_a, R_c, A, Ar, X and Y are defined as described in claims 1 to 8.
Justified and R_b"" Represents R in the claims 1 to 8._bRepresents one of the groups described for
Which is linked to the adjacent bicyclic moiety through a carbonyl group) with the general formula HR₁₃ (XVI) (wherein, R₁₃Is an optionally substituted amino group, for example, R_bIs adjacent to a bicyclic ring via a methyl group substituted by an amino group which may be optionally substituted
In the case where it is combined with the formula portion, R_bDescribed about
Reductive amination with an amine of the formula_bIs R in the claims 1 to 8._bReplaced as necessary
Represents one of the phenyl groups which may be_cIs a cyano group;
To prepare the compound, a compound of the general formula(Where R_a, A, Ar, X and Y are defined as in claims 1-8.
And V is a trifluoromethanesulfonyloxy group, a bromine atom or an iodine atom
Of the general formula R₁₄ − Z_Five (XVIII) (wherein, R₁₄Is R in the claims 1 to 8._bRepresents one of the optionally substituted phenyl groups described for_FiveIs a boric acid group or tri- (C_1-3 -Alkyl) -tin group) or j) R_cRepresents an amidino group, which comprises one or two C_1-3-To prepare compounds of general formula I which may be replaced by alkyl groups, the general formula which may optionally be formed in the reaction mixture(Where R_a, R_b, A, Ar, X and Y are defined as described in claims 1 to 8.
Justified and Z₆Is an alkoxy, alkylthio, aralkoxy or aralkyl group
A compound of the general formula HR₁₅NR₁₆ (XX) (where R₁₅And R₁₆(These may be the same or different)
Is a hydrogen atom or C, respectively_1-3-Representing an alkyl group) or a salt thereof, or k) R_cIs a compound of the general formula I which represents an amidino group substituted by a hydroxy group
To prepare, the general formula(Where R_a, R_b, A, Ar, X and Y are defined as described in claims 1 to 8.
Or nitrile) with hydroxylamine or a salt thereof, or l) R_bContains a carboxy group, and R_cAs in claims 1 to 8
Or defined as R_bIs defined as in claims 1 to 8, and R_c Is optionally a hydroxy group or one or two C_1-3In order to prepare compounds of the general formula I representing an amidino group which may be substituted by an -alkyl group, a compound of the general formula(Where R_a, A, Ar, X and Y are defined as in claims 1-8.
And R_b"" 'And R_c'Is R in claims 1 to 8_bAnd R_cThe meaning indicated for
Yes, but R_bFor hydrolysis, treatment with acids or bases, thermal decomposition or hydrogenolysis
Provided that it contains a group that can be converted to a carboxy group, and R_cIs the claim number
Defined as in paragraphs 1 to 8, or R_cIs hydrolyzed by acid or base
Hydroxy or 1 or 2 hydroxy groups as required by treatment, thermal decomposition or hydrogenolysis
C_1-3-Represents a group convertible to an amidino group which may be substituted by an alkyl group, and_bIs as defined in claims 1 to 8) by hydrolysis, treatment with an acid or a base, thermal decomposition or hydrogenolysis.
Compounds of general formula I wherein R_bContains a carboxy group, and R_cAre claims 1 to
Defined as in paragraph 8, or R_bIs as described in claims 1 to 8
Defined and R_cIs optionally a hydroxy group or one or two C_1-3-Represents an amidino group which may be substituted by an alkyl group), or m) R_cIs an amidino group (this is one or two C_1-8-Substituted by an -alkoxycarbonyl group or a group capable of being cleaved in a living body).
To prepare it, the general formula(Where R_a, R_b, A, Ar, X and Y are defined as described in claims 1 to 8.
Justified and R_c"Represents an amidino group) of the general formula Z₇ − R₁₇ (XXIV) (wherein, R₁₇Is C_1-8-Alkoxycarbonyl group or claims 1 to 8
Represents an acyl moiety of one of the groups that can be cleaved in vivo, and Z₇Is a nucleophilic group or nitro
With a protecting group used in these reactions to protect the reactive group, if necessary.
Cleaving and / or subsequently, if desired, R_cRepresents an amidino group, the compound of general formula I thus obtained
The product is reacted with a haloacetic acid derivative, followed by hydrolysis and decarboxylation to give 1
Or a corresponding amidino compound substituted by one or two methyl groups.
And / or R_cWherein the compound of the formula I thus obtained represents a hydroxyamidino group,
Can be converted to the corresponding amidino compound by oxidation and / or_bThe compound of general formula I thus obtained contains a carboxy group.
And / or R_bWherein the compound of general formula I thus obtained contains an O-alkyl-phosphinyl group, can be converted into the corresponding phosphinyl compound by ether cleavage, and / or
Or R_bContains a halogen atom. The compound of general formula I thus obtained is subjected to dehalogenation.
Can be converted to a more corresponding dehalogenated compound and / or R_bWhich comprises a quinolyl group by catalytic hydrogenation
May be converted to the corresponding tetrahydroquinolyl compound and / or if desired, the compound of general formula I thus obtained can be resolved into its stereoisomers,
And / or the compound of the general formula I thus obtained is treated with an inorganic or organic acid or base,
Characterized in that it is converted into its physiologically acceptable salt for pharmaceutical use.
9. A method for preparing the compound according to claim 1.