HRP980614A2 - N-(4-carbamimido-phenlyamino)-phenylglycinamidderivate - Google Patents

Description

The proposed invention relates to new derivatives of N-(4-carbamimidophenyl)glycinamide, especially to those having the formula

[image]

where

E is hydrogen or OH,

Q is hydrogen or alkyl,

R is aryl, cycloalkyl or alkyl substituted by R1, R2 and R3,

R1 is hydrogen, COOH, COO-alkyl or aryl,

R2 is hydrogen, aryl, cycloalkyl or heteroaryl,

R3 is hydrogen, aryl or (in a position different from the α-position with respect to the nitrogen atom touched by the alkyl group R) OH, alkoxy or, if necessary, a protected amino group,

N(Q,R) is COOH- or COO-alkyl-substituted pyrrolidino, piperidino or 1,2,3,4-tetrahydroisoquinolin-3-yl,

three of the radicals X1 to X4 independently represent the group C(Ra), C(Rb) or C(Rc) and the fourth radical is the group C(Rd) or N,

Ra to Rd independently represent H, OH, NO2, dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkyloxy, heteroarylalkyloxy, heterocyclylalkyloxy, COOH, COO-alkyl, NH-SO2-alkyl, NHSO2-aryl, NHCO-alkyl, NHCO- aryl, NHCOO-alkyl, NHCO-alkyl-NH2, NHCO-alkyl-NH-G, aralkyl-CONH, alkyl-O-alkyl-CONH, aryl-O-alkyl-CONH, alkyl-COOH, alkyl-COO-alkyl, O-alkyl-COOH or O-alkyl-COO-alkyl, or

two adjacent groups Ra to Rd together form alkylenedioxy, whereby a maximum of three of the radicals Ra to Rd may have the same meaning and X1 may not be CCOOH or CCOO-alkyl,

G is an amino protecting group and

one of the radicals G1 and G2 is hydrogen, and the other radical is hydrogen, alkyl, OH, alkoxy, aroyl, alkanoyl-OCH2, aroyl-OCH2 or the group COO-Rg or OCO-Rg,

Rg is alkyl optionally substituted with halogen, OH, alkoxy, COOH or with COO-alkyl,

and their hydrates or solvates and their physiologically acceptable salts.

The invention further relates to a process for the preparation of the above compounds, to pharmaceutical preparations of these compounds and to the use of these compounds for the preparation of pharmaceutical preparations.

Examples of physiologically acceptable salts of these compounds of formula I are salts with physiologically tolerable mineral acids, such as hydrochloric acid, sulfuric acid, sulfuric acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

The compounds of formula I can be solvated, especially hydrated. Hydration occurs during the preparation process or slowly as a consequence of the hygroscopic properties of the initial anhydrous compound of formula I.

Compounds of formula I contain at least one asymmetric carbon atom and can therefore exist as a mixture of enantiomers or as optically pure compounds.

In the context of the proposed invention "alkyl" alone or in combination, such as COO-alkyl, alkoxy, dialkylamino, aralkyloxy, heteroarylalkyloxy, heterocyclylalkyloxy, NHSO2-alkyl, NHCO-alkyl, aralkyl-CONH, alkyl-O-alkyl-CONH , alkyl-COOH, CCOO-alkyl, alkanoyl and the like, denotes a straight or branched group having up to 6, preferably up to 4 carbon atoms. Examples include methyl, ethyl and butyl.

"Aryl" by itself or in combination, such as aryloxy, aralkyl, NHSO2-aryl, NHCO-aryl, aralkyl-CONH, aryl-O-alkyl-CONH, aroyl and the like, means groups such as phenyl or naphthyl which may be substituted, for example with halogen, such as bromine, fluorine or chlorine; alkoxy such as methoxy, ethoxy or propoxy; alkylene-dioxy, such as methylenedioxy; hydroxyl, nitro, amino, amidino, sulfamoyl, phenyl, phenoxy, COOH or COO-alkyl, such as COOCH 3 or COOC 2 H 5 . Examples of aryl groups include phenyl and amidinophenyl, and of aralkyl groups: benzyl, phenethyl, naphthylmethyl, mono- or dimethoxybenzyl, aminobenzyl or nitrobenzyl, of aryloxy groups: phenoxy or methoxycarbonylphenoxy, of aralkyloxy groups: benzyloxy, nitrobenzyloxy, bromobenzyloxy, dichlorobenzyloxy, methoxybenzyloxy, phenoxybenzyloxy, phenethoxy or biphenylylmethoxy.

"Cycloalkylalkyl" means saturated groups having 3 to 7 carbon atoms linked through an alkyl group. An example of this group is cyclopropylmethyl.

"Heteroarylalkyl" by itself or in "heteroaryl-alkoxy" means an aromatic group having 5 to 10 members, which is connected through an alkyl or alkoxy group, and which consists of one or two rings and contains one or more nitrogen atoms. Examples of these are imidazolylethyl, indolylethyl, pyrimidinylmethoxy, indolylmethoxy, quinolylmethoxy or isolinolylmethoxy. "Heterocyclylalkyloxy" means a five- to ten-membered saturated or unsaturated non-aromatic group, which is connected through an alkoxy group, has one or two rings and contains one or more heteroatoms N, O and/or S. Examples of such groups are morpholinylethoxy, thiomorpholinylethoxy and tetrahydroquinolylmethoxy. Examples of COO-alkyl, NHSO2-alkyl and NHSO2-aryl groups are COOCH3, NHSO2CH3 and NHSO2C6H5. An example of an alkylenedioxy group is methylenedioxy.

Preferred compounds of formula I are those in which R 1 represents aryl, especially phenyl or amidinophenyl; aralkyl, especially benzyl, phenethyl, naphthylmethyl, mono- or dimethoxy-benzyl, aminobenzyl or nitrobenzyl; benzhydryl; cycloalkylalkyl, especially cyclopropylmethyl; or heteroarylalkyl, especially imidazolylethyl or indolylethyl.

Preferred compounds of formula I are further those in which Q is hydrogen or methyl, and/or in which R is aryl, such as phenyl, amidophenyl or carboxyphenyl, or in which R is alkyl substituted by R1, R2 and R3 and in which R1 is a COOH or COO-alkyl group, R 2 is aryl or H, and R 3 is aryl, H, amino or protected amino, or wherein R 1 is H, R 2 is aryl or heteroaryl and R 3 is H or OH.

Preferred alkyl groups R substituted by R1, R2 and R3 are methyl, ethyl, propyl and isopropyl.

Preferred aryl groups R, R1, R2 and R3 are phenyl groups substituted with COOH or COO-alkyl, such as COOCH3 or COOC2H5; NO 2 , NH 2 , SO 2 NH 2 , or with one or two OH groups or alkoxy, such as OCH 3 or OC 2 H 5 .

Preferred cycloalkyl groups R or R2 are cyclopentyl groups optionally substituted with COOH or COO-alkyl.

Preferred heteroaryl groups R2 are imidazolyl, indolyl or pyridinyl.

Preferred COO-alkyl groups R1 are COOCH3 and COOC2H5.

A preferred amino protected group R2 is NH-Boc (t-butoxycarbonylamino).

Preferred compounds of formula I are furthermore those in which one of the radicals G1 or G2 represents an OH or COO-alkyl group, such as COOCH3 or COOC2H5.

Preferred compounds of formula I are furthermore those in which X1 represents the group C(Ra) in which Ra is H, OH, NO2, halogen, especially fluorine; alkoxy, especially methoxy; NHSO2-alkyl or NHSO2-aryl, especially methanesulfonylamino or phenylsulfonylamino and/or in which X2 represents the group C(Rb) in which Rb is H, OH, NO2, alkyl, especially methyl; alkoxy, especially methoxy, ethoxy or butoxy; aryloxy, especially phenoxy; aralkyloxy, especially benzyloxy, and/or in which X3 represents the group C(Rc) in which Rc is H, OH, NO2, dialkylamino, especially dimethylamino; halogen, especially bromine; alkyl, especially methyl; alkoxy, especially methoxy, ethoxy or propoxy; aryloxy, especially methoxycarbonylphenoxy; aralkyloxy, especially benzyloxy, nitrobenzyloxy, bromobenzyloxy, dichlorobenzyloxy, methoxybenzyloxy, phenoxybenzyloxy, phenethoxy or biphenylylmethoxy; heteroarylalkyloxy, especially pyridinylmethoxy, indolylmethoxy, quinolylmethoxy or isoquinolylmethoxy; or heterocyclylalkyloxy, in particular morpholinylethoxy, thio-morpholinylethoxy or tetrahydroquinolinylmethoxy, or in which Rb and Rc together form an alkylenedioxy group, in particular a methylenedioxy group, and/or in which X4 represents a group C(Rd) in which Rd is H, NO2, alkoxy, in particular methoxy; or aralkyloxy, especially benzyloxy.

Preferred compounds of formula I are furthermore those in which X1 to X4 independently of each other represent the group C(Ra) to C(Rd) in which Ra to Rd represent NHCO-alkyl, such as NH-acetyl, NHCO-aryl such as NH- benzoyl, NHCOO-alkyl such as NHCOOCH 3 , NHCO-alkyl- (optionally protected amino), such as NHCOCH 2 NH 2 , NHCOCH 2 CH 2 NH 2 and NHCOCH 2 NH-Boc; aralkyl-CONH, such as benzyl-CONH, alkyl-O-alkyl-CONH, such as CH3OCH2CONH, alkyl-COOH, such as CH2CH2COOH, O-alkyl-COOH, such as O(CH2)1 or 3COOH and OCH(CH3)COOH, aryloxy, such as OC6H4COOH and aralkyloxy, such as OCH2C6H4COOH, where the COOH group can be replaced by a COO-alkyl group, such as COO(CH3 or C2H5).

Preferred compounds of the formula I are furthermore those in which one of X1 to X4 represents a nitrogen atom, and the remaining three independently of each other represent the group C(Ra), C(Rb) or C(Rc), especially those in which one of the groups Ra, Rb and Rc represents H and the remaining two represent lower alkoxy such as methoxy or ethoxy.

Preferred compounds of formula I are furthermore those in which one of the groups G1 and G2 represents hydrogen, and the other group is aroyl, especially benzoyl optionally substituted with halogen, such as fluorobenzoyl, alkyl-COOCH2-benzoyl or phenyl-COOCH2-benzoyl, or haloalkyl- OCO, as trichloroethyl-OCO.

Particular preference is given to compounds in which E, G1 and G2 and Q represent hydrogen, and/or in which R is alkyl substituted with R1, R2 or R3, especially methyl or ethyl, and especially where R1 is aryl, especially phenyl, or COOH, R2 is hydrogen or aryl, especially phenyl, and R3 is hydrogen, and/or in which X1 to X4 represent groups C(Ra) to C(Rd), especially a group in which Ra is H, aralkyloxy, especially carboxybenzyloxy; NHSO2-aryl, especially phenylsulfonyl-amino; aralkyl-CONH, especially phenylacetylamino, or O-alkyl-COOH, especially carboxymethoxy, Rb is H or alkoxy, especially methoxy or ethoxy, Rc is H, alkoxy, especially methoxy or aralkyloxy, especially benzyloxy, and Rd is H or alkoxy, especially methoxy.

Examples of such compounds are:

(R,S)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide,

2-(2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-(4-carbamimidoylphenylamino)acetamide and further

(RS)-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]diphenylacetic acid,

(RS)-and (SR)-3-[(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-3-phenylpropionic acid,

(S)-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid,

(S)-[(S)-2-(4-carbamimidoylphenylamino)-2-(3,5-di-methoxyphenyl)acetylamino]phenylacetic acid,

(RS)-3-[2-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenoxymethyl]benzoic acid,

(RS)-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)-methyl]-4,5-dimethoxyphenoxy]acetic acid,

(S)-[(R)-2-(2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-phenylacetic acid,

(S)-[(S)-2-(2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-phenylacetic acid,

(S)-[(R)-2-(2-benzyloxy-5-methoxy-2-phenylacetylamino-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid,

(S)-[(S)-2-(2-benzyloxy-5-methoxy-2-phenylacetylamino-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid.

Further examples of compounds of formula I are the following compounds:

(S)-2-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]propionic acid,

(S)-2-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]propionic acid,

(S)-2-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-3-phenylpropionic acid,

(S)-2-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-3-phenylpropionic acid,

(S)-2-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-3-(4-hydroxyphenyl)-propionic acid,

(S)-2-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-3-(4-hydroxyphenyl)-propionic acid,

(S)-1-[(R)- and -[(S)-(4-benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)acetyl]pyrrolidine-2-carboxylic acid,

(RS)-2-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoyl)phenylamino)acetylamino]-2-methylpropionic acid,

(S)-[[(R)-(4-benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)acetyl]methylamino]phenylacetic acid,

(S)-[[(S)-(4-benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)acetyl]methylamino]phenylacetic acid,

(RS)- and (SR)-[[(RS)-(4-benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)acetyl]pyrrolidine-3-carboxylic acid,

(RS)- or (SR)-2-[[(RS)-(4-benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)acetyl]-1,2,3,4-tetrahydro-

isoquinoline-3-carboxylic acid,

(RS)-1-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]cyclopentanecarboxylic acid,

(S)-2-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-4-tert.butoxycarbonyl-aminobutyric acid,

(S)-2-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-4-tert.butoxycarbonyl-aminobutyric acid,

(S)-2-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-3-tert.butoxycarbonyl-aminopropionic acid,

(S)-2-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-4-tert.butoxycarbonyl-aminopropionic acid,

(RS)-2-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-

Amimidoylphenylamino)acetylamino]benzoic acid,

(RS)-3-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-

Amimidoylphenylamino)acetylamino]benzoic acid,

(RS)-4-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]benzoic acid,

(E)- and/or (Z)-(S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl )phenylamino]-

acetylamino]propionic acid,

(E)- and/or (Z)-(S)-2-[(R)-2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetyl- amino]-3-

phenylpropionic acid,

(E)- and/or (Z)-(S)-2-[(S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetyl- amino]-3-

phenylpropionic acid,

(E)- and/or (Z)-(S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl )phenylamino]-

acetylamino]-3-(4-hydroxyphenyl)propionic acid,

(E)- and/or (Z)-(S)-1-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl )phenylamino]-

acetyl]pyrrolidine-2-carboxylic acid,

(E)- and/or (Z)-(RS)-2-[2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetyl-amino]-2 -

methylpropionic acid,

(E)- and/or (Z)-(S)-[[(R)- and -[[(S)-(4-benzyloxy-3-methoxyphenyl)-[4-(N-hydroxycarbamimidoyl)phenylamino]-

acetyl]methylamino]phenylacetic acid,

(E)- and/or (Z)-(RS)- and (SR)-1-[(RS)-(4-benzyloxy-3-methoxyphenyl)-[4-(N-hydroxycarbamimidoyl)phenylamino]-

acetyl]pyrrolidine-3-carboxylic acid,

(E)- and/or (Z)-(RS)- and (SR)-2-[(RS)-(4-benzyloxy-3-methoxyphenyl)-[4-(N-hydroxycarbamimidoyl)phenylamino]-acetyl] -

1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

(E)- and/or (Z)-(RS)- and (SR)-1-[2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-

acetylamino]cyclopentane-carboxylic acid,

(E)- and/or (Z)-(RS)- and (RS)-[2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-

acetylamino]diphenylacetic acid,

(S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-[(E)- and/or -[(Z)-N -hydroxycarbamimidoyl]phenylamino]-acetylamino]-4-tert.butoxycarbonylaminobutyric acid,

(S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-[(E)- and/or -[(Z)-N -hydroxycarbamimidoyl]phenylamino]-acetylamino]-3-tert.butoxycarbonylaminopropionic acid,

(E)- and/or (Z)-(RS)-3-[2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-acetyl-amino]- 3-tert.butoxycarbonylaminopropionic acid,

(E)- and/or (Z)-(RS)-4-[2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetyl-

amino]benzoic acid,

(E)- and/or (Z)-(RS)-3-[(SR)-2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetyl- amino]-3-phenylpropionic acid,

(S)-4-amino-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]butyric acid,

(S)-3-amino-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]propionic

acid,

(E)- and/or (Z)-(S)-[(R)- or -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino ]-

acetylamino-phenyl acetic acid,

(S)-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]phenyl acetic acid,

(R)-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoyl)phenylamino)acetylamino]phenyl acetic acid,

(R)-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]phenyl acetic acid,

ethyl (E)- and/or (Z)-(S)-3-(4-aminophenyl)-2-[(R)- and

-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetylamino]propionate,

ethyl (S)-3-(4-aminophenyl)-2-[(R)- and -[(S)-2-(4-benzyl-oxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetyl-

amino]propionate,

(S)-3-(4-aminophenyl)-2-[(R)-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]propionic acid,

(S)-3-(4-aminophenyl)-2-[(S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]propionic acid,

(S)-[(R)-2-(4-carbamimidoylphenylamino)-2-(3,5-di-methoxyphenyl)acetylamino]phenylacetic acid,

(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimido-ylphenylamino)-N-[2-(3,4-dihydroxyphenyl)ethyl]-acetamide,

(RS)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-methylacetamide,

(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[2-(4-sulfamoylphenyl)ethyl]acetamide,

(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-(2-pyridin-2-ylethyl)acetamide,

(RS)-N-[2-(4-aminophenyl)ethyl]-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide,

(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[(R)-2-hydroxy-1-phenylethyl]acetamide,

(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[(R)-2-hydroxy-1-phenylethyl]acetamide,

(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[(S)-2-hydroxy-1-phenylethyl]acetamide,

(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[(S)-2-hydroxy-1-phenylethyl]acetamide,

(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[(R)-1-phenylethyl]acetamide,

(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[(R)-1-phenylethyl]acetamide,

(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[(S)-1-phenylethyl]acetamide,

(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[(S)-1-phenylethyl]acetamide,

(E)- and/or (Z)-(RS)-N-benzyl)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimoyl)phenylamino]-N-

methylacetamide,

(E)- and/or (Z)-(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[2-(4-sulfamoyl-

phenyl)ethyl]acetamide,

(E)- and/or (Z)-(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-(2-pyridin-2-yl -

ethyl)acetamide,

(E)- and/or (Z)-(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[2-(4-nitro-

phenyl)ethyl]acetamide,

(E)- and/or (Z)-(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[(R)-2-hydroxy -1-

phenylethyl]acetamide,

(E)- and/or (Z)-(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[(R)-2-hydroxy -1-

phenylethyl]acetamide,

(E)- and/or (Z)-(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[(S)-2-hydroxy -1-

phenylethyl]acetamide,

(E)- and/or (Z)-(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[(S)-2-hydroxy -1-

phenylethyl]acetamide,

(E)- and/or (Z)-(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[(R)-1-phenyl -

ethyl]acetamide,

(E)- and/or (Z)-(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[(R)-1-phenyl -

ethyl]acetamide,

(E)- and/or (Z)-(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[(S)-1-phenyl -

ethyl]acetamide,

(E)- and/or (Z)-(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[(S)-1-phenyl -

ethyl]acetamide,

(RS)-N-[2-[benzyloxycarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-5-benzyloxy-4-methoxyphenyl]benzamide acetate,

methyl (RS)-[2-[benzyloxycarbamoyl-(4-carbamimidoyl-phenylamino)methyl]-5-benzyloxy-4-methoxyphenyl]carbamate acetate,

(RS)-2-(2-acetamino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-(4-carbamimidoylphenylamino)acetamide,

(RS)-N-benzyl-2-(4-benzyloxy-5-methoxy-2-phenylacetyl-aminophenyl)-2-(4-carbamimidoylphenylamino)acetamide,

(RS)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(4,5-dimethoxy-2-phenylacetylaminophenyl)acetamide,

methyl (RS)-[2-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenyl]carbamate,

(RS)-N-[2-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenyl]benzanide,

(RS)-N-[2-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4-methoxyphenyl]benzanide,

(RS)-2-(2-benzenesulfonylamino-5-methoxyphenyl)-N-benzyl-2-(4-carbamimidoylphenylamino)acetamis,

(RS)-N-(2-[benzylcarbamoyl-[4-(N-hydroxycarbamimido-ylphenylamino)methyl]-5-benzyloxy-4-methoxyphenoxy)-benzamate,

methyl (RS)-(2-[benzylcarbamoyl-[4-(N-hydroxycarbamidoyl)phenylamino]methyl]-5-benzyloxy-4-methoxyphenoxy)-

carbamate,

(E)- and/or (Z)-(RS)-2-(2-acetylamino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-[4-(N-hydroxycarbamimidoyl)-

phenylamino]acetamide,

(E)- and/or (Z)-(RS)-N-benzyl-2-(4-benzyloxy-5-methoxy-2-phenylacetylaminophenyl)-2-[4-(N-hydroxycarbam-

imidoyl)phenylamino]acetamide,

(E)- and/or (Z)-(RS)-N-benzyl-2-(4,5-dimethoxy-2-phenyl-acetylaminophenyl)-2-[4-(N-hydroxycarbamimidoyl)phenyl-

amino]acetamide,

methyl (E)- and/or (Z)-(RS)-[2-[benzylcarbamoyl-[4-(N-hydroxycarbamimoyl)phenylamino]methyl]-4,5-dimethoxy-

phenyl]carbamate,

(E)- and/or (Z)-(RS)-[2-[benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenyl]benzamide,

(E)- and/or (Z)-(RS)-N-[2-[benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4-methoxyphenyl]-benzamide,

(E)- and/or (Z)-(RS)-2-(2-phenylsulfonylamino-5-methoxy-phenyl)-N-benzyl-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-

acetamide,

(RS)-2-[4-benzyloxy-5-methoxy-2-(2-methoxyacetyl-amino)phenyl]-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-acetamide,

(RS)-N-benzyl-2-[4-benzyloxy-5-methoxy-2-(2-methoxy-acetylamino)phenyl]-2-(4-carbamimidoylphenylamino)acetamide,

tert.butyl (RS)-[(2-[benzylcarbamoyl-[4-(N-hydroxy-carbamimidoyl)phenylamino]methyl]-5-benzyloxy-4-methoxy-

phenylcarbamoyl)methyl]carbamate,

(RS)-2-[2-(2-aminoacetylamino)-4-benzyloxy-5-methoxy-phenyl]-N-benzyl-2-(4-carbamimidoylphenylamino)acetamide,

(RS)-4-[2-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenoxymethyl]benzoic acid,

(RS)-4-[2-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenoxy]butyric acid,

(RS)-[2-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4-methoxyphenoxymethyl]acetic acid,

(RS)-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)-methyl]-4,6-dimethylphenoxy]acetic acid,

(E)- and/or (Z)-(RS)-3-[2-[benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxymethyl]benzoic acid,

(E)- and/or (Z)-(RS)-[2-[benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxy]acetic acid,

(E)- and/or (Z)-(RS)-4-[2-[benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxymethyl]benzoic acid,

(E)- and/or (Z)-(RS)-4-[2-[benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxy]butyric acid,

(E)- and/or (Z)-(RS)-[2-[benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4-methoxyphenoxy]-acetic acid,

(E)- and/or (Z)-(RS)-[2-[benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,6-dimethyl-phenoxy]acetic acid,

(E)- and/or (Z)-(R)-2-[2-[(R)-benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxy]propionic acid,

(E)- and/or (Z)-(R)-2-[2-[(S)-benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxy]propionic acid,

(R)-2-[2-[(R)-benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenoxy]propionic acid,

(R)-2-[2-[(S)-benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenoxy]propionic acid,

(E)- and/or (Z)-(S)-2-[2-[(R)-benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxy]propionic acid,

(E)- and/or (Z)-(S)-2-[2-[(S)-benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxy]propionic acid,

(S)-2-[2-[(R)-benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenoxy]propionic acid,

(S)-2-[2-[(S)-benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenoxy]propionic acid,

(RS)-3-[4-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-2-methoxyphenoxy]benzoic acid,

(RS)-2-[4-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-2-methoxyphenoxy]benzoic acid,

(RS)-4-[4-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-2-methoxyphenoxy]benzoic acid,

(RS)-3-(4-[benzylcarbamoyl-[4-(N-hydroxycarbamidoyl)phenylamino]methyl]-2-methoxyphenoxy)benzoic acid,

(RS)-4-(4-[benzylcarbamoyl-[4-(N-hydroxycarbamidoyl)phenylamino]methyl]-2-methoxyphenoxy)benzoic acid,

methyl (RS)-5-[benzylcarbamoyl-[4-(N-hydroxycarbam-

imidoyl)phenylamino]methyl]-2,3-dimethoxybenzoate,

methyl (RS)-5-[benzylcarbamoyl-[4-carbamimidoylphenyl-amino)methyl]-2,3-dimethoxybenzoate,

(RS)-5-[benzylcarbamoyl-(4-carbamimidoylphenylamino)-methyl]-2,3-dimethoxybenzoic acid,

(RS)-2-(4-[benzylcarbamoyl-[4-(N-hydroxycarbamidoyl)phenylamino]methyl]-2-methoxyphenoxy)benzoic acid,

(E)- and/or (Z)-(RS)-3-[2-[benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenyl]propionic acid,

(RS)-3-[2-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenyl]propionic acid,

(E)- and/or (Z)-(RS)-2-(3-acetylaminophenyl)-N-benzyl-2-[4-(N-(N-hydroxycarbamimidoyl)phenylamino]acetamide,

(RS)-2-(3-acetylaminophenyl)-N-benzyl-2-(4-carbamimidoylphenylamino)acetamide,

(RS)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3-nitrophenyl)acetamide,

(RS)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(2,6-dimethoxypyridin-4-yl)acetamide,

(RS)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(4,6-dimethoxypyridin-2-yl)acetamide,

(RS)-N-benzyl-2-(4-benzyloxy-3,5-dimethylphenyl)-2-(4-carbamimidoylphenylamino)acetamide,

(RS)-N-benzyl-2-(3-benzyloxy-5-propoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide hydrochloride,

(RS)-N-benzyl-2-(3,5-bisbenzyloxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide hydrochloride,

(RS)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(2,6-diethoxypyridin-4-yl)acetamide,

(RS)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-[3-hydroxy-4-(N-hydroxycarbamimidoyl)phenylamino]acetamide,

(RS)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-(4-carbamimidoyl-3-hydroxyphenylamino)acetamide,

(S)-[(R)- and -[(S)-2-(2-phenylsulfonylamino-4-benzyl-oxy-5-methoxyphenyl)-2-[4-[(E)- and/or -[( Z)-(N-hydroxy-

carbamimidoyl)phenylamino]acetylamino]phenylacetic acid,

(S)-[(R)- and -[(S)-2-(4-benzyloxy-5-methoxy-2-phenyl-acetylaminophenyl)-2]-4-[(E)- and/or -[( Z)-(N-hydroxy-

carbamimidoyl)phenylamino]acetylamino]phenylacetic acid,

(S)-[(R)-2-(2-acetylamino-4-benzyloxy-5-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenyl-acetic acid,

(S)-[(S)-2-(2-acetylamino-4-benzyloxy-5-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenyl-acetic acid,

(RS)-N-[amino-(4-[[benzylcarbamoyl-(4-benzyloxy-3-ethoxyphenyl)methyl]amino]phenyl)methylene]-4-fluorobenzamide,

(RS)-2-[[amino-(4-[[benzylcarbamoyl-(4-benzyloxy-3-ethoxyphenyl)methyl]amino]phenyl)methylene]carbamoyl]benzyl benzoate,

2,2,2-trichloroethyl (RS)-[amino-(4-[[benzylcarbamoyl-(4-benzyloxy-3-ethoxyphenyl)methyl]amino]phenyl)methylene]-carbamate,

methyl (RS)-[amino-(4-[[benzylcarbamoyl-(4-benzyloxy-3-ethoxyphenyl)methyl]amino]phenyl)methylene]carbamate.

Compounds of formula I according to the invention can be prepared

a) by the reaction of the aldehyde of the formula

[image]

with isonitrile of the formula R1NC and 4-aminobenzamidine of the formula

[image]

or

b) by converting the cyano group CN, which is in the corresponding nitrile of the formula below

to the amidino group C(N-G1)NH-G2,

c) if desired, the reactive group contained in compound I can be functionally changed, i

d) the compound of formula I can, if desired, be converted into a physiologically acceptable salt, or the salt of compound I can be converted into a free acid or base.

The reaction of substituted benzaldehyde of formula II, isonitrile of formula RCN and 4-aminobenzamidine of formula III is expediently carried out in a solvent such as methanol, isopropanol, ethanol, dioxane, tetrahydrofuran, or in a mixture of solvents, such as tetrahydrofuran and water, or isopropanol and water, expediently using an inorganic acid as hydrochloric acid, sulfuric acid or boron trifluoride etherate, or organic acids such as toluenesulfonic acid, or in an acidic ion exchanger, such as Amberlyst K10, as a catalyst, at a temperature between 0°C and 100°C, thereby obtaining compounds of formula I. Reaction of a substituted aldehyde of formula II, isonitrile of formula R1CN and 4-aminobenzonitrile under similar reaction conditions leads to compounds of formula IV in which Q represents hydrogen.

Compounds of formula IV were also obtained

a) by the reaction of aldehyde of formula II, benzyl isonitrile and, if necessary, hydroxylated 4-aminobenzonitrile in anhydrous methanol and boron trifluoride etherate,

b) followed by treatment with water, i

c) hydrolysis of the obtained compound of formula V

[image]

for example, expediently in THF using lithium hydroxide and then

d) conversion of the obtained acid of formula VI

[image]

to the corresponding nitrile of formula IV by reaction with an amine of formula HN(R,Q) in a solvent such as DMF or dichloromethane with the addition of a coupling agent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) in the presence of carbodiimide such as diisopropylcarbodiimide or dichlorohexylcarbodiimide, and if appropriate, a tertiary amine such as diisopropylamine.

Compounds of formula IV can also be obtained by converting a compound of formula IV, in which one of the groups X 2 , X 3 and X 4 represents C-O-allyl or C-O-benzyl, into the corresponding phenol, and then, if desired, by alkylation. The allyl group is preferably removed in an aprotic solvent, such as tetrahydrofuran (THF), using a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium in THF, in the presence of a reducing agent such as sodium borohydride. The benzyl group is primarily removed by catalytic hydrogenation (Pd/C) in a solvent, for example ethanol and dioxane. The resulting phenol can then, if desired, be alkylated in a solvent such as THF, using triphenylphosphine and diethyl azodicarboxylate as catalysts, and in the appropriate alcohol. Alkylation can also be carried out using a suitable alkyl bromide in acetone or DMF in the presence of K 2 CO 3 .

Reactive groups, which are present in the compounds of formulas I and IV to VI, can be functionally changed for example as follows:

The C-NO2 group in X1, X2, X3 or X4 can be reduced by catalytic hydrogenation (Pd, Pt or Ni) in a solvent, for example ethyl acetate and ethanol, to give the C-NH2 group.

The C-NH2 group in X1, X2, X3 or X4 can be acylated, for example in THF, in the presence of diisopropylethylamine, using an acyl chloride, such as benzoyl chloride, to give the C-NH-acyl group. A suitable acid chloride can be used instead of the acyl chloride. In this case, proceed as described above for the reaction of the amine HN(R,Q) with the acid of formula VI.

C-Br in the groups X1, X2, X3 or X4 can be converted to a C-alkyl group, or to a group X1, X2, X3 or X4 which is connected via alkyl. In the first step, for example, bromide IV is converted to dimethylacetamide, using a terminally unsaturated compound such as CH2=CH-alkyl-COOH, triethylamine, Pd acetate and tri-o-tolyl phosphine, to the corresponding compound IV in which X1 , X2, X3 or X4 denotes CCH=CH-alkyl-COOH. The resulting unsaturated acid IV is hydrogenated, for example, in ethanol and THF using hydrochloric acid and Pd/C to give the corresponding acid IV in which X1, X2, X3 or X4 represents the group CCH2CH2-alkyl-COOH.

The COO-alkyl group present in the R group can be hydrolyzed in THF using LiOH to give COOH.

To convert CN to the group C(N-G1)NH-G2, in which one of the groups G1 and G2 is H and the other is OH, the nitrile starting material of formula IV is dissolved in a solvent such as DMF, ethanol or methanol and added to a reaction solution containing a base such as diisopropylethylamine or triethylamine, sodium hydride, sodium methoxide or sodium hydroxide, and hydroxylamine or a salt of hydroxylamine with an inorganic acid such as hydroxylamine hydrochloride, preferably at a temperature of up to 80oC.

To convert CN to C(NH)NH2, the nitrile starting material can be gas-treated in a solvent such as ethanol or methanol, or in a mixed solvent such as chloroform and methanol or chloroform and ethanol, using a stream of dry hydrogen chloride, preferably at below 10oC. The reaction solution is mixed with a solvent such as diethyl ether, and the intermediate thus precipitated is filtered off. The intermediate can then be dissolved in water, neutralized with a base such as sodium carbonate or sodium hydroxide, and extracted from the aqueous phase using a solvent such as dichloromethane, chloroform or ethyl acetate. The obtained material is processed in a solvent such as methanol or ethanol with gaseous ammonia or with an ammonium salt such as ammonium chloride, preferably at a temperature up to 80oC. Alternatively, the intermediate is filtered off and treated immediately with gaseous ammonia or with the ammonium salt in methanol or ethanol.

For the conversion of CN to C(NH)NH2, it is also possible to hydrogenate a mixture of the compound of formula I obtained after the conversion of CN to the group C(N-G1)NH-G2, in which one of the groups G1 and G2 is H and the other is OH, in a solvent such as ethanol, methanol, dioxane, THF or in glacial acetic acid or in a solvent mixture such as ethanol and glacial acetic acid, using hydrogen and a catalyst such as palladium, platinum or nickel. The nitro group Ra, Rb, Rc or Rd, contained in the compound of formula I, is reduced to an amino group. If the hydrogenation is carried out using palladium, the benzyloxy group Ra, Rb, Rc or Rd, present in the amidoxime of formula I, is converted to a hydroxyl group.

By reacting a compound of formula I, in which G1 and G2 represent hydrogen, in a solvent such as dichloromethane, dioxane or DMF, or in a solvent mixture such as dichloromethane and water or ethyl acetate and water in the presence of an organic base such as pyridine or triethylamine, or an inorganic base such as of sodium hydroxide, sodium carbonate or potassium bicarbonate, with chloroformate of the formula ClC(O)O-A or 2,4-dinitrophenyl formate of the formula [2,4(NO2)2-C6H5]OC(O)O-A gives the corresponding compound in which G1 and G2 represent the group C(O)O-A and A denotes alkyl.

By reacting the compound of formula I, in which G1 and G2 represent hydrogen, with acyl chloride, such as aroyl chloride, the corresponding compound of formula I is obtained, in which one of the groups G1 and G2 represents hydrogen, and the other group is acyl. Analogously, a compound of formula I can be converted into a compound of formula I in which G1 and G2 represent hydrogen with a p-nitrophenyl carbonate of the formula p-NO3C6H4OCOO-R into the corresponding compound I in which one of the groups G1 and G2 represents COO-R. To carry out this reaction, acyl chloride or p-nitrophenyl carbonate in THF and DMF is mixed first with N,N-diisopropylethylamine and then with unsubstituted amidine of formula I.

The protected amino group, which is in the R group, can be converted into a free amino group. Thus, the compound of formula I, which contains a Boc-protected amino group, can be converted in methylene chloride with trifluoroacetic acid to free amine I.

Furthermore, some of the examples below contain more details regarding the preparation of certain starting materials and intermediates.

The compounds of formula IV, V and VI are new and therefore also form part of the main subject of the proposed invention. Compounds of formulas II and III are known or can be produced analogously to known compounds. Thus, if necessary, 2-substituted 4-aminobenzamidines III were obtained from the corresponding 4-amino-benzonitriles via 4-nitrobenzonitrile.

The compounds of formula I or their solvates and salts inhibit the formation of coagulation factors Xa, IXa and thrombin induced with factor VIIa and tissue factor.

The compounds in question influence the aggregation of platelets induced with these factors and the coagulation of plasmatic blood. They therefore inhibit the formation of thrombus and can be used to suppress or prevent diseases such as thrombosis, apoplexy, marrow blockage, inflammation and arteriosclerosis. Furthermore, these compounds affect tumor cells and prevent metastases. They can therefore also be used as antitumor agents.

Inhibition of the amidolytic activity of factor VIIa/tissue factor complexes with compounds of the invention was demonstrated using a chromogenic peptide substrate, as described below.

Measurements were performed on microtiter plates at room temperature. To carry out the experiment in each well of the plate k 25 μl inhibitor solution in buffer (pH 7.5, 100 mM, containing 0.14 M NaCl, 0.1 M N(2-hydroxyethyl)-piperazine-N'-(2 -ethanesulfonic acid) (HEPES), 0.5 mg/l BSA without fatty acids (albumin from calf serum) and 0.05% NaN3) were added to 100 μl of a solution of 26 nM tissue factor, 9 nM solution of factor VIIa and 8 mM calcium chloride. After incubation for 15 minutes, the reaction was initiated by the addition of 50 μl of the chromogenic substrate Chromazym-tPA (3.5 mM, MeSO2-D-Phe-Gly-Arg-paranitroanilide) and then the hydrolysis of the substrate was read for 10 minutes spectrophotometrically on a kinetic microtiter plate reader. By means of a graphical display of the inhibition curves, Ki values were determined in accordance with the method described in Biochem. J. 55, 1953, 170-171. The results are shown in the table below (Ki and microM):

[image]

As mentioned at the beginning, drugs containing a compound of formula I, its solvate or its salt, are also part of the main subject of the proposed invention, and furthermore also the process for the preparation of such drugs, which is characterized by the fact that one or more such compounds, its solvates or salts, and optionally, other therapeutically useful substances prepared as pharmaceutical formulations. These drugs can be administered orally, for example in the form of sugar-coated tablets, as hard and soft gelatin capsules, as solutions, emulsions or suspensions, or rectally, for example in the form of suppositories, or as a spray. However, administration can also be carried out parenterally, for example in the form of solutions for injections.

To prepare tablets, film-coated tablets, sugar-coated tablets and hard gelatin capsules, the active ingredient is mixed with pharmaceutically inert inorganic or organic excipients. Excipients suitable for tablets, film-coated tablets, sugar-coated tablets and hard gelatin capsules are, for example, lactose, corn starch or their derivatives, talc, stearic acid or its salts. Excipients suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; however, depending on the properties of the active ingredient, some soft gelatin capsules require no excipients at all. Excipients suitable for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose; suitable excipients for use in injectable solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils; and natural and hardened oils, waxes, fats, semi-solid or liquid polyols are suitable for use in suppositories. In addition, pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, dyes, aromas, salts for adjusting osmotic pressure, buffers, coatings or antioxidants.

The dosage of the active ingredient for the control and/or prevention of the above-mentioned diseases can vary widely and must, of course, be adapted to the individual circumstances in each individual case. In general, for oral or parenteral, for example intravenous or subcutaneous administration, an adequate dose for adults should be 0.1 to 20 mg/kg, preferably approx. 0.6 to 4 mg/kg, but the upper limit just mentioned may be exceeded, or the dose may be lower if appropriate.

Example 1

At room temperature, 1 mmol of 4-aminobenzamidine dihydrochloride (208 mg), 1 mmol of triethylamine (101 mg), 1 mmol of benzyl isonitrile (117 mg) and 1 mmol of 4-benzyloxy-3-methoxybenzaldehyde (260 mg) are mixed for 5 days in a solvent mixture of 1.2 ml of isopropanol and 0.8 ml of water. Then the mixture is mixed with 0.5 ml of 25% hydrochloric acid and stirred for 1 hour at room temperature, the secreted crystals are filtered off and washed with 5 ml of water. This gives 218 mg (41%) of (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide hydrochloride as colorless crystals. ISP-MS: 495.5 ([M+H] + , 100).

Example 2

The following compounds were produced by the method described in example 1:

2.a) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3,4-dimethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3,4-dimethoxy-phenyl)acetamide hydrochloride as colorless crystals.

ISP-MS: 455 ([M+H] + , 100).

2.b) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and piperonylbenzaldehyde gave (R,S)-2-benzo[1,3]dioxol-5-yl-N-benzyl-2-(4-carbamimidoylphenyl-amino)acetamide hydrochloride as colorless crystals.

ISP-MS: 439 ([M+H] + , 100).

2.c) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2-hydroxy-4-methoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(2-hydroxy-4-methoxyphenyl) )acetamide hydrochloride as colorless crystals. ISP-MS: 405 ([M+H] + , 100).

2.d) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 4-hydroxy-3-methoxy-5-nitrobenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(4-hydroxy -3-methoxy-5-nitrophenyl)acetamide hydrochloride as colorless crystals. ISP-MS: 450 ([M+H] + , 100).

2.e) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 4-hydroxy-3,5-dimethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(4-

hydroxy-3,5-dimethoxyphenyl)acetamide hydrochloride as colorless crystals. ISP-MS: 435 ([M+H] + , 100).

2.f) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and methyl 4-formylbenzoate gave (R,S)-4-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]benzoate hydrochloride as colorless crystals.

ISP-MS: 417 ([M+H] + , 100).

2.g) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2,3,4-trimethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(2,3,4-trimethoxyphenyl) )acetamide hydrochloride as colorless crystals. ISP-MS: 449 ([M+H] + , 100).

2.h) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3,4-dimethylbenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3,4-dimethylphenyl)-acetamide hydrochloride as colorless crystals.

ISP-MS: 387 ([M+H] + , 100).

2.i) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 4-methoxy-3-methylbenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(4-methoxy-3-methylphenyl) )acetamide hydrochloride as colorless crystals. ISP-MS: 403 ([M+H] + , 100).

2.j) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 4,5-dimethoxy-2-nitrobenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(4,5-dimethoxy -2-nitrophenyl)acetamide hydrochloride as colorless crystals. ISP-MS: 464 ([M+H] + , 100).

2.k) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2,3-dimethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(2,3-dimethoxy-phenyl)acetamide hydrochloride as colorless crystals.

ISP-MS: 419 ([M+H] + , 100).

2.l) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2,4,5-trimethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(2,4,5-trimethoxyphenyl) )acetamide hydrochloride as colorless crystals. ISP-MS: 449 ([M+H] + , 100).

2.m) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3-hydroxy-4-methoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3-hydroxy-4-methoxyphenyl) )acetamide hydrochloride as colorless crystals. ISP-MS: 405 ([M+H] + , 100).

2.n) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2,4-dimethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(2,4-dimethoxy-phenyl)acetamide hydrochloride as colorless crystals.

ISP-MS: 419 ([M+H] + , 100).

2.o) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2-fluoro-4,5-dimethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(2-fluoro-4 ,5-dimethoxyphenyl)acetamide hydrochloride as colorless crystals. ISP-MS: 437 ([M+H] + , 100).

2.p) 4-aminobenzamidine dihydrochloride, triethylamine, cyclopropylmethylisonitrile and 3,4,5-trimethoxybenzaldehyde gave (R,S)-2-(4-carbamimidoylphenylamino)-N-cyclopropyl-methyl-2-(3,4,5 -trimethoxyphenyl)acetamide hydrochloride as colorless crystals. ISP-MS: 413 ([M+H] + , 100).

2.q) 4-aminobenzamidine dihydrochloride, triethylamine, 3,4-dimethoxybenzylisonitrile and 3,4,5-trimethoxybenzaldehyde gave (R,S)-2-(4-carbamimidoylphenylamino)-N-(3,4-di-

methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)acetamide

hydrochloride as colorless crystals.

ISP-MS: 509 ([M+H] + , 100).

2.r) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and methyl 2-(formyl-2-methoxyphenoxy)benzoate gave (R,S)-2-{4-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]- 2-Methoxyphenoxy}benzoate hydrochloride as colorless crystals. ISP-MS: 539.4 ([M+H] + , 100).

2.s) 4-aminobenzamidine dihydrochloride, triethylamine, 2-phenylethylisonitrile and 4-dimethylamino-3-nitrobenzaldehyde gave (R,S)-N-(2-phenylethyl)-2-(4-carbamimidoylphenylamino)-2-(4 -dimethylamino-3-nitrophenyl)acetamide hydrochloride as colorless crystals. ISP-MS: 461.7 ([M+H] + , 100).

2.t) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3,5-dimethoxy-4-methylbenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3,5-dimethoxy -4-methylphenyl)acetamide hydrochloride as colorless crystals. ISP-MS: 433 ([M+H] + , 100).

2.u) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3-phenoxybenzaldehyde gave (R,S)-N-benzyl-2-(3-phenoxyphenyl)-2-(4-carbamimidoylphenylamino)-acetamide hydrochloride as colorless crystals.

ISP-MS: 451.6 ([M+H] + , 100).

2.v) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3,5-bis-benzyloxybenzaldehyde gave (R,S)-N-benzyl-2-(3,5-bis-benzyloxyphenyl)-2-(4-carbam -imidoylphenylamino)acetamide hydrochloride as colorless crystals. ISP-MS: 571 ([M+H] + , 100).

2.w) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3-benzyloxy-4-hydroxybenzaldehyde gave (R,S)-N-benzyl-2-(3-benzyloxy-4-hydroxyphenyl)-2-(4-carbamimidoylphenylamino )acetamide hydrochloride as colorless crystals. ISP-MS: 481 ([M+H] + , 100).

2.x) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 4-bromo-3,5-dimethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-bromo-3,5-dimethoxyphenyl)-2- (4-Carbamimidoylphenylamino)acetamide hydrochloride as colorless crystals. ISP-MS: 498 ([M+H] + , 100).

2.y) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3,5-dimethoxy-4-nitrobenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3,5-di -methoxy-4-nitrophenyl)acetamide hydrochloride as colorless crystals. ISP-MS: 464 ([M+H] + , 100).

Example 3

10 mmol of 4-aminobenzamidine dihydrochloride (2.8 g), 10 mmol of triethylamine (1.01 g), 0.5 ml of water, 10 mmol of 4-benzyloxy-3-methoxybenzaldehyde (2.6 g) and 10 mmol of benzyl isonitrile (1 .2 ml) are first mixed in 40 ml of methanol and then 3.8 ml of boron trifluoride ether (30 mmol) is added drop by drop while cooling in an ice bath for 2 hours. The mixture was stirred for an additional hour at room temperature, then the solvent was removed under reduced pressure and the crude product was chromatographed on an RP-18 column using water/methanol as the flow phase. Alternatively, the crude product is cooled with ice, mixed with 5 ml of 25% hydrochloric acid, 10 ml of dichloromethane and 10 ml of water are added and the precipitated crystals are filtered off with suction after 5 hours. This gives 1.6 g (30%) of (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide hydrochloride as colorless crystals. ISP-MS: 495.5 ([M+H] + , 100). Chromatography of the crude product on an RP-18 column using water/methanol as the flow phase with 0.1% trifluoroacetic acid gave 0.8 g (15%) of (R,S)-N-benzyl-2-(4-benzyloxy-3- methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide trifluoroacetate as colorless crystals.

ISP-MS: 495.2 ([M+H] + , 100).

Example 4

10 mmoles of 4-aminobenzonitrile (1.2 g), 0.5 ml of water and 10 mmoles of 4-benzyloxy-3-methoxybenzaldehyde (2.6 g) are first mixed in 40 ml of methanol and stirred for one hour at room temperature. 10 mmoles (1.2 ml) of benzyl isonitrile are added and then 3.8 ml of boron trifluoride ether is added drop by drop while cooling in an ice bath and stirring for 2 hours. The mixture was stirred for another hour at room temperature, then the solvent was removed under reduced pressure and the crude product was filtered through a column of silica gel using hexane/ethyl acetate as the flow phase. The main fraction was concentrated and the resulting crude (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)acetamide was dissolved in a solvent mixture of 20 ml of chloroform and 4 ml of methanol, and then dry gaseous hydrogen chloride is introduced with stirring and at a temperature below 5oC for 20 minutes. Then the reaction mixture is allowed to stand for 24 hours at 5oC, then 20 ml of diethyl ether is added and the precipitated crystals are filtered off by suction and washed with diethyl ether, and the residue is taken up in methanol saturated with ammonia. The ammonia solution was refluxed for 2 hours and then the solvent was removed using a water vacuum pump. Then 5 ml of 1N hydrochloric acid solution was added to the residue and the solvent was removed once again using a water vacuum pump. The obtained crude product is chromatographed on an RP-18 column using water/methanol as the flow phase. This gives 228 mg (43%) of (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-

carbamimidoylphenylamino)acetamide hydrochloride as colorless crystals. ISP-MS: 495.5 ([M+H] + , 100).

Example 5

The following compounds were produced by the method described in example 4:

5.a) 4-aminobenzonitrile, benzylisonitrile and 3,4,5-tri-methoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3,4,5- trimethoxyphenyl)acetamide hydrochloride as colorless crystals. ISP-MS: 449.2 ([M+H] + , 100).

5.b) 4-aminobenzonitrile, benzyl isonitrile and 3,5-di-methoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3,5-dimethoxyphenyl)acetamide hydro -chloride as colorless crystals. ISP-MS: 419 ([M+H] + , 100).

5.c) 4-aminobenzonitrile, benzhydryl isonitrile and 3,4-di-methoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3,4-dimethoxyphenyl)acetamide hydro -chloride as colorless crystals. ISP-MS: 495 ([M+H] + , 100).

5.d) 4-aminobenzonitrile, benzyl isonitrile and 3,4-di-ethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3,4-diethoxyphenyl)acetamide hydro -chloride as colorless crystals. ISP-MS: 447.2 ([M+H] + , 100).

5.e) 4-aminobenzonitrile, benzhydryl isonitrile and 4-benzyloxy-3-methoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenyl-amino) -acetamide hydrochloride as colorless crystals.

ISP-MS: 571.4 ([M+H] + , 100).

5.f) 4-aminobenzonitrile, benzhydryl isonitrile and 4-benzyloxy-3-ethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-(4-carbamimidoylphenylamino)-acetamide hydrochloride as colorless crystals.

ISP-MS: 585.4 ([M+H] + , 100).

5.g) 4-aminobenzonitrile, benzylisonitrile and 4-benzyl-oxy-3-ethoxybenzaldehyde gave (R,S)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-(4-carbamimidoylphenylamino) -acetamide hydrochloride as colorless crystals.

ISP-MS: 509.4 ([M+H] + , 100).

5.h) 4-aminobenzonitrile, 4-methoxybenzylisonitrile and 4-benzyloxy-3-methoxybenzaldehyde gave (R,S)-2-(4-benzyl-oxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N -(4-

methoxybenzyl)acetamide hydrochloride as colorless crystals. ISP-MS: 525.2 ([M+H] + , 100).

5.i) 4-aminobenzonitrile, 1-naphthyl-1-yl-methylisonitrile and 4-benzyloxy-3-methoxybenzaldehyde gave (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4- carbamimidoylphenylamino)-N-naphthalen-1-ylmethylacetamide hydrochloride as colorless crystals. ISP-MS: 545.3 ([M+H] + , 100).

5.j) 4-aminobenzonitrile, benzylisonitrile and 3-butoxy-5-methoxybenzaldehyde gave (R,S)-N-benzyl-2-(3-butoxy-5-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide hydro -chloride as colorless crystals. ISP-MS: 461.3 ([M+H] + , 100).

5.k) 4-aminobenzonitrile, benzylisonitrile and 3-benzyl-oxy-5-ethoxybenzaldehyde gave (R,S)-N-benzyl-2-(3-benzyloxy-5-ethoxyphenyl)-2-(4-carbamimidoylphenylamino) -acetamide hydrochloride as colorless crystals.

ISP-MS: 509.4 ([M+H] + , 100).

5.l) 4-aminobenzonitrile, benzylisonitrile and 3-benzyl-oxy-5-methoxybenzaldehyde gave (R,S)-N-benzyl-2-(3-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoylphenylamino) -acetamide hydrochloride as colorless crystals.

ISP-MS: 495.3 ([M+H] + , 100).

Example 6

Under an argon atmosphere, a fresh NaOMe solution was prepared from 130 mg (5.6 mmol) of sodium and 10 ml of MeOH and the solution was mixed with 474 mg (6.8 mmol) of hydroxylamine hydrochloride. The suspension was stirred for 30 minutes at room temperature. ,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(3-methoxybenyloxy)phenyl]acetamide (Example 18) and the reaction mixture was heated under reflux overnight. distilled under reduced pressure. The residue was taken up in water and extracted with EtOAc. The organic phase was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure.

The residue was taken up in 10 ml of ethanol, 1 ml of THF and 1 ml of HOAc and mixed with a teaspoon of Raney nickel. The reaction mixture is hydrogenated for 5 hours. The catalyst is filtered off. The filtrate is concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc/acetone/water/HOAc 6:2:1:1). This gives 191 mg (53%) of (R,S)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-[3-methoxy-4-(3-methoxybenzyl-oxy)phenyl]acetamide acetate as colorless crystals .

ISP-MS: 525.2 ([M+H], 100).

Example 7

The following compounds were produced by the method described in example 6:

7.a) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(pyridin-4-ylmethoxy)phenyl]acetamide (example 19.a) was obtained N-benzyl-2-(4-carbamimidoylphenylamino)-2-[3-methoxy-4-(pyridin-4-ylmethoxy)phenyl]acetamide acetate with a yield of 18%. Colorless solid.

ISP-MS: 496.2 [M+H].

7.b) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]acetamide (example 19.b) (R,S)-N-benzyl-2-(4-carbamimidoylphenyl-amino)-2-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]acetamide acetate was obtained with a yield of 15%. Colorless solid.

ISP-MS: 518.3 [M+H].

7.c) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(2-thiomorpholin-4-ylethoxy)phenyl]acetamide (example 19.c) (R,S)-N-benzyl-2-(4-carbamimido-ylphenylamino)-2-[3-methoxy-4-(2-thiomorpholine-4-ylethoxy)-phenyl]acetamide acetate was obtained with a yield of 22% . Colorless solid. ISP-MS: 534.3 [M+H].

7.d) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(3-phenoxybenyloxy)phenyl]acetamide (example 19.d) was obtained (R ,S)-N-benzyl-2-(4-carbamimidoylphenyl-amino)-2-[3-methoxy-4-(3-phenoxybenzyloxy)phenyl]acetamide acetate with a yield of 28%. Colorless solid.

ISP-MS: 587.4 [M+H].

7.e) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[4-(1H-indol-5-ylmethoxy)-3-methoxyphenyl]acetamide (example 19.e) obtained is (R,S)-N-benzyl-2-(4-carbamimidoylphenyl-amino)-2-[4-(1H-indol-5-ylmethoxy)-3-methoxyphenyl]acetamide acetate with a yield of 23%. Colorless solid.

ISP-MS: 534.3 [M+H].

7.f) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(quinolin-7-ylmethoxy)phenyl]acetamide (example 19.f) was obtained (R,S)-N-benzyl-2-(4-carbamimidoylphenyl-amino)-2-[3-methoxy-4-(1,2,3,4-tetrahydroquinolin-7-yl-methoxyphenyl]acetamide acetate with yield of 13%. Colorless solid. ISP-MS: 550.2 [M+H].

7.g) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(quinolin-7-ylmethoxy)phenyl]acetamide (example 19.f) was obtained (R,S)-N-benzyl-2-(4-carbamimidoylphenyl-amino)-2-[3-methoxy-4-(quinolin-7-yl-methoxyphenyl]acetamide acetate in 16% yield. Light pink solid. .ISP-MS: 546.3 [M+H].

7.h) (R,S)-N was obtained from (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-phenethyloxyphenyl]acetamide (example 19.g) -benzyl-2-(4-carbamimidoylphenylamino)-2-[3-methoxy-4-phenethyloxyphenyl]acetamide acetate with a yield of 21%. Colorless solid. ISP-MS: 509.4 [M+H].

7.i) From (R,S)-N-benzyl-2-[4-(biphenyl-4-ylmethoxy)-3-methoxyphenyl]-2-(4-cyanophenylamino)acetamide (example 19.h) was obtained ( R,S)-N-benzyl-2-[4-(biphenyl-4-ylmethoxy)-3-methoxyphenyl]-2-(4-cyanophenylamino)acetamide acetate with a yield of 58%. Colorless solid.

ISP-MS: 571.3 [M+H].

7.j) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[4-(2,6-dichlorobenzyloxy)-3-methoxyphenyl]acetamide (example 19.i) was obtained ( R,S)-N-benzyl-2-(4-carbamimidoylphenyl-amino)-2-[4-(2,6-dichlorobenzyloxy)-3-methoxyphenyl]acetamide acetate with a yield of 58%. Colorless solid.

ISP-MS: 563.3 [M+H].

7.k) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[4-(3,5-dichlorobenzyloxy)-3-methoxyphenyl]acetamide (example 19.j) was obtained ( R,S)-N-benzyl-2-(4-carbamimidoylphenyl-amino)-2-[4-(3,5-dichlorobenzyloxy)-3-methoxyphenyl]acetamide acetate with a yield of 47%. Colorless solid.

ISP-MS: 563.3 [M+H].

7.l) From (R,S)-N-benzyl-2-[4-(3-bromobenzyloxy)-3-methoxyphenyl]-2-(4-cyanophenylamino)acetamide (example 19.k) (R, S)-N-benzyl-2-[4-(3-bromobenzyloxy)-3-methoxyphenyl]-2-(4-carbamimidoylphenylamino)acetamide acetate with a yield of 35%. Colorless solid.

ISP-MS: 573 [M+H].

7.m) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]acetamide (example 19.l) was obtained (R,S)-N-benzyl-2-(4-carbamimidoylphenyl-amino)-2-[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]acetamide acetate with a yield of 34%. Colorless solid.

ISP-MS: 496.3 [M+H].

7.n) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[4-(isoquinolin-6-ylmethoxy)-3-methoxyphenyl]acetamide (example 19.m) was obtained ( R,S)-N-benzyl-2-(4-carbamimidoylphenyl-amino)-2-[4-(isolinolin-6-ylmethoxyphenyl]acetamide acetate in 11% yield. Colorless solid.

ISP-MS: 546.3 [M+H].

7.o) From (R,S)-N-benzyl-3-methoxyphenyl)-2-(4-cyano-phenylamino)-N-(3,4-dimethoxybenzyl)acetamide (example 24.a) (R ,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[3,4-dimethoxybenzyl]acetamide acetate with a yield of 5%. Colorless solid.

ISP-MS: 555.3 ([M+H]).

7.p) From (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-cyanophenylamino)-N-phenylethylacetamide (example 23) was obtained (R,S )-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-phenethylacetamide acetate with a yield of 30%. Colorless solid.

ISP-MS: 555.3 ([M+H]).

7.q) From (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-(4-nitrobenzyl)acetamide (example 24.b) was obtained (R, S)-N-(4-aminobenzyl)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide acetate with a yield of 52%. Colorless solid.

ISP-MS: 510.4 ([M+H]).

7.r) From (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-N-(4-cyanophenyl)-2-(4-cyanophenylamino)acetamide (example 24.d) (R, S)-2-(4-benzyloxy-3-methoxyphenyl)-N-(4-carbamimidoylphenyl)-2-(4-carbamimidoylphenylamino)acetamide acetate with a yield of 30%. Colorless solid.

ISP-MS: 523.3 ([M+H]).

7.s) From (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-phenylacetamide (example 24.c) (R,S)-2- (4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimido-ylphenylamino)-N-phenylacetamide acetate with a yield of 12%. Colorless solid. ISP-MS: 481.4 ([M+H]).

7.t) From (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[2-(3H-imidazol-4-yl)ethyl]acetamide (example 24.e) (R,S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)-N-[2-(3H-imidazol-4-yl)ethyl] acetamide acetate with a yield of 9%. Colorless solid. ISP-MS: 482.4 ([M+H]).

7.u) From (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[2-(1H-indol-3-yl)ethyl]acetamide (example 24.f) obtained (R,S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)-N-[2-(1H-indol-3-yl)-ethyl ]acetamide acetate with a yield of 68%. Colorless solid. ISP-MS: 553.3 ([M+Na]), 548.3 ([M+NH 4 ]), 531.3 ([M+H]).

Example 8

440 mg of N-benzyl-2-(4-benzyloxy-2-phenylsulfonylamino-5-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-acetamide (0.66 mmol) (example 14) are dissolved in 10 ml of MeOH, mixed with a drop of AcOH and mixed with 200 mg of 5% Pt/C. The reaction mixture is hydrogenated overnight. The catalyst is filtered off. The filtrate is concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/acetone/water/HOAc). This gives 263 mg of 2-(2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-(4-carbamimidoylphenylamino)acetamide acetate as a colorless solid. ISP-MS: 650 (M+H).

Example 9

By the method described in example 8 from N-benzyl-2-(4-benzyloxy-2-methanesulfonylamino-5-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetamide (example 15), after purification by HPLC on RP -18 using a CH3CN/water flow phase with 0.1% trifluoroacetic acid, N-benzyl-2-(4-benzyloxy-2-methanesulfonylamino-5-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetamide trifluoroacetate was obtained as colorless solid. ISP-MS: 588 (M+H).

Example 10

350 mg of N-benzyl-2-(4-benzyloxy-2-phenylsulfonylamino-5-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-acetamide (0.53 mmol) (Example 14) was dissolved in 3 ml AcOH, mixed with 100 ml Ac2O and hydrogenated in the presence of 150 mg 5% Pd/C. The catalyst is filtered off. The filtrate is concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/acetone/water/HOAc). This gives 188 mg (64%) of 2-(2-phenylsulfonylamino-4-hydroxy-5-methoxyphenyl)-N-benzyl-2-(4-carbamimidoylphenylamino)acetamide acetate as a colorless solid. ISP-MS: 560 (M+H).

Example 11

By the method described in example 10 from N-benzyl-2-(4-benzyloxy-2-methanesulfonylamino-5-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetamide (example 15), after purification by HPLC on RP -18 using a CH3CN/water flow phase with 0.1% trifluoroacetic acid, N-benzyl-2-(4-carbamimidoylphenylamino)-2-(4-hydroxy-2-methanesulfonylamino-5-methoxyphenyl)acetamide trifluoroacetate was obtained as colorless solid. ISP-MS: 498 (M+H).

Example 12

Under argon, a fresh solution of 115 mg (5 mmol) of sodium and 15 ml of MeOH was prepared and this solution was mixed with 420 mg (6 mmol) of hydroxylamine hydrochloride. The suspension is stirred for 30 minutes at room temperature. Add 261 mg (0.5 mmol) of (R,S)-N-benzyl-2-(4-cyanophenyl-amino)-2-[3-methoxy-4-(4-nitrobenzyloxy)phenyl]acetamide (Example 19 .n) and then the reaction mixture is heated under reflux overnight. The solvent is then distilled off under reduced pressure. The residue was taken up in water and extracted with EtOAc. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc). This gives 166 mg (60%) of (R,S)-N-benzyl-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-2-[3-methoxy-4-(4-nitrobenzyloxy)phenyl]acetamide as colorless rigid foam. ISP-MS: 556.3 [M+H].

Example 13

Using the method described in example 12, the following were produced:

13.a) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(pyridin-4-ylmethoxy)phenyl]acetamide (example 19.a) was obtained (R,S)-N-benzyl-2-[4-(N-hydroxy-carbamimoyl)phenylamino]-2-[3-methoxy-4-(pyridin-4-ylmethoxy)-phenyl]acetamide with a yield of 35 %. Colorless rigid foam. ISP-MS: 512.4 [M+H].

13.b) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]acetamide (example 19.b) (R,S)-N-benzyl-N-benzyl-2-[4-(N-hydroxy-carbamimidoyl)phenylamino]-2-[3-methoxy-4-(2-morpholin-4-yl-ethoxy) was obtained )phenyl]acetamide with a yield of 28%. Colorless rigid foam. ISP-MS: 534.4 [M+H].

13.c) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(3-phenoxybenzyloxy)phenyl]acetamide (example 19.d) was obtained (R ,S)-N-benzyl-2-[4-(N-hydroxycarbamidoyl)phenylamino]-2-[3-methoxy-4-(4-phenoxybenzyloxy)-phenyl]acetamide with a yield of 40%. Slightly grayish rigid foam. ISP-MS: 603.2 [M+H].

13.d) From (R,S)-2-(4-benzylkai-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-(4-nitrobenzyl)acetamide (example 24.b) (R, S)-2-(4-benzyliso-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-(4-nitrobenzyl)acetamide with a yield of 98%. Tuesday oil. ISP-MS: 545.2 [M+Na], 540.3 [M+NH4], 523.3 [M+H].

13.e) From (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[2-(3H-imidazol-4-yl)ethyl]acetamide (example 24.e) (R,S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[2-(3H-imidazole-4 -yl)ethyl]acetamide with a yield of 85%. Greyish-green rigid foam. ISP-MS: 515.3 [M+H].

13.f) From (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[2-(1H-indol-3-yl)ethyl]acetamide (example 24.f) (R,S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[1H-indol-3-yl) was obtained ethyl]acetamide with a yield of 85%. Greyish-green rigid foam. ISP-MS: 564.4 [M+H].

13.g) From (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-(3,4,5-trimethoxyphenyl)acetamide (example 17.a) (R,S)-N -benzyl-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-2-(3,4,5-trimethoxyphenyl)acetamide as a colorless solid. ISP-MS: 465.6 ([M+H] + , 100).

13.h) (R,S)-N-benzyl was obtained from (R,S)-N-benzyl-2-(3,5-dimethoxyphenyl)-2-(4-cyanophenylamino)acetamide (example 17.b) -2-(3,5-dimethoxyphenyl)-2-[4-(N-hydroxycarbamidoyl)phenylamino]acetamide as a colorless solid.

ISP-MS: 435.5 ([M+H] + , 100).

13.i) (R,S) was obtained from (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-cyanophenylamino)acetamide (example 17.c) -N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetamide as a colorless solid. ISP-MS: 511.6 ([M+H] + , 100).

13.j) (R,S) was obtained from (R,S)-N-benzyl-2-(4-benzyloxy-3-ethoxy-phenyl)-2-(4-cyanophenylamino)acetamide (example 17.d) -N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetamide as a colorless solid. ISP-MS: 525.5 ([M+H] + , 100).

Example 14

995 mg of 2-(2-phenylsulfonylamino-4-benzyl-oxy-5-methoxyphenyl)-N-benzyl-2-(4-cyanophenylamino)acetamide (1.57 mmol) (Example 28), 547 mg of hydroxylamine hydrochloride (7, 87 mmol) and 2.2 ml of triethylamine (15.7 mmol) are first mixed in 5 ml of EtOH. The reaction mixture is heated under reflux for 5 hours. The solvent is then distilled off under reduced pressure, the residue is taken up in water and extracted with EtOAc. The organic phase is washed with saturated NaCl solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gave 885 mg (85%) of 2-(2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-[4-(N-hydroxycarbamimidoyl)phenyl-amino]acetamide as an oily yellow solid.

ISP-MS: 666 (M+H).

Example 15

Using the method described in example 14, N-benzyl-2-(4-benzyloxy-2-methanesulfonylamino-5-methoxyphenyl)-2-(4-cyanophenylamino)acetamide (example 29) was obtained from N-benzyl-2-(4-benzyloxy -2-methanesulfonylamino-5-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetamide as a yellow oil, 95% yield. ISP-MS: 604 (M+H).

Example 16

10 g of 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde (34.8 mmol) and 4.11 g of 4-aminobenzonitrile (34.8 mmol) were dissolved in 140 ml of methanol and stirred for one hour at room temperature. The mixture was then mixed with 4.25 ml of benzyl isonitrile (34.8 mmol). Then, 12.9 ml of boron trifluoride ether (104.4 mmol) was added to this mixture, drop by drop over the course of one hour and while cooling with ice. After 30 minutes, the ice bath is removed. The reaction mixture was stirred for another two days at room temperature. The solvent is then distilled off under reduced pressure. The residue was taken up in EtOAc and washed with water. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using acetone/toluene (3/97). This gave 8.9 g (48%) of N-benzyl-2-(4-benzyloxy-5-methoxy-2-nitrophenyl)-2-(4-cyanophenyl-amino)acetamide as an oily orange solid.

ISP-MS: 523 (M+H).

Example 17

Using the method described in example 16, the following were produced:

17.a) (R,S)-N-benzyl-2-(4-cyanolphenylamino-2-(3,4,5-trimethoxyphenyl) was obtained from 4-aminobenzoniryl, 3,4,5-trimethoxybenzaldehyde and benzylisonitrile acetamide as colorless crystals. 1H NMR (DMSO-D6): 8.80 (t, NH, 1H); 5.02 (d, CH, 1H); 4.28 (d, CH2, 2H); 3.75 ( s, CH3, 6H); 2.61 (s, CH3, 3H).

17.b) (R,S)-N-benzyl-2-(3,5-di-methoxyphenyl)-2-(4-cyanophenylamino)acetamide was obtained from 4-aminobenzoniryl, 3,5-dimethoxybenzaldehyde and benzylisonitrile as colorless crystals. 1H NMR (DMSO-D 6 ): 8.82 (t, NH, 1H); 5.15 (d, CH, 1H); 4.28 (d, CH2, 2H); 3.72 (s, CH3, 6H).

17.c) (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-cyanophenylamino)acetamide was obtained from 4-aminobenzoniryl, 4-benzyloxy-3-methoxy-benzaldehyde and benzylisonitrile as colorless crystals. 1 NMR (DMSO-D 6 ): 8.80 (t, NH, 1H); 5.07 (d, CH, 2H); 4.99 (d, CH, 2H); 4.28 (d, CH2, 2H); 3.73 (s, CH3, 3H).

17.d) (R,S)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-cyanophenylamino)acetamide was obtained from 4-aminobenzoniryl, 4-benzyloxy-3-ethoxy-benzaldehyde and benzylisonitrile as colorless crystals. 1 NMR (DMSO-D 6 ): 8.75 (t, NH, 1H); 5.10 (s, CH2, 2H), 4.95 (d, CH, 1H); 4.28 (d, CH2, 2H); 4.05 (q, CH2, 2H), 1.32 (t, CH3, 3H).

Example 18

A solution of 290 mg (0.75 mmol) of (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-(4-hydroxy-3-methoxyphenyl)acetamide (Example 20) was mixed in an argon atmosphere. 110 ml (0.9 mmol) of 3-methoxybenzyl alcohol and 236 mg (0.9 mmol) of triphenylphosphine in 15 ml of THF with 140 ml (0.9 mmol) of diethyl azodicarboxylate, and the mixture was stirred overnight at room temperature. The reaction solution is concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2Cl2/EtOAc 9:1). This gives 326 mg (86%) of (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(3-methoxy-benzyloxy)phenyl]acetamide as a colorless solid .

ISP-MS: 530.2 [M+Na], 525.2 [M+NH4], 508.4 [M+H], 390.2.

Example 19

By the method described in example 18 from (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-(4-hydroxy-3-methoxyphenyl)acetamide

19.a) and 4-hydroxymethylpyridine, (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(pyridin-4-yl-methoxy)phenyl]acetamide was obtained with with a utilization of 72%. ISP-MS: 479.3 [M+H],

19.b) and N-(2-hydroxyethyl)morpholine gave (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(2-morpholin-4-ylethoxy) )phenyl]acetamide with a yield of 66%. Colorless resin. ISP-MS: 501.3 [M+H],

19.c) and N-(2-hydroxyethyl)thiomorpholine (L.A. Burrows, E.E. Reid, Journal of American Chemical Society (1934) 56, 1720) (R,S)-N-benzyl-2-(4-cyanophenylamino) was obtained )-2-[3-methoxy-4-(2-thiomorpholine-4-ylethoxy)phenyl]acetamide with a yield of 84%. Colorless rigid foam.

ISP-MS: 517.3 [M+H],

19.d) and 3-phenoxybenzylalcohol, (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(3-phenoxy-benzyloxy)phenyl]acetamide was obtained using 44%. Colorless rigid foam. ISP-MS: 628.3 [M+AcOH-H], 568.3 [M-H],

19.e) and 5-hydroxymethylindole (M. Somei, Y. Saida, N. Komura, Chem. Pharm. Bull. (1986) 34, 4116) (R,S)-N-benzyl-2-(4 -cyanophenylamino)-2-[4-(1H-indol-5-yl-methoxy)-3-methoxyphenyl]acetamide with a yield of 67%. Light yellow rigid foam.

ISP-MS: 539.3 [M+Na], 534.3 [M+NH4], 517.2 [M+H], 399.3,

19.f) and 7-hydroxymethylquinoline (C.E. Kaslow, W.R. Clark, Journal of Organic Chemistry (1953) 18, 55) (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3 -methoxy-4-(quinolin-7-ylmethoxy)phenyl]acetamide with a yield of 100%. Colorless solid. ISP-MS: 529.2 [M+H],

19.g) and 2-phenylethyl alcohol, (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-phenethyloxy-phenyl)acetamide was obtained with a yield of 90%. Light green resin. ISP-MS: 492.2 [M+H],

19.h) and 7-hydroxymethylbiphenyl, (R,S)-N-benzyl-2-[4-(biphenyl-4-ylmethoxy)-3-methoxyphenyl]-2-(4-cyanophenylamino)acetamide was obtained with a yield of 25 %. Colorless solid. ISN-MS: 612.3 [M+AcOH-H], 552.2 [M-H],

20.i) and 2,6-dichlorobenzyl alcohol, (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[4-(2,6-dichlorobenzyloxy)-3-methoxyphenyl]acetamide was obtained with with a utilization of 70%. Colorless crystals. ISN-MS: 604.1 [M+AcOH-H], 544.1 [M-H],

20.j) and 3,5-dichlorobenzyl alcohol, (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[4-(3,5-dichlorobenzyloxy)-3-methoxyphenyl]acetamide was obtained with with a utilization of 74%. Colorless crystals. ISN-MS: 604.1 [M+AcOH-H], 544.1 [M-H],

20.k) and 3-bromobenzyl alcohol, (R,S)-N-benzyl-2-[4-(3-bromobenzyloxy)-3-methoxyphenyl]-2-(4-cyano-phenylamino)acetamide was obtained using 51%. Colorless crystals. ISN-MS: 614.2 [M+AcOH-H], 556.0 [M-H],

19.l) and 2-hydroxymethylpyridine gave (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(pyridin-2-yl-methoxy)phenyl]acetamide with utilization of 89%. Colorless resin. ISP-MS: 479.3 [M+H],

19.m) and 6-hydroxymethylisoquinoline (EP 385 662) obtained (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[4-(isoquinolin-6-ylmethoxy)-3-methoxyphenyl] acetamide with a yield of 100%. Colorless solid.

ISP-MS: 529.3 [M+H],

19.n) and 4-nitrobenzyl alcohol, (R,S)-N-benzyl-2-(4-cyanophenylamino)-2-[3-methoxy-4-(4-nitro-benzyloxy)phenyl]acetamide was obtained using of 71%. Light yellow rigid foam. ISN-MS: 581.2 [M+AcOH-H], 521.2 [M+H].

Example 20

460 mg (0.4 mmol) of tetrakis(triphenylphosphine)palladium is added to a solution of 8.5 g (20 mmol) of (R,S)-2-(4-allyloxy-3-methoxyphenyl)-N-benzyl-2- of (4-cyanophenylamino)-acetamide (Example 21) in 250 ml of THF. The solution was stirred for 10 minutes at room temperature and then 1.13 g (30 mmol) of NaBH4 were mixed in. The mixture is stirred for 2 hours at room temperature and then concentrated under reduced pressure. The residue was taken up in CH2Cl2/EtOAc 9:1 and stirred for 30 minutes in the presence of activated charcoal. The suspension is filtered through Dicalite. The filtrate was concentrated under reduced pressure and the residue was recrystallized from EtOAc/hexane. This gave 6.81 g (88%) of (R,S)-N-benzyl-2-(4-cyanophenyl-amino)-2-(4-hydroxy-3-methoxyphenyl)acetamide as colorless crystals. ISP-MS: 386.1 [M-H], 268.3.

Example 21

A solution of 17.8 g (35 mmol) of methyl (R,S)-2-(4-allyloxy-3-methoxyphenyl)-N-benzyl-2-(4-cyanophenylamino)-acetamide (Example 22) in 35 ml of DMSO -and is stirred overnight at room temperature. The solvent is evaporated under high vacuum. The residue was purified by chromatography on silica gel (CH2Cl2/EtOAc 19:1). This gave 10.6 g (71%) of (R,S)-2-(4-allyloxy-3-methoxyphenyl)-N-benzyl-2-(4-cyanophenyl-amino)acetamide as a colorless solid.

ISN-MS: 486.1 [M+AcOH-H], 426.1 [M-H].

Example 22

A solution of 17.72 g (150 mmol) of 4-aminobenzonitrile and 28.8 g of 4-allyloxy-3-methoxy-benzaldehyde is mixed under an argon atmosphere (W.A. Ayer, P.A. Craw, Can. J. Chem. (1991) 69, 1909) 1 hour at room temperature. 18.3 ml (150 mmol) of benzyl isonitrile are added. Then slowly, drop by drop, at 0oC, 56 ml (450 mmol) of boron trifluoride ethyl ether is added. After a short time, crystals form, which are filtered off in an argon atmosphere and dried under high vacuum. This gave 74.1 g (87%) of methyl (R,S)-2-(4-allyloxy-3-methoxyphenyl)-N-benzyl-2-(4-cyanophenylamino)-acetamide as a slightly yellow solid. ISP-MS: 442.3 [M+H].

Example 23

Under an argon atmosphere, 144 mg (0.75 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride was added to a solution of 194 mg (0.5 mmol) of (R,S)-(4-benzyloxy- 3-Methoxyphenyl)-(4-cyanophenylamino)acetic acid (Example 25), 75 ml (0.6 mmol) of phenethylamine, 115 mg (0.75 mmol) of 1-hydroxybenzotriazole and 128 ml (0.75 mmol) of N,N -diiso-propylethylamine in 25 ml of THF. The reaction mixture was stirred for 5 hours at room temperature and then concentrated under reduced pressure. The residue was taken up in EtOAc and washed with saturated KHCO3 solution, with 2% citric acid solution, with water and then with saturated NaCl solution. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (cyclohexane/EtOAc 2:1). This gave 210 mg (86%) of methyl (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-phenethylacetamide as a colorless solid foam.

ISP-MS: 492.3 [M+Na], 509.4 [M+NH4], 523.3 [M+H].

Example 24

By the method described in example 23 from (R,S)-(4-benzyloxy-3-methoxyphenyl)-(4-cyanophenylamino)acetic acid

24.a) and veratrilamine, (R,S)-2-(4-benzyl-oxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-(3,4-di-methoxybenzyl)acetamide was obtained using of 80%. Light yellow solid foam. ISP-MS: 560.4 [M+Na], 555.3 [M+NH4], 538.4 [M+H],

24.b) and 4-nitrobenzylamine hydrochloride, (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenyl-amino)-N-(4-nitrobenzyl)acetamide was obtained using 43%. Colorless solid. ISP-MS: 545.2 [M+Na], 540.3 [M+NH4], 523.2 [M+H],

24.c) and aniline gave (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-(4-phenylacetamide) with a yield of 52%. Colorless solid.

ISP-MS: 486.2 [M+Na], 464.2 [M+H],

24.d) and 4-aminobenzonitrile, (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenyl)-2-(4-cyano-phenylamino)acetamide was obtained with a yield of 10 %. Colorless solid. ISN-MS: 547.2 [M+AcOH-H], 487.2 [M-H],

24.e) and histamine dihydrochloride gave (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[2-(3H-imidazol-4-yl)ethyl ]acetamide with a yield of 74%. Colorless rigid foam. ISP-MS: 482.4 [M+H],

24.f) and tryptamine, (R,S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[2-(1H-indol-3-yl)-ethyl was obtained ]acetamide with a yield of 92%. Orange rigid foam. ISP-MS: 553.3 [M+Na], 548.3 [M+NH4], 531.3 [M+H].

Example 25

A solution of 1.17 g (2.9 mol) of (R,S)-(4-benzyloxy-3-methoxyphenyl)-(4-cyanophenylamino)acetate in 6 ml of THF was cooled to 0°C and mixed with 14, 5 ml (14.5 mmol) of 1N LiOH solution. The mixture is stirred for 30 minutes at 0oC and 2 hours at room temperature. THF is distilled off under reduced pressure. The remaining solution is adjusted to pH 3 using 1N HCl. A colorless precipitate forms, which is filtered off and washed with water. The solid is recrystallized from EtOH/water. This gives 788 mg (70%) of (R,S)-(4-benzyloxy-3-methoxyphenyl)-(4-cyanophenylamino)acetic acid as a colorless solid. ISN-MS: 387.1 [M-H].

Example 26

In an atmosphere of argon, a solution of 970 mg (4 mol) of 4-benzyloxy-3-methoxybenzaldehyde and 473 mg (4 mmol) of 4-aminobenzonitrile in 16 ml of MeOH was stirred for 1 hour at room temperature. A slightly yellow precipitate forms. The suspension was mixed with 488 mg (4 mmol) of benzyl isonitrile and cooled to 0°C. Then slowly, drop by drop, 1.52 ml (12 mmol) of boron trifluoride ethyl ether is added. After 2 hours, the mixture is allowed to warm to room temperature and thickened under reduced pressure. The residue is taken up in MeOH. The solution is slowly mixed with water until crystallization occurs. Let the mixture stand at 4oC. The solid is filtered off and dried under high vacuum. The residue is recrystallized from cyclohexane/EtOH. This gives 1.17 g (73%) of methyl (R,S)-(4-benzyloxy-3-methoxyphenyl)-(4-cyanophenylamino)acetate as a colorless solid. ISP-MS: 425 [M+Na], 420.2 [M+NH4].

Example 27

2.0 g of N-benzyl-2-(4-benzyloxy-5-methoxy-2-nitro-phenyl)-2-(4-cyanophenylamino)acetamide (3.8 mmol) (Example 16) was dissolved in 50 ml of EtOAc and 50 ml of EtOH, mixed with 1.2 g of 5% Pt/C and hydrogenated for 3 hours. The catalyst is filtered off. The filtrate is concentrated under reduced pressure. This gives 1.42 g (76%) of 2-(2-amino-4-benzyloxy-5-methoxy-phenyl)-N-benzyl-2-(4-cyanophenylamino)acetamide as an oily yellow solid. ISP-MS: 493 [M+H].

Example 28

1.7 g of 2-(2-amino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-(4-cyanophenylamino)acetamide (Example 27) was dissolved in 60 ml of CH2Cl2 and 20 ml of DMF and mixed with 0.7 ml of Hünig's base. Then, 0.7 ml (3.8 mmol) of phenylsulfonyl chloride is added drop by drop at 0°C. The reaction mixture was stirred for 4 hours at room temperature and then diluted with 100 ml of CH2Cl2 and washed with a 5% NaHCO3 solution. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using acetone/toluene (10/90). This gave 995 mg (46%) of 2-(2-phenyl-sulfonylamino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-(4-cyanophenylamino)acetamide as an oily orange solid. ISN-MS: 631 [M-H].

Example 29

Using the method described in example 28 from 2-(2-amino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-(4-cyanophenylamino)-acetamide (example 27) and methanesulfonyl chloride, N-benzyl-2- (4-Benzyloxy-5-methanesulfonylamino-5-methoxy-phenyl)-2-(4-cyanophenylamino)acetamide as an orange solid in 36% yield. ISN-MS: 569 [M-H].

Example 30

120 mg (0.2 mmol) of (R,S)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide trifluoroacetate (example 3) are mixed in an argon atmosphere at 0°C. in 1.3 ml of tetrahydrofuran with 66 mg (0.335 mmol) of O-methyl O'-(4-nitrophenyl) carbonate. The reaction mixture is then allowed to warm to room temperature overnight, the solvent is removed under reduced pressure and the residue is extracted with ethyl acetate and water. The combined organic phases are dried over sodium sulfate. The mixture is filtered and the solvent is removed, and the residue is then suspended in diethyl ether and filtered. This gives 88 mg (82%) of methyl [amino-(4-

{[benzylcarbamoyl-(4-benzyloxy-3-methoxyphenyl)methyl]amino}-phenyl)methylene]carbamate as a colorless solid.

ISP-MS: 553.3 ([M+H] + 100).

Example 31

The following compounds were produced by the method described in example 30:

31.a) Methyl [amino-(4-{[benzylcarbamoyl -(3,4-dimethoxy-phenyl)methyl]amino}phenyl)methylene]carbamate as a colorless solid. ISP-MS: 477.5 ([M+H] + 100).

31.b) Methyl [amino-(4-{[benzylcarbamoyl -(3,5-dimethoxy-phenyl)methyl]amino}phenyl)methylene]carbamate as a colorless solid. ISP-MS: 477.5 ([M+H] + 100).

31.c) Methyl [amino-(4-{ [benzylcarbamoyl-(3,4,5-tri-methoxyphenyl)methyl]amino}phenyl)methylene]carbamate as a colorless solid. ISP-MS: 507.6 ([M+H] + 100).

A compound of formula I, its hydrate, solvate or salt, can be used as an active ingredient for the preparation of pharmaceutical compositions, such as those below.

Example 32

A degassed solution of 369 mg of the material prepared according to Example 36.3 in 5 mL of EtOH, 5 mL of THF, 2 mL of water, and 1 mL of HOAc was mixed with a teaspoon of Raney nickel and hydrogenated for 5 hours. The catalyst is filtered off. The filtrate thickens. The residue was purified by chromatography over silica gel (EtOAc/acetone/water/HOAc 6:2:1:1). This resulted in two epimers:

1. (S)-2-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]propionic acid acetate (1:1) and

2. (S)-2-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]propionic acid acetate (1:1), both as colorless lyophilisates,

ISP-MS: 477.3 [M+H].

Example 33

The method described in example 32 produced:

33.a

from the mixture of epimers from example 37a.1 was obtained

1. (S)-2-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-3-phenylpropionic acid acetate (1:1), and from mixture of epimers from example 37.a was obtained

2. (S)-2-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-3-phenylpropionic acid acetate (1:1), ISP- MS: 553.3 [M+H],

33.b

after separation by chromatography of the product from example 37.b, two epimers were obtained:

1. (S)-2-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-3-(4-hydroxyphenyl)-propionic acid acetate (1 :1) i

2. (S)-2-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-3-(4-hydroxyphenyl)-propionic acid acetate (1 :1), ISP-MS: 569.3 [M+H],

33. c

a mixture of (S)-1-[(R)- and -[(S)-(4-benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)acetyl]pyrrolidine 2- was obtained from the product from example 37.c carboxylic acid acetate, ISP-MS: 503.3 [M+H],

33.d

(RS)-2-[2-(4-) was obtained from the product from example 37.d

Benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)-acetylamino]-2-methylpropionic acid acetate (1:0.5), ISP-MS: 491.5 [M+H], 513.5 [M+Na] ,

33.e

from the product from example 37.e, after separation by chromatography, two epimers were obtained:

1. (S)-[[(R)-(4-benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)acetyl]methylamino]phenylacetic acid acetate (1:2) and

2. (S)-[[(S)-(4-benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)acetyl]methylamino]phenylacetic acid acetate (1:1), ISP-MS: 553.3 [ M+H], 571.1 [M+Na],

33. f

a mixture of (RS)- and (SR)-1-[(RS)-(4-benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)acetyl]pyrrolidine-3-carboxylic acetic acid, ISP-MS: 503.3 [M+H],

33rd year

from the product from example 37.g, after separation by chromatography, two diastereomeric racemates (RS)- or (SR)-2-[(RS)-(4-benzyloxy-3-methoxyphenyl)-(4-carbamimidoylphenylamino)acetyl]-1 were obtained ,2,3,4-tetrahydroiso-quinoline-3-carboxylic acid acetate (1:1),

ISP-MS: 565.3 [M+H], 587.2 [M+Na],

33 h

(RS)-1-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-acetylamino]cyclopentanecarboxylic acid acetate (1:2) was obtained from the product from example 37.h, ISP-MS : 517.2 [M+H], 539.3 [M+Na],

33.i

(RS)-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-acetylamino]diphenylacetic acid acetate (1:1) was obtained from the product from example 37.i.

ISP-MS: 615.3 [M+H],

33.j

two epimers were obtained from the product from example 37.j after separation by chromatography:

1.(S)-2-[[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-4-tert.butoxycarbonyl-aminobutyric acid acetate (1: 3) i

2.(S)-2-[[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-4-tert.butoxycarbonyl-aminobutyric acid acetate (1: 3),

ISP-MS: 606.1 [M+H], 628.2 [M+H],

33rd k

two epimers were obtained from the product from example 37.k after separation by chromatography:

1.(S)-2-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-3-tert.butoxy-carbonyl-aminopropionic acid acetate (1 :1) i

2.(S)-2-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetylamino]-3-tert.butoxycarbonyl-aminopropionic acid acetate (1:1 ), ISP-MS: 592.2 [M+H].

Example 34

By the method described in example 32

34.a

(RS)-2-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-acetylamino]benzoic acid acetate (1:1) was obtained from the product from example 38.a.

ISP-MS: 525.1 [M+H],

34.b

(RS)-3-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-acetylamino]benzoic acid acetate (1:1) was obtained from the product from example 38.b.

ISP-MS: 525.1 [M+H],

34. c

(RS)-4-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-acetylamino]benzoic acid acetate (1:1) was obtained from the product from example 38.c.

ISP-MS: 525.1 [M+H].

Example 35

Using the method described in example 32, a mixture of (RS)- and (SR)-3-[(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)- was obtained from the product of example 39 acetylamino]-3-phenylpropionic acid.

Example 36

36.1

335 mg of methyl L-alaninate hydrochloride, 1.03 ml of diiso-propylethylamine and 1.06 g of (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate were added to a solution of 777 mg of the material prepared in Example 25 in 10 ml of DMF. -And. The reaction mixture was stirred for 2 hours at room temperature and then concentrated under high vacuum. The residue is taken up in ethyl acetate and then washed with 10% KHCO3 solution, 2% citric acid, water and saturated NaCl solution. The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is purified by chromatography on silica gel. This gives 823 mg (87%) of a 1:1 mixture of methyl (S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino) )acetylamino]propionate as a solid colorless foam.

ISP-MS: 474.3 [M+H], 496.1 [M+Na], 512.2 [M+K].

36.2

8.4 ml of 1N LiOH solution was added to a solution of 792 mg of the material prepared according to Example 36.1 in 10 ml of THF and cooled to 0°C. The mixture is stirred for 30 minutes at 0oC and 2 hours at room temperature. THF is distilled off under reduced pressure. The remaining aqueous solution is acidified with 1N HCl and a colorless precipitate is formed. This precipitate is filtered off and dried under high vacuum. This gives 712 mg (91%) of a 1:1 mixture of (S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino) acetylamino]propionic acid as a colorless solid. ISN-MS: 458.3 [M-H].

36.3

4.1 ml of triethylamine and then 683 mg of the material prepared according to Example 36.2 were added to a suspension of 1.04 g of hydroxylamine hydrochloride in 25 ml of EtOH. The reaction mixture is heated under reflux overnight and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc/acetone/water/HOAc 6:2:1:1). This gives 625 mg (86%) of a 1:1 mixture of (E)- and (Z)-(S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl) )-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetylamino]-propionic acid as a small purple lyophilisate.

ISP-MS: 493.3 [M+H], 515.3 [M+Na].

Example 37

By the method described in Example 36, from the material produced in Example 25

37.a

and from methyl L-phenylalaninate hydrochloride a 1:1 mixture of methyl (S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino) was obtained )acetylamino]-3-phenyl-propionate, from which a mixture of (S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4- cyanophenylamino)acetyl-amino]-3-phenylpropionic acid and from it, after separation by chromatography, two products:

1. (E)- and/or (Z)-(S)-2-[(R)-2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino] acetyl-amino]-3-phenylpropionic acid i

2. (E)- and/or (Z)-(S)-2-[(S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino] acetyl-amino]-3-phenylpropionic acid,

37.b

and from ethyl L-tyrosinate hydrochloride a 1:1 mixture of ethyl (S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4 -cyanophenylamino)acetylamino]-3-(4-hydroxy-phenyl)propionate, from which a mixture of (S)-2-[(R)- and

-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenyl-amino)acetylamino]-3-(4-hydroxyphenyl)propionic acid and from it a mixture of (E)- and /or (Z)-(S)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamidoyl)phenylamino] acetylamino]-3-(4-hydroxyphenyl)-propionic acid,

37. c

and from methyl L-prolinate a 1:1 mixture of methyl (S)-1-[(R)- and -[(S)-(4-benzyloxy-3-methoxyphenyl)-(4-cyano-phenylamino)acetyl] was obtained pyrrolidine-2-carboxylate from which a mixture of (S)-1-[(R)- and -[(S)-(4-benzyloxy-3-methoxyphenyl)-(4-cyanophenylamino)acetyl]pyrrolidine-2-carboxylate is obtained acid and a 1:1 mixture (E)- and/or (Z)-(S)-1-[(R)- and -[(S)-(4-benzyloxy-3-methoxyphenyl)-[ 4-(N-hydroxycarbamidoyl)phenylamino]acetyl]pyrrolidine-2-carboxylic acids,

37.d

and from methyl 2-aminoisobutyrate hydrochloride a mixture of (RS)-2-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyano-phenylamino)acetylamino]-2-methylpropionate was obtained from which (RS )-2-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenyl-amino)acetylamino]-2-methylpropionic acid and (E)- and/or (Z)-( RS)-2-[2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetyl-amino]-2-methylpropionic acid,

37.e

and from ethyl N-methyl-L-phenylglycinate hydrochloride a 1:1 mixture of ethyl (S)-[[(R)- and -[[(S)-(4-benzyl-oxy-3-methoxyphenyl)-2- (4-cyanophenylamino)acetyl]methyl-amino]phenyl acetate from which a 1:1 mixture of (S)-[[(R)- and -[[(S)-(4-benzyloxy-3-methoxyphenyl)-( 4-cyanophenyl-amino)acetyl]methylamino]phenylacetic acid and from it a mixture (E)- and/or (Z)-(S)-[[(R)- and -[[(S)-(4- benzyl-oxy-3-methoxyphenyl)-[4-(N-hydroxycarbamimidoyl)phenyl-

amino]acetyl]methylamino]phenylpropionic acid,

37.f

and from ethyl beta-D,L-prolinate hydrochloride a mixture of ethyl (RS)- and (SR)-1-[(RS)-(4-benzyloxy-3-methoxy-phenyl)-(4-cyanophenylamino)acetyl] was obtained pyrrolidine-3-carboxylate from which a mixture of (RS)- and (SR)-1-[(RS)-(4-benzyl-oxy-3-methoxyphenyl)-(4-cyanophenylamino)acetyl]pyrrolidine-3-carboxylate is obtained acid and the mixture (E)- and/or (Z)-(RS)- and -(SR)-1-[(RS)-(4-benzyloxy-3-methoxyphenyl)-[4-(N -hydroxycarbamimidoyl)phenylamino]acetyl]pyrrolidine-3-carboxylic acids,

37.g

and from ethyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate hydrochloride a mixture of ethyl (RS)- and (SR)-2-[(RS)-(4-benzyloxy-3-methoxyphenyl)-2-( 4-cyanophenylamino)-acetyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate from which a mixture of (RS)- and (SR)-2-[(RS)-(4-benzyloxy-3-methoxyphenyl) is obtained )-(4-cyanophenylamino)acetyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and from it a mixture of (E)- and/or (Z)-(RS)- and -( SR)-2-[(RS)-(4-benzyloxy-3-methoxyphenyl)-[4-(N-hydroxycarbamimidoyl)phenylamino]-acetyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

37 h

and from ethyl 1-amino-1-cyclopentanecarboxylate hydrochloride, ethyl (RS)-1-[2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-cyanophenylamino)acetylamino]cyclopentanecarboxylate was obtained from which yields (RS)-1-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)acetylamino]cyclo-pentanecarboxylic acid and from it yields (E)- and/or (Z) -(RS)-1-[2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetylamino]cyclopentanecarboxylic acid,

37.i

and methyl (RS)-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyano-phenylamino)acetylamino]diphenylacetate was obtained from methyl α,α-diphenylglycinate hydrochloride, from which (RS)-[ 2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenyl-amino)acetylamino]diphenylacetic acid and (E)- and/or (Z)-(RS)-[2-(4 -benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetylamino]diphenyl-acetic acid,

37.j

and from methyl N-γ-Boc-L-α,γ-diaminobutyrate hydrochloride, a 1:1 mixture of methyl (S)-2-[(R)- and [(S)-2-(4-benzyl-oxy-) was obtained 3-methoxyphenyl)-2-(4-cyanophenylamino)acetylamino]-4-tert.butoxycarbonylaminobutyrate, from which a 1:1 mixture of (S)-2-[(R)- and [(S)-2-(4- benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)acetylamino]-4-tert.butoxycarbonyl-aminobutyric acid and a 1:1 mixture (S)-2-[(R)- or [(S) -2-(4-benzyloxy-3-methoxyphenyl)-2-[4-[(E)- and/or [(Z)-N-hydroxycarbamimidoyl)phenylamino]acetylamino]-4-tert.butoxycarbonylaminobutyric acid,

37. k

and from methyl N-β-Boc-α,β-diaminopropionate hydrochloride, a 1:1 mixture of methyl (S)-2-[(R)- and [(S)-2-(4-benzyloxy-3-methoxyphenyl) was obtained -2-(4-cyanophenylamino)acetyl-amino]-3-tert.butoxycarbonylaminopropionate, from which a 1:1 mixture of (S)-2-[(R)- and [(S)-2-(4-benzyloxy- 3-methoxyphenyl)-2-(4-cyanophenylamino)acetylamino]-3-tert-butoxycarbonylamino-propionic acid and a 1:1 mixture (S)-2-[(R)- or [(S)-2 -(4-benzyloxy-3-methoxy-phenyl)-2-[4-[(E)- and/or -[(Z)-N-hydroxycarbamimidoyl)phenyl-amino]acetylamino]-3-tert.butoxycarbonylaminopropionic acid.

Example 38

By the method described in Example 36, from the material produced in Example 25

38.a

and ethyl 2-aminobenzoate, ethyl (RS)-2-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)acetyl-amino]benzoate is obtained, from which (RS)-2-[ 2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)acetylamino]benzoic acid, from which (E)- and/or (Z)-(RS)-2-[2-(4 -benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)-phenylamino]acetylamino]benzoic acid,

38.b

and ethyl 3-aminobenzoate, ethyl (RS)-3-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)acetyl-amino]benzoate is obtained, from which (RS)-3- [2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenyl amino)acetylamino]benzoic acid, and from it (E)- and/or (Z)-(RS)-3-[2 -(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimoyl)-phenylamino]acetylamino]benzoic acid,

38. c

and ethyl 4-aminobenzoate, ethyl (RS)-4-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)acetyl-amino]benzoate is obtained, from which (RS)-4-[ 2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)acetylamino]benzoic acid, from which (E)- and/or (Z)-(RS)-4-[2-(4 -benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)-phenylamino]acetylamino]benzoic acid.

Example 39

Using the method described in example 36, from the material produced in example 25 and methyl D,L-3-amino-3-phenylpropionate hydrochloride, a mixture of diastereomers of the corresponding nitrile esters is obtained, from which the corresponding nitrile acids and finally the mixture (E)- and/ or (Z)-(RS)- and -(SR)-3-[(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]acetylamino]-3 -phenylpropionic acid.

Example 40

40.a

A suspension of 107 mg of the mixture of epimers obtained according to example 33.j in 3 ml of CH2Cl2 was mixed with 0.5 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The reaction mixture is thickened. The residue was purified by chromatography on silica gel (EtOAc/acetone/water/HOAc 6:2:2:4). This gives 79 mg (85%) of a mixture of (S)-4-amino-2-[(R) and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbam- imidoyl)phenylamino]acetylamino]butyric acid acetate (1:1) as a beige lyophilisate.

40.b

Using the method described in example 40.a, a 1:1 mixture of (S)-3-amino-2-[(R)- and -[(S)-2-( 4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]propionic acid acetate (1:1) with a yield of 44% as a beige lyophilisate.

Example 41

41.a

By the method described in example 32 and via (E)- and/or (Z)-(S)-[(R)- or -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4 -(N-hydroxycarbamimidoyl)phenylamino]acetylamino]phenylacetic acid, the following compounds were obtained:

a) (S)-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid and

b) (S)-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid.

41.b

The amidoxime used in 41.a was produced by the method described in example 37 starting from the material obtained in accordance with example 25 and methyl (S)-phenylglycinate via the appropriate nitrile ester and the appropriate nitrile acid produced from it.

Example 42

42.a

By the method described in example 41, but using methyl (R)-phenylglycinate hydrochloride instead of methyl (S)-phenylglycinate hydrochloride, two epimers were obtained

1. (R)-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid and

2. (R)-[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid.

42.b

Using the method described in example 41, but using ethyl p-amino-L-phenylalaninate dihydrochloride instead of methyl (S)-phenylglycinate hydrochloride, a 1:1 mixture of ethyl (S)-3-(4-aminophenyl)-2-[( R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)acetylamino]propinate, from which it was obtained

1. 1:1 mixture of ethyl (E)- and/or (Z)-(S)-3-(4-aminophenyl)-2-[(R)- and -[(S)-2-(4-benzyloxy) -3-methoxyphenyl)-2-[4-(N-

hydroxycarbamimidoyl)phenylamino]acetylamino]propionate, from which it was obtained

2. 1:1 mixture of ethyl (S)-3-(4-aminophenyl)-2-[(R)- and -[(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4- carbamimidoylphenyl-amino)acetylamino]propionate acetate (1:1), from which finally, after separation by chromatography, was obtained

3. (S)-3-(4-aminophenyl)-2-[(R)-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]propionic acid acetate (1: 3) i

4. (S)-3-(4-aminophenyl)-2-[(S)-2-(4-benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]propionic acid acetate (1: 3), ISP-MS: 568.3 [M+H], 590.3 [M+Na].

Example 43

43.1

Using the method described in example 26, methyl (RS)-(4-cyanophenylamino)-(3,5-dimethoxyphenyl)acetate was obtained from 3,5-dimethoxybenzaldehyde, 4-aminobenzonitrile and benzylisonitrile.

43.2

By the method described in example 26, (RS)-(4-cyanophenyl-amino)-(3,5-dimethoxyphenyl)acetic acid was obtained from the product prepared under 43.1.

43.3

Using the method described in example 41, from the acid produced under 43.2 and methyl (S)-phenylglycinate hydrochloride, after separation of the epimer mixture by chromatography, two products were obtained

a) (S)-[(R)-2-(4-carbamimidoylphenylamino)-2-(3,5-di-methoxyphenyl)acetylamino]phenylacetic acid acetate

(1:1,6) i

b) (S)-[(S)-2-(4-carbamimidoylphenylamino)-2-(3,5-di-methoxyphenyl)acetylamino]phenylacetic acid acetate

(1:1.75), ISP-MS: 463.2 [M+H].

Example 44

Using the method described in example 26, (RS)-(4-cyanophenylamino)-(3,4-diethoxyphenyl)-acetic acid was obtained from 3,4-diethoxybenzaldehyde, 4-aminonitrile and benzisonitrile.

Example 45

A degassed solution of 147 mg of the product from example 47.b in 5 ml of EtOH, 5 ml of THF, 2 ml of water and 1 ml of HOAc was mixed with a teaspoon of Raney nickel and hydrogenated for 5 hours. The catalyst is filtered off. The filtrate thickens. The residue was purified by chromatography over silica gel (EtOAc/acetone/water/HOAc 6:2:1:1). This gave 80 mg (56%) of (RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(carbamimidoylphenylamino)-N-[2-(3,4-dihydroxyphenyl)ethyl]acetamide acetate (1: 1) as a colorless lyophilizate. ISP-MS: 541.2 [M+H].

Example 46

Applying the method described in example 45

46.a

(RS)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoyl-phenylamino)-N-methylacetamide was obtained from the product from example 48.a, ISP-MS: 509.5 [M+H],

46.b

(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[2-(4-sulfamoylphenyl)ethyl]acetamide was obtained from the product from example 48.b, ISP-MS : 588.4 [M+H],

46. c

(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-(2-pyridin-2-ylethyl)acetamide acetate was obtained from the product from example 48.c, ISP-MS : 510.3 [M+H],

46.d

(RS)-N-[2-(4-aminophenyl)ethyl]-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)acetamide acetate was obtained from the product from example 48.d 1:1),

ISP-MS: 523.4 [M+H],

46.e

1. from the diastereomer from example 48.e.1, the corresponding (R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[(R)-2-hydroxy -1-phenylethyl]acetamide acetate (1:1) i

2. from the diastereomer from example 48.e.2 the corresponding (S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)-N-[(R)-2-hydroxy -1-phenylethyl]acetamide acetate (1:1), ISP-MS: 525.2 [M+H],

46. f

1. from the diastereomer from example 48.f.1, the corresponding (R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)-N-[(S)-2-hydroxy -1-phenylethyl]acetamide acetate (1:1) i

2. from the diastereomer from example 48.f.2 the corresponding (S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)-N-[(S)-2-hydroxy -1-phenylethyl]acetamide acetate (1:1), ISP-MS: 525.4 [M+H],

46. Mr

1. the corresponding (R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)-N-[(R)-1-phenylethyl) was obtained from the diastereomer from example 48.g.1 ]acetamide acetate

(1:1) i

2. the corresponding (S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)-N-[(R)-1-phenylethyl) was obtained from the diastereomer from example 48.g.2 ]acetamide acetate

(1:1), ISP-MS: 509.4 [M+H],

46 h

1. the corresponding (R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)-N-[(S)-1-phenylethyl) was obtained from the diastereomer from example 48.h.1 ]acetamide acetate

(1:1) i

2. the corresponding (S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carb-amimidoylphenylamino)-N-[(S)-1-phenylethyl) was obtained from the diastereomer from example 48.h.2 ]acetamide acetate

(1:1), ISP-MS: 509.4 [M+H].

Example 47

47.a

Using the method described in example 36.1, from 388 mg of the product from example 25 and 184 mg of 3-hydroxytyramine, 323 mg (62%) of (RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyano- phenylamino)-N-[2-(3,4-dihydroxyphenyl)ethyl]acetamide as a solid colorless foam. ISN-MS: 522.1 [M-H].

47.b

Using the method described in example 36.3, 222 mg (81%) of (RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyano-phenylamino) were obtained from 258 mg of the product produced in accordance with example 47.a )-N-[2-(3,4-dihydroxyphenyl)ethyl]acetamide as a colorless powder. ISP-MS: 557.2 [M+H].

Example 48

The following compounds were produced by the method described in examples 36.1 and 36.3:

From the product from example 25

48.a

and N-benzylamine, through the intermediate (RS)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-methylacetamide, (E)- and/or (Z )-(RS)-N-benzyl-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamidoyl)phenylamino]-N-methylacetamide,

48.b

and 4-(2-aminomethyl)benzenesulfonamide, via

intermediate (RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[2-(4-sulfamoylphenyl)ethyl]acetamide, (E)- and/or (Z )-(RS)-2-(4-benzyloxy-3-methoxy-phenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[2-(4-sulfamoylphenyl)ethyl]acetamide,

48. c

and 2-(2-aminoethyl)pyridine, via the intermediate (RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-(2-(2-pyridin-2-ylethyl) acetamide, (E)- and/or (Z)-(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-(2 -pyridin-2-ylethyl)acetamide,

48.d

and 4-nitrophenylethylamine, through intermediate (RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[2-(4-nitrophenyl)ethyl]acetamide, (E) was obtained - and/or (Z)-(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[2-(4-nitrophenyl)ethyl ]acetamide,

48.e

and (R)-phenylglycinol, after chromatographic separation of the two diastereomers, (R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[(R)-2-hydroxy-1- phenylethyl]acetamide and (S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[(R)-2-hydroxy-1-phenylethyl]acetamide;

1. (E)- and/or (Z)-(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamidoyl)phenylamino]-N was obtained from the first diastereomer -[(R)-2-hydroxy-1-phenylethyl]acetamide, i

2. (E)- and/or (Z)-(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamidoyl)phenylamino]-N was obtained from the second diastereomer -[(R)-2-hydroxy-1-phenylethyl]acetamide,

48.f

and (S)-phenylglycinol, after chromatographic separation of the two diastereomers, (R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[(S)-2-hydroxy-1- phenylethyl]acetamide and (S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[(S)-2-hydroxy-1-phenylethyl]acetamide;

1. (E)- and/or (Z)-(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamidoyl)phenylamino]-N was obtained from the first diastereomer -[(S)-2-hydroxy-1-phenylethyl]acetamide, i

2. (E)- and/or (Z)-(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamidoyl)phenylamino]-N was obtained from the second diastereomer -[(S)-2-hydroxy-1-phenylethyl]acetamide,

48.g

and (R)-1-phenylethylamine, after chromatographic separation of the two diastereomers was obtained

1. (E)- and/or (Z)-(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[(R)-1 -phenylethyl]-acetamide, i

2. (E)- and/or (Z)-(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino]-N-[(R)-1 -phenylethyl]-acetamide,

48 h

and (S)-1-phenylethylamine, after chromatographic separation of the two diastereomers, (R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[(S)-1-phenylethyl] -acetamide and (S)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-cyanophenylamino)-N-[(S)-1-phenylethyl]acetamide;

1. (E)- and/or (Z)-(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamidoyl)phenylamino]-N was obtained from the first diastereomer -[(S)-1-phenylethyl]acetamide, a

2. (E)- and/or (Z)-(S)-2-(4-benzyloxy-3-methoxyphenyl)-2-[4-(N-hydroxycarbamidoyl)phenylamino]-N was obtained from the second diastereomer -[(S)-1-phenylethyl]acetamide.

Example 49

By the method described in example 45

49.a

(RS)-N-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]-5-benzyl-oxy-4-methoxyphenyl]benzamide acetate (1:1.5) was obtained from the product from example 50.2 as a colorless solid ,

49.b

(RS)-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]-5-benzyloxy-4-methoxyphenyl]carbamate acetate (1:1.3) was obtained from the product from example 51.a as a colorless solid,

49. c

from the product from example 51.b, (RS)-2-(2-acetylamino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-(4-carbamimidoylphenylamino)acetamide acetate (1:1) was obtained as a colorless solid matter,

49.d

from the product from example 51.c, (RS)-N-benzyl-2-(4-benzyloxy-5-methoxy-2-phenylacetylaminophenyl)-2-(4-carbamimidoylphenylamino)acetamide acetate (1:1) was obtained as light brown solid matter,

49.e

(RS)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(4,5-dimethoxy-2-phenylacetylaminophenyl)acetamide acetate (1:1) was obtained from the product from example 52.3 as a colorless solid,

49. f

methyl (RS)-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]-4,5-dimethoxyphenyl]carbamate acetate was obtained from the product from example 53.a, (1:1) as a slightly brown solid,

49.g

methyl (RS)-N-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]-4,5-dimethoxyphenyl]benzamide acetate was obtained from the product from example 53.b, (1:1) as a colorless solid, ISP -MS: 588.3 [M+H],

49 h

(RS)-N-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]-4-methoxyphenyl]benzamide acetate was obtained from the product from example 54.3, (1:1) as a colorless lyophilizate, ISP-MS: 508.3 [M+H],

49.i

from the product from example 55, (RS)-2-(2-benzenesulfonylamino-5-methoxyphenyl)-N-benzyl-2-(4-carbamidoylphenylamino)acetamide acetate was obtained, (1:1) as a colorless lyophilisate, ISP- MS: 544.1 [M+H].

Example 50

50.1

0.26 ml of diisopropylethylamine and 0.08 ml of benzoyl chloride were added to a solution of 300 mg of the nitrile obtained according to Example 27 in 10 ml of THF. The reaction solution was stirred for 3 hours at room temperature. The THF is then distilled off under reduced pressure. The residue is taken up in CH2Cl2 and washed with saturated NaCl solution. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is recrystallized from cyclohexane/toluene/acetone. This gives 288 mg (79%) of (RS)-N-{2-[benzylcarbamoyl-(4-cyano-phenylamino)methyl]-5-benzyloxy-4-methoxyphenyl}benzamide as a slightly brown solid.

50.2

Using the method described in example 36.3, from 280 mg of the material produced above, 254 mg (86%) of (RS)-N-2-{benzylcarbamoyl-[4-(N-hydroxycarbamimoyl)phenylamino]-methyl}-5-benzyloxy-4- methoxyphenyl)benzamide as a slightly brown solid.

Example 51

By the method described in example 50.1 from the product from example 27 i

51.a

of methyl chloroformate, (RS)-2-{benzylcarbamoyl-[4-(N-hydroxycarbamimidoyl)phenylamino]methyl}-5-benzyloxy-4-methoxyphenyl)carbamate was obtained,

51.b

of acetyl chloride, (E)- and/or (Z)-(RS)-2-(2-acetylamino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-[4-(N-hydroxycarbamimidoyl)phenylamino ]acetamide,

51. c

of phenylacetyl chloride, (E)- and/or (Z)-(RS)-N-benzyl-2-(4-benzyloxy-5-methoxy-2-phenylacetylaminophenyl)-2-[4-(N-hydroxycarbamimidoyl)phenylamino ]acetamide.

Example 52

52.1

By the method described in example 16 and starting from 6-nitro-veratraldehyde, 4-aminobenzonitrile and benzylisonitrile, (RS)-N-benzyl-2-(4-cyanophenylamino)-2-(4,5-dimethoxy-2-nitrophenyl) was obtained )acetamide in 10% yield as yellow crystals.

52.2

Using the method described in example 27, (RS)-2-(2-amino-4,5-dimethoxyphenyl)-N-benzyl-2-(4-cyanophenylamino)acetamide was obtained from the nitro compound produced in example 52.1 in a yield of 25. Mild gray crystals.

52.3

Using the method described in example 50, (E)- and/or (Z)-(RS)-N-benzyl-2-(4,5-dimethoxy-2-phenylacetyl-aminophenyl)- was obtained from the aniline compound produced above and phenylacetyl chloride. 2-[4-(N-Hydroxycarbamimidoyl)phenylamino]acet-amide.

Example 53

By the method described in example 50 from the aniline compound produced in example 52.2 i

53.a

of methyl chloroformate, (E)- and/or (Z)-(RS)-[2-[benzylcarbamoyl-[4-(N-hydroxycarbamimidoyl)phenylamino]-methyl]-4,5-dimethoxyphenyl]carbamate was obtained,

53.b

of benzoyl chloride gave (E)- and/or (Z)-(RS)-N-[2-[benzylcarbamoyl-[4-(N-hydroxycarbamimidoyl)phenylamino]-methyl]-4,5-dimethoxyphenyl]benzamide.

Example 54

54.1

Using the method described in example 16 and starting from 6-nitro-veratraldehyde, 4-aminobenzonitrile and benzylisonitrile, (RS)-N-benzyl-2-(4-cyanophenylamino)-2-(5-methoxy-2-nitrophenyl)acetamide was obtained with a utilization of 24%. @uti crystals.

54.2

Using the method described in example 27, (RS)-N-benzyl-2-(4-cyanophenyl-amino)-2-(2-amino-5-methoxyphenyl)acetamide was obtained from the nitro compound produced above with a yield of 79. ISP-MS : 387.1 [M+H], 409.2 [M+Na].

54.3

Using the method described in example 50, from the nitrile produced in example 54.2 and benzoyl chloride, (E)- and/or (Z)-(RS)-N-[2-[benzylcarbamoyl-[4-(N-hydroxycarbamimoyl)-phenylamino] was obtained. methyl]-4-methoxyphenyl]benzamide.

Example 55

Using the method described in example 50, from the nitrile produced in example 54.2 and phenylsulfonyl chloride, (E)- and/or (Z)-(RS)-N-(2-(benzenesulfonylamino-5-methoxyphenyl)-N-benzyl-2- [4-(N-Hydroxycarbamimidoyl)phenylamino]acetamide.

Example 56

56.1

Using the method described in example 36.1, from the material produced in accordance with example 27 and methoxyacetic acid, (RS)-N-benzyl-2-[4-benzyloxy-5-methoxyacetylamino)phenyl]-2-(4-cyanophenylamino)acetamide was obtained with the yield of 66%. Solid substance.

56.2

Using the method described in Example 36.3, the nitrile produced in Example 56.1 was reacted in 81% yield to give (RS)-N-benzyl-2-[4-benzyloxy-5-methoxy-2-(2-methoxyacetylamino)phenyl] -2-[4-(N-Hydroxycarbamimidoyl)-phenylamino]acetamide. Light brown solid.

56.3

By the method described in Example 45, the amidoxime produced in Example 56.2 was reduced to (RS)-N-benzyl-2-[4-benzyloxy-5-methoxy-2-(2-methoxyacetylamino)phenyl]-2-(4-carbam- imidoylphenylamino)acetamide hydrochloride (1:2).

Example 57

57.1

Using the method described in example 36.1, tert.butyl (RS)-({2-[benzylcarbamoyl-(4-cyanophenylamino)methyl]-5-benzyloxy-4-methoxyphenylcarbamoyl}methyl) was obtained from the product from example 27 and N-Boc-glycine )carbamate with a yield of 65%.

57.2

The product obtained above is reacted with the method from example 36.3, which gives tert.butyl (RS)-[(2-{benzylcarbamoyl-[4-(N-hydroxycarbamimoyl)phenylamino]methyl}-5-benzyloxy-4-methoxyphenylcarbamoyl)methyl]carbamate with with a utilization of 65%. Light brown solid.

57.3

A solution of 170 mg of amidoxime obtained according to Example 57.2 in 10 ml of EtOH was mixed with a teaspoon of Raney nickel and a few drops of acetic acid. The mixture is hydrogenated for 2 hours and then the catalyst is filtered off. The filtrate thickens. The residue was purified by chromatography on silica gel (EtOAc/acetone/water/HOAc 6:2:1:1). The product fractions are concentrated. The residue is dissolved in CH2Cl2, mixed with 5 ml of trifluoroacetic acid and stirred for 3 hours at 0°C. The mixture is thickened under reduced pressure. The residue crystallizes from Et2O. This gives 107 mg (76%) of (RS)-2-[2-(2-aminoacetylamino)-4-benzyloxy-5-methoxyphenyl-N-benzyl-2-(4-carbamimidoyl-phenylamino)acetamide trifluoroacetate (1: 2) as a slightly brown solid.

Example 58

Using the method from example 45

58.a

from the product produced in example 59.5 (RS)-3-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)-methyl]-4,5-dimethoxyphenoxymethyl]benzoic acid acetate (1:1), ISP-MS: 569, 3 [M+H],

58.b

(RS)-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]-4,5-dimethoxyphenoxy]acetic acid acetate (1:1) is obtained from the product produced in example 60.a.

58. c

(RS)-4-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)-methyl]-4,5-dimethoxyphenoxy]benzoic acid acetate (1:1) is obtained from the product produced in example 60.b.

ISP-MS: 569.3 [M+H],

58.d

(RS)-4-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)-methyl]-4,5-dimethoxyphenoxy]butyric acid is obtained from the product produced in example 60.c,

58.e

(RS)-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]-4-methoxyphenoxy]acetic acid is obtained from the product produced in example 61, ISP-MS: 463.2 [M+H],

58.f

from the product produced in example 62, (RS)-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]-4,6-dimethoxyphenoxy]acetic acid acetate (1:0.5) is obtained,

ISP-MS: 461.3 [M+H], 483.4 [M+Na].

Example 59

59.1

1.18 g of 4-aminobenzonitrile and 1.22 ml of benzyl isonitrile were added to a solution of 2.78 mg of 2-benzyloxy-4,5-dimethoxybenzaldehyde in 36 ml of THF and 4 ml of water. The mixture is stirred for 5 minutes at room temperature and then mixed with 2.85 g of p-toluenesulfonic acid. The reaction solution was stirred for 24 hours at room temperature and then concentrated under reduced pressure. The residue is taken up in CH2Cl2 and then washed with saturated NaHCO3 solution and with saturated NaCl solution. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (toluene/acetone 9:1). This gave 2.13 g (42%) of (RS)-N-benzyl-2-(2-benzyloxy-4,5-dimethoxyphenyl)-2-(4-cyanophenylamino)acetamide as a slightly yellow solid.

59.2

A solution of 1.4 g of the material produced in 59.1 in 140 ml of EtOH was mixed with 420 mg of Pd/C 10% and hydrogenated for 5 hours, during which a colorless precipitate formed. It is dissolved again by the addition of 75 ml of dioxane. The catalyst is then removed by filtration. The filtrate is concentrated under reduced pressure. The residue crystallizes from EtOH. This gives 907 mg (79%) of (RS)-N-benzyl-2-(4-cyanophenylamino)-2-(2-hydroxy-4,5-dimethoxyphenyl)acetamide as colorless crystals.

59.3

A solution of 418 mg of the material obtained in 59.2 in 30 ml of acetone was mixed with 415 mg of K2CO3 and 252 mg of methyl 3-bromo-methylbenzoate. The reaction mixture is heated for 3 hours under reflux and then filtered. The filtrate thickens. The residue is taken up in CH2Cl2 and washed with water. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc/hexane 2:3). This gives 365 mg (65%) of methyl (RS)-3-[2-[benzylcarbamoyl-(4-cyanophenylamino)-methyl]-4,5-dimethoxyphenoxymethyl]benzoate as a colorless solid.

59.4

Using the method described in example 36.2, from the material obtained in example 59.3, (RS)-3-[2-[benzyl-carbamoyl-(4-cyanophenylamino)methyl]-4,5-dimethoxyphenoxy-methyl]benzoic acid was obtained with quantitative yield. Colorless solid.

59.5

Using the method described in example 36.3, from the material obtained in example 59.4, (E)- and/or (Z)-(RS)-3-[2-[benzylcarbamoyl-[4-(N-hydroxycarbamimidoyl)phenyl-amino]methyl] was obtained. -4,5-dimethoxyphenoxymethyl]benzoic acid with a yield of 70%. Colorless solid.

Example 60

By the methods described in examples 59.3 - 59.5, from the material obtained in example 59.2 and

60.a

of ethyl bromoacetate, via nitrile, obtained ethyl (RS)-[2-[benzylcarbamoyl-(4-cyanophenylamino)methyl]-4,5-di-methoxyphenoxy]acetate and (RS)-[2-[benzylcarbamoyl-(4- cyano-phenylamino)methyl]-4,5-dimethoxyphenoxy]acetic acid, (E)- and/or (Z)-(RS)-[2-[benzylcarbamoyl-[4-(N-hydroxycarbamimoyl)phenylamino]methyl ]-4,5-dimethoxy-phenoxy]acetic acid,

60.b

of methyl 4-bromo-methylbenzoate, via nitrile, methyl (RS)-4-[2-[benzylcarbamoyl-(4-cyanophenylamino)methyl]-4,5-dimethoxyphenoxymethyl]benzoate and (RS)-4-[2- [benzylcarb-amoyl-(4-cyanophenylamino)methyl]-4,5-dimethoxyphenoxy]-benzoic acid, (E)- and/or (Z)-(RS)-4-[2-[benzylcarb-amoyl-[4 -(N-hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxyphenoxymethyl]benzoic acid,

60. c

of ethyl 4-bromobutyrate, via nitrile, obtained ethyl (RS)-4-[2-[benzylcarbamoyl-(4-cyanophenylamino)methyl]-4,5-dimethoxyphenoxy]butyrate and (RS)-4-[2-[benzylcarbamoyl -(4-cyanophenylamino)methyl]-4,5-dimethoxyphenoxy]butyric acid, (E)- and/or (Z)-(RS)-4-[2-[benzylcarbamoyl-[4-(N-hydroxycarbamimoyl)phenylamino ]methyl]-4,5-dimethoxy-phenoxy]butyric acid.

Example 61

Using the method described in example 60, ethyl (RS)-[2 -[benzylcarbamoyl-(4-cyanophenylamino)methyl]-4-methoxyphenoxy]acetate and (RS)-[2-[benzylcarbamoyl-(4-cyanophenylamino)methyl]-4-methoxyphenoxy]acetic acid, (E) - and/or (Z)-(RS)-[2-[benzylcarbamoyl-[4-(N-hydroxycarbamimoyl)-phenylamino]methyl]-4-methoxyphenoxy]acetic acid.

The starting material was produced as follows:

61.1

A solution of 30 g of 2-hydroxy-5-methoxybenzaldehyde in 200 ml of acetone was mixed with 51.2 ml of allyl bromide and 81.75 g of K 2 CO 3 and then heated under reflux for 2 hours. Then the reaction mixture is filtered. The filtrate is concentrated under reduced pressure. The residue is taken up in CH2Cl2 and washed with water. The organic phases are dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is distilled under high vacuum. This gives 24.5 g (65%) of 2-allyloxy-5-methoxybenzaldehyde as a light green oil.

61.2

Using the method described in example 59.1, (RS)-2-(2-allyloxy-5-methoxyphenyl)-N-benzyl-2-(4-cyano-phenylamino)acetamide was obtained from the obtained aldehyde, 4-aminobenzonitrile and benzylisonitrile with a yield of 35 %.

ISP-MS: 428.3 [M+H], 450.1 [M+Na].

61.3

A solution of 4.6 g of the nitrile obtained above in 140 ml of THF was mixed with 249 mg of tetrakis(triphenylphosphine)palladium(0). The mixture is stirred for 10 minutes at room temperature and then 626 mg of NaBH4 is added in a short time. The mixture is stirred for 2 hours at room temperature and then concentrated under reduced pressure. The residue was taken up in EtOAc and washed with water. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in CH2Cl2/EtOAc 9:1 and the color was removed with activated charcoal. The product is then crystallized from Et2O/CH2Cl2. This gives 3.22 g (77%) of (RS)-N-benzyl-2-(4-cyanophenylamino)-2-(2-hydroxy-5-methoxyphenyl)acetamide as a slightly brown crystalline substance. ISN-MS: 386.1 [M-H].

Example 62

Using the method described in example 60, ethyl (RS)-[ 2-[benzyl-carbamoyl-(4-cyanophenylamino)methyl]-4,6-dimethylphenoxy]-acetate, from which (E)- and/or (Z)-(RS)-4-[2-[benzylcarbamoyl -[4-(N-Hydroxycarbamimidoyl)phenylamino]-methyl]-4,6-dimethylphenoxy]acetic acid.

The starting material was produced by the method described in example 16 from 3,5-dimethyl-2-hydroxybenzaldehyde (G. Casiraghi et al., J. Chem. Soc. (1980), 1862) 4-amino-benzonitrile and benzyl isonitrile.

Example 63

63.1

A solution of 1.04 g of the nitrile produced in Example 59.2, 0.35 ml of methyl (S)-lactate and 785 mg of triphenylphosphine in 75 ml of THF was mixed with 0.475 ml of diethyl azodicarboxylate and stirred for 4 hours at room temperature. The THF is then distilled off under reduced pressure. The residue was taken up in EtOAc and washed with saturated NaCl solution. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2Cl2/EtOAc 9:1). This gives 1.145 g (88%) of a 1:1 mixture of ethyl (R)-2-[2-[(R)- i -[(S)-benzylcarbamoyl-(4-cyanophenyl-amino)methyl]-4,5 -dimethoxyphenoxy]propionate as a yellow foam. ISP-MS: 518.2 [M+H], 540.3 [M+Na].

63.2

Using the method described in example 36.2, two diastereomers (R)-2-[2-(R)-benzylcarbamoyl-(4-cyanophenylamino)methyl]-4,5-dimethoxyphenoxy are obtained from the ester produced above, after separation by chromatography on silica gel. ]propionic acid and (R)-2-[2-(S)-benzylcarbamoyl-(4-cyanophenyl-amino)methyl]-4,5-dimethoxyphenoxy]propionic acid in 49% yield, both as slightly yellow resins.

ISP-MS: 490.3 [M+H], 512.3 [M+Na].

63.3

By the method described in example 36.2, from the first of the diastereomers produced above, it was obtained

a) (E)- and/or (Z)-(R)-2-[2-(R)-benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxy]propionic acid, and from the second of the above

of produced diastereomers was obtained

b) (E)- and/or (Z)-(R)-2-[2-(S)-benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxy]propionic acid, both as colorless powders.

ISP-MS: 523.2 [M+H], 545.2 [M+Na], 567.2 [M+2Na].

63.4

Using the method described in example 33, amidines were obtained from the respective diastereomeric amidoximes from example 63.3

a) (R)-2-[2-(R)-benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenoxy]propionic acid acetate (1:1) and

c) (R)-2-[2-(S)-benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenoxy]propionic acid acetate (1:1), ISP-MS: 507.4 [ M+H].

Example 64

64.1

By the method described in examples 63.1 - 3.3, from the material produced in example 59.2 and ethyl (R)-lactate, via a mixture of epimers of the corresponding nitrile esters, two diastereomeric nitrile acids were obtained from which the epimers in question were obtained

a) (E)- and/or (Z)-(S)-[2-[(R)-benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxy]propionic acid and

b) (E)- and/or (Z)-(S)-[2-[(S)-benzylcarbamoyl-[4-(N-

hydroxycarbamimidoyl)phenylamino]methyl]-4,5-dimethoxy-phenoxy]propionic acid, both as colorless lyophilisates.

64.2

By the method described in Example 33, the corresponding amidines were obtained from the amidoximes produced above

a) (S)-2-[2-[(R)-benzylcarbamoyl-(4-carbamimoyl)phenyl-amino)methyl]-4,5-dimethoxyphenoxy]propionic acid and

b) (S)-2-[2-[(S)-benzylcarbamoyl-(4-carbamimoyl)phenyl-amino)methyl]-4,5-dimethoxyphenoxy]propionic acid, both as colorless lyophilisates. ISP-MS: 507.4 [M+H], 529.2 [M+Na].

Example 65

By the method described in example 45

65.a

(RS)-3-{4-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]-2-methoxyphenoxy}benzoic acid was obtained from the product from example 66.4 with a yield of 44%. Colorless solid. ISP-MS: 525.2 [M+H],

65.b

(RS)-2-{4-[benzylcarbamoyl-(4-carbamimidoyl)phenylamino)methyl]-2-methoxyphenoxy}benzoic acid was obtained from the product from example 67.a, ISP-MS: 525.2 [M+H] ,

65. c

(RS)-4-{4-[benzylcarbamoyl-(4-carbamimidoylphenylamino)methyl]-2-methoxyphenoxy}benzoic acid was obtained from the product from example 67.b. Light brown solid. ISP-MS: 525.2 [M+H].

Example 66

66.1

A solution of 3 g of vanillin, 11 g of ethyl 3-iodobenzoate and 2.9 g of Cu2O in 5 ml of dimethylacetamide is heated for 24 hours at 165oC. The mixture is allowed to cool to room temperature and filtered. The filtrate is concentrated under high vacuum. The residue was purified by chromatography on silica gel (EtOAc/hexane 3:7). This gives 1.93 g (32%) of ethyl 3-(4-formyl-2-methoxyphenyl)benzoate as a slightly brown oil.

66.2

Using the method described in example 59.1, (RS)-3-{4-[benzylcarbamoyl-(4-cyano-phenylamino)methyl]-2-methoxyphenoxy}benzoate was obtained from the aldehyde produced above with a yield of 58%. Colorless solid.

66.3

Using the method described in example 36.2, (RS)-3-{4-[benzylcarbamoyl-(4-cyanophenylamino)methyl]-2-methoxyphenoxy}benzoic acid was obtained from the nitrile ester produced above with a yield of 51%. Colorless solid.

ISN-MS: 506.2 [M-H].

66.4

Using the method described in example 36.3, from the nitrile acid produced above, (RS)-3-(4-{benzylcarbamoyl-[4-(N-hydroxycarbamimoyl)phenylamino]methyl}-2-methoxy-phenoxy)benzoic acid was obtained with a yield of 94% . Colorless solid. ISP-MS: 541.2 [M+H], 563.3 [M+Na].

Example 67

By the method described in example 66

67.a

and by using methyl 2-iodobenzoate instead of ethyl 2-iodo-benzoate, (RS)-2-(4-{benzylcarbamoyl-[4-(N-hydroxycarbamimidoyl)phenylamino]methyl}-2-methoxyphenoxy)-benzoic acid was obtained via of the corresponding intermediates 4-(2-carbomethoxy)phenoxy-3-methoxybenzaldehyde, methyl (RS)-2-[4-[benzylcarbamoyl-(4-cyanophenylamino)methyl]-2-methoxy-phenoxy]benzoate and (RS)-2- {4-[benzylcarbamoyl-(4-cyano-phenylamino)methyl]-2-methoxyphenoxy}benzoic acid,

67.b

and by using methyl 4-iodobenzoate instead of ethyl 3-iodo-benzoate, (RS)-4-(4-{benzylcarbamoyl-[4-(N-hydroxycarbamimidoyl)phenylamino]methyl}-2-methoxyphenoxy)-benzoic acid was obtained via of the corresponding intermediates methyl 4-(4-formyl-2-methoxyphenoxybenzoate, methyl (RS)-4-{4-[benzylcarbamoyl-(4-cyanophenylamino)methyl]-2-methoxy-phenoxy}benzoate and (RS)-4-{ 4-[benzylcarbamoyl-(4-cyano-phenylamino)methyl]-2-methoxyphenoxy}benzoic acid.

Example 68

By the method described in examples 66.2 - 66.4, from methyl 5-formyl-2,3-dimethoxybenzoate (F.Y. Wu, D.L. Brink, J. Agric. Food Chem. (1977), 25, 692), via the intermediate methyl (RS)-5 -[benzylcarbamoyl-(4-cyanophenylamino)methyl]-2,3-dimethoxybenzoate, was obtained

a) methyl (RS)-5-{benzylcarbamoyl-[4-(N-cyanocarbam-

imidoyl)phenylamino]methyl}-2,3-dimethoxybenzoate i

b) methyl (RS)-5-[benzylcarbamoyl-(4-carbamimidoylphenyl-

amino)methyl]-2,3-dimethoxybenzoate i

c) methyl (RS)-5-[benzylcarbamoyl-(4-carbamimidoylphenyl-

amino)methyl]-2,3-dimethoxybenzoic acid. Light brown solid.

Example 69

69.1

Using the method described in example 59.1, (RS)-N-benzyl-2-(2-bromo-4,5-dimethoxyphenyl)-2-(4-cyano-phenylamino) was obtained from 6-bromoveratrum-aldehyde, 4-aminobenzonitrile and benzylisonitrile )acetamide with a yield of 74%. Colorless solid.

69.2

A solution of 2.4 g of the nitrile produced in Example 69.1 in 10 ml of dimethylacetamide was mixed with 0.41 ml of acrylic acid, 1.51 ml of triethylamine, 22 mg of palladium acetate and 122 mg of tri-o-tolylphosphine and heated for 2 hours at 120oC. . The reaction mixture was diluted with water, adjusted to pH 1 using 1N HCl and then extracted with EtOAc. The organic phase is concentrated under reduced pressure. The residue was dissolved in MeOH and filtered. The filtrate is concentrated under reduced pressure. The residue was stirred in Et2O. The solid is filtered off and dried under high vacuum. This gives 1.71 g (73%) of (E)-(RS)-3-[2-[benzylcarbamoyl-(4-cyanophenylamino)methyl]-4,5-dimethoxyphenyl]acrylic acid as a beige solid.

69.3

A solution of the nitrile prepared above in 2 ml of EtOH and 3 ml of THF was mixed with 5 ml of 1N HCl and 106 mg of Pd/C 10% and hydrogenated for 2 hours. The reaction mixture is filtered. The filtrate was extracted with EtOAc. The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is purified by chromatography on silica gel. This gives 44 mg (18%) of (RS)-3-[2-[benzylcarbamoyl-(4-cyanophenylamino)methyl]-4,5-dimethoxyphenyl]propionic acid as a slightly yellow solid.

69.4

Using the method described in example 36.3, (E)- and/or (Z)-(RS)-3-[2-[benzylcarbamoyl-[4-(N-hydroxycarbamimoyl)phenylamino]-methyl]- was obtained from the nitrile obtained in example 69.3 4,5-dimethoxyphenyl]propionic acid s

with a utilization of 26%. Beige lyophilisate.

69.4

Reduction according to the method described in example 45 above produced amidoxime yielded (RS)-3-[2-[benzyl-carbamoyl-(4-carbamimidoylphenylamino)methyl]-4,5-dimethoxy-phenyl]propionic acid with a yield of 63%. White lyophilisate.

Example 70

70.1

Using the method described in example 16, (RS)-N-benzyl-2-(4-cyanophenylamino)-2-(3-nitrophenyl)acetamide was obtained from 3-nitrobenzaldehyde, 4-aminobenzonitrile and benzylisonitrile with a yield of 11 %. A slightly yellow crystalline solid. ISP-MS: 387.2 [M+H], 409.3 [M+Na].

70.2

A solution of 1.4 g of the nitro compound produced above in 80 ml of THF was mixed with 140 mg of Pd/C 10% and hydrogenated for 6 hours. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (CH2Cl2/MeOH 19:1). This gives 1.15 g (89%) of (RS)-2-(3-aminophenyl)-N-benzyl-2-(4-cyanophenylamino)acetamide as a yellow foam. ISP-MS: 357.2 [M+H], 379.3 [M+Na].

70.3

Using the method described in Example 50.1, the amine produced above is reacted with acetyl chloride to give colorless (RS)-2-(3-acetylaminophenyl)-N-benzyl-2-(4-cyanophenylamino)acetamide in 99% yield.

ISP-MS: 399.4 [M+H], 421.3 [M+Na], 437.3 [M+K].

70.4

Using the method described in example 36.3 and starting from the above nitrile, (E)- and/or (Z)-(RS)-2-(3-acetylamino-phenyl)-N-benzyl-2-[4-(N-hydroxycarbamimidoyl) was obtained )phenylamino]-acetamide with quantitative recovery. colorless solid.

70.5

Using the method described in example 45, from the amidoxime produced in accordance with example 70.4, (RS)-2-(3-acetylaminophenyl)-N-benzyl-2-(4-carbamimidoylphenyl-amino)acetamide acetate (1:1) was obtained using 65%. Colorless powder.

Example 71

At 5-10oC, dry HCl gas is introduced for 2 hours into a solution of 386 g of nitrile from example 70.1 in 20 ml of MeOH and 10 ml of CHCl3. The reaction solution is then concentrated under reduced pressure. The residue is taken up in 30 ml of MeOH saturated with ammonia. The solution is allowed to stand overnight at room temperature and then heated for 4 hours at 40oC and finally thickened under reduced pressure. The residue is purified by chromatography on silica gel. This gives 160 mg (35%) of (RS)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(3-nitrophenyl)acetamide acetate (1:1) as a yellow solid. ISP-MS: 404.4 [M+H].

Example 72

A solution of 201 mg of 2,6-dimethoxyisonicotinaldehyde (I. Kompis et al., Eur. J. Med. Chem. - Chim. Ther. (1977), 12, 531) and 575 mg of 4-aminobenzamidine ditoluenesulfonate in 4.8 ml THF/water 9:1 was mixed with 0.15 ml of benzyl isonitrile. The reaction mixture was stirred for 6 hours and then concentrated under reduced pressure. The residue is suspended in diethyl ether. The solid was filtered off and recrystallized from EtOH/water. This gives 2.02 g (28%) of (RS)-N-benzyl-2-(4-carbamimidoylphenylamino)-2-(2,6-dimethoxypyridin-4-yl)acetamide as a colorless crystalline solid.

Example 73

By the method described in example 72

73.a

(RS)-N- benzyl-2-(4-carbamimidoylphenylamino)-2-(2,6-dimethoxypyridin-2-yl)acetamide with a yield of 41%, as a colorless crystalline solid,

73.b

(RS)-N-benzyl-2-(4-benzyloxy-3,5-dimethylphenyl)-2-(4-carb-amimidoylphenylamino )acetamide with a yield of 23%. Colorless crystalline solid.

Example 74

By the method described in example 1

74.a

(RS)-N-benzyl-2-(3-benzyloxy-5-propoxyphenyl)-2-(4-carbamimidoyl-phenylamino)acetamide hydrochloride was obtained from 3-benzyloxy-5-propoxybenzaldehyde, 4-aminobenz-amidine dihydrochloride and benzyl isonitrile .

74.b

(RS)-N-benzyl-2-(3,5-bis-benzyloxyphenyl)-2-(4-carbamimidoylphenylamino)-acetamide hydrochloride was obtained from 3,5-bis(benzyloxy)benzaldehyde, 4-aminobenzamidine dihydrochloride and benzylisonitrile.

Example 75

75.a

By the method described in example 59.1, from 2,6-diethoxy-pyridine-4-carbaldehyde (I. Kompis et al., Eur. J. Med. Chem. - Chim. Ther. (1977), 12, 531), 4- of aminobenzonitrile and benzylisonitrile, (RS)-N-benzyl-2-(4-cyanophenyl-amino)-2-(2,6-diethoxypyridin-4-yl)acetamide was obtained.

75.b

Using the method described in example 71, (RS)-N-benzyl-2-(4-carbamimidoyl-phenylamino)-2-(2,6-diethoxypyridin-4-yl)acetamide hydrochloride was obtained from the product from example 75.a.

Example 76

76.1

A solution of 5 g of 2-hydroxy-4-nitrobenzoisonitrile (W. Borsche, Ann. Chem. (1912) 390, 1) in 80.5 ml of isopropanol was mixed with 1 g of Pd/C and hydrogenated for 1.5 hours. Then the catalyst is removed from the mixture by filtration and the filtrate is concentrated. This gives 3.3 g (80%) of 4-amino-2-hydroxy-benzonitrile.

76.2

Using the method described in example 59.1, (RS)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-(4- cyano-3-hydroxyphenylamino)acetamide.

76.3

Using the method described in example 13, (RS)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-[3-hydroxy-4-(N-hydroxycarbamimidoyl)-phenylamino]acetamide was obtained from the material produced above. .

76.4

By reducing the amidoxime from example 76.3 by the method described in example 45, (RS)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-(4-carbamimidoyl-3-hydroxy-phenylamino)acetamide was obtained.

Example 77

77.1

A solution of 14.35 g of 4-benzyloxy-5-methoxy-2-nitro-benzaldehyde in 175 ml of MeOH was mixed with 5.9 g of 4-amino-benznitrile and stirred for 1 hour at room temperature. This gives a suspension which is mixed with 6.1 ml of benzyl isonitrile and then cooled to 0°C. then 19 ml of boron trifluoride ethyl ether is added drop by drop over a period of 15 minutes. The mixture is allowed to warm to room temperature and stirred for another 1.5 hours to obtain a solution. It thickens under reduced pressure. The residue was dissolved in 330 ml of MeOH and 3.6 ml of water. The reaction mixture is stirred overnight at room temperature and the solid crystallizes. This was filtered off, washed with MeOH/water 8:2 and Et2O and dried under high vacuum. This gives 16.3 g (61%) of (RS)-(4-benzyloxy-5-methoxy-2-nitrophenyl)-(4-cyanophenylamino)-acetate as a slightly yellow crystalline substance.

77.2

A solution of 4.47 g of the nitrile prepared above in 150 ml of THF was mixed with 1.79 g of Pd/C 5% and hydrogenated for 1 day. The mixture is then freed from the catalyst by filtration and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (toluene/EtOAc 2:1). This gives 2.24 g (50%) of methyl (RS)-(2-amino-4-benzyloxy-5-methoxyphenyl)-(4-cyano-phenylamino)acetate as a slightly orange solid.

ISP-MS: 440.3 [M+Na].

77.3

A solution of 1.79 g of the material prepared in Example 77.2 in 60 ml of CH 2 Cl 2 was mixed with 4 ml of DMF and 2.21 ml of diisopropylethylamine and cooled to 0°C. 1.21 ml of phenylsulfonyl chloride in 10 ml of CH2Cl2 is added dropwise over 20 minutes. The mixture is allowed to warm to room temperature over a period of 3 hours. The reaction solution is concentrated under reduced pressure. The residue was purified by chromatography on silica gel (toluene/EtOAc 4:1). This gave 635 mg (21%) of methyl (RS)-[4-benzyloxy-2-(bisphenylsulfonylamino)-5-methoxyphenyl]-(4-cyanophenylamino)acetate as a light brown solid. ISP-MS: 698.2 [M+H], 720.2 [M+Na].

77.4

Using the method described in example 25, (RS)-[4-benzyloxy-2-(bisphenylsulfonylamino)-5-methoxyphenyl]-(4-cyanophenylamino)acetic acid was obtained from 795 mg of the nitrile produced in example 77.3 above. It reacts according to the method from example 36.1, but using methyl (S)-phenylglycinate instead of methyl L-alaninate hydrochloride, which gives a 1:1 mixture of methyl (S)-[(R)- and -[(S)-2- [4-Benzyloxy-2-(bisphenyl-sulfonylamino)-5-methoxyphenyl]-2-(4-cyanophenylamino)-acetylamino] phenyl acetate. The latter is redissolved in 20 ml of THF and mixed with 11 ml of 1N LiOH solution. The reaction mixture is heated for 6 hours at 60oC and overnight at 40oC. The THF is then distilled off under reduced pressure. The remaining aqueous solution was diluted with 2% citric acid and extracted with EtOAc. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in 25 ml of EtOH and mixed with 3.07 ml of triethylamine and 794 mg of hydroxylamine hydrochloride. The reaction solution was heated under reflux overnight and then concentrated under reduced pressure. The residue was purified by double chromatography on silica gel (EtOAc/acetone/water/HOAc 6:2:1:1). This gives 256 mg (29%) of a 1:1 mixture of (S)-[(R)- and -[(S)-2-(2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-2-[4- [(E)- and/or -[(Z)-N-hydroxycarbamidoyl)phenylamino]acetylamino]phenylacetic acid as a slightly brown lyophilisate. ISP-MS: 710.1 [M+H], 732.2 [M+Na].

77.5

A solution of 190 mg of the above-produced amidoxime in 8 ml of ETOH and 1 ml of HOAc was mixed with a teaspoon of Raney nickel and hydrogenated overnight. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel. This results in two epimers

a) (S)-[(R)-2-(2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-phenylacetic acid acetate (1:1) and

b) (S)-[(S)-2-(2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-phenylacetic acid acetate (1:1), both as colorless lyophilisates . ISP-MS: 694.2 [M+H].

Example 78

78.1

5.9 g of 4-aminobenzonitrile is added to a solution of 14.3 g of 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde in 350 ml of alkyl alcohol. The hot suspension was stirred for 1.5 hours at room temperature. Then 6.1 ml of benzyl isonitrile was added and the reaction mixture was cooled to 0°C. Add 19 ml of boron trifluoride ether drop by drop. Allow the suspension to warm to room temperature. Then the solid substance is filtered off, washed with diethyl ether and suspended in 200 ml of allyl alcohol and 18 ml of water. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue is purified by chromatography on silica gel (toluene/acetone 9:1). The product is recrystallized from THF/hexane. This gives 7.35 g (45%) of allyl (RS)-(4-benzyloxy-5-methoxy-3-nitrophenyl)-(4-cyanophenylamino)acetate as slightly yellow crystals. ISN-MS: 472.1 [M-H].

78.2

2 g of dimedone(5,5-dimethyl-1,3-cyclohexanedione) and 1.8 g of tetrakis(triphenylphosphine)palladium are added to a solution of 7.1 g of the nitrile prepared according to Example 78.1 in 75 ml of THF. The reaction mixture is stirred for 30 minutes at room temperature and then mixed with activated carbon, stirred for another 30 minutes at room temperature and then filtered. The filtrate is concentrated under reduced pressure. The residue was purified by double chromatography on silica gel (first CH2Cl2/MeOH 19:1, then EtOAc). This gave 2.25 g (35%) of (RS)-(4-benzyloxy-5-methoxy-2-nitrophenyl)-(4-cyanophenylamino)acetic acid as a yellow solid.

ISP-MS: 434.3 [M+H].

78.3

By the method described in example 36.1, using 1.67 g of the nitrile produced in accordance with example 78.2 and methyl (S)-phenylglycinate, instead of methyl L-alaninate hydrochloride, 1.03 g (46%) of a 1:1 mixture of methyl (S )-[(R)- i-[(S)-2-(4-benzyloxy-5-methoxy-2-nitrophenyl)-2-(4-cyanophenyl-amino)acetylamino]phenyl acetate as a red brown solid foam. ISP-MS: 581.1 [M+H], 603.0 [M+Na].

78.4

Using the method described in example 27, from 636 mg of the nitro compound from example 78.3, 235 mg (40%) of a 1:1 mixture of methyl (S)-[(R)- i-[(S)-2-(2-amino- 4-benzyloxy-5-methoxyphenyl)-2-(4-cyanophenylamino)acetylamino]phenyl acetate as a colorless crystalline solid. ISN-MS: 549.1 [M+H].

78.5

Using the method described in example 50.1, 118 mg (98%) of a 1:1 mixture of methyl (S)-[(R)- i-[(S)-2-(4-benzyloxy) was obtained from 100 mg of the above amino nitrile and phenylacetyl chloride. -5-methoxy-2-phenylacetylphenylamino)-2-(4-cyanophenylamino)-acetylamino]phenyl acetate as a colorless solid foam.

ISN-MS: 667.2 [M-H].

78.6

Using the method described in example 36.2, from 108 mg of nitrile produced in example 78.5, 104 mg (98%) of a 1:1 mixture of (S)-[(R)- i-[(S)-2-(4-benzyloxy-5- methoxy-2-phenyl-acetylaminophenyl)-2-(4-cyanophenylamino)acetylamino]phenyl-acetic acid as a solid, slightly yellow foam.

ISP-MS: 655.1 [M+H].

78.7

Using the method described in example 36.3, 133 mg (70%) of a 1:1 mixture of methyl (S)-[(R)- i-[(S)-2-(4-benzyloxy-5-methoxy-) was obtained from 180 mg of the above nitrile. 2-phenylacetylaminophenyl)-2-[4-[(E)-i/or -[(Z)-N-hydroxycarbamimidoyl]phenylamino]-

acetylamino]phenylacetic acid as a colorless powder.

ISP-MS: 688.2 [M+H], 710.1 [M+Na].

78.8

Two epimers were obtained from the epimeric mixture from example 78.8 by the method from example 33 and after separation of the product by chromatography on silica gel

a) (S)-[(R)-2-(2-benzenesulfonylamino-4-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-phenylacetic acid acetate (1:1) and

b) (S)-[(S)-2-(2-benzenesulfonylamino-4-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-phenylacetic acid acetate (1:1), both in the form of colorless powder. ISP-MS: 672.3 [M+H].

Example 79

Using the methods from examples 78.5 - 78.8, but using acetic anhydride instead of phenylacetyl chloride, from the product from example 78.4, after chromatographic separation, two epimers (S)-[(R)-2-(2-acetylamino-4-benzyl-oxy) were obtained -5-methoxyphenyl)-2-(4-cyanophenylamino)acetylamino]-phenylacetic acid and (S)-[(S)-2-(2-acetylamino-4-benzyl-oxy-5-methoxyphenyl)-2-(4 -cyanophenylamino)acetylamino]-phenylacetic acid. They reacted via the respective amidoximes, resulting in two epimers

a) (S)-[(R)-2-(2-acetylamino-4-benzyloxy-5-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid acetate and

b) (S)-[(S)-2-(2-acetylamino-4-benzyloxy-5-methoxy-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid acetate. ISP-MS: 596.2 [M+H].

Example 80

A solution of 0.024 ml of 4-fluorobenzoyl chloride in 1.0 ml of THF and 0.5 ml of DMF was mixed with 0.038 ml of N,N-diisopropylethylamine and stirred for 5 minutes at room temperature. Then 100 mg of the product from example 5.g is added. The reaction mixture was stirred overnight at room temperature. Another 0.024 ml of 4-fluorobenzoyl chloride and 0.1 ml of N,N-diisopropylethylamine were added and the mixture was stirred for 3 hours at room temperature. The reaction mixture is concentrated under reduced pressure. The residue was taken up in saturated NaHCO3 solution and extracted with EtOAc. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane/EtOAc 2:1). The product crystallizes from Et2O. This gives 20 mg (17%) of (RS)-N-[amino-4-{[benzyloxycarbamoyl-(4-benzyloxy-3-ethoxyphenyl)methyl]amino}phenyl)methylene]-4-fluorobenzamide as a crystalline solid. ISP-MS: 631.2 [M+H].

Example 81

Using the method described in example 80, (RS)-2-{[amino-4-{[benzylcarbamoyl-(4-benzyloxy-3-ethoxy-phenyl)methyl]amino} was obtained from the product from example 5.g and 2-benzyloxymethylbenzoyl chloride phenyl)methylene]carbamoyl}benzyl benzoate with a yield of 21%. @uta crystalline solid.

ISP-MS: 747.4 [M+H].

Example 82

Using the method described in example 80, 2,2,2-trichloroethyl (RS)-[amino-(4-{[benzyl-carbamoyl- (4-benzyloxy-3-ethoxyphenyl)methyl]amino}phenyl)-methylene]carbamate with a yield of 60%. Crystalline solid. ISP-MS: 683.1 [M+H].

Example 83

By the method described in example 80, methyl (RS)-[amino-(4-{[benzylcarbamoyl-(4-benzyloxy-3-ethoxy-phenyl)methyl]amino}phenyl was obtained from the product from example 5.g and methyl 4-nitrophenyl carbonate )methylene]carbamate with a yield of 91% as a solid. ISP-MS: 567.3 [M+H].

The compounds of formula I, their hydrates or solvates, can be used as an active ingredient for the preparation of pharmaceutical compositions such as those below.

Example A

[image]

Example B

[image]

Claims (12)

1. N-(carbamimidophenyl) glycinamide derivatives of the formula [image] indicated by that E is hydrogen or OH, Q is hydrogen or alkyl, R is aryl, cycloalkyl or alkyl substituted by R1, R2 and R3, R1 is hydrogen, COOH, COO-alkyl or aryl, R2 is hydrogen, aryl, cycloalkyl or heteroaryl, R3 is hydrogen, aryl or (in a position different from the α-position with respect to the nitrogen atom touched by the alkyl group R) OH, alkoxy or, if necessary, a protected amino group, N(Q,R) is COOH- or COO-alkyl-substituted pyrrolidino, piperidino or 1,2,3,4-tetrahydroisoquinolin-3-yl, three of the radicals X1 to X4 independently represent the group C(Ra), C(Rb) or C(Rc) and the fourth radical is the group C(Rd) or N, Ra to Rd independently represent H, OH, NO2, dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkyloxy, heteroarylalkyloxy, heterocyclylalkyloxy, COOH, COO-alkyl, NH-SO2-alkyl, NHSO2-aryl, NHCO-alkyl, NHCO- aryl, NHCOO-alkyl, NHCO-alkyl-NH2, NHCO-alkyl-NH-G, aralkyl-CONH, alkyl-O-alkyl-CONH, aryl-O-alkyl-CONH, alkyl-COOH, alkyl-COO-alkyl, O-alkyl-COOH or O-alkyl-COO-alkyl, or two adjacent groups Ra to Rd together form alkylenedioxy, whereby a maximum of three of the radicals Ra to Rd may have the same meaning and X1 may not be CCOOH or CCOO-alkyl, G is an amino protecting group and one of the radicals G1 and G2 is hydrogen, and the other radical is hydrogen, alkyl, OH, alkoxy, aroyl, alkanoyl-OCH2, aroyl-OCH2 or the group COO-Rg or OCO-Rg, Rg is alkyl optionally substituted with halogen, OH, alkoxy, COOH or COO-alkyl, and their hydrates or solvates and their physiologically acceptable salts. 2. Compounds according to claim 1, characterized in that E, G2 and Q represent hydrogen, R is alkyl, aryl, aralkyl, benzhydryl, cycloalkylalkyl or heteroarylalkyl, G1 is hydrogen, OH or COO-alkyl, X1 to X4 represent the groups C(Ra) to C(Rd) and Ra to Rd independently represent H, OH, NO2, dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkyloxy, heteroarylalkyloxy, heterocyclylalkyloxy, COO-alkyl, NHSO2-alkyl or NHSO2-aryl, where a maximum of three of the radicals Ra to Rd may have the same meaning and X1 may not be COO-alkyl. 3. Compounds according to claim 1 or 2, characterized in that E, G1, G2 and Q represent hydrogen. 4. Compounds according to claim 1 or 3, characterized in that R represents alkyl, especially methyl or ethyl, which is substituted by R1, R2 and R3, especially in which R1 is aryl, especially phenyl, or COOH, R2 is hydrogen or aryl , especially phenyl, and R 3 is hydrogen. 5. Compounds according to claim 1, 3 or 4, characterized in that X1 to X4 represent groups C(Ra) to C(Rd), especially a group in which Ra is H, aralkyloxy, especially carboxybenzyloxy; NHSO 2 -aryl, especially phenylsulfonyl-amino; aralkyl-CONH, especially phenylacetylamino, or O-alkyl-COOH, especially carboxymethoxy, Rb is H or alkoxy, especially methoxy or ethoxy, Rc is H, alkoxy, especially methoxy; or aralkyloxy, especially benzyloxy, and Rd is H or alkoxy, especially methoxy. 6. Compounds according to any of claims 1 to 5, characterized in that they are: (R,S)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-(4-carbamimidoylphenylamino)acetamide, 2-(2-Phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-(4-carbamimidoylphenylamino)acetamide. 7. Compounds according to any claim 1 and 3-5, characterized in that they are: (R,S)-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]diphenylacetic acid, (R,S)- and (SR)-3-[(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-3-phenylpropionic acid, (S)-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid, (S)-[(S)-2-(4-carbamimidoylphenylamino)-2-(3,5-di-methoxyphenyl)acetylamino]phenylacetic acid, (RS)-3-[2-[benzylcarbamoyl-(4-carbamimidoylphenyl-amino)methyl]-4,5-dimethoxyphenoxymethyl]benzoic acid, (RS)-[2-[benzylcarbamoyl-(4-carbamimidoylphenylamino)-methyl]-4,5-dimethoxyphenoxy]acetic acid, (S)-[(R)-2-(2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-phenylacetic acid, (S)-[(S)-2-(2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoylphenylamino)acetylamino]-phenylacetic acid, (S)-[(R)-2-(4-benzyloxy-5-methoxy-2-phenylacetylamino-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid, (S)-[(S)-2-(4-benzyloxy-5-methoxy-2-phenylacetylamino-phenyl)-2-(4-carbamimidoylphenylamino)acetylamino]phenylacetic acid. 8. Compounds of formulas characterized in that E, Q, R and X1 to X4 are defined as in claim 1. 9. Pharmaceutical preparations, characterized in that they contain a compound according to any one of claims 1-7 as an active ingredient. 10. Process for preparing compounds of formula I according to claim 1, characterized in that a) aldehyde formula [image] reacts with isonitrile of the formula R1NC and 4-aminobenzamidine of the formula [image] or b) the cyano group found in the corresponding nitrile of the formula [image] turns into an amidino group C(N-G1)NH-G2, c) the reactive group contained in compound I, if desired, is functionally changed, i d) the compound of formula I is, if desired, converted into a physiologically acceptable salt, or the salt of compound I is converted into a free acid or base. 11. Compounds according to any claim 1-7, characterized by the fact that they are used as drugs, in particular as inhibitors of the formation of coagulation factors Xa, IXa and thrombin induced with factor VIIa and with tissue factor, in particular as drugs for the treatment and/or prevention of thrombosis, apoplexy, heart blockage, inflammation and arteriosclerosis, or as antitumor agents. 12. Use of the compound according to any of claims 1-5, characterized in that it is used for the production of drugs for the treatment and/or prevention of thrombosis, apoplexy, heart blockage, inflammation and arteriosclerosis or for the production of antitumor agents.