EP1261321A2 - Carboxylic acid amides, medicaments containing these compounds and the use and production thereof - Google Patents

Abstract

The invention relates to the use of carboxylic acid amides of general formula (I) for inhibiting telomerase, wherein A, B and R1 to R5 are defined as per claim (1). The invention also relates to novel carboxylic acid amides of general formula (I) according to claim (2), to methods for the production thereof, to medicaments containing these compounds and to the use and production thereof. The compounds of formula (I) are analogous agents and derivatives in the broader sense of N-phenyl cinnamic acid amides. Diseases, which can be treated, with said compounds include tumorous diseases, epidermal hyperproliferation, inflammatory processes (rheumatoid arthritis), diseases of the immune system and parasitic diseases, (helminithic diseases, fungal diseases), infections by protozoic pathogens).

Description

Replication of a certain length of their telomeres, a phenomenon that was already recognized by atson in 1972 (atson in Nature New Biol. 233, 197-201 (1972)). The cumulative loss of telomeric DNA across many cell divisions is the reason for the limited replicative potential of somatic cells, while more than 85% of all human tumors reactivate an enzyme, telomerase, to compensate for the loss of telomeres and thus become immortal (see Shay and Bacchetti in European Journal of Cancer, 22, 787-791 (1997)).

Human telomerase is a ribonucleoprotein (RNP) composed of at least one catalytic subunit (hTERT) and one RNA (hTR). Both components have been molecularly cloned and characterized. Biochemically, telomerase is a reverse transcriptase that uses a sequence section in hTR as a template to synthesize a strand of the telomeric DNA (Morin in Cell 5_9_, 521-529 (1989)). Methods of identifying telomerase activity as well as methods for the diagnosis and therapy of replicative senency and immortality by modulating the telomeres and telomerase have been described (Morin in Cell 5_2., 521-529 (1989); Kim et al. In Science £ 2 £, 2011-2014 (1994))

Inhibitors of telomerase can be used for tumor therapy since, unlike tumor cells, somatic cells are not dependent on telomerase.

Furthermore, U.S. Patent No. 3,940,422 et al. describes the compound trans-3, 4-dimethoxy-cinnamic acid-N-anthranilic acid amide, which in particular has anti-allergic properties.

It has now been found that the carbons ureamides of the general formula

their isomers, in particular their trans isomers, and their salts, in particular their physiologically tolerable salts, surprisingly have an inhibitory effect on the telomerase.

In the above general formula I means

R _{x is} a hydrogen atom, a C ₁ . ₃ -alkyl or trifluoromethyl group,

R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C - ^ - alkyl, C ₃ " ₇ cycloalkyl or C ₁ . ₃ -alkoxy group or, if R ₄ and R ₅ each represent a hydrogen atom, R _x and R ₂ together, optionally by a C ₁ . ₃ alkyl group substituted nC _1-3 alkylene group,

R _{3 is} a hydrogen atom or a C 1-4 alkyl group,

R ₄ and R ₅ each represent a hydrogen atom or together a further carbon-carbon bond,

A one through a fluorine, chlorine, bromine or iodine atom, through one , Cyano, trifluoromethyl or nitro group substituted phenyl, naphthyl or tetrahydronaphthyl group, the aforementioned monosubstituted phenyl and naphthyl groups additionally by a fluorine, chlorine or bromine atom, by a C ₁ . ₃ -alkyl- or C ₁ . ₃ -alkoxy group and the abovementioned disubstituted phenyl groups additionally by a C ₁ . ₃ -alkyl or C ₁ _ ₃ -alkoxy group can be substituted, a naphthyl group,

a chroman or chromene group in which a methylene group can be replaced by a carbonyl group,

one in the carbon skeleton, optionally by a fluorine, chlorine or bromine atom, by a C ₁ . _3- alkyl or C 1-4 alkoxy group substituted 5- or 6-membered heteroaryl group, the 6-membered heteroaryl groups having one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C _1-3 -alkyl group , an oxygen or sulfur atom or one optionally by a C ₁ . _3- alkyl group substituted imino group and an oxygen or sulfur atom or one or two nitrogen atoms and in addition to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, a phenyl ring can be fused, which is also in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C ^ Alkyl or C ^ alkoxy group may be substituted,

a phenyl vinyl group or

R- _L together with A and the carbon atom in between is a C ₅ . _7- cycloalkylidene group, to which a phenyl ring may be fused via two adjacent carbon atoms, which may additionally be substituted by one or two C 1-4 alkyl or C 1-4 alkoxy groups, where the substituents may be the same or different, and

B is a 5- or 6-membered heteroaryl group substituted by a carboxy group or by a group which can be converted into a carboxy group in vivo,

a phenyl or naphthyl group, each converted by a carboxy group, by an in vivo carboxy group bare group or may be substituted by a group negatively charged under physiological conditions, the above-mentioned phenyl groups additionally

by a fluorine, chlorine, bromine or iodine atom,

by a C ^ alkyl, trifluoromethyl, phenyl, hydroxy, C ₁ . ₃ -alkoxy-, C ₁ . _3- alkylsulfonyloxy-, phenylsulfonyloxy-, carboxy-, Cι_3 ~ alkoxycarbonyl-, formyl-, Cι_3 ~ alkylcarbonyl-, Cχ_3-alkylsulfonyl-, phenylsulfonyl-, nitro-, pyrrolidino-, piperidino-, morpholino-, N- (C ^ alkyl) piperazino, aminosulfonyl, C ₁ . _3- alkylaminosulfonyl or di- (C _1-3 -alkyl) -aminosulfonyl group,

by a C ^ alkyl group, which is replaced by a hydroxy, C ^ alkoxy, amino, C ₁ . ₄ -alkylamino-, di- (C ^ -alkyl) - amino-, C ₃ _ ₇ -cycloalkylamino-, pyrrolidino-, piperidino-, morpholino-, piperazino- or N- (C _1-3 -alkyl) -piperazino- group is substituted,

by a 3-position in the 2- or by a di- (C _{1 3} alkyl.) - substituted amino group nc _{2. 3} alkoxy, C _2-3 alkenyl or C ₂ _ ₃ alkynyl group,

by an amino group, by an N- (C _{1, 3} -alkyl) amino or N, N-di- (C _{1, 3} -alkyl) amino group, in which the alkyl part is in the 2- or 3-position can be substituted on the nitrogen atom by a C ^ alkoxy group, by an N-phenylamino, N- (phenyl-C ^ alkyl) amino or N- (pyridyl-C _x . ₃ -alkyl) amino group , in each of which a hydrogen atom of the above-mentioned amino groups is represented by a C 1-4 alkylsulfonyl, phenyl-C 1-4 alkylsulfonyl or phenylsulfonyl group or by a C _1-7 alkyl group which is in the 2- to 5-position by a C ₁ . ₃ -alkoxy-, cyano-, amino-, C ₁ . ₃ -alkylamino, di- (C _1-3 -alkyl) -amino or tetrazolyl group can be replaced, by an aminocarbonyl or C ^ alkylaminocarbonyl group, each on the amine nitrogen atom

by a C _1-4 alkyl group which is replaced by a vinyl, ethyl, phenyl, pyridyl, imidazolyl, carboxy or trifluoromethyl group or, with the exception of the 2 position, based on the aminocarbonyl nitrogen atom by a hydroxy , C ₁ _ ₃ alkoxy, C ^ alkylthio, amino, C ₁ . ₃ -alkylamino-, di- (C - ^ - alkyl) -amino-, C ₁ . ₄ -alkanoylamino- or C ₁ . ₅ -alkoxycarbonylamino group can be substituted,

by a C ₃ . _7- cycloalkyl-, C ₅ . _g -azabicycloalkyl, phenyl, pyridyl, C ^ alkoxy or di (C ^ alkyl) amino group,

by a C ₁ . _3- alkyl group which is substituted by a piperidin-3-yl or piperidin-4-yl group optionally substituted in the l-position by a C 1-4 alkyl or C 1-4 alkoxycarbonyl group, or

by an optionally at the amine nitrogen atom by a C ^ alkanoyl, Cj. _j j-Alkoxycarbonyl-, benzoyl-, pyrrolidino-, piperidino-, morpholino- or N- (C ₁ _ ₃ -alkyl) -pi- perazino group substituted amino-, C ^ -alkylamino- or phenyl-C ₁ . ₃ -alkylamino group can be substituted,

carbonyl group substituted by a pyrrolidino, pyrrolino, piperidino, morpholino or N- (C _1-3 -alkyl) -piperazino group,

sulfonyl group substituted by an amino, C 1-4 alkylamino, di (C 1-4 alkyl) amino, pyrrolidino, piperidino, morpholino or N- (C 1-4 alkyl) piperazino group,

by an amino or N- (C _1-3 -alkyl) -amino group, which in each case on the amine nitrogen atom by an aminocarbonyl-, C ^ - _j -alkylaminocarbonyl-, phenyl-C ^ -alkylaminocarbonyl-, Phenylaminocarbonyl, phenoxyphenylaminocarbonyl, pyridylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl or N- (C ^ alkyl) -piperazinocarbonyl group is substituted, wherein in the above-mentioned aminocarbonyl groups an existing hydrogen atom is additionally substituted by a C ^ -Alkyl can be substituted

by a 5- or 6-membered heteroaryl group,

by a dihydro-oxazolyl, dihydro-imidazolyl, 2-oxo-pyrrolidino, 2-oxo-piperidino or 2-oxo-hexamethylene imino group, to which a phenyl ring can be fused via two adjacent carbon atoms,

may be substituted by an ethynyl group substituted by a phenyl, hydroxymethyl or dirthylamino group, where

additionally the above-mentioned mono- or disubstituted phenyl groups by a further fluorine, chlorine or bromine atom or by one or two further C _x _ ₃ alkyl or C ₁ . ₃ alkoxy groups can be substituted and two o-C- _L .- _j alkoxy groups can be replaced by a methylenedioxy group,

in particular R _{x is} a hydrogen atom, a C _1-3 alkyl or trifluoromethyl group,

R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C _1-3 alkyl, C ₃ . _7- cycloalkyl or C ^ -alkoxy group or, if R ₄ and R ₅ each represent a hydrogen atom, R _x and R ₂ together form an nC ₁ optionally substituted by a C ^ -alkyl group. ₃ -alkylene group,

R _{3 is} a hydrogen atom or a C ₁ . ₅ -alkyl group, R ₄ and R ₅ each represent a hydrogen atom or together a further carbon-carbon bond,

A one through a fluorine, chlorine, bromine or iodine atom, through one , Trifluoromethyl or nitro group substituted phenyl, naphthyl or tetrahydronaphthyl group, the aforementioned monosubstituted phenyl and naphthyl groups additionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl or C ^ - _j -alkoxy group can be substituted,

a naphthy1 group,

a chroman or chromene group in which a methylene group can be replaced by a carbonyl group,

one in the carbon skeleton, optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl or group-substituted 5- or 6-membered heteroaryl group, the 6-membered heteroaryl groups having one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C ₃ alkyl group, an oxygen or sulfur atom or an optionally by one C 1-4 alkyl group substituted imino group and an oxygen or sulfur atom or one or two nitrogen atoms and in addition to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, a phenyl ring can be fused, which is also in the carbon structure by a fluorine, chlorine or bromine atom, by a C ^ alkyl or C- _{L. j} -alkoxy group can be substituted,

a phenyl vinyl group or

R _λ together with A and the carbon atom in between is a C _s . ₇ -cycloalkylidene group, to which a phenyl ring can be fused via two adjacent carbon atoms, which rather by one or two C _x . ₃ -Alkyl- or C ^ -alk- oxy groups can be substituted, where the substituents can be the same or different, and

B is a phenyl, naphthyl or heteroaryl group, each of which may be substituted by a carboxy group, by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions, the phenyl groups mentioned above additionally

by a fluorine, chlorine, bromine or iodine atom,

by a C ₁ . _3- alkyl-, hydroxy-, C ^ -alkoxy-, C ₁ . ₃ -alkylsulfonyloxy-, phenylsulfonyloxy-, carboxy-, C] __ 3-alkoxycarbonyl-, formyl-, C _] __3-alkylcarbonyl-, C _] __3-alkylsulfonyl-,

Phenylsulfonyl, nitro, pyrrolidino, piperidino, morpholino, N- (C 1-4 alkyl) piperazino, aminosulfonyl, C ₁ . ₃ -alkylaminosulfonyl or di- (C 1-4 alkyl) -aminosulfonyl group,

by a 3-position in the 2- or by a di- (C _{1 3} alkyl.) - substituted amino group nc _{2. 3} -alkoxy group,

by an amino-, N- (C ^ - _j -alkyl) -amino-, N- (phenyl-C _{1, 3} -alkyl) -amino- or N- -amino group, in each of which a hydrogen atom of the amino group through a C ₁ . ₃ alkylsulfonyl or phenylsulfonyl group or by a C ₁ . _7- alkyl group, which is substituted in the 2- to 5-position by a C _1-3 alkoxy, cyano, amino, C ^ - _j alkylamino, di (C ^ alkyl) amino or tetrazolyl group can be,

by an amino, C ₁ . ₃ alkylamino, di- (C _{x 3} alkyl.) -Amino, pyrrolidino, piperidino, morpholino or N- (C _{1 3} alkyl.) - piperazino substituted carbonyl or sulfonyl group, by an imidazolyl or pyrazolyl group optionally substituted by a C _x .4 alkyl group, which may additionally be substituted by a C _1-3 alkyl, phenyl, trifluoromethyl or furyl group, and

can additionally be substituted by a further fluorine, chlorine or bromine atom, by a further C 1-4 alkyl or C _1-3 alkoxy group,

and the above-mentioned 6-membered heteroaryl groups have one, two or three nitrogen atoms and the above-mentioned 5-membered heteroaryl groups, optionally by a C ₁ . _3- alkyl group substituted imino group, an oxygen or sulfur atom or an imino group optionally substituted by a C 1-4 alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and additionally to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms a phenyl ring can be condensed, which in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C ^ alkyl - or C _x . ₃ -alkoxy group can be substituted, where the abovementioned 5-membered monocyclic heteroaryl groups in the carbon skeleton can additionally be substituted by C ^ _4-alkyl, trifluoromethyl, phenyl or furanyl group and by a further C ^ _3-alkyl group .

wherein the amino and imino groups mentioned in the definition of the above-mentioned radicals can additionally be substituted by a radical which can be split off in vivo.

Among a group which can be converted into a carboxy group in vivo is, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C ₁ . ₆ -alkanol, a phenyl-C ₁ . _3- alkanol, a C _3-9 cycloalkanol, where a C ₅ _ ₈ -cycloalkanol additionally by one or two C ₁ . ₃ alkyl groups can be substituted, a C ₅ . _8- Cycloalkanol, in which a methylene group in 3- or 4 position by an oxygen atom or by an optionally by a C 1-4 alkyl, phenyl-C 1-4 alkyl, phenyl C ₁ . ₃ -alkoxycarbonyl- or C ₂ . ₆ -alkanoyl group substituted imino group and the cycloalkanol part is additionally replaced by one or two C ₁ . ₃ alkyl groups can be substituted, a C ₄ . _7- cycloalkenol, a C _3-5 alkenol, a phenyl-C ₃ . ₅ -alkenol, a C ₃ . ₅ -alkinol or phenyl-C ₃ . _5- alkynol with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C _3-8 -cycloalkyl-C ₁ . _3- alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms, which in the bicycloalkyl part can additionally be substituted by one or two C - ^ - alkyl groups, a 1, 3-dihydro-3-oxo-l-isobenzfuranol or an alcohol of the formula

R _a -C0-0- (R _b CR _c ) -OH,

by doing

R _a is , C ₅ . _7- cycloalkyl-, phenyl- or phenyl-

C _1-3 alkyl group,

R _{b is} a hydrogen atom, a C ^ alkyl, C ₅ . _7- cycloalkyl or phenyl group and

R _{c represents} a hydrogen atom or a C 1-4 alkyl group,

under a group negatively charged under physiological conditions, a carboxy-, hydroxysulfonyl-, phosphono-, tetra-zol-5-yl-, phenylcarbonylaminocarbonyl-, trifluoromethylcarbonylaminocarbonyl-, C ₁ . _6- alkylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, trifluoromethylsulfonylamino, Ci.g-alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, benzylsulfonylaminocarbonyl or perfluoro-C _1-6 -alkylsulfonyl group

and under a residue which can be split off from an imino or amino group in vivo, for example a hydroxyl group, an acyl group group such as the benzoyl or pyridinoyl group or one such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C _x . ₁₆ -alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. Butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl -C ₁ . ₆ -alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C ₁ . _3- alkylsulfonyl - C ₂ . ₄ -alkoxycarbonyl-, C ^ -alkoxy-C ₂ _ ₄ -alkoxy-C ₂ . ₄ -alkoxycarbonyl or R _a -C0-0- (R _b CR _c ) -O-CO group, in which R _a to R _c are defined as mentioned above,

to understand.

Furthermore, the definition of the above-mentioned saturated alkyl and alkoxy parts which contain more than 2 carbon atoms also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc.

The present invention thus relates to the use of the above carboxylic acid amides of the general formula I in the inhibition of telomerase and the production of a corresponding medicament.

The present invention further provides the new carboxamides of the above general formula I and their salts, in particular their physiologically tolerable salts which have an inhibitory effect on telomerase, processes for their preparation, medicaments containing these compounds and their use.

In the new carboxamides of the general formula I above R _{1 is} a hydrogen atom, a C 1-4 alkyl or trifluoromethyl group,

R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C ^ alkyl, C ₃ . _7- cycloalkyl or C _α _ ₃ alkoxy group or, if R ₄ and R ₅ each represent a hydrogen atom, R _λ and R ₂ together form an nC _1-3 alkylene group which is optionally substituted by a C _1-3 alkyl group,

R _{3 represents} a hydrogen atom or a C _1-5 alkyl group,

R ₄ and R ₅ each represent a hydrogen atom or together a further carbon-carbon bond,

A one by a fluorine, chlorine, bromine or iodine atom, by a C ₁ . ₆ -alkyl-, C ₃ . _7- Cycloalkyl, phenyl, C ^ - _j -alkoxy, cyano, trifluoromethyl or nitro group substituted phenyl, naphthyl or tetrahydronaphthyl group, the aforementioned monosubstituted phenyl and naphthyl groups additionally by a fluorine, chlorine - or bromine atom, by a C _1.3 alkyl or and the above-mentioned disubstituted phenyl groups may additionally be substituted by a C _1-3 alkyl or C- _L .- _j alkoxy group, with the proviso that

A does not represent a phenyl group which is represented by a halogen atom, by a methyl, pentyl or C ₁ . ₃ alkoxy or phenyl group or substituted by two C ^ alkoxy groups, if

R _{3 is} a hydrogen atom,

R ₄ and R ₅ each represent a hydrogen atom or

R ₄ and R ₅ together another carbon-carbon

Bond and

B represents a carboxyphenyl or methoxycarbonylphenyl group, and A does not represent a phenyl group substituted by a methyl or phenyl group when

R ₁ and R ₂ each represent a hydrogen atom,

R _{3 is} a hydrogen atom,

R ₄ and R ₅ together another carbon-carbon

Bond and

B represents a carboxyphenyl or methoxycarbonylphenyl group,

a naphthyl group,

a chroman or chromene group in which a methylene group can be replaced by a carbonyl group,

a group in the carbon skeleton are optionally substituted by a fluorine, chlorine or bromine atom, by a C ^ alkyl or C _j ^ alkoxy substituted 5- or 6-membered heteroaryl, wherein said 6-membered heteroaryl groups one, two or three nitrogen atoms and the 5-membered heteroaryl optionally substituted by a C ^ - _J substituted alkyl imino group, an oxygen or sulfur atom or an optionally by a C _1-3 -alkyl substituted imino group and one oxygen or sulfur atom or one or two nitrogen atoms and in addition to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, a phenyl ring may be fused, which may also be substituted in the carbon structure by a fluorine, chlorine or bromine atom, by a C 1-4 alkyl or C _1-3 alkoxy group,

a phenyl vinyl group or

R ₁ together with A and the carbon atom in between is a C _s . _7- cycloalkylidene group, to which a phenyl ring can be fused via two adjacent carbon atoms, which is additionally substituted by one or two C ₁ -alkyl- or C ^ -alk- oxy groups can be substituted, where the substituents can be the same or different, and

B is a 5- or 6-membered heteroaryl group substituted by a carbox group or by a group which can be converted into a carboxy group in vivo,

a phenyl or naphthyl group, each of which can be substituted by a carboxy group, by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions, the above-mentioned phenyl groups additionally

by a fluorine, chlorine, bromine or iodine atom,

by a C ₁ . _3- alkyl-, trifluoromethyl-, phenyl-, hydroxy-, C _1-3 -alkoxy-, C- _{L. 3-} alkylsulfonyloxy-, phenylsulfonyloxy-, carboxy-, C ^ .3 -alkoxycarbonyl-, formyl-, Cι_3-alkylcarbonyl-, C ₁ _3-alkylsulfonyl-, phenylsulfonyl-, nitro-, pyrrolidino-, piperidino-, morpholino- , N- (C ^ alkyl) piperazino, aminosulfonyl, C ₁ . _3- alkylaminosulfonyl or di- (C ₁ _ ₃ -alkyl) -aminosulfonyl group,

by a C ^ alkyl group, which is replaced by a hydroxy, C ^ alkoxy, amino, C ₁ . ₄ alkylamino, di (C 1-4 alkyl) amino, C ₃ . ₇ cycloalkylamino, pyrrolidino, piperidino, morpholino, piperazino or N- (C _{1. 3,} alkyl) -piperazinogruppe substituted,

by a nC ₂ _ ₃ alkoxy-, C ₂ -substituted in the 2- or 3-position by a di- (C ^ -alkyl) - amino group. _3- alkenyl or C ₂ _ ₃ -alkynyl group,

by an amino group, by an N- (C ^ alkyl) amino or N, N-di (C _1-3 alkyl) amino group, in which the alkyl part in each case in the 2- or 3-position based on the Nitrogen atom can be substituted by a C ^ - _j alkoxy group, by an N-phenylamino, N- (phenyl-C ^ alkyl) amino or N- (pyridyl -C _ ₃ alkyl) amino group, in each of which a hydrogen atom of the above-mentioned amino groups by a C ^ alkylsulfonyl -, Phenyl-Ci.- _j -alkylsulfonyl- or phenylsulfonyl group or by a C _1-7 alkyl group, which are in the 2- to 5-position by a C ^ - _j alkoxy, cyano, amino, C ₁ . ₃ -alkylamino, di- (C 1-4 alkyl) -amino or tetrazolyl group can be replaced,

by an aminocarbonyl or C ₁ . ₃ -Alkylaminocarbonyl- group, each on the amine nitrogen atom

by a C _x _ ₄ alkyl group which is replaced by a vinyl, ethyl, phenyl, pyridyl, imidazolyl, carboxy or trifluoromethyl group or, with the exception of the 2 position, based on the aminocarbonyl nitrogen atom by a hydroxy , C ^ - _j -alkoxy-, C ^ -alkylthio-, amino-, C ₁ . ₃ alkyl amino, di- _{(C1. 3,} alkyl) amino, C. _{1 4} -alkanoylamino or C ^ _jj -alkoxycarbonylamino group may be substituted,

by a C ₃ . _7- cycloalkyl-, C ₅ . ₉ -azabicycloalkyl-, phenyl-, pyridyl-, C ^ - _j -alkoxy- or di- (, ^ - alkyl) -amino group,

by a C 1-4 alkyl group, which may be replaced by a C ₁ . ₃ -Alkyl- or C ^ -alkoxycarbonyl group substituted piperidin-3-yl or piperidin-4 -yl group is substituted, or

by a C _1, optionally on the amine nitrogen atom. ₄ -alkanoyl, C ^ - alkoxycarbonyl, benzoyl, pyrrolidino, piperidino, morpholino or N- (C _1-3 -alkyl) -piperazino group substituted amino, C ₁ . ₃ alkyl, amino or phenyl C ₁ . ₃ -alkylamino group can be substituted, carbonyl group substituted by a pyrrolidino, pyrrolino, piperidino, morpholino or N- (C _{1, 3-} alkyl) -piperazino group,

sulfonyl group substituted by an amino, C 1-4 alkylamino, di- (C 1-4 alkyl) amino, pyrrolidino, piperidino, morpholino or N- (C ₁ alkyl) piperazino group,

by an amino or N- (C 1-4 alkyl) amino group, each of which on the amine nitrogen atom by an aminocarbonyl, , Phenyl-C _1-3 alkylaminocarbonyl, phenylaminocarbonyl, phenoxyphenylaminocarbonyl, pyridyl aminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl or N- (C _1-3 alkyl) piperazinocarbonyl group, in which a existing hydrogen atom of one of the above-mentioned aminocarbonyl groups may be substituted by a C 1-4 alkyl group,

by a 5- or 6-membered heteroaryl group,

by a dihydro-oxazolyl, dihydro-imidazolyl, 2-oxo-pyrrolidino, 2-oxo-piperidino or 2-oxo-hexamethylene imino group, to which a phenyl ring can be fused via two adjacent carbon atoms,

may be substituted by an ethynyl group substituted by a phenyl, hydroxymethyl or dirthylamino group, where

additionally the above-mentioned mono- or disubstituted phenyl groups by a further fluorine, chlorine or bromine atom or by one or two further C 1-4 alkyl or C ₁ . ₃ alkoxy groups substituted and two o-position C ₁ . ₃ alkoxy groups can be replaced by a methylenedioxy group, in particular R _{x is} a hydrogen atom, a C 1-4 alkyl or trifluoromethyl group,

R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C _1-3 alkyl, C ₃ . _7- cycloalkyl or C ₁ . ₃ -alkoxy group or, if R ₄ and R ₅ each represent a hydrogen atom, R ₁ and R ₂ together form an nC ^ -alkylene group optionally substituted by a C ^ -alkyl group,

R _{3 represents} a hydrogen atom or a C - ^ - alkyl group,

R ₄ and R ₅ each represent a hydrogen tom or together a further carbon-carbon bond,

A one by a fluorine, chlorine, bromine or iodine atom, by a C ^ alkyl, C ₃ . _7- cycloalkyl, phenyl, C ₁ . _3- alkoxy, trifluoromethyl or nitro group substituted phenyl, naphthyl or tetrahydronaphthyl group, the aforementioned monosubstituted phenyl and naphthyl groups additionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl or C _1-3 alkoxy group may be substituted, with the proviso that

A does not represent a phenyl group which is replaced by a halogen atom, by a methyl, pentyl, C 1 -C alkoxy or phenyl group or by two C _x . ₃ alkoxy groups is substituted if

R _{3 is} a hydrogen atom,

R ₄ and R ₅ each represent a hydrogen atom or

R ₄ and R _s together another carbon-carbon

Bond and

B represents a carboxyphenyl or methoxycarbonylphenyl group,

and A does not represent a phenyl group substituted by a methyl or phenyl group when Ri and R ₂ each represent a hydrogen atom,

R _{3 is} a hydrogen atom,

R ₄ and R ₅ together another carbon-carbon -

Bond and

B represents a carboxyphenyl or methoxycarbonylphenyl group,

a naphthyl group,

a chroman or chromene group in which a methylene group can be replaced by a carbonyl group,

a 5- or 6-membered heteroaryl group optionally substituted by a fluorine, chlorine or bromine atom, by a C _1-3 -alkyl or C _1-3 -alkoxy group, the 6-membered heteroaryl groups being one or two or three nitrogen atoms and the 5-membered heteroaryl groups, one optionally by a C ₁ . _3- alkyl group substituted imino group, an oxygen or sulfur atom or an imino group optionally substituted by a C 1-4 alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and, in addition, a phenyl ring may be fused to the monocyclic heteroaryl groups mentioned above via two adjacent carbon atoms which can also be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-3 -alkyl or C ^ - _j -alkoxy group,

a phenyl vinyl group or

R _x together with A and the carbon atom in between is a C ₅ . _7- cycloalkylidene group, to which a phenyl ring may be fused via two adjacent carbon atoms, which may additionally be substituted by one or two C 1-4 alkyl or C 1-4 alkoxy groups, the substituents being the same or different, and B is a phenyl, naphthyl or heteroaryl group, each of which can be substituted by a carboxy group, by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions, the phenyl groups mentioned above additionally

by a fluorine, chlorine, bromine or iodine atom,

by a C ^ alkyl, hydroxy, C ^ alkoxy, C _1.3 alkyl sulfonyloxy, phenyl sulfonyloxy, carboxy, C _1.3 alkoxy carbonyl, formyl, C ^ alkylcarbonyl, C ₁ , _3- alkylsulfonyl-, phenylsulfonyl-, nitro-, pyrrolidino-, piperidino-, morpholino-, N- (C _{1. 3} -alkyl) -piperazino-, aminosulfonyl-, C 1-4 -alkylaminosulfonyl- or di- {C ₁ _ ₃ -alkyl) -aminosulfonyl group,

by a 3-position in the 2- or by a di- (C _{1 3} alkyl.) - substituted amino group nc _{2. 3} -alkoxy-, C ₂ . _3- alkenyl or C ₂ _ ₃ -alkynyl group,

by an amino, N- (C _1-3 alkyl) amino, N- (phenyl-C ^ alkyl) amino or N- (pyridyl-C ^ alkyl) amino group, in each of which a Hydrogen atom of the amino group through a C ₁ . ₃ -Alkylsulfonyl- or phenylsulfonyl group or by a C ^ -alkyl group, which in the 2- to 5-position by a C ^ - _j alkoxy, cyano, amino, C - ^ - alkylamino, di- (^ - Alkyl) amino or tetrazolyl group can be substituted,

by an amino, C ₁ , ₃ alkylamino, di (C _{1, 3} alkyl) amino, pyrrolidino, piperidino, morpholino or N (Ci. ₃ alkyl) piperazino group substituted carbonyl or sulfonyl group,

by an imidazolyl or pyrazolyl group which is optionally substituted by a C _τ _4 alkyl group and which additionally by a C ₁ . ₃ -alkyl, phenyl, trifluoromethyl or furyl group may be substituted, and

additionally by a further fluorine, chlorine or bromine atom, by a further C 1-4 alkyl or C ₁ . ₃ -alkoxy group can be substituted,

and the above-mentioned 6-membered heteroaryl groups have one, two or three nitrogen atoms and the above-mentioned 5-membered heteroaryl groups have an imino group optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom or an imino group optionally substituted by a ^ alkyl group and contain an oxygen or sulfur atom or one or two nitrogen atoms and, in addition, a phenyl ring can be fused to the abovementioned monocyclic heteroaryl groups via two adjacent carbon atoms, which phenyl ring in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C 1-4 or C ^ - _j -alkoxy group can be substituted, the above-mentioned 5-membered monocyclic heteroaryl groups in the carbon skeleton additionally substituted by C _] __4 ~ alkyl, trifluoromethyl, phenyl or furanyl group and by a further Cχ_3 alkyl group could be,

and the amino and imino groups mentioned in the definition of the abovementioned radicals can additionally be substituted by a radical which can be split off in vivo,

their isomers and their salts.

Preferred compounds of the above general formula I are those in which

B and R2 to R5 are defined as mentioned above,

R _{1 is} a hydrogen atom or a C _] __3 alkyl group and A one through a fluorine, chlorine, bromine or iodine atom, through one , Trifluoromethyl, or nitro substituted phenyl, naphthalene thyl- or tetrahydronaphthyl, where the mono-substituted phenyl and naphthyl groups above additionally by a fluorine, chlorine or bromine atom, by a C ^ - alkyl- or C _{1 j} -Al- , ₃ -alkoxy group can be substituted, with the proviso that

A no phenyl group, which is caused by halogen atoms, C _x . ₄ alkyl - or C ₁ . ₃ -alkoxy groups can be mono- or disubstituted, where the substituents can be the same or different, does not represent a 4-biphenyl or pentylphenyl group, if

R _x and R ₂ each represent a hydrogen atom or a C ₁ . ₄ -alkyl group,

R _{3 is} a hydrogen atom,

R ₄ and R ₅ each represent a hydrogen atom or

R ₄ and R ₅ together another carbon-carbon

Bond and

B represents a carboxyphenyl or methoxycarbonylphenyl group,

a naphthy1 group,

a chroman or chromene group in which a methylene group can be replaced by a carbonyl group,

one in the carbon skeleton, optionally by a fluorine, chlorine or bromine atom, by a C ₁ . _3- alkyl or C _1-3 alkoxy group substituted 5- or 6-membered heteroaryl group, the 6-membered heteroaryl groups having one, two or three nitrogen atoms and the 5-membered heteroaryl group, one optionally with a C _x . ₃ -alkyl group substituted imino group, an oxygen or sulfur atom or a optionally contain an imino group substituted by a C _1-3 alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and, in addition, a phenyl ring may be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, which may also be in the carbon skeleton by a fluorine, Chlorine or bromine atom, which may be substituted by a C 1-4 alkyl or C 1-4 alkoxy group,

their isomers and their salts.

Particularly preferred new compounds of the general formula I above are those in which

R- _{L is} a hydrogen atom or a C ^ alkyl group,

R _{2 represents} a hydrogen atom or a methyl group or, if R ₄ and R ₅ each represent a hydrogen atom, R ₁ and R ₂ together represent a methylene bridge,

R _{3 is} a hydrogen atom or a C 1-4 alkyl group,

R ₄ and R ₅ together form a further carbon-carbon bond,

A is a phenyl group substituted by a fluorine, chlorine, bromine or iodine atom, by a C 1-4 alkyl, cyclohexyl, phenyl, methoxy, cyano or trifluoromethyl group,

a phenyl group substituted by fluorine, chlorine or bromine atoms, by methyl or methoxy groups, it being possible for the substituents to be the same or different, or

a C 1-4 alkylphenyl group which is disubstituted by fluorine, chlorine or bromine atoms, where the substituents can be the same or different, with the proviso that A does not represent a phenyl group through a halogen atom, through a methyl, pentyl, C 1-4 alkoxy or phenyl group or through two is substituted if

R _{3 is} a hydrogen atom,

R ₄ and R ₅ each represent a hydrogen atom or

R ₄ and R ₅ together another carbon-carbon

Bond and

B represents a carboxyphenyl or methoxycarbonylphenyl group,

and A does not represent a phenyl group substituted by a methyl or phenyl group when

R _x and R ₂ each represent a hydrogen atom,

R _{3 is} a hydrogen atom,

R ₄ and R ₅ together another carbon-carbon

Bond and

B represents a carboxyphenyl or methoxycarbonylphenyl group,

a naphthyl group optionally substituted by a fluorine, chlorine or bromine atom, by a methyl or methoxy group,

a tetrahydronaphthyl group,

a chromene group in which a methylene group is replaced by a carbonyl group,

a pyridyl, benzofuryl, benzothienyl, quinolyl or isoquinylyl group optionally substituted by a methyl group and

B is a cyclohexyl, trimethoxyphenyl, methylenedioxyphenyl, naphthyl, pyridyl, thienyl, pyrazolyl, quinolyl or isoquinolyl group substituted by a carboxy group, a phenyl group substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl, hydroxymethyl, sulfo, tetrazolyl, methylsulfonylaminocarbonyl or phenylsulfonylaminocarbonyl group, which additionally

by a fluorine, chlorine, bromine or iodine atom,

by a methyl, trifluoromethyl, phenyl, hydroxymethyl, hydroxy, methoxy, methylsulfonyloxy, 2-dimethylamino-ethoxy, carboxy, nitro, methylsulfonylamino, phenylsulfonylamino, aminosulfonyl, pyrrolidino, Piperidino or morpholino group,

by a methyl group which is substituted by an amino, C _1.3 alkylamino, cyclopentylamino, pyrrolidino or piperidino group,

by an amino, N-methylamino or N- (2-methoxyethyl) amino group, each on the amine nitrogen atom

by a C _1-7 alkyl or phenyl group,

by an ethyl group which is substituted in the 1- or 2-position by a phenyl or pyridyl group,

by a C ₂ . ₄ -alkyl group which is terminally substituted by a methoxy, cyano, dirnethylamino or tetrazolyl group,

by an acetyl, benzoyl, C 1-4 alkoxycarbonyl, aminocarbonyl or methylaminocarbonyl group, the aminocarbonyl part of the above-mentioned groups in each case additionally by a C _1-3 alkyl group optionally substituted by a phenyl group, by a phenyl or phenoxyphenyl - or pyridyl group can be substituted, can be substituted by a methylsulfonyl, phenylsulfonyl or benzylsulfonyl group,

by an aminocarbonyl or methylaminocarbonyl group, each on the amine nitrogen atom

by a ^ alkyl, C _3-6 cycloalkyl, phenyl, benzyl, pyridyl, pyridylmethyl or methoxy group,

by a methyl group by a vinyl, ethynyl, trifluoromethyl, C ₇ . ₉ -Azabicycloalkyl-, carboxy or imidazolyl group or by an optionally 1-position by a methyl or C ₂ _ _s -alkoxycarbonyl --group-substituted piperidin-4-yl group is substituted,

by a straight-chain or branched C ₂ . ₃ -alkyl group, in the 2- or 3-position by a hydroxy, methoxy, methylthio, amino, acetylamino, C ^ alkoxycarbonyl - amino, carboxy, C _1-5 alkoxycarbonyl or dimethylamino group is substituted,

may be substituted by a pyrrolidino, piperidino, morpholino, 4-methyl-piperazino, amino or methylamino group, the above-mentioned amino and methylamino group in each case additionally on the amine nitrogen atom by a methyl, acetyl, benzoyl or C _{1st 5} -alkoxycarbonyl group can be substituted,

by a dihydro-oxazolyl, dihydro-imidazolyl, 2-oxopyrrolidino, 2-0xo-piperidino or 2-oxo-hexamethylene imino group, to which a phenyl ring can be fused via two adjacent carbon atoms,

by an imidazolyl or 4-methyl- which is optionally substituted by a methyl, ethyl or phenyl group imidazolyl group, to which a phenyl ring can additionally be fused via two adjacent carbon atoms,

a group optionally substituted by a C _x _ ₄ alkyl or furanyl substituted pyrazolyl group, which may additionally be substituted by a methyl or trifluoromethyl group,

by an ethynyl group substituted by a phenyl, hydroxymethyl or dirthylamino group, where

the above-mentioned mono- or disubstituted phenyl groups may additionally be substituted by a further fluorine, chlorine or bromine atom or by one or two further methyl or methoxy groups,

especially those connections in which

R _{λ is} a hydrogen atom or a C _1-3 alkyl group,

R _{2 is} a hydrogen atom or R _λ and R ₂ together are a methylene group if R ₄ and R ₅ are each a hydrogen atom,

R _{3 is} a hydrogen atom,

R ₄ and R ₅ together form a further carbon-carbon bond,

A one through a fluorine, chlorine, bromine or iodine atom, through one , C ₃ . _7- cycloalkyl or trifluoromethyl group mono- or disubstituted phenyl or naphthyl group, where the substituents may be the same or different, with the proviso that

A is not a phenyl group which can be mono- or disubstituted by halogen atoms or C - ^ - alkyl groups, the Substituents can be the same or different, does not represent a 4-biphenyl or pentylphenyl group if

R- _{L is} a hydrogen atom or a C _1-3 alkyl group,

R _{2 is} a hydrogen atom,

R _{3 is} a hydrogen atom,

R ₄ and R ₅ each represent a hydrogen atom or

R ₄ and R ₅ together another carbon-carbon

Bond and

B represents a carboxyphenyl or methoxycarbonylphenyl group,

a naphthyl group,

a chromene group in which a methylene group is replaced by a carbonyl group,

a benzothienyl group and

B is a phenyl, naphthyl, thienyl or pyridinyl group, each of which is substituted by a carboxy group, with the phenyl groups mentioned above additionally

by a fluorine, chlorine or bromine atom,

by a C ^ alkyl, hydroxy, C ₁ . ₃ -alkoxy-, C _x . ₃ -alkylsulfonyloxy, pyrrolidino, piperidino, morpholino or N- (C 1-4 alkyl) piperazino group,

by a nC ₂ substituted in the 2- or 3-position by a di- (C 1-4 alkyl) amino group. ₃ -alkoxy group,

₍₂ _ ₃ alkyl nC) by a 3-position in the 2- or by an amino group di-substituted N-methyl-N - amino group, (C _{1 3} alkyl.)

by a di (C _x _ ₃ alkyl) amino group. by an imidazolyl or pyrazolyl group optionally substituted by a C _1-4 alkyl group,

by a C - ^ - alkylaminocarbonyl, N- (pyridinylmethyl) aminocarbonyl, pyrrolidinoaminocarbonyl or piperidinoaminocarbonyl group and

additionally by another fluorine atom, by another can be substituted

mean their isomers and their salts.

Very particularly preferred compounds of general formula I are those in which

R _{x is} a methyl group,

R _{2 is} a hydrogen atom,

R _{3 is} a hydrogen atom,

R ₄ and R ₅ together form a further carbon-carbon bond,

A is a phenyl group substituted by two chlorine or bromine atoms or by a chlorine atom and a bromine atom, a naphthyl, 2-oxo-chromene or benzothienyl group with the proviso that

A does not represent a phenyl group which is disubstituted by halogen atoms if

R _{1 is} a methyl group,

R _{2 is} a hydrogen atom,

R _{3 is} a hydrogen atom,

R ₄ and R _ε each represent a hydrogen atom or R ₄ and R ₅ together another carbon-carbon

Bond and

B represents a carboxyphenyl or methoxycarbonylphenyl group,

and B represents a 2-carboxy-phenyl -, 2-carboxy-thienyl or 2-carb-oxy-pyridinyl group, the above-mentioned 2-carboxy-phenyl group additionally in the phenyl nucleus

by a fluorine, chlorine or bromine atom,

by a C ^ alkyl, hydroxy, ^ alkoxy, C _1.3 alkyl sulfonyloxy or morpholino group,

by an nC ₂ substituted in the 2- or 3-position by a di- (C _{1, 3} -alkyl) amino group. ₃ -alkoxy group,

by a 2- or 3-position by a di- (C _{1. 3,} alkyl) amino group substituted N-methyl-N- (nC _{second 3} alkyl) amino group,

by an imidazolyl or pyrazolyl group optionally substituted by a C ₁ , _i -alkyl group,

by a C ₁ . ₄ -alkylaminocarbonyl, N- (pyridinylmethyl) aminocarbonyl, pyrrolidinoaminocarbonyl or piperidinoaminocarbonyl group and

can additionally be substituted by a further fluorine atom or by a further methoxy group,

their isomers and their salts.

The following may be mentioned as particularly preferred compounds: (1) trans-3 - (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-phenyl) amide,

(2) trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4,5-di-methoxy-phenyl) -amide,

(3) trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-4-fluorophenyl) amide,

(4) trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4, 5-di-fluoro-phenyl) -amide,

(5) trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-5-fluorophenyl) amide,

(6) trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4-methoxy-5-methylphenyl) amide,

(7) trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (morpholin-4-yl) phenyl] amide,

(8) trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4-dimethylamino-phenyl) -amide,

(9) trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-4-hydroxy-phenyl) -amide,

(10) trans-3- (naphth-2-yl) but-2-enoic acid-N- (3-carboxy-thiophen-4-yl) -amide,

(11) trans-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-4- (imizazol-1-yl) phenyl] amide,

(12) trans-3- (2-oxo-2H-chromen-3-yl) but-2-enoic acid-N- (2-carboxy-phenyl) amide, (13) trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (imizazol-1-yl) -5-fluorophenyl] amide,

(14) trans-3- (benzthiophene-2-yl) but-2-enoic acid N- (2-carboxyphenyl) amide,

(15) trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-4-methanesulfonyloxy-phenyl) -amide,

(16) trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (2-N, N-dimethylamino-ethyloxy) phenyl] amide,

(17) trans-3- (naphth-2-yl) but-2-enoic acid-N- (4-carboxypyridin-3-yl) amide,

(18) trans-3- (3, 4-dichlorophenyl) but-2-enoic acid-N- (2-carboxy-4, 5-dimethoxy-phenyl) -amide,

(19) trans-3- (3-chloro-4-bromophenyl) but-2-enoic acid-N- (2-carboxy-phenyl) amide,

(20) trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-6-methyl-phenyl) -amide,

(21) trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-6-fluorophenyl) amide,

(22) trans-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-5- (propylaminocarbonyl) phenyl] amide,

(23) trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (pyrrolidin-1-yl-aminocarbonyl) phenyl] amide,

(24) trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (N- (pyridin-3-yl-methyl) aminocarbonyl) phenyl] amide . (25) trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-6-chlorophenyl) amide

as well as their salts.

The carboxylic acid amides of the general formula I above are obtained, for example, by the following processes which are known per se:

a. Acylation of an amine of the general formula

f ³ in the

R ₃ and B are defined as mentioned above, with a carboxylic acid of the general formula

in the

R ₁ , .R ₂ , R ₄ , R ₅ and A are defined as mentioned at the outset, or their reactive derivatives.

The acylation is expediently carried out using an appropriate halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, optionally in the presence of an inorganic or organic base such as triethylamine, N-ethyl diisopropylamine, N-methylmorpholine or pyridine at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.

be converted into a carboxyl group by hydrolysis,

their esters with tertiary alcohols, e.g. the tert. Butyl esters which are expediently converted into a carboxyl group by treatment with an acid or thermolysis, and

their esters with aralkanols, e.g. the benzyl ester, which are expediently converted into a carboxyl group by means of hydrogenolysis.

The hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / ethanol, Water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture.

The transfer of a tert. Butyl or tert. Butyloxycarbonyl group in a carboxy group can also by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or also thermally optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling point of the solvent used, for example at temperatures between 40 and 120 ° C. The conversion of a benzyloxy or benzyloxycarbonyl group into a carboxy group can also be carried out hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ° C , for example at room temperature, and a hydrogen pressure of 1 to 5 bar.

If, according to the invention, a compound of the general formula I is obtained which contains a hydroxyl group, this can be converted into a corresponding sulfonyloxy compound by means of a sulfonyl halide, or

a compound of the general formula I which contains a cyano group, this can be converted into a corresponding tetrazolyl compound using nitrogen-hydrochloric acid, or

a compound of the general formula I which contains an amino or imino group with a basic hydrogen atom, this can be converted into a correspondingly acylated compound or into a corresponding prodrug compound by means of acylation or sulfonylation, or

a compound of the general formula I which contains a carboxy group, this can be converted into a compound which contains a group which can be converted into a carboxy group in vivo, or

a compound of the general formula I which contains one or two carboxy groups, this can be converted into a compound which contains one or two hydroxymethyl groups by reduction with a complex metal hydride. l_l. J CD Ω ω Mi tr <b ö w tQ Hh O D. ö C 03 i H OJ μ- ^ α dd S! O to ι ^ 3 φ σ

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- HJ ω CD d H tr iQ CD CD 3 rt O Hh N tr 3 Hj σ ib 0 tQ μ- O 3 tQ b TJ 0 ⁾ b HJ 0 CD J μ- HJ Cb HJ μ- HJ: ti μ- <Φ N TJ 0J rt Ml μ- Φ d <! tr 03 CD OJ HJ b HJ 0 03 tu μ- CD CD CD 175 d 3 0 Hj N Hj b HJ Hh rt HJ

Hj 0 0 CD bb μ- D- O D. CD <CD CD H- ¹ HJ μ- b μ- tQ CD HJ μ- S 0 μ- μ- - rt €

Ω Hj H Mi "_" CD 1 CD rt CD 0 ⁾ d iQ b U3 03 rt N OJ 03 μ- TJ 03 M "Φ φ tr N μ- £ OJ a U Hj N HJ> r IQ 3 CD μ- t σ CD S tr d Ω 03 ^ Ω M μ- tQ db μ- H ü Hj rt Cb r CD μ- CD 03 b Di Hj CD ^ IQ tr Ω tr O rt 03

CD iQ D H- ¹ μ- O to d Cb • d = μ- IQ b HJ CD CD S μ- H 03 tQ Φ tr J Φ D- tr S φ

Ml 03 0 03 0 tr J: IQ μ- a O CD μ- μ- rt Ω Hj CD 03 Hi S Φ a Φ 3 a Φ φ μ- d = i H X -> d 1 CD a b tr d <! N CD μ- CD 0 CD 3 b μ- Hj HJ φ 3 tr Φ CD HJ μ- J 0 Hj rt 03 CD 3 OJ rt tQ d ω Hj μ- φ 1 a 0 μ-

Hj μ- Hj μ- bb Hj CD CD 1 b J rt • CD 3 CD tr 3 03 μ- H 1 σ α rt rt 03 1 0 1 b CD N b 1 CD 1 CD b to φ CD 1 b μ- 1 μ- φ o Hj

1 Cb b

The subsequent conversion of a carboxy group into a group which can be converted into a carboxy group in vivo is preferably carried out by esterification with an appropriate alcohol or by alkylation of the carboxy group. The esterification is advantageously carried out in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an excess of the alcohol used in the presence of a dehydrating agent, e.g. in the presence of hydrochloric acid, sulfuric acid, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, 2- (1H-benzotriazol-1-yl) - 1,1,3, 3 -tetramethyluronium tetrafluoroborate, N, N '-Dicyclohexyl- carbodiimide, N, N' -dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N '-Carbonyldiimidazol- or N, N' -Thionyldiimidazol, triphenylphosphine / carbon tetrachloride or triphenylphosphine / - diethyl azodicarboxylate optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N, N-dimethylamino-pyridine advantageously at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, and the alkylation with a corresponding halide expediently in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone, if appropriate in the presence of a reaction ion accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C.

The subsequent reduction is preferably carried out in the presence of a complex metal hydride such as lithium aluminum hydride or lithium triethyl borohydride in a solvent such as tetrahydro furan conveniently carried out at the boiling point of the solvent used.

In the reactions described above, any reactive groups present, such as hydroxyl, carboxy, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are split off again after the reaction.

For example, the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group,

as protective radicals for a carboxy group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and

as protective residues for an amino, alkylamino or imino group, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group in addition the phthalyl group into consideration.

The subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, for example using hydrogen in the presence of a catalyst such as palladium. ladium / coal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.

The cleavage of a tert-butyl or tert. -Butyloxycarbonyl residue is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

A trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C. ,

A phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

Some of the compounds of the general formulas II to IV used as starting materials are known from the literature, but these can be prepared by processes known from the literature (see, for example, Fulton et al. In J.chem.Soc. 1323., page 200, S. Sano et al. In Chem. Commun. £, page 539

(1997) and D.H. Klaubert et al. in J.Med.Chem. 2A, 742-748

(1981)). Furthermore, the compounds of general formula I obtained, as already mentioned at the beginning, can be separated into their enantiomers and / or diastereomers. For example, compounds with at least one optically active carbon atom can be separated into their enantiomers.

For example, the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) Compounds of the general formula I with at least 2 stereogenic centers on the basis of their physical and chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids. Examples of suitable acids for this are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the new compounds of formula I thus obtained, if they contain an acidic group such as a carboxy group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts. Examples of bases which can be used here are sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. As already mentioned at the beginning, the carboxamides of the general formula I and their salts, in particular their physiologically tolerable salts, have an inhibitory effect on telomerase.

The inhibitory effect of the carboxylic acid amides of the general formula I on the telomerase was investigated as follows:

Material and methods:

1.Hfirst.pl 1 πng of nuclear extracts from HeT.a cells: The production of nuclear extracts was based on Dignam (Dignam et al. In Nucleic Acids Res. 11, 1475-1489 (1983)). All work steps were carried out at 4 ° C, all devices and solutions were pre-cooled to 4 ° C. At least 1 x 10 ⁹ HeLa-S3 cells (ATCC catalog number CCL-2.2) growing in suspension culture were harvested by centrifugation for 5 minutes at 1000 xg and washed once with PBS buffer (140 mM KCl; 2.7 mM KCl; 8.1 mM Na ₂ HP0 ₄ ; 1.5 mM KH ₂ PO ₄ ). After the cell volume had been determined, the cells were suspended in 5-fold volume of hypotonic buffer (10 mM HEPES / KOH, pH 7.8; 10 mM KCl; 1.5 mM MgCl ₂ ) and then left at 4 ° C. for 10 minutes. After centrifugation for 5 minutes at 1000 xg, the cell pellet was suspended in a 2-fold volume of hypotonic buffer in the presence of 1 mM DTE and 1 mM PMSF and broken up with a Dounce homogenizer. The homogenate was made isotonic with 0.1 volume of 10-fold salt buffer (300 mM HEPES / KOH, pH 7.8; 1.4 M KCl; 30 mM MgCl ₂ ). The cell nuclei were separated from the components of the cytoplasm by centrifugation and then in a 2-fold volume of core extraction buffer (20 mM HEPES / KOH, pH 7.9; 420 mM KCl; 1.5 mM MgCl ₂ ; 0.2 mM EDTA; 0.5 mM DTE; 25% Glycerin) suspended. The cores were broken up with a dounce homogenizer and incubated for 30 minutes at 4 ° C with gentle stirring. Insoluble components were separated by centrifugation for 30 minutes at 10,000 rpm (SS-34 rotor). The core extract was then against buffer AM-100 for 4-5 hours (20 mM Tris / HCl, pH 7.9; 100 mM KCl; 0.1 mM EDTA; 0.5 mM DTE; 20% glycerin) dialyzed. The core extracts obtained were frozen in liquid nitrogen and stored at -80 ° C.

2. Telomerase Test: The activity of telomerase in nuclear extracts from HeLa cells was determined based on morin (Morin in Cell 59, 521-529 (1989)). The core extract (up to 20 μl per reaction) was in a volume of 40 μl in the presence of 25 mM Tris / HCl pH 8.2, 1.25 mM dATP, 1.25 mM TTP, 6.35 μM dGTP; 15 μCi α- ³² P-dGTP (3000 Ci / mmol), 1 mM MgCl ₂ , 1 mM EGTA, 1.25 mM spermidine, 0.25 U RNasin, and 2.5 μM of an oligonucleotide primer (for example TEA-fw [CAT ACT GGC GAG CAG AGT T], or TTA GGG TTA GGG TTA GGG) for 120 minutes at 30 ° C (= telomerase reaction). If the inhibition constant of potential telomerase inhibitors should be determined, then these were additionally added in each case in the concentration range from 1 nM to 100 μM for the telomerase reaction. The reaction was then carried out by adding 50 μl RNase Stop buffer (10 mM Tris / HCL, pH 8.0; 20 mM EDTA; 0.1 mg / ml

RNase A 100 U / ml RNase T1; 1000 cpm of an α- ³ P-dGTP-labeled, 430 bp DNA fragment) was terminated and incubated at 37 ° C. for a further 15 minutes. Proteins present in the reaction mixture were cleaved by adding 50 μl Proteinase K buffer (10 mM Tris / HCL, pH 8.0; 0.5% SDS; 0.3 mg / ml Proteinase K) and then incubating for 15 min at 37 ° C. The DNA was purified by double phenol-chloroform extraction and precipitated by adding 2.4 M ammonium acetate, 3 μg tRNA and 750 μl ethanol. The precipitated DNA was then washed with 500 μl 70% ethanol, dried at room temperature, in 4 μl formamide sample buffer (80% (V / V) formamide; 50 mM Tris-borate, pH 8.3; 1 mM EDTA; 0.1 (w / v ) Xylene cyanol; 0.1% (w / V) bromophenol blue) and electrophoresed on a sequence gel (8% polyacrylamide, 7 M urea, 1 x TBE buffer). The DNA synthesized by telomerase in the absence or presence of potential inhibitors was identified and quantified using phospho-imager analysis (Molecular Dynamics) and in this way the content determined bitor concentration that inhibits telomerase activity by 50% (IC _S0 ). The radio-labeled DNA fragment added with the RNase Stop buffer served as an internal control for the yield.

The following table shows an example of the IC ₅₀ values of some inhibitors:

The following abbreviations have been used above

bp base pairs

DNA deoxyribonucleic acid

DTE 1,4-dithioerythritol dATP deoxyadenosine triphosphate dGTP deoxyguanosine triphosphate

EDTA ethylenediamine tetraacetic acid

EGTA ethylene glycol bis (2-aminoethyl) tetraacetic acid

HEPES 4- (2-hydroxyethyl) piperazin-1-ethanesulfonic acid

PMSF phenylmethanesulfonyl fluoride

RNase ribonuclease

RNasin ^® ribonuclease inhibitor (Promega GmbH, Mannheim) tRNA Transfer ribonucleic acid

TTP thymidine triphosphate

TRIS tris (hydroxymethyl) aminomethane

TBE TRIS borate EDTA

RPM revolutions per minute Because of their biological properties, the carboxamides of the general formula I are suitable for the treatment of pathophysiological processes which are characterized by an increased telomerase activity. These are, for example, tumor diseases such as carcinomas, sarcomas and leukaemias including skin cancer (eg, squamous cell carcinoma, basal cell carcinoma, melanoma), small cell lung carcinoma, non-small cell lung cancer, salivary gland carcinoma, esophagus carcinoma, laryngeal carcinoma, oral cavity carcinoma, thyroid carcinoma, gastric carcinoma, colorectal carcinoma, pancreatic carcinoma, pancreatic carcinoma Liver carcinoma, breast carcinoma, uterine carcinoma, vaginal carcinoma, ovarian carcinoma, prostate carcinoma, testicular carcinoma, bladder carcinoma, kidney carcinoma, Wilms tumor, retinoblastoma, astrocytoma, oligodendroglomoma, meningirosomomomoma, neuro blastoma, neuro blastoma, neuro blastoma Histiocytoma, dermatofibrosarcoma, synovialoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma, chronic myeloid leukemia, chronic lymphatic leukemia, acute promyelocytic leukemia, acute lymphoblas table leukemia and acute myeloid leukemia.

In addition, the compounds can also be used to treat other diseases which have an increased cell division rate or increased telomerase activity, such as e.g. epidermal hyperproliferation (psoriasis), inflammatory processes (rheumatoid arthritis), diseases of the immune system etc.

The compounds are also useful for the treatment of parasitic diseases in humans and animals, e.g. Worm or fungal diseases as well as diseases caused by protozoan pathogens, such as Zooflagellata (Trypanosoma, Leishmania, Giardia), Rhizopoda (Entamoeba spec.), Sporozoa (Plasmodium spec, Toxoplasma spec), Ciliata etc.

For this purpose, the carboxamides of the general formula I, if appropriate in combination with other pharmacologically H

O d rt

Φ

Hj b

• ^•

CT.

Example 1

trans-3-N-romic acid-N- (2-methoxycarbony] phenyl) -amide 965 mg (5.0 mmol) of trans-3-nitrocinnamic acid are refluxed in 3 ml of thionyl chloride after the addition of a drop of dimethylformamide for 20 minutes heated. The mixture is then evaporated to dryness in vacuo and the acid chloride thus obtained is dissolved in 10 ml of dioxane. This solution is slowly added dropwise to a solution of 756 mg (5.0 mmol) of anthranilic acid methyl ester and 1.5 ml of triethylamine in 10 ml of dioxane with stirring at room temperature. After one hour the solvent is evaporated off in vacuo, the residue is stirred in about 10 ml of water, then filtered off and the crude product thus obtained is purified by column chromatography on silica gel (eluent: dichloromethane / petroleum ether = 2: 1). Yield: 990 mg (61% of theory), CHN _O (326.32)

R _f value: 0.20 (silica gel; dichloromethane / petroleum ether = 2: 1) R _f value: 0.88 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 326

Example 2

trans-3 itro imtsänre-N- ( ^" 2-carboyyphenyl) -ami d

500 mg (1.53 mmol) of trans-3-nitrocinnamic acid-N- (2-methoxycarbonyl-yl-phenyl) -amide are stirred in a mixture of 20 ml of methanol and 8 ml of 2N sodium hydroxide solution at 50 ° C. for two hours.

Then the methanol is distilled off in vacuo, the residue is diluted with about 150 ml of water and adjusted to about pH 2.5 with stirring. The product which then precipitates is filtered off with suction, washed with about 10 ml of water and dried.

Yield: 420 mg (88% of theory),

C H N 0 (312.29)

R _f value: 0.39 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 311 Example 3

trans-3- (3, 4-dichlorophenyl) but-2-enoic acid-N- (3-ethoxycarbonyl-henyl) -am d

Prepared analogously to Example 1 from trans-3- (3, 4-dichlorophenyl) but-2-enoic acid and 3-amino-benzoic acid ethyl ester.

Yield: 29% of theory,

C ₁₉ H ₁₇ C1 ₂ N0 ₃ (378.27)

R _f value: 0.84 (silica gel; petroleum ether / ethyl acetate = 2: 1)

Mass spectrum: M ⁺ = 377/379/381

At sp e]!

trans-3- (3, 4-dichlorophenyl) but-2-enoic acid-N- (3-carboxy-pheny) amide

Prepared analogously to Example 2 from trans-3- (3, 4-dichlorophenyl) -but-2-enoic acid-N- (3-ethoxycarbonyl-phenyl) -amide and sodium hydroxide solution in ethanol.

Yield: 69% of theory,

C ₁₇ H ₁₃ C1 ₂ N0 ₃ (350.21)

R _f value: 0.21 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 349/351/353

Example 5

trans-3- (3,4-dichlorophenyl) but-2-enoic acid-N- (4-ethoxycarbonylphenyl) amide

Prepared analogously to Example 1 from trans-3- (3,4-dichlorophenyl) but-2-enoic acid and ethyl 4-aminobenzoate.

Yield: 16% of theory,

C ₁₉ H ₁₇ C1 ₂ N0 ₃ (378.27)

R _f value: 0.46 (silica gel; petroleum ether / ethyl acetate = 2: 1)

Mass spectrum: M ⁺ = 377/379/381 Example 6

trans-3- (3, 4-dichlorophenyl) but-2-enoic acid-N- (4-carboxyphenyl) amide

Prepared analogously to Example 2 from trans-3 - (3,4-dichlorophenyl) but-2-enoic acid-N- (4-ethoxycarbonyl-phenyl) -amide and sodium hydroxide solution in ethanol.

Yield: 78% of theory,

C ₁₇ H ₁₃ C1 ₂ N0 ₃ (350.21)

R _f value: 0.24 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 349/351/353

Example 7_

trans-3- (3, -Dichlorophenyl) -but-2-enoic acid-N- (5-chloro-2-meth-oxycarbonyl-phenyl) -ami •

Prepared analogously to Example 1 from trans-3- (3, 4-dichlorophenyl) but-2-enoic acid and 2-amino-4-chloro-benzoic acid methyl ester.

Yield: 33% of theory,

C ₁₈ H ₁₄ C1 ₃ N0 ₃ (398.69)

R _f value: 0.43 (silica gel; petroleum ether / ethyl acetate = 2: 1)

Mass spectrum: M ⁺ = 397/399/401

Example 8

trans-3- (3, 4-dichlorophenyl) but-2-enoic acid-N- (2-carboxy-

5-chlorophenyl) amide

Prepared analogously to Example 2 from trans-3- (3, 4-dichlorophenyl) but-2-enoic acid-N- (5-chloro-2-methoxycarbonyl-phenyl) -amide and

Sodium hydroxide solution in ethanol.

Yield: 69% of theory,

C ₁₇ H ₁₂ C1 ₃ N0 ₃ (384.66)

R _f value: 0.27 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 383/385/387 Example 9.

trans-3- (3, 4-dichlorophenyl) -but-2-enoic acid-N- (2-methoxycarbonyl-phenyl) -a i d

Prepared analogously to Example 1 from trans-3- (3, 4-dichlorophenyl) but-2-enoic acid and 2-amino-benzoic acid methyl ester.

Yield: 73% of theory,

C ₁₈ H ₁₅ C1 ₂ N0 ₃ (364.23)

R _£ value: 0.39 (silica gel; petroleum ether / ethyl acetate = 2: 1)

Mass spectrum: M ⁺ = 363/365/367

At sp l Iß

trans-3- (3, 4-dichlorophenyl) but-2-enoic acid N- (2-carboxyphenyl) amide

Prepared analogously to Example 2 from trans-3- (3,4-dichlorophenyl) but-2-enoic acid-N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in ethanol. Yield: 76% of theory, C ₁₇ H ₁₃ C1 ₂ N0 ₃ (350.20)

R _f value: 0.25 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 349/351/353

Example 11

tranπ-4-n-Pen yl vλ mtsäure-N- (2-carboxy- -chl or-phenyl) -amide

Prepared analogously to Example 2 from trans-4-n-pentylcinnamic acid

N- (5-chloro-2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in

Ethanol.

Yield: 71% of theory,

C ₂₁ H ₂₂ C1N0 ₃ (371.86)

R _f value: 0.33 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 371/373 At game 12.

trans-4-n-pentyl 7. \ mtsäure-N- (3-carboyy-phenyl) -a i d

Prepared analogously to Example 2 from trans-4-n-pentylcinnamic acid

N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol.

Yield: 77% of theory,

C ₂₁ H ₂₃ N0 ₃ (337.42)

R _f value: 0.30 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 337

At spi e] 12.

trans-3- (4-trifluoromethylphenyl) but-2-enoic acid-N- (2-carboxyphenyl-ami

Prepared analogously to Example 2 from trans-3- (4-trifluoromethylphenyl) but-2-enoic acid N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 31% of theory, C ₁₈ H ₁₄ F ₃ N0 ₃ (349.32)

R _f value: 0.25 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 349

Example] 14.

trans-3- (biphenyl-4-yl) but-2-enoic acid-N- (2-carboxyphenyl) amide

Prepared analogously to example 2 from trans-3- (biphenyl-4-yl) -but-

2-enoic acid-N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in

Ethanol.

Yield: 11% of theory,

C ₂₃ H ₁₉ N0 ₃ (357.41)

R _f value: 0.38 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 357 Be i πpi el 15.

trans-3- (3, 4-dichlorophenyl) but-2-enoic acid-N- (2-carboxy-4-methyl-phenyl-ami

Prepared analogously to Example 2 from trans-3- (3,4-dichlorophenyl) -but-2-enoic acid-N- (2-methoxycarbonyl-4-methylphenyl) -amide and

Sodium hydroxide solution in ethanol.

Yield: 20% of theory,

C _ιe H ₁₅ Cl ₂ N0 ₃ (364.24)

R _f value: 0.30 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 363/365/367

Example 1

trans-3- (3,4-dichlorophenyl) -but-2-enoic acid-N- (2-carboxy-4,5-di-ethoxy-phenyl) -am d

Prepared analogously to Example 2 from trans-3- (3,4-dichlorophenyl) but-2-enoic acid-N- (4,5-dimethoxy-2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in ethanol.

Yield: 54% of theory,

C ₁₉ H ₁₇ C1 ₂ N0 _S (410.27)

R _f value: 0.31 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 409/411/413

Example 1 1

trans-3- (3, 4-dichlorophenyl) but-2-enoic acid-N- (2-carboxy-4-methoxy-5-methylphenyl amide

Prepared analogously to Example 2 from trans-3- (3, 4-dichlorophenyl) -but-2-enoic acid-N- (4-methoxy-2-methoxycarbonyl-5-methyl-phenyl) amide and sodium hydroxide solution in methanol.

Yield: 44% of theory,

C ₁₉ H ₁₇ C1 ₂ N0 ₄ (394.26)

R _f value: 0.32 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 393/395/397 Example 18

trans-3- (naphth-2-yl) -bnt-2-eno-N- (2-boyy-phenyl) -ami d

Prepared analogously to Example 2 from tran-s-3- (naphth-2-yl) -but-

2-enoic acid-N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in

Ethanol.

Yield: 18% of theory,

C ₂₁ H ₁₇ N0 ₃ (331.38)

R _f value: 0.30 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 331

Example 1

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (methoxy-i noπarbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (methoxyaminocarbonyl) phenyl] amide and lithium hydroxide in methanol / water. Yield: 52% of theory, C ₂₃ H ₂₀ N ₂ O ₅ (404.42) mass spectrum: (MH) ^" = 403

(M + Na) ⁺ = 427

Example 20

trans-3- (3,4-dichlorophenyl) -but-2-enoic acid-N- (4-bromo-2-carboxy-methyl-pheny) -ami d

Prepared analogously to Example 2 from trans-3- (3,4-dichlorophenyl) -but-2-enoic acid-N- (4-bromo-2-methoxycarbonyl-6-methylphenyl) amide and sodium hydroxide solution in methanol.

Yield: 43% of theory,

C ₁₈ H ₁₄ BrCl ₂ N0 ₃ (443.15)

R _f value: 0.31 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 441/443/445 Example ZI

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (2-acetyl-hydrazino-carbonyl) -phenyl] -ami

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (2-acetylhydrazino-carbonyl) phenyl] amide and lithium hydroxide in methanol / water , Yield: 35% of theory, C ₂₄ H ₂₁ N ₃ 0 ₅ (431.45)

R _f value: 0.18 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 430

(M + Na) ⁺ = 454

Example 22

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (N-pyridine-

3-yl -amio carbonyl) phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (N-pyridin-3-yl-aminocarbonyl) phenyl] amide and lithium hydroxide in methanol / water. Yield: 62% of theory, C ₂₇ H ₂₁ N ₃ 0 ₄ (451.48) mass spectrum: (MH) ^" = 450

Example 23

trans-3- (3, 4-dichlorophenyl) but-2-enoic acid N- (2-carboxy-5-ni-ro-phenyl-ami d

Prepared analogously to Example 2 from trans-3- (3,4-dichlorophenyl) ^■ but-2-enoic acid-N- (2-methoxycarbonyl-5-nitro-phenyl) -amide and

Sodium hydroxide solution in methanol.

Yield: 16% of theory,

C ₁₇ H ₁₂ C1 ₂ N ₂ 0 _S (395.21)

R _£ value: 0.24 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 394/396/398 Example 24

trans-3- (3, 4-dichlorophenyl) but-2-enoic acid N- (3-carboxy-naphth-

2-yl amide

Prepared analogously to Example 2 from trans-3- (3, 4-dichlorophenyl) -but-2-enoic acid-N- (3-methoxycarbonyl-naphth-2-yl) -amide and sodium hydroxide solution in methanol. Yield: 14% of theory, C ₂₁ H ₁₅ C1 ₂ N0 ₃ (400.27)

R _f value: 0.29 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 399/401/403

Example] 25.

trans-4-chlorocinnamic acid-N- (2-carboxy-phenyl-ami

Prepared analogously to Example 2 from trans-4-chlorocinnamic acid

N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol

Yield: 53% of theory,

C ₁₆ H ₁₂ C1N0 ₃ (301.73)

R _f value: 0.26 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 301/303

Example £ 2

trans-3- (3,4-dichlorophenyl) but-2-enoic acid-N- (2-carboxy-4-iodophenyl) amide

Prepared analogously to Example 2 from trans-3- (3, 4-dichlorophenyl) -but-2-enoic acid-N- (2-methoxycarbonyl-4-iodophenyl) -amide and sodium hydroxide solution in methanol. Yield: 23% of theory, C ₁₇ H ₁₂ C1 ₂ IN0 ₃ (476.11)

R _f value: 0.23 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 475/477/479 Example 27

trans-3- (3, 4-dichlorophenyl) but-2-enoic acid-N- (2-carboxy-

4-chloro-phenyl) -ami d

Prepared analogously to Example 2 from trans-3- (3,4-dichlorophenyl) -but-2-enoic acid-N- (2-methoxycarbonyl-4-chlorophenyl) amide and

Sodium hydroxide solution in methanol.

Yield: 18% of theory,

C ₁₇ H ₁₂ C1 ₃ N0 ₃ (384.66)

R _f value: 0.31 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ^* = 383/385/387

Example 28

trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-4,5-dimethoxy-phenyl) -am d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- (2-methoxycarbonyl -4, 5-dimethoxy-phenyl) -amide and

Sodium hydroxide solution in methanol.

Yield: 59% of theory,

C ₂₃ H ₂₁ N0 ₅ (391.43)

R _f value: 0.30 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 391

Example 29

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-5-chlorophenyl amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-5-chlorophenyl) amide and sodium hydroxide solution in ethanol. Yield: 13% of theory, C ₂₁ H ₁₆ C1N0 ₃ (365.82)

R _f value: 0.26 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 365/367 At game 30

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4-methoxy-phenyl) -am d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- (2-methoxycarbonyl-4-methoxy-phenyl) -amide and

Sodium hydroxide solution in methanol.

Yield: 56% of theory,

C ₂₂ H ₁₉ N0 ₄ (361.40)

R _f value: 0.25 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 361

Example 31

trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-4-fluorophenyl) -ami

577 mg (2.5 mmol) of trans-3- (naphth-2-yl) -but-2-enoic acid chloride, dissolved in 10 ml of tetrahydrofuran, are slowly stirred at room temperature in a solution of 388 mg (2.5 mmol) of 2-amino- 5-fluoro-benzoic acid and 303 mg of triethylamine added dropwise in 20 ml of tetrahydrofuran. The mixture is stirred for a further 17 hours at room temperature, then the solvent is evaporated off in vacuo and the crude product thus obtained is purified by column chromatography on silica gel (eluent: dichloromethane with 1 to 2% ethanol). Yield: 180 mg (21% of theory), C ₂₁ H _1S FN0 ₃ (349.37)

R _f value: 0.21 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 349

Example 32

trans-3- (naphth-2-yl) but-2-enoic acid-N- (3-carboxy-naphth-2-yl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (3-methoxycarbonyl-naphth-2-yl) -amide and sodium hydroxide solution in methanol. Yield: 50% of theory,

C ₂₅ H ₁₉ N0 ₃ (381.44)

R _f value: 0.31 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 381

Example 2

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4-chlorophenyl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-4-chlorophenyl) -amide and sodium hydroxide solution in methanol. Yield: 27% of theory, C ₂₁ H ₁₆ C1N0 ₃ (365.82)

R _£ value: 0.24 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 365/367

At game 3_4.

trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-4-methyl-henyl) -amide.

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-5-methylbenzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 34% of theory, C ₂₂ H ₁₉ N0 ₃ (345.40)

R _f value: 0.34 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 345

Example 35

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4-acetyl-mi o-phenyl-amide

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-5-acetylamino-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 29% of theory, C ₂₃ H ₂₀ N ₂ O ₄ (388.43)

R _£ value: 0.14 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 388

Ex.] £ 2.

trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-4-bromophenyl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-4-bromophenyl) amide and sodium hydroxide solution in methanol. Yield: 10% of theory, C ₂₁ H ₁₆ BrN0 ₃ (410.28)

R _f value: 0.27 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 409/411

(MH) ^" = 408/410

Example 37

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (3-carboxy-pyridine-

2-yl) amide

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) but-2-enoic acid chloride and 2-aminonicotinic acid in a mixture of tetrahydrofuran and N, N'-dimethyl-imidazolidinone with the addition of triethylamine. Yield: 18% of theory, C ₂₀ H ₁₆ N ₂ O ₃ (332.36)

R _£ value: 0.17 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 332

At game 3_ &

trans-3- (3, 4-dichlorophenyl) pent-2-enoic acid N- (2-carboxy-

4, 5-dimethoyyphenyl) amide

Prepared analogously to Example 2 from trans-3- (3,4-dichlorophenyl) pent-2-enoic acid-N- (4,5-dimethoxy-2-methoxycarbonylphenyl) amide and sodium hydroxide solution in ethanol. Yield: 12% of theory,

C ₂₀ H ₁₉ C1 ₂ NO _S (424.29)

R _f value: 0.33 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 423/425/427

Example 23

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4,5-difluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-4, 5-difluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 11% of theory, C ₂₁ H _1S F ₂ N0 ₃ (367.36)

R _f value: 0.24 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 367

Example 40

trans-3- (naphth-2-yl) -but-2-enoic acid N- (2-carboxy-3-fluorophenyl-ami d

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-6-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 16% of theory, C ₂₁ H ₁₆ FN0 ₃ (349.37)

R _f value: 0.23 (silica gel; ethyl acetate) mass spectrum: M ⁺ = 349

Example 41

trans-3- (6-methoxy-naphth-2-yl) but-2-enoic acid-N- (2-carboxy-

4-fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (6-methoxy-naphth-2-yl) but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 8% of theory, C ₂₂ H ₁₈ FN0 ₄ (379. 39)

R _f value: 0.25 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 379

At game 42

trans-3- (6-methoxy-naphth-2-yl) but-2-enoic acid-N- (2-carboxy-

4, -d methoxy-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (6-methoxy-naphth-2-yl) but-2-enoic acid N- (4,5-dimethoxy-2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 10% of theory, C ₂₄ H ₂₃ N0 ₆ (421.46)

R _£ value: 0.27 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 421

Example 43

trans-3- (Benzofuran-2-yl) but-2-enoic acid-N- (2-carboxy-4-fluoro-henyl) -amide

Prepared analogously to Example 31 from trans-3- (benzofuran-2-yl) -but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 19% of theory, C ₁₉ H ₁₄ FN0 ₄ (339.33)

R _f value: 0.21 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 339

Example 44

tranε-3- (benzofuran-2-yl) -but-2-enoic acid-N- (2-carboxy-4,5-di-methoxy-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (benzofuran-2-yl) -but-2-enoic acid-N- (4,5-dimethoxy-phenyl-2-methoxycarbonyl) -amide and sodium hydroxide solution in methanol. Yield: 27% of theory, C ₂₁ H ₁₉ N0 ₆ (381.39)

R _f value: 0.29 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ^* = 381

At game 4_5_

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2- (tetrazol-5-yl) phenyl] amide

a) trans-3- (naphth-2-yl) -but -? - enoic acid-N- (2-cyanophenyl) -am Manufactured analogously to Example 31 from trans-3- (naphth-2-yl) -but-2- Acid chloride and 2-amino-benzonitrile in tetrahydrofuran with the addition of triethylamine.

Yield: 21% of theory,

C ₂₁ H ₁₆ N ₂ 0 (312.38

R _£ value: 0.49 (silica gel; petroleum ether / ethyl acetate = 4: 1)

b) trans-3- (naphth-2-yl) but-2-enoic acid N- [2- (tetrazol-5-yl) phenyl 1-amide

312 mg (1.0 mmol) of trans-3- (naphth-2-yl) -but-2-enoic acid N- (2-cyano-phenyl) -amide are combined with 0.98 g (15 mmol) of sodium azide and 0.8 ammonium chloride stirred in 20 ml of dimethylformamide at 120 ° C for 16 hours. After cooling, the reaction mixture is stirred into about 300 ml of water and this solution is saturated with sodium chloride. The product which crystallizes out is filtered off with suction, washed with about 10 ml of water and dried.

Yield: 300 mg (84% of theory),

C ₂₁ H ₁₇ N _E 0 (355.41)

R _£ value: 0.18 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 355 Example £ 4

trans-3- (6,7,8,9-tetrahydro-naphth-2-yl) but-2-enoic acid - (2-carboxy-4-fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (6, 7, 8, 9-tetra-hydro-naphth-2-yl) but-2-enoic acid chloride and 2-amino-5-fluorobenzoic acid in tetrahydrofuran with the addition of triethylamine , Yield: 16% of theory, C ₂₁ H ₂₀ FNO ₃ (353.40)

R _f value: 0.26 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 353

Example 47

trans-2-methyl-3- (naphth-2-yl) acrylic acid-N- (2-carboxy-

4-finor-phenyl-amide

Prepared analogously to Example 31 from trans-2-methyl-3- (naphth-

2-yl) -acrylic acid chloride and 2-amino-5-fluoro-benzoic acid in

Tetrahydrofuran with the addition of triethylamine.

Yield: 17% of theory,

C ₂₁ H ₁₆ FN0 ₃ (349.37)

R _f value: 0.26 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 349

Example 48

trans-3- (3-bromophenyl) but-2-enoic acid N- (2-carboxy-4-fluorophenylXami

Prepared analogously to Example 31 from trans-3- (3-bromophenyl) but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 35% of theory, C ₁₇ H ₁₃ BrFN0 ₃ (378.20)

R _£ value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 377/379 At game el .49

trans-3- (3,4-dimethyl-phenyl) -but-2-enoic acid-N- (2-carboxy-

4-fluoro-phenyl) -ami

Prepared analogously to Example 31 from trans-3- (3, 4-dimethylphenyl) but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 52% of theory, C ₁₉ H ₁₈ FN0 ₃ (327.36)

R _f value: 0.25 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 327

Example 50

trans-3- (3-pyridyl) but-2-enoic acid N- (2-carboxy-4-fluoro-phenyl) amide

Prepared analogously to Example 31 from trans-3- (3-pyridyl) but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 8% of theory, C ₁₆ H ₁₃ FN ₂ 0 ₃ (300.29)

R _f value: 0.12 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 299

Example 5.1

trans-3- (4-bromophenyl) but-2-enoic acid-N- (2-carboxy-fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (4-bromophenyl) but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 35% of theory, C ₁₇ H ₁₃ BrFN0 ₃ (378.20)

R _£ value: 0.45 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 377/379 At game 52.

trans-3- (2,4-dimethyl-phenyl) -but-2-enoic acid-N- (2-carboxy-

4-fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (2,4-dimethylphenyl) but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine.

Yield: 22% of theory,

C ₁₉ H ₁₈ FN0 ₃ (327.36)

R _£ value: 0.40 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 327

At sp l 5_3_

trans-3- (naphth-1-yl) but-2-enoic acid N- (2-carboxy-4-fluoro-phenyl) -amide

Prepared analogously to Example 31 from trans-3- (naphth-1-yl) -but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 24% of theory, C ₂₁ H ₁₆ FN0 ₃ (349.37)

R _£ value: 0.15 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 349

Example 54

trans-2-methyl-3- (naphth-2-yl) acrylic acid-N- (2-carboxy-4,5-di-methoxy-phenyl-ami d

Prepared analogously to Example 2 from trans-2-methyl-3- (naphth-

2-yl) acrylic acid-N- (4,5-dimethoxy-2-methoxycarbonylphenyl) amide and sodium hydroxide solution in methanol.

Yield: 47% of theory,

C ₂₃ H ₂₁ N0 _B (391.43)

R _£ value: 0.21 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 391 Example 55

trans-3- (4-cyclohexyl-phenyl) -but-2-enoic acid-N- (2-carboxy-

4-fluorophenyl) -am d

Prepared analogously to Example 31 from trans-3- (4-cyclohexyl-phenyl) -but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 22% of theory, C ₂₃ H ₂₄ FN0 ₃ (381.45)

R _£ value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 381

Example 56

trans-3- (4-cyclohexyl-phenyl) -but-2-enoic acid-N- (2-carboxy-

4 _f -dimethoxy-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (4-cyclohexyl-phenyl) but-2-enoic acid N- (4,5-dimethoxy-phenyl-2-methoxycarbonyl) amide and sodium hydroxide solution in methanol. Yield: 38% of theory, C _2S H ₂₉ N0 ₅ (423.50)

R _f value: 0.42 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 423

Example 5_7_

trans-3- (naphth-2-yl) -but-2-enoic acid-N-methyl-N- (2-carboxy-phenyl) -amide

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and N-methyl-anthranilic acid in tetrahydrofuran with the addition of triethylamine. Yield: 14% of theory, C ₂₂ H ₁₉ N0 ₃ (345.40)

R _f value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 345 Example 58

trans -3 - (naphth-2-yl) - acrylic acid -N- (2 - carboxy-4 - f fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -acrylic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 26% of theory, C ₂₀ H ₁₄ FNO ₃ (335.34)

R _f value: 0.18 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 335

Example 59

trans-3- (naphth-2-yl) acrylic acid-N- (2-carboxy-4,5-dimethoxyphenyl) -ami

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) acrylic acid-N- (4,5-dimethoxy-2-methoxycarbonylphenyl) amide and sodium hydroxide solution in methanol. Yield: 34% of theory, C ₂₂ H ₁₉ N0 ₅ (377.40)

R _£ value: 0.23 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 377

Example 6_Ω.

trans- (4-methyl-indan-1-ylidene) acetic acid-N- (2-carboxy-

4-fluorophenyl amide

a) trans- (4-methyl-dan-1-yl den) -ess gsäυreethyl ester 6.73 g (30 mmol) phosphonoacetic acid triethyl ester are dissolved in 60 ml dirnethylformamide, then 3.37 g (30 mmol) potassium tert-butoxide are added and 15 minutes stirred at room temperature. 4.39 g (30 mmol) of 4-methylindane are then added and the mixture is stirred at room temperature for a further two days. The reaction mixture is poured onto about 200 ml of water, saturated with sodium chloride and extracted three times with ethyl acetate. The extract is washed with water, dried over sodium sulfate and concentrated. The crude product thus obtained is purified by column chromatography on silica gel (eluent: petroleum ether with 2% ethyl acetate). Yield: 1.7 g (26% of theory), C ₁₄ H ₁₆ 0 ₂ (216.28) R _f value: 0.78 (silica gel; petroleum ether / ethyl acetate = 4: 1)

b) trans- (4-methyl-indan-1-ylidene) acetic acid

Prepared analogously to example 2 from trans- (4-methyl-indane

1-ylidene) ethyl acetate and sodium hydroxide solution in methanol.

Yield: 91% of theory,

C ₁₂ H ₁₂ 0 ₂ (188.23)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1)

- Trans (4-methyl-indan-l-ylidene) acetic acid chloride

941 mg (5 mmol) of trans- (4-methyl-indan-l-ylidene) acetic acid are refluxed in 10 ml of thionyl chloride after the addition of a drop of dimethylformamide for 15 minutes. The mixture is then evaporated to dryness and the crude acid chloride obtained is further reacted.

d) trans- (4-methyl-indan-l-ylidene) acetic acid-N- (2-carboxy-

4-f1 uor-phenyl) amide

Prepared analogously to Example 31 from trans- (4-methyl-indane

1-ylidene) acetic acid chloride and 2-amino-5-fluoro-benzoic acid in

Tetrahydrofuran with the addition of triethylamine.

Yield: 28% of theory,

C ₁₉ H ₁₆ FN0 ₃ (325.35)

R _£ value: 0. 24 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 325 In game 61

trans- (4-methyl-indan-l-ylidene) acetic acid-N- (2-carboxy-

4,5-dimethoxy-phenyl-am d

Prepared analogously to Example 2 from trans- (4-methyl-indan-1-ylidene) acetic acid-N- (4,5-dimethoxy-phenyl-2-methoxycarbonyl) -amide and sodium hydroxide solution in methanol. Yield: 64% of theory, C ₂₁ H ₂₁ N0 ₅ (367.41)

R _£ value: 0.27 (silica gel; petroleum ether / ethyl acetate = 19: 1) mass spectrum: M ⁺ = 367

Example 62

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-5-fluorophenyl amide

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-4-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 11% of theory, C ₂₁ H ₁₆ FN0 ₃ (349.37)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 349

At spi l £

trans-3- (3, 4-dimethoxy-phenyl) -but-2-enoic acid-N- (2-carboxy-

4-fluorophenyl) amide:

Prepared analogously to Example 31 from trans-3- (3,4-dimethoxyphenyl) but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 27% of theory, C ₁₉ H ₁₈ FN0 ₅ (359.36)

R _£ value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 359 At game £ L4

trans-3- (4-isobutyl-phenyl) -but-2-enoic acid-N- (2-carboxy-

4-fluoro-pheny) -ami d

Prepared analogously to Example 31 from trans-3- (4-isobutyl-phenyl) -but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 38% of theory, C ₂₁ H ₂₂ FN0 ₃ (355.42)

R _f value: 0.31 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 355

At, sp l £ 5.

trans-3- (4-isobutyl-phenyl) -but-2-enoic acid-N- (2-carboxy-4,5-di-methoxy-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (4-isobutylphenyl) but-2-enoic acid N- (4,5-dimethoxy-2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol.

Yield: 22% of theory,

C ₂₃ H ₂₇ N0 ₅ (397.48)

R _£ value: 0.30 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 397

At piel 66

trans-3- (benzthiophene-3-yl) but-2-enoic acid N- (2-carboxy-

4-fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (benzthiophene

3-yl) -but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in

Tetrahydrofuran with the addition of triethylamine.

Yield: 19% of theory,

C ₁₉ H ₁₄ FN0 ₃ S (355.40)

R _£ value: 0.24 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 355 Example 67

trans-3- (Benzthiophene-3-yl) but-2-enoic acid N- (2-carboxy-4,5-di-ethoyyphenyl) amide

Prepared analogously to Example 2 from trans-3- (benzthiophene-3-yl) -but-2-enoic acid-N- (4,5-dimethoxy-2-methoxycarbonylphenyl) amide and sodium hydroxide solution in methanol.

Yield: 27% of theory,

C ₂₁ H ₁₉ N0 ₅ S (397.46)

R _f value: 0.24 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 397

Example 68

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4-methoxy-methylphenyl - amid

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2 -enoic acid-N- (2-methoxycarbonyl-4-methoxy-5-methyl-phenyl) -amide and sodium hydroxide solution in methanol.

Yield: 40% of theory,

C ₂₃ H ₂₁ N0 ₄ (375.43)

R _f value: 0.37 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 375

Example 69

trans- (5, 7-dimethyl-3, 4-dihydro-2ff-naphthalene-l-ylidene) acetic acid N- (2-carboxy-4-f1 uor-phenyl) -amide

a) trans- (5, 7-dimethyl-3, 4-dihydro-2H-naphthalen-l-ylidene) - acetic acid ethyl s r

Prepared analogously to Example 60a from ethyl phosphonoacetate and 5, 7-dimethyl-1-tetralone.

Yield: 22% of theory,

C _ιε H ₂₀ O ₂ (244.34)

R _f value: 0.70 (silica gel; petroleum ether / ethyl acetate = 19: 1) b) trans- (5, 7-dimethyl-3,4,4-dihydro-2H-naphthalene-l-ylidene) acetic acid

Prepared analogously to Example 2 from trans- (5, 7-dimethyl-3, 4-di-hydro-2H-naphthalene-l-ylidene) ethyl acetate and sodium hydroxide solution in methanol. Yield: 96% of theory, C ₁₄ H _lβ 0 ₂ (216.28) R _£ value: 0.30 (silica gel; dichloromethane / ethanol = 19: 1)

c) trans- (5, 7-dimethyl-3, 4-dihydro-2H-naphthalene-l-ylidene) - acetic acid chloride

Prepared analogously to example 60c from trans- (5, 7-dimethyl-

3, 4-dihydro-2H-naphthalene-l-ylidene) acetic acid and thionyl chloride. C ₁₄ H ₁₅ C10 (234.73)

d) trans- (5, 7-dimethyl-3,4-dihydro-2H-naphthalen-l-ylidene) acetic acid-N- (2-carboxy-4-fluorophenyl) amide

Prepared analogously to Example 31 from trans- (5, 7-dimethyl-3,4-di-hydro-2H-naphthalene-l-ylidene) acetic acid chloride and 2-amino-

5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine.

Yield: 12% of theory, C ₂₁ H ₂₀ FNO ₃ (353.40)

R _£ value: 0.28 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 353

trans-3- (quinolin-2-yl) but-2-enoic acid N- (2-carboxy-4-fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (quinolin-2-yl) -but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 13% of theory, C ₂₀ H ₁₅ FN ₂ O ₃ (350.35)

R _£ value: 0.14 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 350

(M + H) ⁺ = 351

(MH) ^" = 349

Example 21

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (morpholine-

4 -yl) -phenyl 1 -ami d _____

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-ethoxycarbonyl-4- (morpholin-4-yl) phenyl] amide and sodium hydroxide solution in ethanol.

Yield: 64% of theory,

C ₂₅ H ₂₄ N ₂ 0 ₄ (416.48)

R _f value: 0.32 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 416

Example 72

trans-3- (3,4-dichlorophenyl) but-2-enoic acid N- [2-carboxy-

4- (morphol in-4-yl) phenyl 1 amide

Prepared analogously to Example 2 from trans-3- (3,4-dichlorophenyl) but-2-enoic acid N- [2-ethoxycarbonyl-4- (morpholin-4-yl) phenyl] amide and sodium hydroxide solution in ethanol.

Yield: 73% of theory,

C ₂₁ H ₂₀ Cl ₂ N ₂ O ₄ (435.31)

R _£ value: 0.46 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 434/436

(M + H) ⁺ = 435/437

(MH) ^" = 433/435 Example 73

trans-3- (6-methyl-naphth-2-yl) -but-2-enoic acid-N- (2-carboxyphenyl) amide

Prepared analogously to Example 31 from trans-3- (6-methyl-naphth-2-yl) but-2-enoic acid chloride and anthranilic acid in tetrahydrofuran with the addition of triethylamine. Yield: 23% of theory, C ₂₂ H ₁₉ N0 ₃ (345.40)

R _£ value: 0.18 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 345

(M + H) ⁺ = 346

(MH) ^" = 344

In game 1A

trans-3- (6 -methyl-naphth-2-yl) but-2-enoic acid-N- (2-carboxy-fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (6-methyl-naphth-

2-yl) -but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in

Tetrahydrofuran with the addition of triethylamine.

Yield: 18% of theory,

C ₂₂ H ₁₈ FN0 ₃ (363.39)

R _f value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 363

Example 13.

trans-3- (6-methyl-naphth-2-yl) but-2-enoic acid-N- (2-carboxy-fluorophenyl) -ami

Prepared analogously to Example 31 from trans-3- (6-methyl-naphth-

2-yl) -but-2-enoic acid chloride and 2-amino-4-fluoro-benzoic acid in

Tetrahydrofuran with the addition of triethylamine.

Yield: 32% of theory,

C ₂₂ H ₁₈ FN0 ₃ (3 63. 39)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 363 At game 7L

trans-3- (6-methyl-naphth-2-yl) -but-2-enoic acid-N- (2-carboxy- _r 5-dimethoxy-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (6 -methyl-naphth-

2-yl) but-2-enoic acid N- (4,5-dimethoxy-methoxycarbonyl-phenyl) amide and sodium hydroxide solution in methanol.

Yield: 67% of theory,

C ₂₄ H ₂₃ NO _s (405.45)

R _£ value: 0.21 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 405

(M + Na) ⁺ = 428

(MH) ^" = 404

At game 77

trans-3- (3,4-dichloro-phenyl) -but-2-enoic acid-N- (2-carboxy-4-di-ethyl ami no-phenyl) -ami d

Prepared analogously to Example 2 from trans-3- (3, 4-dichlorophenyl) but-2-enoic acid N- (2-ethoxycarbonyl-4-dimethylamino-phenyl) amide and sodium hydroxide solution in ethanol.

Yield: 47% of theory,

C ₁₉ H ₁₈ C1 ₂ N ₂ 0 ₃ (393.27)

R _£ value: 0.55 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 392/394

(M + H) ⁺ = 393/395

(MH) ^" = 391/393

Example 78

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4-dimethyl-i no-phenyl-am d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-ethoxycarbonyl-4-dimethylamino-phenyl) -amide and sodium hydroxide solution in ethanol. Yield: 84% of theory, C ₂₃ H ₂₂ N ₂ 0 ₃ (374.44)

R _f value: 0.59 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 374

(MH) ^" = 373

Example 79

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (n-pentyl) -N- (3-carboxy-

4 -amino no-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- (n-pentyl) -N- (3-ethoxycarbonyl-4-amino-phenyl) amide and sodium hydroxide solution in ethanol.

Yield: 65% of theory,

C ₂₆ H ₂₈ N ₂ 0 ₃ (416.52)

R _f value: 0.51 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 416

(M + H) ⁺ = 417

(MH) ^" = 415

Example 80

trans-3- (2,4-dichlorophenyl) but-2-enoic acid-N- (2-carboxy-

4-fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (2,4-dichlorophen-yl) but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in

Tetrahydrofuran with the addition of triethylamine.

Yield: 16% of theory,

C ₁₇ H ₁₂ C1 ₂ FN0 ₃ (368.19)

R _f value: 0.21 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 367/369/371 Example 81

trans-3- (2,4-dichlorophenyl) but-2-enoic acid N- (2-carboxy-4,5-dimethoxy-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (2,4-dichlorophenyl) -but-2-enoic acid-N- (2-methoxycarbonyl-4,5-dimethoxy-phenyl) -amide and sodium hydroxide solution in methanol.

Yield: 97% of theory,

C ₁₉ H ₁₇ C1 ₂ N0 _S (410.26)

R _£ value: 0.25 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 409/411/413

Example 82

trans-2-methyl-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-

4-fluorophenyl) amide

Prepared analogously to Example 31 from trans-2-methyl-3- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 12% of theory, C ₂₂ H ₁₈ FN0 ₃ (363.39)

R _£ value: 0.21 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 363

(MH) ^" = 362

At piel 83

cis-2-fluoro-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-

4-fluorophenyl) amide

Prepared analogously to Example 31 from cis-2-fluoro-3- (naphth-

2-yl) -but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in

Tetrahydrofuran with the addition of triethylamine.

Yield: 9% of theory,

C ₂₁ H ₁₅ F ₂ N0 ₃ (367.36)

R _£ value: 0.18 (silica gel; dichloromethane / ethanol = 19: 1) Mass spectrum: M ⁺ = 367

(M + H) ⁺ = 368 (MH) ^" = 366

At piel 84

trans-2-methyl-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-

4,5-dimethoxy-phenyl) -amide

Prepared analogously to Example 2 from trans-2-methyl-3 - (naphth-2-yl) -but-2-enoic acid N- (2-methoxycarbonyl-4, 5-dimethoxy-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 48% of theory, C ₂₄ H ₂₃ N0 ₅ (405.45)

R _f value: 0.32 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (M + H) ^* = 406

(M + Na) ⁺ - 428

(MH) ^' = 404

Example 85

trans-2-methoxy-3- (naphth-2-yl) acrylic acid-N- (2-carboxy-

4-fluorophenyl amide

Prepared analogously to Example 31 from trans-2-methoxy-3 - (naphth-2-yl) acrylic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 29% of theory, C ₂₁ H ₁₆ FN0 ₄ (365.36)

R _£ value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 365

(MH) ^" = 364 At spi el ßü.

trans-2-methoxy-3- (naphth-2-yl) acrylic acid-N- (2-carboxy-

4,5-dimethoxy-phenyl) -ami

Prepared analogously to Example 2 from trans-2-methoxy-3- (naphth-2-yl) -acrylic acid-N- (2-methoxycarbonyl-4, 5-dimethoxy-phenyl) amide and sodium hydroxide solution in methanol. Yield: 75% of theory, C ₂₃ H ₂₁ N0 ₆ (407.43)

R _f value: 0.46 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 407

(MH) ^" = 406

At game 87

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (cis-2-carboxy-cyclohexyl) -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (cis-2-ethoxycarbonyl-cyclohexyl) -amide and sodium hydroxide solution in methanol. Yield: 96% of theory, C ₂₁ H ₂₃ N0 ₃ (337.42)

R _f value: 0.31 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 337

(M + Na) ⁺ = 360

(MH) ^" = 336

Example 88

trans-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-4- (N '-methyl-

N "-benzylamino) phenyl 1 amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-ethoxycarbonyl-4- (N'-methyl-N'-benzylamino) phenyl] amide and sodium hydroxide solution in ethanol. Yield: 74% of theory, C ₂₉ H ₂₆ N ₂ 0 ₃ (450.54)

R _£ value: 0.32 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 450

(MH) ^" = 449

Example 89

trans-3- (naphth-2-yl) -but-2-enoic acid-N- {2-carboxy-4- [N-methyl- - (2 - CN _'r N "-dimethylamino) ethyl) -a nol -phenyl} -am d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- {2-ethoxycarbonyl-4- [N-methyl-N- (2- (N ', N'-dime - thylamino) -ethyl) -amino] -phenyl} -amide and sodium hydroxide solution in ethanol.

Yield: 69% of theory, C ₂₆ H ₂₉ N ₃ 0 ₃ (431.54)

R _£ value: 0.13 (silica gel; dichloromethane / ethanol = 4: 1) mass spectrum: M ⁺ = 431

(M + H) ⁺ = 432

(M + Na) ⁺ = 454

(MH) ^" = 430

Example 90

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (N'-methyl-

N'- (2-phenylethylamino) phenyl amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-ethoxycarbonyl-4- (N'-methyl-N "- (2-phenylethyl) • amino) - phenyl] -amide and sodium hydroxide solution in ethanol. Yield: - 49% of theory, C ₃₀ H ₂₈ N ₂ O ₃ (464.57)

R _f value: 0.31 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 464

(MH) ^" = 463 Example 1

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (N'-methyl-

N'-n-hep yl -amino) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-ethoxycarbonyl-4- (N'-methyl-N '-n-heptylamino) phenyl] amide and sodium hydroxide solution in ethanol.

Yield: 39% of theory,

C ₂₉ H ₃₄ N ₂ 0 ₃ (458. 61)

R _f value: 0.39 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 458

(M + H) ⁺ = 459

(M + NaX = 481

(MH) ^" = 457

Example 92

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (N'-methyl -

N'- (-pyridylmethyl) amino) phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-ethoxycarbonyl -4- (N '-methyl-N'- (3-pyridylmethyl-amino) -phenyl] -amide and sodium hydroxide solution in ethanol.

Yield: 41% of theory,

C ₂₈ H ₂₅ N ₃ 0 ₃ (451.53)

R _f value: 0.58 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 451

(M + H) ⁺ = 452

(MH) ^" = 450

At game 2_L

trans-3- (Naphth-2-yl) but-2-enoic acid N- [2-carboxy-4- (N'-methyl- '- (2- (pyrid-2-yl) ethyl) amino ) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2 -ethoxycarbonyl-4- (N'-methyl-N'- (2- (pyrid-2-yl ) - ethyl) amino) phenyl] amide and sodium hydroxide solution in ethanol. Yield: 75% of theory, C ₂₉ H ₂₇ N ₃ 0 ₃ (465.56)

R _£ value: 0.52 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 465

(M + H) ⁺ = 466

(MH) ^" = 464

In game _4

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (N-methyl- - (3- (N ' _r N' -di ethylami.no) propyl ) -amino) -phenyl 1 -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-ethoxycarbonyl-4- (N-methyl-N- (3- (N ', N'-dimethylamino) propyl) amino) phenyl] amide and sodium hydroxide solution in

Ethanol.

Yield: 56% of theory,

C ₂₇ H ₃₁ N ₃ 0 ₃ (445.57)

R _f value: 0.11 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 445

(M + H) ⁺ = 446

(M + Na) ⁺ = 468

Example 95

trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-5-nitro-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-5-nitro-phenyl) -amide and sodium hydroxide solution in ethanol. Yield: 48% of theory, C ₂₁ H ₁₆ N ₂ 0 ₅ (376.37)

R _f value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 376

(MH) ^" = 375 Example 96

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-5-methanesulfonyl aminophenyl) -ami d

Prepared analogously to Example 2 from trans-3 - (naphth-2-yl) -but-2-enoic acid N- (2-methoxycarbonyl-5-methanesulfonylamino-phenyl) amide and sodium hydroxide solution in methanol. Yield: 87% of theory, C ₂₂ H ₂₀ N ₂ O ₅ S (424.48)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 424

(MH) ^" = 423

Example 9_Z

5-phenyl-penta-2, 4-dienoic acid-N- (2-carboxy-4-fluorophenyl) -ami d Prepared analogously to Example 31 from 5-phenyl-penta-2, 4-dienoic acid chloride and 2-amino -5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 27% of theory, C ₁₈ H ₁₄ FN0 ₃ (311.32)

R _f value: 0.24 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 311

(MH) ^" = 310

Example 98

trans-3- (3,4-dichlorophenyl) but-2-enoic acid N- (2-carboxy-fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (3,4-dichlorophenyl) but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in

Tetrahydrofuran with the addition of triethylamine.

Yield: 16% of theory,

C ₁₇ H ₁₂ C1 ₂ FN0 ₃ (368. 19)

R _£ value: 0. 21 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: (MH) ^" = 366/368/370 Example 99

trans-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-4- (N'-methyl- '- (2-methoxyethyl) amino) pheny 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-ethoxycarbonyl-4- (N'-methyl-N'- (2-methoxyethyl) amino) phenyl] amide and sodium hydroxide solution in ethanol.

Yield: 80% of theory,

C ₂₅ H ₂₆ N ₂ 0 ₄ (418.50)

R _f value: 0.51 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 418

(M + HX- = 419

(M + Na) ⁺ = 441

(MH) ^" = 417

At game 1 0

trans-3 - (naphth-2-yl) -but -2 -enoic acid-N- (2-carboxy-5-benzenesul - f nyl ami no-phenyl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-5-benzenesulfonylamino-phenyl) amide and sodium hydroxide solution in methanol. Yield: 92% of theory, C ₂₇ H ₂₂ N ₂ 0 ₅ S (486.55)

R _f value: 0.31 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 486

(MH) ^" = 485

Example 101

trans-3- (naphth-2-yl) -but-2-enoic acid N- (2-carboxy-5-aminosulonylphenyl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-5-aminosulfonyl-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 15% of theory, C ₂₁ H ₁₈ N ₂ 0 ₅ S (410.45)

R _£ value: 0.11 (silica gel; ethyl acetate / petroleum ether = 1: 1) mass spectrum: M ⁺ = 410

(MH) ^" = 409

Example 102

3- (Naphth-2-yl) butanoic acid N- (2-carboxy-5-acetylamino-phenyl) amide

Prepared analogously to Example 2 from 3- (naphth-2-yl) -butanoic acid- N- (2-methoxycarbonyl-5-acetylamino-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 46% of theory, C ₂₃ H ₂₂ N ₂ 0 ₄ (390.44)

R _f value: 0.20 (silica gel; dichloromethane / ethanol = 50: 1) mass spectrum: M ⁺ = 390

(M + Na) ⁺ = 413

(MH) ^" = 389

Example 1 3

3- (Naphth-2-yl) butanoic acid N- (2-carboxy-5-benzoylamino-phenyl) -amide

Prepared analogously to Example 2 from 3- (naphth-2-yl) -butanoic acid- N- (2-methoxycarbonyl-5-benzoylamino-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 96% of theory, C ₂₈ H ₂₄ N ₂ 0 ₄ (452.51)

R _f value: 0.24 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 452

(M + Na) ⁺ = 475

(MH) ^" = 451 Example 1 4

trans-3- (quinolin-3-yl) -but-2-enoic acid-N- (2-carboxy-4-fluorophenyl) -ami d

Prepared analogously to Example 31 from trans-3 - (quinolin-3-yl) - but-2-enoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 19% of theory, C ₂₀ H ₁₅ FN ₂ O ₃ (350.35)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (M + Na) ⁺ = 373

(MH) ^" = 349

At game 1 05

trans-3- (naphth-2-yl) but-2-enoic acid N- (2,5-dicarboxyphenyl) ami

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2,5-dimethoxycarbonyl-phenyl) -amide and sodium hydroxide solution in ethanol. Yield: 88% of theory, C ₂₂ H ₁₇ N0 ₅ (375.38)

R _f value: 0.11 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 375

(MH) ^" = 374

At game 1 06

trans -3 - (1-methoxy-naphth-2-yl) -but -2 -enoic acid-N- (2-carboxy-phenyl) -ami d

Prepared analogously to Example 2 from trans-3- (1-methoxy-naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in ethanol. Yield: 96% of theory, C ₂₂ H ₁₉ N0 ₄ (361.40) R _f value: 0.56 (silica gel; dichloromethane / ethanol = 9: 1) Mass spectrum: M ^* = 361

(M + Na) ⁺ = 384 (MH) ^" = 360

Example 1 7

trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-thiophene-yl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-thiophene-3-yl) -amide and sodium hydroxide solution in ethanol. Yield: 93% of theory, C ₁₉ H ₁₅ N0 ₃ S (337.40)

R _f value: 0.53 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 337

(M + Na) ⁺ = 360

(MH) ^" = 336

Example 108

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-4- (N'-methyl- '- (-cyanoethyl-amin) -phenyl 1 -ami d

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-5- (N-methyl-N- (2-cyanoethyl) amino) -benzoic acid in tetrahydrofuran with addition of triethylamine.

Yield: 16% of theory, C ₂₅ H ₂₃ N ₃ 0 ₃ (413.48)

R _f value: 0.50 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 413

(M + Na) ⁺ = 436

(MH) ^" = 412 Example 109

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4-hydroxyhenyl) amide

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 5-hydroxy-anthranilic acid in tetrahydrofuran with the addition of triethylamine. Yield: 34% of theory, C ₂₁ H ₁₇ N0 ₄ (347.37)

R _f value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 347

(M + Na) ⁺ = 370

(MH) ^" = 346

Example 110

traπs-3- (naphth-2-yl) -but-2-enoic acid-N- (2-sulphophenyl) -amide prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2 -enoic acid chloride and 2-amino-benzenesulfonic acid in tetrahydrofuran with the addition of triethylamine. Yield: 43% of theory, C ₂₀ H ₁₇ NO ₄ S (367.43)

R _f value: 0.28 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 367

(MH) ^" = 366

Example 111

trans-3- (naphth-2-yl) -but-2-enoic acid N- (3-carboxy-thiophene-

4-yl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (3-methoxycarbonyl-thiophene-4-yl) -amide and sodium hydroxide solution in ethanol. Yield: 88% of theory, C ₁₉ H ₁₅ N0 ₃ S (337.40) R _f value: 0.41 (silica gel; dichloromethane / ethanol = 19: 1) Mass spectrum: M ⁺ = 337

(M + Na) ⁺ = 360 (MH) ^" = 336

Example 112

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (N'-methyl-

N'- (4-cyanobutyl) amino) phenyl amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2 -ethoxycarbonyl-4- (N '-methyl-N'- (4-cyanobutyl) - amino) - phenyl] -amide and sodium hydroxide solution in ethanol. Yield: 90% of theory, C ₂₇ H ₂₇ N ₃ 0 ₃ (441.54)

R _f value: 0.68 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 441

(MH) ^" = 440

At game 113

trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-5-amino-phe-yl) -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-5-amino-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 76% of theory, C ₂₁ H ₁₈ N ₂ 0 ₃ (346.39)

R _f value: 0.37 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 346

(MH) ^" = 345 Be isi ^ l 114

trans-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-4- (N'-methyl - N'- (4- (tetrazol -5-yl) butyl) - am no) -phenyll -amid

a) trans-3- (Naphth-2-yl) -but-2-enoic acid-N- [2 -ethoxycarbonyl - 4- (N'-methyl -N'- (4- (tetrazol -5-yl) butyl ) -amino) -phenyl 1 -ami A solution of 3.90 g (8.3 mmol) of trans-3 - (naphth-2-yl) -but-

2-enoic acid-N- [2-ethoxycarbonyl-4- (N'-methyl-N'- (4-cyanobutyl) amino) phenyl] amide, 9.75 g (150 mmol) sodium azide and 8.02 g (150 mmol) Ammonium chloride in 70 ml of dimethylformamide is stirred at 130 ° C for six hours. After cooling, the reaction mixture is diluted with about 150 ml of water, then extracted with ethyl acetate. The crude product obtained from the extract is purified by column chromatography on silica gel (eluent: dichloromethane with 1 to 5% ethanol). Yield: 2.30 g (54% of theory), C ₂₉ H ₃₂ N ₆ 0 ₃ (512.62)

R _f value: 0.48 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 512

(MH) ^" = 511

b) trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-4- (N'-methyl -N'- (4- (tetrazol -5-yl) -butyl) -amino) -pheny 1 -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2 -ethoxycarbonyl-4- (N '-methyl-N'- (4- (tetrazole-

5-yl) butyl) amino) phenyl] amide and sodium hydroxide solution in ethanol.

Yield: 87% of theory,

C ₂₇ H _2B N ₆ 0 ₃ (484.56)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 483 Example 115

trans-3- (l-bromo-naphth-2-yl) acrylic acid-N- (2-carboxyphenyl) amide

Prepared analogously to Example 2 from trans-3- (1-bromo-naphth-2-yl) acrylic acid-N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 87% of theory, C ₂₀ H ₁₄ BrNO ₃ (396.24)

R _f value: 0.18 (silica gel; dichloromethane / ethanol = 50: 1) mass spectrum: M ⁺ = 395/397

(MH) ^' = 394/396

Example 116

trans-3- (3,4-difluorophenyl) but-2-enoic acid N- (2-carboxy-phenyl) amide

Prepared analogously to Example 2 from trans-3- (3,4-difluorophenyl) -but-2-enoic acid-N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 54% of theory, C ₁₇ H ₁₃ F ₂ N0 ₃ (317.30)

R _f value: 0.41 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 317

(MH) ^" = 316

Example 117

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (2-ethyl -

4 -methyl -imi dazol -1 -yl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-methoxycarbonyl-4- (2-ethyl-4-methyl-imidazole-

1-yl) phenyl] amide and sodium hydroxide solution in methanol.

Yield: 89% of theory,

C ₂₇ H ₂₅ N ₃ 0 ₃ (439.52)

R _£ value: 0.13 (silica gel; dichloromethane / ethanol = 9: 1) Mass spectrum: M ⁺ = 439

(MH) ^" = 438

Example 118

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (imidazol-l-yl) phenyl 1 -ami

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid N- [2-methoxycarbonyl -4- (imidazol-1-yl) phenyl] amide and sodium hydroxide solution in methanol.

Yield: 69% of theory,

C ₂₄ H ₁₉ N ₃ 0 ₃ (397.44)

R _f value: 0.12 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 397

(M + H) ⁺ = 398

(MH) ^" = 396

At piel 119

trans-3- (naphth-2-yl) -but-2 -enoic acid-N- [2-carboxy-4- (3,5-di-ethyl-pyra ol -1 -yl) -phenyl 1 -ami d

a) 2-Nitro-5- (3, 5-dimethyl-pyrazol-l-yl) -benzoic acid methyl ester

A solution of 2.84 g (10 mmol) of 3-methoxycarbonyl-4-nitrophenylhydrazine, 1.0 g (10 mmol) of acetylacetone and 3.0 ml of triethylamine in 40 ml of methanol is stirred overnight at room temperature. It is then evaporated to dryness, the residue is dissolved in about 50 ml of dichloromethane, the solution is washed with 5% sodium hydrogen carbonate solution, dried and evaporated again. The crude product thus obtained is purified by column chromatography on silica gel (eluent: dichloromethane).

Yield: 1.50 g (55% of theory), C ₁₃ H ₁₃ N ₃ 0 ₄ (275.27)

R _f value: 0.68 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (M + Na) ⁺ = 298 b) 2-Amino-5- (3, 5-dimethyl-pyrazol-l-yl) benzoic acid methyl ester

Manufactured by catalytic reduction (palladium, 10% on carbon) of 2-nitro-5- (3, 5-dimethyl-pyrazol-1-yl) -benzoic acid methyl ester in methanol.

Yield: 80% of theory,

C ₁₃ H ₁₅ N ₃ 0 ₂ (245.28)

R _f value: 0.48 (silica gel; dichloromethane / ethanol = 19: 1)

c) trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-methoxycarbonyl -

4- (T, _r R -dimethyl -pyrazole-1 -yl) -phenyl 1 -ami

Prepared analogously to Example 1 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-5- (3, 5-dimethyl-pyrazol-1-yl) - benzoic acid methyl ester

Yield: 62% of theory,

C ₂₇ H _2S N ₃ 0 ₃ (439.52)

R _f value: 0.55 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 439

d) trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-4- (3, 5-di-ethyl-pyrazole-1-yl) -phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-4- (3,5-dimethyl-pyrazol-1-yl) phenyl] -amide and sodium hydroxide solution in methanol.

Yield: 80% of theory, C ₂₆ H ₂₃ N ₃ 0 ₃ (425.49)

R _f value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 425

(MH) ^" = 424 Example 120

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-4- (3-methyl-phenyl-pyr ol -1 -yl) -phenyl! amide

Prepared analogously to Example 119 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-4- (3-methyl-5-phenyl-pyrazol-1-yl) phenyl] -amide and sodium hydroxide solution in methanol. Yield: 84% of theory, C ₃₁ H ₂₅ N ₃ 0 ₃ (487.56)

R _f value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 487

(MH) ^" = 486

With game 1 1

trans-3 - (naphth-2 -yl) but-2-enoic acid-N- [2-carboxy-4 - (3-tri-luormethyl -5- (furan -1 -yl) -pyrazole -1 -yl) phenyl 1 amide

Prepared analogously to Example 119 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-4- (3-trifluoromethyl-5- (furan-1-yl) pyrazole -1 -yl) -phenyl] -amide and sodium hydroxide solution in methanol. Yield: 81% of theory, C ₂₉ H ₂₀ F ₃ N ₃ O ₄ (531.50)

R _f value: 0.21 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 531

(MH) ^" = 530

At pi l 1 2

trans - 3 - (2-oxo-2ff-chromen-3 -yl) -acrylic acid-N- (2-carboxy-phenyl) -ami d

Prepared analogously to example 31 from trans-3- (2-oxo-2H-chromen-

3 -yl) acrylic acid chloride and anthranilic acid in tetrahydrofuran with the addition of triethylamine.

Yield: 30% of theory,

C ₁₉ H ₁₃ N0 ₅ (335.31)

R _f value: 0.33 (silica gel; dichloromethane / ethanol = 9: 1) Mass spectrum: M ⁺ = 335

(MH) ^" = 334

Example 123

trans-3- (2-0xo-2H-chromen-3-yl) -but-2-enoic acid-N- (2-carboxy-he.nyl) -amide

Prepared analogously to Example 31 from trans-3- (2-oxo-2H-chromen-3-yl) but-2-enoic acid chloride and anthranilic acid in tetrahydrofuran with the addition of triethylamine. Yield: 13% of theory, C ₂₀ H ₁₅ NO ₅ (349.35)

R _f value: 0.35 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 349

(M + Na) ⁺ = 372

(MH) ^" = 348

With game 1 24

trans - 3 - (naphth-2-yl) -but-2-enoic acid N- [2-carboxy-4 - (3-methyl - -ter .butyl -pyrazole-1 -yl) -phenyl 1-amide

Prepared analogously to Example 119 from transτ3- (naphth-2-yl) -but-

2-enoic acid-N- [2-methoxycarbonyl-4- (3-methyl-5-tert-butyl-pyrazol-l-yl) phenyl] amide and sodium hydroxide solution in methanol.

Yield: 66% of theory,

C ₂₉ H ₂₉ N ₃ 0 ₃ (467.57)

R _f value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: (MH) ^" = 466

Example 125

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (3-carboxy-IH-pyrazole-

4-yl) amide

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 4-amino-1H-pyrazole-3-carboxylic acid in dimethylformamide with the addition of pyridine. Yield: 19% of theory, C ₁₈ H ₁₅ N ₃ 0 ₃ (321.34)

R _f value: 0.21 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ^* = 321

(MH) ^" = 320

With game 1 6

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-benzenesulfonylamino-carbonylphenyl) amide

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 2-benzenesulfonylaminocarbonyl-aniline in tetrahydrofuran with the addition of pyridine. Yield: 85% of theory, C ₂₇ H ₂₂ N ₂ 0 ₄ S (470.55)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 470

(MH) ^" = 469

Example 1 7

trans-3- (3-methyl-benzthiophene-2-yl) but-2-enoic acid-N- (2-carboxy-phenyl) -ami

Prepared analogously to Example 2 from trans-3- (3-methyl-benzthiophene-2-yl) -but-2-enoic acid-N- (2-methoxycarbonylphenyl) amide and sodium hydroxide solution in methanol. Yield: 71% of theory, C ₂₀ H ₁₇ NO ₃ S (351.43)

R _f value: 0.34 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 351

(MH) ^" = 350 Example 1 8

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methanesulfonylamino-carbonylphenyl) -ami d

Prepared analogously to example 126 from trans-3 - (naphth-2-yl) -but-

2-ene chloride and 2-methanesulfonylaminocarbonyl-aniline in

Tetrhydrofuran with the addition of pyridine.

Yield: 68% of theory,

C ₂₂ H ₂₀ N ₂ O ₄ S (408.48)

R _f value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 408

(M + Na) ⁺ = 431

(MH) ^" = 407

Example 1 9

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-4- (2-phenyl-imidazole-1-yl) -phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid N- [2-methoxycarbonyl-4- (2-phenylimidazol-l-yl) phenyl] amide and sodium hydroxide solution in methanol.

Yield: 89% of theory,

C ₃₀ H ₂₃ N ₃ O ₃ (473.54)

R _f value: 0.23 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (M + H) ⁺ = 474

(M + Na) ⁺ = 496

(MH) ^" = 472

Example 130

trans-3- (naphth-2-yl) -but -2 -enoic acid-N- [2-carboxy-4- (2-methylbenzene imi dazol -1 -yl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-4- (2-methyl-benzimidazol-1-yl) ^■ phenyl] -amide and sodium hydroxide solution in methanol. Yield: 87% of theory, C ₂₉ H ₂₃ N ₃ 0 ₃ (461.52)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (M + H) ⁺ = 462

(M + Na) ⁺ = 484

(MH) ^" = 460

Example 131

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2,3-dicarboxyphenyl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2,3-dimethoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 80% of theory, C ₂₂ H ₁₇ N0 ₅ (375.38)

R _f value: 0.09 (silica gel; dichloromethane / ethanol, = 9: 1) mass spectrum: (M + Na) ⁺ = 398

(MH) ^" = 374

Example 1 2

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (imidazole-

1 -yl) -5-fluorophenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-4- (imidazol-1-yl) -5-fluorophenyl] amide and sodium hydroxide solution in methanol. Yield: 62% of theory, C ₂₄ H ₁₈ FN ₃ 0 ₃ (415.43)

R _f value: 0.17 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: M ⁺ = 415

(MH) ^" = 414 At game 1 33

trans-3 - (benzthiophene-2-yl) -but -2 -enoic acid-N- (2-carboxy-phenyl) - ami d

Prepared analogously to Example 2 from trans-3- (benzthiophene-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 89% of theory, C ₁₉ H ₁₅ N0 ₃ S (337.40)

R _£ value: 0.43 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (M + Na) ⁺ = 360

(MH) ^" = 336

Example 134

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4-methanesulfonyl oxy-phenyl) -ami d

In a solution of 0.21 g (0.605 mmol) of trans-3- (naphth-2-yl) -but-2-enoic acid N- (2-carboxy-4-hydroxy-phenyl) -amide in 15 ml of 1N sodium hydroxide solution 0.5 ml (4.37 mmol) of methanesulfonyl chloride was slowly added dropwise at room temperature, the solution being kept alkaline by adding sodium hydroxide solution. When the reaction was complete, the mixture was acidified with 2N hydrochloric acid, then extracted three times with 20 ml of ethyl acetate, the extracts dried over sodium sulfate and evaporated to dryness in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; eluent: dichloromethane with 2 to 3% ethanol). Yield: 35% of theory, C ₂₂ H ₁₉ N0 ₆ S (425.46)

R _f value: 0.27 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 425

(MH) ^" = 424 Example 1 5

trans - 3 - (6-fluoro-naphth-2-yl) -acrylic acid-N- (2-carboxy-phenyl) - amid

Prepared analogously to Example 2 from trans-3 - (6-fluoro-naphth-2-yl) acrylic acid-N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 91% of theory, C ₂₀ H ₁₄ FNO ₃ (335.34)

R _f value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (M + H) ⁺ = 336

(M + Na) ⁺ = 358

(MH) ^" = 334

Example 136

trans-2-methyl-3- (6-fluoro-naphth-2-yl) acrylic acid-N- (2-carboxy-phenyl) amide

Prepared analogously to Example 2 from trans-2-methyl-3- (6-fluoro-naphth-2-yl) -acrylic acid-N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 82% of theory, C ₂₁ H ₁₆ FN0 ₃ (349.37)

R _f value: 0.24 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 349

(MH) ^" = 348

Example 137

trans-3- (6-fluoro-naphth-2-yl) acrylic acid-N- (2-carboxy-4-fluorophenyl) amide

Prepared analogously to Example 31 from trans-3- (6-fluoro-naphth-2-yl) acrylic acid chloride and 4-fluoroanthranilic acid in tetrahydrofuran with the addition of pyridine. Yield: 14% of theory, C ₂₀ H ₁₃ F ₂ NO ₃ (353.32) R _f value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1) Mass spectrum: M ⁺ = 353

(MH) ^" = 352

Example 1 8

trans-2-methyl-3- (6-fluoro-naphth-2-yl) acrylic acid-N- (2-carboxy-4-fluoro-phenyl) -amide

Prepared analogously to Example 31 from trans-2-methyl-3- (6-fluoro-naphth-2-yl) acrylic acid chloride and 4-fluoroanthranilic acid in tetrahydrofuran with the addition of pyridine. Yield: 20% of theory, C ₂₁ H ₁₅ F ₂ N0 ₃ (367.36)

R _f value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 367

(MH) ^" = 366

Example 1 39

trans - 3 - (naphth-2 -yl) -but - 2 -enoic acid -N- [2 - carboxy-4 - (2 -N, N-di - methylami no-ethyl xy) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-ethoxycarbonyl-4- (2-N, N-dimethylamino-ethyl-oxy) -phenyl] -amide and sodium hydroxide solution in methanol. Yield: 20% of theory, C ₂₅ H ₂₆ N ₂ 0 ₄ (418.50) mass spectrum: M ⁺ = 418

(MH) ^" = 417

Example 140

3- (Naphth-2-yl) butanoic acid-N- (2-carboxyphenyl) amide

Prepared analogously to Example 2 from 3- (naphth-2-yl) butanoic acid

N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol.

Yield: 83% of theory,

C ₂₁ H ₁₉ N0 ₃ (333.39)

R _f value: 0.24 (silica gel; dichloromethane / ethanol = 19: 1) Mass spectrum: (M + H) ⁺ = 334

(M + Na) ⁺ = 456 (MH) ^" = 332

At sp l 141

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4,5-methylene-ioxy-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2 -enoic acid-N- (2-methoxycarbonyl-4, 5-methylenedioxy-phenyl) -amide and sodium hydroxide solution in methanol.

Yield: 95% of theory,

C ₂₂ H ₁₇ N0 ₅ (375.38)

R _f value: 0.21 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: (MH) ^" = 374

At piel 142

trans-3- (naphth-2-yl) cyclopropanecarboxylic acid N- (2-carboxyhenyl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) cyclopropanecarboxylic acid N- (2-methoxycarbonylphenyl) amide and sodium hydroxide solution in methanol. Yield: 59% of theory C ₂₁ H ₁₇ N0 ₃ (331.38)

R _f value: 0.18 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 330

Example 143

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4-iodophenyl) amide

Prepared analogously to Example 31 from trans-3- (naphth-2-yl) -but-2-enoic acid chloride and 4-iodo-anthranilic acid in tetrahydrofuran with the addition of triethylamine. Yield: 32% of theory, C ₂₁ H ₁₆ IN0 ₃ (457.27) R _f value: 0.19 (silica gel; dichloromethane / ethanol = 50: 1) mass spectrum: (MH) ^" = 456

Example 144

trans-3- (naphth-2-yl) but-2-enoic acid N- (4-carboxypyridine-yl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (4-methoxycarbonyl-pyridin-3-yl) -amide and sodium hydroxide solution in methanol. Yield: 26% of theory, C ₂₀ H ₁₆ N ₂ O ₃ (332.36)

R _f value: 0.18 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (M + Na) ⁺ = 355

(MH) ^" = 331

Example 145

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (morpholine-

1 -yl-carbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-methoxycarbonyl-5- (morpholin-1-yl-carbonyl) phenyl] -amide and sodium hydroxide solution in methanol.

Yield: 90% of theory,

C ₂₆ H ₂₄ N ₂ 0 ₅ (444.49)

R _f value: 0.27 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: M ⁺ = 444

(MH) ^" = 443

(M + Na) ⁺ = 467

At pi l 146

trans-3 - (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (N-ethyl-N-ethyl-amiocarbonyl) phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl -5- (N-ethyl-N-methyl-aminocarbonyl) phenyl] amide and sodium hydroxide solution in methanol. Yield: 71% of theory, C ₂₅ H ₂₄ N ₂ 0 ₄ (416.48)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 416

(MH) ^" = 415

Example 147

trans-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-5- (piperidine-

1 -yl-carbonyl) -phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (piperidin-1-yl-carbonyl) phenyl] amide and sodium hydroxide solution in methanol , Yield: 77% of theory C ₂₇ H ₂₆ N ₂ 0 ₄ (442.51)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: M ⁺ = 442

(MH) ^" = 441

At sp el

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (pyrrole-di n-1-yl-carbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (pyrrolidin-1-yl-carbonyl) phenyl] amide and sodium hydroxide solution in methanol , Yield: 80% of theory, C ₂₆ H ₂₄ N ₂ 0 ₄ (428.49)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 427

(M + Na) ⁺ = 451 Example 149

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (N-isopropyl-N-methyl-carbonyl) -phenyl 1 -ami

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (N-isopropyl-N-methyl-carbonyl) -phenyl] -amide and sodium hydroxide solution in methanol. Yield: 69% of theory C ₂₆ H ₂₆ N ₂ 0 ₄ (430.50)

R _f value: 0.24 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 429

(M + Na) ⁺ = 453

Example 150

trans-3- (Naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (4-methylpiperazin-l -yl-carbonyl) -phenyl1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid N- [2-methoxycarbonyl-5- (4-methyl-piperazin-l-ylcarbonyl) phenyl] amide and sodium hydroxide solution in methanol.

Yield: 40% of theory,

C ₂₇ H ₂₇ N ₃ 0 ₄ (457.53)

R _f value: 0.19 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 457

(MH) ^" = 456

(M + Na) ⁺ = 480

Example 151

trans-3- (naphth-2-yl) -4, 4, 4-trif luor-but-2-enoic acid-N- (2-carboxy-phenyl) -am d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -

4,4,4-trifluorobut-2-enoic acid N- (2-methoxycarbonylphenyl) amide and sodium hydroxide solution in methanol.

Yield: 76% of theory,

C ₂₁ H ₁₄ F ₃ N0 ₃ (385.34) R _£ value: 0.22 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 384

(M + Na) ⁺ = 408

With game 1 2

trans-3 - (3, 4-dibromophenyl) but-2-enoic acid-N- (2-carboxy-phenyl) amide

Prepared analogously to Example 31 from trans-3- (3,4-dibromophenyl) but-2-enoic acid chloride and 2-aminobenzoic acid in dimethylformamide.

Yield: 16% of theory,

C ₁₇ H ₁₃ Br ₂ N0 ₃ (439.10)

R _f value: 0.15 (silica gel; dichloromethane / ethanol = 50: 1)

Mass spectrum: (MH) ^" = 438

At game 153

trans-3- (4 -Ethynylphenyl) but-2-enoic acid N- (2-carboxyphenyl) amide

Prepared analogously to Example 2 from trans-3- (4-trimethylsilanylethynylphenyl) but-2-enoic acid N- (2-methoxycarbonylphenyl) amide and potassium hydroxide solution in methanol.

Yield: 53% of theory,

C ₁₉ H ₁₅ N0 ₃ (305.34)

R _f value: 0.6 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 304

Example 154

trans-3- (3 -Ethynylphenyl) but-2-enoic acid N- (2-carboxyphenyl) amide

Prepared analogously to Example 2 from trans-3- (3-trimethylsilanylethynylphenyl) but-2-enoic acid N- (2-methoxycarbonylphenyl) amide and potassium hydroxide solution in methanol. Yield: 60% of theory, C ₁₉ H _1S N0 ₃ (305.34) R _f value: 0.5 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 304

At game 155

trans-3- (3,4-dibromophenyl) but-2-enoic acid N- (2-carboxy-4,5-di-methoxy-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (3,4-dibromophenyl) -but-2-enoic acid-N- (2-methoxycarbonyl-4,5-dimethoxy-phenyl) -amide and sodium hydroxide solution in methanol / dichloromethane.

Yield: 40% of theory,

C ₁₉ H ₁₇ Br ₂ N0 ₅ (499. 16)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 497/499/501 (bromine isotopes)

For example 156

trans-3- (3,4-dibromophenyl) but-2-enoic acid-N- (2-carboxy-4-methoxy-5-methyphenyl) amide

Prepared analogously to Example 2 from trans-3- (3,4-dibromophenyl) -but-2-enoic acid N- (2-methoxycarbonyl-4-methoxy-5-methylphenyl) amide and sodium hydroxide solution in methanol / dichloromethane.

Yield: 59% of theory,

C ₁₉ H ₁₇ Br ₂ N0 ₄ (483.15)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: M ⁺ = 481/83/85 (bromine isotopes)

Example 1 7

trans-3- (3,5-dibromo-4-ethylphenyl) but-2-enoic acid-N- (2-carboxyphenyl) -ami

Prepared analogously to Example 2 from trans-3- (3,5-dibromo-4-ethyl-phenyl) -but-2-enoic acid-N- (2-methoxycarbonyl-phenyl) -amide and

Sodium hydroxide solution in methanol.

Yield: 49% of theory,

C ₁₉ H ₁₇ Br ₂ N0 ₃ (467.16)

R _£ value: 0.5 (silica gel; dichloromethane / ethanol = 19: 1) Mass spectrum: M ⁺ = 465/67/69 (bromine isotopes)

Example 158

trans-3- (3-bromo-4-chlorophenyl) but-2-enoic acid-N- (2-carboxyphenyl) -ami

Prepared analogously to Example 2 from tranε-3- (3-bromo-4-chlorophenyl) -but-2-enoic acid N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol. ^'' Yield: 36% of theory, C ₁₇ H ₁₃ BrClN0 ₃ (394.65)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 392/94/96 (chloro-bromine isotopes)

At game 159

trans-3- (3-chloro-4-bromophenyl) but-2-enoic acid-N- (2-carboxyhenyl) am d

Prepared analogously to Example 2 from trans-3- (3-chloro-4-bromophenyl) -but-2-enoic acid-N- (2-methoxycarbonyl-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 36% of theory, C ₁₇ H ₁₃ BrClN0 ₃ (394.65)

R _f value: 0.4 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 392/94/96 (chloro-bromine isotopes)

Example 160

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-6-methylhenyl) am d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2 -enoic acid-N- (2-methoxycarbonyl-6-methylphenyl) amide and

Sodium hydroxide solution in methanol.

Yield: 76% of theory,

C ₂₂ H ₁₉ N0 ₃ (345.41)

R _f value: 0.4 (silica gel; dichloromethane / ethanol - 19: 1)

Mass spectrum: (MH) ^" = 344 (M + Na) ⁺ = 368

Example 161

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-6-methoxyphenyl) amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-6-methoxy-phenyl) -amide and sodium hydroxide solution in methanol. Yield: 80% of theory, C ₂₂ H ₁₉ N0 ₄ (361.40)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 360

(M + Na) ⁺ = 384

With game 1 2

trans - 3 - (naphth-2-yl) -but -2 -enoic acid-N- (2-carboxy-6-chlorophenyl) -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-6-chlorophenyl) amide and sodium hydroxide solution in methanol. Yield: 67% of theory, C ₂₁ H ₁₆ C1N0 ₃ (365.81)

R _f value: 0.15 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 364/366 (chlorine isotopes)

Example 1 fi

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4-methyl-ami no-phenyl) -am-tri fluoroacetate

650 mg (1.4 mmol) of trans-3- (naphth-2-yl) but-2-enoic acid- N- [2-carboxy-4- (N-methyl-N-tert-butoxycarbonylamino-phenyl] amide are stirred in 10 ml of dichloromethane and 2 ml of trifluoroacetic acid for 18 hours, the solvent is distilled off and the residue is purified by column chromatography on silica gel (eluent: dichloromethane with 1 to 5% ethanol).

Yield: 79% of theory, C ₂₂ H ₂₀ N ₂ O ₃ X CF ₃ COOH (360.42 / 474.44)

R _f value: 0.7 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 359

M ⁺ = 360

Example 164

trans-3- (Naphth-2-yl) -but-2-ene-acid- N- [2-carboxy-4- (bis-methoxy-ethyl-amino) -phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-methoxycarbonyl-4- (bis-2-methoxy-ethyl-amino) -phenyl] -amide and sodium hydroxide solution in methanol.

Yield: 79% of theory,

C ₂₇ H ₃₀ N ₂ O _s (462.55)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: (M + H) ⁺ = 463

Example 165

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4, 5, 6-tri-hoyy-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but -

2 -enoic acid-N- (2-methoxycarbonyl-4, 5, 6-trimethoxy-phenyl) -amide and sodium hydroxide solution in methanol.

Yield: 46% of theory,

C ₂₄ H ₂₃ N0 ₆ (421.45)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: (MH) ^" = 420 Example 1 6

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4-aminophenyl) amide tri fluoroacetate

Prepared analogously to example 163 from trans-3- (naphth-2-yl) -but-

2 -enoic acid-N- (2-carboxy-4-tert .butoxycarbonylamino-phenyl) -amide and trifluoroacetic acid in dichloromethane.

Yield: 81% of theory,

C ₂₁ H _1B N ₂ 0 ₃ x CF ₃ COOH (346.39 / 460.413)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 345

Example 1 7

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4-benzenesulfonyl ami no-phenyl) -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- (2-ethoxycarbonyl-4-benzenesulfonylamino-phenyl) amide and sodium hydroxide solution in methanol.

Yield: 82% of theory,

C ₂₇ H ₂₂ N ₂ O _s S (486.55)

R _£ value: 0.4 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 485

Example 168

trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-6-fluoro-henyl) -amide

Prepared analogously to Example 31 from trans- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-3-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 33% of theory, • C ₂₁ H ₁₆ FN0 ₃ (349.36)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 348 Example 169

trans - 3 - (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-4-methane sulfon f.onyl amino-pheny]) -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-ene-acid- N- (2-ethoxycarbonyl-4-methanesulfonylamino-phenyl) amide and sodium hydroxide solution in methanol. Yield: 80% of theory, C ₂₂ H ₂₀ N ₂ O ₅ S (424.48)

R _f value: 0.15 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 423

(M + Na) ⁺ = 447

With game 1 70

trans -3 - (3-bromo-4-chlorophenyl) -but -2 -enoic acid-N- (2-carboxy-

4,5-dimethoxy-phenyl-amide

Prepared analogously to Example 2 from trans-3- (3-bromo-4-chlorophenyl) but-2-enoic acid N- (2-methoxycarbonyl-4, 5-dimethoxy-phenyl) • amide and potassium hydroxide solution in methanol / dichloromethane ,

Yield: 15% of theory,

C ₁₉ H ₁₇ BrClN0 ₅ (454.70)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: (MH) ^" = 452/54/56 (bromine-chlorine isotopes)

Example 171

trans-3- (3-chloro-4-bromophenyl) but-2-enoic acid-N- (2-carboxy-

4, 5-di ethoyyphenyl) amide

Prepared analogously to Example 2 from trans-3- (3-chloro-4-bromophenyl) but-2-enoic acid N- (2-methoxycarbonyl-4, 5-dimethoxy-phenyl) amide and potassium hydroxide solution in methanol.

Yield: 45% of theory,

C ₁₉ H ₁₇ BrClN0 ₅ (454.70)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: (MH) ^" = 452/54/56 (bromine-chlorine isotopes) Example 1 72

tran s - 3 - (4 - todphenyl) -but - 2 - enoic acid -N- (- ca rboxyphenyl) - on i d

Prepared analogously to Example 2 from trans-3- (4-iodophenyl) -but-

2 -enoic acid-N- (2-methoxycarbonylphenyl) amide and sodium hydroxide solution in

Methanol / water.

Yield: 16% of theory,

C ₁₇ H ₁₄ IN0 ₃ (407.21)

Mass spectrum: (MH) ^" = 406

Example 173

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-5-methylhenyl) amide

Manufactured analogously to Example 31 from trans- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-4-methylbenzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 4% of theory, C ₂₂ H ₁₉ N0 ₃ (345.40)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 344

Example 174

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4, 6-difluorophenyl) amide

Prepared analogously to Example 31 from trans- (naphth-2-yl) -but-2-enoic acid chloride and 2-amino-3, 5-difluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine. Yield: 8% of theory, C ₂₁ H ₁₅ F ₂ N0 ₃ (367.35)

R _f value: 0.1 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 366 Example 175

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (isopropylaminocarbonyl) phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (isopropylaminocarbonyl) phenyl] amide and potassium hydroxide solution in methanol. Yield: 5% of theory, C ₂₅ H ₂₄ N ₂ 0 ₄ (416.48)

R _f value: 0.3 (silica gel; petroleum ether / ethyl acetate = 1: 9) mass spectrum: (MH) ^" = 415

(M + H) ⁺ = 417

(M + Na) ⁺ = 439 M ⁺ - 416

Example 176

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (ethyl-mi nocarbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) but-2-enoic acid N- [2-methoxycarbonyl-5- (ethylaminocarbonyl) phenyl] amide and potassium hydroxide solution in ethanol. Yield: 33% of theory, C ₂₄ H ₂₂ N ₂ 0 ₄ (402.45)

R _f value: 0.4 (silica gel; dichloromethane / ethanol = 4: 1) mass spectrum: (MH) ^" = 401

(M + Na) ⁺ = 425

Example 177

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4-nitro-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-4-nitro-phenyl) -amide and lithium hydroxide in water / tetrahydrofuran. Yield: 93% of theory, C ₂₁ H ₁₆ N ₂ 0 ₅ (376.37) R _£ value: 0.2 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 375

Example 178

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (propyl-mi-nocarbonyl) -phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (propylaminocarbonyl) phenyl] amide and potassium hydroxide solution in ethanol. Yield: 58% of theory, C ₂₅ H ₂₄ N ₂ 0 ₄ (416.41)

R _f value: 0.15 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 415

Example 179

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2,5-bis-hydroxymethylhenyl) amide

1.0 g (2.5 mmol) of trans-3- (naphth-2-yl) -but-2-enoic acid- N- (2,5-bis-methoxycarbonyl-phenyl) -amide are dissolved in 70 ml of tetrahydrofuran at -70 ° C 10 ml (10 mmol) of lithium triethyl borohydride (1 molar in tetrahydrofuran) are added and the mixture is slowly warmed to room temperature. 100 ml of water are then added dropwise and the mixture is extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 7: 3). Yield: 25% of theory, C ₂₂ H ₂₁ N0 ₃ (347.41)

R _f value: 0.2 (silica gel; petroleum ether / ethyl acetate = 4: 6) mass spectrum: (MH) ^" = 346

(M + Na) ⁺ = 370 Example 180

tranε-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (methyl-qmi nocarbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (methylaminocarbonyl) phenyl] amide and lithium hydroxide in methanol / water. Yield: 30% of theory, C ₂₃ H ₂₀ N ₂ O ₄ (388.42)

R _f value: 0.36 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 387

(M + Na) ⁺ = 411

At sp el l__l

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (dimethyl-am nocarbonyl) -phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid N- [2-methoxycarbonyl-5- (dimethylaminocarbonyl) phenyl] amide and lithium hydroxide in methanol / water. Yield: 41% of theory, C ₂₄ H ₂₂ N ₂ 0 ₄ (402.45)

R _f value: 0.43 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 401

(M + Na) ⁺ = 425

Example 182

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-5-bromophenyl) -ami

Prepared analogously to Example 31 from trans- (naphth-2-yl) -but-

2-enoic acid chloride and 2-amino-4-bromo-benzoic acid in pyridine.

Yield: 58% of theory,

C ₂₁ H ₁₆ BrN0 ₃ (410.27)

R _f value: 0.65 (silica gel; dichloromethane / ethanol = 3: 1)

Mass spectrum: (MH) ^" = 408/410 Example 183

trans-3- (naphth-2-yl) -but-2-enoic acid N- (2-hydroxymethylphenyl) amide

1.0 g (1.8 mmol) of trans-3- (naphth-2-yl) -but-2-enoic acid- N- [2- (tert-butyl-diphenylsilanyloxymethyl) phenyl] amide are dissolved in 30 ml of tetrahydrofuran and 2 ml ( 2 mmol) of tetrabutylammonium fluoride (1 molar in tetrahydrofuran) was stirred for 6 hours. The solvent is distilled off, the residue is distributed in ethyl acetate / water, the combined organic extracts are dried and evaporated. The crude product is purified by column chromatography on silica gel (eluent: dichormethane / - ethanol 0 to 2%). Yield: 67% of theory, C ₂₁ H ₁₉ N0 ₂ (317.39)

R _f value: 0.7 (silica gel; toluene / ethyl acetate / egg liquor = 50: 45: 5) mass spectrum: (MH) ^" = 316

(M + Na) ⁺ = 340

Example 184

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-5-hydroxymethyl-phenyl) -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-5-hydroxymethyl-phenyl) -amide and potassium hydroxide solution in ethanol. Yield: 33% of theory, C ₂₂ H ₁₉ N0 ₄ (361.39)

R _f value: 0.5 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 360

(M + Na) ⁺ = 384 Example 185

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4- (N-methyl

Nth. butoxycarbonyl ami no) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-ene acid-N- [2-ethoxycarbonyl-4- (N-methyl-N-tert. Butoxycarbonylamino) phenyl] amide and sodium hydroxide solution in methanol. Yield: 77% of theory, C ₂₇ H _2B N ₂ 0 ₅ (460.53)

R _f value: 0.7 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 459

(M + Na) ⁺ = 483

Example 186

trans-3- (naphth-2-yl) -but-2-enoic acid N- [2-carboxy-

4- (N-tert.utoxycarbonylamino) phenyl 1 amide

Prepared analogously to Example 2 from tranε-3- (naphth-2-yl) -but-2-enoic acid-N- [2-ethoxycarbonyl-4- (N-tert. Butoxycarbonylamino) phenyl] -amide and sodium hydroxide solution in methanol. Yield: 96% of theory, C ₂₆ H ₂₆ N ₂ 0 ₅ (446.50)

R _f value: 0.6 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" - 445

(M + Na) ⁺ = 469

Example 187

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-4- (phenyl-i nocarbonyl mi no) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-ethoxycarbonyl-4- (phenylaminocarbonylamino) phenyl] -amide and sodium hydroxide solution in methanol.

Yield: 97% of theory,

C ₂₈ H ₂₃ N ₃ 0 ₄ (465.51)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 9: 1) Mass spectrum: (MH) ^" = 464

(M + Na) ⁺ = 488

Example 188

trans-3- (naphth-2-yl) -but-2-ene-acid- N- [2-carboxy-4- (methylaminocarbonyl mi no) -phenyl 1 -ami d

Prepared analogously to Example 2 from tranε-3- (naphth-2-yl) -but-2-enoic acid N- [2 -ethoxycarbonyl -4- (methylaminocarbonylamino) phenyl] amide and sodium hydroxide solution in methanol. Yield: 91% of theory, C ₂₃ H ₂₁ N ₃ 0 ₄ (403.44)

R _f value: 0.15 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 402

(M + Na) ⁺ = 426

Example 189

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-5-trifluoromethyl-phenyl) -amide

Manufactured analogously to example 31 from trans- (naphth-2-yl) -but-

2-ene acid chloride and 2-amino-5-trifluoromethyl-benzoic acid in

Tetrahydrofuran with the addition of triethylamine.

Yield: 13% of theory,

C ₂₂ H ₁₆ F ₃ N0 ₃ (399.37)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: (MH) ^" = 398

At game 1 90

trans - 3 - (naphth-2-yl) -but -2 -enoic acid -N- [2 - carboxy-4 - (phenyl-thyl m nocarbonyl mino) -phenyl 1 -am d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid N- [2 -ethoxycarbonyl-4- (phenylethylaminocarbonylamino) phenyl] amide and sodium hydroxide solution in methanol. Yield: 95% of theory, C ₃₀ H ₂₇ N ₃ O ₄ (493.56) R _f value: 0.2 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 492

Example 191

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-4- (4-phenoxy-phenylminocarbonylamino) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3 - (naphth-2-yl) -but-

2-enoic acid N- [2-ethoxycarbonyl-4- (4-phenoxyphenylaminocarbonylamino) phenyl] amide and sodium hydroxide solution in methanol.

Yield: 98% of theory,

C ₃₄ H ₂₇ N ₃ O _s (557. 61)

R _f value: 0. 2 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 556

With game 1 2

trans-3 - (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-4 - (benzylsulfonyl amino) phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid N- [2-ethoxycarbonyl-4- (benzylsulfonylamino) phenyl] amide and sodium hydroxide solution in methanol.

Yield: 100% of theory,

C ₂₈ H ₂₄ N ₂ O _s S (500.58)

R _f value: 0.4 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 499

Example 193

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-4- (pyridine-yylaminocarbonylmino) -phenyl 1-amide

Manufactured analogously to example 2 from trans-3- (naphth-2-yl) -but-

2-ene acid-N- [2-ethoxycarbonyl-4- (pyridin-3 -yl-aminocarbonylamino) -phenyl] -amide and sodium hydroxide solution in methanol.

Yield: 53% of theory,

C ₂₇ H ₂₂ N ₄ 0 ₄ (466.50)

R _f value: 0.25 (silica gel; dichloromethane / ethanol = 4: 1) Mass spectrum: (MH) ^" = 465

Example 1 4

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (carboxy-ethyl-aminocarbonyl) phenyl.1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2 -enoic acid-N- [2-methoxycarbonyl-5- (methoxycarbonylmethylaminocarbonyl) phenyl] amide and potassium hydroxide solution in ethanol.

Yield: 37% of theory,

C ₂₄ H ₂₀ N ₂ 0 ₆ (432.43)

R _f value: 0.4 (silica gel; dichloromethane / ethanol = 1: 4)

Mass spectrum: (MH) ^" = 431

Example 1 5

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (N-methyl-carboxymethyl-aminocarbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-ene acid-N- [2-methoxycarbonyl-5- (N-methyl-N-methoxycarbonyl-methyl-aminocarbonyl) -phenyl] -amide and potassium hydroxide solution in ethanol.

Yield: 6% of theory,

C _2S H ₂₂ N ₂ 0 ₆ (446.46)

R _f value: 0.35 (silica gel; dichloromethane / ethanol = 1: 4)

Mass spectrum: (MH) ^" = 445

Example 1 6

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (N-benzyl-aminocarbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-methoxycarbonyl-5- (N-benzylaminocarbonyl) phenyl] amide and potassium hydroxide solution in ethanol.

Yield: 100% of theory,

C ₂₉ H ₂₄ N ₂ 0 ₄ (464.52)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 9: 1) Mass spectrum: (MH) ^" = 463

(M + Na) ⁺ = 487

Example 197

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (pyrrole-in-1-yl-am nocarbonyl) -phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (pyrrolidin-1-yl-aminocarbonyl) phenyl] amide and potassium hydroxide solution in ethanol. Yield: 58% of theory, C ₂₆ H ₂₅ N ₃ 0 ₄ (443.50)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 4: 1) mass spectrum: (MH) ^" = 442

(M + Na) ⁺ = 466

Example 1 8

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (2-aminethylamino-nocarbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3 - (naphth-2-yl) -but-2-ene acid-N- [2-methoxycarbonyl-5- (2-aminoethylaminocarbonyl) phenyl] amide and potassium hydroxide solution in ethanol. Yield: 58% of theory, C ₂₄ H ₂₃ N ₃ 0 ₄ (417.46)

R _f value: 0.15 (silica gel; dichloromethane / ethanol / ammonia = 50: 45: 5)

Mass spectrum: (MH) ^" = 416

(M + Na) ⁺ = 440

Example 1 9

trans-3- (Naphth-2-yl) -but-2-enoic acid N- [2-carboxy-5- (2-tert-butoyycarbonyl minoethyl-am nocarbonyl) -phenyl 1-amide

To a solution of 0.1 g (0.24 mmol) of trans-3- (naphth-2-yl) - but-2-enoic acid-N- [2-carboxy-5- (2-aminoethyl-aminocarbonyl) phenyl] amide, 0.25 ml 1 molar sodium hydroxide solution and 1 ml tetrahydro furan, 60 mg (0.27 mmol) of di-tert-butyl dicarbonate are added and the mixture is stirred for 2 hours. The tetrahydrofuran is distilled off in vacuo. The residue is diluted with water, acidified with citric acid and extracted with ethyl acetate. The combined organic extracts are dried and evaporated.

Yield: 64% of theory, C ₂₉ H ₃₁ N ₃ 0 ₆ (517.58)

R _f value: 0.8 (silica gel; dichloromethane / ethanol / ammonia = 50: 45: 5)

Mass spectrum: (MH) ^" = 516

(M + Na) ⁺ = 540

For example 200

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-5-phenyl-aminocarbonyl-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2 -enoic acid-N- (2-methoxycarbonyl-5-phenylaminocarbonyl-phenyl) amide and potassium hydroxide solution in ethanol.

Yield: 83% of theory,

C ₂₈ H ₂₂ N ₂ 0 ₄ (450.49)

R _f value: 0.15 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 449

Example 201

trans-3- (naphth-2-yl) -but-2-enoic acid-N- {2-carboxy-5- [N- (2-methoxy-1-methylethyl) aminocarbonyl 1-phenyl} - amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2 -enic acid-N- {2-methoxycarbonyl-5- [N- (2-methoxy-1-methylethyl) aminocarbonyl] phenyl} amide and potassium hydroxide solution in ethanol.

Yield: 69% of theory,

C ₂₆ H ₂₆ N ₂ 0 ₅ (446.50)

R _f value: 0.15 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 445 At game 202

trans-3 - (naphth-2-yl) -but -2 -enoic acid-N- [2-carboxy-5 - (N-piperi - in-1-yl-aminocarbonyl) -phenyl 1 -ami

Manufactured analogously to Example 2 from tranε-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl -5- (N-piperidin-1-yl-amino-carbonyl) -phenyl] -amide and potassium hydroxide solution in ethanol. Yield: 51% of theory, C ₂₇ H ₂₇ N ₃ 0 ₄ (457.53)

R _f value: 0.2 (silica gel; toluene / ethyl acetate / glacial acetic acid = 50: 45: 5) mass spectrum: (MH) ^" = 456

M ⁺ = 457

Example 203

trans- 3 - (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5 - (N-cyclopentyl-aminocarbonyl) -phenyl 1 -am d

Manufactured analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid N- [2-methoxycarbonyl-5- (N-cyclopentylaminocarbonyl) phenyl] amide and potassium hydroxide solution in ethanol , Yield: 58% of theory, C ₂₇ H ₂₆ N ₂ 0 ₄ (442.52)

_Rf value: 0.6 (silica gel; ^'toluene / Essigester / Eiseεsig = 50: 45: 5) Massenεpektrum: (MH) ^"= 441

M ⁺ = 457

At sp el ^" 204

trans-3- (Naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (N-cyclohexylamino-nocarbonyl) -phenyl 1 -ami d

Manufactured analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-ene acid-N- [2-methoxycarbonyl-5- (N-cyclohexyl-aminocarbonyl) phenyl] -amide and potassium hydroxide solution in ethanol.

Yield: 81% of theory,

C ₂₈ H ₂₈ N ₂ 0 ₄ (456.54)

R _f value: 0.42 (silica gel; dichloromethane / ethanol = 4: 1)

Mass spectrum: (MH) ^" = 455 Example 205

trans-3- (naphth-2-yl) -but-2-enoic acid N- [2-carboxy-5- (N-cyclopropylamino carbonyl) phenyl 1 -amido

Manufactured analogously to Example 2 from trans-3- (naphth-2-yl) but-2-enoic acid N- [2-methoxycarbonyl-5- (N-cyclopropylaminocarbonyl) phenyl] amide and potassium hydroxide solution in ethanol. Yield: 59% of theory, C _2E H ₂₂ N ₂ 0 ₄ (414.46)

R _f value: 0.35 (silica gel; dichloromethane / ethanol = 4: 1) mass spectrum: (MH) ^" = 413

Example 206

trans -3- (naphth-2-yl) -but -2 -enoic acid-N- {2-carboxy- 5- [N- (2,2,2-trifluoroethyl) aminocarbonyl 1-phenyl} -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-ene acid-N- {2-methoxycarbonyl-5- [N- (2,2,2-trifluoroethyl) aminocarbonyl] phenyl} amide and potassium hydroxide solution in ethanol.

Yield: 65% of theory,

C ₂₄ H ₁₉ F ₃ N ₂ 0 ₄ (456.42)

R _f value: 0.35 (silica gel; dichloromethane / ethanol = 4: 1)

Mass spectrum: (MH) ^" = 455

Example 207

trans-3- (naphth-2-yl) -but-2-enoic acid-N- {2-carboxy-5- [N- (2-dimethyl inoethyl) aminocarbonyl] phenyl} amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2 -enoic acid-N- {2-methoxycarbonyl -5- [N- (2-dimethylaminoethyl) aminocarbonyl] phenyl} -amide and potassium hydroxide solution in ethanol.

Yield: 37% of theory, ₂₆ H ₂₇ N ₃ 0 ₄ (445.52)

R _f value: 0.1 (silica gel; dichloromethane / ethanol = 4: 1)

Mass spectrum: (MH) ^" - 444 Example 208

trans-3- (naphth-2-yl) -but-2-enoic acid-N- {2-carboxy-5- [N- (3-diethylaminopropyl) -aminocarbonyl-1-phenyl} -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid N- {2-methoxycarbonyl-5- [N- (3-dimethylaminopropyl) aminocarbonyl] phenyl} amide and potassium hydroxide solution in ethanol.

Yield: 29% of theory,

C ₂₇ H ₂₉ N ₃ 0 ₄ (459.55)

R _f value: 0.1 (silica gel; dichloromethane / ethanol = 4: 1)

Mass spectrum: (MH) ^" = 458

Example 209

trans-3- (naphth-2-yl) -but-2-enoic acid-N- {2-carboxy-5- [N- (2-meth-oxyethyl) -amino-carbonyl-1-phenyl} -ami d

Prepared analogously to Example 2 from tranε-3- (naphth-2-yl) -but-2-enoic acid N- {2-methoxycarbonyl-5- [N- (2-methoxyethyl) aminocarbonyl] phenyl} amide and potassium hydroxide solution in ethanol. Yield: 71% of theory, C ₂₅ H ₂₄ N ₂ 0 ₅ (432.48)

R _f value: 0.35 (silica gel; dichloromethane / ethanol = 4: 1) mass spectrum: (MH) ^" = 431

Example 21

trans-3- (Naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (N-morpholine-4-yl-am nocarbonyl) phenyl] amide

Manufactured analogously to Example 2 from tranε-3- (naphth-2-yl) -but-2-enoic acid N- [2-methoxycarbonyl-5- (N-morpholin-4-ylaminocarbonyl) phenyl] amide and potassium hydroxide solution in ethanol. Yield: 69% of theory, C ₂₆ H ₂₅ N ₃ 0 ₅ (459.50)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 4: 1) mass spectrum: (MH) ^" = 458

(M + Na) ⁺ = 482 Be sp., 1 211

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (N-cyclobutyl-aminocarbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2 -enoic acid-N- [2-methoxycarbonyl-5- (N-cyclobutylaminocarbonyl) phenyl] amide and potassium hydroxide solution in ethanol.

Yield: 87% of theory,

C ₂₆ H ₂₄ N ₂ 0 ₄ (428.49)

R _f value: 0.47 (silica gel; dichloromethane / ethanol = 4: 1)

Mass spectrum: (MH) ^" = 427

Example 212

trans-3- (naphth-2-yl) but-2-enoic acid-N- {2-carboxy-5- [N- (4-methylpiperazin-1-yl) -am nocarbonyl 1-phenyl} -amide

Prepared analogously to Example 2 from trans-3 - (naphth-2-yl) -but-

2-ene acid-N- {2-methoxycarbonyl-5- [N- (4-methylpiperazin-l-yl) aminocarbonyl] phenyl} amide and potassium hydroxide solution in ethanol.

Yield: 36% of theory,

C ₂₇ H ₂₈ N ₄ 0 ₄ (472.55)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 3: 7)

Mass spectrum: (MH) ^" = 471

(M + Na) ⁺ = 495

(M + H) ⁺ = 473

At pi el 21

tranε- 3 - (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5 - (2-methyl-hydrazino-carbonyl) -phenyl 1-am d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-ene acid-N- [2-methoxycarbonyl-5- (2-methylhydrazino-carbonyl) phenyl] -amide and lithium hydroxide in tetrahydrofuran / water. Yield: 62% of theory, C ₂₃ H ₂₁ N ₃ 0 ₄ (403.44) mass spectrum: (MH) ^" = 402

(M + Na) ⁺ = 426 At game 214

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (2-benzoyl-hydrazino-carbonyl) -phenyl 1 -ami d

Manufactured analogously to Example 2 from tran-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-methoxycarbonyl-5- (2-benzoylhydrazino-carbonyl) phenyl] amide and potassium hydroxide solution in ethanol.

Yield: 21% of theory,

C ₂₉ H ₂₃ N ₃ 0 ₅ (493.52)

R _f value: 0.55 (silica gel; dichloromethane / ethanol = 3: 1)

Mass spectrum: (MH) ^" = 492

At pi l 215.

trans-3- (naphth-2-yl) -but-2-enoic acid N- [2-carboxy-5- (2, 2-dimethyl-hydrazine nocarbonyl) phenyl 1 -am d

Manufactured analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid N- [2-methoxycarbonyl-5- (N, N-dimethyl-hydrazino-carbonyl) phenyl] amide and lithium hydroxide in tetrahydrofuran / water.

Yield: 77% of theory, C ₂₄ H ₂₃ N ₃ 0 ₄ (417.46)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 4: 1) mass spectrum: (MH) ^" = 416

(M + Na) ⁺ = 440

For example 216

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (1, 2-diethyl hydrazi no-carbonyl) -phenyl 1 -ami d

Manufactured analogously to Example 2 from tran-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (1,2-dimethylhydrazino-carbonyl) phenyl] amide and lithium hydroxide in tetrahydrofuran /- Water .

Yield: 77% of theory, C ₂₄ H ₂₃ N ₃ 0 ₄ (417.46) R _f value: 0.3 (silica gel; dichloromethane / ethanol = 4: 1) mass spectrum: (MH) ^" = 416

(M + Na) ⁺ = 440

At game 21 7

trans-3 - (naphth-2-yl) -but -2 -enoic acid-N- [2-carboxy-5 - (N-prop-yn-yl aminocarbonyl) phenyl amide

Manufactured analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (N-prop-2-yn-aminocarbonyl) phenyl] amide and lithium hydroxide in methanol / water. Yield: 65% of theory, C ₂₅ H ₂₀ N ₂ O ₄ (412.44)

R _f value: 0.46 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 411

(M + Na) ⁺ = 435

Example 21.8

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (N-isobuyl minocarbonyl) phenyl amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-ene acid-N- [2-methoxycarbonyl -5- (N-isobutylaminocarbonyl) phenyl] amide and lithium hydroxide in methanol / water. Yield: 58% of theory, C _2g H ₂₆ N ₂ 0 ₄ (430.50)

R _f value: 0.41 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 429

(M + Na) ⁺ = 453

At game 21

trans-3 - (naphth-2-yl) -but -2 -enoic acid-N- [2-carboxy-5 - (N- (pyrid-3-yl-methyl) -aminocarbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-ene-acid- N- [2-methoxycarbonyl-5- (N- (pyridin-3-yl-methyl) - aminocarbonyl) phenyl] amide and lithium hydroxide in methanol / -

Water.

Yield: 39% of theory,

C ₂₈ H ₂₃ N ₃ 0 ₄ (465.51)

R _f value: 0.21 (silica gel; dichloromethane / ethanol = 3: 1)

Mass spectrum: (MH) ^" = 464

Example 220

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (N- (2-methylh-ethyl) - am nocarbonyl) -phenyl 1 - am d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-ene acid N- [2-methoxycarbonyl-5- (N- (2-methylthio-ethyl) aminocarbonyl) phenyl] amide and lithium hydroxide in methanol / -

Water.

Yield: 45% of theory,

C ₂₅ H ₂₄ N ₂ 0 ₄ S (448.54)

R _f value: 0.41 (silica gel; dichloromethane / ethanol = 3: 1)

Mass spectrum: (MH) ^" = 447

Example 221

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (N- (2-hydroxyethyl) aminocarbonyl) phenyl 1-amide

Manufactured analogously to Example 2 from tranε-3- (naphth-2-yl) but-2-enoic acid-N- [2-methoxycarbonyl-5- (N- (2-hydroxyethyl) aminocarbonyl) phenyl] amide and lithium hydroxide in methanol / water. Yield: 68% of theory, C ₂₄ H ₂₂ N ₂ 0 ₅ (418.45)

R _f value: 0.20 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 417 Example 222.

trans-3- (naphth-2-yl) -but-2-enoic acid N- [2-carboxy-5- (2-tert-butoxycarbonyl hydrazino-carbonyl) phenyl amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-ene acid N- [2-methoxycarbonyl-5- (2-tert. Butoxycarbonylhydrazino-carbonyl) phenyl] amide and lithium hydroxide in methanol / water.

Yield: 48% of theory,

C ₂₇ H ₂₇ N ₃ 0 ₆ (489.53)

R _f value: 0.38 (silica gel; dichloromethane / ethanol = 3: 1)

Mass spectrum: - (MH) ^" = 488

Example 223

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (2,5-dihy-dropyrrol-1 -yl-carbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (2,5-dihydropyrrol-1-yl-carbonyl) phenyl] amide and lithium hydroxide in methanol / water. Yield: 73% of theory, C ₂₆ H ₂₂ N ₂ 0 ₄ (426.47)

R _f value: 0.48 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 425

(M + Na) ⁺ = 449

Example 224

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (allyl-i nocarbonyl) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-carboxy-5- (allylaminocarbonyl) phenyl] amide and

Lithium hydroxide in methanol / water.

Yield: 68% of theory,

C ₂₅ H ₂₂ N ₂ 0 ₄ (414.46)

R _f value: 0.44 (silica gel; dichloromethane / ethanol = 3: 1) Mass spectrum: (MH) ^' = 413

(M + Na) ⁺ = 437

Example 225

trans-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-5- (3-hydroxy-

1 -propi n -yl) -phenyl l -amide

Manufactured analogously to example 2 from trans -3 - (naphth-2-yl) -but -

2 -ene acid-N- [2-methoxycarbonyl - 5 - (3-hydroxy-1-propynyl) phenyl] -amide and lithium hydroxide in tetrahydrofuran / water.

Yield: 27% of theory,

C ₂₄ H ₁₉ N0 ₄ (385.42)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 384

Example 226

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5-benzyl-ami no-phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- [2-methoxycarbonyl-5-benzylamino-phenyl] -amide and

Potash lye in methanol.

Yield: 87% of the. Theory,

C ₂₈ H ₂₄ N ₂ 0 (436.51)

R _f value: 0.25 (silica gel; dichloromethane / ethanol = 49: 1)

Mass spectrum: (MH) ^" = 435

Example 227

trans-3- (naphth-2-yl) -but-2-ene acid-N- [2-carboxy-5- (N- (2-dimethylamino no-ethyl) -amino) -phenyl 1-amide

Prepared analogously to Example 2 from tranε-3- (naphth-2-yl) -but-2-ene acid-N- [2-methoxycarbonyl-5- (N- (2-dimethylaminoethyl) amino) phenyl] amide and lithium hydroxide in tetrahydrofuran / water. Yield: 86% of theory, C ₂₅ H ₂₇ N ₃ 0 ₃ (417.51) R _f value: 0.15 (silica gel; dichloromethane / ethanol = 1: 1) mass spectrum: (MH) ^" = 416

Example 228

trans-3- (naphth-2-yl) but-2-enoic acid N- (6-carboxy-quinoline-yl-amide

Prepared analogously to Example 31 from trans- (naphth-2-yl) -but-2-enoic acid chloride and 5-amino-6-carboxyquinoline in dimethylformamide with the addition of triethylamine and subsequent reaction analogously to Example 2 with lithium hydroxide in methanol / water.

Yield: 17% of theory, C ₂₄ H _ιe N ₂ 0 ₃ (382.42)

R _f value: 0.7 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 381

Example 229

trans-3- (naphth-2-yl) but-2-enoic acid N- (4-carboxy-3-biphenyl) amide

Prepared analogously to Example 31 from trans- (naphth-2-yl) -but-

2-ene acid chloride and 3-amino-biphenyl-4-carbonic acid in pyridine with the addition of 2-dimethylamino-pyridine.

Yield: 29% of theory,

C ₂₇ H ₂₁ N0 ₃ (407.47)

R _f value: 0. 7 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 406

At game 230

trans-3 - (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-5-isopropyl-aminocarbonyl mi no) -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid N- (2-methoxycarbonyl-5-isopropylaminocarbonylamino) amide and potassium hydroxide solution in ethanol. Yield: 31% of theory, C ₂₅ H ₂₅ N ₃ 0 ₄ (431.49) mass spectrum: (MH) ^" = 430

At game 231

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy-5- (N- (pyridine-2-yl-methyl) -aminocarbony) -phenyl 1 -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid N- [2-methoxycarbonyl-5- (N- (pyridin-2-yl-methyl) aminocarbonyl) phenyl] amide and lithium hydroxide in tetrahydrofuran / water. Yield: 34% of theory, C ₂₈ H ₂₃ N ₃ 0 ₄ (465.51)

R _f value: 0.35 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 464

Example 232

trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-carboxy _τ 5- (N- (pyridine-4-yl-methyl) aminocarbonyl) phenyl 1 -am

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl-5- (N- (pyridin-4-yl-methyl) aminocarbonyl) phenyl] amide and lithium hydroxide in tetrahydrofuran / water. Yield: 31% of theory, C ₂₈ H ₂₃ N ₃ 0 ₄ (465.51)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 464

Example 233

trans-3- (naphth-2-yl) but-2-enoic acid-N- {2-carboxy-5- [N- (pyridine-3-ylmethyl) -N-methylamino) carbonyl 1 -phenyl} -amide Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but- 2 -enoic acid-N- {2-methoxycarbonyl- 5- [N- (pyridin-3-yl-methyl) - N-methyl-amino) -carbonyl] -phenyl} -amide and lithium hydroxide in tetrahydrofuran / water. Yield: 51% of theory,

C ₂₉ H ₂₅ N ₃ 0 ₄ (479.54)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 3: 1)

Mass spectrum: (MH) ^" = 478

Example 234

trans-3- (Naphth-2-yl) but-2-enoic acid N- [2-carboxy-5- (N- (pyri- in-4-yl) aminocarbonyl) phenyl 1-amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-ene acid-N- [2-methoxycarbonyl -5- (N- (pyridin-4-yl) aminocarbonyl) phenyl] amide and lithium hydroxide in tetrahydrofuran / water.

Yield: 44% of theory, C ₂₇ H ₂₁ N ₃ 0 ₄ (451.48)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 450

M ⁺ = 451

Example 235

trans-3- (naphth-2-yl) but-2-enoic acid-N- {2-carboxy-5- [(1-methylpiperidin-4-yl-methyl) aminocarbonyl] phenyl} amide hydrochloric acid

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- {2-methoxycarbonyl-5- [(l-methyl-piperidin-4-yl-methyl) -aminocarbonyl] - phenyl} -amide and lithium hydroxide in tetrahydrofuran / water and subsequent treatment with HCl. Yield: 52% of theory, C ₂₉ H ₃₁ N ₃ 0 ₄ x HCl (485.58 / 522.05)

R _f value: 0.2 (Reverεed phase RP 8; methanol / 5% sodium chloride 6: 4)

Mass spectrum: (MH) ^" = 484

(M + H) ⁺ = 486 Example 236

trans-3- (naphth-2-yl) but-2-enoic acid-N- {2-carboxy-

5- [(1-tert. Butoxycarbonyl-piperidin-4-yl -methyl) -amino-carhonyl 1 -phenyl} -ami d

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid-N- {2-methoxycarbonyl-5- [(1-tert-butoxycarbonyl-piperidin-4-yl-methyl) -aminocarbonyl ] -phenyl} -amide and lithium hydroxide in tetrahydrofuran / water. Yield: 39% of theory, C ₃₃ H ₃₇ N ₃ 0 ₆ (571.67)

R _f value: 0.5 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 570

Example 237

trans-3 - (naphth-2-yl) -but-2-enoic acid-N- {2-carboxy-5- [(1-aza-bi cycl o \. 2. 21 ct - 3 -yl ami no) - carbonyl 1 -phenyl} -ami

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2 -enoic acid-N- {2-methoxycarbonyl-5- [(1-aza-bicyclo [2.2.2] oct-

3 -ylamino) -carbonyl] -phenyl} -amide and lithium hydroxide in

Tetrahydrofuran / water.

Yield: 31% of theory,

C ₂₉ H ₂₉ N ₃ 0 ₄ (483.57)

R _f value: 0.2 (reversed phase RP 8; methanol / 5% sodium chloride

= 6: 4)

Mass spectrum: (M + H) ⁺ = 484

Example 238

trans-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-5- (2-carboxy-et yl aminocarbonyl) phenyl amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-ene acid-N- [2-methoxycarbonyl-5- (2-methoxycarbonyl-ethylaminocarbonyl) phenyl] amide and lithium hydroxide in tetrahydro - furan / water. Yield: 80% of theory, C ₂₅ H ₂₂ N ₂ 0 ₆ (446.46)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 3: 1)

Mass spectrum: (MH) ^" = 445

At pi l 239

trans-3- (naphth-2-yl) -but-2-enoic acid-N- {2 -carboxy-5- [(1H-imidol-4-yl ethyl) -am nocarbonyl 1-phenyl} -ami d

Prepared analogously to Example 2 from tranε-3- (naphth-2-yl) -but-2-enoic acid N- {2-methoxycarbonyl-5- [(1H-imidazol-4-ylmethyl) aminocarbonyl] phenyl} amide and lithium hydroxide in tetrahydrofuran / water. Yield: 26% of theory, C ₂₆ H ₂₂ N ₄ 0 ₄ (454.48)

R _f value: 0.7 (silica gel; ethyl acetate / ethanol / ammonia = 10: 9: 1) mass spectrum: (MH) ^" = 453

Example 240

trans-3- (naphth-2-yl) but-2-enoic acid-N- {2-carboxy-5- [N- (2-acyl-aminoethyl) aminocarbonyl-1-phenyl} -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-ene-acid N- {2-methoxycarbonyl-5- [N- (2-acetylaminoethyl) aminocarbonyl] phenyl} amide and lithium hydroxide in tetrahydrofuran / water.

Yield: 100% of theory, C _2ε H ₂₅ N ₃ 0 ₅ (459.50)

R _f value: 0.2 (silica gel; dichloromethane / ethanol = 3: 1) mass spectrum: (MH) ^" = 458

At p l 241

trans-3- (naphth-2-yl) -but-2 -enoic acid-N- {2 -carboxy-5- [N- (piperid-n-4-ylmethyl) aminocarbonyl 1 -phenyl} -am d-tri fluoroacetate Prepared analogously to Example 163 from trans-3- (naphth-2-yl) -but- 2 -enoic acid-N- {2-carboxy-5- [N- (1-tert. butoxycarbonyl-piperidine- 4 -ylmethyl) aminocarbonyl] phenyl} amide and trifluoroacetic acid in dichloromethane. Yield: 98% of theory, C ₂₈ H ₂₉ N ₃ 0 ₄ x CF-COOH (471.58 / 585.58)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 4: 1) mass spectrum: (MH) ^" = 470

(M + HX = 472

At game 242

trans-3 - (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-5-pyrrolidinophenyl) amide

Manufactured analogously to example 2 from trans-3- (naphth-2-yl) -but-

2-enoic acid-N- (2-methoxycarbonyl-5-pyrrolidino-phenyl) -amide and

Potash lye in tetrahydrofuran.

Yield: 41% of theory,

C ₂₅ H ₂₄ N ₂ 0 ₃ (400.48)

R _f value: 0.3 (silica gel; dichloromethane / ethanol = 49: 1)

Mass spectrum: (MH) ^" = 399

Example 243

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-5-isopropyl-mi no-phenyl) -ami d

Manufactured analogously to Example 2 from trans-3- (naphth-2-yl) -but-2-enoic acid N- (2-methoxycarbonyl-5-isopropylamino-phenyl) -amide and potassium hydroxide solution in tetrahydrofuran. Yield: 83% of theory, C ₂₄ H ₂₄ N ₂ 0 ₃ (388.47)

R _f value: 0.4 (silica gel; dichloromethane / ethanol = 19: 1) mass spectrum: (MH) ^" = 387

M ⁺ = 388 Example 244

trans-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-5-propylamino-no-phenyl) -ami d

Manufactured analogously to example 2 from trans-3- (naphth-2-yl) -but -

2 -ene acid-N- (2-methoxycarbonyl-5-propylamino-phenyl) -amide and

Potash lye in methanol.

Yield: 74% of theory,

C ₂₄ H ₂₄ N ₂ 0 ₃ (388.47)

R _f value: 0.4 (silica gel; dichloromethane / ethanol = 19: 1)

Mass spectrum: (MH) ^" = 387

At sp el 245

tranε-3- (naphth-2-yl) -but-2-enoic acid-N- (2-carboxy-5-morpholino-phenyl) -amide

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2 -enoic acid-N- (2-methoxycarbonyl-5-morpholino-phenyl) -amide and

Potash lye in methanol.

Yield: 71% of theory,

C ₂₅ H ₂₄ N ₂ 0 ₃ (416.48)

R _£ value: 0.6 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 415

Example 246

trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-5-phenylamino-phenyl) -ami

Prepared analogously to Example 2 from trans-3- (naphth-2-yl) -but-

2-ene acid-N- (2-methoxycarbonyl-5-phenylamino-phenyl) -amide and

Potash lye in methanol.

Yield: 97% of theory,

C ₂₇ H ₂₂ N ₂ 0 ₃ (422.49)

R _f value: 0.79 (silica gel; dichloromethane / ethanol = 9: 1)

Mass spectrum: (MH) ^" = 421 Example 247

trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (3-dimethylamino-prop-1-ynyl) phenyl amide

Prepared analogously to Example 2 from trans-3 - (naphth-2-yl) -but-2-enoic acid-N- [2-methoxycarbonyl -5- (3-dimethylamino-prop-1-ynyl) -phenyl] -amide and lithium hydroxide in a mixture of tetrahydrofuran and water. Yield: 82% of theory, C ₂₆ H ₂₄ N ₂ 0 ₃ (412.49)

R _f value: 0.22 (silica gel; dichloromethane / ethanol = 4: 1) mass spectrum: (MH) ^" = 411

(M + H) ⁺ = 413 M ⁺ = 412

At game 248

trans -3 - (isoquinolin-3-yl) -but -2 -enoic acid-N- (2-carboxy-phenyl) ami d

Manufactured analogously to Example 2 from trans-3 - (isoquinolin-3-yl) -but-2-enoic acid-N- (2-methoxycarbonyl-phenyl) -amide and lithium hydroxide in a mixture of tetrahydrofuran and water. Yield: 69% of theory, C ₂₀ H _ιε N ₂ O ₃ (332.36)

R _f value: 0.48 (silica gel; dichloromethane / ethanol = 9: 1) mass spectrum: (MH) ^" = 331

(M + H) ⁺ = 333 M + Na) ⁺ = 355

Example 249

Tablets containing 50 mg of active ingredient r

Active ingredient 50.0 mg

Calcium phosphate 70.0 mg

Milk sugar 40.0 mg May strength 35.0 mg

Polyvinylpyrrolidone 3.5 mg

Magnesium stearate 1.5 mg

200.0 mg

Manufacture:

The active ingredient, CaHPO4, milk sugar and corn starch are moistened evenly with an aqueous PVP solution. The mass is passed through a 2 mm sieve, dried in a forced-air drying cabinet at 50 ° C. and sieved again.

After the lubricant has been mixed in, the granules are pressed on a tabletting machine.

Example 250

Dragees containing 50 mg of active ingredient

Active ingredient 50.0 mg

Lysine 25.0 mg

Milk sugar 60.0 mg

May strength 34.0 mg

Gelatin '10.0 mg

Magnesium stearate 1.0 mg

180.0 mg

Manufacture length:

The active ingredient is mixed with the excipients and moistened with an aqueous gelatin solution. After sieving and drying, the granulate is mixed with magnesium stearate and pressed into cores.

The cores produced in this way are coated with a shell by known methods. Colorant can be added to the coating suspension or solution. Example 251

Dragees containing 100 mg of active ingredient

Active ingredient 100.0 mg

Lysine 50.0 mg

Milk sugar 86.0 mg

Corn starch 50.0 mg

Polyvinyl pyrrolidone 2.8 mg

Microcrystalline cellulose 60.0 mg

Magnesium stearate 1.2 mg

350.0 mg

Manufacture:

The active ingredient is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm sieve and dried at 45 ° C. After drying, sieving is carried out again and magnesium tearate is added. This mixture is pressed into cores.

The cores produced in this way are covered with a casing by known processes. Dyes can be added to the coating suspension or solution.

Example 252

Capsules containing 250 mg of active ingredient

Active ingredient 250.0 mg

Corn starch 68.5 mg

Magnesium stearate 1.5 mg

320.0 mg Manufacture 1 ung •

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

Claims

Patent claims 1. Use of the carboxylic acid amides of the general formula in the R _{x is} a hydrogen atom, a, ^ - alkyl or trifluoromethyl group, R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C ^ -, - alkyl, C ₃ . _7- cycloalkyl or C ₁ . ₃ -alkoxy group or also if R ₄ and R _s each represent a hydrogen atom, R _x and R ₂ together represent an nC ^ - _j -alkylene group optionally substituted by a C ^ -alkyl group, R _{3 is} a hydrogen atom or a C 1-4 alkyl group, R ₄ and R ₅ each represent a hydrogen atom or together a further carbon-carbon bond, A one through a fluorine, chlorine, bromine or iodine atom, through a C _1-6 alkyl, C ₃ . _7- cycloalkyl, phenyl, C _1-3 alkoxy, cyano, trifluoromethyl or nitro group substituted phenyl, naphthyl or tetrahydronaphthyl group, the aforementioned monosubstituted phenyl and naphthyl groups additionally by a fluorine, chlorine - or bromine atom, by a C ^ alkyl or C _x . ₃ -alkoxy group and the abovementioned disubstituted phenyl groups additionally by a C ₁ . ₃ -Alkyl- or C ^ -alkoxy group can be substituted, a naphthyl group, a chroman or chromene group in which a methylene group can be replaced by a carbonyl group, optionally in the carbon device by a fluorine, chlorine or bromine atom, by a C _x . _3- alkyl or C ^ - alkoxy group substituted 5- or 6-membered heteroaryl group, the 6-membered heteroaryl groups having one, two or three nitrogen atoms and the 5-membered heteroaryl group, one optionally substituted by a C _1-3 alkyl group Contain imino group, an oxygen or sulfur atom or an imino group optionally substituted by a C _1-3 alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and, in addition, a phenyl ring can be fused to the abovementioned monocyclic heteroaryl groups via two adjacent carbon atoms, which is also in the carbon structure by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl or C ₁ . ₃ -alkoxy group can be substituted, a phenyl vinyl group or R _x together with A and the carbon atom in between is a C ₅ . _7- cycloalkylidene group, to which a phenyl ring can be fused via two adjacent carbon atoms, which can additionally be substituted by one or two C 1-4 alkyl or C 1-4 alkoxy groups, where the substituents can be the same or different, and B is a 5- or 6-membered heteroaryl group substituted by a carboxy group or by a group which can be converted into a carboxy group in vivo, a phenyl or naphthyl group, each converted by a carboxy group, by an in vivo carboxy group bare group or may be substituted by a group negatively charged under physiological conditions, the above-mentioned phenyl groups additionally by a fluorine, chlorine, bromine or iodine atom, by a C ^ alkyl, trifluoromethyl, phenyl, hydroxy, C ₁ . ₃ -alkoxy-, C _x _ ₃ -alkylsulfonyloxy-, phenylsulfonyloxy-, carboxy-, C _! .3 -alkoxycarbonyl-, formyl-, C ₁ _3 ~ alkylcarbonyl-, Ci ..3-alkylsulfonyl-, phenylsulfonyl-, nitro-, pyrrolidino-, piperidino-, morpholino-, N- (C ^ -alkyl) - piperazino, aminosulfonyl, C 1-4 alkylaminosulfonyl or di- (Ci. ₃ alkyl) -aminosulfonyl group, by a C _ ₃ alkyl group, which is replaced by a hydroxy, C ^ - alkoxy, amino, C ₁ . ₄ alkylamino, di (C 1-4 alkyl) amino, C ₃ . ₇ cycloalkylamino, pyrrolidino, piperidino, morpholino, piperazino or N- (C ^ - _j alkyl) -piperazinogruppe is εubstituiert, by a nC ₂ substituted in the 2- or 3-position by a di- (C - ^ - alkyl) - amino group. ₃ -alkoxy-, C ₂ . ₃ alkenyl or C ₂ . ₃ -alkynyl group, by an amino group, by an N- (C ^ -alkyl) -amino- or N, N-di- (C _x . ₃ -alkyl) -amino group in which the alkyl part in the 2- or 3-position based on the Nitrogen atom through a C ₁ . ₃ -alkoxy group may be substituted by an N-phenylamino, N- (phenyl-C _1-3 -alkyl) -amino or N- (pyridyl-C _1-3 -lkyl) -amino group, in each of which a water atom the above-mentioned amino groups by a C ^ alkylsulfonyl, phenyl-C ^ alkylsulfonyl or phenylsulfonyl group or by a C _1-7 -alkyl group, which in 2- to 5-position by a C ^ - _ä alkoxy, cyano -, amino, ^ alkylamino, di- (C _{1 3} alkyl.) -amino or tetrazolyl group may be replaced, by an aminocarbonyl or C ₁ . ₃ -Alkylaminocarbonyl- group, each on the amine nitrogen atom by a C _1-4 alkyl group which is replaced by a vinyl, ethyl, phenyl, pyridyl, imidazolyl, carboxy or trifluoromethyl group or, with the exception of the 2 position, based on the aminocarbonyl nitrogen atom by a hydroxy , C ₁ . ₃ -alkoxy-, C _1-3 -alkylthio-, amino-, C ^ -alkyl- amino-, di- (C - ^ - alkyl) -amino-, C ^ -alkanoylamino- or C _x . ₅ -alkoxycarbonylamino group can be substituted, by a C ₃ . _7- cycloalkyl, C _s . ₉ -Azabicycloalkyl-, phenyl-, pyridyl-, C ₁ . ₃ -alkoxy or di- (C 1-4 -alkyl) amino group, by a C 1-4 alkyl group, which may be replaced by a C 1-4 alkyl or C ₁ . ₅ -alkoxycarbonyl group substituted piperidin-3-yl or piperidin-4 -yl group is substituted, or by a C _1, optionally on the amine nitrogen atom. ₄ -alkanoyl-, C _{λ- s} -alkoxycarbonyl-, benzoyl-, pyrrolidino-, piperidino-, morpholino- or N- (C _{1, 3} -alkyl) -piperazino group substituted amino-, C ₁ . ₃ -alkylamino or phenyl-C - ^ - alkylamino group may be substituted, carbonyl group substituted by a pyrrolidino, pyrrolino, piperidino, morpholino or N- (C _1-3 -alkyl) -piperazino group, sulfonyl group substituted by an amino, C - ^ - alkylamino, di- (C ^ - _j -alkyl) -amino, pyrrolidino, piperidino, morpholino or N- (C _1-3 -alkyl) - piperazino group, , amino group by an amino or N- (C _{1. 3,} alkyl) each on Aminstickεtoffatom by an aminocarbonyl, C _1.3 alkylaminocarbonyl, phenyl -C ^ alkylaminocarbonyl, Phenylaminocarbonyl, phenoxyphenylaminocarbonyl, pyridyl - aminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl or N- (C - ^ - alkyl) -piperazinocarbonyl group is substituted, wherein in the above-mentioned aminocarbonyl groups an existing water atom is additionally substituted by a carbon atom Alkyl group can be substituted, by a 5- or 6-membered heteroaryl group, by a dihydro-oxazolyl, dihydro-imidazolyl, 2-oxo-pyrrolidino, 2-oxo-piperidino or 2-oxo-hexamethylene imino group, to which a phenyl ring can be fused via two adjacent carbon atoms, can be substituted by an ethynyl group substituted by a phenyl, hydroxymethyl or dimethylamino group, where additionally the above-mentioned mono- or disubstituted phenyl groups by a further fluorine, chlorine or bromine atom or by one or two further C _λ . ₃ -Alkyl- or C ^ - _j -alkoxy groups substituted and two o-C ^ -alkoxy groups can be replaced by a methylenedioxy group, and the above-mentioned 6-membered heteroaryl groups have one, two or three nitrogen atoms and the above-mentioned 5-membered heteroaryl groups have an imino group optionally substituted by a C 1-4 alkyl group, an oxygen or sulfur atom or one optionally substituted by a C ₁ . _3- alkyl group-substituted imino group and an oxygen or sulfur atom or one or two nitrogen atoms and in addition to the above-mentioned monocyclic heteroaryl groups, a phenyl ring can be fused onto two adjacent carbon atoms, which can be formed in the carbon structure by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl or can be substituted, the pre- -mentioned 5-membered monocyclic heteroaryl groups in Kohlenstoffgerüεt zuεätzlich by _{Cι_-C4} alkyl, tri- fluoromethyl, phenyl or furanyl group and may be substituted by a How-tere _C] __3 alkyl group, mean, the amino and imino groups mentioned in the definition of the abovementioned radicals additionally being able to be substituted by an in vivo cleavable residue, their isomers and their salts, in particular their physiologically tolerable salts, for the inhibition of telomerase. 2. carboxylic acid amides of the general formula I according to claim 1, in which R _{1 is} a hydrogen atom, a C _1-3 alkyl or trifluoromethyl group, R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C ₁ . ₃ -alkyl-, C ₃ . _7- cycloalkyl or C ₁ . ₃ -alkoxy group or also if R ₄ and R ₅ each represent a hydrogen atom, R _x and R ₂ together form an nC ^ -alkylene group which is optionally substituted by a ^ -alkyl group, R _{3 is} a hydrogen atom or a C _1-5 alkyl group, R ₄ and R ₅ each represent a hydrogen atom or together a further carbon-carbon bond, A one through a fluorine, chlorine, bromine or iodine atom, through a C ₁ . ₆ -alkyl-, C ₃ . _7- cycloalkyl, phenyl, C ₁ . ₃ -alkoxy, cyano, trifluoromethyl or nitro group substituted phenyl, naphthyl or tetrahydronaphthyl group, the above-mentioned monosubstituted phenyl and naphthyl groups additionally by a fluorine, chlorine or bromine atom, by a C - ^ - Al - kyl or C _1-3 alkoxy group and the disub- mentioned above substituted phenyl groups may additionally be substituted by a C 1-4 alkyl or C 1-4 alkoxy group, with the proviso that A does not represent a phenyl group which is replaced by a halogen atom, by a methyl, pentyl, C 1 -C alkoxy or phenyl group or by two C ₁ . ₃ alkoxy groups are substituted if R _{3 is} a hydrogen atom, R ₄ and R ₅ each represent a hydrogen atom or R ₄ and R ₅ together another carbon-carbon Bond and B represents a carboxyphenyl or methoxycarbonylphenyl group, and A does not represent a phenyl group substituted by a methyl or phenyl group when R ₁ and R ₂ each represent a hydrogen atom, R _{3 is} a hydrogen atom, R ₄ and R ₅ together another carbon-carbon Bond and B represents a carboxyphenyl or methoxycarbonylphenyl group, a naphthyl group, a chroman or chromene group in which a methylene group can be replaced by a carbonyl group, optionally in the carbon structure by a fluorine, chlorine or bromine atom, by a C ₁ . _3- alkyl or C _1-3 - alkoxy group substituted 5- or 6-membered heteroaryl group, the 6-membered heteroaryl groups having one, two or three nitrogen atoms and the 5-membered heteroaryl group, one optionally substituted by a C ₃ alkyl group Imino group, an oxygen or sulfur atom or an imino group optionally substituted by a C 1-4 alkyl group and contain an oxygen or sulfur atom or one or two nitrogen atoms and, in addition, a phenyl ring can be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, which phenol ring is also in the carbon structure by a fluorine, chlorine or bromine atom, by a C 1-4 alkyl or C ^ -Alkoxy group may be substituted, a phenyl vinyl group or R ₁ together with A and the carbon atom in between is a C _s . _7- cycloalkylidene group, to which a phenyl ring can be fused via two adjacent carbon atoms, which is additionally substituted by one or two C 1-4 alkyl or C ₁ . ₃ -alkoxy groups may be substituted, where the substituents may be the same or different, and B is a 5- or 6-membered heteroaryl group substituted by a carbox group or by a group which can be converted into a carboxy group in vivo, a phenyl or naphthyl group, each of which may be substituted by a carboxy group, by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions, the phenyl groups mentioned above additionally by a fluorine, chlorine, bromine or iodine atom, by a C ₁ . ₃ -Alkyl-, trifluoromethyl-, phenyl-, hydroxy-, C- _L .- _j -alkoxy-, C _1-3 -alkylεulfonyloxy-, phenylεulfonyloxy-, carboxy-, C _] __3 -alkoxycarbonyl-, formyl-, C ^ _3 -Alkylcarbonyl-, Cι_3-Alkylεulfonyl-, Phenylεulfonyl-, Nitro-, Pyrrolidino-, Piperidino-, Morpholino-, N- (C _{1, 3} -Alkyl) -piperazino-, Aminoεulfonyl-, C - ^ - Alkylaminoεulfonyl- or di- (C 1-4 alkyl) aminosulfonyl group, by a C _1-3 alkyl group which is formed by a hydroxy, C ₁ . ₃ -alkoxy-, amino-, C _1-4 -alkylamino-, di- (c _1-4 -alkyl) -amino-, C ₃ . _7- cycloalkylamino, pyrrolidino, piperidino, morpholino, piperazino or N- (C _x . ₃ -alkyl) -piperazino group is substituted, by a nC ₂ substituted in the 2- or 3-position by a di- (C _1.3 alkyl) amino group. ₃ alkoxy, C ₂ _ ₃ alkenyl or C ₂ . ₃ -alkynyl group, by an amino group, by an N- (C ^ alkyl) -amino or N, N-di- (C _ ₃ -alkyl) -amino group, in which the alkyl part in each case in the 2- or 3-position based on the nitrogen atom by a C ₁ . ₃ -alkoxy group can be substituted by an N-phenylamino, N- (phenyl-C _1-3 -alkyl) -amino or N- (pyridyl-C ^ -alkyl) -amino group, in each of which a hydrogen atom of the above mentioned amino groups by a C ₁ . ₃ -Alkylsulfonyl-, Phenyl-C _1-3 -alkylsulfonyl- or Phenylεulfonylgruppe or by a C _1-7 -alkyl group, which in 2- to 2-5-position by a C ₁ . ₃ -alkoxy, cyano, amino, C ^ alkylamino, di- (C ^ - _j alkyl) -amino or tetrazolyl group may be erεetzt, by an aminocarbonyl or C 1-4 alkylaminocarbonyl group, each on the amine nitrogen atom by a C 1-4 alkyl group, by a vinyl, ethyl, phenyl, pyridyl, imidazolyl, carboxy or trifluoromethyl group or with the exception of the 2-position based on the amino carbonyl atom by a hydroxy, C ^ -Alkoxy-, C - ^ - alkylthio-, amino-, ^ -alkylamino-, di- (C _x . ₃ -alkyl) -amino-, C _1-4 -alkanoylamino- or Ci. _g -alkoxycarbonylamino group may be substituted, by a C ₃ . _7- cycloalkyl, C _s . ₉ -azabicycloalkyl-, phenyl-, pyridyl-, or di (C _x . ₃ alkyl) amino group, by a C 1-4 alkyl group, which may be replaced by a C ₁ . _3- alkyl or C ^ -alkoxycarbonyl group substituted piperidin-3-yl or piperidin-4 -yl group is substituted, or by an optionally on the amine nitrogen atom by a , Benzoyl, pyrrolidino, piperidino, morpholino or N- (C ^ -alkyl) -piperazino group ε-substituted amino, C ₁ . ₃ -alkyl- amino- or phenyl-C 1-4 -alkylamino group may be substituted, carbonyl group substituted by a pyrrolidino, pyrrolino, piperidino, morpholino or N- (C - ^ - alkyl) -piperazino group, by an amino, C _x . _3- alkylamino, di- (C 1-4 alkyl) amino, pyrrolidino, piperidino, morpholino or N- (C 1-4 alkyl) piperazino group substituted sulfonyl group, by an amino or N- (C _{1, 3} -alkyl) -amino group, each of which on the amine nitrogen atom by an aminocarbonyl, C ₁ . ₃ alkylaminocarbonyl, phenyl-C ^ alkylaminocarbonyl, aminocarbonyl phenylaminocarbonyl, Phenoxyphenylaminocarbonyl-, pyridyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl or N- (C _{1. 3,} alkyl) -piperazinocarbonyl- group, in which additionally an existing hydrogen atom of one of the abovementioned aminocarbonyl groups by means of a C ₁ . ₃ -alkyl group may be substituted, is substituted, by a 5- or 6-membered heteroaryl group, by a dihydro-oxazolyl-, dihydro-imidazolyl-, 2-oxo-pyrrolidino-, 2-oxo-piperidino- or 2-oxo-hexamethylene- imino group to which a phenyl ring can be fused via two adjacent carbon atoms, may be substituted by an ethynyl group substituted by a phenyl, hydroxymethyl or dimethylamino group, where in addition, the substituted alkoxy groups _1-3 above-mentioned mono- or disubstituted phenyl groups by a weitereε fluorine, chlorine or bromine atom or by one or two C ^ _j alkyl or C and two o-constant C ^ -alk - Oxy groups can be replaced by a methylenedioxy group, and the above-mentioned 6-membered heteroaryl groups have one, two or three nitrogen atoms and the above-mentioned 5-membered heteroaryl groups have an imino group optionally substituted by a C 1-4 alkyl group, an oxygen or sulfur atom or, if appropriate, a C ₁ . Contain _3- alkyl group-substituted imino group and an oxygen or sulfur atom or one or two nitrogen atoms and in addition to the above-mentioned monocyclic heteroaryl groups a phenyl ring may be fused onto two adjacent carbon atoms, which may be condensed in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C ₁ . ₃ -Alkyl- or C - ^ - alkoxy group can be substituted, the above-mentioned 5-membered monocyclic heteroaryl groups in the carbon skeleton additionally by C _} _.4 -alkyl, trifluoromethyl, phenyl or furanyl group and by a like tere C] __ 3 alkyl group may be substituted, and the amino and imino groups mentioned in the definition of the abovementioned radicals can additionally be substituted by a radical which can be split off in vivo, their isomers and their salts. 3. carboxylic acid amides of the general formula I according to claim 1, in which B and R2 to R5 are defined as mentioned in claim 2, Rl is a hydrogen atom or a C _] _-3 alkyl group and A one by a fluorine, chlorine, bromine or iodine atom, by a C _x _ ₆ alkyl, C ₃ . _7- Cycloalkyl, phenyl, C ^., - Alkoxy, trifluoromethyl or nitro group substituted phenyl, naphthyl or tetrahydronaphthyl group, the above-mentioned monosubstituted phenyl and naphthyl groups additionally by a fluorine, chlorine or bromine atom , by a C _1-3 alkyl or C ₁ . ₃ -alkoxy group can be substituted, with the proviso that A is not a phenyl group which is formed by halogen atoms, C ₁ . ₄ -Alkyl- or C ₁ _ ₃ -alkoxy groups can be mono- or di-substituted, where the substituents can be the same or different, does not represent a 4-biphenyl or pentylphenyl group if R _x and R ₂ each represent a hydrogen atom or a C _x _ ₄ alkyl group, R _{3 is} a hydrogen atom, R ₄ and R ₅ each represent a hydrogen atom or R ₄ and R ₅ together a further carbon-carbon bond and B represents a carboxyphenyl or methoxycarbonylphenyl group, a naphthyl group, a chroman or chromene group in which a methylene group can be replaced by a carbonyl group, one in the carbon skeleton, if appropriate by a fluorine, chlorine or bromine atom, by a C 1-4 alkyl or C ₁ . _3- alkoxy group substituted 5- or 6-membered heteroaryl group, the 6-membered heteroaryl groups having one, two or three nitrogen atoms and the 5-membered heteroaryl group an imino group optionally substituted by a C _λ _ ₃ alkyl group, an oxygen or sulfur atom or optionally contain an imino group substituted by a C 1-4 alkyl group and an oxygen or sulfur atom or one or two nitrogen atoms and, in addition to the abovementioned monocyclic heteroaryl groups, a phenyl ring which can also be condensed in the fluorine by means of two adjacent carbon atoms , Chlorine or bromine atom, which may be substituted by a C 1-4 alkyl or C 1-4 alkoxy group, their isomers and their salts. 4. carboxylic acid amides of the general formula I according to claim 1, in which R _{x is} a hydrogen atom or a C ₁ . ₃ -alkyl group, R _{2 is} a hydrogen atom or a methyl group or, if R ₄ and R ₅ each represent a hydrogen atom, R _x and R ₂ together form a methylene bridge, R _{3 is} a hydrogen atom or a _λ , ₅ alkyl group. R ₄ and R ₅ together form a further carbon-carbon bond, A one by a fluorine, chlorine, bromine or iodine atom, by a C ₁ . _s -alkyl, cyclohexyl, phenyl, methoxy, cyano or trifluoromethyl group substituted phenyl group, a phenyl group substituted by fluorine, chlorine or bromine atoms, by methyl or methoxy groups, where the substituents can be the same or different, or a C 1-4 alkylphenyl group which is disubstituted by fluorine, chlorine or bromine atoms, where the substituents can be the same or different, with the proviso that A does not represent a phenyl group which is replaced by a halogen atom, by a methyl, pentyl, C 1 -C alkoxy or phenyl group or by two C ₁ . ₃ alkoxy groups are substituted if R _{3 is} a hydrogen atom, R ₄ and R ₅ each represent a hydrogen atom or R ₄ and R ₅ together another carbon-carbon Bond and B represents a carboxyphenyl or methoxycarbonylphenyl group, and A does not represent a phenyl group substituted by a methyl or phenyl group when R _x and R ₂ each represent a hydrogen atom, R _{3 is} a hydrogen atom, R ₄ and R ₅ together form a further carbon-carbon Bond and B represents a carboxyphenyl or methoxycarbonylphenyl group, a naphthyl group optionally substituted by a fluorine, chlorine or bromine atom, by a methyl or methoxy group, a tetrahydronaphthyl group, a chromene group in which a methylene group has been replaced by a carbonyl group, an optionally substituted by a methyl group pyridyl, benzofuryl, benzothienyl, quinolyl or isoquinylyl group and B is a cyclohexyl, trimethoxyphenyl, methylenedioxyphenyl, naphthyl, pyridyl, thienyl, pyrazolyl, quinolyl or isoquinolyl group substituted by a carboxy group, a phenyl group substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl, hydroxymethyl, sulfo, tetrazolyl, methylsulfonylaminocarbonyl or phenylsulfonylaminocarbonyl group, which additionally by a fluorine, chlorine, bromine or iodine atom, by a methyl, trifluoromethyl, phenyl, hydroxymethyl, hydroxy, methoxy, methylεulfonyloxy, 2-dimethylamino-ethoxy, carboxy, nitro, methylεulfonylamino, phenylsulfonylamino, aminosulfonyl, pyrrolidino, Piperidino or morpholino group, by a methyl group which is substituted by an amino, C _1-3 alkylamino, cyclopentylamino, pyrrolidino or piperidino group, by an amino, N-methyl-amino or N- (2-methoxyethyl) amino group, each on the amine nitrogen atom by a C _1-7 alkyl or phenyl group, by an ethyl group which is substituted in the 1- or 2-position by a phenyl or pyridyl group, by a C _2-4 alkyl group which is terminally substituted by a methoxy, cyano, dimethylamino or tetrazolyl group, by an acetyl, benzoyl, C ₁ . ₅ -alkoxycarbonyl, aminocarbonyl or methylaminocarbonyl group, where the aminocarbonyl part of the above-mentioned groups can each additionally be substituted by a C 1-4 alkyl group optionally substituted by a phenyl group, by a phenyl, phenoxyphenyl or pyridyl group, can be substituted by a methylsulfonyl, phenylsulfonyl or benzylsulfonyl group, by an aminocarbonyl or methylaminocarbonyl group, each on the amine nitrogen atom by a C _1-4 alkyl, C ₃ . ₆ -cycloalkyl, phenyl, benzyl, pyridyl, pyridylmethyl or methoxy group, by a methyl group by a vinyl, ethynyl, trifluoromethyl, C ₇ . ₉ -azabicycloalkyl, carboxy or imidazolyl group or by a piperidin-4-yl group which is optionally substituted in the 1-position by a methyl or C 1-4 alkoxycarbonyl group, by a straight-chain or branched C ₂ . ₃ -alkyl group, in the 2- or 3-position by a hydroxy, methoxy, methylthio, amino, acetylamino, C ^ alkoxycarbonylamino, carboxy, C _λ . _s -alkoxycarbonyl or dimethylamino group is substituted, can be substituted by a pyrrolidino, piperidino, morpholino, methyl-piperazino, amino or methylamino group, the abovementioned amino and methylamino group in each case on the amine nitrogen atom additionally by a methyl, acetyl, benzoyl or C _{1 .s} -Alk- oxycarbonyl group can be substituted, by a dihydro-oxazolyl, dihydro-imidazolyl, 2-oxo-pyrrolidino, 2-oxo-piperidino or 2-oxo-hexamethylene imino group, to which a phenyl ring can be fused via two adjacent carbon atoms, by an imidazolyl or 4-methylimidazolyl group, optionally substituted by a methyl, ethyl or phenyl group, to which a phenyl ring may additionally be fused via two adjacent carbon atoms, one optionally by a C _x . ₄ -alkyl or furanyl group substituted pyrazolyl group, which may additionally be substituted by a methyl or trifluoromethyl group, by an ethynyl group substituted by a phenyl, hydroxymethyl or dimethylamino group, where the above-mentioned mono- or disubstituted phenyl groups may additionally be substituted by a further fluorine, chlorine or bromine atom or by one or two further methyl or methoxy groups, mean their isomers and their salts. 5. carboxylic acid amides of the general formula I according to claim 1, in which R _{x is} a hydrogen atom or a C 1-4 alkyl group, R _{2 is} a hydrogen atom or R. ^ and R ₂ together are a methylene group if R ₄ and R ₅ are each a hydrogen atom, R _{3 is} a hydrogen atom, R ₄ and R ₅ together form a further carbon-carbon bond, A one by a fluorine, chlorine, bromine or iodine atom, by a C ₁ . ₆ -alkyl-, C ₃ . _7- cycloalkyl or trifluoromethyl group mono- or disubstituted phenyl or naphthyl group, where the substituents may be the same or different, with the proviso that A is not a phenyl group, which can be mono- or disubstituted by halogen atoms or C _x _ ₄ -alkyl groups, where the substituents can be the same or different, does not represent a 4-biphenyl or pentylphenyl group, if R _{x is} a hydrogen atom or a C ₁ . ₃ -alkyl group, R _{2 is} a hydrogen atom, R _{3 is} a hydrogen atom, R ₄ and R ₅ each represent a hydrogen atom or R ₄ and R _s together form a further carbon-carbon Bond and B represents a carboxyphenyl or methoxycarbonylphenyl group, a naphthyl group, a chromene group in which a methylene group is replaced by a carbonyl group, a benzothienyl group and B is a phenyl, naphthyl, thienyl or pyridinyl group, each of which is substituted by a carboxy group, the phenyl groups mentioned above additionally by a fluorine, chlorine or bromine atom, by a C ^ alkyl, hydroxy, C ₁ . ₃ -alkoxy-, ^ .-- alkylsulfonyloxy, pyrrolidino, piperidino, morpholino or N- (C ^ -alkyl) -piperazino group, by a nC ₂ substituted in the 2- or 3-position by a di- (C _1.3 alkyl) amino group. ₃ -alkoxy-, C ₂ . _3- alkenyl or C ₂ _ ₃ -alkynyl group, by an N-methyl-N- (nC _2.3 -alkyl) -amino group substituted in the 2- or 3-position by a di- (C _1.3 -alkyl) amino group, by a di (C _{1, 3} alkyl) amino group, by a possibly by a C _x . ₄ -alkyl group substituted imidazolyl or pyrazolyl group, by a C _1-4 alkylaminocarbonyl, N- (pyridinylmethyl) aminocarbonyl, pyrrolidinoaminocarbonyl or piperidinoaminocarbonyl group and additionally by a further fluorine atom, by a further C 1-4 alkyl or C ₁ . ₃ -alkoxy group can be substituted, mean their isomers and their salts. 6. carboxylic acid amides of the general formula I according to claim 1, in which R is a methyl group, R _{2 is} a hydrogen atom, R _{3 is} a hydrogen atom, R ₄ and R ₅ together form a further carbon-carbon bond, A is a phenyl group substituted by two chlorine or bromine atoms or by a chlorine atom and a bromine atom, a naphthyl, 2-oxo-chromene or benzothienyl group with the proviso that A does not represent a phenyl group which is disubstituted by halogen atoms if R _{x is} a methyl group, R _{2 is} a hydrogen atom, R _{3 is} a hydrogen atom, R ₄ and R ₅ each represent a hydrogen atom or R ₄ and R ₅ together form a further carbon-carbon Bond and B represents a carboxyphenyl or methoxycarbonylphenyl group, and B represents a 2-carboxy-phenyl, 2-carboxy-thienyl or 2-carboxypyridinyl group, the above-mentioned 2-carboxy-phenyl group additionally being in the phenyl nucleus by a fluorine, chlorine or bromine atom, by a C ^ alkyl, hydroxy, C - ^ - alkoxy, C _1-3 alkylsulfonyloxy or morpholino group, by a nC ₂ substituted in the 2- or 3-position by a di- (C 1-4 alkyl) - amino group. ₃ -alkoxy group, by a N- methyl-N- (nC _{2. 3} -alkyl) amino group substituted in the 2- or 3-position by a di- (C _{1. 3} -alkyl) amino group, by an imidazolyl or pyrazolyl group optionally substituted by a C 1-4 alkyl group, by a C 1-4 alkylaminocarbonyl, N- (pyridinylmethyl) aminocarbonyl, pyrrolidinoaminocarbonyl or piperidinoaminocarbonyl group and can additionally be substituted by a further fluorine atom or by a further methoxy group, their isomers and their salts. 7. The following compounds of general formula I according to claim 2: (1) trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxyphenyl) amide, (2) trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4,5-di-methoxy-phenyl) -amide, (3) trans-3- (naphth-2-yl) -but-2-ene-acid- N- (2-carboxy-4-fluorophenyl) amide, (4) tranε-3- (naphth-2-yl) -but-2-ene-acid- N- (2-carboxy-4, 5-di-fluorophenyl) amide, (5) trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-5-fluorophenyl) amide, (6) trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-4-methoxy-5-methylphenyl) amide, (7) tranε-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-4- (morpholin-4-yl) phenyl] amide, (8) trans-3- (naphth-2-yl) -but-2-ene-acid- N- (2-carboxy-4-dimethylamino-phenyl) -amide, (9) trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-4-hydroxy-phenyl) amide, (10) trans-3- (naphth-2-yl) but-2-enoic acid-N- (3-carboxy-thiophen-4-yl) amide, (11) tranε-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-4- (imizazol-1-yl) phenyl] amide, (12) trans-3- (2-oxo-2H-chromen-3-yl) but-2-enoic acid-N- (2-carboxy-phenyl) amide, (13) trans-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-4- (imizazol-1-yl) -5-fluorophenyl] amide, (14) trans-3- (benzthiophene-2-yl) but-2-enoic acid N- (2-carboxyphenyl) amide, (15) trans-3- (naphth-2-yl) but-2-enoic acid-N- (2-carboxy-4-methanesulfonyloxyphenyl) amide, (16) trans-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy- 4- (2-N, N-dimethylamino-ethyloxy) phenyl] amide, (17) trans-3- (naphth-2-yl) but-2-enoic acid-N- (4-carboxypyridin-3-yl) amide, (18) trans-3- (3, 4-dichlorophenyl) but-2-enoic acid-N- (2-carboxy-4, 5-dimethoxy-phenyl) -amide, (19) tranε-3- (3-chloro-4-bromophenyl) but-2-enoic acid N- (2-carboxy-phenyl) -amide, (20) tranε-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-6-methylphenyl) amide, (21) trans-3- (naphth-2-yl) but-2-enoic acid N- (2-carboxy-6-f luorphenyl) amide, (22) tranε-3- (naphth-2-yl) but-2-enoic acid N- [2-carboxy-5- (propyl aminocarbonyl) phenyl] amide, (23) trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (pyrrolidin-1-yl-aminocarbonyl) phenyl] amide, (24) trans-3- (naphth-2-yl) but-2-enoic acid-N- [2-carboxy-5- (N- (pyridin-3-yl-methyl) aminocarbonyl) phenyl] amide . (25) trans-3- (naphth-2-yl) -but-2-ene-acid- N- (2-carboxy-6-chlorophenyl) amide and their salts. 8. Physiologically acceptable salts of the compounds according to claims 2 to 7. 9. Medicament containing a compound according to at least one of claims 2 to 7 or a salt according to claim 8 in addition to optionally one or more inert carriers and / or diluents. 10. Use of a compound according to at least one of claims 1 to 7 or a salt according to claim 8 for the manufacture of a medicament with an inhibitory effect on telomerase, 11. A process for the manufacture of a medicament according to claim 9, characterized in that a compound according to at least one of claims 2 to 7 or a salt according to claim 8 is incorporated into one or more inert carriers and / or diluents in a non-chemical way. 12. A process for the preparation of the compounds according to claims 2 to 8, characterized in that a. an amine of the general formula R in the R ₃ and B are defined as mentioned in claims 2 to 7, with a carboxylic acid of the general formula in the R _lf R ₂ , R ₄ , R ₅ and A are defined as mentioned in claims 2 to 7, or are acylated with their reactive derivatives or b. for the preparation of a carboxamide of the general formula I which contains a carboxy group, a compound of the general formula in the R _x to R ₅ , A and B are defined with the proviso as mentioned in claims 2 to 7 that A or B or A and B contain a group which can be converted into a carboxy group, into a compound of the general formula I which has a carboxy group contains is transferred and if desired, a compound of the general formula I thus obtained, which contains a hydroxyl group, is converted into a corresponding sulfonyloxy compound by means of a sulfonyl halide and / or a compound of the general formula I thus obtained, which contains a cyano group, is converted into a corresponding tetrazolyl compound by means of nitrogenous acid and / or a compound of general formula I obtained in this way, which contains an amino or imino group with a basic hydrogen atom, is converted into a correspondingly acylated compound or into a corresponding pro-drug compound by means of acylation or sulfonylation and / or a compound of the general formula I thus obtained, which contains a carboxy group, is converted into a compound which contains a group which can be converted into a carboxy group in vivo, and / or a compound of the general formula I which contains one or two carboxy groups is converted by reduction into a compound which contains one or two hydroxymethyl groups and / or if necessary, a protective residue used during the reactions to protect reactive groups is split off and / or a compound of the general formula I thus obtained is separated into its isomers and / or a εo obtained compound of the general formula I in its salts, in particular for pharmaceutical use is converted into their physiologically acceptable salts.