DE10133665A1 - Carboxylic acid derivatives, medicaments containing these compounds, their use and preparation - Google Patents

Abstract

The invention relates to the use of carboxylic acid derivatives of general formula (I) R1 - A - B - R2, in which R1, R2, A and B are defined as per Claim No. 1, and to their isomers and salts, particularly their physiologically compatible salts, which have an inhibitory effect on the telomerase. The invention also relates to a method for producing said derivatives, to medicaments containing these compounds, and to their use and production thereof.

Description

The last decade of oncological research enabled for the first time a molecular understanding of the Tumor formation involved regulatory mechanisms. Such as the function of oncogenes, tumor suppressor genes, Growth factors, receptors, signal transduction cascades, pro- and anti-apoptotic genes, in the control of cell growth, Differentiation, migration and cell death. These new ones Findings also showed that cancer is a molecular factor multifactorial disease is during its onset Malignant tissues degenerate through different mechanisms can. This heterogeneity of the malignant cells in turn explains the clinical problems of tumor therapy.

As early as 1965, Hayflick (Hayflick, Exp. Cell Res. 32, 614-636 (1965)) postulates that the limited proliferative lifespan of normal somatic cells, the replicative senescence, act as a tumor suppressor mechanism can. This hypothesis was confirmed by experimental work supported, which showed that the replicative Senescence is a prerequisite for malignant transformation of cells (Newbold et., al. in Nature, 299, 633-636 (1989); Newbold and Overell in Nature, 304, 648-651 (1983)). However, understanding has only emerged in recent years of the molecular mechanisms due to which somatic cells achieve the state of replicative senescence.

The ends of eukaryotic chromosomes, the telomeres, exist from simple repetitive sequences, their integrity is essential for the function and structure of the chromosomes. However, linear chromosomes lose DNA every round Replication of a certain length of their telomeres, a phenomenon that Watson recognized as early as 1972 (Watson in Nature New Biol. 239, 197-201 (1972)). The cumulative loss of telomeres DNA across many cell divisions is the reason for the limited replicative potential of somatic cells, while more than 85% of all human tumors have an enzyme that Telomerase, reactivate to prevent the loss of telomeres compensate and thus become immortal (see Shay and Bacchetti in European Journal of Cancer, 33, 787-791 (1997)).

Human telomerase is a ribonucleoprotein (RNP) that consists of at least one catalytic subunit (hTERT), as well as an RNA (hTR). Both Components have been molecularly cloned and characterized. Biochemically, telomerase is a reverse transcriptase that unites one Sequence section in hTR used as a template to form a strand to synthesize the telomeric DNA (Morin in Cell 59, 521-529 (1989)). Methods to identify telomerase activity as also methods for diagnosis and therapy of replicative Senescence and immortality through modulation of the telomeres and Telomerase has been described (Morin in Cell 59, 521-529 (1989); Kim et al. in Science 266, 2011-2014 (1994)).

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

It has now been found that the carboxylic acid derivatives of the general formula

R ¹ -ABR ² (I)

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

In the above general formula I means
R ^{1 is} a phenyl, phenyl-C _1-3 alkyl, phenyl C _2-4 alkenyl or naphthyl group, in each of which the aromatic parts are represented by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl or C _1-3 alkoxy group can be mono- or disubstituted, where the substituents can be the same or different,
a phenyl group to which an n-propylene, n-butylene, methylenedioxy or ethylenedioxy bridge is fused onto two adjacent carbon atoms,
a phenyl group, to which a 5-membered heteroaromatic group is fused via two adjacent carbon atoms, in the heteroaromatic part
an imino group optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom,
an imino group optionally substituted by a C _1-3 alkyl group and an oxygen, sulfur or nitrogen atom,
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
a pyridinyl or pyronyl group optionally substituted by a C _1-3 alkyl group, to each of which a phenyl ring may be fused via two adjacent carbon atoms, with a methine group in the 2- or 4-position additionally being replaced by a hydroxymething group in the pyridine ring mentioned above can
A is a phenylene group optionally substituted by a C _1-3 alkyl group, in which one, two or three methine groups in the aromatic part can be replaced by nitrogen atoms, or
a 5-membered heteroarylene group optionally substituted by a C _1-3 alkyl group, the heteroaromatic part being defined as mentioned above,
B is a -HN-, -NH-CO-, -CO-NH-, -NH-CS or -CS-NH group, in which the -NH group can in each case be substituted by a C _1-3 alkyl group , and
R ^{2 is} a C _3-7 cycloalkyl or C _4-7 cycloalkenyl group substituted by a carboxy group,
a phenyl or naphthyl group substituted by a carboxy group, in each of which the aromatic part is substituted by a nitro, amino, C _1-3 alkyl amino, di (C _1-3 alkyl) amino, C _{1- 3} -alkanoylamino, N- (C _1-3 alkyl) -C _1-3 alkanoylamino or carboxy group, through an aminocarbonyl or C _1-3 alkylaminocarbonyl group, in each of which the hydrogen atom of the aminocarbonyl group is through a C _{1- 3} alkyl or C _3-7 cycloalkyleneimino group can be replaced, monosubstituted or by a fluorine, chlorine, bromine or iodine atom, mono- or disubstituted by a C _1-3 alkyl or C _1-3 alkoxy group where the substituents can be the same or different,
a 5- or 6-membered heteroaryl group substituted by a carboxy group, the 5-membered heteroaryl group being defined as mentioned above and
the 6-membered heteroaryl group contains one or two nitrogen atoms,
or a straight-chain or branched C _1-6 alkyl or C _2-6 alkenyl group substituted by a carboxy group,
wherein the carboxy groups mentioned in the definition of the above-mentioned radicals can additionally be replaced by a radical which is converted into a carboxy group in vivo.

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 can additionally be substituted by one or two C _1-3 -alkyl groups, a C _5-8 -cycloalkanol in which a methylene group in the 3- or 4-position by an oxygen atom or is replaced by an imino group which is optionally substituted by a C _1-3 alkyl, phenyl C _1-3 alkyl, phenyl C _1-3 alkoxycarbonyl or C _2-6 alkanoyl group and the cycloalkanol part is additionally substituted by 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 alkynol or phenyl C _{3- 5-} alkynol with the proviso that no bond to the oxygen atom starts from a carbon atom which is a double or triple 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 _1-3 alkyl groups, a 1,3- Dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula

R _a -CO-O- (R _b CR _c ) -OH,

by doing
R _{a is} a C _1-8 alkyl, C _5-7 cycloalkyl, phenyl or phenyl C _1-3 alkyl group,
R _{b is} a hydrogen atom, a C _1-3 alkyl, C _5-7 cycloalkyl or phenyl group and
R _{c represents} a hydrogen atom or a C _1-3 alkyl group.

Under a negatively charged under physiological conditions a carboxy, hydroxysulphonyl, phosphono, tetrazol-5-yl, Phenylcarbonylaminocarbonyl-, Trifluormethylcarbonylaminocarbonyl-, C _1-6 alkylsulfonylamino, phenylsulfonylamino, Benzylsulfonylamino-, Trifluormethylsulfonylamino-, C _{1 -6} -Alkylsulfonylaminocarbonyl-, Phenylsulfonylaminocarbonyl- Benzylsulfonylaminocarbonyl- or Perfluor-C _1-6 -alkylsulfonylaminocarbonylgruppe
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 such as the benzoyl or pyridinoyl group or a C _1-16 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C _1-16 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. Butoxycarbonyl, Pentoxycarbonyl-, Hexoxycarbonyl-, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, Undecyloxycarbonyl-, dodecyloxycarbonyl or Hexadecyloxycarbonylgruppe, a phenyl-C _1-6 alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or Phenylpropoxycarbonylgruppe, a C _1-3 -Alkylsulfonyl- C _2-4 -alkoxycarbonyl-, C _1-3 -alkoxy-C _2-4 -alkoxy-C _2-4 -alkoxycarbonyl- or R _a -CO-O- (R _b CR _c ) -O-CO Group in which R _a to R _c are defined as mentioned above,
to understand.

Furthermore, those included in the definition of the above mentioned saturated alkyl and alkoxy parts, which more than 2 Contain carbon atoms, including their branched isomers such as for example the isopropyl, tert-butyl, isobutyl group etc. a.

Preferred compounds of general formula I are those in which
R _{1 is} a phenyl group which can be mono- or disubstituted by a chlorine, bromine or iodine atom, by a methyl or methoxy group, where the substituents can be identical or different,
a phenylvinyl, benzothiophenyl or naphthyl group, a phenyl group to which an n-propylene, n-butylene, methylenedioxy or ethylenedioxy bridge is fused onto two adjacent carbon atoms,
a pyridinyl or pyronyl group optionally substituted by a methyl group, to each of which a phenyl ring is fused via two adjacent carbon atoms, in which case a methine group in the 2- or 4-position may additionally be replaced by a hydroxymething group in the pyridine ring mentioned above,
A is a phenylene, furanylene, thiophenylene, thiazolylene, imidazolylene, thiadiazolylene, pyridinylene or pyrimidylene group which is optionally substituted by a methyl group, with the proviso that the linkage with the adjacent radicals R ₁ and B does not have the o position of the above-mentioned aromatics,
B is a -HN-, -NH-CO-, -CO-NH-, -NH-CS or -CS-NH group, in which the -NH group can in each case be substituted by a methyl group, and
R _{2 is} a C _3-6 cycloalkyl or C _4-6 cycloalkenyl group substituted by a carboxy group,
a phenyl group substituted by a carboxy group which is monosubstituted in the phenyl part by a nitro, amino, acetylamino, carboxy, aminocarbonyl or pyrrolidinoaminocarbonyl group or by a fluorine, chlorine, bromine or iodine atom, by a methyl or methoxy group - or is disubstituted, where the substituents can be the same or different,
a naphthyl, furanyl, thiophenyl, triazolyl or pyridinyl group substituted by a carboxy group,
is an aminocarbonylmethyl group or a methyl or 1,2-dimethylvinyl group substituted by a carboxy group,
their isomers and their salts.

In this connection, those of the above-mentioned compounds of the general formula I are preferred in particular in which R ₁ , R ₂ and A are each defined as mentioned above and
B represents an -NH or -NH-CO group, the -NH-CO group being linked to the radical R ₂ via the -CO group,
their isomers and their salts.

Very particularly preferred compounds of the above general formula I are those in which
R _{1 is} a phenyl group which is mono- or disubstituted by a chlorine, bromine or iodine atom, where the substituents can be identical or different,
a naphthyl or (2-oxo-2H-chromen-3-yl) group,
A is a 1,3-phenylene, 2,5-thiazolylene, 2,4-pyridinylene, 2,6-pyridinylene or 2,4-pyrimidylene group,
B represents an -NH or -NH-CO group, the -NH-CO group being linked to the rest 1% via the -CO group,
R _{2 is} a 2-carboxy-cyclopent-2-enyl, 2-carboxy-cyclohex-2-enyl, 3-carboxy-thien-2-yl or 2-carboxy-1,2-dimethylvinyl group or
a 2-carboxyphenyl group which is optionally monosubstituted by a fluorine, chlorine or bromine atom or by a methyl or nitro group,
their isomers and their salts.

• a) 2-[4-(Naphthalin-2-yl)-thiazol-2-ylaminocarbonyl]-benzoesäure,
• b) 2-[4-(Naphthalin-2-yl)-thiazol-2-ylaminocarbonyl]-cyclopent-1-en-carbonsäure und
• c) 2-[4-(Naphthalin-2-yl)-pyrimidin-2-ylamino]-benzoesäure sowie deren Salze.

The following may be mentioned as particularly preferred compounds of the above general formula I:

• a) 2- [4- (naphthalen-2-yl) thiazol-2-ylaminocarbonyl] benzoic acid,
• b) 2- [4- (Naphthalin-2-yl) thiazol-2-ylaminocarbonyl] cyclopent-1-ene carboxylic acid and
• c) 2- [4- (Naphthalin-2-yl) pyrimidin-2-ylamino] benzoic acid and its salts.

• a) Umsetzung einer Verbindung der allgemeinen Formel
  
  R₁ - A - U (II),
  
  mit einer Verbindung der allgemeinen Formel
  
  V - R₂ (III),
  
  in denen
  R₁, R₂ und A wie eingangs erwähnt definiert sind,
  einer der Reste U oder V eine gegebenenfalls durch eine C_1-3-Alkylgruppe substituierte Aminogruppe und
  der andere der Reste U oder V eine Carboxygruppe bedeuten, oder deren reaktionsfähigen Derivaten.

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

• a) implementation of a compound of the general formula
  
  R ₁ - A - U (II),
  
  with a compound of the general formula
  
  V - R ₂ (III),
  
  in which
  R ₁ , R ₂ and A are defined as mentioned at the beginning,
  one of the radicals U or V is an amino group which is optionally substituted by a C _1-3 alkyl group and
  the other of the radicals U or V represents a carboxy group, or their reactive derivatives.

The implementation is conveniently carried out with an appropriate Halide or anhydride in a solvent such as Methylene chloride, chloroform, carbon tetrachloride, ether, Tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, Dimethyl sulfoxide or sulfolane optionally in the presence an inorganic or tertiary organic base such as Triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or Pyridine, the latter also being used as Solvents can be used at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.

• a) Zur Herstellung einer Verbindung der allgemeinen Formel I, in der R₂ mit der Maßgabe wie eingangs erwähnt definiert ist, dass die Carboxygruppe des Restes R₂ in 2-Stellung steht, und B eine -NHCO-Gruppe darstellt, wobei die Carbonylgruppe des Restes B mit dem Rest R₂ verbunden ist:
  Hydrolyse einer Verbindung der allgemeinen Formel
  
  
  oder der allgemeinen Formel
  
  
  in denen
  R₁ und A wie eingangs erwähnt definiert sind,
  R₂' die für R₂ eingangs erwähnten Bedeutungen mit Maßgabe aufweist, dass die von dem Carboxysubstituenten stammende Carbonylgruppe des Restes R₂ in 2-Stellung steht, und
  A' die für A eingangs erwähnten Bedeutungen mit der Maßgabe aufweist, dass A ein Stickstoffatom enthält, das mit der Carbonylgruppe verknüpft ist.

However, the reaction can also be carried out with a free acid, if appropriate in the presence of an acid-activating agent or a dehydrating agent, for. B. in the presence of chloroformic acid isobutyl ester, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / nodroxy-1-hydroxydisuccinyl or nodohydroxychloride , N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.

• a) For the preparation of a compound of general formula I in which R _{2 is defined} with the proviso that the carboxy group of the radical R _{2 is} in the 2-position, and B represents an -NHCO group, the carbonyl group of Rest B is connected to the rest R ₂ :
  Hydrolysis of a compound of the general formula
  
  
  or the general formula
  
  
  in which
  R ₁ and A are defined as mentioned at the beginning,
  R ₂ 'has the meanings mentioned above for R ₂ with the proviso that the carbonyl group of the radical R ₂ originating from the carboxy substituent is in the 2-position, and
  A 'has the meanings mentioned above for A with the proviso that A contains a nitrogen atom which is linked to the carbonyl group.

• a) Zur Herstellung einer Verbindung der allgemeinen Formel I, in der B eine gegebenenfalls durch eine C_1-3-Alkylgruppe substituierte -NH-Gruppe darstellt:
  Umsetzung einer Verbindung der allgemeinen Formel
  
  R₁ - A - X (VI),
  
  mit einer Verbindung der allgemeinen Formel
  
  Y - R₂ (VII),
  
  in denen
  R₁, R₂ und A wie eingangs erwähnt definiert sind,
  einer der Reste X oder Y eine gegebenenfalls durch eine C_1-3 -Alkylgruppe substituierte Aminogruppe und
  der andere der Reste X oder Y eine Austrittsgruppe wie eine substituierte Sulfonyloxygruppe oder ein Halogenatom, z. B. eine Trifluormethylsulfonyloxygruppe, ein Chlor-, Brom- oder Iodatom, bedeuten.

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, e.g. B. at temperatures between room temperature and the boiling point of the reaction mixture.

• a) For the preparation of a compound of the general formula I in which B represents an --NH group which is optionally substituted by a C _1-3 alkyl group:
  Implementation of a compound of the general formula
  
  R ₁ - A - X (VI),
  
  with a compound of the general formula
  
  Y - R ₂ (VII),
  
  in which
  R ₁ , R ₂ and A are defined as mentioned at the beginning,
  one of X or Y is an amino group optionally substituted by a C _1-3 alkyl group and
  the other of X or Y is a leaving group such as a substituted sulfonyloxy group or a halogen atom, e.g. B. a trifluoromethylsulfonyloxy group, a chlorine, bromine or iodine atom.

• a) Zur Herstellung einer Verbindung der allgemeinen Formel I, in der B eine gegebenenfalls am Amidstickstoffatom durch eine C_1-3-Alkylgruppe substituierte -NHCS- oder -CS-NH-Gruppe darstellt:
  Umsetzung einer Verbindung der allgemeinen Formel
  
  R₁ - A - B' - R₂ (VIII),
  
  in der
  R₁, R₂ und A wie eingangs erwähnt definiert sind und
  B' eine gegebenenfalls am Amidstickstoffatom durch eine C_1-3 -Alkylgruppe substituierte -NH-CO- oder -CO-NH-Gruppe bedeutet,
  mit einem schwefeleinführenden Mittel.

The reaction is conveniently carried out at elevated temperatures in a solvent such as ethanol, dimethoxyethane, tetrahydrofuran, acetonitrile, toluene or xylene, e.g. B. at the boiling point of the solvent used, and preferably in the presence of a reaction accelerator such as concentrated hydrochloric acid, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl / palladium acetate, palladium tetrakistriphenylphosphine / 2,2'-bis ( diphenylphosphio) -1,1'-binaphthyl or catalysts such as those described in Angew. Chemistry Int. Ed. Engl. 37, 2090 (1998), in the presence of a base such as cesium carbonate, sodium or potassium tert-butoxide.

• a) For the preparation of a compound of the general formula I in which B represents an -NHCS or -CS-NH group which is optionally substituted on the amide nitrogen atom by a C _1-3 -alkyl group:
  Implementation of a compound of the general formula
  
  R ₁ - A - B '- R ₂ (VIII),
  
  in the
  R ₁ , R ₂ and A are defined as mentioned at the beginning and
  B 'denotes an -NH-CO or -CO-NH group which is optionally substituted on the amide nitrogen atom by a C _1-3 alkyl group,
  with a sulfur introducing agent.

• a) Zur Herstellung einer Verbindung der allgemeinen Formel I, in der R₂ die für R₂ eingangs erwähnten Bedeutungen mit der Maßgabe aufweist, dass der Carboxysubstituent durch eine invivo in eine Carboxygruppe überführbare Gruppe ersetzt ist:
  Umsetzung einer Verbindung der allgemeinen Formel
  
  R₁ - A - B - R₂" (IX),
  
  in der
  R₁, A und B wie eingangs erwähnt definiert sind und
  R₂" die für R₂ eingangs erwähnten Bedeutungen mit der Maßgabe aufweist, dass diese durch eine Carboxygruppe substituiert ist, oder dessen Alkalisalz mit einer Verbindung der allgemeinen Formel
  
  Z - R (X),
  
  in der
  R eine C_1-6-Alkyl-, Phenyl-C_1-3-alkyl- oder C_3-9-Cycloalkylgruppe, wobei der C_5-8-Cycloalkylteil zusätzlich durch eine oder zwei C_1-3-Alkylgruppen substituiert sein kann, eine C_5-8 -Cycloalkylgruppe, in der eine Methylengruppe in 3- oder 4-Stellung durch ein Sauerstoffatom oder durch eine gegebenenfalls durch eine C_1-3-Alkyl-, Phenyl-C_1-3-alkyl-, Phenyl-C_1-3-alkoxycarbonyl- oder C_2-6-Alkanoylgruppe substituierte Iminogruppe ersetzt ist und der Cycloalkylteil zusätzlich durch eine oder zwei C_1-3 -Alkylgruppen substituiert sein kann, eine C_4-7-Cycloalkenyl-, C_3-5 -Alkenyl-, Phenyl-C_3-5-alkenyl-, C_3-5-Alkinyl- oder Phenyl-C_3-5 -alkinylgruppe mit der Maßgabe, daß keine Bindung an das Sauerstoffatom von einem Kohlenstoffatom ausgeht, welches eine Doppel- oder Dreifachbindung trägt, eine C_3-8-Cycloalkyl-C_1-3 -alkylgruppe, eine Bicycloalkylgruppe mit insgesamt 8 bis 10 Kohlenstoffatomen, wobei der Bicycloalkylteil zusätzlich durch eine oder zwei C_1-3-Alkylgruppen substituiert sein kann, eine 1,3-Dihydro-3-oxo-1-isobenzfuranylgruppe oder eine Gruppe der allgemeinen Formel
  
  R_a-CO-O-(R_bCR_c)-,
  
  in der
  R_a bis R_c wie eingangs erwähnt definiert sind,
  und Z eine nukleofuge Austrittsgruppe wie ein Halogenatom, z. B. ein Chlor-, Brom- oder Jodatom, eine Hydroxy- oder p-Nitrophenyloxygruppe bedeuten.

The reaction is conveniently carried out in the presence of a sulfur-introducing agent such as, for example, 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) or phosphorus pentasulfide in a solvent such as Tetrahydrofuran, dioxane, toluene, xylene, 1,2-dichlorobenzene or pyridine at temperatures up to the boiling point of the solvent used, e.g. B. at temperatures between 20 and 180 ° C.

• a) For the preparation of a compound of the general formula I in which R _{2 has} the meanings mentioned above for R ₂ with the proviso that the carboxy substituent is replaced by a group which can be converted into a carboxy group in vivo:
  Implementation of a compound of the general formula
  
  R ₁ - A - B - R ₂ "(IX),
  
  in the
  R ₁ , A and B are defined as mentioned at the beginning and
  R ₂ "has the meanings mentioned for R ₂ with the proviso that it is substituted by a carboxy group, or its alkali salt with a compound of the general formula
  
  Z - R (X),
  
  in the
  R is a C _1-6 alkyl, phenyl C _1-3 alkyl or C _3-9 cycloalkyl group, where the C _5-8 cycloalkyl part can additionally be substituted by one or two C _1-3 alkyl groups, a C _5-8 cycloalkyl group in which a methylene group in the 3- or 4-position through an oxygen atom or through one optionally through a C _1-3 -alkyl, phenyl-C _1-3 -alkyl-, phenyl-C _{1 -3} -alkoxycarbonyl- or C _2-6 -alkanoyl group is substituted imino group and the cycloalkyl part can additionally be substituted by one or two C _1-3 -alkyl groups, a C _4-7 -cycloalkenyl-, C _3-5 -alkenyl- , Phenyl-C _3-5 -alkenyl, C _3-5 -alkynyl or phenyl-C _3-5 -alkynyl group 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 alkyl group, a bicycloalkyl group with a total of 8 to 10 carbon atoms, the bicycloalkyl part being additionally substituted by one or two C _1-3 alk yl groups may be substituted, a 1,3-dihydro-3-oxo-1-isobenzfuranyl group or a group of the general formula
  
  R _a -CO-O- (R _b CR _c ) -,
  
  in the
  R _a to R _c are defined as mentioned at the beginning,
  and Z is a nucleofugic leaving group such as a halogen atom, e.g. B. is a chlorine, bromine or iodine atom, a hydroxy or p-nitrophenyloxy group.

• a) Zur Herstellung einer Verbindung der allgemeinen Formel I, in der R₂ eine Carboxygruppe enthält:
  Überführung einer Verbindung der allgemeinen Formel
  
  - A - B - R₂''' (XI),
  
  in der
  R₁, A und B wie eingangs erwähnt definiert sind und
  R₂''' die für R₂ eingangs erwähnten Bedeutungen mit der Maßgabe besitzt, dass R₂ durch eine in eine Carboxygruppe überführbare Gruppe substituiert ist, mittels Hydrolyse, Hydrogenolyse oder Thermolyse in eine entsprechende Carboxyverbindung.

The 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, for. B. 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'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine / diethyl azodicarboxylate, if appropriate in the presence of a base such as potassium , N-ethyl-diisopropylamine or N, N-dimethylaminopyridine expediently 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, tetraydrofuran, dioxane, Dimethyl sulfoxide, dimethylformamide or acetone optionally in the presence of a reaction 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 at the same time, 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.

• a) For the preparation of a compound of general formula I in which R ₂ contains a carboxy group:
  Conversion of a compound of the general formula
  
  - A - B - R ₂ '''(XI),
  
  in the
  R ₁ , A and B are defined as mentioned at the beginning and
  R ₂ '''has the meanings mentioned for R ₂ with the proviso that R ₂ is substituted by a group which can be converted into a carboxy group, by means of hydrolysis, hydrogenolysis or thermolysis into a corresponding carboxy compound.

Comes as a group that can be converted into a carboxy group for example one protected by a protective residue Carboxyl group such as their functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, Trimethylsilyl esters, orthoesters or imino esters, the esters of which tertiary alcohols, e.g. B. the tert-butyl ester, and their esters with Aralkanols, e.g. B. the benzyl ester.

The hydrolysis is advantageously carried out either in the presence an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, Acetic acid, trichloroacetic acid, trifluoroacetic acid or their Mixtures or in the presence of a base such as lithium hydroxide, Sodium hydroxide or potassium hydroxide in a suitable one Solvents such as water, water / methanol, water / ethanol, Water / isopropanol, methanol, ethanol, water / tetrahydrofuran or Water / dioxane at temperatures between -10 and 120 ° C, e.g. B. at Temperatures between room temperature and the boiling temperature of the reaction mixture.

The transfer of a tert-butyl or tert.Butyloxycarbonyl group in a carboxy group can also be treated 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, e.g. B. at temperatures between 0 and 60 ° C, or also thermally, if appropriate, in an inert Solvents 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 in the boiling point of the solvent used, e.g. B. at Temperatures between 40 and 120 ° C are carried out.

The transfer of a benzyloxy or benzyloxycarbonyl group in a carboxy group can also be hydrogenolytically present a hydrogenation catalyst such as palladium / carbon in one suitable solvents such as methanol, ethanol, ethanol / water, Glacial acetic acid, ethyl acetate, dioxane or dimethylformamide preferably at temperatures between 0 and 50 ° C, e.g. B. at Room temperature, and a hydrogen pressure of 1 to 5 bar be performed.

According to the invention, a compound of the general type is obtained Formula I, which contains an amino group, this can by means of Acylation in a correspondingly acylated compound general formula I are transferred.

The subsequent acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, Tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or Sulfolan optionally in the presence of an inorganic or organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.

However, the subsequent acylation can also be carried out with the free one Acid optionally in the presence of an acid activating agent or a dehydrating agent, e.g. B. in Presence of isobutyl chloroformate, thionyl chloride, Trimethylchlorosilane, hydrogen chloride, sulfuric acid, Methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, Phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or Triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.

In the implementations described above optionally present reactive groups such as hydroxyl, carboxy, Amino, alkylamino or imino groups during the reaction are protected by usual protective groups, which after the Implementation to be split off again.

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 residues for a carboxy group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and
as protective radicals for an amino, alkylamino or imino group, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally for the amino group Phthalyl group into consideration.

The subsequent subsequent splitting off of one used Protective residue takes place, for example, hydrolytically in one aqueous solvents, e.g. B. 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. B. in Presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

The cleavage of a benzyl, methoxybenzyl or However, benzyloxycarbonyl radical is, for example, hydrogenolytic, z. B. with hydrogen in the presence of a catalyst such as Palladium / carbon in a suitable solvent such as methanol, Ethanol, ethyl acetate or glacial acetic acid if necessary 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. The secession of a 2,4-dimethoxybenzyl radical, however, is preferably carried out in Trifluoroacetic acid in the presence of anisole.

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

A trifluoroacetyl radical is preferably cleaved off by treatment with an acid such as hydrochloric acid if necessary in the presence of a solvent such as acetic acid 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 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 Temperatures between 20 and 50 ° C.

The compounds used as starting materials general formulas II to XI are known from the literature or can according to methods known from the literature, as this in the Examples will be produced.

Furthermore, the compounds of general Formula I, as already mentioned at the beginning, in its enantiomers and / or diastereomers are separated. So can for example connections with at least one optically active Carbon atom are separated into their enantiomers.

For example, the compounds obtained from general formula I, which occur in racemates, according to known methods (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and connections of the general formula I with at least 2 stereogenic centers on the ground according to their physical-chemical differences as such known methods, e.g. B. by chromatography and / or fractionated Crystallization, separate into their diastereomers, which, if they are obtained in racemic form, then as mentioned above can be separated into the enantiomers.

Furthermore, the compounds of formula I obtained in their salts, especially for pharmaceutical use in their physiologically compatible salts with inorganic or organic acids. Come as acids for this, for example hydrochloric acid, hydrobromic acid, Sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, Succinic acid, lactic acid, citric acid, tartaric acid or Maleic acid into consideration.

In addition, the new compounds of Formula I if this is an acidic group such as a carboxy group included, if desired then in their salts inorganic or organic bases, especially for pharmaceutical application in their physiologically acceptable Salts, transfer. Here come as bases, for example Sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, Ethanolamine, diethanolamine and triethanolamine.

As already mentioned at the beginning, the carboxamides have general formula I and their salts, especially their physiologically acceptable salts, an inhibitory effect on the Telomerase.

The inhibitory effect of the carboxamides of the general formula I for telomerase was examined as follows:

material and methods 1. Production of nuclear extracts from HeLa cells

The core extracts were prepared in accordance with 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 × 10 ⁹ HeLa-53 cells (ATCC catalog number CCL-2.2) growing in suspension culture were harvested by centrifugation for 5 minutes at 1000 × g and washed once with PBS buffer (140 mM KCl; 2.7 mM KCl; 8.1 mM Na ₂ HPO 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 × g, the cell pellet was suspended in twice the 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% glycerol) 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 dialyzed for 4-5 hours against buffer AM-100 (20 mM Tris / HCl, pH 7.9; 100 mM KCl; 0.1 mM EDTA; 0.5 mM DTE; 20% glycerin). 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 marked 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- ³² P-dGTP, 430 bp DNA fragment) 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 by adding 2.4 M ammonium acetate; 3 µg tRNA and 750 µl ethanol precipitated. 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 electrophoretically separated on a sequence gel (8% polyacrylamide, 7 M urea, 1 × TBE buffer). The DNA synthesized by telomerase in the absence or presence of potential inhibitors was identified and quantified by means of phospho-imager analysis (Molecular Dynamics) and in this way the inhibitor concentration was determined, which inhibits telomerase activity by 50% (IC ₅₀ ). 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

Due to their biological properties, the Carboxamides of the general formula I for treatment pathophysiological processes caused by increased telomerase Activity are marked. These are e.g. B. tumor diseases such as carcinomas, sarcomas and leukemias including Skin cancer (e.g. squamous cell carcinoma, basalioma, melanoma), Small cell bronchial carcinoma, non-small cell Bronchial carcinoma, salivary carcinoma, esophageal carcinoma, Larynx 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, oligodendroglioma, meningioma, Neuroblastoma, myeloma, medulloblastoma, neurofibrosarcoma, thymoma, Osteosarcoma, chondrosarcoma, ewing sarcoma, fibrosarcoma, Histiocytoma, dermatoff brosarcoma, synovialoma, leiomyosarcoma, Rhabdomyosarcoma, liposarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma, chronic myeloid leukemia, chronic lymphatic Leukemia, acute promyelocytic leukemia, acute lymphoblastic Leukemia and acute myeloid leukemia.

The compounds can also be used to treat others Diseases are used that are elevated Have cell division rate or increased telomerase activity, such as. B. 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, such as. B. worm or Fungal diseases as well as diseases caused by protozoan Pathogens are caused, such as. B. Zooflagellata (Trypanosoma, Leishmania, Giardia), Rhizopoda (Entamoeba spec.), Sporozoa (Plasmodium spec., Toxoplasma spec.), Ciliata etc.

For this purpose, the carboxamides of the general formula I optionally in combination with other pharmacologically effective compounds and forms of therapy, the one Achieve reduction in tumor size, applied and in the usual galenical application forms are incorporated. These can be used, for example, in tumor therapy Monotherapy or in combination with radiation, surgical Interventions or other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), Mitosis inhibitors (e.g. paclitaxel, vinblastine), Cell cycle inhibitors (e.g. flavopyridol), inhibitors of Signal transduction (e.g. farnesyl transferase inhibitors), with nucleic acid interacting compounds (e.g. cis-platinum, Cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), Inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), tumor vaccines, antibodies etc. are used become. These combinations can be either simultaneous or be administered sequentially.

The daily dose is 20 to 600 mg per os or intravenously, divided into one to four times a day. For this the compounds of the general formula I, optionally in combination with the others mentioned above Active substances together with one or more inert usual carriers and / or diluents, e.g. B. with cornstarch, milk sugar, cane sugar, microcrystalline Cellulose, magnesium stearate, polyvinylpyrrolidone, Citric acid, tartaric acid, water, water / ethanol, Water / glycerin, water / sorbitol, water / polyethylene glycol, Propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable Mixtures in common galenical preparations such as Tablets, coated tablets, capsules, powder, suspensions or suppositories incorporated.

The following examples are intended to illustrate the invention explain:

example 1 2- [4- (2-oxo-2H-chromen-3-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid a. 3-acetyl-2-chroman-2-one

A mixture of 2 g (16.4 mmol) of salicylaldehyde and 2.1 g (16.4 mmol) of acetoacetic ester is mixed with 0 g of piperidine at 0 ° C. and stirred at room temperature until the mixture has solidified to a solid mass. It is then triturated with ethanol, filtered and the residue is recrystallized from water.
Yield: 2.2 g (70% of theory),
C ₁₁ H ₈ O ₃ (188.18)
Mass spectrum: M ⁺ = 188.

b. 3- (2-bromoacetyl) -chroman-2-on

A solution of 2.2 g (11.4 mmol) of 3-acetyl-2-chroman-2-one in 10 ml of chloroform is slowly mixed with 0.6 ml (11.4 mmol) of bromine in 2 ml of chloroform and then heated on a water bath for 30 minutes. It is then cooled in an ice bath, the product is suctioned off and dried.
Yield: 2.4 g (79% of theory),
R _f value: 0.48 (silica gel; ethyl acetate / cyclohexane = 1: 2)
C ₁₁ H ₇ BrO ₃ (267.08)
Mass spectrum: M ⁺ = 266/8 (bromine isotopes).

c. 2-Amino-4- (2-oxo-2H-chroman-3-yl) -thiazol

2.4 g (8.9 mmol) of 3- (2-bromoacetyl) -chroman-2-one are added to a solution of 0.7 g (8.9 mmol) of thiourea in 20 ml of ethanol. The mixture is then heated to reflux for 15 minutes. The reaction mixture is cooled, diluted with water and made alkaline with ammonia solution. The resulting precipitate is suctioned off.
Yield: 2.2 g (99% of theory),
R _f value: 0.21 (silica gel; ethyl acetate / cyclohexane = 1: 2)
C ₁₂ H ₈ N ₂ O ₂ S (244.27)
Mass spectrum: M ⁺ = 244.

d. 2- [4- (2-oxo-2H-chromen-3-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid

0.1 g (0.4 mmol) of 2-amino-4- (2-oxo-2H-chroman-3-yl) thiazole and 0.2 g (1.6 mmol) of phthalic anhydride are stirred in 2 ml of pyridine for 3.5 days. Then water is added and the mixture is evaporated in vacuo. The residue is suspended in acetone / water (3: 1), the crude product is filtered off with suction and recrystallized from acetone.
Yield: 83 mg (52% of theory),
C ₂₀ H ₁₂ N ₂ O ₅ S (392.39)
Mass spectrum: (M + H) ⁺ = 393
(MH) ^- = 391
(MH ₂ O) ^- = 374.

Example 2 2- (4-phenyl-thiazol-2-ylaminocarbonyl) benzoic acid

Prepared analogously to Example 1d from 2-amino-4-phenyl-thiazole and phthalic anhydride in pyridine.
Yield: 55% of theory,
C ₁₇ H ₁₂ N ₂ O ₃ S (324.36)
Mass spectrum: (M + H) ⁺ = 325
(MH) ^- = 323
M ⁺ = 324.

Example 3 2- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl) benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and phthalic anhydride in pyridine.
Yield: 30% of theory
C ₂₁ H ₁₄ N ₂ O ₃ S (374.42)
Mass spectrum: (M + H) ⁺ = 375
(MH) ^- = 373.

Example 4 2- (4-styryl-thiazol-2-ylaminocarbonyl) benzoic acid a. 1-Bromo-bromo-phenyl-but-3-en-2-one

5.0 g (34.2 mmol) of benzylidene acetone are placed in 200 ml of tetrahydrofuran, 20.1 g (34.9 mmol) of triphenylphosphine propionic acid bromide are added in portions and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with cyclohexane / ethyl acetate (7: 1).
Yield: 4.6 g (59% of theory),
R _f value: 0.65 (silica gel; ethyl acetate / cyclohexane = 1: 4)
C ₁₀ H ₉ BrO (225.09)
Mass spectrum: M ⁺ = 224/26 (bromine isotopes).

b. 2-amino-4-styryl-thiazol

Prepared analogously to Example 1c from 1-bromo-4-phenyl-but-3-en-2-one and thiourea in ethanol.
Yield: 47% of theory,
R _f value: 0.14 (silica gel; ethyl acetate / cyclohexane = 1: 4)
C ₁₁ H ₁₀ N ₂ S (202.28)
Mass spectrum: M ⁺ = 202
(M + H) ⁺ = 203.

c. 2- (4-styryl-thiazol-2-ylaminocarbonyl) benzoic acid

Prepared analogously to Example 1d from 2-amino-4-styryl-thiazole and phthalic anhydride in pyridine.
Yield: 63% of theory,
C ₁₉ H ₁₄ N ₂ O ₃ S (350.40)
Mass spectrum: M ⁺ = 350
(MH) ^- = 349.

Example 5 3,6-dichloro-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and 3,6-dichlorophthalic anhydride in pyridine.
Yield: 69% of theory,
C ₂₁ H ₁₂ Cl ₂ N ₂ O ₃ S (443.31)
Mass spectrum: (MH) ^- = 441/3/5 (chlorine isotopes).

Example 6 4,5-dimethoxy-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and 4,5-dimethoxy-phthalic anhydride in pyridine.
Yield: 86% of theory,
C ₂₃ H ₁₈ N ₂ O ₅ S (434.47)
Mass spectrum: (MH) ^- = 433
(MH ₂ O) ^- = 416.

Example 7 2- (4- (naphthalen-1-yl) -thiazol-2-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-1-yl) thiazole and phthalic anhydride in pyridine.
Yield: 51% of theory,
C ₂₁ H ₁₄ N ₂ O ₃ S (374.42)
Mass spectrum: (M + H) ⁺ = 375
(MH) ^- = 373.

Example 8 2- [4- (6-methyl-naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (6-methyl-naphthalin-2-yl) thiazole and phthalic anhydride in pyridine.
Yield: 45% of theory,
C ₂₂ H ₁₆ N ₂ O ₃ S (388.45)
Mass spectrum: (MH) ^- = 387
(MH ₂ O) ^- = 370.

Example 9 2- [4- (naphthalene-2-yl) -thiazol-2-ylcarbonylamino] -benzoic acid a. 4- (naphthalen-2-yl) -thiazol-2-ethyl ylcarbarbonsäure

0.7 g (2.78 mmol) of 2-bromo-1-naphthalin-2-ylethanone are placed in 7 ml of ethanol, 0.4 g (3.06 mmol) of ethyl thiooxamide are added and the mixture is heated under reflux for 1 hour. After cooling to room temperature, water is added and suction filtered.
Yield: 0.7 g (89% of theory),
R _f value: 0.55 (silica gel; ethyl acetate / cyclohexane = 1: 4)
C ₁₆ H ₁₃ NO ₂ S (283.35)
Mass spectrum: M ⁺ = 283.

b. 4- (naphthalen-2-yl) -thiazol-2-carboxylic acid

1.1 g (3.8 mmol) of 4- (naphthalin-2-yl) -thiazol-2-carboxylic acid ethyl ester are placed in a mixture of 10 ml of water and 8 ml of tetrahydrofuran and, after addition of 0.8 g (19.4 mmol) of lithium hydroxide, stirred for 1.5 hours. The mixture is then acidified with 1 N hydrochloric acid, the organic solvent is distilled off and the precipitate is filtered off with suction.
Yield: 0.6 g (58% of theory),
R _f value: 0.10 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
C ₁₄ H ₉ NO ₂ S (255.30)
Mass spectrum: M ⁺ = 255.

c. 4- (naphthalen-2-yl) -thiazol-2-carboxylic acid chloride

0.6 g (2.2 mmol) of 4- (naphthalin-2-yl) thiazol-2-carboxylic acid are suspended in 4 ml of thionyl chloride and, after the addition of a drop of dimethylformamide, heated to reflux for 45 minutes. The solvent is distilled off and the oil obtained is reacted without further purification.
Yield: 0.6 g (100% of theory).

d. 2- [4- (naphthalene-2-yl) -thiazol-2-ylcarbonylamino] -benzoic acid

To a solution of 0.3 g (2.2 mmol) of anthranilic acid in 20 ml of tetrahydrofuran and 0.5 ml (3.2 mmol) of triethylamine, a solution of 0.6 g (2.2 mmol) of 4- (naphthalin-2-yl) -thiazol-2-carboxylic acid chloride in 15 ml of tetrahydrofuran were added dropwise. The reaction mixture is stirred for 2 hours. It is then evaporated, the residue suspended in 1 N hydrochloric acid and suction filtered.
Yield: 0.6 g (75% of theory),
C ₂₁ H ₁₄ N ₂ O ₃ S (374.42)
Mass spectrum: M ⁺ = 374
(MH ₂ O) ^- = 356.

Example 10 2- (4-styryl-thiazol-2-ylcarbonylamino) -benzoic acid

Prepared analogously to Example 9d from anthranilic acid and 4-styryl-thiazole-2-carboxylic acid chloride in tetrahydrofuran.
Yield: 59% of theory,
C ₁₉ H ₁₄ N ₂ O ₃ S (350.40)
Mass spectrum: M ⁺ = 350
(MH ₂ O) ^- = 332.

Example 11 2- [4- (naphthalene-1-yl-thiazol-2-ylcarbonylamino] -benzoic acid

Prepared analogously to Example 9d from anthranilic acid and 4- (naphthalin-1-yl) thiazol-2-carboxylic acid chloride. The crude product obtained is then purified chromatographically on silica gel (methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).
Yield: 14% of theory,
C ₂₁ H ₁₄ N ₂ O ₃ S (374.42)
Mass spectrum: M ⁺ = 374
(MH) ^- = 373.

Example 12 2- [4- (3,4-dimethoxy-phenyl) -thiazol-2-ylaminocarbonyl] -benzoesäureamid

Prepared analogously to Example 1d from 2-amino-4- (3,4-dimethoxyphenyl) thiazole and phthalic anhydride in pyridine. The crude product obtained is then purified chromatographically on silica gel (methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).
Yield: 16% of theory,
C ₁₉ H ₁₇ N ₃ O ₄ S (383.43)
Mass spectrum: (M + H) ⁺ = 384.

Example 13 2- [4- (3,4-dimethoxy-phenyl) -thiazol-2-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (3,4-dimethoxyphenyl) thiazole and phthalic anhydride in pyridine.
Yield: 31% of theory,
C ₁₉ H ₁₆ N ₂ O ₅ S (384.41)
Mass spectrum: (MH) ^- = 383.

Example 14 2- [4- (5,6,7,8-tetrahydro-naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (5,6,7,8-tetrahydro-naphthalin-2-yl) thiazole and phthalic anhydride in pyridine.
Yield: 64% of theory,
C ₂₁ H ₁₈ N ₂ O ₃ S (378.45)
Mass spectrum: (MH) ^- = 377.

Example 15 2- [4- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -thiazol-2-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (2,3-dihydrobenzo [1,4] dioxin-6-yl) thiazole and phthalic anhydride in pyridine.
Yield: 38% of theory,
C ₁₉ H ₁₄ N ₂ O ₅ S (382.40)
Mass spectrum: (MH) ^- = 381.

Example 16 2- [4- (Benzo [1,3] dioxol-5-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid

Prepared analogously to Example 1d from 2-amino-4-benzo [1,3] dioxol-5-yl-thiazole and phthalic anhydride in pyridine.
Yield: 71% of theory,
C ₁₈ H ₁₂ N ₂ O ₅ S (368.37)
Mass spectrum: M ⁺ = 368.

Example 17 2- [4- (3,4-Dimethyl-phenyl) -thiazol-2-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (3,4-dimethylphenyl) thiazole and phthalic anhydride in pyridine.
Yield: 78% of theory,
C ₁₉ H ₁₆ N ₂ O ₃ S (352.41)
Mass spectrum: M ⁺ = 352.

Example 18 2- [5- (naphthalene-1-yl) -thiophene-2-ylcarbonylamino] -benzoic acid a. 5- (naphthalene-1-yl) thiophene-2-carboxaldehyde

1.2 ml (10.4 mmol) of 5-bromothiophene-2-carboxaldehyde and 0.4 g (0.31 mmol) of tetrakis-triphenylphospin-palladium are stirred in 20 ml of dimethoxyethane for 15 minutes. A solution of 2.2 g (12.5 mmol) of 1-naphthylboronic acid in 4 ml of ethanol and 11 ml of 2N sodium carbonate is then added. The reaction mixture is heated to reflux for 5 hours. After cooling, the mixture is diluted with diethyl ether, the organic phase is separated off and evaporated. The residue is purified by chromatography, eluting with cyclohexane / ethyl acetate (95: 5).
Yield: 2.4 g (95% of theory),
R _f value: 0.09 (silica gel; cyclohexane)
C ₁₅ H ₁₀ OS (238.31)
Mass spectrum: M ⁺ = 238.

b. 5- (naphthalene-1-yl) -thiophene-2-carboxylic acid

2.3 g (9.6 mmol) of 5- (naphthalin-1-yl) -thiophene-2-carboxaldehyde are placed in 40 ml of ethanol and after addition of 8.2 g (48.2 mmol) of silver nitrate in 6 ml of water and 2.7 g (48.2 mmol) of potassium hydroxide stirred in 40 ml of water for 1 hour. The precipitate is then filtered off, the aqueous phase is separated off, adjusted to pH 4 with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are dried and evaporated.
Yield: 1.5 g (61% of theory),
R _f value: 0.17 (silica gel; cyclohexane / ethyl acetate = 1: 2)
C ₁₅ H ₁₀ O ₂ S (254.31)
Mass spectrum: M ⁺ = 254.

c. 5- (naphthalene-1-yl) -thiophene-2-ylcarbonsäurechlorid

Prepared analogously to Example 9c from 5- (naphthalin-1-yl) thiophene-2-carboxylic acid and thionyl chloride with the addition of dimethylformamide.
Yield: 100% of theory.

d. 2- [5- (naphthalene-1-yl) -thiophene-2-ylcarbonylamino] -benzoic acid

Prepared analogously to Example 9d from 5- (naphthalin-1-yl-thiophene) -2-carboxylic acid chloride and anthranilic acid in tetrahydrofuran.
Yield: 53% of theory,
C ₂₂ H ₁₅ NO ₃ S (373.43)
Mass spectrum: M ⁺ = 373
(MH) ^- = 372
(MH ₂ O) ^- = 355.

Example 19 2- [5- (naphthalene-2-yl) -thiophene-2-ylcarbonylamino] -benzoic acid

Prepared analogously to Example 9d from 5-naphthalin-2-yl-thiophene-2-carboxylic acid chloride and anthranilic acid in tetrahydrofuran.
Yield: 13% of theory,
C ₂₂ H ₁₅ NO ₃ S (373.43)
Mass spectrum: M ⁺ = 373
(MH ₂ O) ^- = 355.

Example 20 2- [5- (naphthalene-2-yl) -furan-2-ylcarbonylamino] -benzoic acid a. 5-bromo-furan-2-carboxylic acid methylester

A solution of 3.0 g (15.7 mmol) of 5-bromfuran-2-carboxylic acid, 1.9 ml (47.1 mmol) of methanol and 0.5 ml of conc. Sulfuric acid in 10 ml dichloroethane is heated to the rear foot for 20 hours. The reaction mixture is then poured into water, the organic phase is separated off, washed with saturated sodium bicarbonate solution, dried and evaporated.
Yield: 3.0 g (93% of theory),
R _f value: 0.71 (silica gel; cyclohexane / ethyl acetate = 2: 1)
C ₆ H ₅ BrO ₃ (205.01)
Mass spectrum: (M + Na) ⁺ = 227/29 (bromine isotopes).

b. 5- (naphthalene-2-yl) -furan-2-carboxylic acid

3.0 g (14.5 mmol) of methyl 5-bromfuran-2-carboxylate and 0.5 g (0.43 mmol) of tetrakis-triphenylphosphine-palladium are stirred in 30 ml of toluene for 15 minutes. Then 2.7 g (15.9 mmol) of 2-naphthylboronic acid in 7 ml of ethanol and 14.5 ml of 2N sodium carbonate are added. The reaction mixture is heated to reflux for 4.5 hours. After cooling, it is acidified with 1N hydrochloric acid, diluted with ethyl acetate, the organic phase is separated off, dried and evaporated. The crude product is dissolved in 42 ml of tetrahydrofuran, diluted with 55 ml of water and, after addition of 3.0 g (72.5 mmol) of lithium hydroxide, stirred for 5 hours. It is then acidified with hydrochloric acid, the tetrahydrofuran is distilled off and the precipitate is filtered off with suction.
Yield: 3.0 g (88% of theory),
R _f value: 0.24 (silica gel; dichloromethane / methanol = 9: 1)
C ₁₅ H ₁₀ O ₃ (238.25)
Mass spectrum: (M + H) ⁺ = 239
(MH) ^- = 237.

c. 2- [5- (naphthalene-2-yl) -furan-2-ylcarbonylamino] -benzoic acid

Prepared analogously to Example 9c from 5- (naphthalin-2-yl) furan-2-carboxylic acid and thionyl chloride and then reacted analogously to Example 9d with anthranilic acid in tetrahydrofuran.
Yield: 50% of theory,
C ₂₂ H ₁₅ NO ₄ (357.37)
Mass spectrum: M ⁺ = 357
(MH ₂ O) ^- = 339
(M + H) ⁺ = 358 (MH) ^- = 356.

Example 21 2- [4- (naphthalene-2-yl) -1H-imidazol-2-ylaminocarbonyl] -benzoic acid a. N- [4- (naphthalene-2-yl) -1H-imidazol-2-yl] -acetamide

A mixture of 2.4 g (24.1 mmol) of 1-acetylguanidine and 2.0 g (8 mmol) of 2-bromo-1- (naphthalin-2-yl) ethanol is stirred in 28 ml of dimethylformamide at room temperature for 23 hours. The solvent is then distilled off, the residue is washed with water and filtered off. The crude product is recrystallized from ethanol.
Yield: 0.9 g (47% of theory),
R _f value: 0.41 (silica gel; dichloromethane / methanol = 9.5: 0.5)
C ₁₅ H ₁₃ N ₃ O (251.29)
Mass spectrum: M ⁺ = 251.

b. 2-amino-4- (naphthalen-2-yl) -1H-imidazole

0.4 g (1.6 mmol) of N- [4- (naphthalin-2-yl) -1H-imidazol-2-yl] acetamide are suspended in 10 ml of water and 10 ml of methanol and, after adding 0.2 ml of conc. Sulfuric acid heated to reflux for 11 hours. Then the pH is adjusted to 10 with 1% methanolic potassium hydroxide solution and evaporated. The crude product is purified by chromatography, eluting with dichloromethane / methanol / ammonia (10: 1: 0.1).
Yield: 0.2 g (51% of theory),
R _f value: 0.37 (silica gel; dichloromethane / methanol / ammonia = 9: 1: 0.1)
C ₁₃ H ₁₁ N ₃ (209.25)
Mass spectrum: (M + H) ⁺ = 210
(MH) ^- = 208.

c. 2- [4- (naphthalene-2-yl) -1H-imidazol-2-ylaminocarbonyl] - benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) -1H-imidazole and phthalic anhydride in pyridine.
Yield: 31% of theory,
C ₂₁ H ₁₅ N ₃ O ₃ (357.37)
Mass spectrum: (MH ₂ O) ^- = 339
(MH) ^- = 356.

Example 22 2- [1-methyl-4- (naphthalen-2-yl) -1H-imidazol-2-yl-aminocarbonyl] benzoic acid a. N- [1-methyl-4- (naphthalen-2-yl) -1H-imidazol-2-yl] -acetamide

0.5 g (2 mmol) of N- [4- (naphthalen-2-yl) -1H-imidazol-2-yl] acetamide, 0.1 ml (2 mmol) of methyl iodide and 0.1 g (1 mmol) of potassium carbonate are dissolved in 20 ml of acetone Heated to reflux for 4 hours. Then another 0.2 ml (4 mmol) of methyl iodide are added and the mixture is heated under reflux for a further 9 hours. The precipitate is filtered off, the mother liquor is evaporated and the residue is purified by chromatography, eluting with dichloromethane / methanol (98: 2).
Yield: 0.1 g (24% of theory),
R _f value: 0.34 (silica gel; dichloromethane / methanol = 9.5: 0.5)
C ₁₆ H ₁₅ N ₃ O (265.32)
Mass spectrum: (M + H) ⁺ = 266
(MH) ^- = 264.

b. 2- [1-methyl-4- (naphthalen-2-yl) -1H-imidazol-2-yl-aminocarbonyl] benzoic acid

Prepared analogously to Example 21b from N- [1-methyl-4- (naphthalen-2-yl) -1H-imidazol-2-yl] -acetamide and conc. Sulfuric acid in methanol / water and subsequent reaction analogous to Example 1d with phthalic anhydride in pyridine.
Yield: 18% of theory,
C ₂₂ H ₁₇ N ₃ O ₃ (371.40)
Mass spectrum: (MH) ^- = 370
(MH ₂ O) ^- = 353.

Example 23 2- [5- (naphthalene-2-yl) - [1,3,4] thiadiazol-2-ylaminocarbonyl] - benzoic acid a. 2-amino-5- (naphthalen-2-yl) - [1,3,4] thiadiazol

20 g of polyphosphoric acid are heated to 80 to 90 ° C., a mixture of 2 g (11.6 mmol) of 2-naphthylcarboxylic acid and 1.1 g (11.6 mmol) of thiosemicarbazide is added within 30 minutes and the mixture is then stirred at 90 ° C. for 4 hours. It is then cooled, poured onto ice water and made alkaline with ammonia. The crude product is filtered off with suction and purified by chromatography, eluting with dichloromethane / methanol (99: 1 to 95: 5).
Yield: 1.5 g (56% of theory),
R _f value: 0.31 (silica gel; dichloromethane / methanol = 9.5: 0.5)
C ₁₂ H ₉ N ₃ S (227.29)
Mass spectrum: M ⁺ = 227.

b. 2- [5- (naphthalene-2-yl) - [1,3,4] thiadiazol-2-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 1d from 2-amino-5- (naphthalen-2-yl) - [1,3,4] thiadiazole and phthalic anhydride in pyridine.
Yield: 26% of theory,
C ₂₀ H ₁₃ N ₃ O ₃ S (375.41)
Mass spectrum: (MH) ^- = 374
(MH ₂ O) ^- = 357.

Example 24 2- [4- (3,4-dimethoxy-phenyl) -thiazol-2-yl-N-methyl-aminocarbonyl] benzoic acid

Prepared analogously to Example 1c from 2-bromo-1- (3,4-dimethoxyphenyl) ethanone and N-methyl-thiourea in ethanol and subsequent reaction analogously to Example 1d with phthalic anhydride in pyridine.
Yield: 63% of theory,
R _f value: 0.58 (silica gel; dichloromethane / methanol = 9: 1)
C ₂₀ H ₁₈ N ₂ O ₅ S (398.44)
Mass spectrum: M ⁺ = 398
(MH) ^- = 397.

Example 25 2- [4- (3-methoxy-naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid a. 3-methoxy-naphthalene-2-carboxylic acid chloride

Prepared analogously to Example 9c from 3-methoxy-naphthalene-2-carboxylic acid and thionyl chloride.
Yield: 5.5 g (100% of theory).

b. 2- (3-methoxy-naphthalene-2-carbonyl) malonate

0.7 g (30 mmol) of magnesium are placed in 0.7 ml of ethanol and heated until the reaction mixture boils. Then 20 ml of ether and 4.5 ml (30 mmol) of diethyl malonate with 1.7 ml (30 mmol) of ethanol in 10 ml of ether are added dropwise. After the addition has ended, the mixture is heated under reflux for a further 3 hours. After stirring overnight, 5.5 g (25 mmol) of 3-methoxy-naphthalene-2-carboxylic acid chloride in 50 ml of ether are added dropwise, then the mixture is heated under reflux for 1 hour. It is then cooled, 6 g of conc. Added sulfuric acid in 50 ml of water and 80 ml of ether and stirred for 2 hours at room temperature. The ether phase is separated off, dried and evaporated.
Yield: 10.3 g (99% of theory),
R _f value: 0.78 (silica gel; dichloromethane / methanol = 9: 1)

c. 1- (3-methoxy-naphthalen-2-yl) -ethanone

A mixture of 8.6 g (25 mmol) of 2- (3-methoxy-naphthalene-2-carbonyl) -malonic acid diethyl ester, 15 ml of glacial acetic acid, 2 ml of conc. Sulfuric acid and 10 ml of water are refluxed for 4 hours. It is then poured onto ice water and made alkaline with 20% sodium hydroxide solution. After extraction with ether, the mixture is dried and evaporated.
Yield: 3.3 g (65% of theory),
R _f value: 0.6 (silica gel; cyclohexane / ethyl acetate = 2: 1)

d. 2-amino-4- (3-methoxy-naphthalen-2-yl) -thiazol

Prepared analogously to Example 1b from 1- (3-methoxy-naphthalen-2-yl) -ethanone and bromine in dichloromethane and then reacted analogously to Example 1c with thiourea in ethanol.
Yield: 80% of theory,
R _f value: 0.65 (silica gel; dichloromethane / methanol = 9: 1)
C ₁₄ H ₁₂ N ₂ OS (256.33)
Mass spectrum: (M + H) ⁺ = 257.

e. 2- [4- (3-methoxy-naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (3-methoxynaphthalin-2-yl) thiazole and phthalic anhydride in pyridine.
Yield: 20% of theory,
C ₂₂ H ₁₆ N ₂ O ₄ S (404.45)
Mass spectrum: (MH) ^- = 403.

Example 26 2- [4- (naphthalene-2-yl) -thiazol-2-yl-N-methyl-aminocarbonyl] - benzoic acid

Prepared analogously to Example 1d from 2-methylamino-4- (naphthalin-2-yl) thiazole and phthalic anhydride in pyridine.
Yield: 86% of theory,
C ₂₂ H ₁₆ N ₂ O ₃ S (388.45)
Mass spectrum: M ⁺ = 388.

Example 27 2- [4- (2-oxo-1,2-dihydro-quinoline-3-yl) -thiazol-2-ylaminocarbonyl] -benzoic acid a. 2-amino-benzaldehyde

14 g (0.16 mol) of manganese (IV) oxide are suspended in 100 ml of dichloromethane and then a solution of 5 g (0.04 mol) of 2-amino-benzyl alcohol in 100 ml of dichloromethane is slowly added. After 15 hours of stirring, the inorganic salts are filtered off and the mother liquor evaporated.
Yield: 5 g (100% of theory),
R _f value: 0.51 (silica gel; dichloromethane).

b. 3-acetyl-1H-quinolin-2-one

5 g (0.04 mol) of 2-amino-benzaldehyde and 30 ml (0.23 mol) of ethyl acetoacetate are stirred for 1.5 hours at 160 ° C. on a water separator. Then it is diluted with ether and the precipitated product is filtered off with suction.
Yield: 3.4 g (44% of theory),
R _f value: 0.72 (silica gel; cyclohexane / ethyl acetate = 1: 1).

c. 2- [4- (2-oxo-1,2-dihydro-quinoline-3-yl) -thiazol-2-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 1b from 3-acetyl-1H-quinolin-2-one and bromine in ethanol and subsequent reaction analogously to Example 1c with thiourea in ethanol. The 2-amino-4- (2-oxo-1,2-dihydro-quinolin-3-yl) thiazole thus obtained is then reacted with phthalic anhydride in pyridine analogously to Example 1d.
Yield: 68% of theory,
C ₂₀ H ₁₃ N ₃ O ₄ S (391.41)
Mass spectrum: (MH) ^- = 390.

Example 28 2- [4- (quinolin-3-yl) -thiazol-2-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (quinolin-3-yl) thiazole and phthalic anhydride in pyridine.
Yield: 24% of theory,
C ₂₀ H ₁₃ N ₃ O ₃ S (375.41)
Mass spectrum: (MH) ^- = 374.

Example 29 3- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] -thiophen- 2-carboxylic acid and 2- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] -thiophen- 3-carbonsäire

A mixture of 0.7 g (3.2 mmol) of 2-amino-4- (naphthalin-2-yl) thiazole and 0.5 g (3.2 mmol) of thieno [2,3-c] furan-4,6-dione is dissolved in 10 ml 1,2-dichlorobenzene stirred at 150 ° C for 2 hours. The precipitate is filtered off and purified by chromatography, eluting with petroleum ether / ethyl acetate (6: 4).
Yield: 0.2 g (15% of theory),
R _f value: 0.9 (silica gel; toluene / ethyl acetate / glacial acetic acid = 50: 45: 5)

0.1 g (0.19 mmol) of the product thus obtained and 0.6 g (13.6 mmol) of lithium hydroxide are refluxed in 18 ml of tetrahydrofuran / water (4: 5) for 2 hours. Then 10 ml of 20% potassium hydroxide solution and 10 ml of methanol are added and the mixture is heated under reflux for a further 3 hours. The solvent is distilled off and the residue is purified by chromatography, eluting with dichloromethane / methanol (8: 2).
Yield: 13 mg (18% of theory),
C ₁₉ H ₁₂ N ₂ O ₃ S ₂ (380.45)
Mass spectrum: (MH) ^- = 379.

Example 30 4-bromo-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid and 5-bromo-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and 4-bromo-phthalic anhydride in pyridine.
Yield: 0.26 g (16% of theory),
C ₂₁ H ₁₃ BrN ₂ O ₃ S (453.31)
Mass spectrum: (MH) ^- = 451/53 (bromine isotopes).

Example 31 3,4-difluoro-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid and 2,3-difluoro-6- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and 5,6-difluorophthalic anhydride in pyridine.
Yield: 0.15 g (17% of theory),
C ₂₁ H ₁₂ F ₂ N ₂ O ₃ S (410.40)
Mass spectrum: (MH) ^- = 409.

Example 32 2-fluoro-6- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid and 3-fluoro-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and 4-fluorophthalic anhydride in pyridine.
Yield: 0.66 g (51% of theory),
C ₂₁ H ₁₃ FN ₂ O ₃ S (392.41)
Mass spectrum: (MH) ^- = 391.

Example 33 4-nitro-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid and 5-nitro-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and 4-nitro-phthalic anhydride in pyridine.
Yield: 0.38 g (27% of theory),
C ₂₁ H ₁₃ N ₃ O ₅ S (419.42)
Mass spectrum: (MH) ^- = 418.

Example 34 4-methyl-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid and 5-Methyl-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] - benzoic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and 4-methyl-phthalic anhydride in pyridine.
Yield: 0.38 g (30% of theory),
C ₂₂ H ₁₆ N ₂ O ₃ S (388.45)
Mass spectrum: (MH) ^- = 387.

Example 35 2- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] -cyclopent- 1-ene-carboxylic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and cyclopentene-1,2-dicarboxylic acid anhydride in pyridine.
Yield: 8% of theory,
C ₂₀ H ₁₆ N ₂ O ₃ S (364.43)
Mass spectrum: M ⁺ = 364
(MH) ^- = 363.

Example 36 2- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] nicotinic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and pyridine-2,3-dicarboxylic anhydride in pyridine.
Yield: 19% of theory,
C ₂₀ H ₁₃ N ₃ O ₃ S (375.41)
Mass spectrum: (MH) ^- = 374.

Example 37 3- [4- (Naphthalin-2-yl) thiazol-2-ylaminocarbonyl] -isonicotinic acid and 4- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] nicotinic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and pyridine-3,4-dicarboxylic anhydride in pyridine.
Yield: 20% of theory,
C ₂₀ H ₁₃ N ₃ O ₃ S (375.41)
Mass spectrum: (MH) ^- = 374

Example 38 2- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] -cyclohex- 1-ene-carboxylic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and cyclohexene-1,2-dicarboxylic acid anhydride in pyridine.
Yield: 56% of theory,
C ₂₁ H ₁₈ N ₂ O ₃ S (378.45)
Mass spectrum: (MH) ^- = 377.

Example 39 cis-2- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] -cyclopropanecarboxylic

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and cyclopropan-1,2-dicarboxylic acid anhydride in pyridine.
Yield: 73% of theory,
C ₁₈ H ₁₄ N ₂ O ₃ S (338.38)
Mass spectrum: M ⁺ = 338
(MH) ^- = 337.

Example 40 (Z) -2,3-dimethyl-3- [4- (naphthalene-2-yl) -thiazol-2-yl-aminocarbonyl] -acrylic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and 2,3-dimethyl-maleic anhydride in pyridine.
Yield: 8% of theory,
C ₁₉ H ₁₆ N ₂ O ₃ S (352.42)
Mass spectrum: (MH) ^- = 351.

Example 41 2- [4- (naphthalene-2-yl) -thiazol-2-ylaminothiocarbonyl] -benzoic acid

1 g (2.57 mmol) of methyl 2- [4- (naphthalen-2-yl) thiazol-2-ylaminocarbonyl] benzoate and 0.52 g (1.28 mmol) of Lawesson's reagent are refluxed in 25 ml of xylene for 15 hours. It is then evaporated and the crude product is purified by chromatography, eluting with petroleum ether / ethyl acetate (8: 2). The methyl 2- [4- (naphthalen-2-yl) thiazol-2-ylaminothiocarbonyl] benzoate thus obtained is then saponified with lithium hydroxide in tetrahydrofuran / water analogously to Example 9b.
Yield: 40 mg (6% of theory),
C ₂₁ H ₁₄ N ₂ O ₂ S ₂ (390.49)
Mass spectrum: (MH) ^- = 389.

Example 42 4- [4- (naphthalen-2-yl] -thiazol-2-ylaminocarbonyl] -furan-3-carboxylic acid a. 3,4-Furandicarbonsäuredichlorid

1 g (6.4 mmol) of 3,4-furanedicarboxylic acid in 5 ml (68 mmol) Thionyl chloride presented and after adding 1 drop Dimethylformamide heated to reflux for 1 hour. Then will evaporated and the residue dissolved in 10 ml of tetrahydrofuran.

b. 4- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] -furan- 3-carboxylic acid

1.4 g (6.4 mmol) of 2-amino-4- (naphthalin-2-yl) thiazole are dissolved in 10 ml of tetrahydrofuran and mixed with 2.7 ml (19.4 mmol) of triethylamine. The acid chloride prepared according to Example a) is then added dropwise and the mixture is stirred for 25 hours. The solvent is distilled off and the residue is purified by chromatography, eluting with dichloromethane / ethanol (98: 2). A solid product is then obtained analogously to Example 29 and is reacted without further purification.
Yield: 0.55 g (25% of theory),
R _f value: 0.75 (silica gel; dichloromethane / ethanol = 19: 1)
C ₁₉ H ₁₀ N ₂ O ₃ S (346.36)
Mass spectrum: M ⁺ = 346.

0.55 g (1.6 mmol) of the solid product thus obtained and 10 ml (42.3 mmol) of 20% potassium hydroxide solution are refluxed in 16 ml of methanol for 6 hours. Then it is evaporated, the residue is diluted with water, the insoluble components are filtered off with suction, the mother liquor is concentrated with. Hydrochloric acid acidified and the precipitate is suctioned off.
Yield: 40 mg (7% of theory),
R _f value: 0.3 (silica gel; dichloromethane / ethanol = 4: 1)
C ₁₉ H ₁₂ N ₂ O ₄ S (364.38)
Mass spectrum: M ⁺ = 364
(MH) ^- = 363.

Example 43 N- [4- (naphthalene-2-yl) -thiazol-2-yl] -malonsäuremonoamid a. N- [4- (naphthalene-2-yl) -thiazol-2-yl] -malonsäuremonoamidmonomethylester

0.87 g (3.8 mmol) of 2-amino-4- (naphthalin-2-yl) thiazole and 1 ml (7.2 mmol) of triethylamine are placed in 10 ml of tetrahydrofuran and 0.4 ml (3.7 mmol) of malonic acid monomethyl ester chloride in 10 ml of tetrahydrofuran are added dropwise , After stirring for 25 hours, the solvent is distilled off, the residue is distributed in ethyl acetate / water, the organic phase is separated off, dried over sodium sulfate and evaporated.
Yield: 0.7 g (57% of theory),
R _f value: 0.6 (silica gel; dichloromethane / ethanol = 9: 1)
C ₁₇ H ₁₄ N ₂ O ₃ S (326.38)
Mass spectrum: (M + H) ⁺ = 327
(M + Na) ⁺ = 349
(MH) ^- = 325.

b. N- [4- (naphthalene-2-yl] -thiazol-2-yl] -malonsäuremonoamid

Prepared analogously to Example 9b from N- [4- (naphthalen-2-yl) thiazol-2-yl] monoamide malonate and lithium hydroxide in tetrahydrofuran / water.
Yield: 45% of theory,
C ₁₆ H ₁₂ N ₂ O ₃ S (312.35)
Mass spectrum: (MH) ^- = 311.

Example 44 3- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] naphthalene- 2-carboxylic acid

Prepared analogously to Example 1d from 2-amino-4- (naphthalen-2-yl) thiazole and naphthalene [2,3-c] furan-1,3-dione in pyridine and subsequent reaction analogously to Example 42b with 20% potassium hydroxide solution in methanol.
Yield: 47% of theory,
C ₂₅ H ₁₆ N ₂ O ₃ S (424.48)
Mass spectrum: (MH) ^- = 423.

Example 45 5- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] -2H- [1,2,3] - triazole-4-carboxylic acid

Prepared analogously 1d from 2-amino-4- (naphthalin-2-yl) thiazole and 5-chlorocarbonyl-2H- [1,2,3] triazole-4-carboxylic acid methyl ester in tetrahydrofuran and subsequent saponification analogously to Example 9b with lithium hydroxide in tetrahydrofuran / water.
Yield: 22% of theory,
C ₁₇ H ₁₁ N ₅ O ₃ S (365.37)
Mass spectrum: (MH) ^- = 364.

Example 46 2- [4- (naphthalene-2-yl) -thiazol-2-ylaminocarbonyl] -cyclobut- 1-ene carboxylic acid

Prepared analogously to Example 9b from 2- [4- (naphthalin-2-yl) thiazol-2-ylaminocarbonyl] cyclobut-1-encarboxylic acid methyl ester and lithium hydroxide in tetrahydrofuran / water.
Yield: 100% of theory,
C ₁₉ H ₁₄ N ₂ O ₃ S (350.399)
Mass spectrum: (MH) ^- = 349.

Example 47 1- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] -cyclopropanecarboxylic

Prepared analogously to Example 9b from 1- [4- (naphthalen-2-yl) thiazol-2-ylaminocarbonyl] cyclopropanecarboxylic acid ethyl ester and lithium hydroxide in tetrahydrofuran / water.
Yield: 93% of theory,
C ₁₈ H ₁₄ N ₂ O ₃ S (338.388)
Mass spectrum: (MH) ^- = 337
(M + H) ⁺ = 339.

Example 48 trans-2- [4- (naphthalen-2-yl) -thiazol-2-ylaminocarbonyl] -cyclopentane

Prepared analogously to Example 9b from 2- [4- (naphthalin-2-yl) thiazol-2-ylaminocarbonyl] cyclopentanecarboxylic acid methyl ester and lithium hydroxide in tetrahydrofuran / water.
Yield: 67% of theory,
C ₂₀ H ₁₈ N ₂ O ₃ S (366.442)
Mass spectrum: (MH) ^- = 365
(M + H) ⁺ = 367
(M + Na) ⁺ = 389.

Example 49 2- [4- (naphthalene-2-yl] -thiazol-2-ylamino] -nicotinic acid a. 2- [4- (naphthalene-2-yl) -thiazol-2-ylamino] -nikotinsäuremethylester

A mixture of 0.5 g (1.5 mmol) of 2-chloro-nicotinic acid methyl ester, 0.3 g (1.9 mmol) of 2-amino-4- (naphthalin-2-yl) thiazole, 1.3 g (3.99 mmol) of cesium carbonate, 15 mg ( 0.067 mmol) of palladium (II) acetate and 40 mg (0.064 mmol) of 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl is stirred in 10 ml of xylene at 120 ° C. for 6 hours. The solvent is then distilled off, the residue is distributed in dichloromethane / water, the organic phase is separated off and evaporated. The residue is purified by chromatography, eluting with dichloromethane / ethanol (99: 1).
Yield: 0.2 g (41% of theory),
R _f value: 0.6 (silica gel; dichloromethane / ethanol = 19: 1)
C ₂₀ H ₁₅ N ₃ O ₂ S (361.43)
Mass spectrum: (M + H) ⁺ = 362
(M + Na) ⁺ = 384.

b. 2- [4- (naphthalene-2-yl) -thiazol-2-ylamino] -nicotinic acid

Prepared analogously to Example 9b from 2- [4- (naphthalin-2-yl) thiazol-2-ylamino] nicotinic acid methyl ester and lithium hydroxide in tetrahydrofuran / water.
Yield: 91% of theory,
C ₁₉ H ₁₃ N ₃ O ₂ S (347.398)
Mass spectrum: M ⁺ = 347
(MH) ^- = 346.

Example 50 2- [4- (naphthalene-2-yl) -pyrimidin-2-ylamino] -benzoic acid a. 2-Chloro-4- (naphthalene-2-yl) pyrimidine

Prepared analogously to Example 18a from 2,4-dichloropyrimidine, 2-naphthylboronic acid, tetrakis (triphenylphosphine) palladium, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and sodium carbonate in dimethoxyethane.
Yield: 37% of theory,
R _f value: 0.6 (silica gel; petroleum ether / ethyl acetate = 6: 4)
C ₁₄ H ₉ ClN ₂ (240.69)
Mass spectrum: M ⁺ = 240/242 (chlorine isotopes)
(M + H) ⁺ = 241/243.

b. 2- [4- (naphthalene-2-yl) -pyrimidin-2-ylamino] -benzoic acid

A mixture of 0.2 g (0.83 mmol) of 2-chloro-4- (naphthalin-2-yl) pyrimidine and 0.1 g (0.83 mmol) of anthranilic acid is concentrated in 10 ml of ethanol and 0.1 ml. Hydrochloric acid heated to reflux for 9 hours. It is then diluted with water and the precipitate is filtered off with suction. The product obtained in this way is reacted with 20% potassium hydroxide solution in methanol as in Example 42b.
Yield: 42% of theory,
C ₂₁ H ₁₅ N ₃ O ₂ (341.373)
Mass spectrum: (MH) ^- = 340.

Example 51 2- [6- (naphthalene-2-yl) -pyridin-2-ylamino] -benzoic acid

Prepared analogously to Example 9b from 2- [6- (naphthalin-2-yl) pyridin-2-ylamino] benzoic acid methyl ester and lithium hydroxide in tetrahydrofuran / water.
Yield: 4% of theory,
C ₂₂ H ₁₆ N ₂ O ₂ (340.385)
Mass spectrum: M ⁺ = 340.

Example 52 2- [3- (Naphalin-2-yl) -phenylamino] -nicotinic acid a. 2- (3-nitro-phenyl) -naphthalene

Prepared analogously to Example 18a from 1-bromo-3-nitrobenzene, 2-naphthylboronic acid, tetrakis (triphenylphosphine) palladium, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and sodium carbonate in dimethyoxyethane.
Yield: 81% of theory,
R _f value: 0.5 (silica gel; petroleum ether / ethyl acetate = 9: 1).

b. 3- (naphthalene-2-yl] aniline

4.5 g (25.8 mmol) of sodium dithionite in 15 ml of water are added to a solution of 1.6 g (6.4 mmol) of 2- (3-nitro-phenyl) naphthalene in 25 ml of pyridine and the mixture is stirred at 55 ° C. for 1 hour. 50 ml of semi-saturated sodium carbonate solution are then added and the precipitate is filtered off with suction. The mother liquor is extracted with dichloromethane, the combined organic extracts dried and evaporated.
Yield: 0.8 g (57% of theory),
R _f value: 0.6 (silica gel; petroleum ether / ethyl acetate = 5: 5).

c. 2- [3- (naphthalene-2-yl) -phenylamino] -nicotinic acid

Prepared analogously to Example 49a from 3- (naphthalin-2-yl) aniline, 2-chloro-nicotinic acid methyl ester, cesium carbonate, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and palladium (II) acetate in xylene and subsequent saponification of the 2- [3- (naphthalin-2-yl) phenylamino] nicotinic acid methyl ester thus obtained analogously to Example 9b with lithium hydroxide in tetrahydrofuran / water.
Yield: 47% of theory,
C ₂₂ H ₁₆ N ₂ O ₂ (340.385)
Mass spectrum: M ⁺ = 340
(MH) ^- = 339
(M + H) ⁺ = 341.

Example 53 2- [3- (naphthalene-2-yl) phenylamino] -benzoic acid

Prepared analogously to Example 49a from 3- (naphthalin-2-yl) aniline, 2-iodo-benzoic acid methyl ester, cesium carbonate, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and palladium (II) acetate in xylene and subsequent saponification of the methyl 2- [3- (naphthalen-2-yl) phenylamino] benzoate obtained in this way analogously to Example 9b with lithium hydroxide in tetrahydrofuran / water.
Yield: 43% of theory,
C ₂₃ H ₁₇ NO ₂ (339.397)
Mass spectrum: (MH) ^- = 338.

Example 54 2- [4-methyl-6- (naphthalen-2-yl) -pyrimidin-2-ylamino] -5-nitrobenzoic acid a. 2-amino-4-methyl-6- (naphthalen-2-yl) pyrimidine

Prepared analogously to Example 18a from 2-amino-4-chloro-6-methylpyrimidine, 2-naphthalene boronic acid, tetrakis (triphenylphosphine) palladium, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and sodium carbonate in dimethyoxyethane ,
Yield: 55% of theory,
R _f value: 0.4 (silica gel; petroleum ether / ethyl acetate = 4: 6)
C ₁₅ H ₁₃ N ₃ (235.29)
Mass spectrum: (M + H) ⁺ = 236.

b. 2- [4-methyl-6- (naphthalen-2-yl) -pyrimidin-2-ylamino] -5-nitro-benzoic acid

Prepared analogously to Example 49a from 2-amino-4-methyl-6- (naphthalin-2-yl) pyrimidine, 2-bromo-5-nitro-benzoic acid methyl ester, cesium carbonate, 2,2'-bis (diphenylphosphino) - 1,1'-binaphthyl and palladium (II) acetate in xylene and subsequent saponification of the 2- [4-methyl-6- (naphthalin-2-yl) pyrimidin-2-ylamino] -5-nitro-benzoic acid thus obtained. methyl ester analogous to Example 9b with lithium hydroxide in tetrahydrofuran / water.
Yield: 48% of theory,
C ₂₂ H ₁₆ N ₄ O ₄ (400.397)
Mass spectrum: (MH) ^- = 399.

Example 55 5-amino-2- [4-methyl-6- (naphthalen-2-yl) -pyrimidin-2-ylamino] - benzoic acid a. 2- [4-methyl-6- (naphthalen-2-yl) -pyrimidin-2-ylamino] -5-amino-benzoic acid methylester

0.4 g (0.91 mmol) of methyl 2- [4-methyl-6- (naphthalen-2-yl) pyrimidin-2-ylamino] -5-nitro-benzoate are dissolved in 50 ml of tetrahydrofuran and after addition of 250 mg 10 % Palladium on carbon hydrogenated with hydrogen for 2 hours. The catalyst is filtered off and the mother liquor is evaporated. The crude product is purified by chromatography, eluting with petroleum ether / ethyl acetate (6: 4).
Yield: 0.3 g (71% of theory),
R _f value: 0.35 (silica gel; petroleum ether / ethyl acetate = 1: 1)
C ₂₃ H ₂₀ N ₄ O ₂ (384.44)
Mass spectrum: (M + H) ⁺ = 385.

b. 5-amino-2- [4-methyl-6- (naphthalen-2-yl) -pyrimidin-2-ylamino] -benzoic acid

Prepared analogously to Example 9b from 5-amino-2- [4-methyl-6- (naphthalin-2-yl) pyrimidin-2-ylamino] benzoic acid methyl ester and lithium hydroxide in tetrahydrofuran / water.
Yield: 39% of theory,
C ₂₂ H ₁₈ N ₄ O ₂ (370.41)
Mass spectrum: (MH) ^- = 369.

Example 56 5-acetylamino-2- [4-methyl-6- (naphthalen-2-yl) -pyrimidin-2-ylamino-benzoic acid

0.2 g (0.54 mmol) of 2- [4-methyl-6- (naphthalin-2-yl) pyrimidine-2-ylamino] -5-amino-benzoic acid methyl ester are dissolved in 5 ml of pyridine and after addition of 0.1 g ( 0.63 mmol) of acetyl chloride was stirred for 4 hours. The solvent is then distilled off, the residue is taken up in 12 ml of water and 16 ml of tetrahydrofuran and, after addition of 8 ml (8 mmol) of 1 molar lithium hydroxide solution, stirred for a further 6 hours. Then it is neutralized with hydrochloric acid and evaporated. The crude product is purified by chromatography, eluting with ethyl acetate / ethanol (7: 3).
Yield: 0.1 g (58% of theory),
C ₂₄ H ₂₀ N ₄ O ₃ (412.45)
Mass spectrum: (MH) ^- = 411
(M + H) ⁺ = 413.

Example 57 2- [4- (naphthalene-2-yl) -thiazol-2-ylamino] -5-nitro-benzoic acid

Prepared analogously to Example 9b from 2- [4- (naphthalin-2-yl) thiazol-2-ylamino] -5-nitro-benzoic acid methyl ester and lithium hydroxide in tetrahydrofuran / water.
Yield: 39% of theory,
C ₂₀ H ₁₃ N ₃ O ₄ S (391.41)
Mass spectrum: (MH) ^- = 390.

Example 58 5-acetylamino-2- [4- (naphthalen-2-yl) -thiazol-2-ylamino] - benzoic acid

Prepared analogously to Example 56 from 5-amino-2- [4- (naphthalen-2-yl) thiazol-2-ylamino] benzoic acid methyl ester and acetyl chloride in pyridine and subsequent saponification with lithium hydroxide in tetrahydrofuran / water.
Yield: 49% of theory,
C ₂₂ H ₁₇ N ₃ O ₃ S (403.46)
Mass spectrum: (MH) ^- = 402.

Example 59 2- [4- (naphthalene-2-yl) -pyrimidin-2-ylamino] -4- (pyrrolidin 1-ylaminocarbonyl] -benzoic acid

Prepared analogously to Example 9b from 2- [4- (naphthalin-2-yl) pyrimidin-2-ylamino] -4- (pyrrolidin-1-ylaminocarbonyl) benzoic acid methyl ester and sodium hydroxide in methanol.
Yield: 32% of theory,
C ₂₆ H ₂₃ N ₅ O ₃ (453.50)
Mass spectrum: (MH) ^- = 452
(M + H) ⁺ = 454.

Example 60 2- [4- (naphthalene-2-yl) -thiazol-2-ylcarbonylamino] terephthalic acid

Prepared analogously to Example 9b from 2- [4- (naphthalin-2-yl) thiazol-2-ylcarbonylamino] terephthalic acid dimethyl ester and potassium hydroxide in methanol.
Yield: 32% of theory,
C ₂₂ H ₁₄ N ₂ O ₅ S (418.43)
Mass spectrum: (MH) ^- = 417.

Example 61 2- [4- (1,3-dihydro-isoindol-2-yl) -pyrimidin-2-ylamino] -benzoic acid a. 2-chloro-4- (2,3-dihydro-1H-isoindol-2-yl) pyrimidine

A mixture of 0.5 g (3.35 mmol) of 2,4-dichloropyrimidine, 0.5 g (3.2 mmol) of 2,3-dihydro-1H-isoindole hydrochloride and 0.6 ml (3.4 mmol) of N-ethyl-diisopropylamine is dissolved in 40 ml Dichloromethane stirred for 3 hours. The mixture is then evaporated, the residue is distributed in ethyl acetate / water, the organic phase is separated off and evaporated.
Yield: 0.4 g (55% of theory),
R _f value: 0.4 (silica gel; dichloromethane / ethanol = 19: 1).

b. 2- [4- (2,3-dihydro-1H-isoindol-2-yl) -pyrimidin-2-ylamino] - benzoic acid

Prepared analogously to Example 49a from 2-chloro-4- (2,3-dihydro-1H-isoindol-2-yl) pyrimidine, methyl anthranilate, cesium carbonate, palladium (II) acetate and 2,2'-bis (diphenylphosphino) ) -1,1'-binaphthyl in xylene and subsequent saponification of the 2- [4- (2,3-dihydro-1H-isoindol-2-yl) -pyrimidin-2-ylamino) -benzoic acid methyl ester obtained with lithium hydroxide in Tetrahydrofuran / water analogous to Example 9b.
Yield: 4% of theory,
C ₁₉ H ₁₆ N ₄ O ₂ (332.36)
Mass spectrum: (MH) ^- = 331
(M + H) ⁺ = 333.

Example 62 2- [3- (naphthalene-2-yl) -phenylearbonylamino] -benzoic acid

Prepared analogously to Example 9b from methyl 2- [3- (naphthalin-2-yl) phenylcarbonylamino] benzoate and sodium hydroxide in tetrahydrofuran / water.
Yield: 50% of theory,
C ₂₄ H ₁₇ NO ₃ (367.41)
Mass spectrum: (MH) ^- = 366
(M + Na) ⁺ = 390
M ⁺ = 367.

• 1. 2-[4-(Naphthalin-2-yl)-pyrimidin-2-ylamino]-4-(methylaminocarbonyl)-benzoesäure
• 2. 2-[4-(Naphthalin-2-yl)-pyrimidin-2-ylamino]-4-(ethylaminocarbonyl)-benzoesäure
• 3. 2-[4-(Naphthalin-2-yl)-pyrimidin-2-ylamino]-4-(propylaminocarbonyl)-benzoesäure
• 4. 2-[4-(3-Brom-4-chlor-phenyl)-thiazol-2-ylaminocarbonyl]- benzoesäure
• 5. 2-[4-(4-Brom-3-chlor-phenyl)-thiazol-2-ylaminocarbonyl]- benzoesäure
• 6. 2-[4-(3,4-Dibrom-phenyl)-thiazol-2-ylaminocarbonyl]- benzoesäure

Beispiel 63 Tabletten, enthaltend 50 mg Wirkstoff Wirkstoff 50,0 mg Calciumphosphat 70,0 mg Milchzucker 40,0 mg Maisstärke 35,0 mg Polyvinylpyrrolidon 3,5 mg Magnesiumstearat 1,5 mg 200,0 mg The following compounds can be prepared analogously to Example 62:

• 1. 2- [4- (Naphthalin-2-yl) pyrimidin-2-ylamino] -4- (methylaminocarbonyl) benzoic acid
• 2. 2- [4- (Naphthalin-2-yl) pyrimidin-2-ylamino] -4- (ethylaminocarbonyl) benzoic acid
• 3. 2- [4- (Naphthalin-2-yl) pyrimidin-2-ylamino] -4- (propylaminocarbonyl) benzoic acid
• 4. 2- [4- (3-bromo-4-chlorophenyl) thiazol-2-ylaminocarbonyl] benzoic acid
• 5. 2- [4- (4-bromo-3-chlorophenyl) thiazol-2-ylaminocarbonyl] benzoic acid
• 6. 2- [4- (3,4-dibromophenyl) thiazol-2-ylaminocarbonyl] benzoic acid

Example 63 tablets containing 50 mg of active ingredient active substance 50.0 mg calcium phosphate 70.0 mg lactose 40.0 mg corn starch 35.0 mg polyvinylpyrrolidone 3.5 mg magnesium stearate 1.5 mg 200.0 mg

manufacturing

The active ingredient, CaHPO ₄ , 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 64 Dragées containing 50 mg of active ingredient active substance 50.0 mg lysine 25.0 mg lactose 60.0 mg corn starch 34.0 mg gelatin 10.0 mg magnesium stearate 1.0 mg 180.0 mg

manufacturing

The active ingredient is mixed with the excipients and with a aqueous gelatin solution moistened. After screening and Drying, the granules are mixed with magnesium stearate and added Cores pressed.

The cores produced in this way are covered with a casing by known processes. Colorant can be added to the coating suspension or solution. Example 65 Dragées containing 100 mg of active ingredient active substance 100.0 mg lysine 50.0 mg lactose 86.0 mg corn starch 50.0 mg polyvinylpyrrolidone 2.8 mg Microcrystalline cellulose 60.0 mg magnesium stearate 1.2 mg 350.0 mg

manufacturing

The active ingredient is mixed with the excipients and with a aqueous PVP solution moistened. The moist mass is through placed a 1.5 mm sieve and dried at 45 ° C. After this Drying is sieved again and the magnesium stearate admixed. This mixture is pressed into cores.

The cores produced in this way are covered with a casing by known processes. Colorants can be added to the coating suspension or solution. Example 66 capsules containing 250 mg of active ingredient active substance 250.0 mg corn starch 68.5 mg magnesium stearate 1.5 mg 320.0 mg

manufacturing

The active ingredient and corn starch are mixed and mixed with water moistened. The moist mass is sieved and dried. The dry granules are sieved and with magnesium stearate mixed. The final mix is in size 1 hard gelatin capsules bottled.

Claims (10)

1. Carboxylic acid derivatives of the general formula

R ₁ - A - B - R ₂ (I),

in the
R _{1 is} a phenyl, phenyl-C _1-3 alkyl, phenyl C _2-4 alkenyl or naphthyl group, in each of which the aromatic parts are represented by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl or C _1-3 alkoxy group can be mono- or disubstituted, where the substituents can be the same or different,
a phenyl group to which an n-propylene, n-butylene, methylenedioxy or ethylenedioxy bridge is fused onto two adjacent carbon atoms,
a phenyl group, to which a 5-membered heteroaromatic group is fused via two adjacent carbon atoms, in the heteroaromatic part
an imino group optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom,
an imino group optionally substituted by a C _1-3 alkyl group and an oxygen, sulfur or nitrogen atom,
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
a pyridinyl or pyronyl group optionally substituted by a C _1-3 alkyl group, to which a phenyl ring can be fused in each case via two adjacent carbon atoms, with a methine group in the 2- or 4-position additionally being replaced by a hydroxymething group in the pyridine ring mentioned above can
A is a phenylene group optionally substituted by a C _1-3 alkyl group, in which one, two or three methine groups in the aromatic part can be replaced by nitrogen atoms, or
a 5-membered heteroarylene group optionally substituted by a C _1-3 alkyl group, the heteroaromatic part being defined as mentioned above,
B is a -HN-, -NH-CO-, -CO-NH-, -NH-CS or -CS-NH group, in which the -NH group can in each case be substituted by a C _1-3 alkyl group , and
R _{2 is} a C _3-7 cycloalkyl or C _4-7 cycloalkenyl group substituted by a carboxy group,
a phenyl or naphthyl group substituted by a carboxy group, in each of which the aromatic part is replaced by a hitro, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, C _1-3 -Alkanoylamino, N- (C _1-3 alkyl) -C _1-3 alkanoylamino or carboxy group, through an aminocarbonyl or C _1-3 alkylaminocarbonyl group, in each of which the hydrogen atom of the aminocarbonyl group through a C _1-3 Alkyl or C _3-7 cycloalkyleneimino group can be replaced, monosubstituted or by a fluorine, chlorine, bromine or iodine atom, by a C _1-3 alkyl or C _1-3 alkoxy group mono- or disubstituted , where the substituents can be the same or different,
a 5- or 6-membered heteroaryl group substituted by a carboxy group, the 5-membered heteroaryl group being defined as mentioned above and
the 6-membered heteroaryl group contains one or two nitrogen atoms,
or a straight-chain or branched C _1-6 alkyl or C _2-6 alkenyl group substituted by a carboxy group,
the carboxy groups mentioned in the definition of the abovementioned radicals can additionally be replaced by a radical which is converted into a carboxy group in vivo or is negatively charged under physiological conditions,
and the imino or amino group mentioned in the definition of the abovementioned radicals can be substituted by a radical which can be split off in vivo,
their isomers and their salts. 2. Carboxylic acid derivatives of the general formula I according to claim 1, in which
R _{1 is} a phenyl group which can be mono- or disubstituted by a chlorine, bromine or iodine atom, by a methyl or methoxy group, where the substituents can be identical or different,
a phenylvinyl, benzothiophenyl or naphthyl group,
a phenyl group to which an n-propylene, n-butylene, methylenedioxy or ethylenedioxy bridge is fused onto two adjacent carbon atoms,
a pyridinyl or pyronyl group optionally substituted by a methyl group, to each of which a phenyl ring is fused via two adjacent carbon atoms, in which case a methine group in the 2- or 4-position can additionally be replaced by a hydroxymething group in the pyridine ring mentioned above,
A is a phenylene, furanylene, thiophenylene, thiazolylene, imidazolylene, thiadiazolylene, pyridinylene or pyrimidylene group, optionally substituted by a methyl group, with the proviso that the linkage with the adjacent radicals R ₁ and B does not have the o position of the above-mentioned aromatics,
B is a -HN-, -NH-CO-, -CO-NH-, -NH-CS or -CS-NH group, in which the -NH group can in each case be substituted by a methyl group, and
R _{2 is} a C _3-6 cycloalkyl or C _4-6 cycloalkenyl group substituted by a carboxy group,
a phenyl group substituted by a carboxy group which is monosubstituted in the phenyl part by a nitro, amino, acetylamino, carboxy, aminocarbonyl or pyrrolidinoaminocarbonyl group or by a fluorine, chlorine, bromine or iodine atom, by a methyl or methoxy group - or is disubstituted, where the substituents can be the same or different,
a naphthyl, furanyl, thiophenyl, triazolyl or pyridinyl group substituted by a carboxy group,
is an aminocarbonylmethyl group or a methyl or 1,2-dimethylvinyl group substituted by a carboxy group,
their isomers and their salts. 3. carboxylic acid derivatives of the general formula I according to claim 1, in which
R ₁ , R ₂ and A are as defined in claim 2 and
B represents an -NH or -NH-CO group, the -NH-CO group being linked to the radical R ₂ via the -CO group,
their isomers and their salts. 4. carboxylic acid derivatives of the general formula I according to claim 1, in which
R _{1 is} a phenyl group which is mono- or disubstituted by a chlorine, bromine or iodine atom, where the substituents can be the same or different,
a naphthyl or (2-oxo-2H-chromen-3-yl) group,
A is a 1,3-phenylene, 2,5-thiazolylene, 2,4-pyridinylene, 2,6-pyridinylene or 2,4-pyrimidylene group,
B represents an -NH or -NH-CO group, the -NH-CO group being linked to the radical R ₂ via the -CO group,
R _{2 is} a 2-carboxy-cyclopent-2-enyl, 2-carboxy-cyclohex-2-enyl, 3-carboxy-thien-2-yl or 2-carboxy-1,2-dimethylvinyl group or
a 2-carboxyphenyl group which is optionally monosubstituted by a fluorine, chlorine or bromine atom or by a methyl or nitro group,
their isomers and their salts. 5. The following carboxylic acid derivatives of the general formula I according to claim 1: a) 2- [4- (naphthalen-2-yl) thiazol-2-ylaminocarbonyl] benzoic acid, b) 2- [4- (Naphthalin-2-yl) thiazol-2-ylaminocarbonyl] cyclopent-1-ene carboxylic acid and c) 2- [4- (Naphthalin-2-yl) pyrimidin-2-ylamino] benzoic acid
and their salts. 6. Physiologically acceptable salts of the compounds according to the Claims 1 to 5. 7. Medicament containing a compound according to at least one of claims 1 to 5 or a salt according to claim 6 in addition to optionally one or more inert carriers and / or diluents. 8. Use of a connection according to at least one of the Claims 1 to 5 or a salt according to claim 6 for the preparation a drug that inhibits telomerase. 9. Method of manufacturing a drug according to Claim 7, characterized in that in a non-chemical way a connection according to at least one of claims 1 to 5 or a salt according to claim 6 in one or more inert Carriers and / or diluents are incorporated. 10. A process for the preparation of the compounds according to claims 1 to 6, characterized in that a) implementation of a compound of the general formula

R ₁ - A - U (II),

with a compound of the general formula

V - R ₂ (III),

in which
R ₁ , R ₂ and A are defined as mentioned in claims 1 to 5,
one of the radicals U or V is an amino group which is optionally substituted by a C _1-3 alkyl group and
the other of the radicals U or V is a carboxy group, or its reactive derivatives are reacted or b) for the preparation of a compound of the general formula I in which R _{2 is defined} with the proviso as mentioned in claims 1 to 5 that the carboxy group of the radical R _{2 is} in the 2-position and B represents an -NHCO group , wherein the carbonyl group of the radical B is connected to the radical R ₂ , a compound of the general formula


or the general formula


in which
R ₁ and A are defined as mentioned in claims 1 to 5,
R ₂ 'has the meanings mentioned for R ₂ in claims 1 to 5 with the proviso that the carbonyl group of the radical R ₂ originating from the carboxy substituent is in the 2-position, and
A 'has the meanings mentioned for A in claims 1 to 5 with the proviso that A contains a nitrogen atom which is linked to the carbonyl group, is hydrolyzed or c) for the preparation of a compound of general formula I, in which B represents an --NH group optionally substituted by a C _1-3 alkyl group, a compound of general formula

R ₁ - A - X (VI),

with a compound of the general formula

Y - R ₂ (VII),

in which
R ₁ , R ₂ and A are defined as mentioned in claims 1 to 5,
one of X or Y is an amino group optionally substituted by a C _1-3 alkyl group and
the other of the radicals X or Y represents a leaving group, is implemented or d) for the preparation of a compound of the general formula I, in which B represents an —NHCS or —CS-NH group which is optionally substituted on the amide nitrogen atom by a C _1-3 alkyl group, a compound of the general formula

R ₁ - A - B '- R ₂ (VIII),

in the
R ₁ , R ₂ and A are as defined in claims 1 to 5 and
B 'denotes an -NH-CO- or -CO-NH group which is optionally substituted on the amide nitrogen atom by a C _1-3 alkyl group, is reacted with a sulfur-introducing agent or e) for the preparation of a compound of the general formula I in which R _{2 has} the meanings mentioned for R ₂ in claims 1 to 5 with the proviso that the carboxy substituent is replaced by a group which can be converted into a carboxy group in vivo, a compound the general formula

R ₁ - A - B - R ₂ "(IX),

in the
R ₁ , A and B are as defined in claims 1 to 5 and
R ₂ "has the meanings mentioned for R ₂ in claims 1 to 5 with the proviso that this is substituted by a carboxy group, or its alkali salt with a compound of the general formula

Z - R (X),

in the
R is a C _1-6 alkyl, phenyl _1-3 alkyl or C _3-9 cycloalkyl group, where the C _5-8 cycloalkyl part can additionally be substituted by one or two C _1-3 alkyl groups, one C _5-8 cycloalkyl group in which a methylene group in the 3- or 4-position through an oxygen atom or through one optionally through a C _1-3 -alkyl-, phenyl-C _1-3 -alkyl-, phenyl-C _{1- 3} -alkoxycarbonyl- or C _2-6 -alkanoyl group substituted imino group and the cycloalkyl part can additionally be substituted by one or two C _1-3 -alkyl groups, a C _4-7 -cycloalkenyl-, C _3-5 -alkenyl-, Phenyl-C _3-5 -alkenyl-, C _3-5 -alkynyl or phenyl-C _3-5 -alkynyl group with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, one C _3-8 cycloalkyl-C _1-3 alkyl group, a bicycloalkyl group with a total of 8 to 10 carbon atoms, the bicycloalkyl part being additionally substituted by one or two C _1-3 alkyls L groups can be substituted, a 1,3-dihydro-3-oxo-1-isobenzfuranylgruppe or a group of the general formula

R _a - CO - O - (R _b CR _c ) -,

in the
R _a to R _{c are} as defined in claims 1 to 5,
and Z represents a nucleofugic leaving group, is reacted or f) for the preparation of a compound of the general formula I in which R ₂ contains a carboxy group, a compound of the general formula

R ₁ - A - B - R ₂ (XI)

in the
R ₁ , A and B are as defined in claims 1 to 5 and
R ₂ '''has the meanings mentioned for R ₂ in claims 1 to 5 with the proviso that R ₂ is substituted by a group which can be converted into a carboxy group, is converted into a corresponding carboxy compound by means of hydrolysis, hydrogenolysis or thermolysis and
if desired, a compound of the general formula I thus obtained which contains an amino group is subsequently converted into an appropriately acylated compound of the general formula I by acylation 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 stereoisomers and / or
a compound of the general formula I thus obtained is converted into its salts, in particular for pharmaceutical use into its physiologically tolerable salts with an inorganic or organic acid or base.