HK1080075A - Thiazolidinones and the use thereof as polo-like kinase inhibitors - Google Patents

Description

Thiazolidinones, their preparation and their use as medicaments

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Technical Field

The present invention relates to thiazolidinone compounds, processes for their preparation and their use as polo-like kinase (Plk) inhibitors for the treatment of various diseases.

Background

Tumor cells are distinguished by uninhibited cell cycle processes. On the other hand, this is based on the loss of control proteins such as RB, p16, p21, p53, etc., and the activation of the so-called promoters of cell cycle processes, the cyclin-dependent kinases (cdks). Cdk has been identified in medicine as an anti-tumor targeting protein. In addition to Cdk, serine/threonine kinases that regulate a new cell cycle, so-called polo-like kinases, are described, which are not only involved in the regulation of the cell cycle, but also coordinate with other processes during mitosis and cytoplasmic separation (spindle formation, chromosome segregation). Thus, this class of proteins represents a point of benefit for therapeutic intervention in proliferative diseases such as cancer (Descombes and Nigg. Embo J, 17, 1328ff, 1998; Glover et al, Genes Dev 12, 3777ff, 1998).

High expression rates of Plk-1 have been found in "non-small cell lung Cancer" (Wolf et al Oncogene, 14, 543ff, 1997), melanoma (Strebhardt et al JAMA, 283, 479ff, 2000), squamous cell carcinoma (Knecht et al Cancer Res, 59, 2794ff, 1999) and esophageal carcinoma (Tokumitsu et al Int JOncol 15, 687ff, 1999).

The correlation between high expression rates and poor predictions in tumor patients was demonstrated in the majority of various tumors (Strebhardt et al, JAMA, 283, 479ff, 2000; Knecht et al, Cancer Res, 59, 2794ff, 1999; and Tokumitsu et al, Int J Oncol 15, 687ff, 1999).

Constitutive expression of Plk-1 in NIH-3T3 cells resulted in malignant transformation (increased proliferation, growth in soft agar, colony formation, and tumor development in hairless mice) (Smith et al, Biochem Biophys Res Comm, 234, 397ff., 1997).

Microinjection of the Plk-1 antibody in HeLa cells results in inappropriate mitosis (Lane et al; Journal cell Biol, 135, 1701ff, 1996).

With "20-mer" antisense oligomers, expression of Plk-1 in a549 cells can be inhibited and their ability to survive stopped. Significant antitumor effects were also demonstrated in hairless mice (Mundt et al, Biochem Biophys Res Comm, 269, 377ff., 2000).

Microinjection of anti-Plk antibodies in non-immortalized human Hs68 cells showed a significantly higher proportion of cells that were still at growth arrest in G2 phase and showed little evidence of inappropriate mitosis compared to HeLa cells (Lane et al; Journal cell Biol, 135, 170lff, 1996).

In contrast to tumor cells, antisense oligonucleotides inhibit the growth and survival of primary human mesangial cells (Mundt et al, Biochem Biophys Res Comm, 269, 377ff., 2000).

In mammals, three other polo kinases are currently described, in addition to Plk-1, which are induced in the form of mitogenic responses and exert their effects during the G1 phase of the cell cycle. On the other hand, they are the so-called Prk/Plk-3 (human homolog of murine Fnk: fibroblast growth factor-induced kinase; Wiest et al, Genes, Chromosomes & Cancer, 32: 384ff, 2001), Snk/Plk-2 (serum-induced kinase, Liby et al, DNASequence, 11, 527-33, 2001) and sak/Plk4(Fode et al, Proc. Natl. Acad. Sci. U.S.A., 91, 6388 ff; 1994).

Thus, inhibition of Plk-1, as well as other kinases of the polo family, such as Plk-2, Plk-3, and Plk-4, represents a promising approach for the treatment of various diseases.

Thiazolidinones have now been found to be suitable inhibitors of polo family kinases.

Sequence identity in the Plk domain of polo family is between 40-60%, allowing partial interaction of a kinase inhibitor with one or more other kinases in the family. However, depending on the structure of the inhibitor, this effect may also occur selectively or preferentially only on one kinase of the polo family.

The compounds according to the invention substantially inhibit polo-like kinases, which have an effect on, for example, the following conditions: cancer, such as solid cancer and leukemia; autoimmune diseases such as psoriasis, alopecia and multiple sclerosis, chemotherapy-induced alopecia and mucositis; cardiovascular diseases such as stenosis, arteriosclerosis and restenosis; infectious diseases, for example caused by single-celled parasites such as trypanosomes, toxoplasma or plasmodia, or infectious diseases produced by fungi; renal diseases, such as glomerulonephritis; chronic neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease; acute neurodegenerative diseases, such as cerebral ischemia and neurotrauma; viral infections, such as giant cell infection, herpes, hepatitis b and c, and HIV disease.

Disclosure of Invention

Accordingly, the present invention relates to compounds of general formula I:

wherein:

x and Y are the same or differentAnd is independently hydrogen, aryl, cyano, C₃-C₆Cycloalkyl or represents

group-COOR⁴、-CONR¹⁵-(CH₂)_n-R²⁵、-COOR²⁵、-CONR¹⁵R¹⁶or-COR¹³，

R¹、R¹¹、R¹²、R¹⁵、R¹⁶、R¹⁹And R²⁰Are identical or different and represent hydrogen, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, (COOR)¹⁴)-(CH₂)_n-、(C₃-C₆Cycloalkyl) -C₁-C₄Alkylene radical, C₃-C₆Cycloalkyl, phenylsulfonyl, phenyl-C₃-C₆Cycloalkyl radical, C₁-C₁₀Alkanoyl radical, C₁-C₆-alkoxy-C₁-C₆Alkylene radical, C₁-C₄-alkoxycarbonyl-C₁-C₄Alkylene, hydroxy-C₁-C₄Alkylene radical, -C₁-C₆alkyl-O-Si (phenyl)₂-C₁-C₆Alkyl, or represents a group COOR¹⁴、-COR¹³、-SO₂R¹⁸、-(CH₂)_n-NR¹⁵R¹⁶Or- (CH)₂)_n-C(CH₃)_q-(CH₂)_nNR¹⁵R¹⁶or-NR¹¹R¹²Or is or

Or represents aryl, heteroaryl, heterocyclyl, aryl-C₁-C₄Alkylene, heteroaryl-C₁-C₄Alkylene, aryloxy-C₁-C₄Alkylene, heteroaryloxy-C₁-C₄Alkylene or aryl-C₁-C₄Alkylene oxy-C₁-C₄Alkylene, which groups are optionally substituted in the same or different manner at one or more positions by: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyloxy, phenyl, cyano, halogen, hydroxy, C₁-C₄Alkoxy, phenoxy, benzyloxy, C₁-C₄Alkylsulfanyl (sulfanyl), benzylsulfanyl, phenylsulfanyl, dimethylamino, acetylamino, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, acetyl, -CO-C₁-C₆Alkyl, 1-iminoethyl or nitro, or represents C substituted in one or more positions by fluorine₁-C₁₀An alkyl group, a carboxyl group,

R²and R³Are identical or different and represent hydrogen, C₁-C₆Alkyl, hydroxy-C₁-C₆Alkylene radical, C₃-C₆-cyclohexyl or represents a radical-COOR¹⁴、-CONR¹⁵R¹⁶、-COR¹³、-SO₂R¹⁸、-NR¹¹R¹²、-(CH₂)n-A，

Or represents aryl, heteroaryl or heterocyclyl, which are optionally substituted in the same or different manner at one or more positions by: c₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkoxy, halogen, cyano, hydroxy-C₁-C₆Alkylene, hydroxy-C₁-C₆Alkyleneoxy, aryl, heteroaryl, heterocyclyl, -C₁-C₆alkyl-COOR⁸Or by the following groups: -OR¹⁰、-COR¹³、-COOR¹⁴、-NR¹¹R¹²、-NR¹¹-CO-NR¹¹R¹²、-NR¹¹-CO-R¹³、-NR¹¹-SO₂-R¹³、-(CH₂)_n-CO-NR¹⁵R¹⁶、-SR¹⁰or-SO₂R¹⁸，

R⁴、R⁸、R⁸、R¹⁰、R¹³、R¹⁴、R¹⁷And R¹⁸Are identical or different and represent hydrogen, C₁-C₁₀Alkyl, hydroxy-C₁-C₆Alkylene oxy-C₁-C₆Alkylene radical, C₁-C₆-alkoxy-CO-C₁-C₆Alkylene, - (CH)₂)_n-CO-NR¹⁵R¹⁶、C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, (C)₃-C₆Cycloalkyl) -C₁-C₄Alkylene, halogeno C₁-C₆Alkyl, hydroxy-C₁-C₆Alkylene, (COOR)¹⁴)-(CH₂)_n-, hydroxy- (CH)₂)_n-O-(CH₂)_n、C₃-C₆Cycloalkyl radical, C₁-C₁₀Alkanoyl or represents the group-NR¹¹R¹²、-(CH₂)_n-CO-R²⁵、-(CH₂)_n-NR¹⁵R¹⁶、COOR¹⁴-(CH₂)_n-or-COR¹³Or represents optionally C at one or more positions in the same or different manner₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyloxy, phenyl, cyano, halogen, hydroxy-C₁-C₆Alkyl radical, C₁-C₄Alkoxy, phenoxy, benzyloxy, C₁-C₄Alkylsulfanyl, benzylsulfanyl, phenylsulfanyl, dimethylamino, acetylamino, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, acetyl, -CO-C₁-C₆Alkyl, 1-iminoAryl, heteroaryl, heterocyclyl, aryl-C substituted by ethyl or nitro groups₁-C₄Alkylene, heteroaryl-C₁-C₄Alkylene, aryloxy-C₁-C₄Alkylene, heteroaryloxy-C₁-C₄Alkylene or aryl-C₁-C₄Alkylene oxy-C₁-C₄Alkylene or represents C substituted in one or more positions by fluorine₁-C₁₀Alkyl, or represents the group-NR¹¹R¹²、-COR¹³、-SO₂R¹⁸、-(CH₂)_n-NR¹⁵R¹⁶、-(CH₂)_n-C(CH₃)_q-(CH₂)_nNR¹⁵R¹⁶Or is or

Or R²And R³、R¹¹And R¹²、R¹⁵And R¹⁶And R¹⁹And R²⁰Each independently of the others, together form a 3-to 10-membered ring, which optionally contains one or more nitrogen, oxygen or sulfur atoms,

R³represents hydrogen, and

R²represents a group- (L-M) in which

L represents a group-C (O) -, -S (O)₂-、-C(O)N(R⁷)-、-S(O)₂N(R⁷)-、-C(S)N(R⁷)-、-C(S)N(R⁷) C (O) O-, -C (O) O-or-C (O) S-, and M represents hydrogen, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, (C)₃-C₆-cycloalkyl) -C₁-C₄Alkylene radical, C₃-C₆Cycloalkyl, phenyl-C₃-C₆Cycloalkyl radical, C₁-C₁₀Alkanoyl radical, C₁-C₄-alkoxy-C₁-C₄Alkylene radical, C₁-C₄-alkoxycarbonyl-C₁-C₄Alkylene, hydroxy-C₁-C₁₀Alkylene or represents aryl, heteroaryl, heterocyclyl, aryl-C optionally substituted in the same or different manner at one or more positions by₁-C₄Alkylene, heteroaryl-C₁-C₄Alkylene, aryloxy-C₁-C₄Alkylene, heteroaryloxy-C₁-C₄Alkylene or aryl-C₁-C₄Alkylene oxy-C₁-C₄Alkylene group: c₁-C₄Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyloxy, phenyl, cyano, halogen, phenoxy, benzyloxy, halogeno C₁-C₄-alkoxy, halo C₁-C₆Alkyl, nitro, -C₁-C₆Alkyl group COOR⁸、-C₂-C₆Alkenyl COOR⁸、-C₂-C₆Alkynyl COOR⁸、-C₁-C₆Alkyl OR⁹、-C₂-C₆Alkenyl radical OR⁹、-C₁-C₆Alkynyl OR⁹OR a group-OR¹⁰、-NR¹¹R¹²、-COR¹³、-COOR¹⁴、-CONR¹⁵R¹⁶、-SR¹⁷、-SO₂R¹⁸、SO₂NR¹⁹R²⁰or-C (NH)₂) Or represents C substituted in one or more positions by fluorine₁-C₁₀Alkyl radicals, and

R⁷represents hydrogen, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₃-C₆-cycloalkyl, (C)₃-C₆Cycloalkyl) -C₁-C₄Alkylene, aryl-C₁-C₄An alkylene group or a substituted alkylene group,

a represents an optionally substituted aryl, heteroaryl or heterocyclyl group,

R²²represents hydrogen,hydroxy-C₁-C₆Alkyl, OR represents the group-OR¹⁰、-NR¹¹R¹²、-COR¹³、-CONR¹⁵R¹⁶、-SO₂R¹⁸、-NR¹⁵-(C＝S)-NR¹⁶-(CH₂)_n-R²⁴、-NR¹⁵-(C＝O)-NR¹⁶-(CH₂)_n-R²⁴，

R²³Represents hydrogen or C₁-C₆An alkyl group, a carboxyl group,

R²⁴represents hydrogen, phenyl, C₁-C₆-alkoxy or a radical- (CH)₂)_n-COO-C₁-C₆An alkyl group, a carboxyl group,

R²⁵represents a group-OR¹⁰Or represents optionally halogen, C in one or more positions in the same or different manner₁-C₆Alkyl, hydroxy-C₁-C₆Alkyl OR a group-OR¹⁰or-COOR¹⁴Substituted C₂-C₆Alkenyl, phenyl, pyridyl, imidazolyl, morpholinyl, piperidinyl, C₃-C₆Cycloalkyl, or

m, p and k independently of one another represent 0 or 1,

n represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

q represents a number of 1 or 2,

and stereoisomers, mixtures thereof and salts thereof, which are valuable for the inhibition of PLK and can be used for the treatment of the above-mentioned diseases.

Stereoisomers are defined as E/Z-and R/S-isomers and as mixtures of E/Z-and R/S-isomers.

Alkyl is defined as straight or branched chain alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.

Alkoxy is defined as a straight or branched alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy.

Alkenyl substituents are, for example, the following groups, straight-chain or branched: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, and allyl.

Alkynyl is defined as a straight or branched chain alkynyl group containing 2 to 6, preferably 2 to 4, carbon atoms. For example, the following groups are possible: ethynyl, propyn-1-yl, propyn-3-yl, but-1-yn-1-yl, but-1-yn-4-yl, but-2-yn-1-yl, but-1-yn-3-yl and the like.

Heterocyclyl represents an alkyl ring containing 3 to 12 such carbon atoms and, in place of the carbon atoms, one or more identical or different heteroatoms, such as oxygen, sulphur or nitrogen, which heterocyclyl may contain further substituents on one or more carbon or nitrogen atoms. Substituents on carbon atoms may be ═ O, -OH, -C₁-C₄-hydroxyalkyl, alkyl or CONR¹⁵R¹⁶. The substituent on the nitrogen atom may be alkyl, COR¹³、-COOR¹⁴、-CONR¹⁵R¹⁶、-SO₂R¹⁸Or SO₂NR¹⁹R²⁰。

Examples of the heterocyclic group include an epoxy group, an oxithenyl group, an aziridinyl group, an azetidinyl group, a tetrahydrofuryl group, a pyrrolidinyl group, a dioxolanyl group, an imidazolidinyl group, a pyrazolidinyl group, a dioxanyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, a trithianyl group, a quinuclidinyl group, a pyrolidinyl group, an N-methylpyrrolidinyl group, a 2-hydroxymethylpyrrolidinyl group, a 3-hydroxypyrrolidinyl group, an N-methylpiperazinyl group, an N-acetylpiperazinyl group, an N-methylsulfonylpiperazinyl group, a 4-hydroxypiperidinyl group, a 4-aminocarbonylpiperidinyl group, a 2-hydroxyethylpiperidinyl group, and a 4-hydroxymethylpiperidinyl group.

Cycloalkyl is defined as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Cycloalkyl is defined as a monocycloalkyl ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but may also be a bicyclic or tricyclic ring, such as adamantyl.

Common parts of 3-to 8-membered saturated, partially saturated or unsaturated rings are defined as ring systems in which one or more possible double bonds may be comprised in the ring, for example cycloalkenyl such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl, where double and single bonds may be attached.

Halogen is defined as fluorine, chlorine, bromine or iodine.

Aryl has 6 to 12 carbon atoms, and is, for example, naphthyl, biphenyl and, in particular, phenyl.

Heteroaryl in each case comprises 3 to 16 ring atoms which, in addition to carbon atoms, may also contain one or more identical or different heteroatoms, such as oxygen, nitrogen or sulfur, in the ring, and the radicals may be mono-, bi-or tricyclic and may additionally be benzo-fused.

For example, the heteroaryl group may be: thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and benzo derivatives thereof, such as quinolinyl, isoquinolinyl, and the like; or oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl and the like and benzo derivatives thereof; or quinolyl, isoquinolyl, cinnolinyl, 2, 3-naphthyridinyl, quinazolinyl, quinoxaline, 1, 5-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl and the like.

Preferred heteroaryl groups are, for example, 5-membered heteroaromatic compounds, such as thiophene, furan, oxazole, thiazole, imidazole and their benzo derivatives, and 6-membered heteroaromatic compounds, such as pyridine, pyrimidine, triazine, quinoline, isoquinoline and their benzo derivatives.

The aryl radicals in each case comprise from 3 to 12 carbon atoms and may be benzo-fused.

For example, aryl can be cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, and the like.

If acidic groups are included, physiologically compatible salts of organic and inorganic bases are suitable, for example readily soluble alkali metal and alkaline earth metal salts and also N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1, 6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxymethyl-amino-methane, aminopropanediol, Sovak base, and 1-amino-2, 3, 4-butanetriol.

If basic groups are included, physiologically compatible salts of organic and inorganic acids are suitable, for example hydrochloric acid, sulphuric acid, phosphoric acid, citric acid, tartaric acid and the like.

The compounds of the general formula I according to the invention may also comprise the possible tautomeric forms and comprise the E-or Z-isomers or, if chiral centers are present, also racemates and enantiomers. Double bond isomers are also included within the scope of the present invention.

Preferred compounds of the formula I are those in which:

x and Y are identical or different and represent hydrogen, phenyl, cyano, C₃-C₆-cycloalkyl or a group-COOR⁴、-CONR¹⁵-(CH₂)_n-R²⁵、-COOR²⁵、-CONR¹⁵R¹⁶or-COR¹³，

R¹、R¹¹、R¹²、R¹⁵、R¹⁶、R¹⁹And R²⁰Are identical or different and represent hydrogen, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, (COOR)¹⁴)-(CH₂)_n-、(C₃-C₆Cycloalkyl) -C₁-C₄Alkylene radical, C₃-C₆Cycloalkyl, phenylsulfonyl, phenyl-C₃-C₆Cycloalkyl radical, C₁-C₁₀Alkanoyl radical, C₁-C₆-alkoxy-C₁-C₆Alkylene radical, C₁-C₄-alkoxycarbonyl-C₁-C₄Alkylene, hydroxy-C₁-C₄Alkylene radical, -C₁-C₆alkyl-O-Si (phenyl)₂-C₁-C₆Alkyl, or represents a group COOR¹⁴、-COR¹³、-SO₂R¹⁸、-(CH₂)_n-NR¹⁵R¹⁶Or- (CH)₂)_n-C(CH₃)_q-(CH₂)_nNR¹⁵R¹⁶or-NR¹¹R¹²Or is or

Or represents aryl, heteroaryl, heterocyclyl, aryl-C₁-C₄Alkylene, heteroaryl-C₁-C₄Alkylene, aryloxy-C₁-C₄Alkylene, heteroaryloxy-C₁-C₄Alkylene or aryl-C₁-C₄Alkylene oxy-C₁-C₄Alkylene, which groups are optionally substituted in the same or different manner at one or more positions by: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical、C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyloxy, phenyl, cyano, halogen, hydroxy, C₁-C₄Alkoxy, phenoxy, benzyloxy, C₁-C₄Alkylsulfanyl, benzylsulfanyl, phenylsulfanyl, dimethylamino, acetylamino, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, acetyl, -CO-C₁-C₆Alkyl, 1-iminoethyl or nitro, or represents C substituted in one or more positions by fluorine₁-C₁₀An alkyl group, a carboxyl group,

R²and R³Are identical or different and represent hydrogen, C₁-C₆Alkyl, hydroxy-C₁-C₆Alkylene radical, C₃-C₆-cyclohexyl or a radical-COOR¹⁴、-CONR¹⁵R¹⁶、-COR¹³、-SO₂R¹⁸、-NR¹¹R¹²、-(CH₂)_n-A，

Or represents aryl, heteroaryl or heterocyclyl optionally substituted in the same or different manner at one or more positions by: c₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkoxy, halogen, cyano, hydroxy-C₁-C₆Alkylene, hydroxy-C₁-C₆Alkyleneoxy, aryl, heteroaryl, heterocyclyl, -C₁-C₆alkyl-COOR⁸OR a group-OR¹⁰、-COR¹³、-COOR¹⁴、-NR¹¹R¹²、-NR¹¹-CO-NR¹¹R¹²、-NR¹¹-CO-R¹³、-NR¹¹-SO₂-R¹³、-(CH₂)_n-CO-NR¹⁵R¹⁶、-SR¹⁰or-SO₂R¹⁸，

R⁴、R⁸、R⁹、R¹⁰、R¹³、R¹⁴、R¹⁷And R¹⁸Are identical or different and represent hydrogen, C₁-C₁₀Alkyl, hydroxy-C₁-C₆Alkylene oxy-C₁-C₆Alkylene radical, C₁-C₆-alkoxy-CO-C₁-C₆Alkylene, - (CH)₂)_n-CO-NR¹⁵R¹⁶、C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, (C)₃-C₆Cycloalkyl) -C₁-C₄Alkylene, halogeno C₁-C₆Alkyl, hydroxy-C₁-C₆Alkylene, (COOR)¹⁴)-(CH₂)_n-, hydroxy- (CH)₂)_n-O-(CH₂)_n、C₃-C₆Cycloalkyl radical, C₁-C₁₀Alkanoyl or represents the group-NR¹¹R¹²、-(CH₂)_n-CO-R²⁵、-(CH₂)_n-NR¹⁵R¹⁶、COOR¹⁴-(CH₂)_n-or-COR¹³Or represents aryl, heteroaryl, heterocyclyl, aryl-C optionally substituted in the same or different manner at one or more positions by₁-C₄Alkylene, heteroaryl-C₁-C₄Alkylene, aryloxy-C₁-C₄Alkylene, heteroaryloxy-C₁-C₄Alkylene or aryl-C₁-C₄Alkylene oxy-C₁-C₄Alkylene group: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyloxy, phenyl, cyano, halogen, hydroxy-C₁-C₆Alkyl radical, C₁-C₄Alkoxy, phenoxy, benzyloxy, C₁-C₄Alkylsulfanyl, benzylsulfanyl, phenylsulfanyl, dimethylamino, acetylamino, trifluoromethyl,Trifluoromethoxy, trifluoromethylsulfanyl, acetyl, -CO-C₁-C₆Alkyl, 1-iminoethyl or nitro, or represents C substituted in one or more positions by fluorine₁-C₁₀Alkyl, or represents the group-NR¹¹R¹²、-COR¹³、-SO₂R¹⁸、-(CH₂)_n-NR¹⁵R¹⁶、-(CH₂)_n-C(CH₃)_q-(CH₂)_nNR¹⁵R¹⁶Or is or

R²And R³、R¹¹And R¹²、R¹⁵And R¹⁶And R¹⁹And R²⁰Each independently of the others, together form a 3-10 ring which may optionally contain one or more nitrogen, oxygen or sulfur atoms,

a represents an optionally substituted aryl, heteroaryl or heterocyclyl group,

R²²represents hydrogen, hydroxy-C₁-C₆Alkyl OR a group-OR¹⁰、-NR¹¹R¹²、-COR¹³、-CONR¹⁵R¹⁶、-SO₂R¹⁸、-NR¹⁵-(C＝S)-NR¹⁶-(CH₂)_n-R²⁴、-NR¹⁵-(C＝O)-NR¹⁶-(CH₂)_n-R²⁴，

R²³Represents hydrogen or C₁-C₆An alkyl group, a carboxyl group,

R²⁴represents hydrogen, phenyl, C₁-C₆-alkoxy or a radical- (CH)₂)_n-COO-C₁-C₆An alkyl group, a carboxyl group,

R²⁵represents a group-OR¹⁰Or represents optionally halogen, C in one or more positions in the same or different manner₁-C₆Alkyl, hydroxy-C₁-C₆Alkyl OR a group-OR¹⁰or-COOR¹⁴Substituted C₂-C₆Alkenyl, phenyl, pyridyl, imidazolyl, morpholinyl, piperidinyl, C₃-C₆Cycloalkyl, or

m, p, k each independently of the others represent 0 or 1,

n represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

q represents a number of 1 or 2,

and stereoisomers thereof, mixtures of such stereoisomers and salts thereof.

Selected compounds are of the following general formula I, wherein:

x and Y are identical or different and represent hydrogen, phenyl, cyano, C₃-C₆-cycloalkyl or a group-COOR⁴、-CONR¹⁵-(CH₂)_n-R²⁵、-COOR²⁵、-CONR¹⁵R¹⁶or-COR¹³，

R¹Represents hydrogen, phenyl, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, hydroxy-C₁-C₄Alkylene radical, C₁-C₆-alkoxy-C₁-C₆Alkylene or radical-C₁-C₆alkyl-O-Si (phenyl)₂-C₁-C₆An alkyl group, a carboxyl group,

R²and R³Are identical or different and represent hydrogen, C₁-C₆Alkyl, hydroxy-C₁-C₄Alkylene, cyclohexyl or the radical-COOR¹⁴、-CONR¹⁵R¹⁶、-COR¹³、-SO₂R¹⁸、-NR¹¹R¹²、-(CH₂)_n-A

Or represents optionally C at one or more positions in the same or different manner₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkoxy, halogen, cyano, triazolyl, tetrazolyl, hydroxy-C₁-C₆Alkylene, hydroxy-C₁-C₆Alkyleneoxy, morpholinyl, -C₁-C₆alkyl-COOR⁸OR a group-OR¹⁰、-COR¹³、-COOR¹⁴、-NR¹¹R¹²、-NR¹¹-CO-NR¹¹R¹²、-NR¹¹-CO-R¹³、-NR¹¹-SO₂-R¹³、-(CH₂)_n-CO-NR¹⁵R¹⁶、-SR¹⁰or-SO₂R¹⁸Substituted phenyl, pyridyl, naphthyl, biphenyl, imidazolyl, indazolyl, isothiazolyl, triazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, thiazolyl, pyrazolyl, anthrazinyl, pyrazolidinyl, oxazolyl, 2, 3-diazanaphthyl, carbazolyl, benzimidazolyl, benzothiazolyl, isoxazolyl, 2, 3-dihydroindenyl, indolyl, pyrimidinyl, thiadiazolyl, and the like,

Or R²And R³Together form a piperidinyl group or a morpholinyl group,

a represents the following group:

R⁴represents hydrogen, C₁-C₆Alkyl, halo C₁-C₆Alkyl, hydroxy-C₁-C₆Alkyl, hydroxy- (CH)₂)_n-O-(CH₂)_n-, or a radical- (CH)₂)_n-CO-R²⁵、-(CH₂)_n-NR¹⁵R¹⁶Or represents optionally hydroxy-C₁-C₆An alkyl-substituted phenyl or benzyl group,

R⁸、R¹¹、R¹²、R¹⁴、R¹⁵and R¹⁶Are identical or different and represent hydrogen, C₁-C₁₀Alkyl, hydroxy-C₁-C₆Alkylene, (COOR)¹⁴)-(CH₂)_n-, or represents optionally halogen or a group-CO-C₁-C₆Alkyl-substituted phenyl, pyridyl or pyrimidinyl radicals, or represent the radical-COR¹³、-SO₂R¹⁸、-(CH₂)_n-NR¹⁵R¹⁶、-(CH₂)_n-C(CH₃)_q-(CH₂)_nNR¹⁵R¹⁶

Or

R¹⁰Represents hydrogen, C₁-C₁₀Alkyl, hydroxy-C₁-C₆Alkylene, hydroxy-C₁-C₆-alkyleneoxy-C₁-C₆Alkylene radical, C₁-C₆-alkoxy-CO-C₁-C₆Alkylene, - (CH)₂)_n-CO-NR¹⁵R¹⁶Or represents optionally halogen or a group-CO-C₁-C₆Alkyl-substituted phenyl, or represents the group-COR¹³、-SO₂R¹⁸Or COOR¹⁴-(CH₂)_n-，

R¹³Represents hydrogen, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkenyl radical, C₁-C₁₀Alkynyl, C₁-C₆-alkyloxy-C₁-C₆Alkenyl radical, C₁-C₆alkyloxy-C₁-C₆alkenyloxy-C₁-C₆Alkenyl, phenyl or represents the following groups:

R¹⁸represents C₁-C₁₀Alkyl, hydroxy-C₁-C₆Alkyl or radicals-NR¹¹R¹²、

Or represents optionally in the same or different manner at one or more positions by C₁-C₆A phenyl group substituted with an alkyl group,

R²²represents hydrogen, hydroxy-C₁-C₆Alkyl, OR represents the group-OR¹⁰、-NR¹¹R¹²、-COR¹³、-CONR¹⁵R¹⁶、-SO₂R¹⁸、-NR¹⁵-(C＝S)-NR¹⁶-(CH₂)_n-R²⁴or-NR¹⁵-(C＝O)-NR¹⁶-(CH₂)_n-R²⁴，

R²³Represents hydrogen or C₁-C₆An alkyl group, a carboxyl group,

R²⁴represents hydrogen, phenyl, C₁-C₆-alkoxy or a radical- (CH)₂)_n-COO-C₁-C₆An alkyl group, a carboxyl group,

R²⁵represents a group-OR¹⁰Or represents optionally the sameOr differently by halogen, C at one or more positions₁-C₆Alkyl, hydroxy-C₁-C₆Alkyl OR with the group-OR¹⁰or-COOR¹⁴Substituted C₂-C₆Alkenyl, phenyl, pyridyl, imidazolyl, morpholinyl, piperidinyl, C₃-C₆Cycloalkyl, or

m, p and k independently of one another represent 0 or 1,

n represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

q represents a number of 1 or 2,

and stereoisomers thereof, mixtures of such stereoisomers and salts thereof.

For use of the compounds according to the invention in the form of medicaments, the compounds according to the invention can be formulated into pharmaceutical preparations which, in addition to the active ingredient, may contain suitable organic or inorganic pharmaceutical carrier media for enteral or parenteral administration, such as water, gelatin, gum arabic, lactose, starch, stearatase, talc, vegetable oils, polyethylene glycol and the like. The pharmaceutical preparations may be in solid form, such as tablets, coated tablets, suppositories or capsules, or in liquid form, such as solutions, suspensions or emulsions. In addition, they may optionally comprise adjuvants, such as preservatives, stabilizers, wetting agents, or lubricants, salts for varying the osmotic pressure, or buffers.

These pharmaceutical preparations are also the subject of the present invention.

For parenteral administration, particularly suitable are injection solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil.

As carrier systems, it is also possible to use surface-active auxiliaries, such as salts of cholic acids or animal or vegetable phospholipids and mixtures thereof, and also liposomes or their constituents.

For oral administration, particularly suitable are tablets, coated tablets or capsules, which may contain talc and/or hydrocarbon carriers or binders, such as lactose, corn or potato starch. It can also be administered in liquid form, such as juice optionally supplemented with sweeteners.

Enteral, parenteral and oral administration are also subjects of the present invention.

The dosage of the active ingredient may vary depending on the method of administration, the age and weight of the patient, the type and severity of the disease to be treated, and the like. The daily dose is 0.5-1000mg, preferably 50-200mg, wherein the dose can be administered in a single dose or divided into two or more daily doses.

The subject of the invention is also the use of a compound of general formula I for the preparation of a medicament for the treatment of the following diseases: cancer, autoimmune diseases, cardiovascular diseases, chemotherapy-induced alopecia and mucositis, infectious diseases, kidney diseases, chronic and acute neurodegenerative diseases, and viral infections, wherein cancer is defined as solid cancer and leukemia, autoimmune diseases are defined as psoriasis, alopecia and multiple sclerosis, cardiovascular diseases are defined as stenosis, arteriosclerosis and restenosis, infectious diseases are defined as those caused by single-celled parasites, kidney diseases are defined as glomerulonephritis, chronic neurodegenerative diseases are defined as huntington's disease, amyotrophic lateral sclerosis, parkinson's disease, AIDS dementia and alzheimer's disease, acute neurodegenerative diseases are defined as cerebral ischemia and neurotrauma, and viral infections are defined as giant cell infections, herpes, hepatitis b and c, and HIV diseases. The subject of the invention is also medicaments for the treatment of the abovementioned diseases which comprise at least one compound according to the general formula I, and also medicaments which comprise suitable formulation substances and carriers.

The compounds of general formula I according to the invention are for example excellent inhibitors of polo-like kinases such as Plk1, Plk2, Plk3 and Plk 4.

If the preparation of the starting compound is not described, the compound is known or can be prepared similarly according to known compounds or methods described herein. All reactions described herein can also be carried out in parallel reactors or by combining individual operating steps.

If the isomers are not in equilibrium with one another, the isomer mixtures can be separated into the isomers, for example into the enantiomers, diastereomers or E/Z isomers, according to the customary methods of use, such as crystallization, chromatography or salt formation.

Salts may be prepared by mixing a solution of a compound of formula I with an equivalent or excess amount of a base or acid, optionally in solution, according to conventional methods, and isolating the precipitate or treating the solution in a conventional manner.

Preparation of the Compounds according to the invention

The following examples illustrate the preparation of the compounds according to the invention, but the scope of the compounds is not limited to these examples.

The compounds of the general formula I according to the invention can be prepared according to the following general synthetic route:

synthesis scheme 1

Wherein X, Y and R¹Is as defined in formula I and Z represents C₁-C₁₀The preparation of the intermediate compounds of the general formulae II and III for alkyl is carried out from X, Y and R¹Starting from reactants of the general formulae (iv) to (vi) as defined in the general formula I. First, the compound of formula (v) is added to the isothiocyanate of formula (iv). As the base, for example, trialkylamine is suitable, but sodium hydride or potassium hydride may also be used.

The intermediate product of formula III is obtained by reacting a compound of formula (vi) with an α -halo substituted acyl halide or acyl ester. The reaction is usually carried out in an inert solvent such as tetrahydrofuran at a temperature of between-20 ℃ and +50 ℃. The intermediate of the formula II can be prepared, for example, from the intermediate of the formula III by reaction with trialkyl orthoformates and acetic anhydride, which is carried out in most cases at relatively high temperatures (100 ℃ C. and 200 ℃ C.).

From the compounds of the formula II, the compounds of the formula I according to the invention are obtained by addition of amines. The reaction can be carried out in all suitable organic solvents, such as acetone, alcohols, dialkyl ethers, alkanes or cycloalkanes.

If the amine used is liquid, the reaction can also be accomplished without the need for a solvent. The reaction temperature is generally between-20 ℃ and +80 ℃. Removing NH₃In addition, the amine introduced may be a primary or secondary amine.

The functional groups of the reactants and intermediates may optionally be protected during introduction.

The addition of the amine to the compound of formula II is accomplished in the following conditions: most of the compounds of formula I can be readily synthesized in parallel.

As an alternative, the compounds of the formula I according to the invention can also be prepared directly from intermediates of the formula III. In this case, already in the reaction with CH (OZ)₃Wherein Z is as defined for formula II, is added. These reactions are in most cases carried out at temperatures of from 80 to 220 ℃.

All functional groups of the formulae I to III and of the formulae iv to vi can still be modified further. For example, in the latter, double and triple bond introduction, double and triple bond hydrogenation, introduction of additional substituents, cleavage of esters, amides, ethers, etc. may be defined. All protecting groups introduced simultaneously can also be cleaved off at a suitable intermediate or final stage.

A substituent R of the general formula I¹、R²Or R³The functional groups, e.g. amines, alcohols, halides or carboxylic acids, may be further functionalized, in particular for obtaining further compounds of the formula IA compound (I) is provided.

If R in the compound of the formula I is²Or R³First represents hydrogen, this group can optionally be synthesized in parallel by reaction with optionally substituted alkanoyl halides, arylalkanoyl halides, alkoxyalkanoyl halides, aryloxyalkanoyl halides, alkyl halides, isocyanates, isothiocyanates or alkyl-or arylsulfonyl halides.

The subject of the invention is therefore also the compounds of the formulae II and III,

and

wherein: x, Y and R¹Has the same definition as formula I, and Z represents C₁-C₁₀Alkyl, is a valuable intermediate for the preparation of the compounds of the general formula I according to the invention.

Preferably wherein Z represents C₁-C₄Alkyl group of the intermediate compound of formula II.

Drawings

FIG. 1 shows regulatory function in the Plk-1 cell cycle.

Detailed Description

The following examples describe the preparation of the compounds of the invention, but the compounds of the invention are in no way limited to these examples.

Example 1

(E or Z) -cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid ethyl ester

Method embodiment A

3.4g of the compound described in example b) are suspended in 15ml of ethylene glycol. 2.8ml of triethyl orthoformate and 1.5ml of aniline were added. The reaction mixture was refluxed in a water separator for 2 hours. It was poured onto ice water. Stirring was continued for 3 hours and then the precipitate was filtered off. The resulting solid was washed with water. Recrystallization from a mixture of ethyl acetate and diisopropyl ether. 2.9g of product are obtained.

Method embodiment B

A solution of 200mg of the substance described in example c) and 0.2ml of aniline in 2ml of acetone is stirred at 50 ℃ for 3 hours. After cooling, the precipitated product is filtered off and then recrystallized from diisopropyl ether. 185mg of product are obtained.

¹H-NMR(CDCl₃): δ 1.30-1.47 (6H); 4.30 (2H); 4.42 (2H); 7.04-7.18 (3H); 7.37 (2H); 7.62 (1H); 8.13(1H, isomer B); 8.13(1H, isomer B); 10.55(1H) ppm.

Example 2

4- { [2- ((E or Z) -cyano-ethoxycarbonyl-methylene) -3-ethyl-4-oxo-thiazolidin-5- (E/Z) -ylidenemethyl ] -amino } -benzoic acid ethyl ester

In analogy to method embodiment A of example 1, from 2g of the substance described in example b), 1.7ml of triethyl orthoformate and 1.65g of ethyl 4-aminobenzoate 1.57g of product are obtained.

¹H-NMR (D6-DMSO): δ 1.20-1.35 (9H); 4.20-4.35 (6H); 7.42 (2H); 7.49(2H, isomer B); 7.90 (2H); 8.22 (1H); 8.51(1H, isomer B); 10.70(1H) ppm.

Example 3

(E or Z) -cyano- { 3-ethyl-5- (E/Z) - [ (4-methoxy-phenylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to the procedure embodiment A of example 1, from 2g of the substance described in example b), 1.7ml of triethyl orthoformate and 1.23g of 4-aminoanisole 1.8g of product are obtained.

¹H-NMR (D6-DMSO): δ 1.22 (6H); 3.61 (3H); 4.22 (4H); 6.93 (2H); 7.28 (2H); 8.10 (1H); 8.38(1H, isomer B); 10.49 (1H); 19.58(1H, isomer B) ppm.

Example 4

(E or Z) - (5- (E/Z) - { [ bis- (2-hydroxy-ethyl) -amino ] -methylene } -3-ethyl-4-oxo-thiazolidin-2-ylidene) -cyanoacetic acid ethyl ester

In analogy to process embodiment B of example 1, from 150mg of the substance described in example c), 0.05ml of diethanolamine in 2ml of acetone 80mg of product are obtained.

¹H-NMR(D6-DMSO)：δ＝1.15-1.28(6H)；3.50-3.70(8H)；4.15-4.30(4H)；4.92(1H)；5.09(1H)；7.80(1H)ppm.

Example 5

(E or Z) -cyano- (3-ethyl-4-oxo-5- (E/Z) - (piperidin-1-ylmethylene) -thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 150mg of the substance described in example c), 0.056ml of piperidine in 2ml of acetone, 126mg of product are obtained.

¹H-NMR(CDCl₃)：δ＝1.32(6H)；1.72(6H)；3.55(4H)；4.29(2H)；4.41(2H)；7.65(1H)ppm.

Example 6

(E or Z) -cyano- (3-ethyl-5- (E/Z) - (morpholin-4-ylmethylene) -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

Analogously to method embodiment B of example 1, from 150mg of the substance described in example c), 0.05ml of morpholine in 2ml of acetone 146mg of product are obtained.

¹H-NMR(CDCl₃)：δ＝1.32(6H)；3.60(4H)；3.78(4H)；4.29(2H)；4.40(2H)；7.60(1H)ppm.

Example 7

(E or Z) -cyano- (5- (E/Z) -cyclohexylaminomethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to process embodiment B of example 1, from 150mg of the material described in example c), 0.065ml of cyclohexylamine in 2ml of acetone 148mg of product are obtained.

¹H-NMR(CDCl₃): δ 1.15-1.45 (12H); 1.78 (2H); 1.97 (2H); 3.25 (1H); 4.22-4.42 (4H); 5.00 (1H); 7.18(1H, isomer B); 7.70 (1H); 8.82 (1H; isomer B) ppm.

Example 8

(E or Z) -cyano- (5- (E/Z) -diethylaminomethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 150mg of the substance described in example c), 0.058ml of diethylamine in 2ml of acetone gives 116mg of product.

¹H-NMR(D6-DMSO)：δ＝1.10-1.30(12H)；3.50(4H)；4.20(4H)；7.80(1H)ppm.

Example 9

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [ (2-hydroxy-ethyl) -methyl-amino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 150mg of the substance described in example c), 0.045ml of N-methylethanolamine in 2ml of acetone gives 156mg of product.

¹H-NMR(D6-DMSO)：δ＝1.22(6H)；3.27(3H)；3.48-3.68(4H)；4.20(4H)；4.91(1H)；7.78(1H)ppm.

Example 10

(E or Z) - {5- (E/Z) - [ (4-carbamoyl-phenylamino) -methylene ] -3-ethyl-4-oxo-thiazolidin-2-ylidene } -cyanoacetic acid ethyl ester

Analogously to method embodiment B of example 1, from 150mg of the substance described in example c), 76mg of 4-aminobenzamide in 2ml of acetone gave 165mg of product.

¹H-NMR (D6-DMSO): δ 1.23 (6H); 4.24 (4H); 7.26 (1H); 7.38 (2H); 7.45(2H, isomer B); 7.89 (3H); 8.24 (1H); 8.51(1H, isomer)B)；10.65(1H)ppm.

Example 11

(E or Z) - (5- (E/Z) -aminomethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -cyanoacetic acid ethyl ester

0.3ml of a 2M ethanol-ammonia solution are added to a solution of 150mg of the compound described in example c) in 2ml of ethanol. Stirring was continued for a further 1 hour at 50 ℃. The product which precipitated after cooling was filtered off and then recrystallized from diisopropyl ether. 109mg of product are obtained.

¹H-NMR(D6-DMSO)：δ＝1.13-1.28(6H)；4.18(4H)；7.70(1H)；8.00-8.20(2H)ppm.

Example 12

(E or Z) -cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid

200mg of the compound described in example 1 were dissolved in 1ml of dioxane. A solution of 200mg of potassium hydroxide in 1ml of ethanol is added and the mixture is stirred at 70 ℃ for a further 6 hours. 1N HCl (pH1) was added. After stirring for a further 2 hours, the precipitate is filtered off. The crude product was recrystallized from dichloromethane/methanol (8+ 2). 100mg of product are obtained.

¹H-NMR (D6-DMSO): δ 1.21 (3H); 4.22 (2H); 7.08 (1H); 7.28-7.41 (4H); 8.17 (1H); 8.43(1H, isomer B); 10.47 (1H); 10.52(1H, isomer B) ppm.

Example 13

2- (3-Ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -malonic acid diethyl ester

In analogy to process embodiment A of example 1, from 440mg of the compound described in example e), 0.4ml of triethyl orthoformate and 0.2ml of aniline in 5ml of ethylene glycol gives 230mg of product.

¹H-NMR(CDCl₃)：δ＝1.15-1.38(9H)；3.79(2H)；4.25-4.38(4H)；7.00-7.15(3H)；7.42(2H)；7.65(1H)；10.46(1H)ppm.

Example 14

2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -malononitrile

In analogy to method embodiment B of example 1, from 150mg of the substance described in example i), 0.06ml of aniline in 2ml of acetone 124mg of product are obtained.

¹H-NMR(D6-DMSO)：δ＝1.21(3H)；4.10(2H)；7.11(1H)；7.30-7.43(4H)；8.33(1H)；10.58(1H)ppm.

Example 15

2- (3-ethyl-4-oxo-5- (E/Z) - [ piperidin-1-ylmethylene ] -thiazolidin-2-ylidene) -malononitrile

In analogy to method embodiment B of example 1, from 150mg of the substance described in example i), 0.066ml of piperidine in 2ml of acetone gives 140mg of product.

¹H-NMR(CDCl₃)：δ＝1.32(3H)；1.72(6H)；3.51(4H)；4.21(2H)；7.69(1H)ppm.

Example 16

2- (3-ethyl-5- (E/Z) - [ morpholin-4-ylmethylene ] -4-oxo-thiazolidin-2-ylidene) -malononitrile

In analogy to method embodiment B of example 1, from 150mg of the substance described in example i), 0.058ml of morpholine in 2ml of acetone, 138mg of product are obtained.

¹H-NMR(CDCl₃)：δ＝1.31(3H)；3.56(4H)；3.78(4H)；4.23(2H)；7.67(1H)ppm.

Example 17

2- { 3-Ethyl-5- (E/Z) - [ (4-methoxy-phenylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -malononitrile

In analogy to process embodiment B of example 1, from 150mg of the substance described in example i), 82mg of 4-aminoanisole in 2ml of acetone, 157mg of product are obtained.

¹H-NMR(D6-DMSO)：δ＝1.20(3H，3.72(3H)；4.07(2H)；6.94(2H)；7.28(2H)；8.23(1H)；10.53(1H)ppm.

Example 18

4- [ (2-dicyanomethylene-3-ethyl-4-oxo-thiazolidin-5- (E/Z) -ylidenemethyl) -amino ] -benzamide

In analogy to process embodiment B of example 1, from 150mg of the substance described in example i), 90mg of 4-aminobenzamide in 2ml of ethanol gave 154mg of product.

¹H-NMR (D6-DMSO): δ 1.22 (3H); 4.08 (2H); 7.28 (1H); 7.38 (2H); 7.83-8.00 (3H); 8.40 (1H); 8.52(1H, isomer B); 10.65(1H) ppm.

Example 19

4- [ (2-Dicyanomethylene-3-ethyl-4-oxo-thiazolidin-5- (E/Z) -ylidenemethyl) -amino ] -benzoic acid ethyl ester

In analogy to method embodiment B of example 1, 140mg of product are obtained from 150mg of the substance described in example i), 110mg of ethyl 4-aminobenzoate and 2ml of acetone.

¹H-NMR (D6-DMSO): δ 1.38 (6H); 4.28 (2H); 4.37 (2H); 7.11 (2H); 7.14(2H, isomer B); 7.69 (1H); 7.90(1H, isomer B); 8.08 (2H); 8.25(2H, isomer B); 10.57ppm.

Example 20

2- (5- (E/Z) -aminomethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -malononitrile

Analogously to example 11, from 150mg of the compound described in example i) and 0.3ml of a 2M ethanol-ammonia solution in 2ml of ethanol, 101mg of product are obtained.

¹H-NMR(CDCl₃)：δ＝1.16(3H)；4.02(2H)；7.82(1H)；8.10-8.40(2H)ppm.

Example 21

(E or Z) - (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetonitrile

85mg of the compound described in example 12 are dissolved in 1ml of methanol. 0.2ml of 2N HCl was added and stirred at 50 ℃ for 30 minutes. Pour over ice water. The precipitate was aspirated and then recrystallized from methanol. 53mg of product are obtained.

¹H-NMR(CDCl₃)：δ＝1.03(3H)；3.70(2H)；5.31(1H)；7.03(1H)；7.22(2H)；7.31(2H)；8.04(1H)；9.76(1H)ppm.

In analogy to process embodiment B of example 1, the following compounds were prepared from the intermediate products described in example c):

in analogy to process embodiment B of example 1, the following compounds were prepared from the intermediate products described in example c):

in analogy to process embodiment B of example 1, the following compounds were prepared from the intermediate products described in example l):

in analogy to process embodiment B of example 1, the following compounds were prepared from the intermediate products described in example o):

in analogy to process embodiment B of example 1, the following compounds were prepared from the intermediate products described in example r):

in analogy to process embodiment B of example 1, the following compounds were prepared from the intermediate products described in example t):

in analogy to process embodiment B of example 1, the following compounds were prepared from the intermediate products described in example w):

in analogy to process embodiment B of example 1, the following compounds were prepared from the intermediate products described in example z):

the following compounds were prepared analogously to example 13 from the intermediate products described in example e):

in analogy to process embodiment a of example 1, the following compounds were prepared from the intermediate products described in example aa):

in analogy to process embodiment a of example 1, the following compounds were prepared from the intermediates described in example ab):

in analogy to process embodiment B of example 1, the following compounds were prepared from the intermediate products described in example ag):

example 129

(E or Z) -cyano- [3- (2-hydroxy-ethyl) -4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene ] -acetic acid ethyl ester

0.3ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to 125mg of the compound of example 123 in 5ml of tetrahydrofuran. Stirring was continued for a further 3 hours at 50 ℃. The reaction mixture was then poured into an ice-cold saturated ammonium chloride solution. Stirred for an additional 2 hours and then filtered. The crude product was recrystallized from a mixture of ethanol and methyl chloride. 38mg of product are obtained.

Molecular weight: 359.40, respectively; ms (esi): [ M +1 ]]⁺-peak: 360.

the following examples 130), 131), 132), 133) and 134) were prepared analogously to example 129) from the compounds described in examples 124), 125), 126), 127) and 128):

example 135

(E or Z) - {5- (E/Z) - [3- (2-chloro-phenyl) -ureidomethylene ] -3-ethyl-4-oxo-thiazolidin-2-ylidene } -cyanoacetic acid ethyl ester

135. mu.l of 2-chlorophenyl isocyanate were added to a solution of 150mg of the compound described in example 11 in 5ml of tetrahydrofuran. Heating in a bomb tube for 48 hours to 100 ℃. After cooling, the reaction mixture was concentrated by evaporation in vacuo. The residue was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate. 181mg of product are obtained.

1H-NMR (DMSO-d6), main isomer: δ 1.30-1.42 (6H); 4.18-4.30 (4H); 7.12 (1H); 7.35 (1H); 7.51 (1H); 8.00 (1H); 8.25 (1H); 8.78 (1H); 11.08(1H) ppm.

In analogy to example 135), the following compounds were prepared:

example 138

(E or Z) -cyano- { 3-ethyl-4-oxo-5- (E/Z) - [ (toluene-4-sulfonylamino) -methylene ] -thiazolidin-2-ylidene } -acetic acid ethyl ester

233. mu.l of triethylamine and 161mg of p-toluenesulfonyl chloride are added to a solution of 150mg of the compound described in example 11 in 5ml of tetrahydrofuran. Reflux for 48 hours. The reaction mixture was poured into ice-cooled 2N hydrochloric acid. Extraction with ethyl acetate and washing of the organic phase with saturated sodium chloride solution, drying over sodium sulfate and concentration by evaporation in vacuo. The residue was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate. 155mg of product are obtained.

1H-NMR(DMSO-d6)：δ＝1.12-1.24(6H)；2.33(3H)；4.15-4.22(4H)；7.31(2H)；7.62(2H)；8.18(1H)ppm.

Example 139

(E or Z) - [5- (E/Z) - (benzenesulfonylamino-methylene) -3-ethyl-4-oxo-thiazolidin-2-ylidene ] -cyanoacetic acid ethyl ester

Example 139 was prepared analogously to the compound described in example 138).

1H-NMR(DMSO-d6)：δ＝1.12-1.25(6H)；4.10-4.22(4H)；7.52-7.67(3H)；7.78(2H)；8.05(1H)ppm.

Example 140

(E or Z) -cyano- [5- (E/Z) - (N, N-dimethylaminosulfonylamino-methylene) -3-ethyl-4-oxo-thiazolidin-2-ylidene ] -acetic acid ethyl ester

470. mu.l of triethylamine and 180. mu.l of N, N-dimethylaminosulfonyl chloride are added to a solution of 150mg of the compound described in example 11 in 5ml of toluene. Reflux for 16 hours. The reaction mixture was poured into ice-cooled 2N hydrochloric acid. Extraction with ethyl acetate and washing of the organic phase with saturated sodium chloride solution, drying over sodium sulfate and concentration by evaporation in vacuo. The residue was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate. 52mg of product are obtained.

1H-NMR(DMSO-d6)：δ＝1.12-1.22(6H)；2.60(6H)；4.10-4.25(4H)；8.05(1H)ppm.

Example 141

(E or Z) -cyano- [3- (2-methoxy-ethyl) -4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene ] -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 150mg of the compound described in example aj) and 46. mu.l of aniline in 3ml of ethanol gives 123mg of product.

1H-NMR (DMSO-d6), main isomer: δ 1.23 (3H); 3.25 (3H); 3.61 (2H); 4.20 (2H); 4.46 (2H); 7.11 (1H); 7.30-7.43 (5H); 8.20(1H) ppm

In analogy to process embodiment B of example 1, the following compounds were prepared from the intermediate products described in example am):

example 150

(E or Z) -cyano- (3-cyclobutyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid ethyl ester

50mg of the compound described in example aq) and 17mg of aniline are introduced into 2ml of ethanol and stirred for 3 hours at reflux. The product precipitated after cooling was filtered off and then recrystallized from ethanol 2 times. 12mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.25 (3H); 1.40-1.90 (2H); 2.35 (2H); 2.90 (2H); 4.23 (2H); 5.13 (1H); 7.10(1H)；7.25-7.43(4H)；8.15(1H)；10.45(1H)ppm.

in analogy to the compound described in example 150), the following compounds were prepared:

example 159

(E or Z) -cyano- { 3-ethyl-4-oxo-5- (E/Z) - [ (4-sulfo-phenylamino) -methylene ] -thiazolidin-2-ylidene } -acetic acid ethyl ester

100mg of the compound described in example c), 0.1ml of triethylamine and 74mg of 4-aminobenzenesulfonic acid are introduced into 2ml of ethanol and stirred under reflux for 3 hours. The solvent was removed and the crude product was recrystallized from ethanol. After treatment with acidic ion exchanger, 40mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.10-1.45 (6H); 4.15-4.35 (4H); 7.27 (2H); 7.57 (2H); 8.21 (1H); 10.60(1H) ppm.

Example 160

(E or Z) -cyano- { 3-ethyl-5- (E/Z) - [ (6-hydroxy-naphthalen-1-ylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

100mg of the compound described in example c) and 68mg of 1-amino-6-hydroxynaphthalene are introduced into 2ml of ethanol and stirred for 3 hours at reflux. The solvent was removed and the crude product was recrystallized from ethanol. 82mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

1H-NMR (DMSO-d6, with K₂CO₃Storage): δ 1.15-1.35 (6H); 4.10-4.30 (4H); 7.08-7.22 (3H); 7.40 (1H); 7.60 (1H); 8.01(1H, isomer A); 8.08 (1H); 8.70(1H, isomer B); 9.95(1H, isomer A); 10.01(1H, isomer B); 10.65(1H, isomer A); 11.40 ppm (1H, isomer B).

The following compounds were also prepared analogously:

example 171

(E or Z) -cyano- { 3-ethyl-4-oxo-5- (E/Z) - [ (3-piperidin-1-ylmethyl-phenylamino) -methylene ] -thiazolidin-2-ylidene } -acetic acid ethyl ester

60mg of the compound described in example ar), 110mg of potassium carbonate and 18. mu.l of piperidine are dissolved in 2ml of DMF and stirred at room temperature for 24 hours. The reaction mixture was mixed with dichloromethane and then washed 3 times with water. After chromatographic purification on silica gel, 22mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.13-1.34 (6H); 1.34-1.57 (6H); 2.20-2.37 (4H); 3.40 (2H); 4.15-4.33 (4H); 7.00 (1H); 7.12-7.34 (3H); 8.20 (1H); 10.56(1H) ppm.

The following compounds were also prepared analogously:

example 178

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [4- (2-morpholin-4-yl-ethoxy) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

84mg of the compound described in example av), 97mg of potassium carbonate and 18. mu.l of morpholine were dissolved in 5ml of DMF and then stirred at room temperature for 18 hours. The solvent was concentrated under high vacuum and the residue was treated with ethyl acetate and washed 3 times with water. After chromatographic purification on silica gel, 23mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.15-1.30 (6H); 2.38-2.55 (4H); 2.68 (2H); 3.54 (4H); 4.05 (2H); 4.15-4.30 (4H); 6.94 (2H); 7.20 (2H); 8.14 (1H); 10.48(1H) ppm.

The following compounds were also prepared analogously:

example 189

(E or Z) - (5- (E/Z) - { [3- (4-acetyl-piperazin-1-ylmethyl) -phenylamino ] -methylene } -3-ethyl-4-oxo-thiazolidin-2-ylidene) -cyanoacetic acid ethyl ester

60mg of the compound described in example at) are dissolved in 2ml of THF, mixed with 41. mu.l of triethylamine and 8.5. mu.l of acetyl chloride and stirred at room temperature for 2 hours. The reaction mixture was mixed with water, followed by extraction with ethyl acetate. After chromatographic purification on silica gel, 19mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.11-1.35 (6H); 1.18 (3H); 2.22-2.42 (4H); 3.38-3.55 (6H); 4.13-4.31 (4H); 7.03 (1H); 7.15-7.38 (3H); 8.20 (1H); 10.57(1H) ppm.

Example 190

(E or Z) - [5- (E/Z) - ({ acetyl- [3- (4-acetyl-piperazin-1-ylmethyl) -phenyl ] -amino } -methylene) -3-ethyl-4-oxo-thiazolidin-2-ylidene ] -cyanoacetic acid ethyl ester

60mg of the compound described in example at) are dissolved in 2ml of THF, mixed with 45. mu.l of triethylamine and 16. mu.l of acetyl chloride and stirred at room temperature overnight. The reaction mixture was mixed with water, followed by extraction with ethyl acetate. After chromatographic purification on silica gel, 42mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.10-1.30 (6H); 1.95 (3H); 2.02 (3H); 2.26-2.47 (4H); 3.25-3.40 (4H); 3.55 (2H); 4.01-4.25 (4H); 7.37-7.49 (2H); 7.51-7.68 (2H); 8.58(1H) ppm.

Example 191

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [3- (4-methanesulfonyl-piperazin-1-ylmethyl) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to example 189), from 60mg of the compound described in example at), 45 μ l of triethylamine and 16mg of methanesulfonyl chloride, after chromatographic purification on silica gel, 35mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.12-1.34 (6H); 2.38-2.56 (4H); 2.88 (3H); 3.04-3.18 (4H); 3.51 (2H); 4.14-4.32 (4H); 7.05 (1H); 7.18-7.38 (3H); 8.20 (1H); 10.56(1H) ppm.

Example 192

(E or Z) - (5- (E/Z) - { [3- (4-tert-butylcarbamoyl-piperazin-1-ylmethyl) -phenylamino ] -methylene } -3-ethyl-4-oxo-thiazolidin-2-ylidene) -cyano-acetic acid ethyl ester

In analogy to example 189), from 60mg of the compound described in example at), 45 μ l of triethylamine and 14mg of tert-butyl isocyanate, after chromatographic purification on silica gel, 31mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.14-1.35 (15H); 2.20-2.35 (4H); 3.15-3.28 (4H); 3.46 (2H); 4.15-4.33 (4H); 5.68-5.79 (1H); 7.03 (1H); 7.15-7.38 (3H); 8.21 (1H); 10.57(1H) ppm.

Example 193

(E or Z) -cyano- (5- (E/Z) - { [3- (4-dimethylsulfamoyl-piperazin-1-ylmethyl) -phenylamino ] -methylene } -3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to example 189), from 60mg of the compound described in example at), 45 μ l of triethylamine and 20mg of N, N-dimethylaminosulfonyl chloride, after chromatographic purification on silica gel, 15mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1-NMR (DMSO-d6, and stock K)₂CO₃Major isomers): δ 1.15-1.35 (6H); 2.35-2.50 (4H); 2.75 (6H); 3.16 (4H); 3.51 (2H); 4.15-4.32 (4H); 7.02 (1H); 7.14-7.37 (3H); 8.22 (1H); 10.59(1H) ppm.

The following compounds were also prepared analogously:

example 197

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [3- (morpholine-4-carbonyl) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

100mg of the compound described in example 24), 0.04ml of triethylamine and 93mg of TBTU were introduced into 2ml of DMF and stirred at room temperature for 30 minutes. 26 μ l of morpholine was added, followed by stirring at room temperature overnight. The reaction mixture was mixed with sodium bicarbonate solution and then extracted with ethyl acetate. After chromatographic purification on silica gel, 57mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.18-1.32 (6H); 3.45-3.75 (8H); 4.15-4.30 (4H); 7.10 (1H); 7.30-7.48 (3H); 8.25 (1H); 10.57(1H) ppm.

Example 198

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [3- (2-morpholin-4-yl-ethylcarbamoyl) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to example 197) from 100mg of the compound described in example 24), 0.04ml of triethylamine, 93mg of TBTU and 39. mu.l of 4- (2-aminoethyl) morpholine, after chromatographic purification on silica gel, 26mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.18-1.35 (6H); 2.35-2.50 (6H); 3.40 (2H); 3.58 (4H); 4.15-4.35 (4H); 7.45 (2H); 7.57 (1H); 7.77 (1H); 8.30 (1H); 8.53 (1H); 10.65(1H) ppm.

Example 199

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [4- (2-morpholin-4-yl-ethylcarbamoyl) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to example 197) from 100mg of the compound described in example 25), 0.04ml of triethylamine, 93mg of TBTU and 39. mu.l of 4- (2-aminoethyl) morpholine, after chromatographic purification on silica gel, 84mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.15-1.34 (6H); 2.34-2.48 (6H); 3.30-3.45 (2H); 3.50-3.64 (4H); 4.15-4.33 (4H); 7.33 (2H); 7.82 (2H); 8.21-8.40 (2H); 10.65(1H) ppm.

Example 200

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [4- (morpholine-4-carbonyl) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to example 197) from 100mg of the compound described in example 25), 0.04ml of triethylamine, 93mg of TBTU and 26. mu.l of morpholine, after chromatographic purification on silica gel, 40mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.15-1.35 (6H); 3.40-3.70 (8H); 4.16-4.32 (4H); 7.27-7.48 (4H); 8.25 (1H); 10.64(1H) ppm.

The following compounds were also prepared analogously:

example 220

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [4- (2-hydroxy-ethoxy) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

2g of the compound described in example c) and 1.14g of the compound described in example au) are introduced into 50ml of ethanol and stirred under reflux for 4 hours. The reaction mixture was filtered hot and the solid was recrystallized from ethanol. 1.78g of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.14-1.34 (6H); 3.70 (2H); 3.95 (2H); 4.15-4.32 (4H); 4.88 (1H); 6.94 (2H); 7.25 (2H); 8.12 (1H); 10.50(1H) ppm.

Example 221

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [3- (2-methoxy-acetylamino) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

75mg of the compound described in example be) are dissolved in 5ml of dichloromethane, mixed with 6ml of 2M diethyl ether hydrochloride solution and stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness in a rotary evaporator and then dissolved in 5ml of ethanol. 93. mu.l of triethylamine and 63mg of the compound described in example c) were added and stirred under reflux for 7 hours. The reaction mixture is concentrated by evaporation and, after chromatographic purification on silica gel, 41mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.14-1.33 (6H); 3.39 (3H); 4.00 (2H); 4.15-4.32 (4H); 6.96 (1H); 7.25 (1H); 7.33 (1H); 7.72 (1H); 8.15 (1H); 9.80 (1H); 10.65(1H) ppm.

Example 222

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [3- (3-morpholin-4-yl-propionylamino) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

92mg of the compound described in example bg) are dissolved in 4ml of dichloromethane and mixed with 5ml of 2M diethyl ether hydrochloride solution and stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness in a rotary evaporator and dissolved in 3ml of ethanol. 166. mu.l of triethylamine and 60mg of the compound described in example c) were added, and the mixture was stirred at reflux for 4 hours. The reaction mixture was concentrated by evaporation, mixed with water and extracted with dichloromethane. The solution is concentrated by evaporation and, after chromatographic purification on silica gel, 65mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.19-1.35 (6H); 2.35-2.46 (6H); 3.40 (2H); 3.58 (4H); 4.18-4.33 (4H); 7.40-7.50 (2H); 7.51-7.59 (1H); 7.75 (1H); 8.53 (1H); 10.64(1H) ppm.

Example 223

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [3- (2-morpholin-4-yl-ethanesulfonylamino) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

52mg of the compound described in example bi) are dissolved in 3ml of dichloromethane and mixed with 6ml of 2M diethyl ether hydrochloride solution and then stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness in a rotary evaporator and dissolved in 3ml of ethanol. 55. mu.l of triethylamine and 30mg of the compound described in example c) are added and the mixture is stirred for 7 hours at reflux. The reaction mixture was concentrated by evaporation, mixed with water and extracted with dichloromethane. The solution is concentrated by evaporation and, after chromatographic purification on silica gel, 11mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

1H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ 1.16-1.31 (6H); 2.29 (4H); 2.67 (2H); 3.20-3.34 (2H); 3.47 (4H); 4.16-4.30 (4H); 6.90 (1H); 7.01 (1H); 7.11 (1H); 7.28 (1H); 8.14 (1H); 9.93 (1H); 10.61 (1H); ppm (wt.%).

The following compounds were prepared analogously to examples 221, 222 and 223) from the intermediate products described in example c):

in analogy to example 160), the following compounds were prepared from the intermediate products described in example c):

the following compounds were prepared analogously to example 178) from the intermediate products described in example ba):

example 255

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [4- (3-morpholin-4-yl-propoxy) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

130mg of the compound described in example bc) are dissolved in 5ml of dichloromethane and mixed with 3ml of 2M diethyl ether hydrochloride solution and then stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness in a rotary evaporator and dissolved in 3ml of ethanol. 168. mu.l of triethylamine and 89mg of the compound described in example c) were added and the mixture was stirred under reflux for 4 hours. The reaction mixture was concentrated by evaporation, mixed with water and extracted with dichloromethane. The solution is concentrated by evaporation and, after chromatographic purification on silica gel, 33mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.15-1.30 (6H); 1.85 (2H); 2.29-2.45 (6H); 3.58 (4H); 3.97 (2H); 4.16-4.30 (4H); 6.95 (2H); 7.25 (2H); 8.12 (1H); 10.48 (1H); ppm (wt.%).

Example 256

(E or Z) -cyano- { 3-cyclopropyl-4-oxo-5- (E/Z) - [ (3, 4, 5-trimethoxy-phenylamino) -methylene ] -thiazolidin-2-ylidene } -acetic acid ethyl ester

Method embodiment C

31mg of the substance described in example ay) and 18mg of 3, 4, 5-trimethoxyaniline in 1ml of DMSO are shaken at 100 ℃ for 6 hours. Ethyl acetate and half-saturated aqueous ammonium chloride were added. The mixture was extracted with ethyl acetate. The crude product obtained after evaporation of the organic solvent was purified by HPLC. 4mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

¹H-NMR(DMSO-d₆)：δ＝1.00(2H)，1.18(2H)，1.28(3H)，3.02(1H)，3.61(3H)，3.81(6H) 4.23(2H), 6.63(2H), 6.78(2H, Z-isomer), 8.18(1H), 8.42(1H, Z-isomer), 11.10(1H), 11.20(1H, Z-isomer) ppm.

Example 257

(E or Z) -cyano- { 3-ethyl-5- (E/Z) - [ (1H-indazol-6-ylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

Method embodiment D

30mg of the substance described in example c) and a solution of 13mg of 6-aminoindazole in 1ml of DMSO are shaken at 100 ℃ for 6 hours. The reaction mixture was purified directly by HPLC. 8mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

¹H-NMR(DMSO-d₆): δ is 1.28(6H), 4.27(4H), 6.75(2H), 7.13(1H), 7.40(1H), 7.55(1H, ethyl-isomer), 7.72(1H), 8.00(1H), 8.28(1H), 8.59(1H, Z-isomer), 11.31(1H), 12.46(1H), 12.55(1H, Z-isomer) ppm.

Example 258

(E or Z) -cyano- { 3-butyl-5- (E/Z) - [ (6-methoxy-pyridin-3-ylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to the procedure embodiment C of example 63, from 31mg of the N-N-butyl derivative prepared analogously to example C) and 12mg of 2-methoxy-5-amino-pyridine in 1ml of DMSO, 12mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

¹H-NMR(DMSO-d₆)：δ＝0.91(3H)，1.27(3H)，1.32(2H)，1.61(2H)，3.82(3H)，4.2(4H)，6.82(1H)，7.77(1H)，8.15(2H)，11.25(1H)，11.30ppm.

Example 259

(E or Z) -cyano- (3-cyclopropyl-5- (E/Z) - { [4- (4-methylamino-benzyl) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to method embodiment C of example 63, from 31mg of the substance described in example yc) and 22mg of 4- (4-N-methylaminobenzyl-) -phenylamine in 1ml of DMSO, 10mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

¹H-NMR(DMSO-d₆): δ is 1.0(2H), 1.15(2H), 1.28(3H), 2.62(3H), 3.02(1H), 3.74(2H), 4.23(2H), 5.43(1H), 6.46(2H), 6.93(2H), 7.16(4H), 8.05(1H), 8.35(1H, Z-isomer), 11.16(1H), 11.25(1H, Z-isomer) ppm.

Example 260

(E or Z) -cyano- [ 3-cyclopropyl-4-oxo-5- (E/Z) - (thiazol-2-ylamino-methylene) -thiazolidin-2-ylidene ] -acetic acid ethyl ester

In analogy to method embodiment C of example 63, from 31mg of the substance described in example yc) and 10mg of 2-aminothiazole in 1ml of DMSO, 7mg of the title compound are obtained as a pH-dependent mixture of 5- (E/Z) -isomers.

¹H-NMR(DMSO-d₆)：δ＝1.02(2H)，1.18(2H)，1.28(3H)，3.04(1H)，4.22(2H)，7.20(1H)，7.39(1H)，8.22(1H，11.86(1H)ppm.

Example 261

(E or Z) -cyano- (3-cyclopropyl-4-oxo-5 (E/Z) -phenylamino-methylene-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 154mg of the substance described in example yc) and 52mg of aniline in 5ml of EtOH 94mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

¹H-NMR(DMSO-d₆): δ is 1.10(2H), 1.17(2H), 1.28(3H), 3.03(1H), 4.22(2H), 7.08(1H), 7.31(4H), 8.11(1H), 8.41(1H, Z-isomer), 10.39(1H), 10.51(1H, Z-isomer) ppm.

Example 262

(E or Z) -cyano- [ 3-cyclopropyl-5- (E/Z) - ({4- [2- (2-hydroxy-ethoxy) -ethoxy ] -phenylamino } -methylene) -4-oxo-thiazolidin-2-ylidene ] -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 154mg of the substance described in example yc) and 111mg of 2- [2- (4-amino-phenoxy) -ethoxy ] -ethanol in 5ml of EtOH gave 160mg of the title compound as a pH-dependent 5- (E/Z) -isomer mixture.

¹H-NMR(DMSO-d₆): δ is 0.99(2H), 1.17(2H), 1.25(3H), 3.02(1H), 3.49(4H), 3.72(2H), 4.07(2H), 4.22(2H), 4.62(1H), 6.93(2H), 7.23(2H), 7.32(2H, Z-isomer), 8.02(1H), 8.31(1H, Z-isomer), 10.31(1H), 10.51(1H, Z-isomer) ppm.

Example 263

6- { [2- (E or Z) - (cyano-ethoxycarbonyl-methylene) -3-cyclopropyl-4-oxo-thiazolidine-5- (E, Z) -ylidene-methyl ] -amino } -naphthalene-2-carboxylic acid

In analogy to method embodiment B of example 1, from 154mg of the substance described in example yc) and 105mg of 6-amino-naphthalene-2-carboxylic acid in 5ml of EtOH 147mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

¹H-NMR(DMSO-d₆): δ is 1.02(2H), 1.20(2H), 1.28(3H), 3.08(1H), 4.24(2H), 7.59(1H), 7.36(1H), 7.92(2H), 8.08(1H), 8.29(1H), 8.52(1H), 10.62(1H), 10.70(1H, Z-isomer), 12.96(1H) ppm.

Example 264

(E or Z) -cyano- { 3-isobutyl-4-oxo-5- (E/Z) - [ (3, 4, 5-trimethoxy-phenylamino) -methylene ] -thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment C of example 63, from 32mg of an N-iso-butyl derivative prepared analogously to example C) and 18mg of 3, 4, 5-trimethoxyaniline in 1ml of DMSO, 9mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

¹H-NMR(DMSO-d₆): δ is 0.88(6H), 1.27(3H), 2.12(1H), 3.63(3H), 3.81(6H), 4.06(2H), 4.22(2H), 6.67(2H), 6.78(2H, Z-isomer), 8.30(1H), 8.54(1H, Z-isomer), 11.20(1H), 11.25ppm.

Example 265

(E or Z) -cyano- [ 3-isobutyl-4-oxo-5- (E/Z) - (thiazol-2-ylamino-methylene) -thiazolidin-2-ylidene ] -acetic acid ethyl ester

In analogy to method embodiment C of example 63, from 32mg of the N-iso-butyl derivative prepared analogously to example C) and 10mg of 2-aminothiazole in 1ml of DMSO, 5mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

¹H-NMR(DMSO-d₆)：δ＝0.89(6H)，1.28(3H)，2.12(1H)，4.05(2H)，4.24(2H)，7.25(1H)，7.42(1H)，8.32(1H，11.95(1H)ppm.

Example 266

(E or Z) -cyano- { 3-isobutyl- (E/Z) -5- [ (6-methoxy-pyridin-3-ylamino) -methylene ] -4-oxo-thiazolidin-2- (Z) -ylidene } -acetic acid ethyl ester

In analogy to method embodiment C of example 63, from 32mg of the N-iso-butyl derivative prepared analogously to example C) and 13mg of 2-methoxy-4-amino-pyridine in 1ml of DMSO, 8mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

¹H-NMR(DMSO-d₆): δ is 0.88(6H), 1.27(3H), 2.12(1H), 3.82(3H), 4.08(2H), 4.22(2H), 6.82(2H), 7.78(1H), 8.18(2H), 8.31(2H, Z-isomer), 11.25(1H), 11.30(1H, Z-isomer) ppm.

Example 267

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [4- (4-methylamino-benzyl) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

Procedure in analogy to example 64, example D from 30mg of the substance described in example c) and 21mg of 4- (4-N-methylaminobenzyl-) -phenylamine in 1ml of DMSO gives 9mg of the title compound as a pH-dependent 5- (E/Z) -isomer mixture.

¹H-NMR(DMSO-d₆): δ is 1.22(6H), 2.64(3H), 3.73(2H), 4.21(4H), 6.51(2H), 6.95(2H), 7.19(4H), 8.16(1H), 8.42(1H, Z-isomer), 11.25(1H), 11.30(1H, Z-isomer) ppm.

Example 268

(E or Z) -cyano- { 3-ethyl-5- (E/Z) - [ (4-hydroxy-phenylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 50mg of the substance described in example c) and 20mg of 4-hydroxyaniline in 1ml of EtOH, 37mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

¹H-NMR(DMSO-d₆): δ ═ 1.24(6H), 4.20(4H), 6.75(2H), 7.15(2H), 7.21(2H, Z-isomer), 8.05(1H), 8.35(1H, Z-isomer), 9.40(1H), 9.45(1H, Z-isomer), 11.45(1H), 11.60(1H, Z-isomer) ppm.

The following compounds are prepared analogously according to process embodiments B), C) or D):

the following compounds are prepared analogously according to process embodiments B), C) or D):

the following compounds are prepared analogously according to process embodiments B), C) or D):

the following compounds are prepared analogously according to process embodiments B), C) or D):

the following compounds are prepared analogously according to process embodiments B), C) or D):

the following compounds are prepared analogously according to process embodiments B), C) or D):

example 479

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [4- (3-morpholin-4-yl-propylcarbamoyl) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

First, a solution of 0.018ml of triethylamine and 42mg of TBTU in 0.5ml of DMF was added to a suspension of 39mg of the compound described in example 25) in 1ml of DMF. A solution of 19mg of N- (3-aminopropyl) -morpholine in 0.5ml of DMF was added. The mixture was shaken overnight at room temperature. The solvent was evaporated and the crude product obtained was purified by preparative HPLC. 11mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

1H-NMR(DMSO-d6)：δ＝1.32-1.48(6H)；1.77-1.90(2H)；2.52-2.68(6H)；3.58(2H)；3.70-3.80(4H)；4.23-4.35(2H)；4.40-4.50(2H)；7.1(2H)；7.85(2H)；8.03(1H)；9.00(1H)；11.65(1H)ppm.

Example 480

(E or Z) -cyano- {5- (E/Z) - [ (4- { [ (2-dimethylamino-ethyl) -methyl-carbamoyl ] -methyl } -phenylamino) -methylene ] -3-ethyl-4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

25mg of the title compound are prepared in analogy to example 479 as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR(DMSO-d6)：δ＝1.20-1.32(6H)；2.80-2.88(6H)；3.05(3H)；3.20-3.26(2H)；3.58-3.73(4H)；4.18-4，4.30(4H)；7.21(2H)；7.28(2H)；8.18(1H)；8.87(1H)；10.53(1H)ppm.

Example 481

(E or Z) -cyano- [5- ({4- [2- (2-dimethylamino-1, 1-dimethyl-ethylcarbamoyl) -ethyl ] -phenylamino } -methylene) -3-ethyl-4-oxo-thiazolidin-2-ylidene ] -acetic acid ethyl ester

17mg of the title compound are prepared in analogy to example 479 as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR(DMSO-d6)：δ＝0.90(6H)；1.20-1.32(6H)；2.65-2.90(10H)；3.03(2H)；4.19-4.31(4H)；7.17-7.29(4H)；7.28(2H)；8.18(1H)；8.80(1H)；10.50(1H)ppm.

The following compounds were also prepared analogously:

example 699

(E or Z) -cyano- { 3-ethyl-5- (E/Z) - [ (7-hydroxy-naphthalen-1-ylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to process embodiment B of example 1, from 98mg of the substance described in example c) and 52.5mg of 7-hydroxy-1-naphthylamine 91.8mg of the product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.13-1.35(6H), 4.08-4.39(4H), 7.16(1H), 7.23-7.38(3H), 7.73(1H), 7.84(1H), 8.05(1H), 9.99(1H), 10.57(1H) ppm.

Example 700

(E or Z) -cyano- { 3-ethyl-5- (E/Z) - [ (5-hydroxy-naphthalen-2-ylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 98mg of the substance described in example c) and 47.8mg of 5-hydroxy-2-naphthylamine 111mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.26(3H), 1.27(3H), 4.18-4.34(4H), 6.76(1H), 7.22-7.35(2H), 7.44(1H), 7.70(1H), 8.10(1H), 8.36(1H), 10.11(1H), 10.70(1H) ppm.

Example 701

(E or Z) - (5- (E/Z) - { [4- (2-carboxy-ethylcarbamoyl) -phenylamino ] -methylene } -3-ethyl-4-oxo-thiazolidin-2-ylidene) -cyanoacetic acid ethyl ester

In analogy to process embodiment B of example 1, from 98mg of the substance described in example c) and 68.7mg of 3- (4-amino-benzoylamino) -propionic acid 111mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.27(3H), 2.46-2.54(2H), 3.38-3.50(2H), 4.18-4.31(4H), 7.37(2H), 7.83(2H), 8.27(1H), 8.46(1H), 10.6(br, 2H) ppm.

Example 702

(E or Z) - {5- (E/Z) - [ (4-carboxymethylsulfanyl-phenylamino) -methylene ] -3-ethyl-4-oxo-thiazolidin-2-ylidene } -cyanoacetic acid ethyl ester

In analogy to process embodiment B of example 1, from 98mg of the substance described in example c) and 60.5mg of (4-amino-phenylsulfanyl) -acetic acid 112mg of the product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.27(3H), 3.74(2H), 4.16-4.32(4H), 7.25-7.41(4H), 8.18(1H), 10.54(1H), 12.74(1H) ppm.

Example 703

(E or Z) -cyano- { 3-ethyl-5- (E/Z) - [ (1H-indol-6-ylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 98mg of the substance described in example c) and 43.6mg of 1H-indol-6-ylamine there are obtained 81.6mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.26(3H), 4.15-4.32(4H), 6.42(1H), 7.08(1H), 7.33-7.43(2H), 7.47(1H), 8.19(1H), 10.59(1H), 11.14(1H) ppm.

Example 704

(E or Z) -cyano- { 3-ethyl-5- (E/Z) - [ (3-hydroxy-4-methyl-phenylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 98mg of the substance described in example c) and 40.6mg of 5-amino-2-methyl-phenol 89.9mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.26(3H), 2.07(3H), 4.16-4.29(4H), 6.66(1H), 6.71(1H), 7.03(1H), 8.04(1H), 9.56(1H), 10.49(1H) ppm.

Example 705

(E or Z) -cyano- { 3-ethyl-5- (E/Z) - [ (3-hydroxy-4-methoxy-phenylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 98mg of the substance described in example c) and 46.0mg of 5-amino-2-methoxy-phenol 88.0g of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.26(3H), 3.75(3H), 4.16-4.30(4H), 6.67-6.79(2H), 6.90(1H), 8.02(1H), 9.31(1H), 10.42(1H) ppm.

Example 706

(E or Z) - {5- (E/Z) - [ (4-bromo-phenylamino) -methylene ] -3-ethyl-4-oxo-thiazolidin-2-ylidene } -cyanoacetic acid ethyl ester

In analogy to method embodiment B of example 1, from 98mg of the substance described in example c) and 56.8mg of 4-bromo-aniline 90.7mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.26(3H), 4.17-4.31(4H), 7.29(2H), 7.52(2H), 8.18(1H), 10.55(1H) ppm.

Example 707

(E or Z) - [ cyano- [ 3-ethyl-4-oxo-5- (E/Z) - (2, 3-naphthyridin-5-ylaminomethylene) -thiazolidin-2-ylidene ] -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 196mg of the substance described in example c) and 106mg of 2, 3-naphthyridin-5-ylamine gave 172mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.26(3H), 1.27(3H), 4.17-4.35(4H), 7.84-8.06(3H), 8.21(1H), 9.68(1H), 9.94(1H), 10.89(1H) ppm.

Example 708

(E or Z) - [ cyano- { 3-ethyl-5- [ (2-methyl-1, 3-dioxo-2, 3-dihydro-1H-isoindol-5- (E/Z) -ylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 98.0mg of the substance described in example c) and 58.0mg of 4-amino-N-methylphthalimide 108mg of product were obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.26(3H), 1.28(3H), 3.05(3H), 4.16-4.37(4H), 7.67(1H), 7.72(1H), 7.79(1H), 8.29(1H), 10.57(1H) ppm.

Example 709

(E or Z) - [ cyano- { 3-ethyl-5- (E/Z) - [ (5-methyl-1H- [1, 2, 4] triazol-3-ylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 98.0mg of the substance described in example c) and 32.4mg of 3-amino-5-methyl-1, 2, 4-triazole are obtained 95.0mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.23(3H), 1.26(3H), 2.33(3H), 4.23(4H), 8.30(1H), 11.31(1H), 13.39(1H) ppm.

Example 710

(E or Z) - [ cyano- { 3-ethyl-5- (E/Z) - [ (1H-indazol-5-ylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 98.0mg of the material described in example c) and 43.9mg of 5-aminoindazole 101mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.25(3H), 1.26(3H), 4.23(2H), 4.25(2H), 7.37(1H), 7.55(1H), 7.68(1H), 8.04(1H), 8.23(1H), 10.62(1H), 13.09(1H) ppm.

Example 711

(E or Z) - [ cyano- { 3-ethyl-5- (E/Z) - [ (1H-indazol-7-ylamino) -methylene ] -4-oxo-thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 148.2mg of the material described in example c) and 146.5mg of 7-aminoindazole 64.0mg of the product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.25(3H), 1.26(3H), 4.14-4.35(4H), 6.99-7.18(1H), 7.31(1H), 7.44-7.63(1H), 8.07-8.30(2H), 10.20(1H), 13.04(1H) ppm.

Example 712

(E or Z) -cyano- { 3-ethyl-4-oxo-5- (E/Z) - [ (1-oxo-2, 3-dihydro-1H-isoindol-4-ylamino) -methylene ] -thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, from 101mg of the substance described in example c) and 200mg of 4-amino-2, 3-dihydro-isoindol-1-one 214mg of product are obtained.

¹H-NMR(DMSO-d6, and K₂CO₃Storage, major isomer): δ is 1.15(3H), 1.17(3H), 4.04-4.22(4H), 4.38(2H), 7.31-7.44(3H), 8.07(1H), 8.56(1H), 10.26(1H) ppm.

Example 713

(E or Z) -cyano- { 3-ethyl-4-oxo-5- (E/Z) - [ (1-oxo-1, 2-dihydro-isoquinolin-5-ylamino) -methylene ] -thiazolidin-2-ylidene } -acetic acid ethyl ester

In analogy to method embodiment B of example 1, 284mg of product are obtained from 111mg of the substance described in example c) and 204mg of 5-amino-2H-isoquinolin-1-one.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.23(3H), 1.25(3H), 4.13-4.30(4H), 6.74(1H), 7.26(1H), 7.43-7.63(2H), 8.00-8.11(2H), 10.50(1H), 11.41(1H) ppm.

Example 714

(E or Z) - [ [5- (E/Z) - ({4- [2- (4-amino-phenyl) -ethyl ] -phenylamino } -methylene) -3-ethyl-4-oxo-thiazolidin-2-ylidene ] -cyanoacetic acid ethyl ester

In analogy to process embodiment B of example 1, from 296mg of the substance described in example c) and 212mg of 4, 4' -ethylenedianiline 178mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.26(3H), 2.71(4H), 4.14-4.32(4H), 4.82(2H), 6.47(2H), 6.85(2H), 7.10-7.25(4H), 8.18(1H), 10.51(1H) ppm.

Example 715

(E or Z) - [ (5- (E/Z) - { [4- (4-amino-benzyl) -phenylamino ] -methylene } -3-ethyl-4-oxo-thiazolidin-2-ylidene) -cyanoacetic acid ethyl ester

In analogy to process embodiment B of example 1, from 980mg of the substance described in example c) and 654g of bis- (4-aminophenyl) -methane 1.24g of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.27(3H), 3.70(2H), 4.15-4.30(4H), 4.88(2H), 6.49(2H), 6.86(2H), 7.16(2H), 7.24(2H), 8.15(1H), 10.52(1H) ppm.

Example 716

(E or Z) - [ cyano- [ 3-ethyl-5- (E/Z) - ({4- [4- (3-ethyl-thioureido) -benzyl ] -phenylamino } -methylene) -4-oxo-thiazolidin-2-ylidene ] -acetic acid ethyl ester

17.5. mu.l of ethyl isothiocyanate was added to a solution of 89.7mg of the compound prepared in example 715 in 0.1ml of DMSO, followed by stirring at 25 ℃ for 18 hours. Subsequently, the mixture was mixed with 8ml of ethanol, heated to 50 ℃ and filtered on G4-fritted glass, and then washed again with ethanol. After drying in vacuo, 66.0mg of the desired product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.09(3H), 1.24(3H), 1.26(3H), 3.46(2H), 3.87(2H), 4.15-4.30(4H), 7.08-7.34(8H), 7.66(1H), 8.17(1H), 9.36(1H), 10.52(1H) ppm.

Example 717

(E or Z) - [ cyano- [ 3-ethyl-4-oxo-5- (E/Z) - ({4- [4- (3-phenyl-ureido) -benzyl ] -phenylamino } -methylene) -thiazolidin-2-ylidene ] -acetic acid ethyl ester

In analogy to example 716, from 89.7mg of the substance described in example 715 and 21.7. mu.l of phenyl isocyanate 92.0mg of product were obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.26(3H), 3.85(2H), 4.16-4.30(4H), 6.95(1H), 7.13(2H), 7.17-7.32(6H), 7.36(2H), 7.43(2H), 8.17(1H), 8.59(2H), 10.53(1H) ppm.

Example 718

(E or Z) - [ cyano- [ 3-ethyl-5- (E/Z) - ({4- [4- (3-methoxymethyl-ureido) -benzyl ] -phenylamino } -methylene) -4-oxo-thiazolidin-2-ylidene ] -acetic acid ethyl ester

In analogy to example 716, from 89.7mg of the substance described in example 715 and 17.4. mu.l of methoxymethyl isocyanate 85.0mg of the product were obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.26(3H), 3.18(3H), 3.82(2H), 4.16-4.29(4H), 4.50(2H), 6.91(1H), 7.09(2H), 7.18(2H), 7.24(2H), 7.32(2H), 8.16(1H), 8.56(1H), 10.52(1H) ppm.

Example 719

(E or Z) - [ cyano- [ 3-ethyl-4-oxo-5- (E/Z) - ({4- [4- (3-phenyl-thioureido) -benzyl ] -phenylamino } -methylene) -thiazolidin-2-ylidene ] -acetic acid ethyl ester

In analogy to example 716, from 89.7mg of the substance described in example 715 and 24.0. mu.l of phenyl isothiocyanate there were obtained 91.0mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.26(3H), 3.88(2H), 4.17-4.30(4H), 7.14(1H), 7.15-7.41(9H), 7.46(2H), 8.17(1H), 9.73(2H), 10.53(1H) ppm.

Example 720

(E or Z) - [ cyano- [5- (E/Z) - ({4- [4- (3-ethoxycarbonylmethyl-ureido) -benzyl ] -phenylamino } -methylene) -3-ethyl-4-oxo-thiazolidin-2-ylidene ] -acetic acid ethyl ester

In analogy to example 716, from 89.7mg of the substance described in example 715 and 23.0. mu.l of ethyl isocyanatoacetate there are obtained 106mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(6H), 1.26(3H), 3.78-3.89(4H), 4.10(2H), 4.17-4.30(4H), 6.39(1H), 7.07(2H), 7.18(2H), 7.24(2H), 7.30(2H), 8.17(1H), 8.71(1H), 10.51(1H) ppm.

Example 721

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetylamino ] -acetic acid ethyl ester

60.0mg of the acid prepared in reference example x were dissolved in 0.75ml of dimethylformamide and then stirred at 25 ℃ for 30 minutes with 67.1mg of TBTU and 21.1mg of triethylamine. 26.2mg of glycine methyl ester hydrochloride were then added and stirred at 25 ℃ for 20 hours. Diluted with 200ml of ethyl acetate and washed 1 time each with 20ml of saturated sodium bicarbonate solution and 20ml of saturated sodium chloride solution. After drying over sodium sulfate and filtration, concentration is carried out by evaporation in vacuo. The crude product obtained is purified by thin layer chromatography using hexane/ethyl acetate 1: 1. In this way 25.1mg of the desired product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.26(3H), 3.65(3H), 3.91(2H), 4.24(2H), 7.07(1H), 7.26-7.40(4H), 8.06(1H), 8.12(1H), 10.34(1H) ppm.

Example 722

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N-pyridin-3-ylmethyl-acetamide

In analogy to example 721, from 60mg of the acid prepared in example xx) and 22.6mg of 3-picolylamine 47.3mg of product were obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.25(3H), 4.23(2H), 4.38(2H), 7.07(1H), 7.24-7.39(4H), 7.43(1H), 7.80(1H), 8.09(1H), 8.43(1H), 8.49(1H), 8.58(1H), 10.29(1H) ppm.

Example 723

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- (3-imidazol-1-yl-propyl) -acetamide

In analogy to example 721, from 60mg of the acid prepared in example xx) and 26.2mg of 1- (3-aminopropyl) -imidazole 34.1mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.25(3H), 1.93(2H), 3.17(2H), 3.97(2H), 4.23(2H), 6.90(1H), 7.05(1H), 7.20(1H), 7.24-7.39(4H), 7.66(1H), 7.78(1H), 8.11(1H), 10.31(1H) ppm.

Example 724

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- (4-fluoro-benzyl) -acetamide

In analogy to example 721, from 100mg of the acid prepared in example xx) and 43.6mg of 4-fluorobenzylamine gave 122.3mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 4.23(2H), 4.32(2H), 7.06(1H), 7.15(2H), 7.25-7.42(6H), 8.09(1H), 8.34(1H), 10.29(1H) ppm.

Example 725

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- (3-morpholin-4-yl-propyl) -acetamide

In analogy to example 721, from 60mg of the acid prepared in example xx) and 30.1mg of 4- (3-aminopropyl) -morpholine are obtained 34.9mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.64(2H), 2.27-2.39(6H), 3.25(2H), 3.61(4H), 4.22(2H), 7.05(1H), 7.22-7.39 (4H)H)，7.76(1H)，8.10(1H)，10.30(1H)ppm.

Example 726

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- (2-morpholin-4-yl-ethyl) -acetamide

In analogy to example 721, from 60mg of the acid prepared in example xx) and 37.2mg of 4- (2-aminoethyl) -morpholine, 37.2mg of the product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 2.35-2.47(6H), 3.30(2H), 3.57(4H), 4.22(2H), 7.06(1H), 7.24-7.40(4H), 7.54(1H), 8.10(1H), 10.31(1H) ppm.

Example 727

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- [3- (2-oxo-pyrrolidin-1-yl) -propyl ] -acetamide

In analogy to example 721, from 60mg of the acid prepared in example xx) and 29.6mg of 1- (3-aminopropyl) -2-pyrrolidone 36.7mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.65(2H), 1.93(2H), 2.23(2H), 3.08-3.23(4H), 3.28-3.38(2H), 4.22(2H), 7.05(1H), 7.22-7.38(4H), 7.66(1H), 8.11(1H), 10.30(1H) ppm.

Example 728

(E or Z) - [ 2-cyano-N-cyclohexyl-2- (3-ethyl-4-oxo-5- (E/Z) -phenylamino-methylene-thiazolidin-2-ylidene) -acetamide

Analogously to example 721, 24.4mg of product were obtained from 60mg of the acid prepared in example xx) and 21.1mg of cyclohexylamine.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 1.25-1.80(10H), 3.56-3.72(1H), 4.22(2H), 6.87(1H), 7.07(1H), 7.18-7.40(4H), 8.08(1H), 10.27(1H) ppm.

Example 729

(E or Z) - [4- [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetylamino ] -piperidine-1-carboxylic acid ethyl ester

In analogy to example 721, from 60mg of the acid prepared in example xx) and 36.0mg of ethyl 4-aminopiperidine-1-carboxylate there are obtained 41.2mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.19(3H), 1.24(3H), 1.50(2H), 1.65-1.80(2H), 2.85(2H), 3.84(1H), 3.96(2H), 4.04(2H), 4.22(2H), 7.05(1H), 7.19-7.43(5H), 8.11(1H), 10.29(1H) ppm.

Example 730

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- (3-hydroxy-propyl) -acetamide

In analogy to example 721, from 100mg of the acid prepared in example xx) and 26.2mg of 3-amino-1-propanol 61.6mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.23(3H), 1.63(2H), 3.36(2H), 3.46(2H), 4.23(2H), 4.53(1H), 7.05(1H), 7.20-7.38(4H), 7.62(1H), 8.10(1H), 10.29(1H) ppm.

Example 731

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- (4-methoxy-benzyl) -acetamide

In analogy to example 721, from 80.0mg of the acid prepared in example xx) and 38.3mg of 4-methoxybenzylamine gave 35.7mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.23(3H), 3.73(3H), 4.22(2H), 4.27(2H), 6.88(2H), 7.04(1H), 7.20-7.37(6H), 8.06-8.23(2H), 10.28(1H) ppm.

Example 732

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- [2- (4-hydroxy-phenyl) -ethyl ] -acetamide

In analogy to example 721, from 80.0mg of the acid prepared in example xx) and 38.3mg of 2- (4-hydroxyphenyl) -ethylamine there are obtained 19.4mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ ═ 1.24(3H), 2.67(2H), 3.32(2H), 4.21(2H), 6.70(2H), 6.88(1H), 7.01(2H), 7.13-7.38(5H)，8.15(1H)，9.18(1H)，10.32(1H)ppm.

Example 733

(E or Z) - [ N-allyl-2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetamide

In analogy to example 721, from 80.0mg of the acid prepared in example xx) and 16.0mg of allylamine 65.3mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.24(3H), 3.79(2H), 4.22(2H), 5.06(1H), 5.12(1H), 5.84(1H), 7.03(1H), 7.19-7.37(4H), 7.65-7.76(1H), 8.12(1H), 10.29(1H) ppm.

Example 734

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- (2-hydroxy-ethyl) -acetamide

In analogy to example 721, from 80.0mg of the acid prepared in example xx) and 17.1mg of ethanolamine 15.1mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.22(3H), 3.25(2H), 3.46(2H), 4.21(2H), 4.73(1H), 7.00(1H), 7.10-7.39(5H), 8.16(1H), 10.32(1H) ppm.

Example 735

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- (4-hydroxy-butyl) -acetamide

In analogy to example 721, from 80.0mg of the acid prepared in example xx) and 24.9mg of 4-amino-1-butanol 57.9mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.22(3H), 1.37-1.56(4H), 3.17(2H), 3.40(2H), 4.21(2H), 4.39(1H), 7.01(1H), 7.12-7.39(5H), 8.15(1H), 10.27(1H) ppm.

Example 736

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -N- (6-hydroxy-hexyl) -acetamide

In analogy to example 721, from 80.0mg of the acid prepared in example xx) and 32.7mg of 4-amino-1-hexanol 10.7mg of the product were obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.16-1.53(11H), 3.15(2H), 3.38(2H), 4.21(2H), 4.34(1H), 6.87(1H), 7.01(1H), 7.14-7.40(4H), 8.13(1H), 10.28(1H) ppm.

Example 737

(E or Z) - [ 2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetamide

Analogously to example 721, 73.1mg of product were obtained from 100mg of the acid prepared in example xx) and 0.1ml of an approximately 7M methanolic ammonia solution.

¹H-NMR (DMSO-d6, withK₂CO₃Storage, major isomer): δ ═ 1.24(3H), 4.22(2H), 7.05(1H), 7.09-7.40(6H), 8.10(1H), 10.34(1H) ppm.

Example 738

(E or Z) - [ N-ethyl-2-cyano-2- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetamide

Analogously to example 721, 144mg of product were obtained from 200mg of the acid prepared in example xx) and 0.35ml of 2M ethylamine in THF.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.07(3H), 1.23(3H), 3.21(2H), 4.22(2H), 7.06(1H), 7.22-7.40(4H), 7.66(1H), 8.10(1H), 10.28(1H) ppm.

Example 739

(E or Z) - [ cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid-3-hydroxy-propyl ester

100mg of the acid prepared in reference example x were dissolved in 1.25ml of dimethylformamide and then mixed with 112mg of TBTU, 34.5. mu.l of triethylamine, 10mg of 4-N, N-dimethylaminopyridine and 50.6. mu.l of 1, 3-propanediol and stirred at a temperature between 60 and 90 ℃ for 4 hours, followed by stirring at 25 ℃ for 16 hours. It is diluted with 70ml of ethyl acetate and washed 1 time sequentially with 10ml of saturated sodium bicarbonate solution, 10ml of 1N sulfuric acid and 10ml of water. After drying over sodium sulfate and filtration, concentration is carried out by evaporation in vacuo. The crude product obtained is purified by column chromatography on silica gel with hexane/0-100% ethyl acetate/0-20% ethanol. In this way 29.8mg of the desired product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.25(3H), 1.79(2H), 3.52(2H), 4.19-4.31(4H), 4.57(1H), 7.10(1H), 7.29-7.41(4H), 8.21(1H), 10.55(1H) ppm.

Example 740

(E or Z) - [ cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid-2- (2-hydroxy-ethoxy) -ethyl ester

In analogy to example 739, 59.6mg of product were obtained from 100mg of the acid prepared in example xx) and 66.0. mu.l of diethylene glycol.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.25(3H), 3.46-3.54(4H), 3.69(2H), 4.20-4.35(4H), 4.62(1H), 7.10(1H), 7.29-7.41(4H), 8.22(1H), 10.55(1H) ppm.

Example 741

(E or Z) - [ cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid-2- [ bis- (2-hydroxy-ethyl) -amino ] -ethyl ester

Analogously to example 739, 17.9mg of product were obtained from 100mg of the acid prepared in example xx) and 139. mu.l of triethanolamine.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.25(3H), 2.63(4H), 2.83(2H), 3.44(4H), 4.17-4.41(6H), 7.06-7.15(1H), 7.25-7.42(4H), 8.17-8.26(1H), 10.48-10.62(1H) ppm.

Example 742

(E or Z) - [ cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid-4-hydroxymethyl-phenyl ester

Analogously to example 739, from 100mg of the acid prepared in example xx) and 86.9mg of 4-hydroxybenzyl alcohol 47.1mg of product are obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.30(3H), 4.32(2H), 4.52(2H), 5.25(1H), 7.09(1H), 7.16(2H), 7.23-7.44(6H), 8.27(1H), 10.66(1H) ppm.

Example 743

(E or Z) - [ cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid-4- (3-hydroxy-propyl) -phenyl ester

In analogy to example 739, from 100mg of the acid prepared in example xx) and 106.5mg of 3- (4-hydroxyphenyl) propanol 51.3mg of product were obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.31(3H), 1.73(2H), 2.64(2H), 3.43(2H), 4.32(2H), 4.49(1H), 7.07-7.16(3H), 7.26(2H), 7.30-7.43(4H), 8.21-8.30(1H), 10.60-10.70(1H) ppm.

Example 744

(E or Z) - [ cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid-3- (2-hydroxy-ethyl) -phenyl ester

In analogy to example 739, from 100mg of the acid prepared in example xx) and 89.3. mu.l of 2- (3-hydroxyphenyl) ethanol 32.8mg of product were obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.31(3H), 2.76(2H), 3.63(2H), 4.32(2H), 4.67(1H), 7.01-7.18(4H), 7.23-7.43(5H), 8.22-8.31(1H), 10.61-10.69(1H) ppm.

Example 745

(E or Z) - [ cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid-4, 4, 4-trifluorobutyl ester

Analogously to example 739, 28.0mg of product were obtained from 100mg of the acid prepared in example xx) and 34.5. mu.l of 4, 4, 4-trifluorobutanol.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.25(3H), 1.90(2H), 2.38(2H), 4.18-4.33(4H), 7.11(1H), 7.28-7.44(5H), 8.21(1H), 10.56(1H) ppm.

Example 746

(E or Z) -cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid 4-hydroxymethylbenzyl ester

In analogy to example 739, from 100mg of the acid prepared in example xx) and 96.7mg of 1, 4-benzenedimethanol gave 39.4mg of product.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer):δ＝1.24(3H)，4.25(2H)，4.49(2H)，5.20(1H)，5.25(2H)，7.11(1H)，7.26-7.44(8H)，8.21(1H)，10.55(1H)ppm.

example 747

(E or Z) -cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid-2- (2-hydroxy-ethyl) -phenyl ester

In analogy to example 739, from 100mg of the acid prepared in example xx) and 83.7. mu.l of 2- (hydroxyphenyl) -ethanol 32.0mg of product were obtained.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.32(3H), 2.69(2H), 3.61(2H), 4.32(2H), 4.68(1H), 7.02-7.44(9H), 8.26(1H), 10.65(1H) ppm.

Example 748

(E or Z) - [ cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid-2- (4-bromo-phenyl) -2-oxo-ethyl ester

300mg of the acid prepared in reference example x were dissolved in a mixture consisting of 3ml of acetone and 0.9ml of DMSO and then mixed with 73.8mg of lithium carbonate and 277.6mg of 2, 4' -dibromoacetophenone. After stirring for 18 hours at 25 ℃ it is diluted with 200ml of ethyl acetate and washed 2 times with 20ml of half-saturated sodium chloride solution each. After drying over sodium sulfate and filtration, concentration is carried out by evaporation in vacuo. The crude product obtained is purified by column chromatography on silica gel with hexane/0-40% ethyl acetate. 278.4mg of the desired product are obtained in this way

¹H-NMR (DMSO-d6, with K)₂CO₃The storage is carried out in a storage way,major isomers): δ is 1.25(3H), 4.26(2H), 5.59(2H), 7.08(1H), 7.13-7.48(4H), 7.63-8.05(4H), 8.24(1H), 10.56(1H) ppm.

Intermediate compounds which are preferably used for the preparation of the thiazolidinone compounds according to the invention are prepared as follows.

Example a)

Cyano-ethylthiocarbamoyl-acetic acid ethyl ester

4.25ml of ethyl isothiocyanate were added to a mixture consisting of 5g of ethyl cyanoacetate and 5ml of triethylamine at 25 ℃. Stirring was continued for a further 6 hours at 50 ℃. The reaction mixture was concentrated by evaporation in vacuo. The residue was treated in ethanol and poured into 150ml of ice-cooled 1N hydrochloric acid. Stirring was continued for a further 3 hours at 25 ℃ and the residue was filtered off. The resulting solid was rewashed with water. 7g of product are obtained.

Example b)

(E or Z) -cyano- (3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

7.82g of the compound described in example a) are dissolved in 100ml of tetrahydrofuran. A solution of 3.9ml of bromoacetyl chloride was slowly added and stirred at 25 ℃ for 8 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate. Stirring was continued for 1 hour, followed by extraction with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude product obtained is recrystallized from a mixture of ethyl acetate/diisopropyl ester. 7.7g of product are obtained.

¹H-NMR(CDCl₃)：δ＝1.36(6H)；3.70(2H)；4.32(4H)ppm.

Example c)

(E or Z) -cyano- (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

A mixture of 1.54g of the substance described in example b), 2.5ml of triethyl orthoformate and 3.5ml of acetic anhydride was refluxed for 8 hours. The reaction mixture was poured onto ice water. Stirring was continued for 3 hours and then the residue was filtered off. The resulting solid was washed with water again. 1.28g of product are obtained.

¹H-NMR(CDCl₃)：δ＝1.38(9H)；4.20-4.40(6H)；7.72(1H)ppm.

Example d)

2-ethylthiocarbamoyl-malonic acid diethyl ester

In analogy to example a) 8.5g of product were obtained from 6g of diethyl malonate, 5.7ml of triethylamine and 4.9ml of ethyl isothiocyanate.

Example e)

2- (3-Ethyl-4-oxo-thiazolidin-2-ylidene) -malonic acid diethyl ester

Analogously to example b), 12.5g of the substance described in example d) and 5ml of bromoacetyl chloride in tetrahydrofuran gave 10.2g of product.

¹H-NMR(CDCl₃)：δ＝1.16(3H)；1.25(3H)；1.31(3H)；3.66(2H)；3.76(2H)；4.20-4.35(4H)ppm.

Example f)

2- (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -malonic acid diethyl ester

In analogy to example c), 1.3g of product were obtained from 1.8g of the compound described in example e), 2.5ml of triethyl orthoformate and 3.5ml of acetic anhydride.

¹H-NMR(CDCl₃)：δ＝1.15-1.40(12H)；3.75(2H)；4.20-4.45(6H)；7.75(1H)ppm.

Example g)

2, 2-dicyano-N-ethyl-thioacetamide

Analogously to example a), 31.8g of product are obtained from 20g of malononitrile, 20ml of triethylamine and 17ml of ethyl isothiocyanate.

Example h)

2- (3-ethyl-4-oxo-thiazolidin-2-ylidene) -malononitrile

In analogy to example b), 8.1g of product are obtained from 8.73g of the substance described in example g) and 4.8ml of bromoacetyl chloride in tetrahydrofuran.

¹H-NMR(CDCl₃)：δ＝1.36(3H)；4.00(2H)；4.19(2H)ppm.

Example i)

2- (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -malononitrile

In analogy to example c), 3.4g of product are obtained from 3.4g of the compound described in example h), 6.9ml of triethyl orthoformate and 9.6ml of acetic anhydride.

¹H-NMR(CDCl₃)：δ＝1.31(3H)；1.39(3H)；4.18-4.35(4H)；7.81(1H)ppm.

Example j)

Cyano-ethylthiocarbamoyl-acetic acid propyl ester

In analogy to example a) 5.6g of product were obtained from 3.5g of cyanopropyl acetate, 3.5ml of triethylamine and 2.55ml of ethyl isothiocyanate.

Example k)

(E or Z) -cyano- (3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid propyl ester

In analogy to example b), 4.95g of product are obtained from 7g of the compound described in example 1) and 2.7ml of bromoacetyl chloride in 100ml of tetrahydrofuran.

1H-NMR(CDCl₃)：δ＝1.00(3H)；1.37(3H)；1.73(2H)；3.69(2H)；4.20(2H)；4.31(2H)ppm.

Example l)

(E or Z) -cyano- (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid propyl ester

4.26g of product are obtained analogously to example c) from 4.95g of the compound described in example 2), 7.45ml of triethyl orthoformate and 10ml of acetic anhydride.

1H-NMR(CDCl₃)：δ＝0.99(3H)；1.30-1.45(6H)；1.75(2H)；4.15-4.30(4H)；4.38(2H)；7.71(1H)ppm.

Example m)

Cyano-ethylthiocarbamoyl-acetic acid isopropyl ester

Analogously to example a), 6.7g of product are obtained starting from 4g of isopropyl cyanoacetate, 4ml of triethylamine and 3ml of ethyl isothiocyanate.

Example n)

(E or Z) -cyano- (3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid isopropyl ester

Analogously to example b), 6.18g of product are obtained from 6.7g of the compound described in example 1) and 3.15ml of bromoacetyl chloride in 100ml of tetrahydrofuran.

1H-NMR(CDCl₃)：δ＝1.28-1.40(9H)；3.70(2H)；4.30(2H)；5.13(1H)ppm.

Example o)

(E or Z) -cyano- (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid isopropyl ester

Analogously to example c), 1.77g of product were obtained starting from 2g of the compound described in example 2), 3ml of triethyl orthoformate and 4.3ml of acetic anhydride.

1H-NMR(CDCl₃)：δ＝1.25-1.45(12H)；4.23(2H)；4.37(2H)；5.12(1H)；7.70(1H)ppm.

Example p)

Cyano-ethylthiocarbamoyl-acetic acid-tert-butyl ester

In analogy to example a), 8g of product are obtained from 5g of tert-butyl cyanoacetate, 5.6ml of triethylamine and 5ml of ethyl isothiocyanate.

Example q)

(E or Z) -cyano- (3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid-tert-butyl ester

In analogy to example b), 7.1g of product are obtained from 9.8g of the compound described in example 1) and 3.6ml of bromoacetyl chloride in 150ml of tetrahydrofuran.

1H-NMR(CDCl₃)：δ＝1.32(3H)；1.55(9H)；3.68(2H)；4.30(2H)ppm.

Example r)

(E or Z) -cyano- (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid tert-butyl ester

In analogy to example c) 4.6g of product were obtained from 6.16g of the compound described in example 2), 8.8ml of triethyl orthoformate and 12.6ml of acetic anhydride.

1H-NMR(CDCl₃)：δ＝1.30-1.45(6H)；1.55(9H)；4.24(2H)；4.35(2H)；7.69(1H)ppm.

Example s)

(E or Z) -cyano- (3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid benzyl ester

A solution of 1.75g of benzyl cyanoacetate in 10ml of dimethylformamide is added at 0 ℃ to a suspension of 0.4g of sodium hydride (60%) in 5ml of dimethylformamide. After stirring at 0 ℃ for 10 minutes, 876. mu.l of a solution of ethyl isothiocyanate in 5ml of dimethylformamide were added. Stirring was continued for a further 2 hours at 25 ℃. At 0 ℃ a solution of 1ml of bromoacetyl chloride in 5ml of dimethylformamide is added and stirring is carried out for a further 15 hours at 25 ℃. The reaction mixture was poured onto a saturated sodium bicarbonate solution. Extraction with dichloromethane and washing of the organic phase with saturated sodium chloride solution, drying over sodium sulfate and concentration by evaporation in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate. 1.1g of product are obtained.

1H-NMR(CDCl₃)：δ＝1.35(3H)；3.70(2H)；4.30(2H)；5.31(2H)，7.30-7.48(5H)ppm.

Example t)

(E or Z) -cyano- (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -acetic acid benzyl ester

In analogy to example c) 1.26g of product were obtained from 11g of the compound described in example 1), 1.49ml of triethyl orthoformate and 2.1ml of acetic anhydride.

1H-NMR(CDCl₃)：δ＝1.30-1.45(6H)；4.25(2H)；4.38(2H)；5.29(2H)；7.30-7.48(5H)，7.72(1H)ppm.

Example u)

2-cyano-2-ethylthiocarbamoyl-N, N-dimethyl-acetamide

Analogously to example a), 3.3g of product were obtained starting from 3g of N, N-dimethylcyanoacetamide, 4ml of triethylamine and 2.8ml of ethyl isothiocyanate.

Example v)

2- (E or Z) -cyano-2- (3-ethyl-4-oxo-thiazolidin-2-ylidene) -N, N-dimethyl-acetamide

Analogously to example b), 2.3g of the compound described in example 1) and 1.54ml of bromoacetyl chloride in 70ml of tetrahydrofuran gave 1.77g of product.

1H-NMR(CDCl₃)：δ＝1.33(3H)；3.05-3.20(6H)；3.70(2H)；4.24(2H)ppm.

Example w)

2- (E or Z) -cyano-2- (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -N, N-dimethyl-acetamide

In analogy to example c) 1.65g of product were obtained from 1.77g of the compound described in example 2), 2.83ml of triethyl orthoformate and 4.05ml of acetic anhydride.

1H-NMR(CDCl₃)：δ＝1.30-1.40(6H)；3.05-3.15(6H)；4.20(2H)；4.31(2H)；7.63(1H)ppm.

Example x)

2-cyano-N-ethyl-3-oxo-3-phenyl-thiopropionamide

Analogously to example a), 2.24g of product were obtained from 1.5g of benzoylacetonitrile, 1.6ml of triethylamine and 1.45ml of ethyl isothiocyanate.

Example y)

2- (E or Z) - (3-ethyl-4-oxo-thiazolidin-2-ylidene) -3-oxo-3-phenyl-propionitrile

Analogously to example b), 2.24g of the compound described in example 1) and 1.29ml of bromoacetyl chloride in 50ml of tetrahydrofuran gave 1.82g of product.

1H-NMR(CDCl₃)：δ＝1.43(3H)；3.71(2H)；4.43(2H)；7.48-7.60(3H)；7.80-7.88(2H)ppm.

Example z)

2- (E or Z) - (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxo-thiazolidin-2-ylidene) -3-oxo-3-phenyl-propionitrile

In analogy to example c) 1.46g of product were obtained from 1.8g of the compound described in example 2), 2.52ml of triethyl orthoformate and 3.63ml of acetic anhydride.

1H-NMR(CDCl₃)：δ＝1.38-1.50(6H)；4.31(2H)；4.49(2H)；7.40-7.58(3H)；7.80-7.88(3H)ppm.

Example aa)

3-ethyl-2- (E or Z) - (2-oxo-1, 2-diphenyl-ethylene) -thiazolidin-4-one

A solution of 1.96g of benzylphenyl ketone in 10ml of dimethylformamide is added at 0 ℃ to a suspension of 0.4g of sodium hydride (60%) in 5ml of dimethylformamide. Stirring was continued for 10 minutes at 0 ℃ and then 876. mu.l of a solution of ethyl isothiocyanate in 5ml of dimethylformamide were added. Stirring was continued for a further 2 hours at 25 ℃. A solution of 1ml of bromoacetyl chloride in 5ml of dimethylformamide is added at 0 ℃ and stirring is carried out for a further 15 hours at 25 ℃. The reaction mixture was poured onto a saturated sodium bicarbonate solution. Dichloromethane was extracted and the organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate. 1.24g of product are obtained.

1H-NMR(CDCl₃)：δ＝0.74(3H)；3.25(2H)；3.70(2H)；7.10-7.30(10H)ppm.

Example ab)

(E or Z) - (3-ethyl-4-oxo-thiazolidin-2-ylidene) -phenyl-acetonitrile

A solution of 1.15g of benzyl cyanide in 10ml of dimethylformamide is added at 0 ℃ to a suspension of 0.4g of sodium hydride (60%) in 5ml of dimethylformamide. After stirring at 0 ℃ for a further 10 minutes, 876. mu.l of a solution of ethyl isothiocyanate in 5ml of dimethylformamide are added. Stirring was continued for a further 2 hours at 25 ℃. A solution of 1ml of bromoacetyl chloride in 5ml of dimethylformamide is added at 0 ℃ and then stirred for a further 15 hours at 25 ℃. The reaction mixture is poured onto an upper saturated sodium bicarbonate solution, dichloromethane is extracted, the organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate. 1.4g of product are obtained.

1H-NMR(CDCl₃)：δ＝1.45(3H)；3.71(2H)；4.30(2H)；7.30-7.50(5H)ppm.

Example ac)

2- (tert-butyl-diphenyl-silanyloxy) -ethylamine

34g of imidazole and 78ml of tert-butyldiphenylsilyl chloride are added at 0 ℃ to a solution of 15ml of 2-aminoethanol in 150ml of N, N-dimethylformamide. Stirring was continued for a further 16 hours at 25 ℃. The reaction mixture was poured onto ice-cooled saturated sodium bicarbonate solution. Extraction with ethyl acetate and washing of the organic phase with saturated sodium chloride solution, drying over sodium sulfate and concentration by evaporation in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate. 45.4g of product are obtained.

Example ad)

Tert-butyl- (2-isothiocyano-ethoxy) -diphenylsilane

A solution of 5.23ml of thiophosgene in 50ml of tetrahydrofuran is slowly added at 0 ℃ to a solution of 18.7g of the compound described in example 1) in 250ml of tetrahydrofuran. Stirring was continued for a further 1.5 h at 25 ℃. The reaction mixture was poured onto ice water. Extraction with ethyl acetate and washing of the organic phase with saturated sodium chloride solution, drying over sodium sulfate and concentration by evaporation in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate. 7.9g of product are obtained.

1H-NMR(CDCl₃)：δ＝1.08(9H)；3.58(2H)；3.79(2H)；7.38-7.48(6H)；7.65-7.70(4H)ppm.

EXAMPLES ae)

[2- (tert-butyl-diphenyl-silanyloxy) -ethylsulfanylcarbamoyl ] -cyano-acetic acid ethyl ester

A solution of 8.9g of the compound described in example 2) in 2ml of tetrahydrofuran is added to a solution of 2.53ml of ethyl cyanoacetate and 3.5ml of triethylamine. Stirring was continued for a further 16 hours at 75 ℃. Followed by concentration by evaporation in vacuo. The residue was treated in ethanol and then poured into ice-cooled 2N hydrochloric acid. Stirring was continued for a further 1 hour at 25 ℃ and extraction was then carried out with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. 10.7g of product are obtained.

Examples af)

(E or Z) - {3- [2- (tert-butyl-diphenyl-silanyloxy) -ethyl ] -4-oxo-thiazolidin-2-ylidene } -cyanoacetic acid ethyl ester

A solution of 2.2ml of bromoacetyl chloride in 20ml of tetrahydrofuran is slowly added to a solution of 10.7g of the compound described in example 3) in 250ml of tetrahydrofuran. After stirring at 25 ℃ for a further 5 hours, the reaction mixture is poured into saturated sodium bicarbonate solution. Stirring was continued for 1 hour, followed by extraction with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate. 6.87g of product are obtained.

1H-NMR(CDCl₃)：δ＝0.97-1.05(9H)；1.34(3H)；3.59(2H)；3.95(2H)；4.29(2H)；4.58(2H)；7.30-7.48(6H)；7.55-7.65(4H)ppm.

Example ag)

(E or Z) - {3- [2- (tert-butyl-diphenyl-silanyloxy) -ethyl ] -5- (E/Z) -ethoxymethylene-4-oxo-thiazolidin-2-ylidene } -cyanoacetic acid ethyl ester

Analogously to example c), 2.0g of product were obtained starting from 2g of the compound described in example 4), 1.57ml of triethyl orthoformate and 2.2ml of acetic anhydride.

1H-NMR(CDCl₃)：δ＝0.95-1.00(9H)；1.30-1.48(6H)；3.93(2H)；4.22-4.35(4H)；4.62(2H)；7.30-7.45(6H)；7.55-7.62(4H)；7.68(1H)ppm.

Example ah)

Cyano- (2-methoxy-ethylthiocarbamoyl) -acetic acid ethyl ester

1.49g of product are obtained in analogy to example a) from 1g of ethyl cyanoacetate, 1ml of triethylamine and 1.14g of 2-methoxyethyl isothiocyanate.

Example ai)

(E or Z) -cyano- [3- (2-methoxy-ethyl) -4-oxo-thiazolidin-2-ylidene ] -acetic acid ethyl ester

Analogously to example b), 940mg of product were obtained from 1.49g of the compound described in example 1) and 645. mu.l of bromoacetyl chloride in 7ml of tetrahydrofuran.

1H-NMR(CDCl₃)：δ＝1.35(3H)；3.35(3H)；3.69(2H)；3.74(2H)；4.30(2H)；4.56(2H)ppm.

Example aj)

(E or Z) -cyano- [5- (E/Z) -ethoxymethylene-3- (2-methoxy-ethyl) -4-oxo-thiazolidin-2-ylidene ] -acetic acid ethyl ester

In analogy to example c) 675mg of product were obtained from 940mg of the compound described in example 2), 1.3ml of triethyl orthoformate and 1.8ml of acetic anhydride.

1H-NMR(CDCl₃)：δ＝1.32-1.42(6H)；3.33(3H)；3.70(2H)；4.20-4.35(4H)；4.59(2H)，7.72(1H)ppm.

Example ak)

Cyano-methylthiocarbamoyl-acetic acid ethyl ester

Analogously to example a), 6g of product were obtained from 5g of cyanopropyl acetate, 5ml of triethylamine and 3.6g of methylisothiocyanate.

Example al)

(E or Z) -cyano- (3-methyl-4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to example b), 4.35g of product are obtained from 4.95g of the compound described in example 1) and 2.7ml of bromoacetyl chloride in 100ml of tetrahydrofuran.

1H-NMR(CDCl₃)：δ＝1.35(3H)；3.70(3H)；3.73(2H)；4.32(2H)ppm.

Example am)

(E or Z) -cyano- (5- (E/Z) -ethoxymethylene-3-methyl-4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

3.5g of product are obtained analogously to example c) from 4.33g of the compound described in example 2), 7.4ml of triethyl orthoformate and 10ml of acetic anhydride.

1H-NMR(CDCl₃)：δ＝1.32-1.42(6H)；3.72(3H)；4.20-4.38(2H)；7.71(1H)ppm.

Example an)

Isothiocyanato-cyclobutanes

2.0g of cyclobutylamine were introduced into 50ml of THF, mixed with 2.3ml of thiophosgene at 0 ℃ and then stirred at room temperature for 30 minutes. The reaction mixture was mixed with sodium bicarbonate solution and then extracted with ethyl acetate. After removal of the solvent, 3g of the title compound are obtained as crude product.

1H-NMR(CDCl₃)：δ＝1.63-1.93(2H)；2.15-2.50(4H)；4.05(1H)ppm.

Example ao)

Cyano-cyclobutyl thiocarbamoyl-acetic acid ethyl ester

Analogously to example a), 2.7g of ethyl cyanoacetate, 4.3ml of triethylamine and 3.0g of the compound described in example an) gave, after chromatographic purification on silica gel (dichloromethane/methanol 80: 20), 2.6g of the title compound.

Example ap)

(E or Z) -cyano- (3-cyclobutyl-4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

In analogy to example b), from 2.0g of the compound described in example ao) and 1.1ml of bromoacetyl chloride in tetrahydrofuran, 340mg of the title compound are obtained after recrystallization from ethanol.

¹H-NMR(CDCl₃)：δ＝1.35(3H)；1.70-1.95(2H)；2.40-2.52(2H)；2.70-2.90(2H)；3.65(2H)；4.30(2H)；5.10(1H)ppm.

Example aq)

(E or Z) -cyano- (3-cyclobutyl-5- (E or Z) -ethoxymethylene-4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

Analogously to example c), from 450mg of the compound described in example ap), 0.66ml of triethyl orthoformate and 0.93ml of acetic anhydride, 434g of the title compound are obtained after recrystallization.

¹H-NMR(CDCl₃)：δ＝1.30-1.45(6H)；1.70-1.98(2H)；2.35-2.52(2H)；2.80-3.00(2H)；4.15-4.38(4H)；5.20(1H)；7.65(1H)ppm.

Example ar)

(E or Z) - {5- (E/Z) - [ (3-bromomethyl-phenylamino) -methylene ] -3-ethyl-4-oxo-thiazolidin-2-ylidene } -cyanoacetic acid ethyl ester

752mg of the compound described in example 60), 2.70g of triphenylphosphine and 2.66g of carbon tetrabromide were dissolved in 100ml of THF, followed by stirring at room temperature for 1 hour. The reaction mixture was mixed with water and extracted with ethyl acetate. After chromatographic purification on silica gel, 685mg of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.18-1.35 (6H); 4.18-4.32 (4H); 4.78 (2H); 7.16 (1H); 7.25-7.41 (2H); 7.45 (1H); 8.20 (1H); 10.60(1H) ppm.

Example as)

4- (3- { [2- ((E or Z) -cyano-ethoxycarbonyl-methylene) -3-ethyl-4-oxo-thiazolidin-5- (E/Z) -ylidenemethyl ] -amino } -benzyl) -piperazine-1-carboxylic acid tert-butyl ester

In analogy to example 225) from 750mg of the compound described in example ar), 700mg of potassium carbonate and 480mg of 1-tert-butyloxycarbonylpiperazine in 50ml of DMF gave 680mg of the title compound after chromatographic purification on silica gel as a pH-dependent mixture of 5- (E/Z) -isomers.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.16-1.32 (6H); 1.40 (9H); 2.21-2.40 (4H); 3.21-3.45 (4H); 3.46 (2H); 4.15-4.33 (4H); 7.04 (1H); 7.16-7.47 (3H); 8.20 (1H); 10.56(1H) ppm.

Example at)

(E or Z) -cyano- { 3-ethyl-4-oxo-5- (E/Z) - [ (3-piperazin-1-yl-methyl-phenylamino) -methylene ] -thiazolidin-2-ylidene } -acetic acid ethyl ester

680mg of a solution of the compound described in example as) in 20ml of dichloromethane are mixed with 10ml of trifluoroacetic acid and then stirred at room temperature for 2 hours. The solvent was distilled off on a rotary evaporator to give 850mg of the title compound in the form of a crude product as a pH-dependent 5- (E/Z) -isomer mixture.

Example au)

2- (4-amino-phenoxy) -ethanol

2g of 2- (4-nitrophenoxy) ethanol are dissolved in 80ml of THF, mixed with 420mg of palladium-on-charcoal solution in ethanol and then hydrogenated at normal pressure and room temperature overnight. The reaction mixture was filtered over Celite and after distilling off the solvent in a rotary evaporator 1.6g of the title compound were obtained as crude product.

1H-NMR(CDCl₃)：δ＝3.00-3.70(3H)；3.85-3.95(2H)；3.95-4.08(2H)；6.55-6.70(2H)；6.70-6.84(2H)ppm.

Example av)

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [4- (2-iodo-ethoxy) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

560mg of the compound described in example 219), 440mg of triphenylphosphine and 144mg of imidazole were dissolved in 50ml of THF, mixed in portions with 426mg of iodine and then stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. After chromatographic purification on silica gel, 550mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.18-1.32 (6H); 3.51 (2H); 4.18-4.30 (6H); 6.98 (2H); 7.27 (2H); 8.13 (1H); 10.50(1H) ppm.

Example aw)

Cyano-cyclopropylthiocarbamoyl-acetic acid ethyl ester

4.85ml of ethyl cyanoacetate, 5.24ml of triethylamine and 5.0g of cyclopropyl isothiocyanate were stirred at 50 ℃ overnight. The resulting reaction mixture was diluted with 10ml of EtOH and then slowly added to 220ml of 1M HCl. Stirred for 2 hours. The precipitate formed is filtered off with suction and washed with water. The solid was dissolved in medium dichloromethane and then washed with saturated aqueous sodium chloride solution. The organic phase was dried (MgSO)₄) And removing the solvent from the product. 6.9g of product are obtained.

¹H-NMR(CDCl₃)：δ＝0.78(2H)，0.94(2H)，1.29(3H)，2.73(1H)，4.18(2H)，4.89(1H)，11.18(1H)ppm.

Examples ax)

(E or Z) -cyano- (3-cyclopropyl-4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

Analogously to example b), 6.9g of the compound described in example ya) and 3.3ml of bromoacetyl chloride in 210ml of tetrahydrofuran gave 6.2g of product after recrystallization from diethyl ether/hexane.

MS(CI/NH₃)m/z＝270(M+H₂O)⁺

Example ay)

(E or Z) -cyano- (3-cyclopropyl-5- (E or Z) -ethoxy-methylene-4-oxo-thiazolidin-2- (Z) -ylidene) -acetic acid ethyl ester

In analogy to example c), from 6.22g of the compound described in example yb), 9.61ml of triethyl orthoformate and 13.46ml of acetic anhydride, 4.22g of product were obtained after stirring with diethyl ether.

¹H-NMR(CDCl₃)：δ＝1.10(2H)，1.37(6H)，1.90(2H)，3.12(1H)，4.21(2H)，4.31(2H)，7.65(1H)ppm.

Example az)

(E or Z) - [ cyano- (3-ethyl-4-oxo-5- (E/Z) -phenylaminomethylene-thiazolidin-2-ylidene) -acetic acid

1.50g of the ester prepared in example 1 was dissolved in 19ml of dioxane, mixed with 7.5ml of an ethanol solution of potassium hydroxide, and then stirred at 25 ℃ for 18 hours. Diluted with 150ml of water, acidified to pH2 with 1N sulfuric acid, filtered off the solid by suction on a porous glass and then dried at 70 ℃ under vacuum. The product thus obtained was used in the next reaction without purification.

¹H-NMR (DMSO-d6, with K)₂CO₃Storage, major isomer): δ is 1.23(3H), 4.25(2H), 7.08(1H), 7.27-7.42(4H), 8.14(1H), 10.42(1H), 13.05(1H) ppm.

Example ba)

(E or Z) -cyano- (3-ethyl-5- (E/Z) - { [4- (2-iodo-ethyl) -phenylamino ] -methylene } -4-oxo-thiazolidin-2-ylidene) -acetic acid ethyl ester

Analogously to example av) from 1.0g of the compound described in example 459), 817mg of triphenylphosphine, 267mg of imidazole and 793mg of iodine, after chromatographic purification on silica gel, 1.06g of the title compound are obtained as a pH-dependent 5- (E/Z) -isomer mixture.

1H-NMR (DMSO-d6, with K₂CO₃Storage, major isomer): δ 1.19-1.32 (6H); 3.10 (2H); 3.46 (2H); 4.17-4.32 (4H); 7.20-7.31 (4H); 8.20 (1H); 10.51(1H) ppm.

Example bb)

(4-hydroxyphenyl) -carboxylic acid tert-butyl ester

3g of 4-aminophenol are dissolved in 50ml of methylene chloride and mixed at 0 ℃ with 15ml of diisopropylamine and 6.6g of di-tert-butyl-dicarbonate and then stirred at room temperature for 18 hours. After aqueous workup and recrystallization from ethyl acetate/hexane, 1.06g of the title compound are obtained.

Examples bc)

[4- (3-morpholin-4-yl-propoxy) -phenyl ] -carboxylic acid tert-butyl ester

89mg of the compound described in example bb) are dissolved in 4ml of butanone and then mixed with 130ml of potassium carbonate, 35mg of tetrabutylammonium iodide and 100. mu.l of 4- (3-chloro-propyl) -morpholine and stirred under reflux for 4 hours. After aqueous workup and chromatographic purification on silica gel, 160mg of the title compound are obtained.

1H-NMR(DMSO-d6)：δ＝1.46(9H)；1.85(2H)；2.28-2.45(6H)；3.56(4H)；3.93(2H)；6.81(2H)；7.31(2H)；9.10(1H)ppm.

Example bd)

(3-amino-phenyl) -carboxylic acid-tert-butyl ester

5g of 1, 3-phenylenediamine are dissolved in 50ml of methylene chloride and mixed at 0 ℃ with 24ml of diisopropylamine and 10.8g of di-tert-butyl-dicarbonate and stirred at room temperature for 18 hours. After aqueous workup and recrystallization from ethyl acetate/hexane, 4.74g of the title compound are obtained.

1H-NMR(CDCl₃)：δ＝1.50(9H)；3.68(2H)；6.35(1H)；6.40(1H)；6.52(1H)；6.96(1H)；7.04(1H)ppm.

Example be)

[3- (2-methoxy-acetylamino) -phenyl ] -carboxylic acid-tert-butyl ester

200mg of the compound described in example bd) are dissolved in 10ml of tetrahydrofuran, mixed with 400. mu.l of triethylamine and 136. mu.l of methoxy-acetyl chloride and stirred at room temperature for 18 hours. After aqueous workup and chromatographic purification on silica gel, 75mg of the title compound are obtained.

1H-NMR(DMSO-d6)：δ＝1.45(9H)；3.32(3H)；3.95(2H)；7.06(1H)；7.15(1H)；7.28(1H)；7.83(1H)；9.34(1H)；9.70(1H)ppm.

Example bf)

(3-acryloylamino-phenyl) -carboxylic acid-tert-butyl ester

300mg of the compound described in example bd) are dissolved in 10ml of tetrahydrofuran, mixed with 400. mu.l of triethylamine and 156. mu.l of acryloyl chloride and stirred at room temperature for 18 hours. After aqueous workup and chromatographic purification on silica gel, 290mg of the title compound are obtained.

1H-NMR(DMSO-d6)：δ＝1.49(9H)；5.73(1H)；6.24(1H)；6.45(1H)；7.05(1H)；7.16(1H)；7.40(1H)；7.84(1H)；9.47(1H)；10.10(1H)ppm.

Example bg)

[3- (3-morpholin-4-yl-propionylamino) -phenyl ] -carboxylic acid tert-butyl ester

100mg of the compound described in example bf) are dissolved in 3ml of tetrahydrofuran, mixed with 158. mu.l of triethylamine and 50. mu.l of morpholine and stirred under reflux for 4 hours. After aqueous workup and chromatographic purification on silica gel, 92mg of the title compound are obtained.

1H-NMR(DMSO-d6)：δ＝1.47(9H)；2.33-2.49(6H)；2.60(2H)；3.58(4H)；7.03(1H)；7.13(1H)；7.30(1H)；7.74(1H)；9.34(1H)；10.01(1H)ppm.

Example bh)

(3-vinylsulfonylamino-phenyl) -carboxylic acid tert-butyl ester

640mg of the compound described in example bd) are dissolved in 10ml of tetrahydrofuran, mixed with 1.3ml of triethylamine and 430. mu.l of 2-chloroethanesulfonyl chloride and stirred at room temperature for 18 hours. After aqueous workup and chromatographic purification on silica gel, 550mg of the title compound are obtained.

1H-NMR(DMSO-d6)：δ＝1.46(9H)；6.04(1H)；6.11(1H)；6.65-6.80(2H)；7.12(2H)；7.40(1H)；9.38(1H)；9.91(1H)ppm.

Example bi)

[3- (2-Morpholin-4-yl-ethanesulfonylamino) -phenyl ] -carboxylic acid tert-butyl ester

100mg of the compound described in example bh) were dissolved in 3ml of tetrahydrofuran, mixed with 139. mu.l of triethylamine and 44. mu.l of morpholine and stirred under reflux for 12 hours. After aqueous workup and chromatographic purification on silica gel, 52mg of the title compound are obtained.

1H-NMR(DMSO-d6)：δ＝1.46(9H)；2.30(4H)；2.55(2H)；3.21(2H)；3.48(4H)；6.78(1H)；7.04-7.19(2H)；7.40(1H)；9.33(1H)；9.73(1H)ppm.

The following examples describe the biological effects of the compounds of the present invention.

PLK enzyme assay

Recombinant human Plk-1(6xHis) was purified from baculovirus-infected insect cells (Hi 5).

10ng of the PLK enzyme (prepared recombinantly and purified) were incubated at room temperature for 90 minutes in 384-well Greiner small-volume microtiter plates together with a volume of 15. mu.l biotinylated casein and 33P-. gamma. -ATP as substrate (final concentration in buffer: 660ng/ml PLK; 0.7. mu. mol casein, 0.5. mu. mol ATP, including 400nCi/ml 33P-. gamma. -ATP; 10mmol MgCl2, 1mmol MnCl 2; 0.01% NP 40; 1mmol DTT, protease inhibitors; 0.1mmol Na2VO3 in 50mmol HEPES, pH 7.5). To complete the reaction, 5. mu.l of stop solution (500. mu. mol ATP; 500mmol EDTA; 1% Triton X100; 100mg/ml SPA beads coated with streptavidin in PBS) was added. After sealing the microtiter plate with the membrane, the beads were pelleted by centrifugation (10 min, 1500 rpm). The amount of 33P- γ -ATP incorporated into casein was measured by β -counting as a measure of enzyme activity. The magnitude of the inhibitor activity was the average of a reference solvent control (═ 0% inhibition of uninhibited enzyme activity) and several experiments containing 300 μmol wortmannin (═ 100% inhibition of completely inhibited enzyme activity).

Various concentrations of test substance (0. mu. mol, and in the range of 0.01-30. mu. mol) were used. The final concentration of the solvent, dimethyl sulfoxide, was 1.5% in all experiments.

Experiment of proliferation

Cultured human MaTu breast tumor cells were spread in 96-well multi-titer plates at a density of 5000 cells/measurement spot, corresponding to a volume of 200. mu.l growth medium. After 24 hours, cells from one plate (zero plate) were stained with crystal violet (see below) while the medium from the other plate was replaced with fresh medium (200. mu.l) and various concentrations of the test substance (0 μm, and in the range of 0.01-30 μm; final concentration of solvent dimethyl sulfoxide was 0.5%) were added. Cells were cultured for 4 days in the presence of the test substance. Cell proliferation was determined by staining the cells with crystal violet: cells were fixed by adding 20. mu.l of 11% glutaraldehyde solution at each measurement point for 15 minutes at room temperature. After washing the fixed cells with water for 3 cycles, the plates were dried at room temperature. Cells were stained by adding 100. mu.l of a 0.1% crystal violet solution (pH was set to 3 by adding acetic acid) to each measurement point. After washing the stained cells with water for 3 cycles, the plates were dried at room temperature. 100. mu.l of a 10% acetic acid solution was added to each measurement point, thereby dissolving the dye. The extinction was measured photometrically at 595 nm. The change in cell growth (%) was calculated by normalizing the extinction value of the zero point plate (═ 0%) and the measurement value of the extinction of untreated (0 μm) cells (═ 100%).

The results of both experiments are shown in the following table:

compound number	Inhibition of PLK-1 IC50[ nmol ]]	Inhibition of tumor cell proliferation (MaTu) IC50[ mu mol [)]
			10	200	4
11	400	15
			12	100	2
21	230
			22	510
24	230
			26	6300
28	2300
			30	250
31	1900
			32	1700
33	420
			35	2800
36	1800
			37	3500
38	3000
			39	5900
40	1700
			45	680
47	410
			48	270
50	240
			52	260

Compound number	Inhibition of PLK-1 IC50[ nmol ]]	Inhibition of tumor cell proliferation (MaTu) IC50[ mu mol [)]
			53	460
55	1500
			56	2200
58	270
			59	180
60	290

FIG. 1 shows the function of Plk-1. Here:

1. entry into mitosis: plk-1 activated CDC 25C. This results in activation of the CDK/cyclin B complex and converts the cell from G2 to the M state.

2. Initiation of mitosis: plk1 plays an important role in cytokinesis, particularly in the formation of bipolar spindle devices and mitotic late chromosome segregation. Plk-1 is also required during centrosome maturation and incorporates so-called "kinesin motors".

3. Completion of mitosis: plk-1 activates APC/C complexes (anaphase-promoting complexes/cyclosomes; Kotani et al 1998). APC/C as E3 enzyme catalyzes polyubiquitination of specific substrates such as cyclin B. Such polyubiquitination of proteins only results in their degradation to the proteasome. This in turn leads to a decrease of cell cycle regulators below the critical value and a break out of mitosis in cells of the so-called G1 state (M → G1 transition).

Claims (13)

1. A compound of the general formula I:

wherein:

x and Y are identical or different and represent hydrogen, aryl, cyano, C₃-C₆Cycloalkyl or represents a group-COOR⁴、-CONR¹⁵-(CH₂)_n-R²⁵、-COOR²⁵、-CONR¹⁵R¹⁶or-COR¹³，

R¹、R¹¹、R¹²、R¹⁵、R¹⁶、R¹⁹And R²⁰Are identical or different and represent hydrogen, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, (COOR)¹⁴)-(CH₂)_n-、(C₃-C₆Cycloalkyl) -C₁-C₄Alkylene radical, C₃-C₆Cycloalkyl, phenylsulfonyl, phenyl-C₃-C₆Cycloalkyl radical, C₁-C₁₀Alkanoyl radical, C₁-C₆-alkoxy-C₁-C₆Alkylene radical, C₁-C₄alkoxycarbonyl-C₁-C₄Alkylene, hydroxy-C₁-C₄Alkylene radical, -C₁-C₆alkyl-O-Si (phenyl)₂-C₁-C₆Alkyl, or represents a group COOR¹⁴、-COR¹³、-SO₂R¹⁸、-(CH₂)_n-NR¹⁵R¹⁶Or- (CH)₂)_n-C(CH₃)_q-(CH₂)_nNR¹⁵R¹⁶or-NR¹¹R¹²Or is or

Or represents aryl, heteroaryl, heterocyclyl, aryl-C₁-C₄Alkylene, heteroaryl-C₁-C₄Alkylene, aryloxy-C₁-C₄Alkylene, heteroaryloxy-C₁-C₄Alkylene or aryl-C₁-C₄Alkylene oxy-C₁-C₄Alkylene, which groups are optionally substituted in the same or different manner at one or more positions by: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyloxy, phenyl, cyano, halogen, hydroxy, C₁-C₄Alkoxy, phenoxy, benzyloxy, C₁-C₄Alkylsulfanyl, benzylsulfanyl, phenylsulfanyl, dimethylamino, acetylamino, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, acetyl, -CO-C₁-C₆Alkyl, 1-iminoethyl or nitro, or represents C substituted in one or more positions by fluorine₁-C₁₀An alkyl group, a carboxyl group,

R²and R³Are identical or different and represent hydrogen, C₁-C₆Alkyl, hydroxy-C₁-C₆Alkylene radical, C₃-C₆-cyclohexyl or represents a radical-COOR¹⁴、-CONR¹⁵R¹⁶、-COR¹³、-SO₂R¹⁸、-NR¹¹R¹²、-(CH₂)n-A，

Or represents aryl, heteroaryl or heterocyclyl, which are optionally substituted in the same or different manner at one or more positions by: c₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkoxy, halogen, cyano, hydroxy-C₁-C₆Alkylene, hydroxy-C₁-C₆Alkyleneoxy, aryl, heteroaryl, heterocyclyl, -C₁-C₆alkyl-COOR⁸OR a group-OR¹⁰、-COR¹³、-COOR¹⁴、-NR¹¹R¹²、-NR¹¹-CO-NR¹¹R¹²、-NR¹¹-CO-R¹³、-NR¹¹-SO₂-R¹³、-(CH₂)_n-CO-NR¹⁵R¹⁶、-SR¹⁰or-SO₂R¹⁸，

R⁴、R⁸、R⁹、R¹⁰、R¹³、R¹⁴、R¹⁷And R¹⁸Are identical or different and represent hydrogen, C₁-C₁₀Alkyl, hydroxy-C₁-C₆Alkylene oxy-C₁-C₆Alkylene radical, C₁-C₆-alkoxy-CO-C₁-C₆Alkylene, - (CH)₂)_n-CO-NR¹⁵R¹⁶、C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, (C)₃-C₆Cycloalkyl) -C₁-C₄Alkylene, halogeno C₁-C₆Alkyl, hydroxy-C₁-C₆Alkylene, (COOR)¹⁴)-(CH₂)_n-, hydroxy- (CH)₂)_n-O-(CH₂)_n、C₃-C₆Cycloalkyl radical, C₁-C₁₀Alkanoyl or represents the group-NR¹¹R¹²、-(CH₂)_n-CO-R²⁵、-(CH₂)_n-NR¹⁵R¹⁶、COOR¹⁴-(CH₂)_n-or-COR¹³Or represents optionally C at one or more positions in the same or different manner₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyloxy, phenyl, cyano, halogen, hydroxy-C₁-C₆Alkyl radical, C₁-C₄Alkoxy, phenoxy, benzyloxy, C₁-C₄Alkylsulfanyl, benzylsulfanyl, phenylsulfanyl, dimethylamino, acetylamino, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, acetyl, -CO-C₁-C₆Alkyl, 1-iminoethyl or nitro substituted aryl, heteroaryl, heterocyclyl, aryl-C₁-C₄Alkylene, heteroaryl-C₁-C₄Alkylene, aryloxy-C₁-C₄Alkylene, heteroaryloxy-C₁-C₄Alkylene or aryl-C₁-C₄Alkylene oxy-C₁-C₄Alkylene or represents C substituted in one or more positions by fluorine₁-C₁₀Alkyl, or represents the group-NR¹¹R¹²、-COR¹³、-SO₂R¹⁸、-(CH₂)_n-NR¹⁵R¹⁶、-(CH₂)_n-C(CH₃)_q-(CH₂)_nNR¹⁵R¹⁶Or is or

Or R²And R³、R¹¹And R¹²、R¹⁵And R¹⁶And R¹⁹And R²⁰Are respectively independent of each other

Form a 3-to 10-membered ring, which optionally contains one or more nitrogen, oxygen or sulfur atoms, or

R³Represents hydrogen, and

R²represents a group- (L-M) in which

L represents a group-C (O) -, -S (O)₂-、-C(O)N(R⁷)-、-S(O)₂N(R⁷)-、-C(S)N(R⁷)-、-C(S)N(R⁷) C (O) O-, -C (O) O-or-C (O) S-, and

m represents hydrogen, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, (C)₃-C₆Cycloalkyl) -C₁-C₄Alkylene radical, C₃-C₆Cycloalkyl, phenyl-C₃-C₆Cycloalkyl radical, C₁-C₁₀Alkanoyl radical, C₁-C₄alkoxy-C₁-C₄Alkylene radical, C₁-C₄-alkoxycarbonyl-C₁-C₄Alkylene, hydroxy-C₁-C₁₀Alkylene or represents aryl, heteroaryl, heterocyclyl, aryl-C optionally substituted in the same or different manner at one or more positions by₁-C₄Alkylene, heteroaryl-C₁-C₄Alkylene radicalAryl oxy-C₁-C₄Alkylene, heteroaryloxy-C₁-C₄Alkylene or aryl-C₁-C₄Alkylene oxy-C₁-C₄Alkylene group: c₁-C₄Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyloxy, phenyl, cyano, halogen, phenoxy, benzyloxy, halogeno C₁-C₄Alkoxy, halo C₁-C₆Alkyl, nitro, -C₁-C₆Alkyl group COOR⁸、-C₂-C₆Alkenyl COOR⁸、-C₂-C₆Alkynyl COOR⁸、-C₁-C₆Alkyl OR⁹、-C₂-C₆Alkenyl radical OR⁹、-C₁-C₆Alkynyl OR⁹OR a group-OR¹⁰、-NR¹¹R¹²、-COR¹³、-COOR¹⁴、-CONR¹⁵R¹⁶、-SR¹⁷、-SO₂R¹⁸、SO₂NR¹⁹R²⁰or-C (NH)₂) Or represents C substituted in one or more positions by fluorine₁-C₁₀Alkyl radicals, and

R⁷represents hydrogen, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₃-C₆Cycloalkyl group, (C)₃-C₆Cycloalkyl) -C₁-C₄Alkylene, aryl-C₁-C₄An alkylene group or a substituted alkylene group,

a represents an optionally substituted aryl, heteroaryl or heterocyclyl group,

R²²represents hydrogen, hydroxy-C₁-C₆Alkyl, OR represents the group-OR¹⁰、-NR¹¹R¹²、-COR¹³、-CONR¹⁵R¹⁶、-SO₂R¹⁸、-NR¹⁵-(C＝S)-NR¹⁶-(CH₂)_n-R²⁴、-NR¹⁵-(C＝O)-NR¹⁶-(CH₂)_n-R²⁴，

R²³Represents hydrogen or C₁-C₆An alkyl group, a carboxyl group,

R²⁴represents hydrogen, phenyl, C₁-C₆Alkoxy or a radical- (CH)₂)_n-COO-C₁-C₆An alkyl group, a carboxyl group,

R²⁵represents a group-OR¹⁰Or represents optionally halogen, C in one or more positions in the same or different manner₁-C₆Alkyl, hydroxy-C₁-C₆Alkyl OR a group-OR¹⁰or-COOR¹⁴Substituted C₂-C₆Alkenyl, phenyl, pyridyl, imidazolyl, morpholinyl, piperidinyl, C₃-C₆Cycloalkyl, or

m, p and k independently of one another represent 0 or 1,

n represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

q represents a number of 1 or 2,

and stereoisomers, mixtures of stereoisomers and salts thereof.

2. Compounds of the general formula I according to claim 1, wherein:

x and Y are identical or different and represent hydrogen, phenyl, cyano, C₃-C₆Cycloalkyl radicals or radicals-COOR⁴、-CONR¹⁵-(CH₂)_n-R²⁵、-COOR²⁵、-CONR¹⁵R¹⁶or-COR¹³，

R¹、R¹¹、R¹²、R¹⁵、R¹⁶、R¹⁹And R²⁰Are identical or different and represent hydrogen, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, (COOR)¹⁴)-(CH₂)_n-、(C₃-C₆Cycloalkyl) -C₁-C₄Alkylene radical, C₃-C₆Cycloalkyl, phenylsulfonyl, phenyl-C₃-C₆Cycloalkyl radical, C₁-C₁₀Alkanoyl radical, C₁-C₆alkoxy-C₁-C₆Alkylene radical, C₁-C₄alkoxycarbonyl-C₁-C₄Alkylene, hydroxy-C₁-C₄Alkylene radical, -C₁-C₆alkyl-O-Si (phenyl)₂-C₁-C₆Alkyl, or represents a group COOR¹⁴、-COR¹³、-SO₂R¹⁸、-(CH₂)_n-NR¹⁵R¹⁶Or- (CH)₂)_n-C(CH₃)_q-(CH₂)_nNR¹⁵R¹⁶or-NR¹¹R¹²Or is or

Or represents aryl, heteroaryl, heterocyclyl, aryl-C₁-C₄Alkylene, heteroaryl-C₁-C₄Alkylene, aryloxy-C₁-C₄Alkylene, heteroaryloxy-C₁-C₄Alkylene or aryl-C₁-C₄Alkylene oxy-C₁-C₄Alkylene, which groups are optionally substituted in the same or different manner at one or more positions by: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyloxy, phenyl, cyano, halogen, hydroxy, C₁-C₄Alkoxy, phenoxy, benzyloxy, C₁-C₄Alkylsulfanyl, benzylsulfanyl, phenylsulfanyl, dimethylamino, acetylamino, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, acetyl, -CO-C₁-C₆Alkyl, 1-iminoethyl or nitro, or represents C substituted in one or more positions by fluorine₁-C₁₀An alkyl group, a carboxyl group,

R²and R³Are identical or different and represent hydrogen, C₁-C₆Alkyl, hydroxy-C₁-C₆Alkylene radical, C₃-C₆-cyclohexyl or a radical-COOR¹⁴、-CONR¹⁵R¹⁶、-COR¹³、-SO₂R¹⁸、-NR¹¹R¹²、-(CH₂)_n-A，

Or represents aryl, heteroaryl or heterocyclyl optionally substituted in the same or different manner at one or more positions by: c₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkoxy, halogen, cyano, hydroxy-C₁-C₆Alkylene, hydroxy-C₁-C₆Alkyleneoxy, aryl, heteroaryl, heterocyclyl, -C₁-C₆alkyl-COOR⁸OR a group-OR¹⁰、-COR¹³、-COOR¹⁴、-NR¹¹R¹²、-NR¹¹-CO-NR¹¹R¹²、-NR¹¹-CO-R¹³、-NR¹¹-SO₂-R¹³、-(CH₂)_n-CO-NR¹⁵R¹⁶、-SR¹⁰or-SO₂R¹⁸，

R⁴、R⁸、R⁹、R¹⁰、R¹³、R¹⁴、R¹⁷And R¹⁸Are identical or different and represent hydrogen, C₁-C₁₀Alkyl, hydroxy-C₁-C₆Alkylene oxy-C₁-C₆Alkylene radical, C₁-C₆alkoxy-CO-C₁-C₆Alkylene, - (CH)₂)_n-CO-NR¹⁵R¹⁶、C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, (C)₃-C₆Cycloalkyl) -C₁-C₄Alkylene, halogeno C₁-C₆Alkyl, hydroxy-C₁-C₆Alkylene, (COOR)¹⁴)-(CH₂)_n-, hydroxy- (CH)₂)_n-O-(CH₂)_n、C₃-C₆Cycloalkyl radical, C₁-C₁₀Alkanoyl or represents the group-NR¹¹R¹²、-(CH₂)_n-CO-R²⁵、-(CH₂)_n-NR¹⁵R¹⁶、COOR¹⁴-(CH₂)_n-or-COR¹³Or represents aryl, heteroaryl, heterocyclyl, aryl-C optionally substituted in the same or different manner at one or more positions by₁-C₄Alkylene, heteroaryl-C₁-C₄Alkylene, aryloxy-C₁-C₄Alkylene, heteroaryloxy-C₁-C₄Alkylene or aryl-C₁-C₄Alkylene oxy-C₁-C₄Alkylene group: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkyloxy, phenyl, cyano, halogen, hydroxy-C₁-C₆Alkyl radical, C₁-C₄Alkoxy, phenoxy, benzyloxy, C₁-C₄Alkylsulfanyl, benzylsulfanyl, phenylsulfanyl, dimethylamino, acetylamino, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, acetyl, -CO-C₁-C₆Alkyl, 1-iminoethyl or nitro, or represents C substituted in one or more positions by fluorine₁-C₁₀Alkyl, or represents the group-NR¹¹R¹²、-COR¹³、-SO₂R¹⁸、-(CH₂)_n-NR¹⁵R¹⁶、-(CH₂)_n-C(CH₃)_q-(CH₂)_nNR¹⁵R¹⁶Or is or

Or R²And R³、R¹¹And R¹²、R¹⁵And R¹⁶And R¹⁹And R²⁰Each independently of the others, together form a 3-10 ring which may optionally contain one or more nitrogen, oxygen or sulfur atoms,

a represents an optionally substituted aryl, heteroaryl or heterocyclyl group,

R²²represents hydrogen, hydroxy-C₁-C₆Alkyl OR a group-OR¹⁰、-NR¹¹R¹²、-COR¹³、-CONR¹⁵R¹⁶、-SO₂R¹⁸、-NR¹⁵-(C＝S)-NR¹⁶-(CH₂)_n-R²⁴、-NR¹⁵-(C＝O)-NR¹⁶-(CH₂)_n-R²⁴，

R²³Represents hydrogen or C₁-C₆An alkyl group, a carboxyl group,

R²⁴represents hydrogen, phenyl, C₁-C₆Alkoxy or a radical- (CH)₂)_n-COO-C₁-C₆An alkyl group, a carboxyl group,

R²⁵represents a group-OR¹⁰Or represents optionally halogen, C in one or more positions in the same or different manner₁-C₆Alkyl, hydroxy-C₁-C₆Alkyl OR a group-OR¹⁰or-COOR¹⁴Substituted C₂-C₆Alkenyl, phenyl, pyridyl, imidazolyl, morpholinyl, piperidinyl, C₃-C₆Cycloalkyl, or

m, p, k each independently of the others represent 0 or 1,

n represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

q represents a number of 1 or 2,

and stereoisomers thereof, mixtures of such stereoisomers and salts thereof.

3. Compounds of the general formula I according to claim 1 or 2, wherein:

x and Y are identical or different and represent hydrogen, phenyl, cyano, C₃-C₆Cycloalkyl radicals or radicals-COOR⁴、-CONR¹⁵-(CH₂)_n-R²⁵、-COOR²⁵、-CONR¹⁵R¹⁶or-COR¹³，

R¹Represents hydrogen, phenyl, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, hydroxy-C₁-C₄Alkylene radical, C₁-C₆alkoxy-C₁-C₆Alkylene or radical-C₁-C₆alkyl-O-Si (phenyl)₂-C₁-C₆An alkyl group, a carboxyl group,

R²and R³Are identical or different and represent hydrogen, C₁-C₆Alkyl, hydroxy-C₁-C₄Alkylene, cyclohexyl or the radical-COOR¹⁴、-CONR¹⁵R¹⁶、-COR¹³、-SO₂R¹⁸、-NR¹¹R¹²、-(CH₂)_n-A、

Or represents optionally C at one or more positions in the same or different manner₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halo C₁-C₆Alkyl, halo C₁-C₆Alkoxy, halogen, cyano, triazolyl, tetrazolyl, hydroxy-C₁-C₆Alkylene, hydroxy-C₁-C₆Alkyleneoxy, morpholinyl, -C₁-C₆alkyl-COOR⁸OR a group-OR¹⁰、-COR¹³、-COOR¹⁴、-NR¹¹R¹²、-NR¹¹-CO-NR¹¹R¹²、-NR¹¹-CO-R¹³、-NR¹¹-SO₂-R¹³、-(CH₂)_n-CO-NR¹⁵R¹⁶、-SR¹⁰or-SO₂R¹⁸Substituted phenyl, pyridyl, naphthyl, biphenyl, imidazolyl, indazolyl, isothiazolyl, triazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, thiazolyl, pyrazolyl, anthrazinyl, pyrazolidinyl, oxazolyl, 2, 3-diazanaphthyl, carbazolyl, benzimidazolyl, benzothiazolyl, isoxazolyl, 2, 3-dihydroindenyl, indolyl, pyrimidinyl, thiadiazolyl, and the like,

Or R²And R³Together form a piperidinyl group or a morpholinyl group,

a represents the following group:

R⁴represents hydrogen, C₁-C₆Alkyl, halo C₁-C₆Alkyl, hydroxy-C₁-C₆Alkyl, hydroxy- (CH)₂)_n-O-(CH₂)_n-, or a radical- (CH)₂)_n-CO-R²⁵、-(CH₂)_n-NR¹⁵R¹⁶Or represents optionally hydroxy-C₁-C₆An alkyl-substituted phenyl or benzyl group,

R⁸、R¹¹、R¹²、R¹⁴、R¹⁵and R¹⁶Are identical or different and represent hydrogen, C₁-C₁₀Alkyl, hydroxy-C₁-C₆Alkylene, (COOR)¹⁴)-(CH₂)_n-, or represents optionally halogen or a group-CO-C₁-C₆Alkyl-substituted phenyl, pyridyl or pyrimidinyl radicals, or represent the radical-COR¹³、-SO₂R¹⁸、-(CH₂)_n-NR¹⁵R¹⁶、-(CH₂)_n-C(CH₃)_q-(CH₂)_nNR¹⁵R¹⁶Or

R¹⁰Represents hydrogen, C₁-C₁₀Alkyl, hydroxy-C₁-C₆Alkylene, hydroxy-C₁-C₆-alkyleneoxy-C₁-C₆Alkylene radical, C₁-C₆alkoxy-CO-C₁-C₆Alkylene, - (CH)₂)_n-CO-NR¹⁵R¹⁶Or represents optionally halogen or a group-CO-C₁-C₆Alkyl-substituted phenyl, or represents the group-COR¹³、-SO₂R¹⁸Or COOR¹⁴-(CH₂)_n-，

R¹³Represents hydrogen, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkenyl radical, C₁-C₁₀Alkynyl, C₁-C₆alkyloxy-C₁-C₆Alkenyl radical, C₁-C₆alkyloxy-C₁-C₆alkenyloxy-C₁-C₆Alkenyl, phenyl or represents the following groups:

R¹⁸represents C₁-C₁₀Alkyl, hydroxy-C₁-C₆Alkyl or radicals-NR¹¹R¹²、

Or represents optionally in the same or different manner at one or more positions by C₁-C₆A phenyl group substituted with an alkyl group,

R²²represents hydrogen, hydroxy-C₁-C₆Alkyl, OR represents the group-OR¹⁰、-NR¹¹R¹²、-COR¹³、-CONR¹⁵R¹⁶、-SO₂R¹⁸、-NR¹⁵-(C＝S)-NR¹⁶-(CH₂)_n-R²⁴or-NR¹⁵-(C＝O)-NR¹⁶-(CH₂)_n-R²⁴，

R²³Represents hydrogen or C₁-C₆An alkyl group, a carboxyl group,

R²⁴represents hydrogen, phenyl, C₁-C₆-alkoxy or a radical- (CH)₂)_n-COO-C₁-C₆An alkyl group, a carboxyl group,

R²⁵represents a group-OR¹⁰Or represents optionally halogen, C in one or more positions in the same or different manner₁-C₆Alkyl, hydroxy-C₁-C₆Alkyl OR a group-OR¹⁰or-COOR¹⁴Substituted C₂-C₆Alkenyl, phenyl, pyridyl, imidazolyl, morpholinyl, piperidinyl, C₃-C₆Cycloalkyl, or

m, p, k each independently of the others represent 0 or 1,

n represents 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

q represents a number of 1 or 2,

and stereoisomers thereof, mixtures of such stereoisomers and salts thereof.

4. Compounds of formula II and III as intermediates for the preparation of compounds of formula I of the present invention:

and

wherein: x, Y and R¹Has the same definition as formula I, and Z represents C₁-C₁₀An alkyl group.

5. A compound of formula II according to claim 4, which isWherein Z represents C₁-C₄An alkyl group.

6. Use of a compound of general formula I according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of: cancer, autoimmune diseases, chemotherapy-induced alopecia and mucositis, cardiovascular diseases, infectious diseases, kidney diseases, chronic and acute neurodegenerative diseases, and viral infections.

7. The use according to claim 6, wherein the cancer is solid cancer and leukemia, the autoimmune diseases are psoriasis, alopecia and multiple sclerosis, the cardiovascular diseases are stenosis, arteriosclerosis and restenosis, the infectious diseases are those caused by unicellular parasites, the renal diseases are glomerulonephritis, the chronic neurodegenerative diseases are Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease, the acute neurodegenerative diseases are cerebral ischemia and neurotrauma, and the viral infections are giant cell infections, herpes, hepatitis B and C, and HIV disease.

8. A medicament comprising at least one compound of the general formula I as claimed in any of claims 1 to 3.

9. The medicament of claim 8, which is for the treatment of cancer, autoimmune diseases, cardiovascular diseases, infectious diseases, kidney diseases, neurodegenerative diseases, and viral infections.

10. A pharmaceutical composition comprising a compound of general formula I according to any one of claims 1 to 3 together with suitable formulation and carrier substances.

11. Use of a compound of general formula I according to any one of claims 1 to 3 as polo-like kinase inhibitor.

12. The use of claim 11, wherein the kinase is plk1, plk2, plk3, or plk 4.

13. Use of a compound of the general formula I according to any of claims 1 to 3 for the preparation of a pharmaceutical preparation for enteral, parenteral and oral administration.