HK1114615A - Thiazolidinones as inhibitors of polo-like kinases (plk) as pharmaceutical agents - Google Patents
Thiazolidinones as inhibitors of polo-like kinases (plk) as pharmaceutical agents Download PDFInfo
- Publication number
- HK1114615A HK1114615A HK08110231.0A HK08110231A HK1114615A HK 1114615 A HK1114615 A HK 1114615A HK 08110231 A HK08110231 A HK 08110231A HK 1114615 A HK1114615 A HK 1114615A
- Authority
- HK
- Hong Kong
- Prior art keywords
- substituted
- ring
- alkyl
- positions
- same
- Prior art date
Links
Description
The present invention relates to thiazolidinones, their preparation and their use as pole body-like kinase (Plk) inhibitors for the treatment of various diseases.
Tumor cells are characterized by uninhibited cell cycle processes. On the one hand, this is based on the loss of control proteins (control proteins), such as RB, p16, p21, p53, etc., and the activation of the so-called cell cycle process accelerator, cyclin-dependent kinase (Cdks). Cdks is a pharmaceutically-proven anti-tumor target protein. In addition to Cdks, serine/threonine kinases that regulate a novel cell cycle, so-called "polo-like kinases", are described, which are not only involved in the regulation of the cell cycle, but also in the coordination of other processes during mitosis and cytokinesis (spindle formation, chromosome segregation). Such proteins therefore represent useful points of application for therapeutic intervention in proliferative diseases such as cancer (Descombes and Nigg. Embo J, 17; 1328ff, 1998; Glover et al GenesDev 12, 3777ff, 1998).
High expression rates of Plk-1 have been found in "non-small cell lung" carcinomas (Wolf et al, Oncogene, 14, 543ff, 1997), melanomas (Strebhardt et al, JAMA, 283, 479ff, 2000), "squamous cell carcinomas" (Knecht et al Cancer Res, 59, 2794ff, 1999), and "esophageal carcinomas" (Tokumitsu et al, Iht J Oncol 15, 687ff, 1999).
The correlation of the high expression rate of the most altered (the most varied) tumor was shown in patients with poorly-prognosed 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 formation 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 oligonucleotides, it was possible to inhibit the expression of Plk-1 in a549 cells and to terminate their viability. It is also possible to show a pronounced antitumor effect 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 significantly higher cellular components that remained arrested in growth of G2 and showed much fewer signs of inappropriate mitosis compared to HeLa cells (Lane et al; Journal Cell Biol, 135, 1701ff, 1996).
In contrast to tumor cells, antisense oligonucleotide molecules do not inhibit the growth and viability of primary human mesangial cells (Mundt et al, Biochem Biophys Res Comm, 269, 377ff., 2000).
In mammals, to date, in addition to Plk-1, three other polar kinases have been described which are induced by mitogenic responses and exert their function in the G1 phase of the cell cycle. In one aspect, they are the so-called Prk/Plk-3 (human homolog of mouse-Fnk: fibroblast growth factor-induced kinase; Wiest et al, Genes, Chromosomes & Cancer, 32: 384ff, 2001), Snk/Plk-2 (serum-induced kinase, Liby et al, DNA Sequence, 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 polar family such as Plk-2, Plk-3 and Plk-4, represents a promising approach for the treatment of a variety of diseases.
Sequence identity within the Plk domain of the polar family is between 40% and 60%, and therefore there is partial interaction of a kinase inhibitor with one or more other kinases of this family. However, depending on the structure of the inhibitor, the effect may also occur selectively or preferably only on one kinase of the polar family.
In international application WO03/093249 thiazolidinone compounds are disclosed which inhibit kinases of the polar body family.
However, the properties of the compounds of the prior art always need to be improved.
It is therefore an object of the present invention to provide compounds which are improved compared to the prior art, (in particular with respect to the inhibition of polo-like kinases and/or cell proliferation), and/or to obtain alternative compounds which inhibit kinases, in particular polo-like kinases and/or cell proliferation.
It has now been found, very surprisingly, that the compounds of the general formula I and the solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts thereof achieve this object,
wherein
Q represents an aryl or heteroaryl group,
a and B independently of one another represent hydrogen, halogen, hydroxyl, amino or nitro,
or
Represents C1-C6-alkyl or C1-C6Alkoxy, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy, C2-C9-heterocycloalkyl substituted or by a radical-NR3R4or-CO (NR)3) -M-substitution, wherein the heterocycloalkyl comprises in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally in the ring may be substituted by one or more- (CO) -or-SO2-C which is interrupted and optionally may contain one or more double bonds in the ring, and the ring itself optionally may be substituted in the same or different manner in one or more positions by cyano, halogen or in the same or different manner in one or more positions by halogen1-C6Alkyl radical, C3-C6-cycloalkyl or C1-C6Substituted by hydroxyalkyl or by the radical-COR2or-NR3R4The substitution is carried out by the following steps,
or
represents-NR3R4、-NR3(CO)-L、-NR3(CO)-NR3-L、-COR2、-CO(NR3)-M、-NR3(CS)NR3R4、-NR3SO2-L、-SO2-NR3R4or-SO2(NR3)-M，
L represents C1-C6-alkyl or heteroaryl, optionally substituted in one or more positions in the same or different manner by hydroxy, C1-C6-hydroxyalkoxy, C1-C6alkoxy-C2-C6-heterocycloalkyl substituted or by a radical-NR3R4Substituted, wherein the heterocycloalkyl contains in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally may be substituted in the ring by one or more- (CO) -or-SO2The radicals being interrupted and optionally comprising one or more double bonds in the ring, and the ring itself optionally being substituted in the same or different manner in one or more positions by cyano, halogen or in one or more positionsOr C in which a plurality of positions are substituted in the same or different manner by halogen1-C6Alkyl radical, C3-C6-cycloalkyl or C1-C6Substituted by hydroxyalkyl or by the radical-COR2or-NR3R4The substitution is carried out by the following steps,
m represents C1-C6-alkyl, optionally substituted in one or more positions in the same or different manner by a group-NR3R4Or C2-C6-heterocycloalkyl substituted, wherein said heterocycloalkyl comprises in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally in the ring may be substituted by one or more- (CO) -or-SO2-C which is interrupted by a group and optionally may contain one or more double bonds in the ring, and the ring itself optionally may be substituted in the same or different manner in one or more positions by cyano, halogen or in the same or different manner in one or more positions by halogen1-C6Alkyl radical, C3-C6-cycloalkyl or C1-C6Substituted by hydroxyalkyl or by the radical-COR2or-NR3R4The substitution is carried out by the following steps,
w represents heteroaryl or C2-C9-heterocycloalkyl, wherein said heterocycloalkyl comprises in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally in the ring may be substituted by one or more- (CO) -or-SO2The group being interrupted and optionally comprising one or more double bonds in the ring,
x and Y independently of one another represent hydrogen or C1-C6Alkyl or aryl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy, C1-C6-alkoxy, C1-C6Alkylthio or aryl substituted or represent a radical-COOR5or-CONR3R4，
Or
X and Y together being bound by C through the same atom or adjacent atoms of W3-C6-cycloalkyl ring or C2-C6-heterocycloalkyl ring formation, wherein said heterocycloalkyl group comprises in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally in the ring may be substituted by one or more- (CO) -or-SO2The radicals being interrupted and optionally comprising one or more double bonds in the ring, and the ring itself optionally being C-bonded in the same or different manner in one or more positions1-C6Alkyl radical, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl substituted or by a group-NR3R4The substitution is carried out by the following steps,
R1represents C1-C4Alkyl radical, C3-cycloalkyl, allyl or propargyl, optionally substituted in one or more positions in the same or different manner by cyano or halogen,
R2represents hydroxy, C1-C6Alkyl radical, C1-C6-alkoxy or represents a group-NR3R4，，
R3And R4Independently of one another, represents hydrogen or represents C1-C6Alkyl radical, C1-C6-alkoxy, -CO-C1-C6Alkyl or aryl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy, C2-C6-heterocycloalkyl radical, C1-C6Substituted by hydroxyalkoxy groups or by groups-NR3R4Substituted, wherein the heterocycloalkyl contains in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally may be substituted in the ring by one or more- (CO) -or-SO2The radicals being interrupted and optionally may comprise one or more double bonds in the ring, and wherein in each case the C is2-C6The heterocycloalkyl ring itself optionally being substituted in one or more positions, in the same or different manner, by cyano, halogen, C1-C6Alkyl radical, C1-C6-hydroxyalkyl, C1-C6-alkoxy, C3-C6-cycloalkyl substituted, or by-NR3R4or-CO-NR3R4Is substituted, or
R3And R4Together form C2-C6-a heterocycloalkyl ring, wherein said heterocycloalkyl group comprises in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally in the ring may be substituted by one or more- (CO) -or-SO2The radicals being interrupted and optionally comprising one or more double bonds in the ring, and the heterocycloalkyl ring itself optionally being substituted in the same or different manner in one or more positions by halogen, C1-C6Alkyl radical, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6Alkoxyalkyl, cyano, hydroxy or by a radical-NR3R4Is substituted, and
R5represents C1-C6Alkyl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy, C2-C6-heterocycloalkyl radical, C1-C6Substituted by hydroxyalkoxy groups or by groups-NR3R4Substituted, wherein the heterocycloalkyl contains in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally may be substituted in the ring by one or more- (CO) -or-SO2The radicals being interrupted and optionally comprising one or more double bonds in the ring, and the heterocycloalkyl ring itself optionally being substituted in the same or different manner by C in one or more positions1-C6Alkyl radical, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6Alkoxyalkyl, cyano, hydroxy or by a radical-NR3R4And (4) substitution.
The compounds of general formula I according to the invention mainly inhibit polo-like kinases, their action being based on the protection against the following disorders, for example: cancers, such as solid tumors and leukemias; autoimmune diseases such as psoriasis, alopecia and multiple sclerosis, chemotherapy-induced alopecia and mucositis; cardiovascular diseases such as stenosis, arteriosclerosis and restenosis; infectious diseases, such as those produced, for example, by single-celled parasites such as trypanosomes, toxoplasma or plasmodium, or by fungi; renal diseases, such as, for example, 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, for example, giant cell infection, herpes, hepatitis b and c, and HIV disease.
Alkyl is defined in each case as being straight-chain or branched alkyl, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl.
A substituent A, B, L, M, X, Y, R of the general formula (I)1、R2、R3、R4And R5The alkyl groups in (a) have the meaning mentioned in the preceding paragraph. For substituent A, B, M, R2、R3、R4And R5，C1-C6Alkyl is preferred, and C1-C3Alkyl groups are particularly preferred. For M, a very particularly preferred alkyl group is propyl. For R3And R4Very particularly preferred alkyl groups are methyl and ethyl. For R5Very particularly preferred alkyl is methyl. For substituents L, X and Y, C1-C6Alkyl is preferred, and C1-C4Alkyl groups are particularly preferred. For the substituent R1，C1-C4Alkyl groups are preferred, and ethyl groups are particularly preferred.
Alkoxy is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentoxy, isopentoxy, hexoxy, heptoxy, octoxy, nonoxy or decyloxy.
The alkoxy group of the substituent of the general formula (I) has the meaning mentioned in the preceding paragraph. C1-C6Alkoxy is preferred, and C1-C3Alkoxy is particularly preferred. Preferred alkoxyalkoxy radicals are C for the substituents of the formula (I)1-C3-alkoxy-C1-C3-alkoxy groups. C1-alkoxy-C2Alkoxy is particularly preferred.
Alkenyl substituents are in each case straight-chain or branched, where, for example, the following radicals are mentioned: 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-methylprop-2-en-1-yl, 2-methylprop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl and allyl.
Alkynyl is defined in each case as straight-chain or branched alkynyl which contains 2 to 6, preferably 2 to 4, C atoms. For example, the following groups may be mentioned: ethynyl, propyn-1-yl, propyn-3-yl (propargyl), but-1-yn-1-yl, but-1-yn-4-yl, but-2-yn-1-yl, but-1-yn-3-yl, 3-methylbut-1-yn-3-yl and the like.
C2-C9-heterocycloalkyl represents a heterocycloalkyl ring comprising from 2 to 9 carbon atoms, wherein said heterocycloalkyl ring also comprises at least one atom, identical or different, chosen from oxygen, sulphur or nitrogen, and said ring may optionally be substituted by one or more- (CO) -, (CS) or-SO2The groups are interrupted and may optionally comprise one or more double bonds in the ring, and the ring may optionally be substituted in the same or different manner at one or more positions. However, only those combinations are meant, which are useful from the point of view of the person skilled in the art, in particular in terms of loop tension.
As heterocycloalkyl, there may be mentioned, for example: oxiranyl, oxetanyl (oxolanyl), dioxolanyl, dithianyl, dioxanyl, aziridinyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroisoquinolinyl, octahydroisoquinolinyl, decahydroisoquinolinyl, tetrahydroquinolinyl, octahydroquinolinyl, tetrahydroimidazolinyl, pyrazolidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, piperazinyl, piperazinonyl (piperazinonyl), N-methylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 3-hydroxypyrrolidinyl, N-methylpiperazinyl, N-benzylpiperazinyl, N-acetylpiperazinyl, N-methylsulfonylpiperazinyl, 4-hydroxypiperidinyl, 4-aminocarbonylpiperidinyl, 2-hydroxyethylpiperidinyl, 4-hydroxymethylpiperidinyl, imidazolidinyl, tetrahydroimidazonyl, morpholinyl, thiomorpholinyl, 1-dioxothiomorpholinyl, trithianyl, tetrahydrotriazinothinyl, triazinethinyl, quinuclidinyl, nortropyl, pyrridonyl, and the like, or rings thereof which are benzo-fused, such as, for example, benzopyrrolidinyl, benzomorpholinyl, and the like.
Preferred heterocycloalkyl groups for substituents A, B and W according to formula (I) are heterocycloalkyl groups having 5, 6 or 10 ring atoms. More preferably, the heterocycloalkyl group of substituent W has 5 or 6 ring atoms, most preferably 5 ring atoms. Heterocycloalkyl groups having 5, 6 or 10 ring atoms have 1 to 4 nitrogen atoms and/or 1 to 2 oxygen atoms and/or 1 to 2 sulfur atoms, which may be present in all subcombinations of the ring systems, as long as they do not exceed the numbers specified for the respective heteroatoms and the maximum total number of four heteroatoms. Particularly preferred heterocycloalkyl radicals for the substituents A and B according to the general formula (I) are pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydroisoquinoline and/or decahydroisoquinoline. The heterocycloalkyl radicals of the substituents A and B according to the general formula (I) very particularly preferably represent pyrrolidine and/or decahydroisoquinoline. For the substituent W according to formula (I), hydrogenated oxazoles and in particular 4, 5-dihydrooxazoles are particularly preferred heterocycloalkyl groups.
A substituent L, M, X, Y, R according to formula (I)3、R4And R5Preferred heterocycloalkyl groups of (a) are heterocycloalkyl groups having a heterocycloalkyl ring including from 2 to 6 carbon atoms. For L, M, X, Y, R3、R4And R5Other preferred heterocycloalkyl groups are those having 5 or 6 ring atoms and having 1 to 4 nitrogen atoms and/or 1 to 2 oxygen atoms and/or 1 to 2 sulfur atoms, which may be present in all subcombinations of the ring system, as long as they do not exceed the number specified for each heteroatom and the maximum total number of four heteroatoms. Particularly preferred heterocycloalkyl radicals for the substituents L and M according to the general formula (I) are pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and/or decahydroisoquinoline. The heterocycloalkyl radical of L according to formula (I) very particularly preferably represents piperidine and/or morpholine. According to the general formula (I), the heterocycloalkyl group of M very particularly preferably represents pyrrolidine.
Substituents on the heterocycloalkyl ring may be, for example: cyano, halogen, hydroxy, C1-C6Alkyl radical, C1-C6-alkoxy, C1-C6Alkoxyalkyl group, C1-C6-hydroxyalkyl, C3-C6Cycloalkyl, or aryl or C1-C6-alkyl, said C1-C6-alkyl is optionally substituted in one or more positions in the same or different manner by halogen, hydroxy or C1-C6Alkylthio substituted or substituted by radicals selected from- (CO) -C1-C6-alkyl, - (CO) -O-C1-C6-alkyl, - (SO)2)-C1-C6-alkyl, - (SO)2) -phenyl, -NH2、-N(C1-C6-alkyl groups)2、-NH(C1-C6-alkyl), and the like.
Cycloalkyl is defined as monocycloalkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as bicyclic or tricyclic rings, such as, for example, adamantyl. Cycloalkyl groups may also optionally be benzo-fused, such as for example (tetrahydronaphthalene) groups and the like. Cycloalkyl for cyclopentyl or cyclohexyl preferably represents the substituents X and Y of formula (I). Cycloalkyl for cyclopropyl preferably represents a substituent R of formula (I)1。
Halogen is defined in each case as fluorine, chlorine, bromine or iodine. Fluorine and chlorine are preferred.
In each case, the heteroaryl group comprises a monovalent aromatic ring system having 5 to 16 ring atoms, preferably 5 to 10 ring atoms, particularly preferably 5 to 6 ring atoms, and having at least one heteroatom other than carbon, such as oxygen, nitrogen or sulfur. In all cases, the heteroaryl group can be monocyclic, bicyclic, or tricyclic, and can additionally be benzofused. However, only those combinations are meant, which are useful from the point of view of the person skilled in the art, in particular in terms of loop tension.
For example, mention may be made of:
thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and benzo derivatives thereof such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as, for example, quinolinyl, isoquinolinyl, and the like; or oxipinyl, azocinyl, indolizinyl, indolyl, indolinyl, isoindolyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, 2, 3-naphthyridinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, tetrahydronaphthyl, and the like.
Preferred heteroaryl groups are thienyl (thienyl), furyl, oxazolyl, oxadiazolyl, triazolyl, thiazolyl, thienyl (thiophenyl), imidazolyl, indolyl, indazolyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, pyrrolyl, isoquinolinyl and their benzo derivatives.
Particularly preferred heteroaryl groups for the substituent Q according to formula (I) are pyridyl, quinolyl, benzimidazolyl, indolyl, indazolyl, thiazolyl, imidazolyl or pyrimidinyl. The heteroaryl group of substituent Q more preferably represents a pyridyl, indolyl or pyrimidinyl group, most preferably a pyridyl group, according to formula (I). Particularly preferred heteroaryl groups for the substituent W according to formula (I) are oxazolyl, oxadiazolyl, triazolyl, thiazolyl, pyridyl, thienyl, benzo [ b ] thienyl, benzimidazolyl, benzothiazolyl or pyrrolyl.
In all cases, the aryl group includes 3 to 12 carbon atoms, and in all cases, it can be benzo-fused.
For example, mention may be made of: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, tetrahydronaphthyl, and the like. Preferred aryl groups of the present invention are phenyl groups having 6 carbon atoms and/or naphthyl groups having 10 carbon atoms. Phenyl is particularly preferred.
Thus, for example, with respect to "C1-C6Definition of-alkyl, "C as used herein1-C6"refers to an alkyl group having a limited number of carbon atoms from 1 to 6, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. "C1-C6The definition of "is further to be construed as any possible sub-area, such as for example, a co-container C1-C6、C2-C6、C3-C6、C4-C6、C5-C6、C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5Or C1-C6。
Similarly, "C1-C6", e.g. with respect to" C1-C6The definition of "alkoxy" refers to alkoxy groups having a limited number of carbon atoms from 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. Thus, "C1-C6"is to be interpreted as any possible partition, such as, for example, C is included in the definition together1-C6、C2-C6、C3-C6、C4-C6、C5-C6、C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5Or C1-C6。
All regional information of the present application not explicitly mentioned herein is identical to the above exemplary "C" mentioned1-C6"are similarly defined.
Isomers are defined as compounds having the same chemical formula (neutralization formula) but different chemical structures. In general, structural isomers and stereoisomers are distinct.
Structural isomers have the same chemical formula but differ in the way in which their atoms or groups of atoms are attached. These include functional isomers, positional isomers, tautomers or valence isomers.
Stereoisomers have essentially the same structure (structural) and therefore also the same chemical formula, but differ in the spatial arrangement of the atoms.
In general, configurational isomers and conformational isomers are different. Configurational isomers are isomers that can be interconverted only by bond cleavage. These include enantiomers, diastereomers and E/Z (cis/trans) isomers.
Enantiomers are stereoisomers that exhibit similarities to each other, as well as mirror images, and do not exhibit any planes of symmetry. All stereoisomers that are not enantiomers are referred to as diastereomers. The E/Z (cis/trans) isomer at the double bond is a special case.
Conformational isomers are stereoisomers that can be converted to each other by single bond rotation.
To define the isomeric types of each other, see IUPAC Rules, Section E (Pure appl. chem.45, 11-30, 1976).
The compounds of the general formula I according to the invention also include the possible tautomeric forms and include the E-or Z-isomers or, if chiral centers are present, the racemates and enantiomers. In the latter, double bond isomers are also defined.
The compounds according to the invention can also be present in the form of solvates, in particular hydrates, wherein the compounds according to the invention therefore comprise polar solvents, in particular water, as structural constituent of the crystal lattice of the compounds according to the invention. The proportion of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios. With respect to stoichiometric solvates and hydrates, also semi-, (semi), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are mentioned.
If acid groups are included, physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali metal and alkaline earth metal salts and also N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1, 6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, Sovak base and 1-amino-2, 3, 4-butanetriol.
Physiologically compatible salts of organic and inorganic acids are suitable if basic groups are included, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, maleic acid, malic acid, and the like.
Among these compounds of the general formula (I), those described below and solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts thereof are preferable, among which
Q represents phenyl, pyridyl, naphthyl, quinolyl, benzimidazolyl, indolyl, indazolyl, thiazolyl, imidazolyl or pyrimidinyl,
further preferred are those compounds of the general formula (I) and solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts thereof, wherein
Q represents phenyl, pyridyl, naphthyl, indolyl or pyrimidinyl,
m represents C1-C6-alkyl, optionally substituted in one or more positions by C, in the same or different manner2-C6-heterocycloalkyl substitution, wherein the heterocycloalkyl contains in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur,
R3and R4Independently of one another, represents hydrogen or represents C1-C6Alkyl radical, C1-C6-alkoxy or-CO-C1-C6Alkyl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy or C1-C6-a hydroxy-alkoxy group substitution,
R5represents C1-C6Alkyl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy, C2-C6-heterocycloalkyl radical, C1-C6Substituted by hydroxyalkoxy groups or by groups-NR3R4Substituted, wherein the heterocycloalkyl contains in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally may be substituted in the ring by one or more- (CO) -or-SO2The group is interrupted and may optionally comprise one or more double bonds in the ring.
Furthermore, those compounds of the general formula (I) and solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts thereof are preferred, among which
Q represents a phenyl group or a pyridyl group,
w represents oxazole, 4, 5-dihydrooxazole, oxadiazole, triazole, thiazole, pyridine, thiophene, benzo [ b ] thiophene, benzimidazole, benzothiazole or pyrrole,
x and Y independently of one another represent hydrogen or represent C1-C6-alkyl or aryl, optionally in one or more positions with or without identityIn the same way by halogen, hydroxy, C1-C6-alkoxy, C1-C6Alkylthio or aryl substituted or represent a radical-COOR5or-CONR3R4，
Or
X and Y together are formed by a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring via the same atom or adjacent atoms of W,
R1represents C1-C4-alkyl, optionally substituted in one or more positions in the same or different manner by halogen,
R5represents C1-C6Alkyl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy or C1-C6-hydroxyalkoxy substitution.
Also preferred are those of the general formula (I) and solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts thereof, wherein
A and B independently of one another represent hydrogen or halogen,
or
Represents C1-C3-alkyl or C1-C6-alkoxy, which is optionally substituted in the same or different manner in one or more positions by pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroisoquinolinyl, or decahydroisoquinolinyl, wherein pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroisoquinolinyl, or decahydroisoquinolinyl itself is optionally substituted in the same or different manner in one or more positions by halogen or C which is optionally substituted in the same or different manner in one or more positions by halogen1-C6Substituted by alkyl or by the radical-COR2The substitution is carried out by the following steps,
or
represents-NR3R4、-NR3(CO) -L or-CO (NR)3)-M，
L represents C1-C6-alkyl, optionally substituted in one or more positions by hydroxy, C, in the same or different manner1-C6-alkoxyalkoxy, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or decahydroisoquinolinyl substituted, wherein pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or decahydroisoquinolinyl may itself optionally be substituted in the same or different manner by halogen at one or more positions or C optionally substituted in the same or different manner by halogen at one or more positions1-C6Substituted by alkyl or by the radical-COR2The substitution is carried out by the following steps,
m represents C1-C6-alkyl, optionally substituted in one or more positions in the same or different manner by pyrrolidinyl,
x and Y independently of one another represent hydrogen or represent C1-C6Alkyl or phenyl, optionally substituted in one or more positions in the same or different manner by halogen, C1-C6-alkoxy, C1-C6Alkylthio or phenyl, or represents a radical-COOR5or-CONR3R4，
Or
X and Y together are formed from a cyclopentyl or cyclohexyl ring through the same atom or through adjacent atoms of W,
R2represents C1-C6-an alkyl group,
R3and R4Independently of one another, represents hydrogen or C1-C6-alkyl, and
R5represents C1-C6-an alkyl group.
Those compounds of the general formula (I) and solvates, hydrates, stereoisomers, diastereomers, enantiomers or salts thereof are particularly preferred, among which
A and B independently of one another represent hydrogen or halogen,
or
Represents C1-C3-alkyl, which is optionally substituted in the same or different manner in one or more positions by pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroisoquinolinyl, or decahydroisoquinolinyl,
or
represents-NR3R4、-NR3(CO) -L or-CO (NR)3)-M，
L represents C1-C6-alkyl, optionally substituted in one or more positions in the same or different manner by hydroxy or C1-C6-alkoxy-C1-C6-an alkoxy group substitution,
m represents C1-C6-an alkyl group substituted by a pyrrolidinyl group,
R1represents C1-C4-an alkyl group.
Those of the general formula (I) and the solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts thereof are particularly preferred, among which
A and B independently of one another represent hydrogen or halogen,
or
Represents C1-C3-alkyl, optionally substituted in the same or different manner in one or more positions by pyrrolidinyl or decahydroisoquinolinyl,
or
represents-NR3R4、-NR3(CO) -L or-CO (NR)3)-M，
L represents isopropyl, tert-butylOr methyl, optionally substituted in one or more positions by hydroxy or C in the same or different manner1-C6-an alkoxy-substitution,
m represents C1-C3-an alkyl group substituted by a pyrrolidinyl group,
x and Y independently of one another represent hydrogen or represent methyl, ethyl, isopropyl, propyl, isobutyl, tert-butyl or phenyl, which is optionally substituted in one or more positions in the same or different manner by halogen, C1-C6-alkoxy, C1-C6Alkylthio or phenyl, or represents a radical-COOR5or-CONR3R4，
Or
X and Y together are formed from a cyclopentyl or cyclohexyl ring through the same atom or through adjacent atoms of W,
R1represents an ethyl group, and the like,
R3and R4Independently of one another, represents hydrogen or C1-C3-alkyl, and
R5represents a methyl group.
A further preferred subject of the invention are compounds of the general formula I according to one of claims 1 to 7, in which R1Represents C1-C4-alkyl or preferably represents ethyl.
A further preferred subject of the invention are compounds of the general formula I according to one of claims 1 to 7, in which R2Represents C1-C6-an alkyl group.
A further preferred subject of the invention are compounds of the general formula I according to one of claims 1 to 7, in which R3And R4Independently of one another, represents hydrogen or C1-C6-alkyl, or preferably represents hydrogen or C1-C3-an alkyl group.
Another preferred subject of the invention is a process according toCompounds of the general formula I as claimed in any of claims 1 to 7, in which R5Represents C1-C6-alkyl, preferably representing C1-C3-alkyl and more preferably represents methyl.
A further preferred subject of the invention are compounds of the general formula I according to one of claims 1 to 7, in which X and Y independently of one another represent hydrogen or represent halogen, C optionally in one or more positions in an identical or different manner1-C6-alkoxy, C1-C6-alkylthio or phenyl substituted C1-C6-alkyl or phenyl, or represents the group-COOR5or-CONR3R4Or X and Y together are formed from a cyclopentyl or cyclohexyl ring through the same atom or adjacent atoms of W.
Another preferred subject of the invention are compounds of the general formula I according to one of claims 1 to 7, in which M represents C1-C6-alkyl, optionally substituted in one or more positions in the same or different manner by pyrrolidinyl, but preferably represents C substituted by pyrrolidinyl1-C3-an alkyl group.
Another preferred subject of the present invention are compounds of general formula I according to one of claims 1 to 7, wherein Q represents phenyl, pyridyl, naphthyl, indolyl or pyrimidinyl. In this case, Q very particularly preferably represents phenyl or pyridyl.
Another preferred subject of the present invention are compounds of the general formula I according to one of claims 1 to 7, wherein W represents oxazole, 4, 5-dihydrooxazole, oxadiazole, triazole, thiazole, pyridine, thiophene, benzo [ b ] thiophene, benzimidazole, benzothiazole or pyrrole.
Another subject of the invention comprises the intermediate products of general formula (II) for the preparation of the compounds of general formula (I) and the solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts thereof,
wherein A, B, Q and R1Has the meaning indicated in the general formula (I) according to one of claims 1 to 7, and
Rxrepresents C1-C3-an alkyl group.
Another preferred subject of the invention comprises intermediates of general formula (II) in which Q represents phenyl; a and B independently of one another represent hydrogen or represent the group-NH (CO) -C1-C6-alkyl or-NH (CO) -C1-C6-alkoxyalkoxy, R1Represents ethyl, and RxRepresents a methyl group.
A particularly preferred subject of the invention is an intermediate product of the general formula (II) having the formula:
3- { [2- [ 1-cyano-1- ((S) -2-hydroxy-1-methylethylcarbamoyl) -methylene- (E or Z) -yl ] -3-ethyl-4-oxothiazolidine- (5- (E/Z)) -ylidenemethyl ] amino } -N- (3-pyrrolidin-1-ylpropyl) benzamide,
3- { [2- [ 1-cyano-1- ((S) -1-hydroxymethylpropylcarbamoyl) -methylene- (E or Z) -yl ] -3-ethyl-4-oxothiazolidine- (5- (E/Z)) -ylidenemethyl ] amino } -N- (3-pyrrolidin-1-ylpropyl) benzamide,
2-cyano-2- [5- [1- [3- (2, 2-dimethylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide,
2-cyano-2- [5- [1- [3- (2, 2-dimethylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- (2-hydroxypropyl) acetamide,
2-cyano-2- [5- [1- [3- (2, 2-dimethylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclohexyl) acetamide,
2-cyano-2- [5- [1- [3- (2, 2-dimethylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1R, 2S) -2-hydroxy-1-methyl-2-phenylethyl) acetamide,
2-cyano-2- [ 3-ethyl-5- [1- [3- (2-hydroxy-2-methylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide,
2-cyano-2- [ 3-ethyl-5- [1- {3- [2- (2-methoxyethoxy) acetylamino ] phenylamino } -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide,
2-cyano-2- [5- [1- [6- (2, 2-dimethylpropionylamino) pyridin-2-ylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide,
2-cyano-2- [ 3-ethyl-5- [1- {6- [2- (2-methoxyethoxy) acetylamino ] pyridin-2-ylamino } -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide and
2-cyano-2- [ 3-ethyl-5- [1- (2-ethylaminopyridin-4-ylamino) -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide.
Another subject of the invention comprises the use of intermediates of the general formula (II) for preparing compounds of the general formula (I).
For the use of the compounds of the general formula I according to the invention as medicaments, the medicaments are brought into the form of pharmaceutical preparations which, in addition to the active ingredient for enteral or parenteral administration, comprise suitable pharmaceutical, organic or inorganic inert carrier media, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like. The pharmaceutical preparations may be in solid form, for example as tablets, coated tablets, suppositories or capsules, or in liquid form, for example as solutions, suspensions or emulsions. Furthermore, they optionally contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers; salts or buffers for varying the osmotic pressure. These pharmaceutical preparations are also the subject of the present invention.
For parenteral administration, in particular injection solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are suitable.
As carrier systems, it is also possible to use surface-active auxiliaries, such as salts of bile acids or animal or vegetable phospholipids, and mixtures thereof, and also liposomes or constituents thereof.
For oral administration, in particular tablets, coated tablets or capsules containing talc and/or hydrocarbon excipients or binders, such as, for example, lactose, corn starch or potato starch, are suitable. Administration can also be carried out in liquid form, such as, for example, as a juice, to which a sweetener is optionally added.
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 from 0.5 to 1000mg, preferably from 50 to 200mg, wherein the dose can be administered as a single dose or in divided doses in two or more daily doses.
The invention also relates to the use of compounds of the general formula I for producing medicaments. Another subject of the invention is the use of a compound of general formula I for the preparation of a medicament for the treatment of cancer, autoimmune diseases, cardiovascular diseases, chemotherapy agent-induced alopecia and mucositis, infectious diseases, renal diseases, chronic and acute neurodegenerative diseases and viral infections, wherein cancer is defined as solid tumors and leukemias; autoimmune diseases are defined as psoriasis, alopecia and multiple sclerosis; cardiovascular disease is defined as stenosis, arteriosclerosis and restenosis; infectious disease is defined as being caused by a single-cell parasite; nephropathy is defined as glomerulonephritis; chronic neurodegenerative diseases are defined as huntington's disease, amyotrophic lateral sclerosis, parkinson's disease, AIDS-induced 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 or c and HIV diseases.
The subject of the invention is also agents for the treatment of the above-mentioned diseases, which comprise at least one compound according to formula I and a drug together with suitable formulation substances and excipients.
The compounds of general formula I according to the present invention are excellent inhibitors of i.a., polo-like kinases such as Plk1, Plk2, Plk3 and Plk 4.
If the preparation of the starting compounds is not described, the latter are known or can be prepared analogously to known compounds or in analogy to the methods described herein. It is also possible to carry out all the reactions described herein in parallel reactors or by combined operating steps. If the isomers are not in equilibrium with one another, the isomer mixtures can be separated into the isomers, such as, for example, into the enantiomers, diastereomers or E/Z isomers, according to customary methods, such as, for example, crystallization, chromatography or salt formation.
The preparation of the salts is carried out in a conventional manner by mixing a solution of the compound of the formula I, optionally in solution, with an equivalent or excess of a base or acid and isolating the precipitate or the work-up solution in a conventional manner.
Graphic composition
FIG. 1:
a) ester cracking; b) performing coupling reaction; c) cyclization; d) subsequent reaction
Wherein R is1A, B, X, Y, Q and W have the meanings indicated in the formula (I).
RAEthyl and allyl
RM、RN、RPAnd RRH or X or Y
FIG. 2 for the synthesis:
a) removing the protection; b) performing coupling reaction; c) substitution; d)1, 4-addition; e) conversion of alcohols to leaving groups PG ═ protecting groups
Spacer ═ C1-C6Alkyl or NH- (CO) -C1-C6-an alkyl group.
RX＝-NR3R4Or C2-C6-heterocycloalkyl, wherein said heterocycloalkyl comprises in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally in the ring may be substituted by one or more- (CO) -or-SO2-C which is interrupted and optionally may contain one or more double bonds in the ring, and the ring itself may optionally be substituted in the same or different manner in one or more positions by cyano or halogen or in the same or different manner in one or more positions by halogen1-C6Alkyl radical, C3-C6-cycloalkyl or C1-C6Substituted by hydroxyalkyl or by the radical-COR2or-NR3R4The substitution is carried out by the following steps,
wherein R is1、R2、R3、R4A, B, X, Y, Q and W have the meanings indicated in the formula (I).
FIG. 3 for the synthesis:
a) deprotonation and continuous reaction with isothiocyanate R1NCS and bromoacetyl chloride or chloroacetyl chloride,
wherein R is1A, B, X, Y, Q and W have the meanings indicated in the formula (I).
Scheme 1 for aniline synthesis:
a) substitution, b) reduction
Wherein A, Q and RXHave the meaning indicated in the synthetic scheme 2.
Scheme 2 for aniline synthesis:
a) bromination, b) reduction of ketones followed by cyclization, c) reaction with RxRing-opening epoxide, d) acetylation, e) reduction
Wherein A, Q and RxHave the meaning indicated in the synthetic scheme 2.
Scheme 3 for aniline synthesis:
a) reduction of
Wherein A, Q and the spacer have the meanings indicated in scheme 2.
Scheme 4 for aniline synthesis:
1, 4-addition, b) reduction
Wherein A, Q and RXHave the meaning indicated in the synthetic scheme 2.
Scheme 5 for aniline synthesis:
a) reduction; b) coupling agent
Wherein A, Q and L have the meanings indicated in the formula (I).
Scheme 6 for aniline synthesis:
a) reduction of
Wherein A and Q have the meanings indicated in the formula (I).
Scheme 7 for aniline synthesis:
a) coupling agent
Wherein A, Q and L have the meanings indicated in the formula (I).
Scheme 8 for aniline synthesis:
a) coupling agent
Wherein A, Q and L have the meanings indicated in the formula (I).
Scheme 9 for aniline synthesis:
substitution, b) reduction
Wherein A, Q and RXHave the meaning indicated in the synthetic scheme 2.
Scheme 10 for aniline synthesis:
a) reduction of
Wherein R is3And R4Have the meaning indicated in the general formula (I).
Scheme 11 for aniline synthesis:
a) reduction of
Wherein A, Q and RXHave the meaning indicated in the synthetic scheme 2.
Scheme 12 for aniline synthesis:
a) reduction of
A, Q, R therein3And L has the meaning indicated in scheme 2.
Scheme 13 for aniline synthesis:
a) reductive amination; b) reduction of
A, Q, R therein3And R4Has the meaning indicated in scheme 2, wherein R3Or R4＝H。
Scheme 14 for aniline synthesis:
a) substitution; b) reduction of
A, Q, R therein3And R4Has the meaning indicated in scheme 2, wherein R3Or R4＝H。
Scheme for aniline synthesis 15:
a) a coupling agent; b) reduction of
A, Q, R therein3And M has the meaning indicated in the formula (I).
Synthesis of intermediates
Intermediate INT1
1- (2-iodoethyl) -3-nitrobenzene
5g of 3-nitrophenylethanol, 9.4g of triphenylphosphine and 3.1g of imidazole were dissolved in 250ml of THF, mixed in portions with 9.1g of iodine and stirred at room temperature for 15 hours. The reaction mixture was mixed with ammonium chloride solution and extracted with dichloromethane. The organic phase is washed successively with sodium thiosulfate solution and water and dried over sodium sulfate. After purification by chromatography on silica gel, 7.51g of the title compound are obtained.
1H-NMR(DMSO-d6)：δ＝3.31(t，2H)；3.41(t，2H)；7.46-7.60(m，2H)；8.09(s，1H)；8.16(d，1H)；ppm。
Intermediate INT2
1- [2- (3-Nitrophenyl) ethyl ] pyrrolidine
1.88g of the compound described under intermediate INT1) were dissolved in 10ml of dimethylformamide, slowly mixed with 0.85ml of pyrrolidine and stirred at room temperature for 15 hours. The solvent was concentrated under high vacuum and the residue was collected in ethyl acetate and washed three times with water. The organic phase was dried over sodium sulfate. After purification by chromatography on silica gel, 350mg of the title compound are obtained.
1H-NMR(CDCl3)：δ＝1.81(m，4H)；2.57(m，4H)；2.74(t，2H)；2.93(t，2H)；7.45(t，1H)；7.56(d，1H)；8.03-8.13(m，2H)ppm。
Intermediate INT3
3- (2-pyrrolidin-1-ylethyl) aniline
650mg of the compound described under intermediate INT2) were dissolved in 250ml of ethanol and mixed with 130mg of palladium on charcoal (10%). Stirred at room temperature under hydrogen atmosphere for 15 hours. After filtration over celite, the solvent was concentrated off on a rotary evaporator to yield 540mg of the title compound.
1H-NMR(DMSO-d6)：δ＝1.78(m，4H)；2.65(t，2H)；2.70-2.92(m，6H)；4.99(s，2H)；6.31-6.45(m，3H)；6.92(t，1H)ppm。
Intermediate INT4
1- (2-iodoethyl) -4-nitrobenzene
15g of 4-nitrophenylethanol, 28.1g of triphenylphosphine and 9.2g of imidazole were dissolved in 500ml of THF, mixed in portions with 27.77g of iodine and stirred at room temperature for 2 hours. The reaction mixture was mixed with ammonium chloride solution and extracted with dichloromethane. The organic phase is washed successively with sodium thiosulfate solution and water and dried over sodium sulfate. After purification by chromatography on silica gel, 23.22g of the title compound are obtained.
1H-NMR(DMSO-d6)：δ＝3.30(t，2H)；3.54(t，2H)；7.57(d，2H)；8.18(d，2H)ppm。
Intermediate INT5
1- [2- (4-Nitrophenyl) ethyl ] pyrrolidine
8g of the compound described under intermediate INT4), 26.4g of potassium carbonate and 3.6ml of pyrrolidine were dissolved in 20ml of dimethylformamide and stirred at room temperature for 5 hours. The solvent was concentrated under high vacuum and the residue was collected in ethyl acetate and washed three times with water. The organic phase was dried over sodium sulfate. After purification by chromatography on silica gel, 5.6 of the title compound is obtained.
1H-NMR(DMSO-d6)：δ＝1.68(m，4H)；2.48(m，4H)；2.67(t，2H)；2.89(t，2H)；7.52(d，2H)；8.13(d，2H)ppm。
Intermediate INT6
4- (2-pyrrolidin-1-ylethyl) aniline
5.67 of the compound described under intermediate INT5) were dissolved in 500ml of ethanol and mixed with 1g of palladium on charcoal (10%). Stirred at room temperature under hydrogen atmosphere for 2 hours. After filtration over celite and concentration of the solvent off on a rotary evaporator, 4.8 of the title compound is obtained.
1H-NMR(DMSO-d6)：δ＝1.67(m，4H)；2.31-2.60(m，8H)；4.81(s，2H)；6.48(d，2H)；6.84(d，2H)ppm。
Intermediate INT7
3-nitro-N- (3-pyrrolidin-1-ylpropyl) benzamide
500mg of 4-nitrobenzoic acid are dissolved in 20ml of dimethylformamide, mixed with 370. mu.l of triethylamine, 342mg of N- (3-aminopropyl) pyrrolidine and 866mg of TBTU and stirred at room temperature for 20 hours. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted with dichloromethane. The organic solution was washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to give 502mg of the title compound.
1H-NMR(DMSO)：δ＝1.84(m，6H)，2.63(m，4H)，2.78(m，2H)，7.61(m，1H)，8.22(dd，1H)，8.32(dd，1H)，8.53(m，1H)，9.41(s，1H)ppm。
Intermediate INT8
3-amino-N- (3-pyrrolidin-1-ylpropyl) benzamide
1g of the compound described under intermediate INT7) is dissolved in 50ml of THF and admixed with 1g of Raney nickel. It was stirred at room temperature under a hydrogen atmosphere for 3 hours. After filtration over celite, the solvent was concentrated off on a rotary evaporator to yield 810mg of the title compound.
1H-NMR(DMSO d6)：δ＝1.79(m，6H)，2.57(m，4H)，2.69(m，2H)，3.55(m，2H)，3.73(s，2H)，6.76(dd，1H)，7.02(m，1H)，7.17(m，2H)，8.52(s，1H)ppm。
Intermediate INT9
N- (3-aminophenyl) -2, 2-dimethylpropionamide
5.0g of 1, 3-phenylenediamine are dissolved in 50ml of dichloromethane and admixed at 0 ℃ with 24ml of diisopropylethylamine and 10.4ml of pivalic anhydride. It was stirred at 0 ℃ for 2 hours and at room temperature for 18 hours. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to yield 5.7g of the title compound.
1H-NMR(DMSO-d6)：δ＝1.20(s，9H)；4.98(s，2H)；6.24(d，1H)；6.70(d，1H)；6.83-6.96(m，2H)ppm。
Intermediate INT10
N- (3-amino-5-chlorophenyl) -2, 2-dimethylpropionamide
5.0g of 5-chloro-1, 3-phenylenediamine are dissolved in 50ml of dichloromethane and 5ml of dimethylformamide and mixed at 0 ℃ with 18.5ml of diisopropylethylamine and 8.5ml of pivalic anhydride. It was stirred at 0 ℃ for one hour and at room temperature for 5 hours. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted with a mixture consisting of ethyl acetate and hexane (1: 3). The organic solution is washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to yield 2.5g of the title compound.
1H-NMR(DMSO-d6)：(DMSO-d6)：δ＝5.37(s，b，2H)；6.28(s，b，1H)；6.88(s，b，1H)；7.48(s，1H)；9.00(s，1H)ppm。
Intermediate INT11
1- (2-iodoethyl) -3-nitrobenzene
1.5g of 2-hydroxy-2-methylpropionic acid in 50ml of dimethylacetamide was mixed with 1.05ml of thionyl chloride at-10 ℃ and stirred for 30 minutes at-10 ℃. A solution of 2g of 3-nitroaniline in 10ml of dimethylacetamide was added dropwise at-10 ℃ and was stirred successively at-10 ℃ for one hour, at 0 ℃ for one hour and at room temperature for 15 hours. The solvent was concentrated under high vacuum and the residue was collected with a mixture consisting of ethyl acetate and dichloromethane (1: 3) and washed twice with half-saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate. After purification by chromatography on silica gel, 2.42g of the title compound are obtained.
1H-NMR(CDCl3)：δ＝1.49(s，6H)；2.35(s，1H)；7.50(t，1H)；7.98(d，2H)；8.49(s，1H)；8.98(s，b，1H)ppm。
Intermediate INT12
N- (3-aminophenyl) -2-hydroxy-2-methylpropanamide
1.92g of the compound described under intermediate INT11) were dissolved in 400ml of ethanol and admixed with 50mg of Raney nickel. It was stirred at room temperature under a hydrogen atmosphere for 18 hours. After filtration over celite, the solvent was concentrated off on a rotary evaporator to yield 1.9g of the title compound.
1H-NMR(CDCl3)：δ＝1.51(s，6H)；2.68(s，1H)；3.71(s，b，2H)；6.42(d，1H)；7.08(t，1H)；7.20(s，1H)；8.60(s，b，1H)ppm。
Intermediate INT13
2- (2-methoxyethoxy) -N- (3-nitrophenyl) acetamide
5g of (2-methoxyethoxy) acetic acid are dissolved in 500ml of tetrahydrofuran. 9.7ml of triethylamine and 5.6ml of isobutyl chloroformate were added at 0 ℃ and stirred for 30 minutes at 0 ℃. 5.0g of 3-nitroaniline were added and stirred at room temperature for a further 15 hours. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to yield 7.5g of the title compound.
1H-NMR(DMSO-d6)：δ＝3.30(s，3H)；3.53(m，2H)；3.70(m，2H)；4.04(s，1H)；7.62(t，1H)；7.93(d，1H)；8.02(d，1H)；8.69(s，1H)；10.20(s，b，1H)ppm。
Intermediate INT14
N- (3-aminophenyl) -2- (2-methoxyethoxy) acetamide
7.5g of the compound described under intermediate INT13) were dissolved in 150ml of ethanol and mixed with 1.3g of palladium on charcoal (10%). It was stirred at room temperature under a hydrogen atmosphere for 15 hours. After filtration over celite, the solvent is concentrated off on a rotary evaporator to yield 6.5g of the title compound.
1H-NMR(DMSO-d6)：δ＝3.31(s，3H)；3.51(m，2H)；3.65(m，2H)；4.02(s，2H)；6.10(s，2H)；6.28(d，1H)；6.70(d，1H)；6.87-6.98(m，2H)；9.27(s，1H)ppm。
Intermediate INT15
N- (6-aminopyridin-2-yl) -2, 2-dimethylpropionamide
10g of 2, 6-diaminopyridine are dissolved in 150ml of tetrahydrofuran. 48ml of diisopropylethylamine and 20.8ml of pivalic anhydride were added and stirred at room temperature for 15 hours. The solvent was concentrated in a rotary evaporator. After purification by chromatography on silica gel, 10.6g of the title compound are obtained.
1H-NMR(DMSO-d6)：δ＝1.20(s，9H)；5.72(s，2H)；6.07(d，1H)；7.18(d，1H)；7.33(t，1H)；8.93(s，1H)ppm。
Intermediate INT16
N- (6-aminopyridin-2-yl) -2- (2-methoxyethoxy) acetamide
4.9ml of (2-methoxyethoxy) acetic acid were dissolved in 500ml of tetrahydrofuran. 9.7ml of triethylamine and 5.6ml of isobutyl chloroformate were added at 0 ℃ and stirred for 30 minutes at 0 ℃. 3.96g of 2, 6-diaminopyridine are added and stirred at room temperature for a further 4 hours. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to yield 5.04g of the title compound.
1H-NMR(DMSO-d6)：δ＝3.31(s，3H)；3.50(m，2H)；3.67(m，2H)；4.07(s，2H)；5.88(s，2H)；6.19(d，1H)；7.21(d，1H)；7.36(t，1H)；9.13(s，1H)ppm。
Intermediate INT17
Ethyl- (4-nitro-1-oxypyridin-2-yl) amine
2.0g of 2-chloro-4-nitro-pyridine 1-oxide are dissolved in 20ml of ethanol. 11.5ml of triethylamine were added and stirred under reflux for 4 hours. The solvent was concentrated in a rotary evaporator. After purification by chromatography on silica gel, 1.5g of the title compound are obtained.
1H-NMR(DMSO-d6)：δ＝1.19(t，3H)；3.39(pentuplet，2H)；7.39(dd，1H)；7.47(d，1H)；7.64(t，1H)；8.35(d，1H)ppm。
Intermediate INT18
4-amino-2-ethylaminopyridine
800mg of the compound described under intermediate INT17) are dissolved in 50ml of ethanol and admixed with 50mg of Raney nickel. Hydrogenation was carried out at room temperature under a hydrogen atmosphere of 3.5bar for 5 hours. After filtration over celite and concentration of the solvent off on a rotary evaporator, 610mg of the title compound are obtained.
1H-NMR(DMSO-d6)：δ＝1.09(t，3H)；3.11(m，2H)；5.48(s，2H)；5.52(d，1H)；5.71(t，1H)；5.78(dd，1H)；7.49(d，1H)ppm。
Intermediate INT19
2- (3-nitrophenyl) oxirane
10g of 2-bromo-1- (3-nitrophenyl) ethanone are dissolved in 200ml of ethanol, mixed with 1.55g of sodium borohydride and stirred at room temperature for 1 hour. 2.1g of potassium hydroxide are added and stirred at room temperature for a further 15 hours. 1000ml of ethyl acetate are added and washed twice with 300ml of half-saturated ammonium chloride solution and once with 100ml of water. The organic phase was dried over sodium sulfate. After purification by chromatography on silica gel, 7.48g of the title compound are obtained.
1H NMR(CDCl3)：
δ＝2.79(dd，1H)；3.19(dd，1H)；3.93(dd，1H)；7.50(t，1H)；7.60(d，1H)；8.08-8.16(m，2H)ppm。
Intermediate INT20
1- (3-Nitrophenyl) -2- (4aR, 8aS) -decahydroisoquinolin-2-ylethanol
(mixture of diastereomers)
5.0g under INT19 compounds dissolved in 50ml tetrahydrofuran, and 7.3g trans decahydroisoquinoline, stirring under reflux for 20 hours. After distillation of the solvent in a rotary evaporator and purification by chromatography on silica gel, 5.75g of the title compound are obtained.
1H NMR(CDCl3)：
δ＝0.72-1.45(m，7H)；1.45-1.85(m，6H)；1.95-3.20(m，5H)；4.43(b，1H)；4.75-4.86(m，1H)；7.51(t，1H)；7.72(d，1H)；8.13(d，1H)；8.25(s，1H)ppm。
Intermediate INT21
Acetic acid (4aR, 8aS) -1- (3-nitrophenyl) -2-decahydroisoquinolin-2-yl-ethyl ester
5.75g of the compound described under INT20 were dissolved in 100ml of tetrahydrofuran and mixed at 0 ℃ with 5.4ml of triethylamine and 3.6ml of acetic anhydride, followed by stirring at room temperature for 48 hours. Half of the solvent was distilled off in a rotary evaporator, 100ml of half-saturated sodium bicarbonate solution were added and extracted three times with 150ml of dichloromethane each time. The combined organic phases were dried over sodium sulfate. After purification by chromatography on silica gel and subsequent recrystallisation, 4.07g of the title compound are obtained.
1H NMR(CDCl3(ii) a Major isomers):
δ＝0.72-1.05(m，3H)；1.06-1.35(m，4H)；1.40-1.89(m，6H)；2.00-2.22(m，4H)；2.55(dd，1H)；2.64-2.96(m，3H)；5.97(dd，1H)；7.51(t，1H)；7.68(d，1H)；8.14(d，1H)；8.22(s，1H)ppm。
intermediate INT22
3- [ (4aR, 8aS) -2- (decahydroisoquinolin-2-yl) ethyl ] aniline
4.07 of the compound described under INT21) was dissolved in 400ml of ethyl acetate and 100m1 of glacial acetic acid and mixed with 400mg of palladium on charcoal (10%). Hydrogenation was carried out at room temperature under 100bar of hydrogen for 15 hours. 1000mg of palladium on charcoal (10%) are added and the mixture is hydrogenated under 100bar of hydrogen at room temperature for a further 15 hours. Half of the solvent was distilled off in a rotary evaporator and about 11 of 2N sodium hydroxide solution was added until the solution pH was 9.5. The solution is subsequently extracted with 300ml of ethyl acetate and with 500ml of a mixture of chloroform and methanol (10: 1). The combined organic phases were washed with water (100ml) and saturated sodium chloride solution (100ml) and dried over sodium sulfate. Filtration and concentration of the solvent on a rotary evaporator gave 2.57g of the title compound.
1H NMR(CDCl3)：
δ＝0.69-1.03(m，3H)；1.03-1.33(m，4H)；1.39-1.73(m，6H)；1.86-2.00(m，1H)；2.41-2.53(m，2H)；2.61-2.71(m，2H)；2.75-2.83(m，1H)；2.88-3.00(m，1H)；3.37-3.70(b，2H)；6.40-6.50(m，2H)；6.54(d，1H)；7.00(t，1H)ppm。
Intermediate INT23
2-chloro-N- (3-nitrophenyl) acetamide
13.8g of 3-nitroaniline were dissolved in 500ml of tetrahydrofuran. 30.5ml of triethylamine and 19.4g of chloroformic anhydride are added at 0 ℃. Stirred at room temperature for 12 hours. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to give 20.0g of the title compound.
1H-NMR(DMSO-d6)：δ＝4.31(s，2H)；7.64(t，1H)；7.89-8.00(m，2H)；8.61(s，1H)；10.79(b，1H)ppm。
Intermediate INT24
N- (3-nitrophenyl) -2-piperidin-1-ylacetamide
2.14g of the compound described under intermediate INT23) were dissolved in 100ml of dimethylformamide. 2.0ml of triethylamine, 248mg of potassium iodide and 1.48ml of piperidine were added. Stir at room temperature for 4 hours. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and, after purification by chromatography on silica gel, 1.97g of the title compound are obtained.
1H-NMR(DMSO-d6)：δ＝1.34-1.48(m，2H)；1.51-1.63(m，4H)；2.45(m，4H)；3.12(s，2H)；7.60(t，1H)；7.91(d，1H)；8.02(d，1H)；8.70(s，1H)；10.18(s，1H)ppm。
Intermediate INT25
(1-methyl-1H-benzimidazol-2-yl) acetonitrile
Methyl iodide (1.24ml, 19.19mmol) was added to a solution of (1H-benzimidazol-2-yl) acetonitrile (3.13g, 19.91mmol) and potassium carbonate (2.75g, 19.91mmol) in 20ml of dimethylformamide. After stirring at room temperature for 24 hours, potassium carbonate (2.8g, 20.27mmol) and methyl iodide (1.3ml, 20.12mmol) were added. It was stirred at room temperature for a further 24 hours, water and methanol were added and the solvent was distilled off in vacuo. The residue is mixed with 200ml of water and extracted three times successively with 200ml of dichloromethane each time. The combined organic phases are dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to yield 502mg of the title compound.
1H NMR(DMSO-d6)：δ＝3.75(s，3H)；4.52(s，2H)；7.23(m，2H)；7.54(d，1H)；7.62(d，1H)ppm。
The following compounds were prepared analogously to the above procedure.
Table 1: aniline intermediate compounds
Synthesis of additional intermediates
Intermediate Compound INTT1)
Cyanoethylthiocarbamoylacetic acid ethyl ester
4.25ml of isothiocyanic acid ethyl ester were added to a mixture consisting of 5g of cyanoacetic acid ethyl ester and 5ml of triethylamine at 25 ℃. Subsequently, it was then stirred at 50 ℃ for 6 hours. The reaction mixture was then concentrated by evaporation in vacuo. The residue was collected in ethanol and poured into 150ml ice-cold 1N hydrochloric acid. It was stirred at 25 ℃ for 3 more hours, and then the residue was filtered off. The solid obtained is washed again with water. 7g of product are obtained.
200.261 molar mass; ms (esi): [ M +1] + -201.
Intermediate Compound INTT2)
(E or Z) -cyano- (3-ethyl-4-oxothiazolidin-2-ylidene) acetic acid ethyl ester
7.82g of the compound described under the intermediate compound INTT1) were dissolved in 100ml of tetrahydrofuran. 3.9ml of bromoacetyl chloride solution was slowly added, followed by stirring at 25 ℃ for 8 hours. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution. Then, it was stirred 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 was 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。
Intermediate Compound INTT3)
(E or Z) -cyano- (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxothiazolidin-2-ylidene) acetic acid ethyl ester
A mixture consisting of 1.54g of the substance described under the intermediate compound INTT2), 2.5ml of triethyl orthoformate and 3.5ml of acetic anhydride was refluxed for 8 hours. Next, the reaction mixture was poured into ice water. It was then stirred for 3 hours, and the residue was filtered off. The solid obtained is washed again with water. 1.28g of product are obtained.
1H-NMR(CDCl3)：δ＝1.38(9H)；4.20-4.40(6H)；7.72(1H)ppm。
Intermediate Compound INTT4)
(E or Z) -cyano- (3-ethyl-4-oxothiazolidin-2-ylidene) acetic acid allyl ester
A solution of 37.6ml of allyl cyanoacetate in 60ml of dimethylformamide is added at 0 ℃ to a suspension of 12.8g of sodium hydride (60%) in 200ml of dimethylformamide. Then stirred at 0 ℃ for 10 minutes, followed by the addition of 28.0ml of a solution of isothiocyanic acid ethyl ester in 60ml of dimethylformamide. Subsequently, the mixture was stirred at 25 ℃ for 2 hours. Then, a solution of 32ml of bromoacetyl chloride in 60ml of dimethylformamide was added at 0 ℃ and then stirred at 25 ℃ for 15 hours. The reaction mixture was then poured into a saturated sodium bicarbonate solution. Extraction with ethyl acetate, 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 with a mixture consisting of hexane/ethyl acetate. 33.9g of product are obtained.
1H-NMR(CDCl3)：δ＝1.23(3H)；4.11(2H)；4.71(2H)；5.25(1H)；5.37(1H)；5.90-6.04(1H)ppm。
Intermediate Compound INTT5)
(E or Z) -cyano- (5- (E/Z) -ethoxymethylene-3-ethyl-4-oxothiazolidin-2-ylidene) acetic acid allyl ester
Analogously to intermediate INTT3), 14.8g of product were obtained starting from 12.8g of the compound described under intermediate INTT4), 20.9ml of triethyl orthoformate and 29.4ml of acetic anhydride.
1H-NMR(CDCl3)：δ＝1.32-1.45(6H)；4.23(2H)；4.38(2H)；4.73(2H)；5.29(1H)；5.41(1H)；5.92-6.05(1H)；7.72(1H)ppm。
Intermediate Compound INTT6)
[ 3-Ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] pyridin-2-ylacetonitrile
Sodium hydride (60% in oil; 0.73g, 18.25mmol) was added to 10ml of dimethylformamide at 0 ℃ under an inert atmosphere of nitrogen. 2-pyridine acetonitrile (2ml, 17.93mmol) dissolved in 30ml of dimethylformamide was added drop by drop over five minutes. Stirring was carried out for 10 minutes, then a solution of ethyl isothiocyanate (1.6ml, 18.36mmol) in 10ml of dimethylformamide was added drop by drop over five minutes. The solution was stirred at room temperature for two hours, cooled again to 0 ℃ and then a solution of bromoacetyl chloride (2.3ml, 27.59mmol) in 10ml of dimethylformamide was added drop by drop. After stirring overnight at room temperature, the reaction mixture was poured into 300ml of cold, saturated sodium bicarbonate solution and extracted three times with 300ml of ethyl acetate in succession. The combined organic phases are washed with 900ml of saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to yield 1.83g of the title compound.
1H NMR (DMSO-d6, main isomer): δ 1.28(t, 3H); 3.84(s, 2H); 4.22(q, 2H); 7.27(dd, 1H); 7.61(d, 1H); 7.90(t, 1H); 8.58(d, 1H) ppm.
The following compounds were prepared analogously to the procedure described above.
Table 2: intermediate compound
| Example numbering | Structure and name | 1H-NMR | Molecular weight/MS(ESI)[M+1]+ | Extract/synthesized as described below |
Synthesis of additional intermediates
Intermediate Compound INTE1
Cyano- [ 3-ethyl-4-oxo-5- [1- [3- (2-pyrrolidin-1-ylethyl) phenylamino ] -methylene- (E/Z) -yl ] -thiazolidine- (2- (E or Z)) -ylidene ] acetic acid ethyl ester
740mg of the compound described under intermediate INT3) were dissolved in 50ml of ethanol. 1.1g of the compound described under the intermediate compound INTT3) were added and stirred under reflux for 5 hours. The solvent was concentrated in a rotary evaporator. After purification by chromatography on silica gel, 540mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.
1H-NMR (CDCl3, main isomer): δ 1.38(t, 3H); 1.42(t, 3H); 1.83(m, 4H); 2.60(m, 4H); 2.72(m, 2H); 2.86(m, 2H); 4.31(q, 2H); 4.43(q, 2H); 6.87-6.97(m, 2H); 7.00(d, 1H); 7.29(t, 1H); 7.62(d, 1H); 10.56(d, 1H) ppm.
Intermediate Compound INTE2
Cyano- [ 3-ethyl-4-oxo-5- [1- [3- (2-pyrrolidin-1-ylethyl) phenylamino ] -methylene- (E/Z) -yl ] -thiazolidine- (2- (E or Z)) -ylidene ] allyl acetate
1.35g of the compound described under intermediate INT3) were dissolved in 400ml of ethanol. 2.19g of the compound described under the intermediate compound INTT5) were added and stirred at reflux for 4 hours. The solvent was concentrated in a rotary evaporator. After purification by chromatography on silica gel, 2.2g of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) isomers.
1H-NMR (DMSO-d6, with K2CO3Stored together, major isomer): δ 1.24(t, 3H); 1.69(m, 4H); 2.50(m, 4H); 2.66(m, 2H); 2.76(m, 2H); 4.25(q, 2H); 4.71(d, 2H); 5.26(d, 1H); 5.38(d, 1H); 5.90-6.08(m, 1H); 6.96(d, 1H); 7.12(d, 1H); 7.22(s, 1H); 7.26(t, 1H); 8.22(s, 1H); 10.53(s, b, 1H) ppm.
Intermediate Compound INTE3
Cyano- [ 3-ethyl-5- [1- [3- (2-hydroxy-2-methylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] allyl acetate
1.26g of the compound described under intermediate INT12) were dissolved in 400ml of ethanol. 2.0g of the compound described under the intermediate compound INTT5) were added and stirred under reflux for 6 hours. After cooling, the reaction mixture was filtered and the resulting solid was recrystallized from ethanol. 1.4g of the title compound are obtained in the form of a pH-dependent mixture of the 5- (E/Z) -isomers. The solvent obtained from the filtration was concentrated by evaporation in a rotary evaporator. After purification by chromatography on silica gel, the residue yields a further 1.1g of the title compound as a pH-dependent mixture of 5- (E/Z) -isomers.
1H-NMR (DMSO-d6, with K2CO3Storage, major isomer): δ 1.28(t, 3H); 1.38(s, 6H); 4.26(q, 2H); 4.72(d, 2H); 5.27(d, 1H); 5.39(d, 1H); 5.76(s, 1H); 5.90-6.08(m, 1H); 6.99(d, 1H); 7.27(t, 1H); 7.46(d, 1H); 7.89(s, 1H); 8.16(s, 1H); 9.67(s, 1H); 10.63(s, 1H) ppm.
Intermediate Compound INTE4
Cyano- [ 3-ethyl-5- [1- (2-ethylaminopyridin-4-ylamino) -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] allyl acetate
0.94g of the compound described under intermediate INT18) was dissolved in 50ml of 1-propanol. 1.85g of the compound described under the intermediate compound INTT5) were added and stirred at reflux for 4 hours. After cooling, the reaction mixture was filtered. After purification by chromatography on silica gel, the solid obtained yields 1.48g of the title compound as a pH-dependent mixture of 5- (E/Z) -isomers.
1H-NMR (DMSO-d6, with K2CO3Stored together, major isomer): δ 1.13(t, 3H); 1.26(t, 3H); 3.24 (pentaplet, 2H); 4.25(q, 2H); 4.72(d, 1H); 5.28(d, 1H); 5.39(d, 1H); 5.90-6.07(m, 1H); 6.25(d, 1H); 6.44(dd, 1H); 6.49(t, 1H); 7.85(d, 1H); 8.13(s, 1H); 10.47(s, 1H) ppm.
Intermediate Compound INTE5
Cyano- [5- [1- [6- (2, 2-dimethylpropionylamino) pyridin-2-ylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] allyl acetate
1.35g of the compound described under intermediate INT15) were dissolved in 50ml of 1-propanol. 2.0g of the compound described under the intermediate compound INTT5) were added and stirred at reflux for 3 hours. After cooling, the reaction mixture was filtered and the resulting solid was recrystallized from ethanol. 2.47g of the title compound are obtained in the form of a pH-dependent mixture of 5- (E/Z) -isomers.
1H-NMR (DMSO-d6, with K2CO3Stored together, major isomer): δ 1.20-1.31(m, 12H); 4.27(q, 2H); 4.72(d, 2H); 5.28(d, 2H); 5.39(d, 2H); 5.91-6.06(m, 1H); 6.29(d, 2H); 7.68-7.80(m, 2H); 8.86(s, 1H); 9.71(s, 1H); 10.94(s, 1H) ppm.
The following compounds were prepared analogously to the procedure described above.
Table 3: ester intermediate compound
| 2.76(d，2H)；2.90(d，2H)；4.21(q，2H)；4.67(d，2H)；5.22(d，1H)；5.34(d，1H)；5.88-6.01(m，1H)；6.91(d，1H)；7.08(d，1H)；7.15-7.26(m，2H)；8.19(s，1H)；10.49(s，b，1H)ppm。 |
Synthesis of additional intermediates
Intermediate Compound INTA1
Preparation of variant 1
Cyano- [ 3-ethyl-4-oxo-5- [1- [3- (2-pyrrolidin-1-ylethyl) phenylamino ] -methylene- (E/Z) -yl ] -thiazolidine- (2- (E or Z)) -ylidene ] acetic acid
1.1g of potassium tert-butyrate were introduced into 50ml of tetrahydrofuran at 0 ℃ and mixed with 45. mu.l of water. 540mg of the compound described under the intermediate compound INTE1) were added and stirred at 0 ℃ for 30 minutes and at room temperature for 20 hours. 0.25ml of triethylamine in diethyl ether and 10.5ml of 2M hydrochloric acid were added at 0 ℃ and stirred at room temperature for one hour. The solvent was concentrated under high vacuum and the residue was reacted further without additional purification.
MW：412.51；MS(ESI)[M+1]+：413
Preparation of variant 2
300mg of the compound described under the intermediate compound INTE2), 80mg of Pd (PPh3)4 and 0.6ml of morpholine are dissolved in 18ml of tetrahydrofuran and stirred for 15 hours. After addition of 40ml of diethyl ether, the solid obtained is filtered off, dried in vacuo and dissolved in 10ml of dimethylformamide. This solution was added to a suspension of 770mg of PL-MIA resin from Polymer Laboratories GmbH Company in 5ml of dimethylformamide and stirred at room temperature for 15 hours. The reaction mixture was filtered and the solvent was concentrated under high vacuum. 280mg of the title compound are obtained as crude product.
1H-NMR (DMSO-d6, with K2CO3Storage): δ 1.20(t, 3H); 1.88(m, 4H); 2.50(m, 4H); 3.09(m, 2H); 3.20(m, 2H); 4.20(q, 2H); 6.93(d, 1H); 7.04-7.12(m, 2H); 7.23(t, 1H); 7.88(s, 1H); 9.97(s, 1H) ppm.
Intermediate Compound INTA2
Cyano- [ 3-ethyl-5- [1- (2-ethylaminopyridin-4-ylamino) -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] acetic acid
1.2g of the compound described under the intermediate compound INTE4), 350mg of Pd (PPh)3)4And 2.6ml of morpholine were dissolved in 60ml of tetrahydrofuran and stirred at room temperature for one hour. After addition of 40ml of hexane, the solid obtained is filtered off, dried in vacuo and dissolved in 20ml of dimethylformamide. This solution was added to a suspension of 6.0 of PL-MIA resin from Polymer Laboratories GmbH Company in 30ml of dimethylformamide and stirred at room temperature for 15 hours. The reaction mixture was filtered and the solvent was concentrated under high vacuum. 970mg of the title compound are obtained as crude product.
MW：359.41；MS(ESI)[M+1]+：360
1H-NMR (DMSO-d6, with K2CO3Stored together): δ 1.11(t, 3H); 1.22(t, 3H); 3.23(m, 2H); 4.22(q, 2H); 6.25(s, 1H); 6.42(d, 1H); 6.54(s, b, 1H); 7.81(d, 1H); 7.95(s, 1H); 10.20(s, 1H) ppm.
Intermediate Compound INTA3
Cyano- [5- [1- [6- (2, 2-dimethylpropionylamino) pyridin-2-ylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] acetic acid
2.2g of the compound described under the intermediate compound INTE5), 560mg of Pd (PPh)3)4And 4.2ml of morpholine in 110ml of tetrahydrofuran, and stirred at room temperature for one hour. After addition of 50ml of hexane, the precipitated solid is filtered off, dried in vacuo and dissolved in 25ml of dimethylformamideIn (1). This solution was added to a suspension of 9.6g of PL-MIA resin from Polymer Laboratories GmbH Company in 50ml of dimethylformamide and stirred at room temperature for 15 hours. The reaction mixture was filtered and the solvent was concentrated under high vacuum. 2.1g of the title compound are obtained as crude product.
MW：415.47；MS(ESI)[M+1]+：416
1H-NMR (DMSO-d6, with K2CO3Stored together): δ 1.15-1.30(m, 12H); 4.23(q, 2H); 6.80(m, 1H); 7.64-7.74(m, 2H); 8.73(d, 1H); 9.68(s, 1H); 10.68(d, 1H) ppm.
The following compounds were prepared analogously to the procedure described above.
Table 4: acid-intermediate compounds
| Example numbering | Structure and name | 1H-NMR | Molecular weight/MS (ESI) [ M +1]]+ | Extract/synthesized as described below |
Synthesis of additional intermediates
Intermediate compound INTB1
2-cyano-2- [ 3-ethyl-4-oxo-5- [1- [3- (2-pyrrolidin-1-ylethyl) phenylamino ] -methylene- (E/Z) -yl ] -thiazolidine- (2- (E or Z)) -ylidene ] -N- (2-hydroxy-1, 1-dimethylethyl) acetamide
170mg of the crude product described under the intermediate compound INTA1) (approx. 0.42mmol) are dissolved in 10ml of dimethylformamide, mixed with 248mg of sodium hydrogencarbonate, 62. mu.l of 2-amino-2-methylpropan-1-ol and 200mg of TBTU and stirred at room temperature for 18 h. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted with dichloromethane. The organic solution is washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to yield 61mg of the title compound as a pH-dependent mixture of the 5- (E/Z) -isomers.
1H-NMR (DMSO-d6, with K2CO3Stored together, major isomer): δ 1.30(t, 3H); 1.36(s, 6H); 1.74(m, 4H); 2.54(m, 4H); 2.69(m, 2H); 2.79(m, 2H); 3.43(d, 2H); 4.27(q, 2H); 5.27(t, 1H); 6.74(s, 1H); 7.00(d, 1H); 7.18(d, 1H); 7.25-7.35(m, 2H); 8.19(s, 1H); 10.31(s, 1H) ppm.
Intermediate compound INTB2
N- [3- [ [ [2- [ (E or Z) -2- [ [ (1-aminoethylene) amino ] oxy ] -1-cyano-2-oxoethylene ] -3-ethyl-4-oxothiazolidin-5- (E/Z) -ylidene ] methyl ] amino ] phenyl ] -2, 2-dimethylpropanamide
1.39g of the crude product described under the intermediate compound INTA6) (ca.1.0 mmol) were dissolved in 12ml of dichloromethane and 12ml of dioxane, mixed with 0.94ml of diisopropylethylamine, 103mg of acetamidoxime (acetamidoxime) and 622mg of PyBOP and stirred at room temperature for 4 hours. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution was dried over sodium sulfate and concentrated by evaporation.
The resulting solid was recrystallized from ethanol. 354mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.
1H-NMR (DMSO-d6, with K2CO3Stored together, major isomer): δ 1.24(s, 9H); 1.27(t, 3H); 1.81(s, 3H); 4.26(q, 2H); 5.30-6.90(b, 2H); 6.98(d, 1H); 7.27(t, 1H); 7.38(d, 1H); 7.75(s, 1H); 8.12(s, 1H); 9.27(s, 1H); 10.65(s, 1H) ppm.
The following compounds were prepared analogously to the procedure described above.
Table 5:
synthesis of the Compounds of formula (I) according to the invention
Example 1
(4, 4-dimethyl-4, 5-dihydrooxazol-2-yl) - [ 3-ethyl-4-oxo-5- [1- [3- (2-pyrrolidin-1-ylethyl) phenylamino ] -methylene- (E/Z) -yl ] -thiazolidine- (2- (E or Z)) -ylidene ] acetonitrile
46mg of the compound described under intermediate INTB1) are dissolved in 10ml of tetrahydrofuran, mixed with 74mg of Burgess' reagent and stirred at room temperature for 2 hours. 75mg of sodium dihydrogenphosphate and 1ml of dimethylformamide were added thereto, and the mixture was stirred at 40 ℃ for 4 hours. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted successively with ethyl acetate and a mixture consisting of dichloromethane and methanol (100: 1). The combined organic phases are dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to yield 6mg of the title compound.
1H-NMR (DMSO-d6, with K2CO3Stored together, major isomer): δ 1.18-1.33(m, 9H); 1.68(m, 4H); 2.45-2.54(m, b, 4H); 2.56-2.67(m, 2H); 2.67-2.78(m, 2H); 4.00(s, 2H); 4.24(q, 2H); 6.92(d, 1H); 7.08(d, 1H); 7.14(s, 1H); 7.22(t, 1H); 8.15(s, 1H); 10.38(s, 1H) ppm.
The compounds of the following general formula (I) were prepared analogously to the above procedure.
Table 6: a compound of the general formula (I)
| Example numbering | Structure and name | 1H-NMR | Molecular weight/MS (ESI) [ M +1]]+ | Extract/synthesized as described below |
| Ethyl-5- [1- {3- [ (4aR, 8aS) -2- (decahydroisoquinolin-2-yl) -ethyl]-phenylamino } -methylene- (E/Z) -yl]-4-oxothiazolidine- (2- (E or Z)) -subunit]Acetonitrile | 16H)；1.36-1.72(m，6H)；1.89(t，1H)；2.35-2.50(m，2H)；2.59-2.95(m，4H)；3.95(s，2H)；4.19(q，2H)；6.87(d，1H)；6.97-7.25(m，3H)；8.10(s，1H)；10.32(s，b，1H)ppm。 | [M+1]+：534 |
Synthesis of further Compounds of the formula (I) according to the invention
EXAMPLE 41
2- { cyano- [5- [1- [3- (2, 2-dimethylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] methyl } oxazole-4-carboxylic acid methyl ester
100mg of the compound described under example 22) are dissolved in 6ml of benzene. 54mg of DDQ was added and stirred at reflux for 10 minutes. The reaction mixture was mixed with water and extracted with ethyl acetate. After washing the organic solution with saturated sodium chloride solution, drying over sodium sulfate, concentration by evaporation, purification by chromatography on silica gel and subsequent crystallization from ethanol, 11mg of the title compound are obtained as a pH-dependent mixture of the 5- (E/Z) -isomers.
1H-NMR (DMSO-d6, with K2CO3Stored together, major isomer): δ 1.24(s, 9H); 1.30(t, 3H); 3.86(s, 3H); 4.30(q, 2H); 6.89-7.02(m, 1H); 7.19-7.33(m, 2H); 7.39(d, 1H); 7.73(s, 1H); 8.17(s, 1H); 8.86(s, 1H); 9.26(s, 1H); 10.81(s, 1H) ppm.
Example 42
N- (3- { [2- [ 1-cyano-1- (3-methyl- [1, 2, 4] oxadiazol-5-yl) -methylene- (E or Z) -yl ] -3-ethyl-4-oxothiazolidine- (5- (E/Z)) -ylidenemethyl ] amino } phenyl) -2, 2-dimethylpropionamide
205mg of the compound described under intermediate compound INTB2) were dissolved in 16ml of tetrahydrofuran, mixed with 270mg of Burgess' reagent and stirred at reflux for one hour. The reaction mixture was mixed with half-saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel to yield 27mg of the title compound.
1H-NMR (DMSO-d6, with K2CO3Stored together, major isomer): δ 1.24(s, 9H); 1.31(t, 3H); 2.40(s, 3H); 4.32(q, 2H); 7.00(d, 1H); 7.28(t, 1H); 7.39(d, 1H); 7.79(s, 1H); 8.20(s, 1H); 9.28(s, 1H); 10.83(s, b, 1H) ppm.
The compounds of the following general formula (I) were produced analogously.
Table 7: a compound of the general formula (I)
| Example numbering | Structure and name | 1H-NMR | Molecular weight/MS (ESI) [ M +1]]+ | Extracts/e.g. combined in the following cases |
Example 45
[ 3-Ethyl-4-oxo-5- [ 1-phenylamino-methylene- (E/Z) -yl ] thiazolidine- (2- (E or Z)) -ylidene ] pyridin-2-ylacetonitrile
0.72g (2.94mmol) of the compound produced in INTT6) and 0.63g (3.21mmol) of N, N' -diphenylformamidine are heated together for 20 minutes at 140 ℃. After cooling, about 0.40g of the crude product was dissolved in 7ml of dimethyl sulfoxide (containing 0.1% added TFA). The resulting solution was purified by reverse phase chromatography (acetonitrile/water, 0.1% TFA). After lyophilization, 0.28g of the title compound is obtained.
1H NMR (DMSO-d6, main isomer): δ 1.31(t, 3H); 4.36(q, 2H); 7.05(t, 1H); 7.22(dd, 2H); 7.27-7.37(m, 3H); 7.62(d, 1H); 7.89(t, 1H); 8.05(d, 1H); 8.62(d, 1H); 10.19(d, 1H) ppm.
MW：348.43；MS(ES+)found：[M+1]+：349。
The compounds of the following general formula (I) were prepared analogously to the above procedure.
Table 8: a compound of the general formula (I)
Examples
The following examples describe the biological effects of the compounds according to the invention:
PLK enzyme assay
Recombinant human Plk-1(6xHis) was purified from baculovirus-infected insect cells (Hi 5).
10ng (recombinantly produced and purified) of PLK enzyme were incubated with 15. mu.l biotinylated casein and 33P-. gamma. -ATP as substrates for 90 min at room temperature in 384 well Greiner small-volume microtiter plates (final concentration in buffer: 660ng/ml PLK; 0.7. mu. mol casein, 0.5. mu. mol ATP comprising 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 in PBS; 500mmol EDTA; 1% Triton X100; 100mg/ml streptavidin-coated SPA beads) was added. After sealing the microtiter plate with the membrane, the beads were pelleted by centrifugation (10 min, 1500 rpm). The 33P- γ -ATP added to the casein was intended to be measured by β -counting as a measure of enzyme activity. The extent of inhibitor activity was based on solvent control (0% inhibition for uninhibited enzyme activity) and the average of several batches containing 300 μmol wortmannin (100% inhibition for fully inhibited enzyme activity).
Different concentrations (0. mu. mol, and ranges between 0.01 and 30. mu. mol) of the test substance were used. The final concentration of solvent dimethylsulfoxide was 1.5% throughout the batch.
Proliferation assay
Cultured human MaTu breast tumor cells were plated out in 96-well multi-titer (multi titer) plates at a density of 5000 cells/measurement spot in 200. mu.l of the corresponding growth medium. After 24 hours, the cells of one plate (zero plate) were stained with crystal violet (see below) while the medium of the other plate was replaced by fresh medium (200 μ l) to which the test substance was added at different concentrations (0 μm, and in the range of 0.01-30 μm; final concentration of solvent dimethylsulfoxide 0.5%). Cells were cultured in the presence of the test substance for 4 days. Cell proliferation was determined by staining the cells with crystal violet: the cells were fixed by adding 20. mu.l/measurement point of 11% glutaraldehyde solution at room temperature for 15 minutes. After washing the fixed cells three times with water, the plates were dried at room temperature. Cells were stained by adding 100 μ l/measurement point of a 0.1% crystal violet solution (pH adjusted to 3 by adding acetic acid). After washing the stained cells three times with water, the plates were dried at room temperature. The dye was dissolved by adding 100. mu.l/measurement point of 10% acetic acid solution. The extinction was determined photometrically at a wavelength of 595 nm. The percentage of cell growth change was calculated by normalizing the measurements to the extinction values (═ 0%) of the zero plates and to the extinction values (═ 100%) of the untreated (0 μm) cells.
Table 9: measured data
Thus, it can be seen from Table 1 that the compounds of general formula (I) have an inhibitory effect both on the enzyme and in the proliferation assay.
Claims (18)
1. Compounds of general formula (I) and solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts thereof,
wherein
Q represents an aryl or heteroaryl group,
a and B independently of one another represent hydrogen, halogen, hydroxyl, amino or nitro,
or
Represents C1-C6-alkyl or C1-C6Alkoxy, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy, C2-C9-heterocycloalkyl substituted or by a radical-NR3R4or-CO (NR)3) -M-substitution, wherein the heterocycloalkyl comprises in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally in the ring may be substituted by one or more- (CO) -or-SO2-C which is interrupted by a group and optionally may contain one or more double bonds in the ring, and the ring itself optionally may be substituted in the same or different manner in one or more positions by cyano, halogen or in the same or different manner in one or more positions by halogen1-C6Alkyl radical, C3-C6-cycloalkyl or C1-C6Substituted by hydroxyalkyl or by the radical-COR2or-NR3R4The substitution is carried out by the following steps,
or
represents-NR3R4、-NR3(CO)-L、-NR3(CO)-NR3-L、-COR2、-CO(NR3)-M、-NR3(CS)NR3R4、-NR3SO2-L、-SO2-NR3R4or-SO2(NR3)-M，
L represents C1-C6-alkyl or heteroaryl, optionally substituted in one or more positions in the same or different manner by hydroxy, C1-C6-hydroxyalkoxy, C1-C6alkoxy-C2-C6-heterocycloalkyl substituted or by a radical-NR3R4Substituted, wherein the heterocycloalkyl contains in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally may be substituted in the ring by one or more- (CO) -or-SO2The radicals being interrupted and optionally comprising one or more double bonds in the ring, and the ring itself optionally being substituted in the same or different manner in one or more positions by cyano, halogen orC substituted in one or more positions in the same or different manner by halogen1-C6Alkyl radical, C3-C6-cycloalkyl or C1-C6Substituted by hydroxyalkyl or by the radical-COR2or-NR3R4The substitution is carried out by the following steps,
m represents C1-C6-alkyl, optionally substituted in one or more positions in the same or different manner by a group-NR3R4Or C2-C6-heterocycloalkyl substituted, wherein said heterocycloalkyl comprises in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally in the ring may be substituted by one or more- (CO) -or-SO2-C which is interrupted by a group and optionally may contain one or more double bonds in the ring, and the ring itself optionally may be substituted in the same or different manner in one or more positions by cyano, halogen or in the same or different manner in one or more positions by halogen1-C6Alkyl radical, C3-C6-cycloalkyl or C1-C6Substituted by hydroxyalkyl or by the radical-COR2or-NR3R4The substitution is carried out by the following steps,
w represents heteroaryl or C2-C9-heterocycloalkyl, wherein said heterocycloalkyl comprises in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally in the ring may be substituted by one or more- (CO) -or-SO2The group being interrupted and optionally comprising one or more double bonds in the ring,
x and Y independently of one another represent hydrogen or C1-C6Alkyl or aryl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy, C1-C6-alkoxy, C1-C6Alkylthio or aryl substituted or represent a radical-COOR5or-CONR3R4，
Or
X and Y together being bound by C through the same atom or adjacent atoms of W3-C6-cycloalkyl ring or C2-C6-a heterocycloalkyl ring formation, wherein the heterocycloalkyl group is enclosed in the ringContaining at least one atom, which may be identical or different, selected from nitrogen, oxygen or sulfur, and optionally being substituted in the ring by one or more- (CO) -or-SO groups2The radicals being interrupted and optionally comprising one or more double bonds in the ring, and the ring itself optionally being C-bonded in the same or different manner in one or more positions1-C6Alkyl radical, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl substituted or by a group-NR3R4The substitution is carried out by the following steps,
R1represents C1-C4Alkyl radical, C3-cycloalkyl, allyl or propargyl, optionally substituted in one or more positions in the same or different manner by cyano or halogen,
R2represents hydroxy, C1-C6Alkyl radical, C1-C6-alkoxy or represents a group-NR3R4，，
R3And R4Independently of one another, represents hydrogen or represents C1-C6Alkyl radical, C1-C6-alkoxy, -CO-C1-C6Alkyl or aryl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy, C2-C6-heterocycloalkyl radical, C1-C6Substituted by hydroxyalkoxy groups or by groups-NR3R4Substituted, wherein the heterocycloalkyl contains in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally may be substituted in the ring by one or more- (CO) -or-SO2The radicals being interrupted and optionally may comprise one or more double bonds in the ring, and wherein in each case the C is2-C6The heterocycloalkyl ring itself optionally being substituted in one or more positions, in the same or different manner, by cyano, halogen, C1-C6Alkyl radical, C1-C6-hydroxyalkyl, C1-C6-alkoxy, C3-C6-cycloalkyl substituted, or by-NR3R4or-CO-NR3R4Is substituted, or
R3And R4Common shapeTo C2-C6-a heterocycloalkyl ring, wherein said heterocycloalkyl group comprises in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally in the ring may be substituted by one or more- (CO) -or-SO2The radicals being interrupted and optionally comprising one or more double bonds in the ring, and the heterocycloalkyl ring itself optionally being substituted in the same or different manner in one or more positions by halogen, C1-C6Alkyl radical, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6Alkoxyalkyl, cyano, hydroxy or by a radical-NR3R4Is substituted, and
R5represents C1-C6Alkyl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy, C3-C6-heterocycloalkyl radical, C1-C6Substituted by hydroxyalkoxy groups or by groups-NR3R4Substituted, wherein the heterocycloalkyl contains in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally may be substituted in the ring by one or more- (CO) -or-SO2The radicals being interrupted and optionally comprising one or more double bonds in the ring, and the heterocycloalkyl ring itself optionally being substituted in the same or different manner by C in one or more positions1-C6Alkyl radical, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6Alkoxyalkyl, cyano, hydroxy or by a radical-NR3R4And (4) substitution.
2. A compound of general formula I according to claim 1, and solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts thereof, wherein
Q represents phenyl, pyridyl, naphthyl, quinolyl, benzimidazolyl, indolyl, indazolyl, thiazolyl, imidazolyl or pyrimidinyl.
3. A compound of general formula I according to claim 1 or 2, and solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts thereof, wherein
Q represents phenyl, pyridyl, naphthyl, indolyl or pyrimidinyl,
m represents C1-C6-alkyl, optionally substituted in one or more positions by C, in the same or different manner2-C6-heterocycloalkyl substitution, wherein the heterocycloalkyl contains in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur,
R3and R4Independently of one another, represents hydrogen or represents C1-C6Alkyl radical, C1-C6-alkoxy or-CO-C1-C6Alkyl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy or C1-C6-a hydroxy-alkoxy group substitution,
R5represents C1-C6Alkyl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy, C2-C6-heterocycloalkyl radical, C1-C6Substituted by hydroxyalkoxy groups or by groups-NR3R4Substituted, wherein the heterocycloalkyl contains in the ring at least one atom, identical or different, chosen from nitrogen, oxygen or sulfur, and optionally may be substituted in the ring by one or more- (CO) -or-SO2The group is interrupted and may optionally comprise one or more double bonds in the ring.
4. A compound of general formula I according to one of claims 1 to 3, and the solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts thereof, wherein
Q represents a phenyl group or a pyridyl group,
w represents oxazole, 4, 5-dihydrooxazole, oxadiazole, triazole, thiazole, pyridine, thiophene, benzo [ b ] thiophene, benzimidazole, benzothiazole or pyrrole,
x and Y independently of one another represent hydrogen or represent C1-C6-alkyl or aryl, whichOptionally substituted in one or more positions by halogen, hydroxy, C in the same or different manner1-C6-alkoxy, C1-C6Alkylthio or aryl substituted or represent a radical-COOR5or-CONR3R4，
Or
X and Y together are formed by a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring via the same atom or adjacent atoms of W,
R1represents C1-C4-alkyl, optionally substituted in one or more positions in the same or different manner by halogen,
R5represents C1-C6Alkyl, optionally substituted in one or more positions in the same or different manner by halogen, hydroxy or C1-C6-hydroxyalkoxy substitution.
5. The compound of the general formula I according to one of claims 1 to 4, and the solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts thereof, wherein
A and B independently of one another represent hydrogen or halogen,
or
Represents C1-C3-alkyl or C1-C6-alkoxy, which is optionally substituted in the same or different manner in one or more positions by pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroisoquinolinyl, or decahydroisoquinolinyl, wherein pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroisoquinolinyl, or decahydroisoquinolinyl itself is optionally substituted in the same or different manner in one or more positions by halogen or C which is optionally substituted in the same or different manner in one or more positions by halogen1-C6Substituted by alkyl or by the radical-COR2The substitution is carried out by the following steps,
or
represents-NR3R4、-NR3(CO) -L or-CO (NR)3)-M，
L represents C1-C6-alkyl, optionally substituted in one or more positions by hydroxy, C, in the same or different manner1-C6-alkoxyalkoxy, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or decahydroisoquinolinyl substituted, wherein pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or decahydroisoquinolinyl may itself optionally be substituted in the same or different manner by halogen at one or more positions or C optionally substituted in the same or different manner by halogen at one or more positions1-C6Substituted by alkyl or by the radical-COR2The substitution is carried out by the following steps,
m represents C1-C6-alkyl, optionally substituted in one or more positions in the same or different manner by pyrrolidinyl,
x and Y independently of one another represent hydrogen or represent C1-C6Alkyl or phenyl, optionally substituted in one or more positions in the same or different manner by halogen, C1-C6-alkoxy, C1-C6Alkylthio or phenyl, or represents a radical-COOR5or-CONR3R4，
Or
X and Y together are formed from a cyclopentyl or cyclohexyl ring through the same atom or through adjacent atoms of W,
R2represents C1-C6-an alkyl group,
R3and R4Independently of one another, represents hydrogen or C1-C6-alkyl, and
R5represents C1-C6-an alkyl group.
6. A compound of general formula I according to one of claims 1 to 5, and solvates, hydrates, stereoisomers, diastereomers, enantiomers or salts thereof, wherein
A and B independently of one another represent hydrogen or halogen,
or
Represents C1-C3-alkyl, which is optionally substituted in the same or different manner in one or more positions by pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroisoquinolinyl, or decahydroisoquinolinyl,
or
represents-NR3R4、-NR3(CO) -L or-CO (NR)3)-M，
L represents C1-C6-alkyl, optionally substituted in one or more positions in the same or different manner by hydroxy or C1-C6-alkoxy-C1-C6-an alkoxy group substitution,
m represents C1-C6-an alkyl group substituted by a pyrrolidinyl group,
R1represents C1-C4-an alkyl group.
7. A compound of general formula I according to one of claims 1 to 6, and the solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts thereof, wherein
A and B independently of one another represent hydrogen or halogen,
or
Represents C1-C3-alkyl, optionally substituted in the same or different manner in one or more positions by pyrrolidinyl or decahydroisoquinolinyl,
or
represents-NR3R4、-NR3(CO) -L or-CO (NR)3)-M，
L represents isopropyl, tert-butyl or methyl, optionally substituted in one or more positions in the same or different manner by hydroxy or C1-C6-an alkoxy-substitution,
m represents C1-C3-an alkyl group substituted by a pyrrolidinyl group,
x and Y independently of one another represent hydrogen or represent methyl, ethyl, isopropyl, propyl, isobutyl, tert-butyl or phenyl, which is optionally substituted in one or more positions in the same or different manner by halogen, C1-C6-alkoxy, C1-C6Alkylthio or phenyl radicals
Substituted, or represents a group-COOR5or-CONR3R4，
Or
X and Y together are formed from a cyclopentyl or cyclohexyl ring through the same atom or through adjacent atoms of W,
R1represents an ethyl group, and the like,
R3and R4Independently of one another, represents hydrogen or C1-C3-alkyl, and
R5represents a methyl group.
8. Intermediates of general formula (II) for the preparation of compounds of general formula (I) and solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts thereof,
wherein, A, B, Q and R1Has the meaning indicated in the general formula (I) according to one of claims 1 to 7, and
Rxrepresents C1-C3-an alkyl group.
9. An intermediate product according to claim 8, wherein
Q represents phenyl;
a and B independently of one another represent hydrogen or represent the group-NH (CO) -C1-C6-alkyl or-NH (CO) -C1-C6-an alkoxy-alkoxy group,
R1represents ethyl, and
Rxrepresents a methyl group.
10. An intermediate product according to claim 8 or 9 having the formula:
3- { [2- [ 1-cyano-1- ((S) -2-hydroxy-1-methylethylcarbamoyl) -methylene- (E or Z) -yl ] -3-ethyl-4-oxothiazolidine- (5- (E/Z)) -ylidenemethyl ] amino } -N- (3-pyrrolidin-1-ylpropyl) benzamide,
3- { [2- [ 1-cyano-1- ((S) -1-hydroxymethylpropylcarbamoyl) -methylene- (E or Z) -yl ] -3-ethyl-4-oxothiazolidine- (5- (E/Z)) -ylidenemethyl ] amino } -N- (3-pyrrolidin-1-ylpropyl) benzamide,
2-cyano-2- [5- [1- [3- (2, 2-dimethylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide,
2-cyano-2- [5- [1- [3- (2, 2-dimethylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- (2-hydroxypropyl) acetamide,
2-cyano-2- [5- [1- [3- (2, 2-dimethylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclohexyl) acetamide,
2-cyano-2- [5- [1- [3- (2, 2-dimethylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1R, 2S) -2-hydroxy-1-methyl-2-phenylethyl) acetamide,
2-cyano-2- [ 3-ethyl-5- [1- [3- (2-hydroxy-2-methylpropionylamino) phenylamino ] -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide,
2-cyano-2- [ 3-ethyl-5- [1- {3- [2- (2-methoxyethoxy) acetylamino ] phenylamino } -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide,
2-cyano-2- [5- [1- [6- (2, 2-dimethylpropionylamino) pyridin-2-ylamino ] -methylene- (E/Z) -yl ] -3-ethyl-4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide,
2-cyano-2- [ 3-ethyl-5- [1- {6- [2- (2-methoxyethoxy) acetylamino ] pyridin-2-ylamino } -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide and
2-cyano-2- [ 3-ethyl-5- [1- (2-ethylaminopyridin-4-ylamino) -methylene- (E/Z) -yl ] -4-oxothiazolidine- (2- (E or Z)) -ylidene ] -N- ((1S, 2S) -2-hydroxycyclopentyl) acetamide.
11. Use of an intermediate product according to one of claims 8 to 10 for the preparation of a compound of general formula (I).
12. Medicament comprising at least one compound according to one of claims 1 to 7.
13. The medicament according to claim 12 for the treatment of cancer, autoimmune diseases, chemotherapy agent-induced alopecia and mucositis, cardiovascular diseases, infectious diseases, kidney diseases, chronic and acute neurodegenerative diseases and viral infections.
14. Use of a compound of the general formula I according to one of claims 1 to 7 for the preparation of a medicament.
15. Use of a compound of general formula I according to one of claims 1 to 7 for the preparation of a medicament for the treatment of cancer, autoimmune diseases, chemotherapy agent-induced alopecia and mucositis, cardiovascular diseases, infectious diseases, kidney diseases, chronic and acute neurodegenerative diseases and viral infections.
16. A compound according to one of claims 1 to 7 or a medicament according to one of claims 12 or 13 with suitable formulation substances and excipients.
17. Use of a compound of general formula I according to one of claims 1 to 7 and a medicament according to one of claims 12 or 13 as inhibitors of polo-like kinases.
18. Use of compounds of the general formula I according to one of claims 1 to 7 in the form of pharmaceutical preparations for enteral, parenteral and oral administration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005005395.5 | 2004-02-03 | ||
| US60/651,232 | 2005-02-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1114615A true HK1114615A (en) | 2008-11-07 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US12295945B2 (en) | Enantiomers of substituted thiazoles as antiviral compounds | |
| JP2005521631A (en) | Thiazolebenzamide derivatives and pharmaceutical compositions for inhibiting cell proliferation and methods of use thereof | |
| JP2005538048A (en) | Thiazolidinones, their production and use as pharmaceutical agents | |
| US20100048891A1 (en) | Metasubstituted thiazolidinones, their manufacture and use as a drug | |
| EP2167490A1 (en) | Triazole derivatives having antifungal activity, method for the preparation thereof, and pharmaceutical composition comprising the same | |
| US20070037862A1 (en) | Thiazolidinones, their production and use as pharmaceutical agents | |
| CN101155791A (en) | Thiazolidinones as polar body-like kinase (PLK) inhibitor agents | |
| JP2007517886A (en) | New chemical compounds | |
| HK1114615A (en) | Thiazolidinones as inhibitors of polo-like kinases (plk) as pharmaceutical agents | |
| US20070010566A1 (en) | Thiazolidinones without basic nitrogen, their production and use as pharmaceutical agents | |
| JP2008538756A (en) | Novel thiazolidinones without basic nitrogen, their production and use as pharmaceutical agents | |
| US20070010565A1 (en) | New thiazolidinones without basic nitrogen, their production and use as pharmaceutical agents | |
| KR20070100830A (en) | Thiazolidinone for use as an inhibitor of polo kinase (PLV) | |
| HK1114097A (en) | Meta-substituted thiazolidinones, the production thereof and their use as medicaments | |
| DE102004061503A1 (en) | New meta-substituted thiazolidinone compounds are polo-like kinase inhibitors useful to treat cancers, autoimmune-, cardiovascular-, infectious-, nephrological-, nephrological- and neurodegenerative-diseases | |
| MXPA06004918A (en) | Thiozolidinones, production and use thereof as medicaments |