CN101208317A - New thiazolidinones without basic nitrogen, their production and use as pharmaceutical agents - Google Patents
New thiazolidinones without basic nitrogen, their production and use as pharmaceutical agents Download PDFInfo
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Abstract
The invention relates to thiazolidinones of general formula (I):, to their production and to their use as inhibitors of the polo-like kinase (Plk) for treating various diseases.
Description
The present invention relates to thiazolidone, they preparation and they are as the purposes of polar body sample kinases (Plk) inhibitor of the multiple disease of treatment.
Tumour cell is a feature with uncontrolled cell cycle process.On the one hand, this is based on loss and so-called cell cycle process accelerator---the activation of cell cycle protein dependent kinase (Cdks) of control albumen (control protein) as RB, p16, p21, p53 etc.Cdks is the anti-tumor target albumen of generally acknowledging in the pharmacopedics.Except that Cdks, the serine/threonine kinase of regulating the new cell cycle has also been described---so-called " polar body sample kinases ", it not only participates in regulation of Cell Cycle, the also coordination of other processes of participation during mitotic division and division of cytoplasm (form spindle body, separate karyomit(e)).Therefore, this proteinoid representative is used for for example useful point of application (Descombes and Nigg, Embo J, 17 of treatment for cancer intervention of proliferative disease; 1328 and following or the like, 1998; People such as Glover, Genes Dev 12,3777 and following or the like, 1998).
In " nonsmall-cell lung cancer " (people such as Wolf, Oncogene, 14,543 and following or the like, 1997), melanoma (people such as Strebhardt, JAMA, 283,479 and following or the like, 2000), " squamous cell carcinoma " (people Cancer Res such as Knecht, 59,2794 and following or the like, 1999) and found the high expression level rate of Plk-1 in " esophageal carcinoma " (people Int J Oncol 15,687 such as Tokumitsu and following or the like, 1999).
In the tumour patient of prognosis mala, dependency (the people JAMA such as Strebhardt that has shown the high expression level rate that changes maximum (the most varied) tumour, 283,479 and following or the like, 2000, people Cancer Res such as Knecht, 59,2794 and following or the like, 1999 and people Int J Oncol 15 such as Tokumitsu, 687 and following or the like, 1999).
The constitutive expression of Plk-1 in the NIH-3T3 cell causes vicious transformation (propagation of increase, growth, colony form and the tumour in nude mice forms in soft agar) (people such as Smith, Biochem Biophys Res Comm, 234,397 and following or the like, 1997).
Micro-injection Plk-1 antibody causes unsuitable mitotic division (people such as Lane in HeLa cell; Journal Cell Biol, 135,1701 and following or the like, 1996).
With " 20-aggressiveness " antisense oligonucleotide, might suppress the expression of Plk-1 in the A549 cell, and stop their survival ability.In nude mice, also may show notable antitumor activity (Mundtetal., Biochem Biophys Res Comm, 269,377 and following or the like, 2000).
Compare with HeLa cell, the anti-Plk antibody of micro-injection shows obviously higher cellular constituent in the human Hs68 cell of non-immortalization, and described cellular constituent remains on the cessation of growth cessation of G2, and demonstrates the unsuitable mitotic division sign (Lane etc. of much less; Journal Cell Biol, 135,1701 and following or the like, 1996).
Compare with tumour cell, the antisense oligonucleotide molecule does not suppress the g and D ability (people such as Mundt, Biochem Biophys Res Comm, 269,377 and following or the like, 2000) of people's mesangial cell of former generation.
In Mammals, except that Plk-1, other three kinds of polar body kinases have been described also up to now, they are induced by mitogenic response and in their function of the interim performance of the G1 of cell cycle.On the one hand, they are so-called Prk/Plk-3 (kinases of human homology's thing of mouse-Fnk=one-tenth fibroblast growth factor-induced; People such as Wiest, Genes, Chromosomes ﹠amp; Cancer, 32:384 and following or the like, 2001), Snk/Plk-2 (serum inductive kinases, people such as Liby, DNA Sequence, 11,527-33,2001) and sak/Plk4 (people such as Fode, Proc.Natl.Acad.Sci.U.S.A., 91,6388 and following or the like; 1994).
Therefore, the method that is hopeful to be used for the treatment of multiple disease has been represented in the kinases of Plk-1 and other polar body families such as the inhibition of Plk-2, Plk-3 and Plk-4.
Sequence homogeny in the polar body family in the Plk territory is between 40 and 60%, thereby other kinases of kinase inhibitor and one or more these families exist part to interact.Yet according to the structure of inhibitor, described effect also optionally takes place or preferably only takes place on a kind of kinases of polar body family.
In International Application No. WO 03/093249, the thiazolidinone compound that suppresses the polar body family kinase is disclosed.
At present, the objective of the invention is to obtain to suppress other materials of polar body family kinase in micromole's level and nmole level.
Now found the compound of general formula I and the suitable inhibitor that solvate, hydrate, steric isomer, diastereomer, enantiomer and salt are the polar body family kinase thereof:
Wherein:
Q represents aryl,
A and B represent independently of one another hydrogen, halogen, hydroxyl ,-NR
3R
4, cyano group or nitro,
Or
The representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4Or-CO (NR
3The C that)-M replaces
1-C
4-alkyl, C
1-C
6-alkoxyl group or C
3-C
6-Heterocyclylalkyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group be interrupted and/or in ring, randomly can comprise one or more pairs of keys and/or described ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl replaces or by group-NR
3R
4Replace,
Or
Representative-NR
3C (O)-L ,-NR
3C (O)-NR
3-L ,-COR
6,-O-(CH
2)
pR
6,-CO (NR
3)-M ,-NR
3(CS) NR
3R
4,-NR
3SO
2-M ,-SO
2-NR
3R
4,-SO
2(NR
3)-M or-O-(CH
2)
pAryl,
P represents integer 0,1,2,3 or 4,
L representative randomly in one or more positions in identical or different mode by C
1-C
6-hydroxy alkoxy base, C
1-C
6-alkoxyl group alkoxyl group, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl or C
3-C
6-Heterocyclylalkyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and/or described ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl replaces or by group-NR
3R
4Replace,
M representative randomly in one or more positions in identical or different mode by group-NR
3R
4Or C
3-C
6The C that-Heterocyclylalkyl replaces
1-C
6-alkyl,
X representative-NH-or-NR
5-,
R
1The C that representative is randomly replaced by halogen in identical or different mode in one or more positions
1-C
4-alkyl, C
3-cycloalkyl, allyl group or propargyl,
R
2Represent hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, cyano group, C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-hydroxyalkyl, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, C
1-C
6That-alkynyl, aryl, aryloxy, heteroaryl replace or by group-S-C
1-C
6-alkyl ,-COR
6,-NR
3R
4,-NR
3C (O)-L or-NR
3COOR
7The C that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-thiazolinyl, C
1-C
6-alkynyl, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, aryl or heteroaryl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2Group is interrupted and/or randomly comprises one or more pairs of keys in ring,
And wherein aryl, heteroaryl, C
3-C
6-cycloalkyl-and/or in each case, described C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, hydroxyl, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl replaces or by the C that is randomly replaced by halogen in identical or different mode in one or more positions
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, aryl, benzyl or heteroaryl replace,
Or
Represent group-NR
3R
4,-NR
3C (O)-L or-NR
3(CS) NR
3R
4,
Or
R
2And R
5The common C that forms
3-C
6-heterocycloalkyl ring, its be interrupted at least once by nitrogen and randomly can be in one or more positions by oxygen or sulphur is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring,
And/or described ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, hydroxyl, C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyalkyl replaces or by group-NR
3R
4Or-COR
6Replace,
And/or can be replaced by aryl or heteroaryl, described aryl or heteroaryl randomly in one or more positions in identical or different mode by halogen, C
1-C
6-alkoxyl group replaces or by group-COR
6Replace,
R
3And R
4Represent independently of one another hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, C
3-C
6-Heterocyclylalkyl, C
1-C
6That-hydroxy alkoxy base replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl group ,-CO-C
1-C
6-alkyl or aryl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2Group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and wherein said C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl substituted is perhaps by group-NR
3R
4Or-CO-NR
3R
4Replace,
Or
R
3And R
4The common C that forms
3-C
6-heterocycloalkyl ring, its be interrupted at least once by nitrogen and randomly can be in one or more positions by oxygen or sulphur is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring,
And/or described heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyalkyl, cyano group, hydroxyl replace or by group-NR
3R
4Replace,
R
5The representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, cyano group, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl, C
1-C
6-thiazolinyl or C
1-C
6-alkynyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2Group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and wherein in each case, described C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl substituted is perhaps by group-NR
3R
4Or-CO-NR
3R
4Replace,
R
6Representation hydroxy, C
1-C
6-alkyl, C
1-C
6-alkoxyl group or group-NR
3R
4,
R
7Representative-(CH
2)
n-aryl or-(CH
2)
n-heteroaryl, and
N represents integer 1,2,3,4,5 or 6.
This is surprising, because the compound of general formula I does not have the D-A die body of common known kinase inhibitor, described D-A die body is well-known and establishes well from document (referring to Structure 1999, the 3rd volume, the 319th page and Science 1998, the 281st volume, the 533rd page), it makes suitably the hinge area with kinase catalytic center be combined into possibility.Therefore may, but be not imperative, the compound of general formula I otherwise combines with described kinases and causes such restraining effect.
Compound according to general formula I of the present invention mainly suppresses polar body sample kinases, and their effect is based on this anti-following illness, for example: cancer, such as solid tumor and leukemia; Autoimmune disorder is such as psoriatic, alopecia and multiple sclerosis, the alopecia of chemotherapeutics inductive and mucositis; Cardiovascular disorder is such as narrow, arteriosclerosis and restenosis; Transmissible disease, for example cause such as those by unicellular parasite such as trypanosoma, toxoplasma or plasmodium or by fungus-caused; Ephrosis is such as for example glomerulonephritis; Chronic neurodegenerative disease is such as Heng Tingdunshi disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and alzheimer's disease; The acute neurodegenerative disease is such as cerebral ischemia and neurotrauma; Virus infection is such as for example giant cells infection, bleb, B-mode and hepatitis C and HIV disease.
The mixture that steric isomer is defined as E/Z-and R/S-isomer and is made up of E/Z-and R/S-isomer.
The following term that is used for this specification sheets and claim preferably has following implication:
In each case, term " alkyl " is defined as the straight or branched alkyl, such as for example: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, heptyl, octyl group, nonyl and decyl and isomer thereof.
In each case, term " alkoxyl group " is defined as the straight or branched alkoxyl group, such as for example: methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, hexyloxy, heptan oxygen base, octyloxy, the ninth of the ten Heavenly Stems oxygen base or the last of the ten Heavenly stems oxygen base and isomer thereof.
In each case, term " thiazolinyl " is defined as the straight or branched thiazolinyl, wherein, for example represent following group: vinyl, propylene-1-base, propylene-2-base, but-1-ene-1-base, but-1-ene-2-base, but-2-ene-1-base, but-2-ene-2-base, 2-methyl-prop-2-alkene-1-base, 2-methyl-prop-1-alkene-1-base, but-1-ene-3-base, fourth-3-alkene-1-base and allyl group.
In each case, term " alkynyl " is defined as comprising 2 to 6, the straight or branched alkynyl of preferred 2 to 4 carbon atoms.For example can mention following group: ethynyl, propine-1-base, propine-3-base, fourth-1-alkynes-1-base, fourth-1-alkynes-4-base, fourth-2-alkynes-1-base, fourth-2-alkynes-1-base, fourth-1-alkynes-3-base etc.
Term " Heterocyclylalkyl " representative comprises the alkyl ring of 3 to 6 carbon atoms, wherein replace one or more carbon atoms such as for example oxygen, sulphur or nitrogen by one or more identical or different heteroatomss and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and can randomly comprise another substituting group on one or more carbon, nitrogen or sulphur atom independently of one another.Substituting group on described heterocycloalkyl ring can be: cyano group, halogen, hydroxyl, C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-alkoxyalkyl, C
1-C
6-hydroxyalkyl, C
3-C
6-cycloalkyl, aryl or group-NR
3R
4,-CO-NR
3R
4,-SO
2R
3Or-SO
2NR
3R
4
Can mention as Heterocyclylalkyl; for example: Oxyranyle; oxetanyl (oxethanyl); '-aziridino; azetidinyl; tetrahydrofuran base; pyrrolidyl; dioxolanyl; imidazolidyl; pyrazolidyl alkyl dioxin; piperidyl; morpholinyl; the dithiane base; thio-morpholinyl (thimorpholinyl); piperazinyl; the trithian base; quinuclidinyl; pyrrolidone-base (pyrolidonyl); N-methylpyrrole alkyl; 2-hydroxymethyl-pyrrolidine base; 3-hydroxyl pyrrolidine base; the N methyl piperazine base; N-ethanoyl piperazinyl; N-methylsulfonyl piperazinyl; 4-hydroxy piperidine base; 4-aminocarboxyl piperidyl; 2-hydroxyethyl piperidine base; 4-hydroxymethyl piperidine base; the nortropine base; 1,1-dioxo thio-morpholinyl etc.
Term " cycloalkyl " is defined as monocyclic alkyl ring (for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl), and dicyclo or three rings (such as for example adamantyl).Cycloalkyl can randomly be benzo-fused also, such as for example (naphthane) base etc.
In each case, term " halogen " is defined as fluorine, chlorine, bromine or iodine.
As used herein, in each case, term " aryl " is defined as having 3 to 12 carbon atoms, preferred 6 to 12 carbon atoms, such as for example cyclopropenyl radical, cyclopentadienyl, phenyl, tropyl, cyclooctadiene base, indenyl, naphthyl, Azulene base, xenyl, fluorenyl, anthryl etc., phenyl is preferred.
As used herein, term " heteroaryl " is understood that to mean and comprises 3 to 16 annular atomses, preferred 5 or 6 or 9 or 10 atoms also comprise at least one identical or different heteroatomic aromatic ring system, described heteroatoms can be monocycle, dicyclo or trinucleated for for example oxygen, nitrogen or sulphur and described aromatic ring system, and can be benzo-fused in addition in each case.Preferably, heteroaryl is selected from thienyl, furyl, pyrrolidyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, sulfo--4H-pyrazolyl etc. and benzo derivative thereof, such as for example benzofuryl, benzothienyl, benzoxazolyl, benzimidazolyl-, benzotriazole base, indazolyl, indyl, pseudoindoyl etc.; Or pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl etc. and benzo derivative thereof, such as for example quinolyl, isoquinolyl etc.; Or oxepinyl, first Xin Yinji, indolizine base, indyl, indolinyl, pseudoindoyl, indazolyl, benzimidazolyl-, purine radicals etc. and benzo derivative thereof; Or quinolyl, isoquinolyl, 2 base, quinazolyl, quinoxalinyl, naphthyridinyl, pteridyl, carbazyl, acridyl, phenol piperazine base, phenothiazine base, Fen oxazinyl, xanthenyl or oxepinyl etc.
Preferred heteroaryl is the heterocycle of for example 5 yuan of rings such as heterocycle such as pyridyl, pyrimidyl, triazinyl, quinolyl, isoquinolyl and the benzo derivative thereof of thiophene, furyl, oxazolyl, thiazole, imidazolyl and benzo derivative and 6 yuan of rings.
As used herein, when running through this paper and use, term " C
1-C
6" at " C
1-C
6-alkyl ", " C
1-C
6-alkoxyl group ", " C
1-C
6-hydroxyalkyl ", " C
1-C
6-hydroxy alkoxy base " or " C
1-C
6-alkoxyl group alkoxyl group " etc. definition in be understood that to mean alkyl with a limited number of 1 to 6 carbon atom (that is: 1,2,3,4,5 or 6 carbon atom).Also can be understood that described term " C
1-C
6" be interpreted as comprising following any subrange, for example: C
1-C
6, C
2-C
5, C
3-C
4, C
1-C
2, C
1-C
3, C
1-C
4, C
1-C
5, C
1-C
6Preferred C
1-C
2, C
1-C
3, C
1-C
4, C
1-C
5, C
1-C
6More preferably C
1-C
4Especially, as used herein, when running through this paper and use, " thiazolinyl " or " alkynyl " is understood that to mean the alkenyl or alkynyl with a limited number of 2 to 6 carbon atoms (that is: 2,3,4,5 or 6 carbon atoms).Also can be understood that described term " C
2-C
6" be interpreted as comprising following any subrange, for example: C
2-C
8, C
2-C
7, C
2-C
6, C
3-C
5, C
3-C
4, C
2-C
3, C
2-C
4, C
2-C
5Preferred C
2-C
3
As used herein, when running through this paper and use, term " C
1-C
4" at " C
1-C
4-alkyl " etc. definition in be understood that to mean alkyl with a limited number of 1 to 4 carbon atom (that is: 1,2,3 or 4 carbon atom).Also can be understood that described term " C
1-C
4" be interpreted as comprising following any subrange, for example: C
1-C
4, C
2-C
3, C
1-C
2, C
1-C
3, C
2-C
4
As used herein, when running through this paper and use, term " C
3-C
6" at " C
3-C
6-cycloalkyl " or " C
3-C
6-Heterocyclylalkyl " definition in be understood that to mean cycloalkyl or have a limited number of 3 to 6 (that is: 3,4,5 or 6) carbon atoms, the Heterocyclylalkyl of preferred 5 or 6 carbon atoms with a limited number of carbon atom.Also can be understood that described term " C
3-C
6" be interpreted as comprising following any subrange, for example: C
3-C
6, C
4-C
5, C
5-C
6Preferred C
5-C
6
Isomer is defined as identical but the compound that chemical structure is different of chemical formula (summation formula).Usually, constitutional isomer and steric isomer are distinguishing.
Constitutional isomer has identical chemical formula, but their atom or atomic group ways of connecting difference.These comprise functional isomer, positional isomers, tautomer or valence isomer.
Difference that steric isomer has essentially identical structure (formation)---and therefore also having identical chemical formula---but atoms in space is arranged.
Usually, configurational isomer is different with conformer.Configurational isomer is to have only the steric isomer that could transform mutually by bond rupture.These comprise enantiomer, diastereomer and E/Z (cis/trans) isomer.
Enantiomer is to show to such an extent that resemble each other to image and mirror image and do not show the steric isomer of any plane of symmetry.All are not that the steric isomer of enantiomer all is called diastereomer.E/Z on two keys (cis/trans) isomer is a special case.
Conformer is to rotate the steric isomer that transforms each other by singly-bound.
In order to define isomery type each other, referring to IUPAC Rules, Section E (Pure Appl.Chem.45,11-30,1976).
Compound according to general formula I of the present invention also comprises possible tautomeric form, and comprises E-or Z-isomer, if perhaps there is chiral centre, also comprises racemic modification and enantiomer.Among the latter, also defined double bond isomer.
Also can be according to compound of the present invention by solvate, especially the form of hydrate exists, and wherein therefore comprises polar solvent, especially water according to compound of the present invention, as the constituent according to the lattice of compound of the present invention.The ratio of polar solvent, especially water can exist by stoichiometric or non-stoichiometric ratio.With regard to stoichiometric solvate and hydrate, also mention half-(partly), singly-, sesquialter-, two-, three-, four-, five-equal solvent compound or hydrate.
If comprise acidic group, the compatible salt of the physiology of organic bases and mineral alkali is fit to as salt, such as for example: diffluent basic metal and alkaline earth salt and N-methylglucosamine, dimethyl glycosamine, ethyl glycosamine, Methionin, 1,6-hexanediamine, thanomin, glycosamine, sarkosine, Serine, trihydroxy methyl aminomethane, amino-propanediol, Sovak alkali and 1-amino-2,3, the 4-trihydroxybutane.
If comprise base, the compatible salt of the physiology of organic acid and mineral acid is fit to, such as: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, citric acid, tartrate, succsinic acid, methylsulfonic acid, tosic acid etc.
Those compounds and solvate, hydrate, steric isomer, diastereomer, enantiomer and the salt that have proved general formula I are effective especially, wherein:
Q represents phenyl,
A and B represent independently of one another hydrogen, halogen, hydroxyl ,-NR
3R
4, cyano group or nitro,
Or
The representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4Or-CO (NR
3The C that)-M replaces
1-C
4-alkyl, C
1-C
6-alkoxyl group or C
3-C
6-Heterocyclylalkyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group be interrupted and/or in ring, randomly can comprise one or more pairs of keys and/or described ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl replaces or by group-NR
3R
4Replace,
Or
Representative-NR
3C (O)-L ,-NR
3C (O)-NR
3-L ,-COR
6,-O-(CH
2)
pR
6,-CO (NR
3)-M ,-NR
3(CS) NR
3R
4,-NR
3SO
2-M ,-SO
2-NR
3R
4,-SO
2(NR
3)-M or-O-(CH
2)
pAryl,
P represents integer 0,1,2,3 or 4,
L representative randomly in one or more positions in identical or different mode by C
1-C
6-hydroxy alkoxy base, C
1-C
6-alkoxyl group alkoxyl group, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl or C
3-C
6-Heterocyclylalkyl,
Wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2Group be interrupted and/or in ring, randomly can comprise one or more pairs of keys and/or described ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl replaces or by group-NR
3R
4Replace,
M representative randomly in one or more positions in identical or different mode by group-NR
3R
4Or C
3-C
6The C that-Heterocyclylalkyl replaces
1-C
6-alkyl,
X representative-NH-or-NR
5-,
R
1The C that representative is randomly replaced by halogen in identical or different mode in one or more positions
1-C
4-alkyl, C
3-cycloalkyl, allyl group or propargyl,
R
2Represent hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, cyano group, C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-hydroxyalkyl, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, C
1-C
6That-alkynyl, aryl, aryloxy, heteroaryl replace or by group-S-C
1-C
6-alkyl ,-COR
6,-NR
3R
4,-NR
3C (O)-L or-NR
3COOR
7The C that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-thiazolinyl, C
1-C
6-alkynyl, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, aryl or heteroaryl,
Wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2Group is interrupted and/or can randomly comprises one or more pairs of keys in ring,
And wherein aryl, heteroaryl, C
3-C
6-cycloalkyl-and/or in each case, described C
3-C
6-heterocycloalkyl ring itself randomly in one or more positions in identical or different mode by cyano group, halogen, hydroxyl, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, or the C that is randomly replaced by halogen in identical or different mode in one or more positions
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, aryl, benzyl or heteroaryl replace,
Or
Represent group-NR
3R
4,-NR
3C (O)-L or-NR
3(CS) NR
3R
4,
Or
R
2And R
5The common C that forms
3-C
6-heterocycloalkyl ring, its be interrupted at least once by nitrogen and randomly can be in one or more positions by oxygen or sulphur is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring,
And/or described ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, hydroxyl, C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyalkyl replaces or by group-NR
3R
4Or-COR
6Replace and/or can be replaced by aryl or heteroaryl, described aryl or heteroaryl randomly in one or more positions in identical or different mode by halogen, C
1-C
6-alkoxyl group replaces or by group-COR
6Replace,
R
3And R
4Represent independently of one another hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, C
3-C
6-Heterocyclylalkyl, C
1-C
6That-hydroxy alkoxy base replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl group ,-CO-C
1-C
6-alkyl or aryl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and wherein in each case, described C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl substituted or by group-NR
3R
4Or-CO-NR
3R
4Replace,
Or
R
3And R
4The common C that forms
3-C
6-heterocycloalkyl ring, its be interrupted at least once by nitrogen and randomly can be in one or more positions by oxygen or sulphur is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring,
And/or described heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyalkyl, cyano group, hydroxyl replace or by group-NR
3R
4Replace,
R
5The representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, cyano group, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl, C
1-C
6-thiazolinyl or C
1-C
6-alkynyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and wherein in each case, described C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl substituted or by group-NR
3R
4Or-CO-NR
3R
4Replace,
R
6Representation hydroxy, C
1-C
6-alkyl, C
1-C
6-alkoxyl group or group-NR
3R
4,
R
7Representative-(CH
2)
n-aryl or-(CH
2)
n-heteroaryl, and
N represents integer 1,2,3,4,5 or 6.
Those compounds and solvate, hydrate, steric isomer, diastereomer, enantiomer and the salt of general formula I are especially very effective, wherein:
Q represents phenyl,
A and B represent that hydrogen, halogen or representative are randomly replaced by halogen, hydroxyl in identical or different mode in one or more positions or by group-NR independently of one another
3R
4Or-CO (NR
3The C that)-M replaces
1-C
4-alkyl or pyrrolidyl,
M representative randomly in one or more positions in identical or different mode by group-NR
3R
4Or C
3-C
6The C that-Heterocyclylalkyl replaces
1-C
6-alkyl,
X representative-NH-,
R
1The C that representative is randomly replaced by halogen in identical or different mode in one or more positions
1-C
4-alkyl,
R
2Represent hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, cyano group or C
1-C
6The C that-alkoxyl group replaces
1-C
6-alkyl or C
1-C
6-alkynyl,
R
3And R
4Represent independently of one another hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, C
3-C
6-Heterocyclylalkyl, C
1-C
6That-hydroxy alkoxy base replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl group ,-CO-C
1-C
6-alkyl or aryl, wherein said Heterocyclylalkyl itself randomly can be interrupted by one or more nitrogen, oxygen and/or sulphur atom, and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and wherein said C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl substituted or by group-NR
3R
4Or-CO-NR
3R
4Replace,
Or
R
3And R
4The common C that forms
3-C
6-heterocycloalkyl ring, its be interrupted at least once by nitrogen and randomly can be in one or more positions by oxygen or sulphur is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring,
And/or described heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyalkyl, cyano group, hydroxyl replace or by group-NR
3R
4Replace, and
R
6Representation hydroxy or C
1-C
6-alkoxyl group.
Those compounds and solvate, hydrate, steric isomer, diastereomer, enantiomer and the salt of general formula I are extremely effective, wherein:
Q represents phenyl,
A and B represent hydrogen, halogen, hydroxyl, methoxyl group or pyrrolidyl independently of one another,
X representative-NH-,
R
1Represent ethyl,
R
2Represent ethyl or proyl.
Purpose of the present invention also is the purposes of the compound of general formula I, and it can be used for preparing the medicament of treatment cancer, autoimmune disorder, the alopecia of chemotherapeutics inductive and mucositis, cardiovascular disorder, transmissible disease, ephrosis, chronic and acute neurodegenerative disease and virus infection.
Purpose of the present invention also is used to prepare the purposes of the medicament for the treatment of following disease for the compound of general formula I: cancer, solid tumor and leukemia; Autoimmune disorder: psoriatic, alopecia and multiple sclerosis; Cardiovascular disorder: narrow, arteriosclerosis and restenosis; Transmissible disease: the disease that causes by unicellular parasite; Ephrosis: glomerulonephritis; Chronic neurodegenerative disease: Heng Tingdunshi disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and alzheimer's disease; Acute neurodegenerative disease: cerebral ischemia and neurotrauma; And virus infection: giant cells infection, bleb, B-mode and hepatitis C and HIV disease.
Compound according to the present invention can be used in the situation of cancer, autoimmune disorder, cardiovascular disorder, transmissible disease, ephrosis, neurodegenerative disease and virus infection.
The present invention also comprises the medicament of the compound that comprises at least a general formula I.
Such medicament is used for the treatment of cancer, autoimmune disorder, cardiovascular disorder, transmissible disease, ephrosis, neurodegenerative disease and virus infection.
Usually, in described medicament, according to compound of the present invention and the formula material and the mixed with excipients that are fit to.
Therefore, theme of the present invention also for be used in the intestines, the pharmaceutical preparation of parenteral and oral administration.
In order to use the compound of formula I as medicament, described medicament is made the form of pharmaceutical preparation, wherein in being used for intestines or the activeconstituents of parenterai administration, also comprise appropriate drug, organic or inorganic inert support medium, such as for example water, gelatin, Sudan Gum-arabic, lactose, starch, Magnesium Stearate, talcum, vegetables oil, polyalkylene glycol etc.Described pharmaceutical preparation can exist by solid form, for example as tablet, coating tablet, suppository or capsule; Perhaps press liquid form and exist, for example as solution, suspensoid or emulsion.In addition, they randomly comprise auxiliary agent, such as sanitas, stablizer, wetting agent or emulsifying agent; Be used to change the salt or the buffer reagent of osmotic pressure.
For administered parenterally, particularly injection solvent or suspensoid, the especially active compound aqueous solution in poly-hydroxyl-oxethyl Viscotrol C is fit to.
As carrier system, also can use the surfactivity auxiliary agent, such as the salt of bile acide or animal or plant phosphatide and composition thereof, and liposome or its composition.
For oral administration, especially comprise talcum and/or hydrocarbon vehicle or binding agent, be fit to such as tablet, coating tablet or the capsule of for example lactose, W-Gum or yam starch.Also can carry out administration, as juice, randomly add sweeting agent or if necessary, add one or more flavoring substances to it such as for example by liquid form.
Can change the dosage of activeconstituents according to the type of method, patient's age and the body weight of administration, disease to be treated and seriousness and similar factor.Per daily dose is 0.5-1000mg, preferred 50-200mg, and wherein said dosage can be used as the single dose single administration or is divided into twice or repeatedly per daily dose administration.
Above-mentioned prescription and forms of distribution also are theme of the present invention.
Especially, be used as the kinase whose inhibitor of polar body sample according to compound of the present invention.Polar body sample kinases is defined as Plk1, Plk2, Plk3 and Plk4 especially.
Preparation is according to the general schematic of compound of the present invention:
Reaction conditions: a) saponification in the presence of tetrakis triphenylphosphine palladium (Pd-tetrakis-triphenylphosphine) and barbituric acid; B) with the aldehyde condensation; C) saponification in the presence of tetrakis triphenylphosphine palladium and barbituric acid; D) form acid amides by the free carboxy acid; E) with the aldehyde condensation; F) form acid amides by the free carboxy acid.
Substantially, can carry out the preparation of the compound of general formula I through two optional synthetic routes.Method variant I comprises intermediate product 2 and 3, and it starts from the raw material 1 that oneself describes in International Application No. WO 03/093249.Method variant II comprises intermediate product 4 and 5, and it starts from identical raw material 1.Two kinds of method variants all are applicable to the parallel synthesis preparation method of the compound of general formula I.Based on this method, in each case, can extensively variation in last synthesis phase according to the radicals X-R2 or the Q of test compounds of the present invention.
In method variant I, in the reaction of intermediate product 2 formation intermediate products 3, observe and form by product 6.About this point, except usual (systematic) saponification of allyl ester functional group, be enough to surprisingly, decarboxylation has also taken place.
Reaction conditions: g) high temperature saponification in the presence of tetrakis triphenylphosphine palladium and barbituric acid.
1. preparation is according to the intermediate product of formula of the present invention (2)
Intermediate product 1 (ZP1)
5-[1-(4-bromophenyl) methylene-(Z)-yl]-3-ethyl-4-oxo thiazolidine-(2Z)-subunit] the cyanoacetic acid allyl ester
The raw material that 1.01g (4.0mmol) is described in patent application PCT/EP2004/012242A is dissolved in the tetrahydrofuran (THF) of 10ml, mixes with the p-bromobenzaldehyde of 740mg (4.0mmol) and the piperidines of 0.04ml, and stirring at room 48 hours.Then by the evaporation concentration reaction mixture to almost dry finishing, and purifying and need not again by ethyl acetate crystallization aftertreatment.Obtain the title compound of (E/Z)-isomer mixture that the pH-of 938mg (56%) relies on.
(DMSO-d6 is with K for 1H-NMR
2CO
3Store main isomer): δ=1.30 (t, 3H); 4.28 (q, 2H); 4.77 (m, 2H); 5.31 (m, 1H); 5.41 (m, 1H); 6.01 (m, 1H); 7.66 (d, 2H); 7.82 (d, 2H); 7.88 (s, 1H) ppm.
Also preparation similarly:
Table 1: aldehyde condensate
2. according to the preparation of the intermediate product of formula of the present invention
Intermediate product (ZP14)
Cyano group-[3-ethyl-4-oxo-5-[1-(4-tetramethyleneimine-1-base phenyl) methylene-(Z)-yl] thiazolidine-(2Z)-and subunit] acetate
With the cyano group of 1.0g (about 2.44mmol)-[3-ethyl-4-oxo-5-[1-(4-tetramethyleneimine-1-base phenyl) methylene-(Z)-yl] thiazolidine-(2Z)-subunit] allyl acetate with the tetrakis triphenylphosphine palladium of the barbituric acid of 341mg (2.66mmol) and 277mg (0.24mmol) in the 10ml tetrahydrofuran (THF) stirring at room 24 hours.For aftertreatment, mixing raw product also with ethyl acetate, suction filtration goes out the precipitation of formation.Then such separated products (648mg, 71%) is used for step then without being further purified.
(DMSO-d6 is with K for 1H-NMR
2CO
3Store main isomer): δ=1.25 (t, 3H); 1.97 (m, 4H); 3.38 (m, 4H); 4.27 (q, 2H); 6.72 (m, 2H); 7.5-7.65 (m, 2H), 7.71 (s, 1H) ppm.
Preparation according to the intermediate product of the formula (4) of method variant II and (5)
ZP15
2-cyano group-2-[3-ethyl-4-oxo-3-base methylene-(Z)-yl] thiazolidine-(2Z)-and subunit] acetate
With the allyl ester of in patent application WO 03/093249, having described of 40g (about 0.16mol) and 22.18g (～barbituric acid 0.17mmol) and the tetrakis triphenylphosphine palladium of 18.3g (10mol%) in the THF of 50ml in stirring at room 72 hours.Behind TLC monitoring reaction mixture, solvent removed in vacuo.Raw product is used for reaction then without being further purified, and comprises 50% required carboxylic acid.
Obtain analytically pure sample by filtering and using toluene to boil filter cake subsequently.
(DMSO-d6 is with K for 1H-NMR
2CO
3Store main isomer): δ=1.20 (t, 3H); 3.60 (s, 2H); 4.12 (q, 2H); 11.1 (s, 1H) ppm.
ZP16
2-cyano group-2-[3-ethyl-4-oxo-3-base methylene-(Z)-yl] thiazolidine-(2Z)-subunit]-the N-ethyl acetamide
With raw product 2-cyano group-2-[3-ethyl-4-oxo of 15g-3-base methylene-(Z)-yl] thiazolidine-(2Z)-subunit] acetate adds among the DMF of 200ml with the ethamine of 21.2ml and the yellow soda ash of 11.8g.Add the TBTU of 13.8g after 30 minutes in stirring at room, and reaction mixture is continued stirring in room temperature spend the night.About aftertreatment, raw product is mixed with ethyl acetate.The ethyl acetate that water is used 100ml at every turn is extracting twice again.The organic phase that merges is used saturated sodium bicarbonate solution and saturated nacl aqueous solution extraction in succession.Then, with organic phase dried over sodium sulfate, filtration and evaporation concentration.
By using alcohol crystal, isolating the content that 4.05g (with respect to 2-cyano group-2-[3-ethyl-4-oxo-3-base methylene-(Z)-yl] thiazolidine-(2Z)-subunit) acetate indicates in raw product from raw product is 48%) required product.
(DMSO-d6 is with K for 1H-NMR
2CO
3Store main isomer): δ=1.00 (t, 3H); 1.16 (t, 3H); 3.14 (m, 2H); 3.77 (s, 2H); 4.05 (q, 2H); 7.74 (m, 1H) ppm.
Also same preparation is:
Table 3a: acid amides
3. according to the preparation of end product of the present invention
Embodiment 1
2-cyano group-N-ethyl-2-[3-ethyl-4-oxo-5-[1-(4-tetramethyleneimine-1-base phenyl) methylene-(Z)-yl] thiazolidine-(2Z)-and subunit] ethanamide
Add cyano group [3-ethyl-4-oxo-5-[4-(tetramethyleneimine-1-base phenyl) methylene-(Z)-yl] thiazolidine of 50mg (0.14mmol)-(2Z)-subunit together] acetate and the ethamine (2M in THF) of 0.2ml (0.41mmol) and the HATU of the 154mg in the DMF of 10ml (0.41mmol), and in stirred overnight at room temperature.About aftertreatment, raw product is mixed with ethyl acetate, the water with 10ml extracts 3 times at every turn.With the organic phase that merges through dried over sodium sulfate, filter and evaporation concentration.By silica gel column chromatography raw product is carried out purifying.Isolate the yellow solid of 32mg (60%).
As the optional method for preparing acid amides by the free carboxy acid, also can be by corresponding amide and aldehyde condensation prepared corresponding compounds:
With 2-cyano group-2-[3-ethyl-4-oxo of 50mg (0.21mmol)-3-base methylene-(Z)-yl] thiazolidine-(2Z)-subunit]-4-tetramethyleneimine-1-benzaldehyde of N-ethyl acetamide and 53mg (0.30mmol) and the piperidines of 10 μ l stirred overnight at room temperature in the THF of 10ml together.After question response is finished, filter out required product; Discard filtrate, isolate the yellow solid of 54mg (70%).As optionally to this, the moisture aftertreatment by ethyl acetate come to required product separate, through dried over sodium sulfate and then on silica gel through column chromatography purification of crude product.
(DMSO-d6 is with K for 1H-NMR
2CO
3Store main isomer; Obtain measuring result at 350K): δ=1.13 (t, 3H); 1.29 (t, 3H); 2.02 (m, 4H); 3.25 (q, 2H); 3.36 (m, 4H); 4.29 (q, 2H); 6.72 (d, 2H); 7.52 (d, 2H); 7.57 (s, 1H); 7.62 (s, 1H) ppm.
Also same preparation is:
Table 3: acid amides:
Embodiment
Following embodiment has described the biological action according to compound of the present invention, but described compound functions is not limited to these embodiment:
The PLK enzymatic determination
Purification of recombinant human Plk-1 (6xHis) from the insect cell (Hi5) of baculovirus infection.
Under the room temperature, at the 384 hole Greiner small volume microtiter plate (PLK of the ultimate density in damping fluid: 660ng/ml; 0.7 the casein of μ mol, the ATP of 0.5 μ mol, it comprises 33P-γ-ATP of 400nCi/ml; The MgCl2 of 10mmol, the MnCl2 of 1mmol; 0.01%NP40; The DTT of 1mmol, proteinase inhibitor; The Na2VO3 of 0.1mmol in the HEPES of 50mmol, pH 7.5) in, (producing and purifying with recombination form) PLK enzyme of 10ng was cultivated 90 minutes with biotinylated casein and 33P-γ-ATP as 15 μ l of substrate.In order to finish reaction, add the stop bath (ATP of 500 μ mol in PBS of 5 μ l; The EDTA of 500mmol; 1%Triton X100; The SPA bead of streptavidin-coating of 100mg/ml).With film with after the microtiter plate sealing, by centrifugal (10 minutes, 1500rpm) precipitation bead.33P-γ-the ATP that is added in the casein is intended to by beta counting measuring as enzymic activity.The degree of inhibitor activity is a benchmark with the solvent control (=do not suppress enzymic activity=0% suppress) and the mean value (=suppress fully enzymic activity=100% inhibition) of several batch of materials that comprises the wortmannin of 300 μ mol.
Use the test substances of different concns (0 μ mol, and between the scope of 0.01-30 μ mol).In whole batch of materials, the ultimate density of solvent methyl-sulphoxide is 1.5%.
Proliferation assay
In the many titration in 96 holes (multititer) plate, in the corresponding growth medium of 200 μ l, the human MaTu breast tumor cell of cultivation is paved with the density of 5000 cell/measurement point.After 24 hours, with the cell dyeing (see below) of Viola crystallina with a plate (plate at zero point), use fresh substratum (200 μ l) to replace the substratum of other plates simultaneously, in the described fresh substratum with different concns (0 μ m, and in the scope of 0.01-30 μ m; The ultimate density of solvent methyl-sulphoxide is 1.5%) the adding substances.In the presence of test substances with cell cultures 4 days.By cell dyeing being measured cell proliferation: cell is fixed 15 minutes in room temperature by 11% glutaraldehyde solution that adds 20 μ l/ measurement point with Viola crystallina.After washing fixed cell three times with water, with described plate in drying at room temperature.By 0.1% crystal violet solution (is 3 by the adding acetate adjusting pH) staining cell that adds 100 μ l/ measurement point.After painted cell washes three times with water, at room temperature dry described plate.By 10% acetic acid solution that adds 100 μ l/ measurement point dyestuff is dissolved.Under wavelength 595nm, measure delustring by photometry.By observed value is calculated the percentage ratio of cell growth change to delustring (=100%) stdn of the extinction value (=0%) of plate at zero point and untreated (0 μ m) cell.
Table 1: determination data
Therefore, can find out that from table 1 compound of general formula (I) all shows the inhibition of nmole level enzyme and proliferation test.
Claims (19)
1. the compound of general formula I and solvate thereof, hydrate, steric isomer, diastereomer, enantiomer and salt,
Wherein:
Q represents aryl,
A and B represent independently of one another hydrogen, halogen, hydroxyl ,-NR
3R
4, cyano group or nitro,
Or
The representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4Or-CO (NR
3The C that)-M replaces
1-C
4-alkyl, C
1-C
6-alkoxyl group or C
3-C
6-Heterocyclylalkyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group be interrupted and/or in ring, randomly can comprise one or more pairs of keys and/or described ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl replaces or by group-NR
3R
4Replace,
Or
Representative-NR
3C (O)-L ,-NR
3C (O)-NR
3-L ,-COR
6,-O-(CH
2)
pR
6,-CO (NR
3)-M ,-NR
3(CS) NR
3R
4,-NR
3SO
2-M ,-SO
2-NR
3R
4,-SO
2(NR
3)-M or-O-(CH
2)
pAryl,
P represents integer 0,1,2,3 or 4,
L representative randomly in one or more positions in identical or different mode by C
1-C
6-hydroxy alkoxy base, C
1-C
6-alkoxyl group alkoxyl group, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl or C
3-C
6-Heterocyclylalkyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and/or described ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl replaces or by group-NR
3R
4Replace,
M representative randomly in one or more positions in identical or different mode by group-NR
3R
4Or C
3-C
6The C that-Heterocyclylalkyl replaces
1-C
6-alkyl,
X representative-NH-or-NR
5-,
R
1The C that representative is randomly replaced by halogen in identical or different mode in one or more positions
1-C
4-alkyl, C
3-cycloalkyl, allyl group or propargyl,
R
2Represent hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, cyano group, C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-hydroxyalkyl, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, C
1-C
6That-alkynyl, aryl, aryloxy, heteroaryl replace or by group-S-C
1-C
6-alkyl ,-COR
6,-NR
3R
4,-NR
3C (O)-L or-NR
3COOR
7The C that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-thiazolinyl, C
1-C
6-alkynyl, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, aryl or heteroaryl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2Group is interrupted and/or randomly comprises one or more pairs of keys in ring,
And wherein aryl, heteroaryl, C
3-C
6-cycloalkyl-and/or in each case, described C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, hydroxyl, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl replaces or by the C that is randomly replaced by halogen in identical or different mode in one or more positions
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, aryl, benzyl or heteroaryl replace,
Or
Represent group-NR
3R
4,-NR
3C (O)-L or-NR
3(CS) NR
3R
4,
Or
R
2And R
5The common C that forms
3-C
6-heterocycloalkyl ring, its be interrupted at least once by nitrogen and randomly can be in one or more positions by oxygen or sulphur is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring,
And/or described ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, hydroxyl, C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyalkyl replaces or by group-NR
3R
4Or-COR
6Replace,
And/or can be replaced by aryl or heteroaryl, described aryl or heteroaryl randomly in one or more positions in identical or different mode by halogen, C
1-C
6-alkoxyl group replaces or by group-COR
6Replace,
R
3And R
4Represent independently of one another hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, C
3-C
6-Heterocyclylalkyl, C
1-C
6That-hydroxy alkoxy base replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl group ,-CO-C
1-C
6-alkyl or aryl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2Group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and wherein said C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl substituted is perhaps by group-NR
3R
4Or-CO-NR
3R
4Replace,
Or
R
3And R
4The common C that forms
3-C
6-heterocycloalkyl ring, its be interrupted at least once by nitrogen and randomly can be in one or more positions by oxygen or sulphur is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and/or described heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyalkyl, cyano group, hydroxyl replace or by group-NR
3R
4Replace,
R
5The representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, cyano group, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl, C
1-C
6-thiazolinyl or C
1-C
6-alkynyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2Group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and wherein in each case, described C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl substituted is perhaps by group-NR
3R
4Or-CO-NR
3R
4Replace,
R
6Representation hydroxy, C
1-C
6-alkyl, C
1-C
6-alkoxyl group or group-NR
3R
4,
R
7Representative-(CH
2)
n-aryl or-(CH
2)
n-heteroaryl, and
N represents integer 1,2,3,4,5 or 6.
2. according to compound and steric isomer, diastereomer, enantiomer and the salt of the general formula I of claim 1, wherein:
Q represents phenyl,
A and B represent independently of one another hydrogen, halogen, hydroxyl ,-NR
3R
4, cyano group or nitro,
Or
The representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4Or-CO (NR
3The C that)-M replaces
1-C
4-alkyl, C
1-C
6-alkoxyl group or C
3-C
6-Heterocyclylalkyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group be interrupted and/or in ring, randomly can comprise one or more pairs of keys and/or described ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl replaces or by group-NR
3R
4Replace,
Or
Representative-NR
3C (O)-L ,-NR
3C (O)-NR
3-L ,-COR
6,-O-(CH
2)
pR
6,-CO (NR
3)-M ,-NR
3(CS) NR
3R
4,-NR
3SO
2-M ,-SO
2-NR
3R
4,-SO
2(NR
3)-M or-O-(CH
2)
pAryl,
P represents integer 0,1,2,3 or 4,
L representative randomly in one or more positions in identical or different mode by C
1-C
6-hydroxy alkoxy base, C
1-C
6-alkoxyl group alkoxyl group, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl or C
3-C
6-Heterocyclylalkyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2Group be interrupted and/or in ring, randomly can comprise one or more pairs of keys and/or described ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl replaces or by group-NR
3R
4Replace,
M representative randomly in one or more positions in identical or different mode by group-NR
3R
4Or C
3-C
6The C that-Heterocyclylalkyl replaces
1-C
6-alkyl,
X representative-NH-or-NR
5-,
R
1The C that representative is randomly replaced by halogen in identical or different mode in one or more positions
1-C
4-alkyl, C
3-cycloalkyl, allyl group or propargyl,
R
2Represent hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, cyano group, C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-hydroxyalkyl, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, C
1-C
6That-alkynyl, aryl, aryloxy, heteroaryl replace or by group-S-C
1-C
6-alkyl ,-COR
6,-NR
3R
4,-NR
3C (O)-L or-NR
3COOR
7The C that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-thiazolinyl, C
1-C
6-alkynyl, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, aryl or heteroaryl,
Wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2Group is interrupted and/or randomly can comprises one or more pairs of keys in ring,
And wherein aryl, heteroaryl, C
3-C
6-cycloalkyl-and/or in each case, described C
3-C
6-heterocycloalkyl ring itself randomly in one or more positions in identical or different mode by cyano group, halogen, hydroxyl, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, the randomly C that is replaced by halogen in identical or different mode in one or more positions
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl, C
3-C
6-Heterocyclylalkyl, aryl, benzyl or heteroaryl replace,
Or
Represent group-NR
3R
4,-NR
3C (O)-L or-NR
3(CS) NR
3R
4,
Or
R
2And R
5The common C that forms
3-C
6-heterocycloalkyl ring, its be interrupted at least once by nitrogen and randomly can be in one or more positions by oxygen or sulphur is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring,
And/or described ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, hydroxyl, C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyalkyl replaces or by group-NR
3R
4Or-COR
6Replace and/or can be replaced by aryl or heteroaryl, described aryl or heteroaryl randomly in one or more positions in identical or different mode by halogen, C
1-C
6-alkoxyl group replaces or by group-COR
6Replace,
R
3And R
4Represent independently of one another hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, C
3-C
6-Heterocyclylalkyl, C
1-C
6That-hydroxy alkoxy base replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl group ,-CO-C
1-C
6-alkyl or aryl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and wherein in each case, described C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl substituted or by group-NR
3R
4Or-CO-NR
3R
4Replace,
Or
R
3And R
4The common C that forms
3-C
6-heterocycloalkyl ring, its be interrupted at least once by nitrogen and randomly can be in one or more positions by oxygen or sulphur is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring,
And/or described heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyalkyl, cyano group, hydroxyl replace or by group-NR
3R
4Replace,
R
5The representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, cyano group, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl, C
3-C
6That-Heterocyclylalkyl replaces or by group-NR
3R
4The C that replaces
1-C
6-alkyl, C
1-C
6-thiazolinyl or C
1-C
6-alkynyl, wherein said Heterocyclylalkyl itself randomly can by one or more nitrogen, oxygen and/or sulphur atom is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and wherein in each case, described C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl substituted or by group-NR
3R
4Or-CO-NR
3R
4Replace,
R
6Representation hydroxy, C
1-C
6-alkyl, C
1-C
6-alkoxyl group or group-NR
3R
4,
R
7Representative-(CH
2)
n-aryl or-(CH
2)
n-heteroaryl, and
N represents integer 1,2,3,4,5 or 6.
3. according to compound and solvate, hydrate, steric isomer, diastereomer, enantiomer and the salt of the general formula I of claim 1 or 2, wherein:
Q represents phenyl,
A and B represent that hydrogen, halogen or representative are randomly replaced by halogen, hydroxyl in identical or different mode in one or more positions or by group-NR independently of one another
3R
4Or-CO (NR
3The C that)-M replaces
1-C
4-alkyl or pyrrolidyl,
M representative randomly in one or more positions in identical or different mode by group-NR
3R
4Or C
3-C
6The C that-Heterocyclylalkyl replaces
1-C
6-alkyl,
X representative-NH-,
R
1The C that representative is randomly replaced by halogen in identical or different mode in one or more positions
1-C
4-alkyl,
R
2Represent hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, cyano group or C
1-C
6The C that-alkoxyl group replaces
1-C
6-alkyl or C
1-C
6-alkynyl,
R
3And R
4Represent independently of one another hydrogen or the representative randomly in one or more positions in identical or different mode by halogen, hydroxyl, C
3-C
6-Heterocyclylalkyl, C
1-C
6That-hydroxy alkoxy base replaces or by group-NR
3R
4The Ca that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl group ,-CO-C
1-C
6-alkyl or aryl, wherein said Heterocyclylalkyl itself randomly can be interrupted by one or more nitrogen, oxygen and/or sulphur atom, and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring, and wherein said C
3-C
6-heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by cyano group, halogen, C
1-C
6-alkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyl group, C
3-C
6-cycloalkyl substituted or by group-NR
3R
4Or-CO-NR
3R
4Replace,
Or
R
3And R
4The common C that forms
3-C
6-heterocycloalkyl ring, its be interrupted at least once by nitrogen and randomly in one or more positions by oxygen or sulphur is interrupted and/or in ring randomly can by one or more-C (O)-or-SO
2-group is interrupted and/or randomly can comprises one or more pairs of keys in ring,
And/or described heterocycloalkyl ring itself randomly can be in one or more positions in identical or different mode by C
1-C
6-alkyl, C
3-C
6-cycloalkyl, C
1-C
6-hydroxyalkyl, C
1-C
6-alkoxyalkyl, cyano group, hydroxyl replace or by group-NR
3R
4Replace, and
R
6Representation hydroxy or C
1-C
6-alkoxyl group.
4. according to compound and solvate, hydrate, steric isomer, diastereomer, enantiomer and the salt of each general formula I in the claim 1 to 3, wherein:
Q represents phenyl,
A and B represent hydrogen, halogen, hydroxyl, methoxyl group or pyrrolidyl independently of one another,
X representative-NH-,
R
1Represent ethyl,
R
2Represent ethyl or proyl.
5. according to the compound of each general formula I in the claim 1 to 4, it is selected from: 2-cyano group-N-ethyl-2-[3-ethyl-4-oxo-5-[1-(4-tetramethyleneimine-1-base phenyl) methylene-(Z)-and yl] thiazolidine-(2Z)-and subunit] ethanamide, 2-cyano group-N-ethyl-2-[3-ethyl-5-[1-(3-hydroxy phenyl) methylene-(Z)-yl]-4-oxo thiazolidine-(2Z)-subunit] ethanamide, 2-cyano group-N-ethyl-2-[3-ethyl-5-[1-(4-hydroxy phenyl) methylene-(Z)-yl]-4-oxo thiazolidine-(2Z)-subunit] ethanamide, 2-[5-[1-(4-bromophenyl) methylene-(Z)-yl]-3-ethyl-4-oxo thiazolidine-(2Z)-subunit]-2-cyano group-N-ethyl acetamide, 2-cyano group-N-ethyl-2-[3-ethyl-5-[1-(4-hydroxy 3-methoxybenzene base) methylene-(Z)-yl)-4-oxo thiazolidine-(2Z)-subunit] ethanamide, 2-cyano group-N-ethyl-2-[3-ethyl-5-[1-(3-p-methoxy-phenyl) methylene-(Z)-yl]-4-oxo thiazolidine-(2Z)-subunit] ethanamide, 2-cyano group-2-[3-ethyl-5-[1-(3-hydroxy phenyl) methylene-(Z)-yl]-4-oxo thiazolidine-(2Z)-subunit]-N-Propargyl ethanamide, 2-cyano group-2-[3-ethyl-5-[1-(4-hydroxy phenyl) methylene-(Z)-yl]-4-oxo thiazolidine-(2Z)-subunit]-N-Propargyl ethanamide, 2-cyano group-2-[3-ethyl-5-[1-(4-hydroxy 3-methoxybenzene base) methylene-(Z)-yl]-4-oxo thiazolidine-(2Z)-subunit]-N-Propargyl ethanamide, 2-cyano group-2-[3-ethyl-4-oxo-5-[1-(4-tetramethyleneimine-1-base phenyl) methylene-(Z)-yl] thiazolidine-(2Z)-subunit]-N-Propargyl ethanamide, 2-cyano group-2-[3-ethyl-5-[1-(3-nitrophenyl) methylene-(Z)-yl]-4-oxo thiazolidine-(2Z)-subunit]-N-Propargyl ethanamide, 2-cyano group-2-[3-ethyl-5-[1-(3-hydroxy phenyl) methylene-(Z)-yl]-4-oxo thiazolidine-(2Z)-subunit]-N-(2-hydroxyl-1, the 1-dimethyl ethyl) ethanamide, 2-cyano group-2-[3-ethyl-5-[1-(3-p-methoxy-phenyl) methylene-(Z)-yl]-4-oxo thiazolidine-(2Z)-subunit]-N-(2-hydroxyl-1, the 1-dimethyl ethyl) ethanamide and 2-cyano group-2-[3-ethyl-5-[1-(3-nitrophenyl) methylene-(Z)-yl]-4-oxo thiazolidine-(2Z)-subunit]-N-(2-hydroxyl-1,1-dimethyl ethyl) ethanamide.
6. preparation is according to the method for the compound of the general formula (I) of claim 1, wherein with the carboxylic acid of general formula (3):
Compound reaction with general formula (3 '):
R
2-XH
(3′)；
Thereby provide the compound of general formula (I):
Its Chinese style (3), (3 ') and (I) in substituent R
1, R
2, A, B, Q and X be according to claim 1 definition.
7. according to the method for claim 6, wherein pass through the allyl ester of saponification general formula (2) in the presence of tetrakis triphenylphosphine palladium and barbituric acid:
The carboxylic acid for preparing described general formula (3), the substituent R in its Chinese style (2)
1, A, B and Q be according to claim 1 definition.
8. according to the method for claim 7, wherein pass through thiazolidone with general formula (1):
Aldehyde with general formula (1 '):
Condensation prepares the allyl ester of described general formula (2), the substituent R in its Chinese style (1) and (1 ')
1, A, B and Q be according to claim 1 definition.
9. preparation is according to the method for the compound of the general formula (I) of claim 1, wherein with the thiazolidone of general formula (5):
Aldehyde with general formula (1 '):
Condensation, thus the compound of general formula (I) is provided:
Its Chinese style (5), (1 ') and (I) in substituent R
1, R
2, A, B, Q and X be according to claim 1 definition.
10. according to the method for claim 9, wherein pass through carboxylic acid with general formula (4):
Compound with general formula (3 '):
R
2-XH
(3′)；
Reaction prepares the thiazolidone of described general formula (5), the substituent R in its Chinese style (4) and (3 ')
1, R
2With X is to define according to claim 1.
11., wherein pass through the thiazolidone of saponification general formula (1) in the presence of tetrakis triphenylphosphine palladium and barbituric acid according to the method for claim 10:
The carboxylic acid for preparing described general formula (4), the substituent R in its Chinese style (1)
1For what define according to claim 1.
12. according to the compound of each general formula I in the claim 1 to 5 or be used to prepare the purposes of the medicament of treatment cancer, autoimmune disorder, the alopecia of chemotherapeutics inductive and mucositis, cardiovascular disorder, transmissible disease, ephrosis, chronic and acute neurodegenerative disease and virus infection according to the compound that each obtains in the claim 6 to 11.
13. according to the purposes of claim 12, wherein cancer is defined as solid tumor and leukemia; Autoimmune disorder is defined as psoriatic, alopecia and multiple sclerosis; That cardiovascular disorder is defined as is narrow, arteriosclerosis and restenosis; Transmissible disease is defined as the disease that caused by unicellular parasite; Ephrosis is defined as glomerulonephritis; Chronic neurodegenerative disease is defined as Heng Tingdunshi disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS dementia and alzheimer's disease; The acute neurodegenerative disease is defined as cerebral ischemia and neurotrauma; And virus infection is defined as giant cells infection, bleb, B-mode and hepatitis C and HIV disease.
14. a medicament, it is characterized in that its comprise at least a according in the claim 1 to 5 each or compound by obtaining according to each method in the claim 6 to 11.
15. according to the medicament of claim 14, it is used for the treatment of cancer, autoimmune disorder, cardiovascular disorder, transmissible disease, ephrosis, neurodegenerative disease and virus infection.
16. according in the claim 1 to 5 each or according to each obtains in the claim 6 to 11 compound or according to the medicament of claim 14 or 15, it combines with the formula material and/or the vehicle that are fit to.
17. according in the claim 1 to 5 each or compound by the general formula I that obtains according to each method in the claim 6 to 11 or according to the medicament of claim 14 or 15 purposes as polar body sample kinase inhibitor.
18. according to the purposes of claim 17, wherein said kinases is Plk1, Plk2, Plk3 or Plk4.
19. according in the claim 1 to 5 each or according to the compound of the general formula I that each obtains in the claim 6 to 11 be used in the intestines, the purposes of the pharmaceutical dosage forms of parenteral and oral administration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10200502010.5 | 2005-04-25 | ||
| DE102005020105A DE102005020105A1 (en) | 2005-04-25 | 2005-04-25 | New thiazolidinone compounds are polo-like kinase inhibitors, useful for the preparation of medicament to treat e.g. cancer, autoimmune disease, cardiovascular disease stenosis and infection disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101208317A true CN101208317A (en) | 2008-06-25 |
Family
ID=36693046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800228878A Pending CN101208317A (en) | 2005-04-25 | 2006-04-24 | New thiazolidinones without basic nitrogen, their production and use as pharmaceutical agents |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1874744A1 (en) |
| JP (1) | JP2008538756A (en) |
| KR (1) | KR20080005971A (en) |
| CN (1) | CN101208317A (en) |
| AU (1) | AU2006239444A1 (en) |
| BR (1) | BRPI0610832A2 (en) |
| CA (1) | CA2605760A1 (en) |
| DE (1) | DE102005020105A1 (en) |
| IL (1) | IL186747A0 (en) |
| MX (1) | MX2007013306A (en) |
| NO (1) | NO20076038L (en) |
| RU (1) | RU2007143513A (en) |
| WO (1) | WO2006114334A1 (en) |
| ZA (1) | ZA200710147B (en) |
Cited By (1)
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|---|---|---|---|---|
| WO2023004994A1 (en) * | 2021-07-28 | 2023-02-02 | 中国医科大学附属第一医院 | Marker in hiv and/or siv-infected cell and application of marker |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014069434A1 (en) * | 2012-10-30 | 2014-05-08 | カルナバイオサイエンス株式会社 | Novel thiazolidinone derivative |
| JP6480629B1 (en) * | 2018-08-07 | 2019-03-13 | キッコーマン株式会社 | Recombinant production method of glucose dehydrogenase |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD147241A1 (en) * | 1979-11-21 | 1981-03-25 | Klaus Peseke | PROCESS FOR THE PREPARATION OF FURANDERIVATES |
| DD267492A1 (en) * | 1987-12-01 | 1989-05-03 | Univ Rostock | PROCESS FOR THE PREPARATION OF THIAZOLIDINE DERIVATIVES |
| US20060079503A1 (en) * | 2002-05-03 | 2006-04-13 | Schering Aktiengesellschaft | Thiazolidinones and the use therof as polo-like kinase inhibitors |
| US20040092561A1 (en) * | 2002-11-07 | 2004-05-13 | Thomas Ruckle | Azolidinone-vinyl fused -benzene derivatives |
-
2005
- 2005-04-25 DE DE102005020105A patent/DE102005020105A1/en not_active Ceased
-
2006
- 2006-04-24 MX MX2007013306A patent/MX2007013306A/en not_active Application Discontinuation
- 2006-04-24 JP JP2008507025A patent/JP2008538756A/en active Pending
- 2006-04-24 CA CA002605760A patent/CA2605760A1/en not_active Abandoned
- 2006-04-24 CN CNA2006800228878A patent/CN101208317A/en active Pending
- 2006-04-24 EP EP06742815A patent/EP1874744A1/en not_active Withdrawn
- 2006-04-24 RU RU2007143513/04A patent/RU2007143513A/en unknown
- 2006-04-24 WO PCT/EP2006/004226 patent/WO2006114334A1/en active Application Filing
- 2006-04-24 AU AU2006239444A patent/AU2006239444A1/en not_active Abandoned
- 2006-04-24 BR BRPI0610832-6A patent/BRPI0610832A2/en not_active Application Discontinuation
- 2006-04-24 KR KR1020077027261A patent/KR20080005971A/en not_active Application Discontinuation
-
2007
- 2007-10-18 IL IL186747A patent/IL186747A0/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023004994A1 (en) * | 2021-07-28 | 2023-02-02 | 中国医科大学附属第一医院 | Marker in hiv and/or siv-infected cell and application of marker |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2007013306A (en) | 2007-12-13 |
| IL186747A0 (en) | 2008-02-09 |
| ZA200710147B (en) | 2009-08-26 |
| AU2006239444A1 (en) | 2006-11-02 |
| RU2007143513A (en) | 2009-06-10 |
| BRPI0610832A2 (en) | 2010-07-27 |
| DE102005020105A1 (en) | 2006-10-26 |
| EP1874744A1 (en) | 2008-01-09 |
| NO20076038L (en) | 2008-01-16 |
| KR20080005971A (en) | 2008-01-15 |
| WO2006114334A1 (en) | 2006-11-02 |
| CA2605760A1 (en) | 2006-11-02 |
| JP2008538756A (en) | 2008-11-06 |
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