CN101045715A - Heterocycle inhibitor for glycogen synthase kinase gsk-3 - Google Patents

Heterocycle inhibitor for glycogen synthase kinase gsk-3 Download PDF

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CN101045715A
CN101045715A CNA2007101010104A CN200710101010A CN101045715A CN 101045715 A CN101045715 A CN 101045715A CN A2007101010104 A CNA2007101010104 A CN A2007101010104A CN 200710101010 A CN200710101010 A CN 200710101010A CN 101045715 A CN101045715 A CN 101045715A
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gsk
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阿纳·马丁内斯希尔
阿纳·卡斯特罗莫雷尔
马里亚·康塞普西翁·佩雷斯马丁
梅塞德斯·阿隆索·卡斯科
伊莎贝尔·多龙索罗·迪亚斯
弗朗西斯科·何塞·莫雷尼奥穆尼奥斯
弗朗西斯科·万德奥塞尔胡拉多
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    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/395—Saturated compounds containing a keto group being part of a ring of a five-membered ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

Compounds of formula (I) where A, E, G, X, Y, and the bond --- take various meanings are of use in the preparation of a pharmaceutical formulation, for example in the treatment of a disease in which GSK-3 is involved, including Alzheimer's disease or the non-dependent insulin diabetes mellitus, or hyperproliferative disease such as cancer, displasias or metaplasias of tissue, psoriasis, arterosclerosis or restenosis.

Description

The heterocycle inhibitor of glycogen synthase kinase GSK-3-3
Invention field
The present invention relates to enzyme inhibitors, more specifically, relate to Glycogen Synthase kinase 3 β, the heterocycle inhibitor of GSK-3.
Background of invention
Alzheimer's disease (AD) is a kind of neurodegenerative process, it is characterized by and the relevant cognitive disorders of the progressive degeneration of cholinergic function, with the damage of the neuropathology that forms by the fibril amyloid beta as senile plaque and the neurofibrillary tangles that forms by the vascular bundle of paired spiral fibril.Usually, AD is limited in the age group more than 60 years old or 60 years old, and the most general reason of normally aged crowd's dementia.Nowadays, AD has worldwide attacked 2,003 million peoples.Along with the increase in life-span, according to estimates to the year two thousand fifty, AD patient's quantity will be above present 3 times.[Amaduci, L.; Fratiglioni, L. " Epidemiology of AD:Impact on thetreatment ", in Alzheimer Disease:Therapeutic Strategies, E.Giacobini and R.Becker, Eds., Birh_user, EEUU, 1994, pp.8].
Two kinds of main, relevant Histological injuries in AD patient's brain, have been found: respectively in cell and the neurofibrillary tangles and the senile plaque [" AlzheimerDisease:From molecular biology to therapy " of extracellular levels with neuron loss, E.Giacobini and R.Becker, Eds., Birh_user, EEUU, 1996].
Neurofibrillary tangles is the structure that is formed by paired spiral fibril (PHFs).They mainly are made up of microtubule-associated protein (MAP) tau under unusual peroxophosphoric acid state.[Grundke-Iqbal，I.；Iqbal，K.；Tung，Y.C.；Quinlan，M.；Wisniewski，H.M.；Binder，L.I.，“Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology”，Proc.Natl.Acad.Sci.USA，1986，83，4913-4917；Grundke-Iqbal，I.；Iqbal，K.；Quinlan，M.；Tung，Y.C.；Zaidi，M.S.；Wisniewski，H.M.，“Microtubule-associatedprotein tau.A component of the Alzheimer paired helical filaments”，J.Biol.Chem.，1986，261，6084-6089；Greenberg，S.G.；Davies，P.；Schein，J.D.；Binder，L.I.，“Hydrofluoric acid-treated tau PHF proteins display thesame biochemical properties as normal tau.”，J.Biol.Chem.，1992，267，564-569]。The unusual phosphorylation of this tau that effect determined by different protein kinases and Phosphoric acid esterase as if to its in conjunction with and the ability of stabilize microtubules causes damage and this may have effect [Moreno, F.J. to the AD pathology; Medina, M.; Perez, M.; Montejo de Garcini, E.; Avila, J., " Glycogen sintase kinase 3 phosphorylation of different residuesin the presence of different factors:Analysis on tau protein ", FEBS Lett., 1995,372,65-68].Therefore, to the blocking-up of this peroxophosphoric acid step, can be an important goal of interrupting pathogenic cascade.The kinase whose selective depressant of tau may become the new active drug of treatment AD.
Research to the tau kinase inhibitor is a very interested field.Protein kinase (PDKs) and non-PDKs phosphorylation that Tau can be instructed by several proline(Pro).But, in AD, still do not know any definite effect in the unusual peroxophosphoric acidization of tau in these kinases, and up to now, do not find that the activity of these enzymes is raised.Undoubtedly, in brain, Glycogen Synthase kinase 3 β (GSK-3 β) is a kind of intravital tau kinases [Lovestone, S.; Hartley, C.L.; Pearce, J.; Anderton, B.H., " Phosphorylation of tau by glycogensynthase-3 in intact mammalian cells:the effects on the organization andstability of microtubules ", Neuroscience, 1996,73,1145-1157; Wagner, U.; Utton, M.; Gallo, J.M.; Miller, C.C., " Cellular phosphorylation oftau by GSK-3 β influences tau binding to microtubules and microtubuleorganisation ", J.Cell.Sci., 1996,109,1537-1543; Ledesma, M.; Moreno, F.J.; Perez, M.M.; Avila, J., " Binding of apolipoprotein E3 totau protein:effects on tau glycation; tau phosphorylation and tau-microtubulebinding, in vitro ", Alzheiiner Res., 1996,2,85-88].These are found to be the GSK-beta inhibitor have been opened wide the gate as the therapeutical agent in the AD treatment.At this moment, has only seldom the known characteristic of compound with this kind of enzyme inhibitor.In external and intact cell, lithium is equivalent to a kind of special inhibitor of protein kinase G SK-3 family.
Figure A20071010101000041
J.R.；Moreno，F.J.；Avila，J.；Diaz-Nido，J.，“Lithium inhibits Alzheimer’sdisease-like tau protein phosphorylation in neurons”，FEBS Lett.，1997，411，183-188]。
At last, discover, Regular Insulin passivation GSK-3, and studies show that because the activation of this kind of enzyme has developed non insulin dependent diabetes.Therefore, the GSK-3 inhibitor will be a kind of new therapy for the treatment of non insulin dependent diabetes.
Our study group's recent findings a kind of little synthesizing heterocyclic molecule new family that has GSK-3 β rejection in micromole's level.
Summary of the invention
The present invention relates to the compound represented with general formula I
Wherein
A is-C (R 1) 2-,-O-or-NR 1-;
E is-NR 1-or-CR 1R 2-, and if---be second key, then substituent R between E and the G 2Do not exist;
G is-S--NR 1-or-CR 1R 2-, and if---be second key, then substituent R between E and the G 2Do not exist;
Second key of---can be between E and the G, this is that the characteristic of E and G allows and E and G randomly form thick aryl subsequently.
R 1And R 2Be independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, aryl ,-(Z) n-aryl, heteroaryl-OR 3,-C (O) R 3,-C (O) OR 3,-(Z) n-C (O) OR 3With-S (O) t-or as pointed, R 2Can be to make E and G form the group of thick aryl subsequently.
Z is independently selected from-C (R 3) (R 4)-,-C (O)-,-O-,-C (=NR 3)-,-S (O) t-, N (R 3)-;
N is 0,1 or 2;
T is 0,1 or 2;
R 3And R 4Be independently selected from hydrogen, alkyl, aromatic base and heterocycle; With
X and Y are independently selected from=O ,=S ,=N (R 3) and=C (R 1) (R 2).
Detailed Description Of The Invention
Unless limit the implication below the term below using has on the contrary in this specification sheets and accessory claim:
" alkyl " refers to the hydrocarbon chain free radical of straight or branching, and these free radicals are made up of carbon atom and hydrogen atom, comprise unsaturation, have 1-8 carbon atom, and be connected on other molecule methyl for example, ethyl, n-propyl by singly-bound, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl or the like.Alkyl diradical can randomly be replaced by one or more substituting groups, and described substituting group independently is selected from halogen, hydroxyl, alkoxyl group, carboxyl, cyano group, carbonyl, acyl group, carbalkoxy, amino, nitro, sulfydryl and alkyl sulfenyl (alkylthio)." alkoxyl group " refers to chemical formula aFree radical, R wherein aBe a kind of alkyl diradical defined above, methoxyl group for example, oxyethyl group, propoxy-or the like
" carbalkoxy " refers to chemical formula aFree radical, R wherein aBe alkyl diradical defined above, methoxycarbonyl for example, ethoxycarbonyl, third oxygen carbonyl or the like.
" alkyl sulfenyl " refers to chemical formula aFree radical, R wherein aBe alkyl diradical defined above, methyl sulfenyl for example, ethyl sulfenyl, propyl group sulfenyl or the like.
" amino " refers to chemical formula 2Free radical.
" aryl " refers to phenyl or naphthyl free radical, preferred phenyl free radical.Ding Yi aryl free radical can randomly be replaced by one or more substituting groups herein, and described substituting group is selected from hydroxyl, sulfydryl, halogen, alkyl, phenyl, alkoxyl group, haloalkyl, nitro, cyano group, dialkyl amido, aminoalkyl group, acyl group and carbalkoxy.
" aralkyl " refers to the aryl that is connected to alkyl.Preferred examples comprises benzyl and styroyl.
" acyl group " refers to chemical formula cWith-C (O)-R dFree radical, R wherein cBe the alkyl diradical of above-mentioned definition, R dBe the aryl free radical of above-mentioned definition, ethanoyl for example, propionyl, benzoyl or the like.
" aroylalkyl " refers to by-C (O)-R dThe alkyl that replaces.Preferred examples comprises the benzoyl methyl.
" carbonyl " refers to the free radical of chemical formula for-C (O) OH.
" cyano group " refers to the free radical of chemical formula for-CN.
" cycloalkyl " refers to monocycle stable, 3-10 unit or dicyclo free radical, and this free radical is saturated or fractional saturation, and only is made up of carbon atom and hydrogen atom.Unless in specification sheets, specify in addition, term " cycloalkyl " intention comprises cyclic alkyl radical, described cyclic alkyl radical is randomly replaced by one or more free radicals, and described free radical independently is selected from alkyl, halogen, hydroxyl, amino, cyano group, nitro, alkoxyl group, carboxyl and carbalkoxy.
" thick aryl " refers to and is thickened to pentacyclic a kind of aryl, particularly phenyl or heterocyclic aryl.
" halogen " refers to bromine, chlorine, iodine, perhaps fluorine.
" haloalkyl " refers to the alkyl diradical of the above-mentioned definition that is replaced by the halo free radical of one or more above-mentioned definition, trifluoromethyl for example, trichloromethyl, 2,2,2-trifluoroethyl, 1-methyl fluoride-2-fluoro ethyl or the like.
" heterocycle " refers to the heterocycle free radical.This heterocycle refers to the first ring of a kind of stable 3-15, this 3-15 unit ring is by carbon atom and the individual nitrogen that is selected from of 1-5, the heteroatoms of oxygen and sulphur is formed, and preferably has the first ring of one or more heteroatomic 4-8, more preferably has one or more heteroatomic 5 yuan of rings or 6 yuan of rings.For the present invention, described heterocycle can be a monocycle, dicyclo or three-ring system, and this system can comprise the fused rings system; And the nitrogen in the heterocycle free radical, carbon or sulphur atom can be randomly oxidized; Nitrogen-atoms can be randomly by quaternized; And the heterocycle free radical can be partly or completely saturated or can be aromatics.These heterocyclic examples include but not limited to azepine, benzoglyoxaline, benzothiazole, furans, isothiazole, imidazoles, indoles, piperidines, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran (THF).Heterocycle can be randomly by the R of definition in the foregoing invention general introduction 3And R 4Replace.
" heteroaryl " refers to aromatic heterocycle.
" sulfydryl " refers to the free radical of chemical formula for-SH.
" nitro " refers to chemical formula 2Free radical.
The present invention be more particularly directed to kinase whose enzymic activity at compound of Formula I.
A is preferably selected from-C (R 1) 2-and-NR 1-.
R preferably 1Be selected from hydrogen, alkyl, cycloalkyl, aryl (randomly be selected from alkyl, the group of halogen and alkoxyl group replaces) ,-C (R 3) (R 4)-aryl (this aryl moiety randomly is selected from alkyl, and the group of halogen and alkoxyl group replaces) ,-OR 3,-C (O) OR 3With-C (R 3) (R 4)-C (O) OR 3, and R 3And R 4Be independently selected from hydrogen and alkyl.
Subscript n preferred 0 or 1, and the possible group that will take known chemical into account is selected n.
X and Y preferred oxygen or sulphur, at least one oxygen preferably of X and Y.
An especially preferred compounds has chemical formula (II).
Figure A20071010101000081
R wherein aAnd R bBe independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, aryl ,-(Z) n-aryl, heteroaryl ,-OR 3,-C (O) R 3,-C (O) OR 3,-(Z) n-C (O) OR 3With-S (O) t-, and Z, n, t, R 3, R 4, X and Y such as above-mentioned definition.
In chemical formula (II), X and Y are preferably selected from oxygen, sulphur and-NR 3-, R wherein 3Be heterocycle, particularly contain 1 and be heteroatomic 6 yuan of heterocycles of nitrogen, optional be aromatics and randomly oxidized or by quaternized.More preferably, X and Y are oxygen.
Preferably, R aAnd R bBe independently selected from hydrogen, alkyl, cycloalkyl, aryl (randomly be selected from alkyl, the group of halogen and alkoxyl group replaces) ,-C (R 3) (R 4)-aryl (this aryl moiety randomly is selected from alkyl, and the group of halogen and alkoxyl group replaces) ,-OR 3,-C (O) OR 3With-C (R 3) (R 4)-C (O) OR 3, and R 3And R 4Be independently selected from hydrogen, alkyl and heterocycle.
More preferably, R aAnd R bIndependently be selected from alkyl, aryl (randomly be selected from alkyl, the group of halogen and alkoxyl group replaces) ,-CH 2-aryl (this aryl moiety randomly is selected from alkyl, and the group of halogen and alkoxyl group replaces) and-CH 2-C (O) OR 3, R wherein 3Be hydrogen or alkyl.
More more preferably, R aAnd R bIndependently be selected from methyl, ethyl, propyl group, benzyl, phenyl (randomly be selected from methyl, fluorine, chlorine, the group of bromine and methoxyl group replaces) and-CH 2-C (O) O-ethyl.
The compound of most preferred chemical formula (II) is listed in the table below in 1.
Table 1
R a R b X Y
CH 2Ph Me O O
Et Me O O
Ph Me O O
CH 2CO 2Et Me O O
4-OMePh Me O O
4-MePh Me O O
4-BrPh Me O O
4-FPh Me O O
4-ClPh Me O O
CH 2Ph CH 2Ph O S
Ph Ph O S
Another kind of preferred compound of the present invention is those compounds of chemical formula (III):
Figure A20071010101000091
Wherein,
B is-NR 7-or C (R 7) (R 8)-(be R wherein 7And R 8Be independently selected from hydrogen, alkyl, aryl, CH 2-W-aryl and-W-CO 2H and W are singly-bounds, CH 2Perhaps CO); R 5And R 6Be independently selected from hydrogen, alkyl, aryl and-CH 2-aryl; And X and Y be independently selected from=O and=S.
In chemical formula (III), B is preferred-NR 7-, R wherein 7Be selected from hydrogen, alkyl and-CH 2-aryl, particularly hydrogen, methyl or benzyl.
R 5And R 6Hydrogen preferably.
X and Y be oxygen preferably.
The compound of most preferred chemical formula (III) is listed in the table below in 2.
Table 2
B X Y R 5 R 6
NH O O H H
N-CH 2Ph O O H H
NMe O O H H
CH 2 O O H H
The example of other classification of the compound of Formula I comprises:
A) A is-CH 2-; E is-CR 1R 2-, preferred-CH 2-; G is-CR 1R 2-, preferred-CH 2-;
B) A is-CH 2-; E is-CR 1-, preferred-CH-; G is-CR 1-, preferred-CH-; And----is second key between G and the E;
C) A is-O-; E is-CR 1-, preferred-CH-; G is-CR 1-, preferred-CR-; And----is second key between G and the E;
D) A is-NR 1-, R wherein 1Preferred hydrogen, alkyl or aralkyl; E is-CR 1-, preferred-CH-; G is-CR 1-, preferred-CH-; And----is second key between G and the E;
E) A is-NR 1-, R wherein 1Be preferred hydrogen or aralkyl; E is-CR 1R 2-, preferred-CH 2-; G is-CR 1R 2-, preferred-CH 2-;
F) A is-NR 1-, R wherein 1Preferred hydrogen or aralkyl; E is-CR 1-; G is-CR 1-;----is second key between E and the G; And E and G formation condensed aryl, preferred phenyl;
G) A is-NR 1-, R wherein 1Be preferred hydrogen, alkyl, carboxyalkyl, aroylalkyl or aralkyl; E is-S; G is-C (R 1) 2-, preferred-CH 2-;
H) A is-NR 1, R wherein 1Preferred aryl groups; E is-NR 1-, R wherein 1Preferred hydrogen or alkyl; G is-NR 1-, R wherein 1Be preferred hydrogen or alkyl.
In the compound of these classifications, although for classification (g), X can be that O and Y can be S, and X and Y preferably are O.When E and G formation condensed phenyl, resulting compound is the phthalimido derivative.
Synthesizing of The compounds of this invention
Can synthesize compound of the present invention by the program that can utilize.
For the compound of preferred chemical formula (II), can use universal program [Martinez, A.; Castro, A.; Cardel ú s, I.; Llenas, J.; Palacios, J.M.Bioorg.Med.Chem., 1997,5,1275-1283].
Particularly; according to the synthesis step of describing in the flow process 1; and utilize N-alkyl-S-[N '-chloro amido formyl radical) amino] reactivity between different thiocarbamyl chlorine and the different alkyl isocyanate, prepare the compound in the chemical formula (II) and be collected in compound in the table 1.By at-15 ℃, the chlorine that adds equimolecular quantity in the hexane solution of above-mentioned lsothiocyanates is carried out the chlorination of lsothiocyanates.Under inert atmosphere, the imino-chlorine alkyl sulfenyl chlorine of formation and the reaction between alkyl or the aryl isocyanate and hydrolysis subsequently produce the thiadiazolidine diketone of describing in the table 1.
Figure A20071010101000121
Flow process 1
Typical compound selectivity of the present invention suppresses GSK-3 β and does not suppress for example PKA of other protein kinase, PKC, and CK-2 and CdK2 may eliminate generally effect to the inhibition of other protein kinase.The cause of disease pathogeny (aetiopathogenesis) of AD relates to GSK-3 β and GSK-3 β is the reason that causes the unusual peroxophosphoric acidization of Protein tau.Selective depressant disclosed by the invention can become the useful treatment preparation of treatment neurodegenerative disease, the especially AD relevant with the pathology of Protein tau, and described selective depressant forms a part of the present invention.These compounds are guiding the design of medicine to the restraining effect of GSK-3 β, and described medicine can stop the formation of neurofibrillary tangles, and described neurofibrillary tangles is one of sign that is present in this neurodegenerative process.These compounds can be used for relating to for example treatment of non insulin dependent diabetes of other pathology of GSK-3 β.
In addition, because the restraining effect of these compound cell cycle, these compounds can be used for the hyper-proliferative disease, and for example psoriasis, arteriosclerosis (artherioschlerosis), restenosis and treatment for cancer are given birth in the displasias and the change of different tissues.
Therefore, the present invention also provides the pharmaceutical composition that comprises a kind of compound of the present invention and pharmaceutical carrier or thinner.According to the practice of routine, can design and adopt suitable formulation and dosed administration ratio.
Embodiment
The enzyme inhibition of embodiment 1-present composition
GSK-3 β suppresses: exists or do not exist under the situation of corresponding test compounds, and by cultivating GSK-3 enzyme (Sigma), the mixture of phosphoric acid salt (ester) source and GSK-3 substrate, and determine the GSK-3 activity by the GSK-3 activity of measuring this mixture.
Particularly, replenishing synthetic peptide GS 1[Woodgett as 15 μ M (final concentration) of substrate, J.R. " Use of peptides for affinity purification of protein-serinekinases ", Anal.Biochem., 1989,180,237-241], 15 μ M ATP, 0.2 μ C j[γ -32P] final volume of ATP and different concns test compounds is damping fluid (50mM tris, pH=7.5,1mM EDTA, 1mM EGTA, 1mM DTT, the 10mM Cl of 12 μ l 2Mg) in, by enzyme was determined the GSK-3 activity in 20 minutes at 37 ℃ of incubations.Come termination reaction by in phosphorylated cotton p81 paper, adding aliquot reaction mixture.These paper are cleaned three times with 1% phosphoric acid, and in liquid scintillation counter, measure the radioactivity that is incorporated in the GS1 peptide.
Compound shown in the table 1 represents that GSK-3 of the present invention suppresses active substance.IC 50(concentration when demonstrating 50% enzyme inhibition) value concentrates in the following table 3.
Table 3
Figure A20071010101000141
Figure A20071010101000151
GSK-3 restraining effect: under variable ATP concentration (until 50 μ M), suppress experiment equally, and all obtained identical IC in all cases 50Value.Therefore infer that the thiadiazolidine diketone does not combine GSK-3 with the ATP competition.
Analyze the restraining effect of preceding four kinds of compounds to other enzyme.
Protein kinase A (PKA) restraining effect: the potential restraining effect of estimating this enzyme by the esthatmine phosphorylation of determining protein kinase A (PKA).Program purifying esthatmine (Belmont, L.D. according to Belmont and Mitchinson description; Mitchinson, T.J. " Identification ofa protein that interact with tubulin dimers and increases the catastrophe rate ofmicrotubule ", Cell, 1996,84,623-631).
Particularly, cumulative volume be 25 μ l, contain 20 μ M (γ -32P) in the damping fluid of ATP, use the PKA (Sigma, catalytic subunit from bovine heart (p2645)) and the 10-15 μ g substrate (esthatmine) of purifying.At the 25mM hepes of 50 μ l, pH 7.4,20mMMgCl 2, 2mM EGTA, 2mM dithiothreitol (DTT), 0.5mM Na 3VO 4The middle cAMP kinase protein (100ng/ reaction) that adds.After reaction takes place, add stop buffer, reactant was boiled under 100 ℃ 5 minutes, with the albumen of gel electrophoresis sign phosphorylation, quantitative with radioautograph.
Under these conditions, there is not a kind of analyzed compound exhibits to go out any restraining effect to PKA.
Protein kinase C (PKC) restraining effect: with phosphatidylserine as stimulant, by determining the phosphorylation of protein kinase C (PKC) to peptide PANKTPPKSPGEPAK, estimate the potential restraining effect (Woodgett of this enzyme, J.R. " Use of peptides for affinitypurification of protein-serine kinases ", Anal.Biochem., 1989,180,237-241).Following method is identical with the above-mentioned method that is used for GSK-3.
Particularly, at cumulative volume be the 10 μ M (γ that contain of 25 μ l -32P) use method (Walsh, the M.P. that describes according to Walsh in enough (adecuated) damping fluids of ATP; Valentine, K.A.; Nagi, P.K.; Corruthers, C.A.; Hollenberg, M.D.Biochem.J., 1984,224, the 117-127) substrate of the PKC of purifying and 1-10mM from rat brain.Under these conditions, there is not a kind of analyzed compound exhibits to go out any restraining effect to PKC.
Casein kinase 2 (CK-2) restraining effect: cumulative volume be 25 μ l enough, contain 20 μ M (γ -32P) use method (Alcazar, the A. that describes according to Alcazar in the damping fluid of ATP; Mar í n, E.; Lopez-Fando, J.; Salina, M. " An improved purification procedureand properties of casein kinase II from brain ", Neurochem.Res., 1988,13,829-836) from the CK-2 of ox brain purifying and the substrate of 3.6 μ M.At the 25mM hepes of 50 μ l, pH 7.4,20mM MgCl 2, 2mM EGTA, 2mM dithiothreitol (DTT), 0.5mM Na 3VO 4With carry out CK-2 with esthatmine as substrate (measuring) among the CK-2 of 100ng purifying and measure referring to PKA.After reaction took place, the method for describing among following step and the PKA was identical.
Under these conditions, there is not a kind of analyzed compound exhibits to go out any restraining effect to CK-2.
Protein kinase 2 (Cdc2) restraining effect that cyclin relies on: cumulative volume be 25 μ l enough, contain 20 μ M (γ -32P) in the damping fluid of ATP, use the method (Kobayashi, the H. that describe according to Kobayashi; Stewart, E.; Poon, R.Y.; Hunt, T. " Cyclin A andcyclin B dissociate from p34cdc2 with half-times of 4and 15h; respectively; regardless of the phase of the cell cycle ", J.Biol.Chem., 1994,269, the substrate of Cdc2 that 29153-29160) obtains (Calbiochem) and 1 μ g/ μ l is measured the phosphorylation activity of this enzyme at histone h1.At the pH 7.5 of 50 μ l, 50mM Tris-HCl, 10mMCl 2Mg, 1mM DTT, 1mM EGTA, 100 μ M ATP in the 0.01%BRIJ-35 damping fluid, carry out Cdc2 with histone 1 as substrate and analyze (measuring referring to PKA).After reaction took place, the method for describing among following step and the PKA was identical.
Under these conditions, there is not a kind of analyzed compound exhibits to go out any restraining effect to Cdc2.
After the embodiment 2-drug treating to the analysis of neurite outgrowth
Cell remained on contain 10% foetal calf serum, in glutamine (2mM) and the antibiotic Dulbecco substratum (DEMEM).In order to analyze potential GSK-3 restraining effect in vivo, use mouse neuroblastoma (neuroblastoms) N 2A culture (Garcia-Perez, J.; Avila, J.; Diaz-Nido, J. " Lithium induces morphological differentiationof mouse neuroblastoma ", J.Neurol. Res., 1999,57,261-270).Test compounds is added in these cell cultures.Adding lithium chloride (10mM), after a kind of known GSK-3 inhibitor, this clone has the characteristic of expressing certain neurone phenotype (aixs cylinder (neuritic) prolongation).Cultivate after 2-3 days, detect the effect that those are collected in the tested compound in the table 1.Found that the generation that aixs cylinder prolongs is more than the prolongation when adding lithium.This fact has confirmed that compound of the present invention is in vivo to the restraining effect of GSK-3.
3. cell cycles of embodiment block
Abreast, at N 2The potential interference effect of these compound cell cycle of research on the A cell.This cell culture remained on contain 10% foetal calf serum, in glutamine (2mM) and the antibiotic Dulbecco substratum (DEMEM).
Under the condition of describing, analyze the preceding 4 kinds of compounds that are collected in the table 3 with general formula (I), the result is presented under the inhibitor concentration of 100nM and 1 μ M and can suppresses the cell cycle.Original observed is blocked to cell under the concentration of 100-200nM, and is in full force and effect under the concentration of 1 μ M.
With after inhibitor continues to contact 10 days, the compound of being tested is nontoxic in immobilized fibroblast cell cultures MRC-5.
The GSK-3 restraining effect of other compound of embodiment 4-
GSK-3 suppresses data
Table 4
Figure A20071010101000181
Figure A20071010101000191
GSK-3 inhibitor:, under (until 50 μ M) under the variable ATP concentration, carry out the experiment of GSK-3 restraining effect equally, and all obtained identical IC in all cases for the compound that belongs to the D of family 50Value.Therefore can infer that these compounds do not combine GSK-3 with the ATP competition.
The embodiment 5.-cell cycle blocks
Some have been collected in the table 5 at N 2The IC of the compound of testing in the A cell culture 50
Table 5
R a R b X Y IC 50(μM)
CH 2Ph Me O O 4-8
Et Me O O 40-100
Et nPr O O 5-10
Et Hexanaphthene O O 6-9
Ph Me O O 4-7
CH 2CO 2Et Me O O 1-2
4-OMePh Me O O 1-2
CH 2Ph Et O O 4-7
CH 2Ph CH 2Ph O O 2-3
Et Et O O 30-80
CH 2Ph CH 2Ph O S 1-2
Ph Ph O S 4-8

Claims (1)

1. compound with general formula (II):
Figure A2007101010100002C1
Wherein said compound is one of following: R a R b X Y CH 2Ph Me O O CH 2CO 2Et Me O O 4-OMePh Me O O 4-MePh Me O O 4-BrPh Me O O
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