Heterocyclic inhibitors of glycogen synthase-kinase gsk-3

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to using compounds represented by the general formula (II): wherein Ra and Rb are chosen independently from hydrogen atom, alkyl, cycloalkyl, aryl (optionally substituted with a group chosen from alkyl, halogen atom and alkoxy-group), -(Z)n-aryl (optionally substituted with a group chosen from alkyl, halogen atom and alkoxy-group), -(Z)nC(O)OR3; Z is chosen independently from -C(R3)(R4)-; R3 and R4 are chosen independently from hydrogen atom, alkyl and 6-membered cycle with nitrogen atom as a heteroatom; n has values 0, 1 or 2; X and Y are chosen independently from =O, =S and =N(R3). These compounds are active component in preparing a pharmaceutical composition designated in treatment of diseases wherein glycogen synthase-kinase 3-beta (GSK-3) is involved. Also, invention relates to compounds represented by the general formula (II) wherein Ra is chosen from -CH2Ph, -CH2CO2Et, 4-OMePh, 4-MePh and 4-BrPh; Rb is chosen from Me and -CH2CO2Et; X and Y represent =O. Also, invention relates to a pharmaceutical composition possessing GSK-3-inhibitory activity and containing compound of the general formula (II) as an active component. Invention provides using heterocyclic inhibitors of glycogen synthase-kinase-3β.

EFFECT: valuable biochemical and medicinal properties of inhibitors.

17 cl, 5 tbl, 5 ex

 

The scope of the invention

The present invention relates to inhibitors of enzymes and, more specifically, to a heterocyclic inhibitors of glycogen synthase kinase 3β, GSK-3.

The Foundation of the inventions

Alzheimer's disease (AD) is a neurodegenerative process characterized by disorders of consciousness, associated with a progressive deterioration of cholinergic function and neuropathological lesions, such as senile plaques formed fibrillar β-amyloid, and neurofibrillary plexus, bundles of paired helical filaments.

Generally speaking, the AD is limited to the group over 60 years of age or more and is the most common cause of dementia in the older population. Today, AD struck 23 million people worldwide. As longevity increases, there is estimated that by 2050 the number of cases of AD may increase more than threefold [Amaduci, L.; Fratiglioni, L., "Epidemiology of AD: Impact on the treatment, in Alzheimer's Disease: Therapeutic Strategies, E.Giacobini and R.Becker, Eds., Birhäuser, EEUU, 1994, p.8].

In the brain of patients with AD, there are two major histological abnormalities associated with loss of neurons, neurofibrillary plexus and senile plaques in the intracellular and extracellular levels, respectively ["Alzheimer's Disease: From molecular biology to therapy", E.Giacobini and R.Becker, Eds., Birhäuser, EEUU, 1996].

Neurofibrillary plexus before the represent patterns, educated paired helical fibers (PHFs). They consist mainly of protein associated with microtubules (MAP) Tau in abnormal hyperphosphorylation [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-associated protein tau. A component of the Alzheimer's paired helical filaments", J. Biol. Chem., 1986, 261, 6084-6089; Greenberg, S.G.; Davies, P.; Schein, J.D.; Binder, L.L., "Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau", J. Biol. Chem., 1992, 267, 564-569]. This abnormal phosphorylation of Tau, which is determined by the actions of various protein kinases and phosphatases, apparently, is consistent with its ability to bind and stabilize microtubules, and this may contribute to the pathology of AD [Moreno, F.J.; Medina, M.; Perez, M.; Montejo de Garcini, E.; Avila, J., "Glycogen sintase kinase 3 phosphorylation of different residues in the presence of different factors: Analysis of tau protein", FEBS Lett., 1995, 372, 65-68]. Thus, blockade of this stage of hyperphosphorylation may be the main target at which to interrupt the pathogenic cascade. Selective inhibitors of Tau kinases can be effective new drugs to treat AD.

The search for inhibitors of Tau kinases is a very interesting area. Tau can be phosphorylated by several polynaphthalene by protein kinases (PDKs) and non-PDKs. Though the AD when the exact role of each of these kinases in the abnormal hyperphosphorylation Tau still not understood, and have not found a way to regulate the activity of these kinases. There is no doubt that glikogensintetazy kinase (GSK-3β) is in vivo Tau kinase in the brain [Lovestone, S.; Hartley, C.L., Pearce, J.; Anderton, B.H., "Phosphorylation of tau by glycogen syntase-3 in intact mammalian cells: the effect on the organization and stability of microtubules", Neuroscience, 1996, 73, 1145-1157; Wagner, U.; Utton, M.; Gallo, J.M.; Miller, C.C., "Cellular phosphorylation of tau by GSK-3β influences tau binding to microtubules and microtubule organisation", J. Cell. Sci., 1996, 109, 1537-1543; Ledesma, M.; Moreno, F.J.; Perez, M.M.; Avila, J., "Binding of apolipoprotein E3 to tau protein: effects on tau glycation, tau phosphorylation and tau-microtubule binding in vitro, Alzheimer's Res., 1996, 2, 85-88]. These findings opened the way for the use of inhibitors of GSK-3β as therapeutic agents in the treatment of AD. At the moment we know only a few compounds with this property of inhibition of enzymes. Lithium behaves as a specific inhibitor of a family of GSK-3β in vitro and in intact cells [Muñoz-Montaño, J.R.; Moreno, F.J.; Avila, J.; Diaz-Nido, J., "Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons", FEBS Lett., 1997, 411, 183-188].

Finally, we discovered that insulin inactivates GSK-3βand it is shown that upon activation of this enzyme is developing non-insulin-dependent diabetes mellitus. Thus, inhibitors of GSK-3β to become a new drug for non-insulin-dependent diabetes mellitus.

Applicants have discovered a new family of small synthetic heterocyclic molecules with GSK-3β inhibited the relevant properties at micromolar concentrations.

Description of the invention

The invention is directed to compounds represented by the General formula I:

where:

A represents-C(R1)2-, -O-, or-NR1-;

E represents-NR1or CR1R2-and the substituent R2no, ifis a second bond between E and G;

G represents-S-, -NR1or CR1R2-and the substituent R2no, ifis a second bond between E and G;

may be a second bond between E and G, if the nature E and G admits it, and then E and G do not necessarily form a condensed aryl group;

R1and R2independently selected from hydrogen, alkyl, cycloalkyl, halogenoalkane, aryl, (Z)n-aryl, heteroaryl, -OR3, -C(O)R3, -C(O)OR3, -(Z)n-C(O)OR3and-S(O)tor, as indicated, R2can be so, what then E and G form a condensed aryl group;

Z is independently selected from-C(R3)(R4)-, -C(O)-, -O-, -C(=NR3)-, -S(O)t-, -N(R3)-;

n is zero, one or two;

t is zero, one or two;

R3and R4independently selected from hydrogen, alkyl, aryl and heterocycle; and

X and Y independently are selected from =O, =S, =N(R3) and C(R 1)(R2).

Detailed description of the invention

The following terms used in this description and the attached claims are, unless otherwise specified, the specified values:

"Alkyl" refers to hydrocarbon radicals with a straight or branched chain consisting of carbon atoms and hydrogen, containing no unsaturation, having from one to eight carbon atoms, which is attached to the rest of the molecule by a single bond, for example, stands, ethyl, n-propylene, isopropyl, n-butile, tert-butile, n-pentile, etc. Alkyl radicals may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio.

"Alkoxy" refers to a radical of the formula-ORawhere Rarepresents an alkyl radical, as defined above, such as methoxy, ethoxy, propoxy, etc.

"Alkoxycarbonyl" refers to a radical of the formula-C(O)ORawhere Rarepresents an alkyl radical, as defined above, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl etc.

"Alkylthio" refers to a radical of the formula-SRawhere Rarepresents an alkyl radical, as defined above, such as methylthio, is tilty, property etc.

"Amino" refers to a radical of the formula-NH2.

"Aryl" refers to phenyl or naftalina the radical, preferably by phenyl radical. The aryl radical may be optionally substituted by one or more substituents selected from the group consisting of hydroxy, mercapto, halogen, alkyl, phenyl, alkoxy, halogenoalkane, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as they are defined here.

"Aralkyl" refers to an aryl group attached to the alkyl group. Preferred examples include benzyl and phenethyl.

"Acyl" refers to a radical of the formula-C(O)-Rcand-C(O)-Rdwhere Rcrepresents an alkyl radical, as defined above, and Rdrepresents aryl radical, as defined above, such as acetyl, propionyl, benzoyl, etc.

"Areilly" refers to an alkyl group, substituted-C(O)-Rd. Preferred examples include benzoylmethyl.

"Carboxy" refers to a radical of the formula-C(O)HE.

"Cyano" refers to a radical of the formula-CN.

"Cycloalkyl" refers to a stable 3 to 10-membered monocyclic or bicyclic the radical, which is saturated or partially saturated and which consists of carbon atoms and hydrogen. Unless otherwise expressly stated in the description, the assumption is that the term "cycloalkyl", includes cycloalkyl radicals, which are optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halogen, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl.

"Condensed aryl" refers to aryl group, in particular phenyl or herereally group condensed with a five-membered ring.

"Halogen" refers to bromo, chloro, iodide or fluorescent.

"Halogenated" refers to the alkyl radical, as defined above, which is substituted by one or more groups of halogen, as defined above, such as trifluoromethyl, trichloromethyl, 2,2,2-triptoreline, 1-vermeil-2-veratile etc.

"Heterocycle" refers to a heterocyclic radical. A heterocycle refers to a stable 3 to 15-membered ring which consists of carbon atoms and 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably, 4 to 8-membered ring with one or more heteroatoms, more preferably, to a 5-6-membered ring with one or more heteroatoms. For the purposes of this invention, the heterocycle may be monocyclic, bicyclic or tricyclic ring system, which may include a condensed ring system; an atom of nitrogen, carbon or sulfur in heterocyclic is an organic radical can be, optionally oxidized, the nitrogen atom can be optionally and stereoselectivity; heterocyclic radical may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepine, benzimidazole, benzothiazole, furan, isothiazol, imidazole, indole, piperidine, piperazine, purine, chinolin, thiadiazole, tetrahydrofuran. The heterocycle may be optionally substituted by R3or R4as defined above in the brief description of the invention.

"Heteroaryl" refers to aromatic heterocycle.

"Mercapto" refers to a radical of the formula-SH.

"Nitro" refers to a radical of the formula-NO2.

The invention, in particular, focused on the enzymatic activity of the compounds of General formula I against kinases.

And preferably selected from-C(R1)2- , and-NR1-.

Preferably R1selected from hydrogen, alkyl, cycloalkyl, aryl (optionally substituted by a group selected from alkyl, halogen and alkoxy), -C(R3)(R4)-aryl (the aryl part is optionally substituted by a group selected from alkyl, halogen and alkoxy), -OR3, -C(O)OR3and-C(R3)(R4)-C(O)OR3and R3and R4independently selected from hydrogen and alkyl.

The number of groups n is preferably zero or one, and n can b shall be chosen in accordance with known chemistry of possible groupings.

X and Y preferably represent oxygen or sulfur, at least one of X and Y represents oxygen.

A particularly preferred class of compounds are the compounds of formula (II):

where Raand Rbindependently selected from hydrogen, alkyl, cycloalkyl, halogenoalkane, aryl, (Z)n-aryl, heteroaryl, -OR3, -C(O)R3, -C(O)OR3, -(Z)n-C(O)OR3and-S(O)tand Z, n, t, R3, R4X and Y are as defined above.

In the formula (II) X and Y are preferably selected from oxygen, sulfur and-NR3-where R3represents a heterocycle, in particular a 6-membered heterocycle having one heteroatom which is a nitrogen, which is optionally aromatic and optionally oxidized or quarternions. More preferably X and Y are oxygen.

Preferably Raand Rbindependently selected from hydrogen, alkyl, cycloalkyl, aryl (optionally substituted by a group selected from alkyl, halogen and alkoxy), -C(R3)(R4)-aryl (the aryl part is optionally substituted by a group selected from alkyl, halogen and alkoxy), -OR3, -C(O)OR3and-C(R3)(R4)-C(O)OR3and R3and R4independently selected from hydrogen, alkyl and heterocyclic compounds.

More predpochtitel is but R aand Rbindependently selected from alkyl, aryl (optionally substituted by a group selected from alkyl, halogen and alkoxy), -CH2-aryl (the aryl part is optionally substituted by a group selected from alkyl, halogen and alkoxy, and-CH2-C(O)OR3and R3represents hydrogen or alkyl.

Even more preferably Raand Rbindependently selected from methyl, ethyl, propyl, benzyl, phenyl (optionally substituted by a group selected from methyl, fluorescent, chloro, bromo and methoxy) and CH2-C(O)-O-ethyl.

The most preferred compounds of formula (II) are listed below in table 1.

Table 1
RaRbXY
CH2PhMeOO
EtMeOO
PhMeOO
CH2CO2EtMeOO
4-OMePhMeOO
4-MePhMeOO
4-BrPhMeOO
4-FPhM OO
4-ClPhMeOO
CH2PhCH2PhOS
PhPhOS

Another preferred class of compounds according to the invention are the compounds of formula (III):

in which:

B is-NR7or C(R7)(R8)- (where R7and R8independently selected from hydrogen, alkyl, aryl, -CH2-W-aryl, and-W-CO2H, and W represents a simple bond, CH2or CO);

R5and R6independently selected from hydrogen, alkyl, aryl, and-CH2-aryl; and

X and Y independently are selected from =O and =s

In the formula (III) B preferably represents-NR7-where R7selected from hydrogen, alkyl, and-CH2-aryl, in particular hydrogen, methyl or benzyl.

R5and R6preferably represent hydrogen.

X and Y preferably represent oxygen.

The most preferred compounds of formula (III) are listed below in table 2.

Table 2
BXYR5R6
NHO OHH
N-CH2PhOOHH
NMeOOHH
CH2OOHH

Examples of additional classes of compounds of formula I include those compounds in which:

a) A represents-CH2-; E represents-CR1R2-, preferably-CH2-; G represents-CR1R2-, preferably-CH2-;

b) A represents-CH2-; E represents-CR1-, preferably-CH-; G represents-CR1-, preferably-CH -;is the second link between G and E;

c) A represents-O-; E is-CR1-, preferably-CH-; G represents-CR1-, preferably-CH-; and -- represents a second connection between G and E;

(d) A is-NR1-where R1preferably represents hydrogen, alkyl or aralkyl; E represents-CR1-, preferably-CH-; G represents-CR1-, preferably-CH -;is the second link between G and E;

(e) A is-NR1-where R1preferably represents hydrogen or aralkyl; E represents-CR1R2-, preferably-CH 2-; G represents-CR1R2-, preferably-CH2-;

f) A is-NR1-where R1preferably represents hydrogen or aralkyl; E represents-CR1-; G represents-CR1-;represents a second bond between E and G, and E with G form a condensed aryl group, preferably phenyl group;

g) A is-NR1-where R1preferably represents hydrogen, alkyl, carboxylic, areilly or aralkyl; E is S; G is C(R1)2-, preferably-CH2-;

h) A is-NR1-where R1preferably represents aryl; E is-NR1-where R1preferably represents hydrogen or alkyl; G is-NR1-where R1preferably represents hydrogen or alkyl.

In these classes of compounds X and Y, preferably, both are About, although for a class g) X can represent Oh, and Y may be s When E with G form a condensed phenyl group, the resulting compounds are derivatives of phthalimide.

The synthesis of compounds according to the invention

Compounds according to the invention can be synthesized by the available methods.

For the preferred compounds of the formula (II) General method described in [Martinez, A.; Castro, A.; Cardelus, I. Llenas, J.; Palacios, J.M., Bioorg. Med. Chem., 1997, 5, 1275-1283].

Specifically, compounds of General formula (II), collected in table 1, were prepared by following the synthesis procedure presented in figure 1, and using the ability of N-alkyl-S-[N'-chlorocarbonyl)amino]socioterritorial to react with various alkylsulfonate. Chlorination isothioscyanates carried out by adding an equimolar amount of chlorine to the hexane solution mentioned isothiocyanate at -15°C. the Reaction formed aminoformaldehyde with alkyl - or arylisocyanates in the atmosphere of inert gas and subsequent hydrolysis to give thiadiazolidine described in table 1.

Scheme 1

Typical compounds of the present invention selectively inhibit GSK-3βnot through the inhibition of other protein kinases, such as PKA, PKC, CK-2 and Cdk2, which allows you to avoid the common side effects. GSK-3β involved in the etiopathogenesis of AD and is responsible for the anomalous hyperphosphorylated Tau protein. Disclosed here are selective inhibitors may be useful therapeutic agents in the treatment of neurodegenerative diseases associated with abnormal Tau protein, particularly when AD that is part of this invention. The inhibitory activity of these compounds against GSK-3β leads to development, in addition to the TV, can stop the formation of neurofibrillary plexus, one of the characteristic features present in this neurodegenerative process.

These compounds may be useful in the treatment of other pathologies involving GSK-3βsuch as non-insulin-dependent diabetes mellitus.

Additionally, these compounds may be used in the treatment of hyperproliferative diseases, such as dysplasia and metaplasia of various tissues, psoriasis, atherosclerosis, restenosis and cancer by inhibition of the cell cycle, which is part of this invention.

Accordingly, the present invention further provides pharmaceutical compositions comprising compounds according to this invention together with a pharmaceutically acceptable carrier or diluent. Suitable dosage forms and dose can be designed and selected in accordance with the usual practice.

Examples

Example 1. Inhibition of enzymes by compounds according to the invention

Inhibition of GSK-3β: the Activity of GSK-3β defined, incubare mixture of the enzyme GSK-3β (Sigma), source of phosphate and substrate GSK-3β in the presence and in the absence of the test compound, and determining the GSK-3β the activity of this mixture.

Specifically, the activity of GSK-3β was determined by incubation of EN zymes is and at 37° C for 20 minutes in a final volume of 12 μl of buffer (50 mm Tris, pH of 7.5, 1 mm EDTA, 1 mm EGTA, 1 mm DTT, 10 mm MgCl2), supplemented with 15 μm (final concentration) of synthetic peptide GS 1 [Woodget, J.R. "Use of peptides for affinity purification of protein-serine kinases", Anal. Biochem., 1989, 180, 237-241] as the substrate, 15 μm ATP, 0.2 µsi_32p]ATP and various concentrations of the test compounds. The reaction was suppressed by the introduction of aliquots of the reaction mixture at phosphocellulose D81 leaves. These sheets are washed three times with 1% phosphoric acid and determine the radioactivity associated with GS1 peptide in a liquid scintillation counter.

Compounds shown in table 1, are represented by the compounds according to the invention, with GSK-3 inhibitory activity. These IR50(the concentration at which reach 50% inhibition of enzyme are summarized in table 3 below.

Table 3

RaRbXYIR50(µm)
CH2PhMeOO1
EtMeOO5
EtNPrOO10
EtcyclohexylOO10
PhMeOO2
CH2CO2EtMeOO5
4-OMePhMeOO5
CH2PhEtOO7
EtiPrOO35
CH2PhEtOS6
CH2PhCH2PhOS10
PhPhOS20
EtEtOS20
CyclohexylMeOO>100
4-MePhMeOO5
4-BrPhMeOO3
4-FPhMeOO4
4-ClPhMeOO4
EtMeO>100
EtEtO>100
EtHO>100
MeMeO>100
EtMeO>100
EtMeO>100
EtMeO>100
EtMeS10

Inhibition of GSK-3: Experiments on inhibition were also conducted at various concentrations of ATP (50 μm), and in all cases were obtained the same values IR50. Therefore, we can assume that thiadiazolidine do not compete with ATP binding c GSK-3.

The first four compounds were tested for inhibition of other enzymes.

Inhibition of protein kinase A (PKA): Potential is ingibirovanie this enzyme was assessed by determining the phosphorylation of astatine protein kinase A (PKA). Astatin was purified following the procedure described Belmont and Mitchinson (Belmont, L.D.; Mitchinson, T.J., "Identification of a protein that interact with tubulin dimers and increase the catastrophe rate of microtubule", Cell, 1996, 84, 623-631).

Specifically, used purified PKA (Sigma, catalytic subunit from bovine heart (p. 2645)and 10-15 μg of substrate (astatin) in 25 ál total volume of buffer solution containing 20 µm (γ-32p) ATP. Protein cAMP kinase (100 ng/reaction) was prepared in 50 μl of 25 mm HEPES, pH of 7.4, 20 mm MgCl2, 2 mm EGTA, 2 mm dithiothreitol, 0.5 mm Na3VO4. After the reaction, was added quenching buffer, the reaction mixture was heated at 100aboutC for 5 minutes, and phosphorylated protein was characterized by gel electrophoresis, were determined by quantitative autoradiography.

Under these conditions, none of the tested compounds did not show any inhibition of PKA.

Inhibition of protein kinase C (PKC): Potential inhibition of this enzyme was assessed by determining the phosphorylation of peptide PANKTPPKSPGEPAK (Woodgett, J.R., "Use of peptides for affinity purification of protein-serine kinases", Anal. Biochem., 1989, 180, 237-241) protein kinase C (PKC), using phosphatidylserine as a stimulating agent. The methodology used was the same as described above for GSK-3.

Specifically, used purified PKC from rat brain, following the procedure described by Walsh (Walsh, M.P.; Valentine, K.A.; Nagi, P.K.; Corruthers, C.A.; Hollenberg, M.D. Biochem. J., 1984, 224, 117-127) and 1-10 mm substrate in a total volume of 25 µl adequate buffer solution containing 10 µm (γ-32p) ATP.

Under these conditions, none of the tested compounds did not show any inhibition of PKC.

Inhibition caseinline 2 (CK-2): Fosforiliruyusciye activity of this enzyme against astatine was measured using purified CK-2 from bovine brain by following the procedure described Alcazar (Alcazar, A.; Marin, E.; Lopez-Fando, J.; Salina, M., "An improved purification procedure and properties of casein kinase II from brain, Neurochem. Res., 1988, 13, 829-836), with 3.6 µm substrate in a total volume of 25 µl adequate buffer solution containing 20 µm (γ-32p) ATP. Experiments with CK-2 was performed, using as substrate astatin (see the definition of PKA) in 50 ml HEPES, pH of 7.4, 20 mm MgCl2, 2 mm EGTA, 2 mm dithiothreitol, 0.5 mm Na3VO4. After the reaction, followed the same methodology described for PKA.

Under these conditions, none of the tested compounds did not show any inhibition of CK-2.

Inhibition of cyclin-dependent protein kinase 2 (Cdc2): Fosforiliruyusciye activity of this enzyme against histone H1 was measured using dc2 (Calbiochem)following the method described by Kobayashi (Kobayashi, H.; Stewart, E.; Poon, R.Y.; Hunt, T., "Cyclin A and cyclin B dissociate from p34cdc2 with half-times of 4 and 15 h, respectively, regardless of the phase of the cell cycle," J. Biol. Chem., 1994, 269, 29153-29160), with 1 μg/μl substrate in a total volume of 25 µl adequate superoperator, containing 20 µm (γ-32p) ATP. Experiments with Cdc2 conducted c by histone H1 as a substrate (see definition PKA) in 50 μl of buffer pH 7.5, 50 mm Tris-HCl, 10 mm MgCl2, 1 mm DTT, 1 mm EGTA, 100 μm ATP, 0.01% of BRIJ-35. After the reaction, followed the same methodology described for PKA.

Under these conditions, none of the tested compounds did not show any inhibition of Cdc2.

Example 2. Analysis of axon growth after treatment drug connection

Cells were kept in an environment of Dulbecco (DEMEM) with 10% fetal bovine serum, glutamine (2 mm) and antibiotics. To analyze the potential of inhibiting GSK-3 in vivo used culture for neuroblastoma mouse N2A (Garcia-Perez, J.; Avila, J.; Diaz-Nido, J., "Lithium dosage morphological differentiation of mouse neuroblastoma", J. Neurol. Res., 1999, 57, 261-270). These cell cultures were added compound. This cell line has the ability to Express a certain kind of neural phenotype (long neurites) after the addition of lithium chloride (10 mm), a known inhibitor of GSK-3. After 2-3 days of cultivation examined the influence of the tested compounds listed in table 1. Were discovered elongated neurites in the same degree as adding lithium. This fact confirms the inhibition of GSK-3 in vivo the compounds according to the invention.

Example 3. Blockade of the cell cycle

Simultaneously investigated the sweat is nsaline the interaction of these compounds with the cell cycle in cells of the N 2A. cell Culture was kept in the environment of Dulbecco (DEMEM) with 10% fetal bovine serum, glutamine (2 mm) and antibiotics.

The first four compounds of General formula I, are shown in table 3, were tested under the described circumstances, and has shown the ability to inhibit the cell cycle at a concentration in the range from 100 nm to 1 μm. Cell blockade began to occur at concentrations between 100 and 200 nm and was completely effective at 1 micron.

Tested compounds are non-toxic in stationary culture of fibroblasts MRC-5 after 10 days of continuous exposure to inhibitors.

Example 4. Inhibition of GSK-3 additional connections

Data on the inhibition of GSK-3

Table 4
FamilyIR50(µm)
and>100
b12
c
dR-H

R=CH2Ph

R=Me
6

1

5
eR=H; X, Y=O

R=CH2Ph; X, Y=O

R=CH2Ph; X=O; Y=H
>100

>100

>100
fR=H

R=CH2Ph
>100

>100
gR=H

R=Me

R=CH2CO2H

R=CH2Ph

R=CH2CH2Ph

R=CH2COPh
>100

>100

>100

25

35

50
hR=H

R=Me
>100

>100

Inhibitors of GSK-3: compounds belonging to the family of D, we also conducted experiments on the inhibition of GSK-3 at various concentrations of ATP (50 μm), and in all cases were obtained the same values IR50. Therefore, it can be assumed that these compounds do not compete with ATP for binding to c GSK-3.

Example 5. Blockade of the cell cycle

IR50for some compounds, defined on cell cultures N2A, are collected in table 5 below.

Table 5
RaRbXYIR50 (µm)
CH2PhMeOO4-8
EtMeOO40-100
EtnPrOO5-10
EtcyclohexylOO6-9
PhMeOO4-7
CH2CO2EtMeOO1-2
4-OMePhMeOO1-2
CH2PhEtOO4-7
CH2PhCH2PhOO2-3
EtEtOO30-80
CH2PhCH2PhOS1-2
PhPhOS4-8

"DETERMINATION of CYTOTOXICITY LDH (LDH)"

The aim of the experiment was to determine whether the cytotoxic effects in cells of the human neuroblastoma SH-SY5Y extract from seaweed or synthetic compounds is ormula (II), in particular, through the quantification of lactate dehydrogenase activity lactate dehydrogenase (LDH).

Lactate dehydrogenase (LDH) is a stable cytoplasmic enzyme present in all cells. When the destruction of cell membranes, it is rapidly released into the supernatant of culture medium. The activity of LDH determine enzymatic test: in the first stage, NAD* restored to NADH/H4" by LDH-catalyzed conversion of lactate to pyruvate. At the second stage catalyst (diaphorase) transfers H/H+ from NADH/H* tetrazolium salt INT, which is restored to formazan. Thus, the number of formed dye in the course of the experiment is proportional to the number lidirovavshy cells. Salt formazan is water-soluble and has a broad absorption band with a maximum around 500 nm, whereas tetrazolium salt INT not shown any significant absorption at this wavelength.

Reagents:

minimum essential medium Needle (MEM), ref: 31095-029 (Gibco)

nutrient mixture HAM''S F12, ref: 21765-029 (Gibco)

non-essential amino acids, ref: 11140-035 (Gibco)

Penicillin-streptomycin, ref: 15140-122 (Gibco)

L-glutamine, ref: 2S030-024 (Gibco)

fetal calf serum (FBS), ref: DE14-801F (INNOGENETICS Bio/Whittaker Europe)

Triton X-100, ref:1086031000 (WRR International)

Kit for determination of cytotoxicity, rf: 1644793 (Roche)

Drip multidimensi 384 (Thermo Lab Systems)

Digital scanning tablet-ELISA reader (ASYS HITECH GmbH)

The original solutions:

- Solution of the synthetic compounds retain at 4°or -20°C.

- The reagent kit Kit 1 (a mixture of diaphorase/NAD*) is stored at -20°C. After recovery up to 1 ml with distilled water and stored at 4°C and is stable for several weeks.

- A set of reagents Kit 2 (iodometrically chloride, INT, and sodium lactate) store at -20°C. After thawing stored at 4°C and is stable for several weeks.

- Cultural medium (Hams F12):MEM (1:1), 10% FBS, nonessential amino acids Ix, L-glutamine Ix and Penicillin-streptomycin (Ix) stored at 4°C.

- Triton X-100 1% in Krebs-Hepes stored at room temperature.

TECHNIQUE:

For two or three days before the start of the experiment, cells human neuroblastoma SH-SY5Y seeded in 96-well microplate for cultivation on 104cells/well.

The medium is removed and cells incubated with different samples of examinees compounds at various concentrations for 24 hours of the Synthesized compounds was tested at a final concentration of 10-5, 10-6and 5×10-8M, depending on the activity in fresh culture medium.

After 24 hours the medium is removed and cells are lysed, and attach the I to the bottom of the wells by adding 50 μl of Krebs-Hepes, Triton X-100 1%, for 5 minutes at room temperature. For a quantitative estimation of lactate dehydrogenase activity lactate dehydrogenase (LDH) lysate incubated for 30 minutes with 50 μl of the reaction mixture (1:45) kit for determination of cytotoxicity, with 15-25°protected from light. Lactate dehydrogenase (LDH) was measured by absorbance 492 nm with a standard wavelength of 620 nm (standard wavelengths exceed 600 nm).

The results of cytotoxicity obtained for a number of compounds of the formula (II), showed their high efficiency.

INFORMATION CONCERNING POSSIBLE USE IN VARIOUS DISEASES:

Alzheimer's DISEASE:

One of the hallmarks of this disease is a specific type of degeneration of neurons in which Tau protein associated with microtubules abnormally hyperphosphorylated, causing rupture of the network of microtubules.

Widely known is the fact that GSK-3 beta is one of the enzymes directly involved in the anomalous hyperphosphorylated Tau. See, for example, the following materials:

- "Tau is phosphorytated by GSK-3 at several sites found in Alzheimer's disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase" Febs Lett. 1998, 436, 28-34.

Cm. summary.

- "Inhibition of tau phosphorylation: a new therapeutic strategy for the treatment of Alzheimer's disease and other neurodegenerative disorders".

Exp. Opin. Ther. Patents.

2000 10(10).

Cm. page 2, right column.

- "Inhibition of cyclin-dependent kinases, GSK#x002DC; 3b and CK1 by hymenialdisine, a marine sponge constituent".

Chem. Biol. 2000751-63.

Cm. "Introduction".

- "Decreased nuclear B-catenin, tau hyperphosphorylation and neurodegeneration in GSK-SV conditional transgenic mice".

EMBO 2001 20(1-2)27-39.

Cm. summary.

- Alzheimer's disease - like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells.

Curr. Biol. 19944(12) 1077-1086.

Cm. "Justification".

- "Expression, purification and crystallization of human tail-protein kinase l/glycogen synthase kinase-3 beta".

Acta Crystallogr D 2000 56 1464-1465.

Cm. "Introduction".

DIABETES

Diabetes observed elevated levels of GSK-3 beta, and thus argues that the use of inhibitors of GSK-3 is a reasonable approach to the treatment of diabetes. For example, "Potential Role of Glycogen Synthase Kinase-3 in Skeletal Muscle Insulin Resistance of Type 2 Diabetes", Diabetes 2000 49 263-271, indicate that diabetes is associated with increased activity of GSK-3 (see summary and str, last paragraph - 796, begin left column). Indeed, when describing the usefulness of inhibitors of GSK-3 States that "such compounds can be used in diseases associated with increased activity of GSK-3, such as diabetes and neurodegenerative disease" (str, right column, second paragraph "Discussion").

According to the "Purification of GSK-3 by Affinity Chromatography on Immobilized Axin", Protein Expr. Purif. 2000 20(3) 394-404, GSK-3 directly involved in the mechanism of diseases such as diabetes. On str, left column, it is indicated that "the involvement of GSK-3 in the various mechanisms for the of olivani, such as cancer, Alzheimer's disease, HIV-induced neurotoxicity or diabetes demonstrates the urgent need for active search and selection of inhibitors of GSK-3". In "Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene reduced", Chem. Biol. 2000 7(10) 793-803, indicated that the development of inhibitors of GSK-3 may be useful when used in the treatment of conditions associated with increased activity of GSK-3, such as non-insulin-dependent diabetes" (see str, "Conclusions"; str, last line; str, the second paragraph of the "discussion"; 800 pages, last row).

HYPERPROLIFERATIVE DISEASES: CANCER, DYSPLASIA, AND METAPLASIA TISSUE, PSORIASIS, ATHEROSCLEROSIS, RESTENOSIS:

It is known that GSK-3 is involved in the mechanism of many physiological processes, including regulation of the cell cycle; thus, it is known that GSK-3 is involved in the overall mechanism hyperproliferative diseases, although the most studied, the most common and severe is cancer. However, the relationship between hyperproperties and GSK-3 is still not fully clear.

So, for example, in "Indirubins Inhibit Glycogen Synthase Kinase-3 beta and CDK5/P25, Two Protein Kinases Involved in Abnormal Tau Phosphorylation in Alzheimer's Disease", J. Biol. Chem. 2001 276(1) 251-260, the postulated relationship between inhibitors of GSK-3 and anti-tumor properties, although the mechanism and their role is not completely clear. Indirubin known for its antitumor its the problem and is a strong inhibitor of GSK-3 (see str, left column). The same correlation is observed for other antitumor compounds (see str.257, right column). This may be due to the fact that GSK-3 is involved in the mechanism of many physiological processes, including cell cycle regulation (see str, left column). In "Purification of GSK-3 by Affinity Chromatography on Immobilized Axin", Protein Expr. Purif. 2000 20(3) 394-404, confirmed that GSK-3 is involved in the mechanism of cancer (see Abstract); indeed, States that "the involvement of GSK-3 in the mechanism of various diseases, such as cancer, [...] indicates the urgent need for active search and selection of inhibitors of GSK-3" (str, left column).

The PHARMACEUTICAL COMPOSITION

The present invention also concerns farmcampsite, including a connection according to this invention, together with a pharmaceutically acceptable carrier, excipient or diluent for administration to a patient.

Examples of farmcampsite include any solid (tablets, pills, capsules, granules, etc.) or liquid form (solutions, suspensions or emulsions) formulations for oral, local or parenteral administration.

The preferred form for oral administration. Suitable forms for oral administration are tablets and capsules containing the usual carriers such as binding agents, nab the emer syrup, gum acacia, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricating agents for tableting, for example magnesium stearate; dezintegriruetsja means, for example starch, polyvinylpyrrolidone, starch nitroglycol or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium laurylsulfate.

Solid forms for oral administration can be obtained by conventional methods of blending, filling or tableting. The procedures for re-mixing can be used to distribute the active ingredient in the whole volume of the composition when using large quantities of fillers. Techniques are common in this area. So, for example, tablets can be obtained by wet or dry granulation and need not be covered, in particular, intersolubility the floor.

Farbkomposition can be used for parenteral administration, for example, in the form of sterile solutions, suspensions or liofilizovannyh products in the form of a corresponding standard dose. Can be used with suitable fillers, buferiruemoi agents or surfactants.

Introduction compounds and compositions according to the invention can be any acceptable for this form of str is obom, such as intravenous infusion, oral, intraperitoneal and intravenous. Oral introduction it is most preferable because it is most convenient for the patient because of the chronic nature of the diseases, which shows their introduction.

Typically, the effective amount of the introduced compound depends on its relative efficiency, the gravity and nature of the condition being treated and the weight of the patient. However, usually the connection is administered once or up to 4 times per day at a standard dose of 0.1 to 1000 mg/kg/day.

The compounds and compositions according to the invention can be used with other drugs in combination therapy. A different medication may be introduced into the same or a different composition or administered separately, either simultaneously or at different times.

The General scheme of the synthesis of 1,2,4-thiadiazolidin-3,5-diones:

Chlorine is slowly bubbled through a solution of the aryl or alkyl of isothiocyanate in dry hexane (25 ml), under nitrogen atmosphere at -15°-10°C. Chlorine was obtained by addition of 35% HCl to KMnO4. The reaction temperature was carefully controlled during the addition. At this stage, the formed N-aryl or N-alkyl-S-chloroisocyanurate. Then add the alkyl isocyanate. The mixture is stirred at room temperature for 8 to 10 h, after which the obtained product was then purified by filtration with suction and Perekrest what lisala or column chromatography on silica gel using a suitable eluent. In some cases it is possible to obtain 5-oxo-1,2,4-thiadiazolidin-3-thione as a by-product.

Synthesis and physico-chemical data specific compounds of the invention:

4-Benzyl-2-methyl-1,2,4-thiadiazolidin-C,5-dione.

Reagents: the Benzyl isothiocyanate (0,86 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4(0.5 g), methyl isocyanate (0,38 ml, 6.5 mmol). Conditions: room temp., 8 o'clock Allocation (1): filtering the reaction mixture. Purification: recrystallization from hexane. Yield: 0.75 g (35%) as a white solid; temp. pl. 60-61°C.1H-NMR (CDCl3): 3,2 (s, 3H, CH3); and 4.8 (s, 2H, CH2-Bn) ; 7,31 was 7.45 (m, 5H, arom.).13C-NMR (CDCl3): of 31.4 (CH3); 46,0 (CH2-Bn) 128,2; of 128.6; 128,8; 135,1 (arom.); 155, 2mm (3-C=O); 165,6 (5-C=O). Analysis. (C10H10N2SO2) C, H, N, S.

4-(Ethoxycarbonylmethyl)-2-methyl-1,2,4-thiadiazolidine-3,5-dione

Reagents: Ethyl isothiocyanatobenzene (0.8 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4(0.5 g), methyl isocyanate (0,38 ml, 6.5 mmol). Conditions: room temp., 8 PM Selection: filtering the reaction mixture. Purification: recrystallization from hexane. Yield 0.28 g (20%) as a white solid; temp. pl. 67-69°C.1H-NMR (CDCl3): 1,3 (t, 3H CH2CO2CH2CH3, J=7,1 Hz); 3,2 (s, 3H, CH3); to 4.2 (s, 2H, CH2CO2CH2CH3, J=7,1 Hz); 4,4 (s, 2H, CH2CO2CH2CH3).13C-NMR (CDCl3): 14,0 (CH2CO2CH2CH 3); 31,5 (CH3); 42,7 (CH2CO2CH2CH3) ; 62,1 (CH2CO2CH2CH3) ; 152,6 (3-C=O); 166,4 (5-C=O); 166,4 (CO2). Analysis. (C7H10N2SO3) C, H, N, S.

(4-methoxyphenyl)-2-methyl-1,2,4-thiadiazolidine-3,5-dione.

Reagents: 4-Methoxyphenylacetylene (0,89 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4(0.5 g), methyl isocyanate (0,38 ml, 6.5 mmol). Conditions: room temp., 8 PM Selection: filtering the reaction mixture. Purification: recrystallization from CH2Cl2/hexane. Output: 0,44 g (30%) as a white solid; temp. pl. 140-144°C.1H-NMR (CDCl3): and 3.31 (s, 3H, CH3); of 3.80 (s, 3H, p-CH3O-Ph); 7,02-to 7.32 (m, 4H, arom.).13C-NMR (CDCl3): 31,7 (CH3); 55,5 (p-CH3O-Ph); 114,7; 125,3; 128,5; 159,9 (With arom.); 152,9 (3-C=O); 165,5 (5-C=O). Analysis. (C10H10N2SO3) C, H, N, S.

4-(4-were)-2-methyl-1,2,4-thiadiazolidine-3,5-dione.

Reagents: 4-methylphenothiazine (0,88 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4(0.5 g), methyl isocyanate (0,38 ml, 6.5 mmol). Conditions: room temp., 6 PM Selection: filtering the reaction mixture. Purification: recrystallization from CH2Cl2/hexane. Output: 0.29 grams (21%) as a white solid; temp. pl. 182-184°C.1H-NMR (CDCl3): of 2.4 (s, 3 h, p-CH3-Ph); of 3.25 (s, 3H, CH3); 7,20-7,34 (m, 4H, arom.).13C-NMR (CDCl3): 21,1 (R-CH3-Ph); 31,7 (CH3); 126,7; 130,0; 130,3; 139,3 (With arom.); 152,9 (3-C=O); 165,3 (5-C=O). Analysis is. (C10H10N2SO2) C, H, N, S.

4-(Ethoxycarbonylmethyl)-2-(ethoxycarbonylmethyl)-1,2,4-thiadiazolidin-3,5-dione.

Reagents: Ethylisothiocyanate (0.8 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4(0.5 g), utilizationfocused (0,73 ml, 6.5 mmol). Conditions: room temp., 9 o'clock Allocation: the evaporation of the solvent. Purification: column chromatography on silica gel using eluent AcOEt/hexane (1:3). Yield: 0.90 g (48%) as a white solid; temp. pl. 72-74°C.1H-NMR (CDCl3): a 1.25 (t, 3H, CH2CO2CH2CH3, J=7,1 Hz); 1.26 in (t, 3H, CH2CO2CH2CH3, J=7,1 Hz); 4.18 (s, 2H, CH2CO2CH2CH3, J=7,1 Hz); 4,20 (s, 2H, (CH2CO2CH2CH3, J=7,1); 4,3 (s, 2H, CH2CO2CH2CH3); and 4.4 (s, 2H, CH2CO2CH2CH3).13C-NMR (CDCl3): 14,0 (CH2CO2CH2CH3); 14,0 (CH2CO2CH2CH3); 42,7 (CH2CO2CH2CH3); 45,6 (CH2CO2CH2CH3); 62,1 (CH2CO2CH2CH3); 62,1 (CH2CO2CH2CH3); 153,0 (3-C=O); 165,7 (5-C=O); 166,1 (CH2CO2CH2CH3); 166,8 (CH2CO2CH2CH3). Analysis. (C10H14N2SO6) C, H, N, S.

4-(4-Bromophenyl)-2-methyl-1,2,4-thiadiazolidine-3,5-dione.

Reagents: 4-Bromonicotinate (1.4 g, 6.5 mmol), 35% HCl (3.1 ml, KMnO4(0.5 g), methyl isocyanate (0,38 ml, 6.5 mmol). Conditions: room temp., 9 o'clock Selection: filtering the reaction mixture. Purification: recrystallization from hexane/CH2Cl2; yield 0.32 g (20%) as a white solid; temp. pl. 182-184°C.1H-NMR (CDCl3): of 3.25 (s, 3H, CH3); 7,25-to 7.61 (2d, 4H, arom., J=8.6 Hz).13C-NMR (CDCl3): 31,6 (CH3); 123,0; 128,6; 131,6; 132,5 (With arom.); 153,4 (3-C=O); 165,7 (5-C=O). Analysis. (C9H7N2SO2Br) C, H, N, S.

1. The use of compounds represented by the General formula (II):

where Raand Rbindependently selected from

hydrogen, alkyl, cycloalkyl, aryl (optionally substituted by a group selected from alkyl, halogen and alkoxy), (Z)n-aryl (optionally substituted by a group selected from alkyl, halogen and alkoxy), -(Z)n-C(O)OR3,

Z is independently selected from-C(R3)(R4)-;

R3and R4independently selected from hydrogen, alkyl, aryl and 6-membered cycle with a nitrogen atom as a heteroatom;

n is zero, one or two;

X and Y independently are selected from =O, =S, =N(R3),

as the active ingredient for a pharmaceutical composition intended for the treatment of diseases involving glycogen synthase kinase 3-beta (GSK-3), when y is the condition that the compound of formula II is different from the following:

RaRbXY
CH2PhMeOO
CH2CO2EtCH2CO2EtOO
CH2CO2EtMeOO
4-OMePhMeOO
4-MePhMeOO
4-BrPhMeOO

2. The use of claim 1, wherein the disease is Alzheimer's disease.

3. The use according to claim 1, in which the disease is non-insulin dependent diabetes mellitus.

4. The use of claim 1, wherein the disease is selected from hyperproliferative diseases such as cancer, dysplasia or metaplasia tissue, psoriasis, arteriosclerosis or restenosis.

5. The use according to any one of claims 1 to 4, where in the compound II Raand Rbindependently selected from hydrogen, alkyl, cycloalkyl, aryl (optionally substituted by a group selected from alkyl, fluorine, chlorine, bromine and alkoxy), -C(R3)(R4)-aryl (the aryl part is optionally substituted by a group selected from alkyl, fluorine,chlorine, bromine and alkoxy), and-C(R3)(R4)-C(O)OR3and R3and R4independently selected from hydrogen, alkyl and 6-membered cycle with a nitrogen atom as a heteroatom.

6. The use according to claim 5 where in the compound II, Ra and Rbindependently selected from alkyl, aryl (optionally substituted by a group selected from alkyl, fluorine, chlorine, bromine and alkoxy), -CH2-aryl (the aryl part is optionally substituted by a group selected from alkyl, fluorine, chlorine, bromine and alkoxy), and-CH2-C(O)OR3and R3represents hydrogen or alkyl.

7. The use according to claim 6, where in the compound II Raand Rbindependently selected from methyl, ethyl, propyl, benzyl, phenyl (optionally substituted by a group selected from methyl, fluorine, chlorine, bromine and methoxy), and CH2-C(O)-O-ethyl.

8. The use according to claims 1, 3 or 4, in which the connection II, X and Y are independently selected from =O, =S or =NR3(where R3is a 6-membered cycle with a nitrogen atom as a heteroatom).

9. The use of claim 8, where in the compound II X is =O.

10. The use according to claim 9, where in the compound II X is =O and Y is =O.

11. The use according to any one of claims 1 to 4, where in the compound II

Raand Rbindependently selected from hydrogen, alkyl, cycloalkyl, aryl (optionally substituted by a group selected from alkyl, fluorine, chlorine, bromine and al is hydroxy), -C(R3)(R4)-aryl (the aryl part is optionally substituted by a group selected from alkyl, fluorine, chlorine, bromine and alkoxy), -C(R3)(R4)-C(O)OR3,

R3and R4independently selected from hydrogen, alkyl and 6-membered cycle with a nitrogen atom as a heteroatom, and

X and Y independently are selected from =O, =S or =NR3.

12. The application of claim 11, where in the compound II

Raand Rbindependently selected from hydrogen, alkyl, cycloalkyl, aryl (optionally substituted by a group selected from alkyl, fluorine, chlorine, bromine and alkoxy), -C(R3)(R4)aryl (which aryl part is optionally substituted by a group selected from fluorine, chlorine, bromine and alkoxy), C(R3)(R4)-C(O)OR3, R3and R4independently selected from hydrogen and alkyl, and X is =O.

13. The application indicated in paragraph 12, where the compound II:

Raand Rbindependently selected from methyl, ethyl, propyl, benzyl, phenyl (optionally substituted by a group selected from methyl, fluorine, chlorine, bromine and methoxy), and CH2-C(O)-O-ethyl;

X is =O;

Y is =O.

14. The use according to claims 1-4, where the compound II are as follows:

RaRbXY
EtMeOO
EtnPrOO
EtcyclohexylOO
PhMeOO
CH2PhEtOO
EtiPrOO
CH2PhEtOS
CH2PhCH2PhOO
EtEtOS
cyclohexylMeAboutO
EtMeO
EtEtO
EtHO
MeMeO
EtMeO
EtMeO
Ete O
EtMeS

15. The application 14, where the compound II are as follows:

RaRbXY
EtMeOO
PhMeOO

16. Compounds represented by the General formula (II):

where

RaRbXY
CH2PhMeOO
CH2CO2EtCH2CO2EtOO
CH2CO2EtMeOO
4-OMePhMeOO
4-MePhMeOO
4-BrPhMeOO

17. Pharmaceutical composition having GSK-3 inhibitory activity containing as the active ingredient compound, defined in any one of claims 1 to 16.

Priorities on items and features:

12.12.2000 - the compounds of formula (II)in which Raand Rbselected from -(Z')n-C(O)OR3; R3and R4selected from the "heterocycle"; 11.05.2000 - other options.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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18 cl, 138 tbl, 527 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

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7 cl, 2 tbl, 59 ex

FIELD: organic chemistry, herbicides.

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18 cl, 24 tbl, 106 ex

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12 cl, 1 tbl, 13 dwg, 5 ex

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33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, chemical technology, medicine, endocrinology.

SUBSTANCE: invention relates to a method for preparing an antidiabetic agent pioglitazone of the formula (I): . Method involves condensation of 4-substituted phenol or phenolate of the general formula (II): wherein R represents organic radical comprising amino-group and chosen from group comprising group of the general formula: -NHRa (IIa) wherein Ra means hydrogen atom or protective group that is removed before the following treatment, and group of the general formula: wherein Rb represents carboxyl group as free acid or as salt or ester; M represents hydrogen atom or alkaline metal with pyridine base of the general formula (III): wherein Z means a removing group distinguishing from halogen atom and wherein the following steps are carried out: (a) diazotization reaction of amino-group as a moiety of organic radical R; (b) conversion of diazotized radical R to derivative of 2-halogenpropionate or 2-halogenpropionitrile of the formula: wherein Rb is determined above; X represents halogen atom; (c) cyclization of derivative of 2-halogenpropionate or 2-halogenpropionitrile with thiourea, and (d) hydrolysis of imine prepared. In case when R represents group of the formula (IIa) method involves firstly carrying out the condensation reaction followed by carrying out steps (a)-(d) to obtain agent of the formula (I); or in case when R represents group of the formula (IIb) then method involves firstly carrying out steps (a)-(d) followed by condensation with pyridine base of the general formula (III) to obtain agent of the formula (I). Also, invention describes compounds of the formula (V): wherein Ra represents a protective group chosen from group comprising acyl, n-alkoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-cyanoethoxycarbonyl as an intermediate substance in synthesis of compound of the formula (I).

EFFECT: improved preparing method of agent.

12 cl, 5 ex

The invention relates to cavemosum derivative of formula (1) with a broad spectrum of antibacterial activity against different species of pathogenic bacteria, including MRSA

< / BR>
where X Is N or CY and Y denotes H or halogen; R1is amino or a protected amino group; R2is hydrogen or optionally substituted (ness.)alkyl; R3denotes hydrogen or lower alkyl; R4indicates Bogoroditse optionally substituted (NISS

The invention relates to aryl - and getelemen carboalkoxylation acids of formula 1

< / BR>
where R1selected from the group of arrow or getarrow, R2selected from the group of Akilov

The invention relates to new heterocyclic substituted phenoxyacetamide, methods for their preparation and use as a means protivodiareynogo

The invention relates to a new above-mentioned compounds, method of their production and the means of containing this compound, useful for combating fungi and insect pests

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

7 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

17 cl, 14 tbl, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

11 cl, 2 tbl, 27 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

EFFECT: improved method for treatment, valuable medicinal properties of compounds and composition.

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

wherein R represents the group:

m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

EFFECT: improved preparing method, improved methods for treatment, valuable medicinal properties of compounds and composition.

20 cl, 283 ex

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