Agent for poly(adp-riboso) polymerase inhibition

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is an agent for poly(ADP-riboso)polymerase inhibition. The agent represents 7-methylguanine(2-amino-7-methyl-1H-purin-6(7H)-one)- a purine derivative of formula (I) The agent has shown the efficacy higher than that in 7-methyl-xanthine and is non-toxic for the human body.

EFFECT: agent can be used in treating conditions caused by necrotic cell death: stroke, myocardial ischemia, diabetes and complications thereof, shock, neurotrauma, arthritis, colitis, allergic encephalomyelitis and other inflammations.

1 dwg, 2 ex

 

The invention relates to biochemistry and molecular biology, particularly to a tool for inhibition of the enzyme poly(ADP-ribose)polymerase (PARP) of the person.

PARP is a eukaryotic enzyme regulation of DNA repair. After the activation of PARP in the binding to break the DNA chain is automaticaly and other modification of nuclear proteins by joining ADP-ribose) with further increase of the polymer, which in turn serves as a signal for activation of cellular repair systems. Members of the family of PARP, first of all isoforms of PARP-1 are promising therapeutic target in Oncology, because the functioning of the repair system causes the resistance of cancer cells to chemo - and radiotherapy. Selective interventions aimed at the inhibition of PARP may be used as an accompanying treatment [Jagtap, P., and Szabo, .Poly(ADP-ribose) polymerase and therapeutic effects of its inhibitors. (2005) Nat. Rev. Drug Discov., 4, 421-440]. In addition to the treatment of cancer, PARP inhibitors may also be used in the treatment of pathophysiological conditions caused necrotic cell death, such as stroke, myocardial ischemia, diabetes and its complications, shock, multiple trauma, arthritis, colitis, allergic encephalomyelitis and other forms of inflammation [Virag, L., and Szabo, .therapeutic potential of poly(ADP-ribose) polymerase inhbitors. (2002) Pharmacol. Rev., 54, 375-429].

Many compounds inhibit the activity of PARP in vitro and in vivo in millimolar-micromolar range [Banasik, M., and Ueda, K. Inhibitors and activators of ADP-ribosylation reactions. (1994) Mol. Cell. Biochem., 138, 185-197; Milam, C.M., and Cleaver, J.E. Inhibitors of poly(adenosine diphosphate-ribose) synthesis: effect on other metabolic processes. (1984) Science 223, 589-591]. However, the known inhibitors are either under active and specific for therapeutic use, or not reviewed pharmacokinetics, pharmacodynamics and toxicity. Thus, at the moment, is still relevant to the development of a wide range of active compounds.

Closest to the claimed means for inhibiting PARP, the prototype, is a natural compound, a metabolite of caffeine - 7-methylxanthines [Geraets, L., Moonen, H.J., Wouters, E.F., Bast, A., and Hageman, G.J. Caffeine metabolites are inhibitors of the nuclear enzyme poly(ADP-ribose)polymerase-l at physiological concentrations. (2006) Biochem. PharmacoL, 72, 902-910]. The disadvantages of the prototype is low inhibitory activity against PARP (IC50172 μm in the case of PARP-1).

An object of the invention is the creation of a more effective inhibitor of PARP-based natural purines. The technical result is to reduce the value of the IC50(the concentration of inhibitor at which the enzyme activity is reduced by 50%) when using the created inhibitor compared to the prototype.

Set t the economic problem is solved by that as a means for inhibiting PARP is suggested to use the purine derivative of formula (I), representing a 7-methylguanine (2 - amino - 7 - methyl - 1H - purine - 6(7H)-one).

The proposed connection will get described in the literature method [Jones, J.W., and Robins, R.K. Purine Nucleosides. III. Methylation Studies of Certain Naturally Occurring Purine Nucleosides. (1963) J. Am. Chem. Soc., 85, 1963], which consists in the methylation of the guanosine dimethylsulfate with subsequent hydrolysis of N-glycosidic bonds. The structure and purity of the obtained compounds were confirmed by the data of NMR spectroscopy. Below are examples of implementation of the proposed technical solution.

The invention is illustrated by figure 1, which presents a graph of the dependence of the reaction rate of poly(ADP-ribosyl)financing from the concentration of inhibitor, demonstrating the inhibitory activity of 7-methylguanine against PARP in Example 1.

Example 1. The study of the influence of 7-methylguanine on the activity of PARP-1

Recombinant protein PARP-1 person (EC 2.4.2.30) was obtained by the literature method [Sukhanov M.V., Khodyreva S.N., Lavrik, I. Poly(ADP-ribose)polymerase 1 inhibits DNA synthesis preemptive chain, catalyzed by DNA polymerase R. (2004) Biochemistry, 69, 686-698]. Reaction of poly(ADP-ribosyl)investments carried out under the following conditions: 50 mm Tris-HCl, pH 8.0, 20 mm MgCl2, 150 mm NaCl, 7 mm β, activated DNA (2 PU280/ml, the degree of activation 25%), 0.6 mm [3H]NAD+(isotope dilution 1:500), temperature 37°C. the Reaction was started by addition of PARP-1 to a final concentration of 200 nm and was stopped after 60 seconds, causing the reaction mixture to paper filters (Whatman-1), soaked in 5%trichloroacetic acid. The filters were washed 4 times in 5%THU, then in 90%ethanol (to remove THU) and air-dried. The amount of radioactive label incorporated into acid-insoluble product, were recorded on a scintillation counter QuantaSmart. The determination of the number of radioactively-labeled product was carried out on the initial part of the dependence of the reaction rate from time to time. Activity 7-methylguanine as an inhibitor of PARP-1 was evaluated in the reaction autopole(ADP-ribosyl)investing in the concentration of NAD+equal to 0.6 mm. The concentration of the inhibitor was varied in the range from 1 to 100 μm. The reaction and detection of the products were performed as described above. Figure 1 shows a typical curve of the dependence of the reaction rate autopole(ADP-ribosyl)investments (in arbitrary units proportional to the number of decays in radioactively-labeled product per minute) on the concentration of 7-methylguanine. The value of the IC50for 7 - methylguanine was 30 μm.

Example 2. The study of the influence of 7-methylguanine on the activity of PARP-2

Measurement of inhibitory actively the tee 7-methylguanine against PARP-2 was performed, as described in Example 1. The concentration of the inhibitor was varied in the range from 1 to 100 μm. The value of the IC50for 7-methylguanine was 50 μm.

Thus, 7-methylguanine shows inhibitory activity against PARP-1 - the most important from a therapeutic point of view of the representative of the family of PARP. The value of the IC50(the concentration of inhibitor at which the enzyme activity is reduced by 50%) in the case of PARP-1 is 30 μm, which is 6 times less than for the prototype. In addition, 7-methylguanine inhibits PARP-2 is most similar to PARP-1 isoforms. It should be noted that 7-methylguanine is a metabolite of nucleic acids and is found in biological fluids [Chao, M.R., Wang, C.J., Yang, H.H., Chang, L.W., and Hu, C.W. Rapid and sensitive quantification of urinary N7-methylguanine by isotope-dilution liquid chromatography/electrospray ionization tandem mass spectrometry with on-line solid-phase extraction. (2005) Rapid Commun. Mass Spectrom., 19, 2427-2432], and, therefore, should not have a toxic effect. The proposed connection, 7-methylguanine, can be used to create medicines applicable in clinical medicine, because it is a more effective inhibitor of PARP, than the prototype, and, as a natural metabolite that is not toxic to the human body.

Means for inhibition of the enzyme poly(ADP-ribose)polymerase person representing a purine derivative of formula (I



 

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FIELD: biotechnology.

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2 tbl, 4 ex

FIELD: chemistry.

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2 cl, 3 dwg, 2 tbl, 4 ex

FIELD: chemistry.

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37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: medicine.

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2 cl, 6 tbl, 3 ex

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5 cl

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1 dwg, 6 tbl, 1 ex

FIELD: medicine.

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2 ex, 3 tbl, 8 dwg

FIELD: medicine, pharmaceutics.

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1 ex

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3 cl, 2 ex

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,

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8 cl, 2 tbl, 2 ex, 1 dwg

FIELD: medicine, pharmaceutics.

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25 cl, 9 tbl, 14 dwg

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20 cl, 1 dwg

FIELD: medicine, pharmaceutics.

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33 cl, 12 dwg, 2 tbl, 6 ex

FIELD: medicine.

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16 cl, 3 ex, 14 tbl

FIELD: medicine.

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1 dwg, 7 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to purine compounds of the formula (I):

,

wherein R1 is specified in a group containing H, halogen and C1-C6alkyl, R2 is specified in a group containing H, CN, an optionally substituted C1-C12alkyl, an optionally substituted C3-C12cycloalkyl, an optionally substituted C2-C12heterocycloalkyl, an optionally substituted C6-C18aryl, an optionally substituted C1-C12alkyloxy, COR8, COOH, COOR8, CONR8R9 and acyl; if R2 represents the optionally substituted C6-C18aryl, the above optional substitute is specified in F and CH3; if R2 represents the optionally substituted C1-C12alkyl, the above optional substitute is specified in CH3, OCH3 and O-C(CH3)3; if R2 represents the optionally substituted C3-C12cycloalkyl, the above optional substitute represents CH3; if R2 represents the optionally substituted C2-C12heterocycloalkyl, the above optional substitute is specified in a group consisting of COOC(CH3)3, CO(CH2)2CH3, COPh and CO(5-methylthiophen-2-yl), each R3 and R4 is independently specified in a group containing H, C1-C6alkyl and OR8, R6 is specified in a group containing H, OH, OR8, CH2OH, NH2 and NR8R9, or R8 and R9 if taken together with atoms attached thereto form a cyclic group, each R8 and R9 is independently specified in a group containing H and C1-C12alkyl; each R2 independently represents C1-C6alkyl, q represents an integer specified in a group containing 0 and 1, X represents a group of formula (CR102)m, each R10 is independently specified in a group containing H and C1-C6 alkyl, m represents an integer specified in a group containing 0, 1, 2 and 3, C2-C12heterocycloalkyl contains at least one heteroatom specified in a group containing O, N and S, in at least one ring; each ring is 3- to 10-merous, or their pharmaceutically acceptable salts or N-oxides.

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31 cl, 3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: blood is examined for angiogenic factors, namely soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF). An angiogenic factor (Ka) is calculated by formula: Ka=sFlt-1/PlGF×10. If Ka is 10 or less, the pregnant woman is stated to require no admission to hospital, no case follow-up; doctor's appointments are scheduled. If Ka falls within the range of 10 to 50, the pregnant woman is admitted to hospital, wherein foetal monitoring, Doppler monitoring are performed; an amniotic fluid index (AFI) is calculated; a therapy aiming at the uterine-placental blood flow improvement is prescribed for 10 days. The amount of infusion makes 400 ml a day. The prescribed preparations are Actovegin, Trental, Instenon, Carnitini chloridum. Control ultrasonography, Doppler monitoring, foetal monitoring, AFI and Ka measurements are performed 2 weeks later. The pregnant woman is discharged from hospital if observing no negative trends. If Ka falls within the range of 50 to 100, the pregnant woman is admitted to hospital, wherein foetal monitoring, Doppler monitoring are performed, and AFI is measured; a therapy aiming at the uterine-placental blood flow improvement is prescribed for 14 days The amount of infusion makes 800 ml a day. The prescribed preparations are Actovegin, Trental, Instenon, Carnitini chloridum. Control Doppler monitoring and foetal monitoring are performed every 3 days; 2 weeks later control Ka is measured. If the trend is positive, the pregnant woman may be discharged from hospital, while no positive trend requires another 2 weeks of the therapy. If Ka is 100 or more, but less than 150, the pregnant woman is admitted to hospital, wherein foetal monitoring, Doppler monitoring are performed, and AFI is measured; a therapy aiming at the uterine-placental blood flow improvement is prescribed for 14 days. The amount of infusion makes not less than 800 ml a day with the same preparations prescribed. Those are added with the preparations for homeostasis correction, including Fraxiparine, Fragmin, Clexane optionally. Control Doppler monitoring and foetal monitoring are daily. Hypamnion also requires measuring control AFI. If a gestational age is less than 34 weeks, respiratory distress syndrome (RDS) should be prevented by administering the preparation Dexon 24 mg according to the schedule: 6 mg every 12 hours 4 times. Control Ka is necessarily measured after 2 weeks of the treatment. If the trend is positive, the pregnant woman may be discharged from hospital, while no positive trend requires another 2 weeks of the therapy. If Ka is 150 or more, and the gestational age is more than 34 weeks, the therapeutic approach is the same, as for Ka being within 100 to 150, control Doppler monitoring, foetal monitoring are performed twice a day, as well as measuring AFI. If observing no foetal weight gain for 2 weeks of the therapy or the functional state of the foetus deteriorates, a Cesarean section is performed. If the gestational age is 34-36 weeks, the therapeutic approach and follow-up are the same as for the gestational age of 34 weeks, except for the prevention of foetal RDS. However, if observing the deterioration of a foetal movement pattern or the functional status of the foetus, a Cesarean section is performed according to the foetal monitoring and Doppler monitoring findings. If the gestational age is more than 36 weeks, and Ka is 150 or more, pre-mature delivery is applied.

EFFECT: optimal selection of the therapeutic approach ensured by determining the values reflecting the severity of the cardiovascular disorder directly in the uterine-placental complex and mother's and foetus's compensatory capacities.

5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, having cell proliferation inhibitor properties. In formula I , Y1 and Y2 each independently denote N or C(R1), but Y1 and Y2 do not simultaneously denote N or do not simultaneously denote C(R1), where R1 is selected from a group consisting of a hydrogen atom, C1-6alkyl, where R1 is substituted with 0 or 1 substitutes RR1, selected from a group consisting of -ORa; where Ra is selected from a hydrogen atom; R2 is selected from a group consisting of a hydrogen atom, C1-6alkyl; R3 is a 6-7-member monocyclic or bridge heterocycloalkyl ring containing 2 heteroatoms, selected from N and O, where the group R3 is substituted with 0-3 substitutes RR3, selected from a group consisting of -Ri, Ri is selected from C1-6alkyl; A1, A2, A3 and A4 each denote C(H); and D denotes -NR4C(O)NR5R6, where R4 is selected from a group consisting of a hydrogen atom; R5 and R6 are each independently selected from a group consisting of a hydrogen atom, C1-6alkyl, C4-6heterocycloalkyl containing one oxygen heteroatom; and where R5 and R6 are further substituted with RD, where RD is selected from -S(O)2Rm, where Rm is selected from C1-6alkyl.

EFFECT: compounds can be used to produce medicine for treating cancer.

21 cl, 1 tbl, 21 ex

FIELD: pharmaceuticals.

SUBSTANCE: invention provides topical blood circulation improving remedy containing simultaneously nitroglycerine and aminophylline. Remedy can be provided in the form of emulsion, gel, or ointment, which are administered 1-2 times a day.

EFFECT: strengthened blood circulation activation effect, which is prolonged to 24 hours.

5 cl, 9 ex

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