Azoles as inhibitors of malonyl-coa-decarboxylase useful as metabolic modulating agents

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

 

This application sought the priority based on provisional patent application, serial No. 60/270034, filed February 20, 2001, included in this description by reference.

The technical field to which the invention relates.

The present invention relates to a method of treatment of certain metabolic diseases (diseases of metabolism), and to new compounds and their prodrugs, and/or pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds useful in the treatment of such diseases. In particular, this invention relates to the use of new compounds and compositions for the prevention, elimination or treatment of cardiovascular diseases, diabetes, cancers and obesity through inhibition of melanisation-A-decarboxylase (malonyl-COA-decarboxylase, MCD).

The level of technology

Malonyl-COA is an important intermediary metabolism produced in the body by the enzyme acetyl-COA-carboxylase (ACC). In the liver, adipocytes and other tissues malonyl-COA is a substrate for fatty acid synthase (FAS). ACC and malonyl-COA was detected in the tissue of skeletal and cardiac muscle, where the content of the fatty acid synthase low. The enzyme malonyl-COA-decarboxylase (MCD, EC 4.1.1.9) catalyzes the conversion of malonyl-COA to acetyl-COA and thereby regulates the content is of malonyl-COA. Described MCD activity in many organisms, including prokaryotes, birds and mammals. It was isolated in pure form from bacteria Rhizobium trifolii (An et al., J. Biochem. Mol. Biol., 32:414-418 (1999)), nadvornik glands waterfowl (Buckner et al., Arch. Biochem. Biophys., 177:539 (1976); Kim and Kolattukudy, Arch. Biochem. Biophys., 190:585 (1978)), of rat liver mitochondria (Kim and Kolattukudy, Arch. Biochem. Biophys., 190:234 (1978)), mammary glands of rats (Kim and Kolattukudy, Biochem. Biophys., Acta, 531:187 (1978)), β-cells of the rat pancreas (Voilley et al., Biochem. J., 340:213 (1999)) and goose (Anser anser) (Jang et al., J. Biol. Chem., 264:3500 (1989)). Identification of patients with deficiency of MCD led to the cloning of a human gene homologous genes MCD goose and rats (Gao et al., J. Lipid. Res., 40:178 (1999); Sacksteder et al., J. Biol. Chem., 274:24461 (1999); FitzPatrick et al., Am. J. Hum. Genet., 65:318 (1999)). Method Nazem Blot find the only MCD mRNA person. The highest levels of mRNA expression are found in muscle and cardiac tissue, followed by liver, kidney and pancreas quantities detectable in all other examined tissues.

Malonyl-COA is a strong endogenous inhibitor of carnitine-palmitoyltransferase-I (CPT-I) - enzyme essential for the metabolism of long-chain fatty acids. CPT-I is an enzyme that limits the rate of fatty acid oxidation and catalyzes the formation of acylcarnitine, which is transferred from cytosol across the mitochondrial membrane acylcarnitine-translocate. Mitochondrial long-chain fatty acids are again transferred in the form of SOA under the action of the complementary enzyme CPT-II, and in the mitochondrial acyl-COA enters the cascade β-oxidation, generating acetyl-COA. In the liver, high content of acetyl-COA takes place, for example, after a meal, which leads to high levels of malonyl-COA, inhibition of CPT-I, which prevents the fat metabolism and favors the synthesis of fats. On the contrary, a low content of malonyl-COA is conducive to fat metabolism owing to the transfer of long-chain fatty acids into the mitochondria. Therefore, malonyl-COA is a key metabolite that plays a key role in balance (equilibrium) synthesis and oxidation of fatty acids (Zammit, Biochem. J., 343:5050-515 (1999)). Recent work indicates that the MCD is able to regulate cytoplasmic and mitochondrial levels of malonyl-COA [Alam and Saggerson, Biochem. J., 334:233-241 (1998); Dyck et al., Am. J. Discrimination, 275:H2122-2129 (1998)].

Although malonyl-COA is present in muscle and heart tissues, these tissues detected only low levels of FAS. I believe that the role of malonyl-COA and MCD in these tissues is to regulate the metabolism of fatty acids. This is achieved through inhibition of malonyl-COA in muscle (M) and liver (L) isoforms of CPT I, encoded by different genes (McGarry and Brown, Eur. J. Biochem., 244:1-14 (1997)). Muscle more isoforms. the d to the inhibition of malonyl-COA (IC 500.03 µm)than liver isoform (IC502.5 μm). Described regulation of CPT-1 malonyl-COA in the liver, heart, skeletal muscle and β-cells of the pancreas. Also described are sensitive to malonyl-COA acyl-COA-transfersa activity present in the microsomes, perhaps part of the system that delivers acyl group in the endoplasmic reticulum (Fraser et al., FEBS Lett., 446:69-74 (1999)).

Cardio-vascular diseases. A healthy human heart uses the available metabolic substrates. When the content of glucose in the blood is high, the absorption and metabolism of glucose provide the main power supply of the heart. In the state of hunger lipids are provided by fat tissue, and the absorption of fatty acids and metabolism in the heart is regulated by the type of negative feedback with glucose metabolism. Regulation of intermediary metabolism serum levels of fatty acids and glucose includes a cycle of the glucose-fatty acid (Randle et al., Lancet, 1:785-789 (1963)). In ischemic conditions of limited oxygen weakens as the oxidation of fatty acids and glucose, and reduces the amount of ATP (ATP)generated by oxidative phosphorylation in the tissues of the heart. In the absence of sufficient oxygen glycolysis increases when you try to save the levels of ATP and accumulation of lacto is a, and as a result decreases the intracellular pH. Energy is spent on the maintenance of ion homeostasis, and there is a loss of myocytes as a result of abnormally low levels of ATP and disturbed cellular osmolarity. In addition, AMRS, activated during ischemia, fosfauriliruetsa and thus inactivates ACC. The total content of cardiac malonyl-COA decreases, therefore increasing the activity of CPT-I, and fatty acid oxidation dominates the oxidation of glucose. The favorable effect of metabolic modulators in the tissue of the heart is improved efficiency of ATP/mol of oxygen to glucose compared to fatty acids and, more importantly, increased coupling of glycolysis to the oxidation of glucose, which is manifested in the total reduction of the proton load in ischemic tissue.

Several clinical and experimental studies shows that shift energy metabolism in heart towards the oxidation of glucose is an effective approach to relieving symptoms associated with cardiovascular diseases such as myocardial ischemia (Hearse, "Metabolic approaches to ischemic heart disease and its management", Science Press), and others. Some recent clinical trials of the medicinal product against angina, including perhexiline and amiodarone, inhibit fatty acid oxidation through inhibition of CPT-I (Kennedy et al., Bichem. Pharmacology, 52:273 (1996)). It is shown that drugs against angina ranolazine, which is in phase III clinical trials, and Trimetazidine inhibit β-oxidation of fatty acids (McCormack et al., Genet. Pharmac., 30:639 (1998); Pepine et al., Am. J. Cardiology, 84:46 (1999)). It is shown that Trimetazidine specifically inhibits long-chain 3-ketoacyl-COA-thiolase is an essential step in oxylene fatty acids (Kantor et al., Circ. Res., 86:580-588 (2000)). Dichloracetate enhances the oxidation of glucose by stimulating the complex piruvatdegidrogenazy and improves cardiac function in patients with Beltrami coronary artery (Wargovich et al., Am. J. Cardiol., 61:65-70 (1996)). Inhibition of the activity of CPT-I through increased content of malonyl-COA inhibitors MCD can lead not only to new, but also to a more safe in comparison with other known inhibitors of CPT-I with small molecules, methods of prevention and treatment of cardiovascular diseases.

Most of the stages included in glycerolipid synthesis occurs in the cytosol membrane of the endoplasmic reticulum (ER) of the liver. Synthesis of triacylglyceride (TAG) for secretion to the ER of diacylglycerol (DAG) and acyl-COA-dependent transport of acyl-COA through the ER membrane. This transport depends on the activity of acyl-COA transferase, sensitive to malonyl-COA (Zammit, Biochem. J., 343:505 (1999); Abo-Hashema, Biochem., 38:15840 (1999); and Abo-Hashema, J. Biol. Chem., 274:35577 (199)). Inhibition of TAG biosynthesis inhibitor MCD can improve the lipid profile of blood and, therefore, reduce the risk factor for coronary artery disease in a patient.

The diabetes. Two metabolic complications, most commonly associated with diabetes, are overproduction ketone cells in the liver (NIDDM) and intoxication bodies associated with long-term high glucose content. Inhibition of fatty acid oxidation may regulate the content of glucose in the blood and improves some of the symptoms of diabetes type II. Inhibition of malonyl-COA CPT-I is the most important regulatory mechanism that regulates the rate of fatty acid oxidation occurs when hypoinsulinemia-hyperglucagonemia state. Some irreversible and reversible active inhibitor of CPT-I were evaluated for their ability to regulate glucose in the blood, and all of them have been hypoglycemic (Anderson, Current Pharmaceutical Design, 4:1 (1998)). Specific for the liver acting and reversible inhibitor of CPT assuming your-ZPI-975 significantly reduces glucose levels in healthy starving for 18 hours primates, non-human, and rats without inducing cardiac hypertrophy (Deems et al., Am. J. Discrimination, 274:R524 (1998)). Malonyl-COA plays an important role as a sensor (sensor element) relative available the minute glucose and fatty acids in pancreatic β -cells and, thus, binds glucose metabolism with cellular energy status and secretion of insulin. It is shown that the means of enhancing insulin secretion, increases the concentration of malonyl-COA in β-cells (Prenki et al., Diabetes, 45:273 (1996)). However, treatment of diabetes directly inhibitor of CPT-I leads to the mechanism associated with the poisoning of the liver and myocardium. The MCD inhibitors, inhibiting CPT-I by increasing the content of its endogenous inhibitor malonyl-COA, are, therefore, more safe and excellent for the treatment of diabetes compared with inhibitors of CPT I.

The cancer. It is assumed that malonyl-COA is a possible mediator of cytotoxicity induced by inhibition of fatty acid synthase in breast cancer cells and xenografts (Pizer et al., Cancer Res., 60:213 (2000)). Found that inhibition of fatty acid synthase with the use of antineoplastic antibiotic cerulenin or synthetic analogue S significantly increases the content of malonyl-COA in breast cancer cells. On the other hand, the inhibitor of fatty acid synthase TOFA (5-(tetradecanoic)-2-francebuy acid), which only suppresses the level of acetyl-COA-carboxylase (ACC), does not show any antitumor activity, while the content of malonica reduced by 60% from the control. I believe that the high content of malonyl-COA is responsible for the antitumor activity of these inhibitors of fatty acid synthase. Thus, regulation of the content of malonyl-COA with the use of inhibitors MCD is extremely important therapeutic strategy in the case of cancer treatment.

The obesity. It is assumed that malonyl-COA may play a key role in the signal about the need for food in the brain through inhibition of the cascade reactions of neuropeptide Y (Loftus et al., Science, 288:2379 (2000)). System or intracerebroventricular administration to mice of an inhibitor of fatty acid synthase (FAS) cerulenin or S leads to inhibition of feed intake and significant weight loss. Discovered that S inhibits the expression of propagovala signaling neuropeptide Y in the hypothalamus and acts latinizations form, which, as it turns out, is mediated by malonyl-COA. Therefore, regulation of the content of malonyl-COA through the inhibition of MCD presents a new approach to prevention and treatment of obesity.

About creating MCD inhibitors for the treatment of cardiovascular diseases, diabetes, cancer or obesity in the literature are not reported. The authors have found a new series of compounds containing triazole and oksazolov, the members of which are strong inhibitors MCD. Compounds tested both in vitro and vivo i, inhibit the activity of malonyl-COA-decarboxylase and increase the concentration of malonyl-COA in the body. In addition, in the experiment, the selected compounds induce a significant increase of glucose oxidation compared to the control in the analysis with isolated perfusion heart rat (McNeill, Measurement of Cardiovascular Function, CRC Press, 1997). Mainly, the preferred compounds of the invention, such as in table 3, no PP 16, and table 8, # PP 7, has a more marked effect on the shift of metabolism than the well-known modulators of metabolism, such as ranolazine or Trimetazidine. Therefore, compounds of the invention and the pharmaceutical composition containing such compounds that are useful in medicine, in particular for the prevention and treatment of various cardiovascular diseases, diabetes, cancer and obesity.

In addition, such compounds are also useful as a diagnostic tool in the case of diseases caused by deficiency or dysfunction of MCD.

Summary of the invention

The present invention relates to new compounds represented by structures I and II, new pharmaceutical compositions containing such compounds, and methods of prevention, elimination and treatment of diseases of metabolism and diseases modulated by the inhibition of MCD. The compounds of this invention are useful for PR is the prevention, removal and treatment of diseases, including metabolic glucose/fatty acids, which is regulated by malonyl-COA. In particular, such compounds and pharmaceutical compositions containing these compounds indicated for the prevention, elimination and treatment of cardiovascular diseases, diabetes, cancer and obesity. Furthermore, the new compounds and compositions of the present invention, intermediate compounds and methods useful for preparing compounds of the invention are also included in the scope of this invention.

The present invention also includes within its scope the diagnostic methods for detecting diseases associated with a deficiency or dysfunction of MCD.

Compounds of the invention are of the following structure

where Y, C, R1, R2, R6and R7have the values listed below. In the scope of the present invention also includes the corresponding enantiomers, diastereoisomers, prodrugs and pharmaceutically acceptable salts of these compounds. Other aspects of this invention will become apparent from the following description of the present invention. So, the above only summarizes some aspects of the invention is not intended and should not be construed as any limitation of the present invention.

Detailed description of the invention

After the respective further detailed description is not intended to be exhaustive or to limit the invention are shown in detail. The details of the selected and described for a better understanding of the invention by other experts in the field of technology.

The present invention relates to compounds represented by the following formula

where

Y is selected from S or O; a is a substituted monocyclic 5-7-membered ring containing one to three heteroatoms, where these heteroatoms selected from O, N or S, and where these substituents chosen, independently of R1and R2;

R1and R2are different and are each selected, independently, from hydrogen, halogen, hydroxy, nitro, cyano, (C1-C12)-alkyl, substituted (C1-C12)-alkyl, alkylamino, alkylsulfonyl, aryl, (C1-C12)-alkoxy, substituted (C1-C12)-alkoxy, -C(X)R3,

-CR11(V)R12, -CH2CR11(V)R12, -S(O)nR3, -NR4P(O)(R5)2, -P(O)(R5)2or substituted or unsubstituted monocyclic 3-7 membered ring containing zero to three heteroatoms, where these heteroatoms selected from O, N or S, and where these substituents chosen, independently of R9; or R1and R2can be a group one of the following formulas

where cycle D is replaced by the Lee unsubstituted monocyclic 3-7-membered ring, containing from zero to three heteroatoms, where these heteroatoms selected from O, N or S, and where these substituents chosen, independently of R9and R3and R4taken together, may form a substituted or unsubstituted monocyclic 3-7 membered ring containing zero to three heteroatoms, where these heteroatoms selected from O, N or S, and where these substituents chosen, independently of R9or R1and R2taken together, may form a substituted or unsubstituted 5-7-membered ring containing from zero to three heteroatoms selected from N, O or S, and where these substituents chosen, independently of R9;

R3selected from hydrogen, hydroxy, amino, (C1-C12)-alkyl, substituted (C1-C12)-alkyl, alkylamino, aryl, (C1-C12)-alkoxy, substituted (C1-C12)-alkoxy or monocyclic 3-7 membered ring containing zero to three heteroatoms, where these heteroatoms selected from O, N or S, and where these substituents chosen, independently of R9;

R4selected from hydrogen, (C1-C12)-alkyl, substituted (C1-C12)-alkyl, aryl or monocyclic 3-7 membered ring containing zero to three heteroatoms, where these heteroatoms selected from O, N or S, and where specified the Deputy shall choose Fort worth, independently, R9;

R5selected from hydrogen, (C1-C12)-alkyl, substituted (C1-C12)-alkyl, alkylamino, alkoxy, aryl or monocyclic 3-7 membered ring containing zero to three heteroatoms, where these heteroatoms selected from O, N or S, and where these substituents chosen, independently of R9;

R6that is, or 5th, or 6th position in the structure II, which are selected from-NR8P(O)(R5)2or group one of the following formulas

where cycle D is substituted monocyclic 5-7-membered ring containing one to three heteroatoms, where these heteroatoms selected from O, N or S, and where these substituents chosen, independently of R9and the cycle E is a substituted 5-membered heteroaromatic ring or a monocyclic 3-, 4-, 6 - or 7-membered heterocycle containing one to three heteroatoms, where these heteroatoms selected from O, N or S, and where these substituents chosen, independently of R9and Q is selected from-NR8, -C(O)- or-O-;

R7selected from hydrogen, (C1-C12)-alkyl, (C1-C12)-alkoxy, halogen, cyano, SO2R4, SO2NR4R4,

or R7and R6taken together, may form a condensed substituted 5-7-membered to what ICO, containing one to three heteroatoms, where these heteroatoms selected from N, O or S, and where these substituents selected from R9;

R8selected from substituted (C2-C12)-alkyl, branched (C3-C12)-alkyl, ((C2-C6)-(alkylene))R14, -CH(CF3)2,

-CH((CF2)nCF3)n, -CH(CF3R11, -CHR12(aryl), -CHR11(heteroaryl), -CHR11(heterocyclyl), cycloalkyl or monocyclic 3-7 membered ring containing zero to three heteroatoms, where these heteroatoms selected from O, N or S, and where these substituents chosen, independently of R9;

R9selected from hydrogen, halogen, -CN, -C(O)CF3,

-S(O)nCF3, -C(O)CH2F, -CH(OH)CF3, -N(CN)2, -C(CN)3, -CHR10R11, (C1-C12)-alkyl, substituted (C1-C12)-alkyl, -CF3, -(CF2)mCF3,

-CH(CF3)2, -CF(CF3)2, -SO3H, alkylamino, alkylsulfonyl, aryl, (C1-C12)-alkoxy, substituted (C1-C12)-alkoxy, -C(X)R10,

-CR11(V)R12, -CH2CR11(V)R12, -S(O)nR12, -S(O)2NHMe(OH), -S(O)2NH(2-thiazolyl), -(4-oxo-2-thioxothiazolidin-5-ylidene), tetrazolyl, -CH2(1,1-dioxo-llambda*6*-thiomorpholine-4-yl),

-S(O)2 CH2NO2, -S(O)2CH2S(O)2R12, -P(O)(OR11R12, -NR11P(O)OR12,

-P(O)(NR11R12), a substituted or unsubstituted monocyclic 3-7-membered ring containing one to three heteroatoms, where these heteroatoms selected from O, N or S;

R10selected from hydroxy, amino, NHCN, (C1-C12)-alkyl, substituted (C1-C12)-alkyl, cycloalkyl, alkylamino, (C1-C12)-alkoxy, -CF3, heterocyclyl, aryl;

R11selected from hydrogen, (C1-C12)-alkyl, substituted (C1-C12)-alkyl, heterocyclyl or aryl;

R12choose from (C1-C12)-alkyl, substituted (C1-C12)-alkyl, heterocyclyl or aryl;

R13selected from substituted (C2-C12)-alkyl, substituted (C2-C12-alkenyl, substituted (C2-C12)-quinil, heterocyclyl, simple alkyl ester, alkylamino and unsubstituted or substituted heteroaryl or p-R9-substituted phenyl;

R14choose from COR3, R6;

A represents a bond, -NR5or CR4R5-;

Represents a bond, -NR4-, -CR4H-, -CR4(OH)- or

-CR4R5-;

G represents a-CH(CH2)m-, >C=CH-, -N(CH2)m-;

L represents the ligature, -O-, -C(O)-, -NR5-, -CR4H-,

-CR4(OH) -, or-CR4R5-, -NHNR5-;

Q is a bond, -NR5-, -C(O)-, -O - or

-CR4R5-;

X represents O, S, NR4, NOR4, NCN, NNO2, CR11NO2, CR11CN, C(CN)2, CR11R12or N-NR11R12;

V represents-OH, -SH, -CN;

m is zero, one, two, or three;

n is equal to one or two;

their respective enantiomers, diastereoisomers or tautomers,

or pharmaceutically acceptable salts, or prodrugs in a pharmaceutically acceptable carrier.

As described above, the compounds of this invention can be provided in the form of prodrugs, such as

In structure III include disulfide bonds, which in vivo is transformed into an active form, meaning, structure I. Structure IV describes ethyl ester, which in vivo is converted to the corresponding acid, i.e. form-CO2N.

The specialist should be borne in mind that the designation

describes the arrangement of the substituents Riand Rjin any available position in the cycle, and any item related to another, and that the relative positions of Riand Rjin the above notation does not imply anything other than their p is the position in the cycle. This rule is used throughout this description to describe radicals, which can be placed on any available valence, and nothing else is implied.

In addition, with regard to the nomenclature in this description, connections, called exactly, usually named using agreement IUPAC, but in compounds, the structure of which is described, use the following numbering in the cycle, regardless of the agreement IUPAC or heteroatoms present in the loop:

Hence, contain or no connection heteroatoms, such as N, for example, 6-membered cycle, the radicals attached to this part of the cycle, described using the numbering above. Thus, examples of heterocycles are

The rule numbering described above, is applied, and, as a rule, in the description reference is made to "structure II", with the exception of compounds called exactly.

There are several preferred variants of the embodiment of the present invention. One such preferred options is the option where Y in structures I and II represents a sulfur atom. Another preferred option is the option where a loop in the structure I represents or pyridine or pyrimidine. Another preference for the equipment option is option where the substituents R1and R2in the structure I take the position 5 or position 6, as shown by the following structure:

In another preferred embodiment, the substituent R2represents hydrogen or, in another case, a is absent and R1attached in position 6, as shown by the following structure:

Another preferred option is the option where the cycle represents a pyridine, Deputy R2represents hydrogen or, in another case, a is absent and R1attached in position 6, as shown by the following structure:

where substituent R1represents a group of one of the following formulas:

Even more preferable is the case where R1represents a group selected from the groups one of the following formulas:

Even more preferable is the case where in the above functional groups, R5'represents hydrogen, and R5choose from a branched (C3-C12)-alkyl, ((C2-C8)-(alkylene))R14, cycloalkyl,

-CH2(heterocyclyl), -CH2(aryl), g is teracycline, and R4represents a substituted (C6-C12)-alkyl, ((C2-C8)-(alkylene))R14substituted heteroaryl, substituted heterocyclic or p-R9-substituted phenyl. Preferably, R4represents a substituted 5-6-membered heterocyclyl, R9-substituted heteroaryl or p-R9-substituted phenyl. Another preferred option is option, where the structure II Deputy R7represents hydrogen, and R6attached in position 6, as shown by the structure

The preferred option is option, where in the above structure, R6represents a group selected from the groups one of the following formulas:

Especially preferred is the case where R6choose from a branched (C3-C12)-alkyl, ((C2-C8)-(alkylene))R14, cycloalkyl, -CH2(heteroaryl),

-CH2(heterocyclyl), heterocyclyl, and R13represents a substituted (C6-C12)-alkyl, ((C2-C8)-(alkylene))R14, heterocyclyl, substituted heteroaryl or p-R9-substituted phenyl. Preferably, R13in the above-mentioned functional groups is an R9-substituted Goethe is aeril or p-R 9-substituted phenyl.

Even more preferable is the case where R8in the above formulas represents a branched (C3-C7)-alkyl, in particular isopropyl or isobutyl, (C3-C7-cycloalkyl, in particular, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, 5-6-membered heterocyclyl, in particular, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl and pyrrolidinyl, -CH2(heteroaryl), in particular, methylpyridine, methylthiazolyl and methylisoxazole, -CH2(heteroaryl), in particular, methyltetrahydrofuran, methyltetrahydrofuran, methylpiperidine and methylpyrrolidinyl; and R13is a ((C2-C8)-(alkylene))R14preferably, -(CH2)2-8R14, the unsubstituted heteroaryl or R9-substituted heteroaryl, in particular, 5-6-membered heteroaryl, for example, pyridyl and oxazolines, thiophenyl, and especially preferred R13represents the p-R9-substituted phenyl.

Preferable embodiments of the invention is the case where in the above formulas, R13represents the p-R9-substituted phenyl, where the most preferred R9selected from-CN, -C(O)CF3, -S(O)nCF3,

-C(O)CH2F, -CH(OH)CF3, -N(CN)2, -C(CN)3, -CHR10R11,(C 1-C12)-alkyl, substituted (C1-C12)-alkyl, -CF3, -(CF2)mCF3, -CH(CF3)2, -CF(CF3)2, -SO3H, (C2-C12)-alkoxy, substituted (C2-C12)-alkoxy, -C(X)R10, -CR11(V)R12, -CH2CR11(V)R12, -S(O)nR12, -S(O)2NHMe(OH),

-S(O)2NH(2-thiazolyl), -(4-oxo-2-thioxothiazolidin-5-ylidene), tetrazolyl, -CH2(1,1-dioxo-llambda*6*-thiomorpholine-4-yl),

-S(O)2CH2NO2, -S(O)2CH2S(O)2R12, -P(O)(OR11R12, -NR11P(O)OR12,

-P(O)(NR11R12or cycle selected from the

attached in position 1 or 2attached in position 2, 4, or 5attached in position 2, 4, or 5attached in position 2, 4, or 5

attached in position 4 or 5attached in position 2 or 4attached in position 2 or 4attached in position 4 or 5

Especially preferable is a version of the formula

where R6choose from

the most preferred R8choose from a branched (C3-C7)-alkyl, (C3-C7)-cycloalkyl, 5-6-membered heterocyclyl, -(CH2)4-8R14and the most preferable R13selected from R9substituted 5-6-membered heteroaryl or p-R9-substituted phenyl, where the most preferred R9selected from F, Cl, Br, I, OH, -CN, -N(CN)2, -C(CN)3, -CF3, -(CF2)mCF3, -CH(CF3)2,

-CF(CF3)2, -SO3H, (C2-C12)-alkylsulfanyl, (C2-C12)-alkoxy, substituted (C2-C12)-alkoxy, -C(X)R10, tetrazolyl, 3-hydroxyethoxy-4-yl, 3-hydroxyethoxy-5-yl, and the most preferred R14selected from-C(X)R10and X represents O, NH2, NCN, NNO2most preferred R10choose from HE, amino, alkylamino, CF3, NHCN, and 5-6-membered heterocyclyl.

Composition

Compositions of the present invention contain

(a) a safe and therapeutically effective amount MCD inhibition of compound I or II, its corresponding enantiomer, diastereoisomer or tautomer, or its pharmaceutically acceptable salt or prodrug; and

(b) a pharmaceutically acceptable carrier.

As described above, many diseases can show the AMB treatment associated with MCD. Thus, the compounds of this invention are useful in the treatment of conditions involving such MCD activity.

Accordingly, the compounds of this invention can be entered into pharmaceutical compositions for use in the prevention, elimination and treatment of such conditions. Use the standard methods of obtaining pharmaceutical compositions, described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

"Safe and therapeutically effective amount" of the compounds of the present invention is an amount effective for inhibition of MCD in place(ahh) activity in the body of the subject in a tissue or cell, and preferably in the body of an animal, preferably a mammal, without undue adverse side effects (such as toxicity, irritation or allergic response), commensurate with a reasonable ratio of benefit/risk, when used in accordance with this invention. The specific "safe and therapeutically effective amount" will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, duration of treatment, the nature of concurrent therapy (if any), the specific dosage form, the medium, the solubility of the compounds in it and sh which we receive, desirable for the composition.

In addition to the target compound compositions of the subject invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used herein, means one or more compatible solid or liquid carriers, diluents or encapsulating substances that are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition is able to be mixed with the target connection and with each other in such a way that outstay interaction which would substantially reduce the pharmaceutical efficacy of the composition under normal conditions of use. Pharmaceutically acceptable carriers must, of course, to be clean enough and sufficiently low toxicity to refer them to suitable for introduction, preferably, an animal, preferably a mammal that is being treated.

Some examples of substances which can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and methylcellulose; chopped tragakant; malt; gelatin; talc; TV rdye lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as twins; wetting agents such as sodium lauryl sulfate; dyes; perfumes; substances that contribute to pelletizing, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline and phosphate buffer solutions.

The choice of pharmaceutically acceptable carrier for use in combination with the target compound is determined mainly by the way in which the connection should be entered.

If the target connection should be injected, the preferred pharmaceutically acceptable carrier is sterile saline solution with suspenders substance that is compatible with blood, the pH is increased to approximately 7.4. In particular, pharmaceutically acceptable carriers for systemic injections include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline solution and erogenous water. Preferred carriers for parenteral administration include propylene glycol, etiloleat, pyrrolidone, ethanol and sesame oil. Preferably, the pharmaceutically acceptable carrier in the compositions for parenteral administration is at least about 90 wt.% from the whole composition.

Compositions of the present invention, preferably, provided in a standard dosage form. The term "standard dosage form", as used herein, refers to compositions of this invention containing an amount of compound that is suitable for administration to an animal, preferably a mammal in a single dose according to a thorough medical practice. (However, the drug only once or standard dosage forms does not mean that the dosage form is entered once per day or once per course of treatment. It is assumed that such dosage form is administered one, two, three or more times a day, and it is expected that in the course of treatment they are taken more than once, although a single injection is not excluded. The specialist will be clear that the composition is not specifically directed for the full course of treatment, and such decisions, not the composition, remain with the experts in this field.) Such compositions preferably contain from about 5 mg (milligrams which is), preferably from about 10 mg to about 1000 mg, preferably to about 500 mg, most preferably to about 300 mg, of the selected connection.

The compositions of this invention can be in any of a variety of forms, suitable (for example) for oral, nasal, rectal, local (including transdermal), eye, intracerebral, intravenous, intramuscular or parenteral administration. (Specialist should be borne in mind that the composition for oral and nasal injection include compositions that are administered by inhalation and receive using available techniques.) Depending on your specific needs as a way of introduction, you can use a variety of pharmaceutically acceptable carriers well known in the art. These include solid and liquid fillers, diluents, hydrotropes, surfactants, and encapsulating substances. You can include, optionally, pharmaceutically active substances, which do not significantly influence the inhibitory activity of the compounds. The number of media used in combination with the compound is sufficient to provide a practical quantity of material for administration per dose connection. Methods and compositions for obtaining dosage forms useful in the methods of this image is etenia, are described in the following papers are included in this description as references: Modern Pharmaceutics, Chapter 9 and 10 (Banker &Rhodes, editors, 1979); Leiberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2d Edition (1976).

You can use various oral dosage forms, including such solid forms as tablets, capsules, granules, and bulk powders. Such oral dosage forms contain a safe and effective amount of a compound, usually at least about 5%, and preferably from about 25% to about 50%. Tablets can be compressed, tablet-trituration, with intersolubility coating, sugar coating, film coating or a multilayer containing suitable binders, lubricants, diluents, substances that contribute to the scattering, dyes, perfumes, agents, fluidity, and fluxes. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions recovered from the pellets without evolution of gas, and effervescent preparations recovered from the pellets with a gas containing suitable solvents, preservatives, emulsifying agents, suspendresume agents, diluents, sweeteners, fluxes, dyes and fragrances.

Pharmaceutically acceptable carriers suitable for received what I standard dosage forms for oral maintenance, well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants, for example inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; substances that promote disintegration, such as starch, alginic acid and crosscarmellose; lubricants such as magnesium stearate, stearic acid and talc. You can use glidant, such as silicon dioxide, to improve the flow characteristics of the powdery mixture. To give the appearance you can add colorants, such as dyes, FD&C Sweeteners and flavouring agents, such as aspartame, saccharin, menthol, peppermint and fruit fragrances are useful adjuvants for chewable tablets. The capsules usually contain one or more solid diluents described above. The selection of carrier components depends on the second order considerations like taste, cost, and stability during storage, which are not critical for the purposes of the invention and can be easily implemented by a person skilled in the technical field.

Oral compositions can also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers that are suitable for obtaining such compositions, horoscopist in the technique. Typical components of media for syrups, elixirs, emulsions and suspensions are ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. In case of suspension of a typical suspendresume agents are methyl cellulose, sodium carboxymethyl cellulose, avicel RC-591, tragakant and sodium alginate; typical wetting agents include lecithin and Polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions can also contain one or more components such as sweeteners, perfumes and dyes described above.

Such compositions can also be applied to the coating by conventional means, typically, coating, pH-dependent or time, such that the target compound is released in the gastrointestinal tract near the desired location of the application or at different times to extend the desired action. Such dosage forms typically contain one or more substances from acatitla cellulose, polivinilatsetatftalat, phthalate of hydroxypropylmethylcellulose, ethyl cellulose, coating Eudragit, waxes and shellac. Compositions of the present invention may contain, optionally, any other medicines.

Other compositions useful for attaining systemic delivery of the target compounds include p is dyazide, buccal and nasal dosage forms. Such compositions typically contain one or more fillers, such as sucrose, sorbitol and mannitol, and binders, such as Arabian gum, microcrystalline cellulose, carboxymethyl cellulose and hypromellose. Can also include glidant, lubricants, sweeteners, colorants, antioxidants and perfumes, as described above.

The compositions of this invention can also enter the subject topically, for example, by direct application or spreading of the composition on epidermal or epithelial tissue of the subject, or through transdermal "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids of the composition. Such compositions for topical application, preferably, contain a safe and effective amount of the compound, generally at least 0.1%and preferably from about 1% to about 5%. Suitable carriers for topical administration, preferably remains on the skin at the application site in the form of a solid film, and a persistent layer is removed with sweat, or submersion in water. Typically, the carrier is organic in nature and capable of dispersing or dissolving soedineniya. The media may include pharmaceutically acceptable softening agent, emulsifiers, C is hostitel, solvents or similar substances.

Applications

Compounds and compositions of this invention can be entered locally or systemically. Systemic application includes any method of introducing the compounds in the tissues of the body, for example, intra-articular, vnutriobolochechnoe, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual introduction, inhalation, reactine or oral administration. Compounds of the present invention are preferably administered orally.

The specific dosage of the input connection and the duration of treatment should be determined individually doctors. Typically, an adult (weighing approximately 70 kg) designate from about 5 mg, preferably from about 10 mg to about 3000 mg, preferably to about 1000 mg, preferably to about 300 mg, selected compounds per day. It should be borne in mind that the dosage intervals are only examples, and that the daily introduction can be specified depending on the factors described above.

When all of the above compounds of the invention of course you can enter alone or as mixtures, and compositions can also include other drugs or excipients which are suitable according to the testimony. For example, in the treatment of cardio-suck the East of diseases clearly assumes, the invention can be used in combination with beta-blockers, calcium antagonists, ACE inhibitors, diuretics, inhibitors angiotensinogen receptors or known cardiovascular medicines or treatments. Therefore, in this example, new compounds or compositions of the present invention is useful when entered together with another active agent and can be United with him in a single dosage form or composition.

The composition can also be entered in form of systems, liposomal delivery, such as single-layer vesicles, large single-layer and multi-layered vesicles vesicles. Liposomes can be obtained from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

Definition

Used in this description, the term "alkyl" denotes a linear alkanoyl, Allenby or alkyne Deputy containing only carbon and hydrogen, such as methyl, ethyl, butyl, pentyl, heptyl, and other Alkyl groups can be saturated or unsaturated (i.e., containing-C=C - or- ≡ -) in one or several positions. When the preferred degree of unsaturation, the Deputy called "alkenyl" or "quinil"denoting the substituents containing-C=C - or- ≡C-, respectively. The number of carbon atoms can is t be noted as "( i-Cj)-alkyl, where i and j denote the minimum and maximum number of carbon atoms, respectively. Typically, the alkyl groups contain 1-12 carbon atoms, preferably 1-10, preferably 2-8, carbon atoms.

Used in this description, the term "substituted alkyl" refers to hydrocarbon Deputy, which is linear, cyclic or branched and in which one or more hydrogen atoms substituted by carboxy, hydroxy, alkoxy, cyano, nitro, carbonyl, aryl, carboxylation, mercapto, amino, amido, ureido, carbamoyl, sulphonamido, sulfamido or halogen. Preferred substituted alkali contain in its alkyl portion (i.e., the part that represents alkyl of 1 to about 5 carbons and may be branched or linear, and may include cyclic substituents or as part or all of its structure. Preferred examples of the substituted Akilov are 4-carboxybutyl, pyridine-2-ylmethyl and 1,3-thiazole-2-ylmethyl, benzyl, phenethyl, and trifluoromethyl. The term "substituted alkyl" may be combined with other terms adopted in the technique. For example, "substituted alkoxy" means alkoxy as he is known in the art, where the alkyl part substituent is substituted.

Used in this description, the term "branched alkyl" about the means subtype "alkyl" and, thus, relates to hydrocarbon Deputy, which is branched. Preferred branched alkali contain from 3 to about 12 carbon atoms and may contain in its structure cycloalkyl. Examples of the branched alkyl is isopropyl, isobutyl, 1,2-dimethylpropyl, cyclopentylmethyl and similar groups. The term "branched alkyl" may be combined with other terms adopted in the technique. For example, "branched alkoxy" means alkoxy as he is known in the art, where the alkyl part substituent is branched.

Used in this description, the term "cycloalkyl" denotes a hydrocarbon Deputy, which is cyclic and may be substituted or unsubstituted. When it is substituted, one or more hydrogen atoms substituted by carboxy, hydroxy, alkoxy, cyano, nitro, carbonyl, aryl, carboxylation, mercapto, amino, amido, ureido, carbamoyl, sulphonamido, sulfamido or halogen. Preferred cyclic alkali contain 3 to 7 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclopentyl, 4-forcelogix, 2,3-dihydrocyclopenta and similar groups.

Used in this description, the term "alkylene" denotes alkyl biradical, ie, alkyl with free valences at two different atoms of plastics technology : turning & is Yes. Therefore, "(alkylene)Rirepresents an alkyl biradical attached to one carbon and having substituent Rithat is attached to another carbon that can defend on one or more carbon atoms from the point of accession. Alkylene can be linear, branched or cyclic. Examples of alkylene are-CH2-, -CH2CH2-, -(CH2)4-,-(cyclohexyl)- and similar groups.

Used in this description, the term "aryl" refers to substituted or unsubstituted aromatic, i.e. applies the hückel rule is 4n + 2, radical, having a single cycle (e.g., phenyl) or multiple condensed cycles (e.g., naphthyl or until), which may contain from zero to 4 heteroatoms. Therefore, the term "heteroaryl", of course, is seen in the term "aryl". Preferred a carbocyclic aryl is phenyl. Preferred monocyclic heterocycles, i.e, heteroaryl are 5 - or 6-membered cycles. Preferably, when the term "aryl" represents an aromatic heterocycle, such aromatic heterocycle called "heteroaryl" or "heteroaromatic", and it contains one or more heteroatoms. The preferred number of such heteroatoms are from one to three N atoms, and preferably, when heteroaryl is" is a heterocycle of the five atoms, it contains one or two heteroatoms selected from O, N or S. Therefore, preferred heterocycles contain up to three, preferably two or less, the heteroatoms present in the aromatic cycle. Specialists will be clear that among heteroaryl there are both five-and six-membered ring. Examples of "heteroaryl are thienyl, pyridyl, pyrimidyl, pyridil, furyl, oxazolyl, imidazolyl, thiazolyl, oxadiazolyl, triazinyl, triazolyl, thiadiazolyl and other groups known in the art. This definition implies that the substitution of aryl cycle is included in the scope of the invention. When the substitution takes place, the radical is called the "substituted aryl". Preferably, aryl-loop join from one to three, preferably one or two substituent, and most preferably one Deputy. Although many deputies will be useful, preferred are substituents, which are commonly found in aryl compounds, such as alkyl, hydroxy, alkoxy, cyano, nitro, halogen, halogenated, mercapto, etc. Such deputies administered using well-known techniques. Such substituents can join in different positions aryl cycle, and when this location preferably, this location is specified as "o-, m-, p-Riaryl". Thus the m if the substituent Riattached in the para-position of the aryl, then such aryl called "p-Risubstituted aryl".

Used in this description, the term "amide" includes both RNR'CO- (alkylaminocarbonyl in the case when R = alkyl)and RCONR'- (alkylcarboxylic in the case when R = alkyl).

Used in this description, the term "ester" includes both ROCO- (alkoxycarbonyl in the case when R = alkyl), and RCOO- (alkylcarboxylic in the case when R = alkyl).

Used in this description, the term "halogen" refers to a radical formed by an atom of chlorine, bromine, fluorine or iodine. The preferred Halogens are chlorine, bromine and fluorine. The term "halogen" is also sometimes assumes the name "halo" or "halide".

Used in this description, the term "alkylamino" means aminoacyl, in which at least one hydrogen atom at the nitrogen atom replaced by an alkyl. Preferred examples are ethylamino, butylamino, isopropylamino and similar groups. The alkyl component can be linear, branched, cyclic, substituted, saturated or unsaturated.

Used in this description, the term "alkylsulfanyl" means tially radical in which a hydrogen atom of sulfur atom is replaced by alkyl. Preferred examples are ethylsulfanyl, butylsulfonyl, isopropylphenyl is similar groups. The alkyl component can be linear, branched, cyclic, substituted, saturated or unsaturated. Used in this description, the term "alkoxy" denotes hydroxyacyl, in which the hydrogen atom from the oxygen atom is replaced by alkyl. Preferred examples are ethoxy, butoxy, benzyloxy and the like, alkyl component can be linear, branched, cyclic, substituted, saturated or unsaturated.

Used in this description, the term "heterocycle(s)" refers to a cyclic system, preferably, 3 to 7-membered ring that is saturated or unsaturated and non-aromatic. They can be substituted or unsubstituted and join other parts of the molecule through any available valence, preferably any available valence of carbon or nitrogen. More preferred are 5 - or 6-membered heterocycles. In six-membered monocyclic-heterocyclic compounds with heteroatom(s) is(are) one to three atom O, S or N, and when the heterocycle is a five-membered, preferably, it contains one or two heteroatoms selected from O, N or S.

Used in this description, the term "heterocyclyl" refers to a radical of a heterocycle. Such radicals can be substituted or unsubstituted and join other parts of the molecule through any available Valais is Tosti, preferably any available valence of carbon or nitrogen.

Used in this description, the term "sulfamido" refers to the group alkyl-N-S(O)2N-, aryl-NS(O)2N - or heterocyclyl-NS(O)2N-, where alkyl, aryl or heterocyclyl group have the meanings specified above.

Used in this description, the term "sulfonamide" refers to the group alkyl-S(O)2N-, aryl-S(O)2N - or heterocyclyl-S(O)2N-, where alkyl, aryl or heterocyclyl group have the meanings specified above.

Used in this description, the term "ureido" refers to the group alkyl-NCON-, aryl-NCON - or heterocyclyl-NCON-, where alkyl, aryl or heterocyclyl group have the meanings specified above.

The Deputy called in this radical may form a cycle with the other moiety of this description. When these radicals are combined, the specialist will be clear that in this case, the unoccupied valences no, but what specific substitution, for example, due to hydrogen. Therefore, some radicals can be described as forming the loops together. The specialist will be clear that such cycles can be formed easily formed by conventional chemical reactions within the competence of the specialist in the views of such cycles, and the FPIC of the scale of their education. Preferred are 3-7-membered cycles, preferably 5 - or 6-membered. Compounds described herein, can include a cyclic structure, such as cycle R1and R2. In this respect, the expert knows that this way of describing conventional in the chemistry of drugs, although may not accurately reflect the way of chemical synthesis. Used in this description, the term "cycle" or "ring"when they formed the Union of two radicals, refers to a heterocyclic or carbocyclic radicals, and these radicals can be saturated, unsaturated or aromatic. For example, the preferred heterocyclic ring systems include heterocyclic rings, such as morpholinyl, piperidinyl, imidazolyl, pyrrolidinyl and pyridyl.

Specialist in the art will understand that the radical of the formula

represents the number of different functionalities. Preferred compounds with functionalities presented such a structure are amides, urea, thiourea, carbamates, esters, complex thioethers, amidine, ketones, oximes, nitroolefins, hydroxyguanidine and guanidine. More preferred compounds with such functionalities are urea, thiourea, amides and carbamates.

Experts who have in the art will understand, some of the patterns described in this description may be the resonance forms or tautomers of compounds that can be to a certain extent provided by other chemical structures. Expert it is clear that such structures are included in the scope of the present invention, although the resonance shapes or tautomers in this description is not presented. For example, the structure

clearly represent the same connection, and a link to one of them clearly presupposes the other. In addition, the compounds of this invention can be obtained in the form of prodrugs, examples of which are

where R represents a group (or Association)that are removed during biological processes. Therefore, this invention also relates to the compounds obtained in the form of prodrugs capable of biological hydrolysis, as it is understood in the art. "Prodrug" in this description represents any compound which under the influence of biological processes in the body undergoes hydrolysis, metabolism, derivatives or undergoing similar with the formation of the active substances possessing the desired activity. Specialist in the art will understand that the prodrugs can have or not have any activity as prodrugs targeted prodrugs, described in this description, no adverse action on the subject, which is treated when you enter in safe and effective amounts. These include, for example, capable of biological hydrolysis of amides and esters. "Amide capable of biological hydrolysis" is an amide, which essentially does not affect the potency of the compound, or that is readily converted in vivo by a cell, tissue or organism, mlekopitayushchie or other animal with the formation of the active compounds of the invention. "Ether, capable of biological hydrolysis" is called ester of the invention, which essentially does not affect the activity of such compounds, or which is easily converted by the body of the animal with the formation of the active compounds of the formula (I). These are capable of biological hydrolysis of prodrugs are known to experts in the art and implemented in accordance with regulatory guidelines.

Compounds and compositions of this invention also involves a pharmaceutically acceptable salt, a cationic or anionic. "Pharmaceutically acceptable salt" is an anionic salt formed any acidic (e.g., carboxyl) group or a cationic salt formed any basic (e.g., amino) group. Many of these salts is swesty in engineering, for example, described in the publication WPP 87/05297, Johnston et al., published September 11, 1987 (included in this description by reference). Preferred counterions of the salts which may be formed by acid groups may include cations of salts, such as alkali metal salts (e.g. sodium and potassium) and alkaline earth metals (e.g. magnesium and calcium) and organic salts. Preferred counterions of the salts which may be formed by alkaline groups may include anions of salts, such as halides (e.g. chlorides). Of course, the specialist in the art will understand that you can use many different salts, and in the literature there are examples and organic, and inorganic salts useful in this case.

For all compounds of the invention, which may contain one or more stereogenic centers, "optical isomer", "stereoisomer, enantiomer, diastereoisomer"mentioned in this description are typical values, known in the art (cf. Hawleys Condensed Chemical Dictionary, 11th Ed.), and included in the inventive compounds as racemates or optical isomers, enantiomers and diastereoisomers.

In a similar manner, all compounds of the invention that may exist in the form of regioisomers, namely, compounds of the formula I, with several relative orientations of the hetero-ATO the RC cycle, this name isomers have the usual technique adopted in value (cf. Hawleys Condensed Chemical Dictionary, 11th Ed.), and included in the inventive connection.

Used in this description, the term "Metabolic disease" (disease of metabolism) denotes the group of identified disorders, which are disorders of metabolism, the imbalance in the metabolism or low metabolism. In this description to diseases of metabolism also refers to a disease that can be treated via modulation of metabolism, although the disease itself may or may not be caused by specific metabolic disorders. Preferably, this disease of metabolism captures the cascade of the reactions of oxidation of glucose and fatty acids. Preferably, this disease of metabolism captures MCD or modulated by the content of malonyl-COA, and is called in this case "disorder associated with MCD or ISA".

Obtaining compounds of the invention

Source materials used in the preparation of the compounds of the invention known, are obtained by known methods or commercially available. To a person skilled in the art it will be obvious that the methods of obtaining precursors and compounds that are functionally related compounds claimed in this invention, typically described in the literature. Specialist in the art, there is a broad literature and the description, will have everything you need to get any of the claimed compounds.

It is clear that the specialist in the field of organic chemistry can easily carry out operations without additional guidance, ie, a specialist competent in theory and in practice to carry out such manipulations. These include the reduction of carbonyl compounds to their corresponding alcohols, reductive alkylation of amines, oxidation, acylation, aromatic substitution as electrophilic and nucleophilic, obtaining simple and complex esters, saponification and similar interactions. Such manipulations are described in the classic works, such as March, Advanced Organic Chemistry (Wiley); Carey and Sundberg, Advanced Organic Chemistry, and similar works.

Specialist in the art will easily imagine that some interaction is best done when other functional groups in the molecule shielded (masked or protected, and thus it is possible to avoid undesirable side reactions and/or to increase the yield of the reaction. Often the experts in this field technicians use a protective group to achieve such high outputs or to avoid unwanted reactions. Such reactions are described in the literature and are also included in the competence of the experts. Examples of many of these manipulations m who should be found, for example, in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis, 2ndEd., John Wiley & Sons (1991).

The following schematic examples are given as a guide for the reader and present preferred methods of making the compounds, examples of which are given in this description. These methods are not restrictive, and it should be borne in mind that, you can use other ways to obtain these compounds. Such methods include, specifically, chemical synthesis in the solid phase, including combinatorial chemistry. Specialist for a specified connection enough of these methods described in the literature, and this specification.

As seen in scheme 1, the amino-2-mercaptobenzothiazoles(s) 1, (e) commercially available(s) or easily obtained using known methods, condense with aldehydes or ketones and restore cyanoborohydride sodium, and receive the corresponding(e) N-alkilani(s) 2. Then, the compound(I) 2 is transformed into the corresponding(s) urea(s) or thiourea(s) (3, R13= aliphatic, aromatic, heterocyclic or heteroaryl), amides (4, R13= aliphatic, aromatic, heterocyclic or heteroaryl), sulfonamides (5, R13= aliphatic, aromatic, heterocyclic or heteroaryl) or carbamates (6, R13= aliphatic, and ematichesky, heterocyclyl or hetero - aryl), in the described reaction conditions.

As seen in scheme 2, analogs of thiohydantoin (7) receive immediate treatment 1 different isocyanate esters of amino acids (R9= alkyl, aryl, heterocyclyl) in hot pyridine.

Pyrimidine(e) and pyridine(e) frames get 10 as shown in scheme 3. Repeated substitution of chlorine atoms in 8 (which is available commercially or readily synthesized using known methods) using sodium diethyldithiocarbamate and primary amine (R4NH2), respectively, gives the intermediate(s) connection(s) 9(s) after recovery/cialisa primary sodium sulfide and condensation with potassium salt, xanthan acid gives(ut) 10.

Specialist in the art it is clear that the compound, such as 10, is used as the compound(I) 1, described in(s) above, to obtain compounds of the present invention. The specialist also it is clear the use of such pyrimidines and pyridines (i.e., their regioisomers), described here, like the compounds 1, to obtain the compounds described in this invention. Other compounds described in this invention, receive similarly to the description in the Arrehenius, Chen et al., application SN-RT, SN-RT and With the 011-01 RST, registered 12 Jan. 2002, included in this description as a reference.

Biological activity

Analysis of inhibition of MCD in vitro

Spectrophotometric method of analysis for determining the activity of malonyl-COA-decarboxylase described in the literature, adapt and modify for analysis of inhibition of MCD activity in high throughput format (Kolattukudy et al., Methods in Enzymology, 71:150 (1981)). In wells of 96-well tiralongo tablet add the following reagents: buffer Tris-HCl - 20 ál; DTE - 10 ál; l-malate - 20 ál; NAD - 10 ál; NADH - 25 µl; water - 80 µl; malic dehydrogenase - 5 ál. The contents are mixed and incubated for 2 min, and then add 5 ál of citrate synthase. Add a connection, and then 5 µl of the malonyl-COA-decarboxylase derived from rat heart, and 20 μl of malonyl-COA. The contents incubated, and measure the absorption at 460 nm.

Active compounds characterized by the concentration of compound that causes 50% ingibirovanie activity MCD (IC50). Preferred compounds have the value of the IC50less than 10 microns. The most preferred compounds have the value of the IC50less than 100 nm (see table 1).

Table 1

IC50inhibitors MCD
ConnectionIC50(µm)
Table 3, no PP 1 0,031
Table 3, # PP 30,093
Table 3, No. 16 PM0,023
Table 3, No. 17 PM0,042
Table 4, # PP 40,075
Table 4, # PP 61,604
Table 7, no PP 10,062
Table 7, # PP 80,052
Table 8, # PP 10,098
Table 8, # PP 70,025

Measurement of the oxidation of glucose and fatty acid oxidation in perfesional heart rat

Isolated working hearts of male rats Sprague-Dawley subjected to 60 min of aerobic perfusion with a modified Krebs solution-Henseleit containing 5 mmol/l glucose; 100 μa/ml insulin; 3% BAS and 1.2 mmol/l palmitate. Working of the heart is used in such research approach to the metabolic needs of the heart observed in vivo (Kantor et al., Circulation Research, 86:580-588 (2000)). Test connection add 5 minutes of perfusion.

The degree of oxidation of glucose to determine quantitatively collecting14CO2produced perfoirmance hearts with buffer containing [U14]-glucose. Oxidation of fatty acids determine quantitatively collecting14CO2produced perfoirmance hearts with buffer containing [14 C]palmitate (McNeill J.H., "Measurment of cardiovascular function", chapter 2, CRC press, New York (1997)).

The active compounds are characterized by increased oxidation of glucose when compared with the control experiment (DMSO). Compounds that cause a statistically significant increased oxidation of glucose, are considered active. Preferred compounds cause a statistically significant increased oxidation of glucose at 20 μm. Statistical significance can be calculated using the criterion Student for paired and unpaired samples, respectively. Results with a P<0.05 is considered as statistically significant.

EXAMPLES

To further illustrate this invention the following examples. The examples should not be construed as specifically limiting the invention. Variations of these examples in the scope of the claims are within the competence of specialists in the art and are considered as falling in the scope of the described invention and claimed. The reader will be clear that the specialist in the art, guided by the present description and working in this area, you may obtain and apply the connection of the invention without exhaustive examples.

Trademarks used in the description, given only as examples and reflect illustrative materials at the time of invention. Special is the specialists in the art will understand, that assumes changes in the party, the methods of obtaining, etc. Therefore, the examples and their trademarks are not restrictive, and they are not intended to be limiting, but are only an illustration of how the expert can select and implement one or more embodiments of the invention.

Spectra1H nuclear magnetic resonance (NMR) measured in CDCl3or other solvents mentioned for the NMR spectrometer Varian (Unity Plus 400, 400 MHz for 1H), unless otherwise indicated, and the position of peaks expressed in chemical shift in ppm (ppm) relative to tetramethylsilane. Forms peaks denoted as follows: s - singlet; d - doublet; t - triplet; K - Quartet, m - multiplet.

Used abbreviations have the following meanings:

AC is acetyl,

Bn is benzyl,

Bz is benzoyl,

CDI - carbonyldiimidazole,

CH2Cl2- dichloromethane,

DIBAL - hydride diisobutylaluminum,

DMAP is 4-(dimethylamino)pyridine,

DMF - N,N-dimethylformamide,

DMSO - dimethyl sulfoxide,

EDCI or ECAC hydrochloride, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide,

ESIMS - mass spectrometry with ionization by electronic sputtering,

Et3N - triethylamine,

EtOAc is ethyl acetate;

NMTA - hexamethylenetetramine,

LDA - diisopropylamide lithium

LHDMS - bis(trimethylsilyl)AMI is lithium

MgSO4- magnesium sulfate

NaH - sodium hydride,

NBS is N-bromosuccinimide,

NCS - N-chlorosuccinimide,

NH4Cl - ammonium chloride,

Ph is phenyl,

Py - pyridinyl,

r.t. - room temperature,

TPA - triperoxonane acid,

THF is tetrahydrofuran,

TLC - thin layer chromatography,

Tf2O - anhydride of triftoratsetata;

abbreviations alkyl groups:

IU - methyl,

Et is ethyl,

n-Pr is normal propyl,

ISO-Pr is isopropyl,

n-Bu - normal butyl,

ISO-Bu is isobutyl,

tert-Bu is tertiary butyl,

second-Bu - secondary butyl,

with-Neh - cyclohexyl.

Table 2

Obtaining N-alkylbenzoates
no PPR8
1isobutyl
24-pyridyl-2-ylmethyl
32-benzyloxyethyl
44-thiazol-2-ylmethyl
5isopropyl
6carboxymethyl
7-CH2(5-methylthiophene)

An example of a procedure of synthesis of N-alkylbenzoates

6-[(2-Methylpropyl)amino]-1,3-besot the azole-2-thiol (table 2, no PP 1)

In a 500-ml round-bottom flask is charged with 6-amino-1,3-benzothiazole-2-thiol (5.0 g, 0.03 mol), hexanal (3.0 g, 0.03 mol), methanol (250 ml), glacial acetic acid (2.5 ml), water (1 ml) and NaCNBH3(1,9 g, 0.03 mol). The mixture is stirred for 4 hours, filtered, and the filtrate is concentrated, and get a light yellow solid. The solid is washed with water and treated with diethyl ether, and obtain 4.0 g (61%) named in the connection header.1H NMR (DMSO-d6) δ = 0,88 (t, 6N), to 1.79 (m, 1H), 2,77 (t, 2H), only 6.64 (d, 1H), 6,72 (s, 1H), 6,99 (d, 2H); ESIMS: m/z 239 (M-N).

Table 3

Getting benzothiazolinone


no PPR8R13
1isobutyl4-(trifluoromethyl)phenyl
2isobutyl4-bromophenyl
3isobutyl4-cyanophenyl
4isobutyl4-pyridin-3-yl
54-pyridin-2-yl4-bromophenyl
64-pyridin-2-yl4-(trifluoromethyl)phenyl
74-pyridin-2-ylChlorethyl
8-CH2(5-methylthiophene)4-bromophenyl
9-CH2(5-methylthiophene)4-(trifluoromethyl)phenyl
102-benzyloxyethyl4-bromophenyl
112-benzyloxyethyl4-(trifluoromethyl)phenyl
124-thiazol-2-ylmethyl2-chloroethyl
134-thiazol-2-ylmethyl4-(trifluoromethyl)phenyl
14isopropyl4-butoxyphenyl
15isopropyl4-cyanomethylene
16isopropyl4-(trifluoromethyl)phenyl
17isopropyl4-carboxymethyl
18isopropyl-(CH2)5CO2Et

An example of a procedure of synthesis of benzothiazolinone

N-(2-Mercapto-1,3-benzothiazol-6-yl)-N-(2-methylpropyl)-N'-[4-(trifluoromethyl)phenyl]urea (table 3, # PP 1)

In a 50 ml round-bottom flask is charged with 6-[(2-methylpropyl)amino]-1,3-benzothiazole-2-thiol (52,36 mg, 0.22 mmol), dichloromethane (10 ml) and α,α,α-Cryptor-p-tallization (41,1 mg, 0.22 mmol). The reaction mixture per mesilat within 8 hours, filtered and the resulting solid is treated with chloroform, then with a mixture of chloroform/methanol (mixture of 9:1), and obtain 60 mg (64%) named in the connection header.1H NMR (DMSO-d6) δ = 0,84 (d, 6N), of 1.66 (m, 1H), 3,49 (d, 2H), 7,30 (s, 2H), 7,50 (d, 2H), 7,60 (d, 2H), 7,71 (s, 1H); ESIMS: m/z 424 (M-H).

Table 4

Getting benzothiazolinone connections
no PPR8R13
1isobutyl4-chlorophenyl
2isobutyl4-methoxyphenyl
3isobutyl4-forfinal
4isopropyl4-chlorophenyl
5isopropyl2-methoxyethyl
6isopropyl2-benzyloxyethyl

An example of the procedure of synthesis benzothiazolinone connections

4-Chlorophenyl-2-mercapto-1,3-benzothiazol-6-yl(methylpropyl " carbamate (table 4, # PP 1)

In a 50 ml round-bottom flask is charged with 6-[(2-methylpropyl)amino]-1,3-benzothiazole-2-thiol (100 mg, 0.42 mmol), acetone (10 ml), N,N-diisopropylethylamine (54,2 mg, 0,42 mm is l) and 4-chlorophenylalanine (78.8 mg, 0.42 mmol). The reaction mixture was stirred for 10 h, filtered and the resulting solid is treated with diethyl ether, and obtain 38 mg (48%) named in the connection header.1H NMR (DMSO-d6) δ = 0,85 (d, 6N), to 1.70 (m, 1H), 3,53 (Ushs, 2H), 7,12 (d, 2H), 7,31 (d, 1H), 7,41 (m, 3H), 7,79 (s, 1H); ESIMS: m/z 393 (M+H).

An example of a procedure of synthesis of benzothiazolesulfonamide

4-Fluoro-N-isopropyl-N-(2-mercaptobenzothiazoles-6-yl)benzosulfimide

In a 50 ml round-bottom flask is charged with 6-[(2-methylpropyl)amino]-1,3-benzothiazole-2-thiol (200 mg, 0.89 mmol), pyridine (10 ml) and 4-forforstarkare (208 mg, 1.07 mmol). The reaction mixture is stirred for 1 hour and then concentrated. The obtained solid is treated with diethyl ether and then purified preparative TLC (5% Meon in CHCl3), and get 11 mg (3%) named in the connection header.1H NMR (DMSO-d6) δ or = 0.90 (d, 6N), to 4.41 (m, 1H), 6,91 (Ushs, 1H), 7,24 (Ushs, 1H), 7,41 (m, 3H), to 7.77 (m, 2H), 13,9 (Ushs, 1H); ESIMS: m/z 381 (M-N).

Table 5

Getting benzothiazolinone
no PPR9
1N
2ethyl
3 isopropyl
4isobutyl
5benzil
62-methylsulfonylmethyl

An example of a procedure of synthesis of benzothiazolinone

3-(2-Mercapto-1,3-benzothiazol-6-yl)-2-dioxoimidazolidin-4-one (table 5, # PP 1)

In a bottle of Pyrex® h mm with screw cap and upload 6-amino-1,3-benzothiazole-2-thiol (108 mg, 0.59 mmol), methyl-2-isothiocyanatobenzene (94,8 mg, to 0.72 mmol) and pyridine (2 ml). Bottle blow Ar, cover with lid and shake in a drying Cabinet at 60aboutC for 8 hours. The solution is concentrated, and the residue is treated with Et2O, and get rusty-brown powder (59 mg, 35%).1H NMR (DMSO-d6) δ = 4,27 (s, 2H), 7,26 (d, 1H), 7,35 (d, 1H), to 7.61 (s, 1H), the 10.40 (s, 1H), 13,86 (Ushs, 1H); ESIMS: m/z 280 (M-H); TPL >266aboutC.

Table 6

Getting 5-alkylamines[5,4-b]pyridine or pyrimidine)-2-thiol(s)
no PPzR5
1SNisopropyl
2SNethyl
3SNN
4 Nethyl
5Nisopropyl

An example of a procedure of synthesis of 5-alkylamines[5,4-b]pyridine-2-thiol(s)

Getting 5-isopropylaminomethyl[5,4-b]pyridine-2-thiol (table 6, # PP 1)

Stage 1. In a 1-l flask is charged with 2,6-dichloro-3-nitropyridine (15,01 g, 77,78 mmol) and anhydrous THF. The solution is cooled in a water bath with ice for 10 min and Tegaserod, and is evacuated from the bowels purging Ar. Get solution of sodium diethyldithiocarbamate (19,34 g, to 85.8 mmol) in 275 ml of THF, and Tegaserod him, and then for 30 min is added dropwise to a solution of chloropyridine. The solution was stirred at 0°C for 5 hours and then left to warm to room temperature. The solvent is evaporated, the dark orange residue was dissolved in EtOAc and the solution washed 3x with water and then 1x salt solution. The organic fraction is dried (MgSO4), filtered and concentrated, and get the oil amber color. Purification on flash column (SiO2gel; 10% EtOAc/hexane) to give 17.3 g (73%) orange oil (6-chloro-3-nitropyridine-2-silt ether pttc acid).

Stage 2. In a 250 ml round-bottom flask is charged with the reaction product obtained in stage 1 (12,38 g, 40,48 mmol), K2CO3(5,64 g and 40.8 mmol) and acetonitrile (100 ml). Added Isopropylamine (3.5 ml, 40,5 mmol) for 5 min, and RA the solution is stirred over night. The reaction solution is filtered through a 2-cm layer of celite, concentrated, the residue is dissolved in EtOAc and the solution washed with 3 1 M citric acid and then a solution of salt. The organic fraction is dried (MgSO4), filtered and concentrated, and get an orange-red oil. Crystallization from a mixture of Et2O/hexane gives 12.3 g (92%) named in the title compounds (9, Z = S, R5= isopropyl) as an orange crystalline substance.1H NMR (CDCl3) δ = 1,98 (d, 6N), of 1.24 (t, 3H), of 1.28 (t, 3H), 3,81 (K, 2N), 4,08 (K, 2N), 5,08 (K, 1H), 6,18 (d, 1H), 8,19 (d, 1H).

Stage 3. In a 250 ml round-bottom flask is charged with (9, Z = S, R5= isopropyl, 4,55 g of 13.8 mmol) and EtOH (100 ml). Slowly add the NaOH solution (to 5.66 g, 141 mmol) and Na2S (5,58 g, to 71.5 mmol) in 50 ml of water, and the reaction mixture is refluxed overnight in Ar atmosphere. The reaction mixture is neutralized to pH 6 with citric acid and then concentrated. The residue is dissolved in EtOAc, and the layers separated. The aqueous fraction is extracted with 2 EtOAc, and the combined organic fractions washed with salt solution, then dried (MgSO4), filtered and concentrated, and the obtained 3-amino-6-isopropylpyridine-2-thiol in the form of Packed brown substance.

Stage 4. In a 250 ml round bottom flask containing the crude reaction product obtained in stage 3 (˜to 13.8 mmol), add potassium salt of etelka is takenaway acid (3.42 g, of 21.3 mmol) and EtOH (100 ml). The reaction mixture is refluxed for 5 hours in an Ar atmosphere, then cooled approx. 40aboutWith and discolor activated carbon. Filtration through a 2-cm layer of celite give a light brown residue on the filter is dissolved in the minimum amount of water, the solution acidified with acetic acid, and receive the crude reaction product in the form of a yellowish-brown solid. Filtration and washing with water and then ether to give 2.55 g (82% from 9) 5-isopropylaminomethyl[5,4-b]pyridine-2-thiol (table 6, # PP 1) in the form of a yellowish-brown powder.1H NMR (DMSO-d6) δ = 1,09 (d, 6N), 3,90 (m, 1H), 6,44 (d, 1H), 6,74 (d, 1H), 7,25 (d, 1H), made 13.36 (Ushs, 1H); ESIMS: m/z 224 (M-N).

Table 7

Getting [5,4-b]pyridinediamine

isopropyl
no PPR5R4
1ethyl4-butoxyphenyl
2ethyl4-(trifluoromethyl)phenyl
3ethyl4-carboxymethyl
4isopropyl4-hexyloxyphenyl
54-carboxymethyl
6isopropyl4-(1-oxoethyl)phenyl
7isopropylisopropyl 4-tert-butoxyphenyl
8isopropyl4-(trifluoromethyl)phenyl

An example of the procedure of synthesis [5,4-b]pyridinediamine

3-(4-Butoxyphenyl)-1-ethyl-1-(2-mercaptothiazole[5,4-b]pyridine-5-yl)urea (table 7, No. PP 1)

In the reaction vial h mm from Pyrex load 5-ethylaminoethanol[5,4-b]pyridine-2-thiol (105 mg, 0.49 mmol), anhydrous pyridine (2 ml) and 4-butoxyaniline (135 μl, of 0.74 mmol). The reaction mixture is stirred for 3.5 hours and then concentrated. Purification preparative TLC (40% EtOAc in hexane) to give 26 mg (13%) named in the connection header.1H NMR (DMSO-d6) δ = of 0.91 (t, 3H), 1,10 (t, 3H), of 1.39 (m, 2H), 1.61 of (m, 2H), 3,91 (m, 1H), 6,80 (d, 2H), 7,30 (m, 3H), 7,99 (USD, 1H), 9,43 (s, 1H); ESIMS: m/z 401 (M-H); TPL 134,3-135aboutC.

Table 8

Getting [5,4-b]pyrizinamide
no PPR5R4
1ethylphenoxymethyl
2ethylbenzo is l
3ethyl4-butoxyphenyl
4ethyl4-hexyloxyphenyl
5ethylpyridine-4-yl
6isopropyl3-methylbutyl
7isopropyl4-(trifluoromethyl)phenyl
8isopropyl4-chlorophenyl

An example of the procedure of synthesis [5,4-b]pyrizinamide

N-Ethyl-N-(2-mercaptothiazole[5,4-b]pyridine-5-yl)-2-phenoxyacetamide (table 8, # PP 1)

In the reaction vial h mm from Pyrex load 5-ethylaminoethanol[5,4-b]pyridine-2-thiol (99 mg, 0.47 mmol), anhydrous pyridine (1.5 ml) and 4-butoxyaniline (100 μl, to 0.72 mmol). The reaction mixture is stirred for 2.5 hours and then concentrated. Purification preparative TLC (40% EtOAc in hexane) to give 36 mg (22%) named in the connection header.1H NMR (DMSO-d6) δ = 1,02 (t, 3H), of 3.73 (m, 2H), 6,70 (d, 2H), 6,86 (t, 1H), 7,19 (t, 2H), 7,29 (d, 1H), to 7.59 (USD, 1H); ESIMS: m/z 344 (M-H); TPL 107,5-109,0aboutC.

An example of the procedure of synthesis [5,4-b]pyridinecarboxylic connections

1.5-ml microwave reactor load 5-isopropylaminomethyl[5,4-b]pyridine-2-thiol (50 mg, 0.22 mmol), anhydrous pyridine (1.5 ml) and 4-chlorophenylalanine (40 μl,0.29 mmol). The reaction mixture is warm microwave at 120aboutC for 15 min and then concentrated. Purification preparative TLC (40% EtOAc in hexane) gives 10,2 mg (12%) named in the connection header.1H NMR (DMSO-d6) δ = 1,21 (d, 6N), was 4.42 (m, 1H), 7,17 (d, 2H), 7,39 (d, 2H), of 7.70 (d, 1H), 8,39 (d, 1H); ESIMS: m/z 378 (M-H).

All references mentioned in this specification, are included as references, such as links included all cited patents, patent applications and publications.

Modification of the described embodiment variants of the invention by virtue of the specialists in the art taking into account the guidance given in the description, and the state of the art.

Although described in certain variations of this embodiment of the invention, specialists in the art it should be borne in mind that various changes and modifications to this invention can be made without departing from the essence and scope of the invention. It is assumed that all such modifications within the scope of the invention covered by the claims. Therefore, the foregoing description is considered sufficient to enable a person skilled in the art to carry out the invention in practice. Indeed, it is understood that various modifications described above works for carrying out the invention that are obvious to experts in the field of mo is collaroy biology, chemistry, medicine, pharmacy or related areas covered by the following claims.

1. A compound selected from the group comprising compounds of the formula

where Y represents S;

C represents a substituted monocyclic 5-7-membered ring containing one nitrogen atom;

R1and R2are different, and each represents hydrogen, (C1-C12)-alkylamino or a group of the formula

where X represents O;

L represents-NR5-, -O-, -CH2or communication;

Q represents-NR5-; and

R4selected from substituted (C1-C12)-alkyl, substituted aryl, where these substituents independently selected from R9defined below;

R5represents hydrogen or straight or branched (C1-C12)-alkyl;

R6located in the 5th or 6th position of the structure II and selected from (C1-C12)-alkylamino, -NR8P(O)(R5)2and one of the following groups of the formulas:

where X represents O;

L represents-NR5-, -O-, -With the 2or communication;

R8represents a branched (C3-C12)-alkyl;

R13represents a substituted (C2-C12)-alkyl or p-R9-substituted phenyl,

where substituent R9selected from hydrogen, halogen, cyano,-CF3, -O-aryl, (C1-C12)-alkoxy, substituted (C1-C12)-alkoxy and carboxy(C1-C12)-alkyl;

Represents a bond;

n is one or two;

ring E represents a substituted 5-membered nitrogen-containing heteroaromatic ring;

R7represents hydrogen;

its corresponding enantiomers, diastereoisomers or tautomers, or pharmaceutically acceptable salt.

2. The compound according to claim 1, where the cycle is a pyridine.

3. The compound according to claim 2, where R1and R2attached at positions 5 or 6 in accordance with the numbering in the cycle specified for structure II.

4. The compound according to claim 3, where R1attached in position 6 in accordance with the numbering in the cycle specified for structure II.

5. The compound according to claim 4, of formula

[5,4-b]pyridine,

where R1represents a group of the formula

6. The compound according to claim 5, where R1you are the RAS group, having the formula

7. Derivative [5,4-b]pyridine according to claim 6, selected from the group which consists of the following aminopropane:

N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-(1-methylethyl)-4-(trifluoromethyl)benzamid,

4-cyano-N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-(1-methylethyl)benzamide,

N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-(2-methylpropyl)-4-(trifluoromethyl)benzamid,

4-cyano-N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-(2-methylpropyl " benzamid,

N-ethyl-N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-4-(trifluoromethyl)benzamid,

4-cyano-N-ethyl-N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)benzamid,

N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-methyl-4-(trifluoromethyl)benzamid,

4-cyano-N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-methylbenzamide.

8. Derivative [5,4-b]pyridine according to claim 6, selected from the group comprising the following ureidosuccinate:

N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-(1-methylethyl)-N'-[4-(trifluoromethyl)phenyl]urea,

N'-(4-cyanophenyl)-N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-(1-methylethyl)urea,

N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-(2-methylpropyl)-N'-[4-(trifluoromethyl)phenyl]urea,

N'-(4-cyanophenyl)-N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-(2-methylprop who yl)urea

N-ethyl-N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N'-[4-(trifluoromethyl)phenyl]urea,

N'-(4-cyanophenyl)-N-ethyl-N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)urea,

N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-methyl-N'-[4-(trifluoromethyl)phenyl]urea,

N'-(4-cyanophenyl)-N-(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)-N-metalmachine.

9. Derivative [5,4-b]pyridine according to claim 6, selected from the group comprising the following karamelnye connection:

4-(trifluoromethyl)phenyl-2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl(1-methylethyl)carbamate,

4-chlorophenyl-2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl(1-methylethyl)carbamate,

4-cyanophenyl-2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl(1-methylethyl)carbamate,

4-(trifluoromethyl)phenyl-2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)(2-methylpropyl " carbamate

4-chlorophenyl-2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl(2-methylpropyl " carbamate,

4-cyanophenyl-2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl(2-methylpropyl " carbamate

4-chlorophenolate(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)carbamate

4-cyanoferrate(2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl)carbamate

4-(trifluoromethyl)phenyl-2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl(methyl)carbamate,

4-chlorophenyl-2-mercapto[1,3]thiazolo[5,4-b]pyridine-5-yl(methyl)carbamate.

10. The compound according to claim 1, where R6attached in position 6, as is indicated is in the following structure:

11. The connection of claim 10, where R6selected from the group comprising the radicals represented by the formula

where R8represents a branched (C3-C12)-alkyl, and R13represents a substituted (C6-C12)-alkyl or p-R9-substituted phenyl.

12. Connection to item 11, where R9represents-CN, -CF3, (C2-C12)-alkoxy or substituted (C2-C12)-alkoxy.

13. Connection to item 11, where R8represents a branched (C3-C7)-alkyl, and R13represents the p-R9-substituted phenyl, where R9represents F, Cl, Br, I, -CN, -CF3, (C2-C12)-alkoxy or substituted (C2-C12)-alkoxy.

14. Connection claim 11, selected from the group comprising the following ureidopropionic:

N-(2-mercapto-1,3-benzothiazol-6-yl)-N-(1-methylethyl)-N'-[4-(trifluoromethyl)phenyl]urea,

N'-(4-cyanophenyl)-N-(2-mercapto-1,3-benzothiazol-6-yl)-N-(1-methylethyl)urea,

N-(2-mercapto-1,3-benzothiazol-6-yl)-N-(2-methylpropyl)-N'-[4-(trifluoromethyl)phenyl]urea,

N'-(4-cyanophenyl)-N-(2-mercapto-1,3-benzothiazol-6-yl)-N-(2-methylpropyl)urea.

15. Connection claim 11, selected from the group comprising the following karamelnye derivatives:/p>

4-(trifluoromethyl)phenyl-2-mercapto-1,3-benzothiazol-6-yl(1-methylethyl)carbamate,

4-chlorophenyl-2-mercapto-1,3-benzothiazol-6-yl(1-methylethyl)carbamate,

4-cyanophenyl-2-mercapto-1,3-benzothiazol-6-yl(1-methylethyl)carbamate,

4-(trifluoromethyl)phenyl-2-mercapto-1,3-benzothiazol-6-yl)(2-methylpropyl " carbamate,

4-chlorophenyl-2-mercapto-1,3-benzothiazol-6-yl(2-methylpropyl " carbamate,

4-cyanophenyl-2-mercapto-1,3-benzothiazol-6-yl(2-methylpropyl " carbamate.

16. Method of inhibiting malonyl-COA-decarboxylase in a patient's body, comprising introducing a therapeutically effective amount of a compound according to claim 1.

17. How to change the metabolism of fatty acids in a patient in the direction of the metabolism of carbohydrates, including the introduction of a therapeutically effective amount of a compound according to claim 1.

18. The method of treatment of diseases or syndromes associated with the metabolism of fatty acids and glucose by increasing the concentration of malonyl-COA in the body of a patient, comprising introducing a therapeutically effective amount of a compound according to claim 1.

19. The method according to p, where the disease is a cardiovascular disease.

20. The method according to claim 19, where the specified cardiovascular disease is a congestive heart failure.

21. The method according to claim 19, where the disease made the focus of an ischemic cardiovascular disease.

22. The method according to p to relieve angina resulting from coronary cardiovascular disease.

23. The method according to p, where the disease is a diabetes.

24. The method according to p, where the disease is an acidosis.

25. The method according to p, where the disease is the obesity.

26. The method according to p, where the disease is a cancer.

27. The pharmaceutical composition inhibiting malonyl-COA-decarboxylase, for treatment related to fatty acid metabolism and glucose diseases by increasing the concentration of SOA in the patient's body containing a therapeutically effective amount of compounds according to claim 1 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to the field of production of new heterocyclic o-dicarbonitriles

The invention relates to a new method for the preparation of 3-substituted cephalosporins of the formula (I):

where R1is a para-nitrobenzyl or allyl, X is a halogen; comprising the stage of: a) cyclization trimethylphosphine the compounds of formula (IIIA):

where R1is a para-nitrobenzyl or allyl, R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; in a solvent to form compounds of the formula (II):

where R1is a para-nitrobenzyl or allyl; R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; and (b) interaction of the compounds of the formula (II) with acid

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

The invention relates to a method for producing [1,2,4]triazolo[3,4-b][1,3]benzothiazol-3(2H)-thione of the formula

including fusion [1,2,4]triazolo[3,4-b][1,3]benzothiazole with excess sulfur in for 5-20 minutes at a temperature of 180-200With subsequent isolation of the target product

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

FIELD: biopharmacology, medicine.

SUBSTANCE: the suggested biotransplant contains an active component: the culture of genetically unmodified neuronal stem cells (NSC) obtained out of anterior cerebral tissue of human embryos of the 1st trimester of pregnancy or periventricular cerebral area of 15-20 wk gestation and selectively multiplied under cultivating conditions up to the quantity of 10 (7) - 10 (9) pluripotent undifferentiated cells in composition of neurospheres, at the content of NSC being 50-500 mln., and 2 ml physiological solution. The method for treating ischemic insult deals with introduction of 50-500 mln. NSC in 2 ml physiological solution. The suggested biotransplant and method for treating ischemic insult enable to quickly restore and improve cerebral functions.

EFFECT: shortened terms of therapy.

5 cl, 2 ex, 1 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes applying the known 2-imidazolyl-substituted carbinols as inhibitor of Na+/H+ exchange in treatment or prophylaxis of diseases caused by ischemia (myocardium infarction, stenocardia, heart ischemic state, ischemic state of peripheral and central nervous system, insult, shock state, hypoxic states of donor organs in removing, storage and transplantation in the recipient body). Also, compounds can be used as anti-arrhythmic agents with cardioprotective effect and for prophylaxis of high blood pressure genesis in essential hypertension.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: medicine, surgery.

SUBSTANCE: medicinal mixture consisting of 10 ml 0.25%-novocaine, 1 ml 1%-emoxypin and 64 c.u. lidase should be injected strictly subcutaneously per 1 ml for each point of injection into the center of plantar surface of nail phalanx of every toe, and for the first inter-toe space - subcutaneously in plantar and rear directions, then, after injections, it is necessary to carry out massage in area if injection with stretching and stroking movements in proximal direction for 10-15 sec, moreover curative seances should be performed every other day , the course being of 5-10 procedures, at repeating this course 3-6 mo later. The present innovation enables to activate transcapillary exchange due to pathogenetically proved impact onto surface and deep lymphatic network of inferior limbs.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves inducing angina pectoris attack on no medicament background. Provoking factor action time is measured to the moment the angina pectoris attack takes place. Nitroglycerine is administered in therapeutic dose to reach rapid relief of symptoms. The provoking factor action is repeated to reproduce attack of the same intensity. Provoking factor action time is measured once more. Prediction coefficient K value is calculated as ratio of the repeated provoking factor action time to the provoking factor action time to the moment the angina pectoris attack takes place. Prognosis is considered to be favorable, unfavorable or uncertain during the nearest year depending on K value.

EFFECT: high accuracy in evaluating coronary reserve.

2 tbl

FIELD: medicine, biochemistry.

SUBSTANCE: invention proposes applying CDP-choline (cytidinediphosphocholine) or its salt as a prophylactic agent for treatment of cerebral ischemia and a method for such prophylactic treatment. Invention found new and unknown early mechanism of action of CDP-choline or its salt: inhibition of activation of caspase cascade being the effectiveness of this effect is high in prophylactic intake of drug.

EFFECT: valuable medicinal properties of agent.

6 cl, 5 dwg, 4 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

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