Application of cyclic bioisoster derivaties of purine system for treatment of disorders caused by abnormalities of nitrergic and dopaminergic systems

FIELD: medicine; veterinary science.

SUBSTANCE: invention refers to application of compounds with common structural formula

R1=-H, -NH2, -Br, -Cl, -ОН, -СООН,

B=-N=, -CH=, Z=-CH=, -N=,

A=-CH- at B=-N=, Z=-CH-,

A=-CH- at В=-СН=, Z=-CH=,

A=-N= at B=-N=, Z=-CH-,

A=-CH- at B=-N=, Z=-N=,

A=-CH= at В=-СН=, Z=-N=.

Structures of specified formula are active for nitrergic and dopaminergic systems of mammal body including human body. These compounds can be applied as neuroprotectors, to improve cognitive function and to normalise psychophysiologic state, to treat consequences of substance abuse, as well as to treat wide range of diseases including neuropsychic, cardiovascular, immune, inflammatory and gastro-intestinal disorders.

EFFECT: application of new and well-known compound to effect nitrergic and dopaminergic systems for treatment purposes.

4 ex, 3 tbl, 8 dwg

 

The technical field

The invention relates to medicine, in particular to medicines, has directed action on the major neurotransmitter systems of the body, in particular for the treatment of various diseases associated with disorders of nitrergic and dopaminergic systems of the body. Such disorders include neurological, neuropsychiatric and cardiovascular diseases and disorders caused by substance abuse, particularly drug violations cognitive and psychophysiological state.

Prior art

It is known that a number of diseases of the nervous system and cardiovascular diseases, in particular the abuse of substances - drugs, alcohol, nicotine and other substances, as well as various mental disorders associated with a dysfunction of neurotransmitter systems. The status of these important systems to a significant extent determines the psychophysiological state of a person and virtually all the functions of the Central and peripheral nervous system in normal and pathological conditions. These systems, in particular, are Nyiregyhaza and dopaminergic systems.

Nitric oxide NO is a low molecular weight gas free radical nature - easily crosses the cell membrane and component of the intercellular substance, fulfilling an important role in various physiological processes. The influence of NO on the state of the cell largely depends on the amount of gas. In small quantities, produced mainly neuronal and endothelial isoforms of NO-synthase, NO action was largely due to the influence on heme group of soluble forms of the enzyme guanylate cyclase. The activated enzyme synthesizes cyclic guanosin monophosphate (hereinafter cGMP), which regulates the function of membrane ion channels, protein phosphorylation, the activity of phosphodiesterase and other reactions. In high concentrations, produced macrophage isoform of NO-synthase, NO can exert on cells of the toxic effects associated with a direct effect on the Fe-containing enzymes, and the formation of the strong oxidant - free radical compound peroxynitrite (ONOO-), which is generated by the interaction of NO with superoxidation (O2-). Toxic effect of nitric oxide is primarily manifested in the inhibition of mitochondrial enzymes, resulting in decreased production of adenosine triphosphate (hereinafter ATP), as well as enzymes involved in DNA replication. The ability of peroxynitrite and NO directly damaging DNA leads to the activation of protective mechanisms, in particular the activation of the farm is the poly(ADP-ribose) synthetase, that, in turn, leads to reduced ATP levels and can lead to cell death.

NO is synthesized in the cell from L-arginine by the enzyme NO-synthase (hereinafter NOC), converting L-arginine to NO and citrulline. This synthetic path is implemented, particularly in the cardiovascular and Central nervous system (hereinafter CNS), where NO performs the function of signaling molecules, including neurotransmitter function. Neurotransmitter function NO is that it is synthesized in the excitation of neuron and diffundere in neighboring cells, activates them in the formation of cGMP, can influence the conductivity of ion channels, and thus, change electrogenic neurons. Along with this NO in the Central nervous system is implementing a new, not synaptic and not mediated by receptors, the path interneuronal communications (Kiss J.P., E.S. Vizi, Nitric oxide: a novel link between synaptic and nonsynaptic transmission. Trends Neurosci., 2001, Apr., 24 (4): 211-5).

Influence nitrergic system on the function of the Central nervous system is both directly and indirectly through other neurotransmitter systems. For example, glutamate and its receptors mediate important functions of the Central nervous system, including memory, and also affect the development of depression and antidepressant activity. NO synthase and nitric oxide are important components of the transmission system with the persecuted in glutamatergic synapse (Paul I.A., Skolnick P. Glutamate and depression: clinical and preclinical studies. Ann. N Y Acad. Sci., 2003, Nov; 1003: 250-72). It is shown that the activity of monoamine oxidase, a key enzyme in the metabolism of monoamines in the brain is associated with the amount of NO in the cell (Girgin Sagin F., Sozmen DURING, Ersoz Century, G. Mentes Link between monoamine oxidase and nitric oxide. Neurotoxicology, 2004, Jan., 25 (1-2): 91-9).

NO effect on the function of monoaminergic transporters (Vizi E.S. Role of high-affinity receptors and membrane transporters in nonsynaptic communication and drug action in the central nervous system. Pharmacol. Rev., 2000, Mar., 52 (1): 63-89). NO facilitates the release of many of monoamines, especially dopamine, and, if necessary, blocks the presynaptic reuptake of dopamine. Therefore, NO increases the life expectancy of dopamine in the synapse. In regard to the involvement of dopamine in motor and psychological processes netservices influence on these processes has received increasing attention (Liu Y. Nitric oxide influences dopaminergic processes. Adv. Neuroimmunol., 1996, 6 (3): 259-64).

NO mediates many of the behavioral and neuroendocrine reactions of the organism, in particular aggressive and impulsive behavior. NO plays an important role in the functioning of the serotonin receptors in the brain (Chiavegatto, S., Nelson R.J. Interaction of nitric oxide and serotonin in aggressive behavior. Horm. Behav., 2003, Sep., 44 (3): 233-41). Monoaminergic system and NO hypothalamus, limbic and brainstem structures involved in the regulation of sexual behavior, control the preference of partner's sexual desire, erection, copulation, ejaculation, the body and sexual satisfaction) (J.G. Pfaus Neurobiology of sexual behavior. Curr. Opin. Neurobiol., 1999, Dec., 9 (6): 751-8).

It is known that NO plays an important role in the formation of different drugs, including opioids, ethanol, stimulants and nicotine. In particular, NO is involved in the manifestation and development of withdrawal symptoms drugs. For example, activation of opioid receptors μ3 accompanied by the release of NO in endothelial cells, granulocytes, monocytes and microglial (Stefano G.B. Autoimmunovascular regulation: morphine and anandamide and ancondamide stimulated nitric oxide release. J.Neuroimmunol., 1998, Mar., 15, 83 (1-2): 70-6), NO plays an important role in the development of dependence of various compounds, addictive. Thus, modulation of NO may be a potential therapeutic target for the treatment of addictions of all kinds (Tayfun Uzbay I., Oglesby M.W. Nitric oxide and substance dependence. Neurosci. Biobehav. Rev., 2001, Jan., 25 (1): 43-52).

NO participates in the regulation of neurotransmission in the Central nervous system, in particular, Poreba nesinapticheskie interaction, adjusting monoaminergic system - dopaminergic, noradrenergic. Thus, dysfunction of NO directly associated with major neuropsychiatric diseases such as depression, Parkinson's disease and other (Kiss J.P. Role of nitric oxide in the regulation of monoaminergicneurotransmission. Brain Res. Bull., 2000, Aug., 52 (6): 459-66).

Elevated levels of monoamine oxidase, oxidative stress, excitotoxicity, and excessive NO synthesis characteristic of neurodegenerative diseases such as Alzheimer's and Parkinson's disease, stroke and other (Mandel s, Grunblatt e, Riederer p, Gerlach m, Levites y, Youdim M. Neuroprotective strategies in PA's disease: an update on progress. CNS Drugs, 2003, 17 (10): 729-62).

The basis for the development of addictions and psychosis lies behavioral sensitization-mediated activation of dopamine receptors D1 and NMDA receptors with subsequent increased activity of the NOC (Ujike H. Advanced findings on the molecular mechanisms for behavioral sensitization to psychostimulants. Nippon Yakurigaku Zasshi., 2001, Jan., 117 (1): 5-12).

Excessive release of NO from blood vessels, perivascular nerve endings or brain consider the molecular mechanism that triggers spontaneous pain in migraine (Olesen j, Jansen-Olesen I. Nitric oxide mechanisms in migraine. Pathol. Biol., Paris, 2000, Sep., 48 (7): 648-57).

Dopamine (hereafter DA) is the most important neurotransmitter and neuromodulator, which plays an important role in the body. In the Central nervous system DA is involved in the control of movement, cognitive function, emotional, neuroendocrine secretion and function of cells of the retina. On the periphery of the DA is involved in the regulation of homeostasis, vascular tone and secretion of hormones. In the Central nervous system dopamine receptors are widely represented in various who's areas of the brain (Missale C., Nash S.R., S.W. Robinson, Jaber m, Caron M.G. Dopamine receptors: from structure to function. Physiol. Rev., 1998, Jan., 78 (1): 189-225). Various physiological functions of DA is mediated, at least five families of DA receptors: D1-D5. Dysfunction of these receptors is observed in various disorders and Central nervous system diseases, in particular Parkinson's disease (Zawilska J.B. Dopamine receptors-structure, characterization and function. Postepy, Hig. Med. Dosw., 2003, 57 (3): 293-322).

Dopamine signaling in certain parts of the brain is a key element in the development of drug dependence (Fagen Z.M., H.D. Mansvelder, Keath J.R., Mc.Gehee D.S. Short - and long-term modulation of synaptic inputs to brain reward areas by nicotine. Ann., NY Acad. Sci., 2003, Nov., 1003: 185-95). Interaction with DA receptors underlies the acute effects of amphetamine and cocaine (Ujike H. Molecular biology of drug dependence and behavioral sensitization. Seishin Shinkeigaku Zasshi., 2002, 104 (11): 1055-68; M.E. Wolf, Mangiavacchi, S., Sun X. Mechanisms by which dopamine receptors may influence synaptic plasticity. Ann. NY Acad. Sci., 2003, Nov., 1003: 241-9). Dopamine agonists mediate dependence on alcohol, nicotine and stimulants (Kosten T.R., George T.P., T.A. Kosten The potential of dopamine agonists in drug addiction. Expert Opin. Investig. Drugs, 2002, Apr., 11 (4): 491-9).

There is a hypothesis that violations of the dopaminergic system underlie schizophrenia (Pearlson G.D., Neurobiology of schizophrenia. Ann. Neurol., 2000, Oct., 48 (4): 556-66). Dopamine hypothesis of schizophrenia postulates imbalance of cortical/subcortical dopamine system and disruption of dopaminoceptive D1 (Abi-Dargham A., Moore H. Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. Neuroscientist, 2003, Oct., 9 (5): 404-16). Along with schizophrenia etiology and other psychotic diseases associated with dysregulation of the dopamine system of the brain (Conley R.R., Kelly D.L. Current status of antipsychotic treatment. Curr. Drug Target CNS. Neurol. Disord., 2002, Apr., 1 (2): 123-8).

Dopamine mechanisms mediate the etiology and manifestations of anxiety (Taylor, D.P., Riblet L.A., Stanton H.C., Eison AS, Eison M.S., Temple DL Jr., Dopamine and antianxiety activity. Pharmacol. Biochem. Behav., 1982, 17, Suppl. 1: 25-35), and many drugs with antipsychotic action modulate the activity of the D2 dopamine receptor (Kapur, S., Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2003, Oct., 27 (7): 1081-90).

Thus, in the development of many pathologies violations nitrergic system directly associated with impaired dopaminergic system. These abnormalities include chemical dependency disorders caused by substance abuse, such as drug addiction, alcohol and nicotine, sleep disorders, sexual dysfunction, including sexual dysfunction, gastrointestinal disorders, psychosis, affective disorders, nonorganic psychosis, personality disorders, psychiatric mood disorders, schizophrenia and schizoaffective disorder, polydipsia, bipolar disorders, dysphoric mania, anxiety and related what her disease, obesity, bacterial infections of the Central nervous system such as meningitis, human learning, memory disorders, Parkinson's disease, depression, extrapyramidal side effects of neuroleptics, the hypothalamic-pituitary disorders, vascular and cardiovascular disease, dystonia, dyskinesia, hyperkinesia, dementia, ischemia, motor disorders, hypertension, and diseases caused by a hyperactive immune system such as allergies and inflammation, in mammals, including humans.

The development of drugs for treatment of disorders caused by impaired function nitrergic and dopaminergic systems by normalizing these systems is a very important task.

Known tricyclic amines with Central dopaminergic activity (US, 4612316, A), as well as the dihydropyridines carboxamide, dihydroquinoline and the isoquinoline carboxamide (US, 4727079, A), new derivatives of aminotriazole and aminoanisole (US, 4904676, A), with the brain-specific dopaminergic activity.

Known application benzothiazolinone for the induction of antipsychotic, antidepressant and antidopaminergic activity in warm-blooded animals (US, 4547507, A).

It is known the use of fenoldopam 4',8-bis-hydrosulfate and its salts as drugs with Pro-dopamine the practical activity (US, 4600714, A).

The proposed application (1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazoline and 4-(hexahydro-1-alkyl-3-pyridinyl)-2-thiazolines with suspected antipsychotic activity for the treatment of psychosis, high blood pressure, Parkinson's disease, hyperprolactinemia and sexual disorders and acromegaly (US, 46508054, A).

Known substituted 1-(alkoxyphenyl)piperazines partial dopamine agonists that are proposed for use for the treatment of disorders of regulation of dopamine and treatment of Parkinson's disease, schizophrenia and drug abuse (US, 5281594, A).

The proposed derivatives benzimidazolone with Central dopaminergic activity (US 5889010, A; US, 5883094, A), and N,N'-duhsasana derivatives benzimidazolone (US, 6521623, A), which may be used to treat a wide range of diseases of the nervous system.

In the above-mentioned analogues presents only the data link corresponding compounds with dopamine receptors, but in any case not proved the existence of a specific therapeutic activity in animal models or in clinical trials.

Disclosure of inventions

The aim of the present invention is to provide medicines for the correction of violations nitrergic and dopaminergic systems and disorders disorders of these systems, often the spine of diseases of the nervous and cardiovascular systems, including disorders caused by substance abuse, disorders of cognitive functions and psychophysiological state.

When creating the present invention was tasked with identifying biologically active compounds possessing the ability to normalize the work as nitrergic and dopaminergic systems by regulating the level of NO in the cell due to the correction of the activity of different isoforms of NO-synthase, and by linking excessively generated reactive nitrogen, in particular peroxynitrite or NO-radical.

As biologically active compounds possessing necessary to solve this problem properties were considered cyclic bioisostere purine derivatives of the system having the General structural formula

R1=-H, -NH2, -Br, -Cl, -OH, -COOH,

B=-N=, -CH=, Z=-CH=, -N=,

A=N= B=N=, Z=-CH-,

A=-CH= at=-N=, Z=-CH-,

A=-CH= at=-N=, Z=, N=,

A=-CH==CH=, Z=-CH=,

A=-CH==CH=, Z=, N=,

and their pharmacologically acceptable salts, has a normalizing effect on intracellular processes, in particular on netservices mechanisms cells (PCT/EN 03/00346). The authors suggested that condensed pyridazinedione systems have specific neurotropic activity, with a positive effect tie is n and the normalization of the specified compounds of the disturbed functions nitrergic and dopaminergic systems.

The mechanisms of the effect of cyclic bioisosteres derivatives of purine system nitrergic system can include changing the pH in the cell, affecting synthase activity of nitric oxide, a direct interaction of these compounds with nitric oxide and peroxynitrite in the cell and outside the cell, which has an impact on nitrergic system in General and on the free radical homeostasis of a biological object. These compounds may also differentially modulate the activity of different isoforms synthase nitric oxide, which is largely responsible for the change in the functional state of cells, organs, tissues, and ultimately, of the whole organism. The effect of the compounds according to the invention on the dopamine system may be provided due to changes in electron density in the protein molecules of dopamine receptors or by changing the properties of the surrounding receptors on the membranes. An additional effect of these compounds on other types of receptors, such as adenosine, may indirectly modulate the activity of dopamine receptors.

Were investigated derivatives of pyrido[2,3-d]-6N-pyridazine-5,8-dione, cyclic bioisostere derivatives of purine system, in which the pyridine ring condensed with pyridazinedione ring having the General formula

atom Li, Na, K,

R1=-N, -NH2, -Br, -OH, -COOH,

in particular:

7-(β-D-ribofuranosyl)pyrido[2,3-d]-6N-pyridazine-5,8-dione sodium salt (1),

4-amino-7-(β-D-ribofuranosyl)pyrido[2,3-d]-6N-pyridazine-5,8-dione sodium salt (2),

3-bromo-7-(β-D-ribofuranosyl)pyrido[2,3-d]-6N-pyridazine-5,8-dione sodium salt (3),

4-hydroxy-7-(β-D-ribofuranosyl)pyrido[2,3-d]-6N-pyridazine-5,8-dione disodium salt (4),

3-carboxy-7-(β-D-ribofuranosyl)pyrido[2,3-d]-6N-pyridazine-5,8-dione disodium salt (5),

pyrido[2,3-d]-6N-pyridazine-5,8-dione lithium salt (6),

pyrido[2,3-d]-6N-pyridazine-5,8-dione sodium salt (7),

pyrido[2,3-d]-6N-pyridazine-5,8-dione potassium salt (8).

And were investigated derivatives of benzo[d]-3H-pyridazine-1,4-dione, cyclic bioisostere derivatives of purine system, in which the benzene ring is condensed with pyridazinedione ring having the General formula

atom Li, Na, K,

R1=-N, -NH2, -Cl, -OH, -COOH,

in particular:

2-(β-D-ribofuranosyl)benzo[d]-3H-pyridazine-1,4-dione sodium salt (9),

5-amino-2-(β-D-ribofuranosyl)benzo[d]-3H-pyridazine-1,4-dione sodium salt (10),

6-amino-2-(β-D-ribofuranosyl)benzo[d]-3H-pyridazine-1,4-dione sodium salt (11),

5-chloro-2-(β-D-ribofuranosyl)benzo[d]-3H-pyridazine-1,4-dione n is trieva salt (12),

5-hydroxy-2-(β-D-ribofuranosyl)benzo[d]-3H-pyridazine-1,4-dione disodium salt (13),

5-amino-benzo[d]-3H-pyridazine-1,4-dione lithium salt (14),

5-amino-benzo[d]-3H-pyridazine-1,4-dione sodium salt (15),

6-amino-benzo[d]-3H-pyridazine-1,4-dione potassium salt (16),

5-hydroxy-benzo[d]-3H-pyridazine-1,4-dione disodium salt (17),

6-carboxy-benzo[d]-3H-pyridazine-1,4-dione disodium salt (18).

Were also investigated derivatives pyrazino[2,3-d]-6N-pyridazine-5,8-dione, cyclic bioisostere derivatives of purine system, in which pyrazinone ring condensed with pyridazinedione having the General formula

atom Li, Na, K,

R1=-N, -NH2, -Br, -OH, -COOH,

in particular:

7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione sodium salt (19),

2-amino-7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione sodium salt (20),

3-amino-7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione sodium salt (21),

3-bromo-7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione sodium salt (22),

2-hydroxy-7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione disodium salt (23),

2-carboxy-7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione disodium salt (24),

pyrazino[2,3-d]-6N-pyridazine-5,8-dione lithium salt (25),

pyrazino[2,3-d]-6N-is ridazin-5,8-dione sodium salt (26),

3-bromo-pyrazino[2,3-d]-6N-pyridazine-5,8-dione potassium salt (27),

2-amino-pyrazino[2,3-d]-6N-pyridazine-5,8-dione sodium salt (28).

Were also investigated derivatives of pyrimido[4,5-d]-6N-pyridazine-5,8-dione, cyclic bioisostere derivatives of purine system, in which the pyrimidine ring condensed with pyridazinedione ring having the General formula

atom Li, Na, K,

R1=-H, -NH2, -Br, -OH, -COOH,

in particular:

7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (29),

2-amino-7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (30),

4-amino-7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (31),

2-bromo-7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (32),

4-hydroxy-7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (33),

4-carboxy-7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (34),

pyrimido[4,5-d]-6N-pyridazine-5,8-dione lithium salt (35),

2-amino-pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (36),

4-bromo-pyrimido[4,5-d]-6N-pyridazin -5,8-dione potassium salt (37).

Compounds 1-8, which are derivatives of pyrido[2,3-d]-6N-pyridazine-5,8-dione, was obtained by condensation of ortho-dicarboximide pyridines with hydrazine guy who Rotom in the acetic acid medium (Hiroshi Taguchi. A new fluorometric assay method for guinolinic acid. Analitic Biochemistry, 1983, 131 (1), p.194-197).

Compounds 9-18 derived benzo [d]-3H-pyridazine-1,4-dione (phthalazinedione), was obtained by condensation of ortho-phthalic acid with hydrazinehydrate on Wednesday acetic acid (Huntress E.H., Stanley L.N., Parker A.S. The preparation of 3-Aminophtalhydrazide for use in the Demonstration of Chemiluminescence, J, Am. Chem. Soc., 1994, v.56, p.241-242).

Connection 19-28 derived pyrazino[2,3-d]-6N-pyridazine-5,8-dione, was obtained by condensation of ortho-dicarboximides of pyrazino hydrazinehydrate in the acetic acid medium (Zyczynska - Baloniak I., R. Czajka, Zinkowska E., Synthesis of Derivatives of 4-Hydroxypyrazine-[2,3-d]pyridazine-1-one. Polish Journal of Chemistry. 1978, v.52, p.2461-2465; Kormendy K., P. Ruff condensed Pyridazines with a Heteroring. W., Acta Chimika Hungarika. 1990, 127 (2), p. 253-262). Connection 29-37, which is the derivative of pyrimido[4,5-d]-6N-pyridazine-5,8-dione, was obtained by condensation of ortho-dicarboximide pyrimidines with hydrazinehydrate with the acetic acid medium (Yurugi, S., M. Hieda Studies on the synthesis of N - Heterocyclic Compounds. Chemistry, Pharmaceutic Bull., 1972, v.20 (7), p.1522-1527, ibid., p.1513-1521).

The task was solved by detecting the biological activity of the above cyclic bioisosteres purine systems and their pharmacologically acceptable salts on netservices and dopaminergic mechanisms of cells with violations of such systems.

The invention is further illustrated by the following examples, not limiting the subject is subramania, illustrating in vivo models of various pathologies effect of the use of these compounds for disorders caused by the violation nitrergic and dopaminergic systems of the animal body.

1. The effect of the compounds according to the invention on disorders of morphine abstinence.

Were investigated the effects of compounds№1, 4, 6, 10, 11, 18, 21, 24, 26, 32, 35, 37 according to the invention on behavioral indicators, and nitrergic system of the brain of the animals with a known model, recognized as a model of heroin abstinence man, was modeled state of physical dependence on morphine - morphine abstinence.

Physical dependence on morphine was modeled on 27 groups of male Wistar rats weighing 250-350 g age 6 months:

animals of group 1 (n=7) morphine was not introduced, and they were control,

- animals of group 2 (n=7) were injected morphine hydrochloride to achieve a pronounced withdrawal syndrome,

- animals of groups No. 3-14 (n=7) was administered one of the compounds pyridopyrimidines row - 1, or 4, or 6 according to the invention (group №3, 4, 5), or one of the compounds benzodiazepinovogo row - 10, or 11, or 18 according to the invention (group №6, 7, 8), or one of the compounds pyrazinediium row - 21, or 24, or 26 according to the invention (gr is PPI No. 9, 10, 11), or one of the compounds pyrimidinemethanol series - 32, or 35, or 37 (group№12, 13, 14),

- animals of groups 15 to 26 (n=7) was administered morphine hydrochloride to create a pronounced withdrawal syndrome, and then each group one of the compounds according to the invention the same for groups No. 3-14.

Injections of morphine hydrochloride was carried out intraperitoneally according to the modified scheme: within 6 days twice a day (10 h 00 20 h 00) in increasing doses of 10-100 mg/kg: day 1 - 10 mg/kg, day 2 - 20 mg/kg, day 3 - 40 mg/kg, 4 day - 60 mg/kg, 5 day, 80 mg/kg, 6 day - 100 mg/kg Injection of the compounds according to the invention was performed three times intramuscularly at a dose of 20 mg/kg / day following your last dose of morphine. (Dum J, Blasig J, Herz A: Buprenorphine: demonstration of physical dependence liability. Eur. J. Pharmacol., 1981, V.70, p.293-300.; Rahman, S., Ali R. Khan, Kumar A. Experimental study of the morphine de-addiction properties of Delphinium denudatum Wall, BMC Complement Altern. Med., 2002, V.29, p.1-6). 36 hours after the last injection in the groups was assessed motor and autonomic signs of animal behavior on grounds that are specific signs of abstinence, in the open-field test (arena with a diameter of 120 cm and a wall height of 40 cm).

The severity of the withdrawal syndrome was assessed for 5 min on a number of specific withdrawal syndrome musculoskeletal symptoms: otrajjjenie type wet abaci", cramps, chewing, squeaking teeth, shake paws, and autonomic signs: diarrhea, ptosis, rhinorrhea, piloerection, dyspnea, squeak when durgiana, aggressiveness (Blasig J., Herz, A., Reinhold, K., Zieglgansberger S. Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia, Berlin, 1973, V.33, p.19-38; Rahman, S., Alt, Khan R., Kumar A. Experimental study of the morphine de-addiction properties of Delphinium denudatum Wall, BMC Complement Altern. Med., 2002, V.29, p.1-6.). The observed signs were recorded quantitatively (if possible) with further assignment to each symptom index (depending on the specificity of the topic) and count the total score. The severity of the withdrawal syndrome was presented in the form of scores. The results were processed with the use of nonparametric statistical analysis using test Mann-Whitney.

Figure 1 shows a diagram of the influence of morphine and compounds according to the invention on the behavioral reactions of the studied animals, on which the impact is estimated on average for a number of compounds the sum of M points on the basis of these indices show signs of withdrawal for the animals of groups No. 1-27.

Table 1 presents the average relative data.

Table 1

The effect of the compounds according to the invention on the development of morphine withdrawal
Specific symptoms of the abstinenceIndexSignificant differences (ChiGK- square) in the manifestation of signs of withdrawal
Control - morphineMorphine(Morphine + connection 1 or 4 or 6)Morphine(Morphine + connection 10, or 11,

or 18)
Morphine(morphine + connection 21, or 24,

or 26)
Morphine(morphine + connection 32, or 35, or 37)
otrajjjenie "wet dog"2is 0.00021,00000,75620,78211,0000
cramps20,05070,78210,75460,34560,5578
chewing20,03080,18880,10320,19750,1888
creak teeth20,12660,71440,86520,29940,7003
shaking paws20,01800,78210,82170,67450,9321
squeak when durgiana10,00530,18880,13420,1968,0,2035
diarrhea1 0,00750,00460,00320,00670,0001
ptosis20,00530,02010,03200,01050,0232
rhinorrhea30,29940,30170,40320,21310,2935
piloerection20,57700,18470,25670,25670,2345
dyspnoea20,00530,07220,08340,05670,0685
aggressiveness10,57700,83270,84560,79210,8456

From table 1 it is seen that the features that characterize the development of withdrawal syndrome, the compounds according to the invention most effectively cut short diarrhea, ptosis and dyspnoea. They influenced the seizures caused by the cancellation of morphine.

Thus, was able to identify certain components of morphine abstinence, sensitive to the correction of the compounds according to the invention.

2. The effect of the compounds according to the invention on netservices indicators in the brain.

2.1. Obtaining material for biochemical studies

After the above experiments in rats has withdrawn the brain and CPA who has put them in ice 0,9%solution of sodium chloride. From the brain after cooling has identified the following patterns: the cerebral cortex, hippocampus, midbrain, striatum, brain stem, hypothalamus and cerebellum. The selected tissue is homogenized in a Potter homogenizer S for 3 min at 1500 rpm in 4-5 volumes of 20 mm HEPES (pH 7.5) at 4°s Supernatant were centrifuged for 30 min at 11000 g at 4°and part of the received supernatants were selected for the determination of nitrate and nitrite (NOx-), and the remaining portion was added a chilled 20 mm HEPES (pH 7.5)containing 0.5 mm ethylenediaminetetraacetate (EDTA), 1 mm dithiothreitol (DDT), 1 mm phenylmethylsulfonyl (FMSF), Aprotinin and leupeptin at a concentration of 5 μg/ml, and used for determination of enzyme activity synthase nitric oxide (NOC).

2.2. Determination of nitrate/nitrite (NOx-)

To assess the intensity of metabolism of nitric oxide in rats conducted quantitative determination of stable metabolites of nitric oxide, nitrite and nitrate (NOx-) the fluorometric method of fluorescence intensity of naturasil, the reaction product of 2,3-diaminonaphthalene (DAN) and nitrite in an acidic environment (Misko BECAUSE, R.J. Schilling, Salvemini D. et al. A fluorometric assay for the measurement of nitrite in biological samples. Anal. Biochem., 1993, V.214, p.11-16) with modifications (Lei C., Adachi N., Nagaro T., Arai T. Measurement of total nitric oxide metabolite (NO(x)(-)) levels in vivo. Brain, Res. Protoc., 1999, V.4, p.415-419).

Deprate sirovaniya at 100° With supernatant brain was placed in nitrite-regenerating system containing 0.125 U/ml nitrate reductase, 25 μm NADFN and 25 μm FAD, prepared in 20 mm Tris-HCl buffer pH 7.6 and incubated for 30 min at 37°C. For the oxidation NADFN used a lactate dehydrogenase (LDG)/pyruvate. Then added 316,0 μm solution GIVEN in 0,62 M HCl and incubated for 10 min in the dark. To stabilize the fluorescence of the formed naturasil was added 280 mm NaOH. The intensity of fluorescence was measured on spectrofluorimeter Hitachi F-3000 wavelength excitation 365 nm and emission at 405 nm. To calculate the concentration of NOx-in the brain was used a standard solution of sodium nitrate. The concentration of NOx-expressed in nmol/mg protein.

2.3. The determination of the activity of the synthase nitric oxide

Synthase activity of nitric oxide (NOC) was determined by a radiometric method for the rate of accumulation of L-citrulline in the oxidation of [3H]L-arginine catalyzed by NOC (Bredt and Snyder. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc. Natl. Acad. Sci., USA, 1989, V.86, p.9030-9033). The formation of L-citrulline in this reaction is equivalent to the biosynthesis of nitric oxide.

The reaction was initiated by adding the supernatant of the brain in reaction medium containing 2 µci/ml of [3H]L-arginine, 20 mm HEPES (pH 7.4), 0.2 mm CaCl25 μm FAD, 5 μm FMN, 1 mm NADFN, 50 µm, NR4when the study is of supernatants brain. After 15-60 minutes incubation at 37°the samples were added to a suspension of Dowex 50WX8-400 (Na+-form), which adsorb unreacted [3H]L-arginine, but not [3H]L-citrulline. After sorption, the radioactivity of the samples was determined on the acquired scintillation counter SL-4000 ("Intertechnique"). The activity of CA2+dependent and CA2+-independent isoforms NOC was determined by the difference of speeds of education [3H]L-citrulline in three parallel samples containing 2 mm EDTA (chelator of CA2+), 2 mm EDTA+ 2 mm L-NAME (inhibitor of all isoforms NOC) and without inhibitors. The enzyme activity was expressed in pmol of [3H]L-citrulline accumulated for 1 min per mg protein in the supernatant.

2.4. Quantitative determination of protein

The protein content in samples was determined by the method of Bradford (Bradford, M. M. And rapid and sensitive method for quantitation of microgram quantities of protein using the principle of protein binding. Anal. Biochem., 1976, V.72, p.248-254) using the dye Kumasi blue. Statistical analysis was performed by methods that are adequate for a particular sample. Data are presented as mean ± error of the mean.

Table 2

The influence of morphine and compounds according to the invention on the performance nitrergic system in the brain
The indicator in the Department of brainGroup 1 (control)G is the SCP No. 2 (morphine) Group No. 3-14 (a Compound from the group 1, 4, 6, 10, 11, 18, 21, 24, 26, 32, 35, 37)Group No. 15-17 (Morphine + connection 1 or 4 or 6Group No. 18-20 (Morphine + connection 10, or 11, or 18)Group No. 21-23 (Morphine + connection 21, or 24, or 26)Group No. 24-27 (Morphine + connection 32, or 35, or 37)
Nitrite, nmol/mg protein:
the cerebral cortex4,63±0,295,31±0,29or 4.31±0,374,72±0,374,93±0,394,62±0,274,84±0,31
the cerebellum6,37±0,646,07±0,426,66±0,635,46±0,445,85±0,475,76±0,495,93±0,54
trunk8,24±1,027,63±0,96of 6.31±0,586,57±0,726,99±0,827,07±0,856,87±0,81
striatum7,25±0,664,92±0,436,11±0,293,57±0,423,57±0,423,57±0,423,57±0,42
the hippocampus4,39±0,236,45±0,696,47±0,725,44±0,435,24±0,495,27±0,415,31±0,33
midbrain5,66±0,199,41±1,206,65±0,705,50±0,485,75±0,395,99±0,585,95±0,52
the hypothalamus6,57±0,504,62±0,716,77±0,836,57±0,886,91±0,586,87±0,756,77±0,46
Activity NOC, pmol/min/mg protein:
striatum1,73±0,071,19±0,141,26±0,081,24±0,081,29±0,091,21±0,101,34±0,09
midbrain2,18±0,09is 3.08±0,092,60±0,291,83±0,231,99±0,292,03±0,311,89±0,27
the hippocampus2,55±0,123,10±0,203,09±0,162,70±0,14of 2.51±0,192,33±0,112,65±0,15
the hypothalamuslower than the 5.37±0,203,42±0,54the 5.45±0,245,26±0,28are 5.36±0,335,47±0,325.56mm±0,34

As can be seen from the results given in table 2, in the brain morphine had a specific influence on the accumulation of nitrite and the asset is ity NOC: in the striatum and hypothalamus were observed decrease netservices indicators and in the midbrain and the hippocampus - their increase (P<0,05; P=0.1 for nitrites in the hypothalamus, T-test). Compounds according to the invention were cut short by the broken morphine activity NOC in the hypothalamus, the midbrain and the hippocampus.

Conclusions

Thus, when the withdrawal syndrome of morphine compounds according to the invention, is entered three times in a dose of 3×20 mg/kg intramuscularly, have the following effects:

- cropped development of withdrawal syndrome, first of all, these components of behavioral disorders like diarrhea, ptosis,dyspnea,

- improve physiological condition due to antidepressant action in the inhibition of the withdrawal syndrome,

- provide differentiated and specific impact on various synthase isoforms of nitric oxide by correction of disturbed netservices mechanisms in the brain.

These data suggest a promising use of the compounds according to the invention for the treatment of disorders caused by substance abuse, particularly drug.

3. The effect of the compounds according to the invention on disorders of sexual function associated with impaired dopaminergic system.

One of the mechanisms that regulate reproductive function of mammals, associated with the functioning of the dopaminergic system of the brain. It is known that non-selective and is honest D1/D2 receptors apomorphine in low doses causes erection of the penis in rodents (Giuliano F., Allard J. Dopamine and male sexual function. Eur. UroL, 2001, 40 (6), 601-608; Giuliano f, Allard j, Rampin O. et. al. Pro-erectile effect of systemic apomorphine: existence of a spinal site of action. J. UroL, 2002, 167 (1), 402-406; Brien S.E., C. Smallegange, Gofton W.T., et. al. Development of a rat model of sexual performance anxiety: effect of behavioral and pharmacological hyperadrenergic stimulation on apomorphine-induced erections. Int. J Impot. Res., 2002, 14 (2), 107-115.). In this regard, the influence of the compounds according to the invention on apomorphine-dependent erection in rats.

In the experiment used the 9 groups of adult rats male Wistar rats weighing 350-450 g, kept under normal light mode. Participated in experiment rats with normal (non-inverted) light cycle. To study the effect of compounds on sexual function were selected nizkoplotnye animals with the same erection. Control group # 1 (n=7) amounted to animals not injected with the compounds according to the invention. Animals of groups No. 2-9 (n=7) one of the compounds according to the invention, selected from the group of compounds 2, 8, 9, 15, 19, 25, 31, 36, was administered intraperitoneally rate: 5 injections at a dose of 10 mg/kg with an interval between injections 48 hours. Apomorphine was dissolved in 0.1%aqueous solution of ascorbic acid and then introduced everyone subcutaneously at a dose of 0.1 mg/kg every 24-28 hours after the last injection of the compounds according to the invention. Registration of sexual activity was performed individually for each animal immediately after BB is the origin of apomorphine; check-in time of 20 minutes were Recorded: time of occurrence of the first erection, the time intervals between erections, the number of erections during the whole period of observation.

For statistical processing of results was used T-test and Chi-square. The results are presented in table 3 in the form of averages ± error of the mean.

Table 3
The effect of the compounds according to the invention on disorders of sexual function in rats
Group (experimental conditions)The latent period of the first erection, minThe number of erections during the whole observation periodThe interval between the 1st and 2nd erection, minThe interval between the 2nd and 3rd erection, min
No. 1 (Control + apomorphine)6,63±0,992,00±0,374,60±0,535,90±0,87
No. 2-3 (compound 2 or 8 + apomorphine)to 5.21±0,30 P=0.13,13±0,35 P<0,053,94±0,605,52±1,14
No. 4-5 (compound 9 or 15 + apomorphine)5,09±0,27 P<0,13,24±0,39 P<0,05a 3.87±0,595,19±0,78
No. 6-7 (compound 19 or 25 + apomorphine)5,24±0,19 P<0,13,29 0,27 P<0,053,75±0,645,12±0,87
No. 8-9 (compound 31 or 36 + apomorphine)5,12±0,24 P<0,13,32±0,31 P<0,053,34±0,695,02±1,01

From the research results presented in table 3, it is seen that the compounds according to the invention significantly increased the number of erections in animals (more than 1.5 times) and showed a statistically significant tendency to decrease the latent period of the first erection 1.3 times.

Conclusions

Thus, revealed a beneficial effect of the compounds according to the invention on sexual function in rats.

Because the model uses certain cerebral mechanisms can be considered that the mechanism of action of the compounds according to the invention is associated with its effect on the dopaminergic system of the brain, in particular, elimination dysfunction D1/D2 dopamine receptors. From the obtained results it is evident that the compounds according to the invention can also be applied for the correction of numerous pathologies of the nervous system associated with dysfunction of the dopaminergic system.

4. The effect of the compounds according to the invention on cognitive function and physiological state of animals

Conducted a screening analysis of the effects of the compounds according to izaberete the Oia on the processes of learning and memory, as well as the psycho-physiological condition of the rats.

4.1. The experimental technique

The study used Wistar rats weighing 220-300 g In each test were used to control №1 (n=10) and experimental group No. 2-9 (n=10).

Animals of groups No. 2-9 introduced one of the compounds from the group of compounds№2, 7, 11, 17, 20, 28, 29, 35 according to the invention intramuscularly single dose of 10 mg/kg of Drugs were dissolved in neutralized water. To study the effect of the compounds according to the invention were selected widely used tests of learning and memory: an active avoidance, passive avoidance, and physiological state of the animals: anxiety, aggression, depression. These tests are usually used for screening neuroprotective and psychopharmacological medications, and also different effects on cognitive and emotional sphere.

4.1.1. Assessment of learning ability and memory

Conditional response passive avoidance (passive avoidance reaction) was developed on the basis of a single skin reinforcement in the system consisting of two cameras - large (25 lit×25×25 cm) and low (dark 17.5×14×14 cm) with electrified floors, connected by a rectangular opening 7×10 see When training a rat was placed for 3 minutes in the middle of the lighted chamber tail to the hole in the dark. Animal examined the camera, found the hole and enters the dark compartment. Due to their biological characteristics rat prefers to be in a dark room. Recorded latent period of the first entry into the dark chamber (T1), then immediately upon entering the rat was thrown out of the dark chamber. After 30 min manipulations were repeated and recorded the latent period of the second time in a dark chamber (T2). After another 30 min were recorded latent period of the third time in a dark chamber (T3) and closed the hole by the door (animal remained inside). Then on the floor electrode was applied alternating electric current (50 Hz, 80) for 5 s, after which the rat was brought into the home cage. Testing for the maintenance of acquired reactions were performed after 24 h, 7 and 14 days. The rat was placed in the installation of 3 min and recorded the latent period of time in a dark chamber. The criterion of learning is latent transition period not less than 180 C. a longer residence time of the animal in the illuminated part of the installation or failure of the transition in a dark chamber is considered as the maintenance of acquired response.

4.1.2. Assessment of psychophysiological status

a) Anxiety.

Anxiety is considered the behavior associated with the prevalence of motivation of fear. Among the various kinds of anxiety, the most common phobias, features the simple phobia and agoraphobia (fear of open spaces). Testing of rats in the elevated cross maze is one of the most widely used methods for the study of anxiety in rodents. We use a labyrinth made of wood, covered with green plastic. The maze consists of two open sleeves (50×15 cm), located opposite each other, and two closed sleeves of the same size, with a wall height of 20 cm along the long sides of the sleeve. The maze is located at a height of 70 cm from the floor surface. Testing was performed in a sound-proofed room. The rat was placed in the Central part of the installation and within 10 minutes was visually recorded the number of entries in open and closed arms of the maze and the time spent in open and closed sleeves. Each animal was tested only once.

b). Depressive

To depressive States include affective disorders mental activity characterized by emotional indifference, feelings of unhappiness, thoughts of death, suicidal manifestations, changes in psychomotor behavior, impaired cognitive functions (primarily the inability to concentrate, impaired memory). One of the most appropriate and widely used methods for detecting similar depression in animals is a method of forced swimming (PL is therefore the Porsolt test). During the test, the animal was placed in a vessel with water without the opportunity to avoid this stress situation. Indicators of depression in the test conditions were the number and duration of periods of passive swimming (hold on the water surface without visible movement of the legs). This type of response reflects the state of behavioral despair". Experiments were performed in a circular pool with a diameter of 40 cm and a height of 50 cm, the Pool was filled with water t=22°C to a height of 30 cm, the Rat was released into the pool and record the following indicators of behavior: the duration of the first period of active swimming (swimming with the disorderly movement of the limbs, climbing), duration passive swimming (periods hung without motion), the duration of active swimming. Testing was carried out for 5 min, once. Statistical analysis was made using in each case the appropriate statistical tests.

The results of the experiments presented in Figa, 2b, 3A, 3b, 3C, 4A, 4b, where:

on Figa, 2b shows the effect of the compounds according to the invention for training in conventional passive avoidance response in animals of groups No. 1-9: Figa - latent period tlthe entrance to the dark compartment after electroshock, Fig.2b - number N trained animals, with values in the area t0 - the initial value of N to the power supply in the area T1, T7, T14 - 1, 7 and 14 days, respectively.

on Figa, 3b, 3C shows the effect of the compounds according to the invention on anxiety in rats group No. 1-9 in an elevated cross maze: Figa - the number of visits N1in an area (O) and closed (area C) a sleeve on Fig.3b the time t spent in the open arm, on Pigs - number of animals N2not coming out into the open sleeve

on Figa, 4b shows the effect of the compounds according to the invention for depression animal groups No. 1-9 in the test forced swim by Porsolt: Figa - time tsswimming to first hang (region a) and the time tsactive swimming (region), Fig.4b - N3deadlocks.

The results are presented as mean ± error of the mean.

Visually found no violations of the behavior or appearance of rats after administration of the drug.

In the test, passive avoidance (Figa, 2b) of the compounds according to the invention significantly (P<0.05, T-test) increased the latent period tlentering the dark compartment through the day after the "shock (Figa), indicating a more efficient working memory as a result of application of the drug. From Fig.2b can be seen that the number N of trained animals twice in the groups that received the connection according to the invention (a statistically significant trend, P<0.07, test Chi-sq is the dratha). Despite the fact that the number N of trained animals, and the latent period tlremained higher in group No. 2-9, which compounds according to the invention than in the control group No. 1, after 1 and 2 weeks, the significance of differences became insignificant.

Test anxiety in the elevated cross maze (Figa, 3b, 3C) revealed a large research activity (and, therefore, less anxiety) in the groups treated with the compounds according to the invention the number of N1inputs in outdoor and indoor sleeve was significantly higher (P<0.05, T-test)than in the control group (Figa), the time t spent in the open arm, was 2.2 times higher in the groups treated with the compounds according to the invention (Fig.3b), although due to the variability of the data, the differences were only at the level of a trend (P=0.01, T-test). The number of N2animals not coming out into the open sleeve (it's animals with the most severe anxiety), the control group exceeded experienced 6 times (6 out of 10 1 out of 10 respectively, P<0.02, test Chi-square) (Figs).

Thus, the compounds according to the invention was significantly reduced anxiety when testing it in an elevated cross maze.

Test for depression (forced swimming) (Figa, 4b) revealed no significant effect of the compounds according to the invention either in total t sactive swimming (Figa), nor by the number of N3hang (Fig.4b). However, rats group No. 2-9 treated with compounds according to the invention, showed a tendency (P=0.07, T-test) increase in the period of tsactive swimming to first hang (time And Figa)that can testify to their original lesser depression, or more stamina.

Thus, on the basis of screening of compounds according to the invention in tests that characterize the training and psycho-physiological condition of the animals, it was found that these compounds improve long-term memory in the passive avoidance test, significantly reduce anxiety and animals tend to decrease depression. In other words, the compounds according to the invention have a positive effect on the ability of animals to learn (cognitive function) and psycho-physiological condition of the animals.

Conclusions

Thus, in the direct in vivo experiments, it is shown that cyclic bioisostere derivatives of purine system modulate nitrergic and dopaminergic systems of the brain of animals.

It is experimentally shown that these compounds can be used as neuroprotective agents in pathological conditions of the nervous system. Introduction compounds according to the invention improves cognitive funkcii psychophysiological state, reducing anxiety and depression.

Compounds according to the invention significantly improve sexual function, but also have a positive impact upon drug withdrawal.

Given the mechanism of action of cyclic bioisosteres derivatives of purine system according to the invention and involvement modulated their dopaminergic and nitrergic systems in the pathogenesis of various diseases, it can be concluded that the above compounds can be used to treat a variety of disorders including chemical dependence disorders caused by substance abuse, such as drug addiction, alcohol and nicotine, sleep disorders, sexual disorders (including sexual dysfunction), gastrointestinal disorders, psychosis, affective disorders, nonorganic psychosis, personality disorders, psychiatric mood disorders, schizophrenia and schizoaffective disorder, polydipsia, bipolar disorders, dysphoric mania, anxiety and related diseases, obesity, bacterial infections of the Central nervous system such as meningitis, human learning, memory disorders, Parkinson's disease, depression, extrapyramidal side effects of neuroleptics, the hypothalamic-pituitary disorders, vascular and cardio-SOS is vascular disease, dystonia, dyskinesia, hyperkinesia, dementia, ischemia, motor disorders, hypertension, and diseases caused by a hyperactive immune system such as allergies and inflammation, in mammals, including humans.

1. The use of cyclic bioisosteres purine derivatives of the system having the General structural formula

where R =the atom of Li, Na, K,

R1=-H, -NH2, -Br, -Cl, -OH, -COOH,

B=-N=, -CH=, Z=-CH=, -N=,

A=N= B=N=, Z=-CH-,

A=-CH - at B=-N=, Z=-CH-,

A=-CH - at B=-N=, Z=, N=,

A=-CH -=CH=, Z=-CH=,

A=-CH==CH=, Z=, N=,

and their pharmacologically acceptable salts as active ingredients possessing activity against nitrergic and dopaminergic systems in pharmaceutical compositions for treatment of disorders caused by disturbances nitrergic system and/or dopaminergic systems of the body containing the active ingredient in a quantity sufficient to impact on these systems, in a pharmaceutically acceptable carrier.

2. The use according to claim 1, characterized in that the active ingredient is derived pyrido[2,3-d]-6N-pyridazine-5,8-dione, having the General formula

where R =and the om Li, Na, K,

R1=-H, -NH2, -Br, -OH, -COOH.

3. The use according to claim 1, characterized in that the active ingredient is selected from the group including:

7-(β-D-ribofuranosyl)pyrido[2,3-d]-6N-pyridazine-5,8-dione sodium salt(1),

4-amino-7-(β-D-ribofuranosyl)pyrido[2,3-d]-6N-pyridazine-5,8-dione sodium salt (2),

3-bromo-7-(β-D-ribofuranosyl)pyrido[2,3-d]-6N-pyridazine-5,8-dione sodium salt (3),

4-hydroxy-7-(β-D-ribofuranosyl)pyrido[2,3-d]-6N-pyridazine-5,8-dione disodium salt (4),

3-carboxy-7-(β-D-ribofuranosyl)pyrido[2,3-d]-6N-pyridazine-5,8-dione disodium salt (5),

pyrido[2,3-d]-6N-pyridazine-5,8-dione lithium salt (6),

pyrido[2,3-d]-6N-pyridazine-5,8-dione sodium salt (7),

pyrido[2,3-d]-6N-pyridazine-5,8-dione potassium salt (8).

4. The use according to claim 1, characterized in that the active ingredient is a derivative of benzo[d]-3H-pyridazine-1,4-dione, having the General formula:

where R =the atom of Li, Na, K,

R1=-H, -NH2, -Cl, -OH, -COOH.

5. The use according to claim 1, characterized in that the active ingredient is selected from the group including:

2-(β-D-ribofuranosyl)benzo[d]-3H-pyridazine-1,4-dione sodium salt (9),

5-amino-2-(β-D-ribofuranosyl)benzo[d]-3H-pyridazine-1,4-dione sodium salt(10),

6-amino-2-(β-D-ribofuranosyl)benzo[d]-3H-pyridazine-1,4-dione sodium salt (11),

5-chloro-2-(β-D-ribofuranosyl)benzo[d]-3H-pyridazine-1,4-dione sodium salt (12),

5-hydroxy-2-(β-D-ribofuranosyl)benzo[d]-3H-pyridazine-1,4-dione disodium salt (13),

5-amino-benzo[d]-3H-pyridazine-1,4-dione lithium salt (14),

5-amino-benzo[d]-3H-pyridazine-1,4-dione sodium salt (15),

6-amino-benzo[d]-3H-pyridazine-1,4-dione potassium salt (16),

5-hydroxy-benzo[d]-3H-pyridazine-1,4-dione disodium salt (17),

6-carboxy-benzo[d]-3H-pyridazine-1,4-dione disodium salt (18).

6. The use according to claim 1, characterized in that the active ingredient is derived pyrazino[2,3-d]-6N-pyridazine-5,8-dione, having the General formula:

where R =the atom of Li, Na, K,

R1=-H, -NH2, -Br, -OH, -COOH.

7. The use according to claim 1, characterized in that the active ingredient is selected from the group including:

7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione sodium salt (19),

2-amino-7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione sodium salt (20),

3-amino-7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione sodium salt (21),

3-bromo-7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine and 5-dione sodium salt (22),

2-hydroxy-7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione disodium salt (23),

2-carboxy-7-(β-D-ribofuranosyl)pyrazino[2,3-d]-6N-pyridazine-5,8-dione disodium salt (24),

pyrazino[2,3-d]-6N-pyridazine-5,8-dione lithium salt (25),

pyrazino[2,3-d]-6N-pyridazine-5,8-dione sodium salt (26),

3-bromo-pyrazino[2,3-d]-6N-pyridazine-5,8-dione potassium salt (27),

2-amino-pyrazino[2,3-d]-6N-pyridazine-5,8-dione sodium salt (28).

8. The use according to claim 1, characterized in that the active ingredient is a derivative of pyrimido[4,5-d]-6N-pyridazine-5,8-dione, having the General formula:

where R =the atom of Li, Na, K,

R1=-H, -NH2, -Br, -OH, -COOH.

9. The use according to claim 1, characterized in that the active ingredient is selected from the group including:

7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (29),

2-amino-7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (30),

4-amino-7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (31),

2-bromo-7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (32),

4-hydroxy-7-(β-D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (33),

4-Carbo is si-7-(β -D-ribofuranosyl)pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (34),

pyrimido[4,5-d]-6N-pyridazine-5,8-dione lithium salt (35),

2-amino-pyrimido[4,5-d]-6N-pyridazine-5,8-dione sodium salt (36),

4-bromo-pyrimido[4,5-d]-6H-pyridazine-5,8-dione potassium salt (37).

10. The use according to claim 1, characterized in that the active ingredient is used as a neuroprotector in pharmaceutical compositions for the protection of the nervous system.

11. The use according to claim 1, characterized in that the active ingredient used in the pharmaceutical compositions for improving cognitive function and normalization of psychophysiological state.

12. The use according to claim 1, characterized in that the active ingredient used in the pharmaceutical compositions anxiolytic and antidepressant actions.

13. The use according to claim 1, characterized in that the active ingredient used in the pharmaceutical compositions for the treatment of diseases selected from the group including: disorders caused by substance abuse, such as drug addiction, alcohol and nicotine; sleep disorders; sexual dysfunction, including sexual dysfunction; gastrointestinal disorders; psychotic disorders; affective disorders; non-organic psychotic disorders; personality disorders; psychiatric mood disorders; schizophrenia and isoeffective disorders; polydipsia; bipolar disorders, dysphoric mania; anxiety and related diseases; obesity; bacterial infections of the Central nervous system such as meningitis; violations of learning; memory disorders; Parkinson's disease; neurovirology diseases such as Alzheimer's disease; depression; extrapyramidal side effects of neuroleptics; the hypothalamic-pituitary disorders; vascular and cardiovascular disease; dystonia; psoriasis; hyperkinesia; dementia; ischemia; musculoskeletal disorders; hypertension and diseases caused by a hyperactive immune system such as allergies and inflammation, in mammals, including humans, in an effective for the treatment of a number.



 

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with growth stimulating activity against pathogenic fungi Verticillium dahlia, Fusarium oxysporium, Thialaviopsis basicola, Risoctonia solani, and ergotaminum strain of ergot, which can find application in biotechnology

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of imidazolyl derivative of the general formula (I) wherein each Ra and Rb represents independently (C1-C6)-alkyl, (C1-C6)-alkoxyalkyl, optionally substituted aryl or heteroaryl, or wherein Ra and Rb form in common additional homocyclic or heterocyclic system comprising one or some rings; each Ra' and Rb' represents hydrogen atom, or they in common form a carbon-carbon double bond wherein indicated carbon-carbon double bond is optionally part of aromatic system; Rc represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxyalkyl or halogen atom; Rd represents hydrogen atom or (C1-C4)-alkyl; Re represents hydrogen atom or (C1-C4)-alkyl; m = 1 or 2; R1 represents hydrogen atom or (C1-C4)-alkyl, and its salts after addition of acid and wherein compound of the general formula (II) wherein values Ra, Ra', Rb, and Rb' are given above is subjected for interaction with compound of the formula (III) wherein R represents hydrogen atom, (C1-C4)-alkyl group optionally substituted with hydroxy-group, or optionally substituted aryl group; each R', R'', R''' and R'''' represents independently hydrogen atom or (C1-C4)-alkyl group followed by interaction with compound of the formula (IV) wherein R, Rd and Re have values given above and the following optional interaction with the corresponding acid. Proposed method shows high effectiveness for synthesis of ondansetron and cilansetron.

EFFECT: improved method of synthesis.

10 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of [1,4]diazepino[6,7,1-IJ]-quinoline of the general formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkanoyl or (C7-C11)-carboarylalkoxy-group; each R2 and R3 represents independently hydrogen atom, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, (C2-C6)-carboalkyloxy-group, (C1-C6)-perfluoroalkyl, (C2-C6)-alkanoyloxy-group, (C2-C6)-alkanoyl, (C6-C8)-aroyl, (C5-C7)-aryl, (C6-C13)-alkylaryl having 5-7 carbon atoms in aryl moiety; R4 and R5 represents independently hydrogen atom or (C1-C6)-alkyl, or R4 and R5 taken in common with carbon atoms with which they are bound form cyclic group chosen from (C4-C8)-cycloalkane, (C4-C8)-cycloalkene; each R6 and R7 represents independently hydrogen atom or (C1-C6)-alkyl; n = 1 or 2; a dotted line means a double bond optionally. Also, invention describes using compounds of the formula (I) in preparing a drug used in treatment of different psychotic disorders. Also, invention relates to a pharmaceutical composition possessing activity as 5-HT2C antagonist based on proposed compounds, and a method for synthesis of compounds of the formula (I). Invention provides synthesis of novel compounds, preparing a pharmaceutical composition and a drug based on thereof.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

53 cl, 1 tbl, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

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

9 cl, 47 ex

The invention relates to medicine, specifically to 2-(2'-hydroxy-2'-substituted)ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a] pyrazines or their fumarate with antiarrhythmic and antiischemic activity

The invention relates to novel condensed polycyclic heterocyclic compounds of the formula I and the way they are received

The invention relates to new, containing in the 3-position of the indole ring is substituted piperazinylcarbonyl the rest of 1.7-bellrowan derivatives of indole and their salts, to the way they are received, as well as containing these compounds, pharmaceutical compositions and the intermediate product to obtain these compounds

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

The invention relates to medicine, namely to the chemical-pharmaceutical production of alkali metal salts of 5-amino-2,3-dihydro-1,4-phthalazinedione and mixtures thereof by reacting 5-amino-2,3-dihydro-1,4-phthalazinedione with hydroxides of alkali metals (Li, Na, K) or a mixture of these metals and the subsequent selection of target products by crystallization from saturated solutions of the reaction mixture

The invention relates to medicine, namely to drugs with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect
The invention relates to chemical-pharmaceutical production

The invention relates to the field exitlinks acids, in particular to the intermediate compounds - derivatives of 1-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(A) where R1-C1-C6-alkyl, and the method of obtaining derivatives complex alilovic esters of 4-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(I) where R1-C1-C6-alkyl, R2and R3may be the same or different and represent a hydrogen atom, chlorine or trifluoromethyl, which are inhibitors oldselected

FIELD: medicine; pharmacology.

SUBSTANCE: invention group refers to compositions containing hapten-carrier conjugate within arranged and repeating matrix, and method of related composition production. Offered hapten-carrier conjugate used for induction of agent-specified immune reaction in case of addiction or abuse, contains cortex particle including at least one first apposition site, where specified cortex particle is virus-like particle of RNA-phage, and at least one nicotine hapten with at least one second apposition site, where specified second apposition site is associated by at least one covalent non-peptide bond with specified first apposition site, thus forming arranged and repeating hapten-carrier conjugate. Offered conjugates and compositions under this invention can include virus-like particles connected to various haptens including hormones, toxins and agent, especially agents causing addiction, as nicotine and can be applied for induction of hapten immune reaction for therapeutic, preventive and diagnostic purposes.

EFFECT: vaccines can induce stable immune reactions for nicotine and fast reduce nicotine availability for brain absorbing.

31 cl, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to application of 17 alpha-acetate-21-pivaloat 17alpha, 21-dihydroxipregn-4-en-3.20 dion as an agent reducing pathological attraction to cocaine.

EFFECT: agent has high efficiency.

3 dwg, 2 ex

FIELD: medicine, narcology, pharmacy.

SUBSTANCE: invention proposes using flumazenil representing 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester for production of drug used in treatment of cocaine abuse, abstinence syndrome from cocaine and relapse of cocaine abuse. Agent is administrated in time periods from 1 to 15 min providing administration of from 0.1 to 0.3 mg of flumazenil that represents the therapeutically effective dose for treatment of cocaine abuse (variants), corresponding drugs (variants) of flumazenil and methods for treatment (variants). In this regimen in the dose 2 mg of flumazenil for less 1 h above 55% of gamma-glutamic acid receptors are occupied. Invention provides attenuation or removing symptoms of cocaine abuse and rapid recovery of psychophysiological functions.

EFFECT: valuable properties of drug and enhanced effectiveness of treatment.

29 cl, 2 tbl

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