4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)pyrazolo[1,5-a]-1,3,5-triazine, pharmaceutical composition comprising thereof and its using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel compound 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]-1,3,5-triazine of the formula (I):

, its steroisomeric forms or pharmaceutically acceptable salts, pharmaceutical composition comprising thereof and its using for preparing pharmaceutical composition used in treatment of anxiety in mammals.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

7 cl, 2 ex

 

The scope of the invention

This invention relates to the treatment of psychiatric disorders and neurological diseases including major depression, disorders associated with anxiety, posttraumatic stress disorder, supranuclear paralysis and eating disorders, as well as treatment of immunological, cardiovascular or related to heart disease and hypersensitivity of the colon associated with psychopathological disorders and stress, by introducing 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)pyrazolo-[1,5-a]-1,3,5-triazine, its enantiomers and pharmaceutically acceptable salts as ligand receptor releasing factor corticotropin.

Background of the invention

Releasing factor corticotropin (here called CRF), a peptide of 41 amino acids, represents the initial physiological regulator of the secretion of peptides derived proopiomelanocortin (O.G. ROMs)from the anterior pituitary [J.Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W.Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the level of the pituitary immunohistochemical localization of CRF showed that the hormone has a wide distribution outside of the hypothalamus in the Central nervous system and produces a wide range of autonomic, electrophysiological and behavioral effects, according to wusasa role of neurotransmitter or neuromodulator in the brain [W.Vale et al., Rec. Prog. Hor. Res. 39:245 (1983); G.F.Koob, Persp. Behav. Med. 2:39 (1985); E.B.De Souza et al., J. Neurosci, 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system on the physiological, psychological and immunological stressors [J.E.Blalock, Physiological Reviews 69:1 (1989); J.E.Morley, Life Sci. 41:527 (1987)].

Clinical data provide evidence that CRF plays a role in psychiatric disorders and neurological diseases including depression, disorders associated with anxiety, and eating disorders. It was also stated that CRF plays a role in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis, since they are related to dysfunction of CRF neurons in the Central nervous system [overview, see publication E.B De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder or major depression, the concentration of CRF significantly increased in the cerebral spinal fluid (CSF) from people who do not take drugs [C.B.Nemeroff et al., Science 226:1342 (1984); C.M.Banki et al., Am. J. Psychiatry 144:873 (1987); R.D.France et al., Biol. Psychiatry 28:86 (1988); M.Arato et al., Biol. Psychiatry 25:355 (1989)]. Moreover, the density of CRF receptors is significantly reduced in the frontal cortex of the victims of suicide, which is consistent with hypersecretion of CRF [C.B.Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition to the, there is a blunted response adrenocorticotropin (ACTH) on CRF (injected)observed in patients with depression [P.W.Gold et al., Am. J. Psychiatry 141:619 (1984); F.Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P.W.Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and not apes provide additional confirmation of the hypothesis that hypersecretion of CRF may be involved in the symptoms observed in depression in humans [R.M.Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can change the levels of CRF and, thus, modulate the number of CRF receptors in the brain [Grigoriadis et al., Neuropsychopharmacology. 2:53 (1989)].

It was also stated that CRF plays a role in the etiology associated with anxiety disorders. CRF causes entries effects in animals, and the interaction between benzodiazepine/no benzodiazepine anxiolytics and CRF has been demonstrated on a variety of behavioral models of anxiety [D.R. Britton et al., Life Sci. 31:363 (1982); C.W.Berridge and A.J.Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the intended receptor antagonist CRF α-spiral bullish CRF (9-41) on a variety of behavioral paradigms show that the antagonist causes "similar anxiolytic effects, which are qualitatively similar to the benzodiazepines [C.W.Brridge and A.J.Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)].

Neurochemical, endocrine research and the study of binding to receptors demonstrated interaction between CRF and benzodiazepine anxiolytics, providing further evidence of the involvement of CRF in these disorders. Chlordiazepoxid weakens "entries" effects of CRF and in the test of conflict [K.T.Britton et al., Psychopharmacology 86:170 (1985); K.T.Britton et al., Psychopharmacology 94:306 (1988)] and in the test of the acoustic startle [N.R.Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. Antagonist benzodiazepinovyh receptors (Ro15-1788), which individually did not show behavioral activity during the test conflict actions, fixed effects dependent CRF dose-dependent manner, while the inverse agonist of the benzodiazepine (FG7142) amplified the action of CRF [K.T. Britton et al., Psychopharmacology 94:306 (1988)].

Mechanisms and sites of action through which the standard anxiolytics and antidepressants exert their therapeutic effects remains to be seen. However, there was a hypothesis that they are involved in the suppression of CRF hypersecretion, which is observed in these disorders. Of particular interest is the fact that a preliminary study of the effects of a CRF receptor antagonist (α-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist causes "such anxiolytic" efficiency is s, qualitatively similar to the benzodiazepines [overview, see the publications G.F.Koob and K.T.Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E.B. De Souza and C.B.Nemeroff eds., CRC Press p221 (1990)].

Further alleged that CRF plays a role in cardiovascular or related to heart diseases, as well as in the gastro-intestinal disorders caused by stress, such as hypertension, tachycardia and congestive heart failure, stroke, irritable bowel syndrome, post-operative intestinal obstruction and hypersensitivity of the colon associated with psychopathological disturbance and stress [overview, see the publications G.F.Koob and K.T.Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E.B. De Souza and C.B.Nemeroff eds., CRC Press p221 (1990) and C.Maillot, M.Million, J.Y.Wei, A.Gauthier, Y.Tache, Gastroenterology, 119, 1569-1579 (2000)].

Excessive expression or lack of expression of CRF were proposed as the main cause of some medical disorders. These treatable disorders include, for example, without limitation: affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, neurotic anorexia or other eating disorders, drug addiction, symptoms of drug is Oh or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart disease, fertility problems, infection with human immunodeficiency virus, hemorrhagic stress, obesity, infertility, head injury and spinal cord, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia, hypertension, tachycardia and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative intestinal obstruction and hypersensitivity of the colon associated with psychopathological disturbance and stress [overview, see the publications J.R.McCarthy, S.C. Heinriches and D.E.Grigoriadis, Curr. Pharm. Res., 5, 289-316 (1999); P.J.Gilligan, D.W.Robertson and R.Zaczek, J. Medicinal Chem., 43, 1641-1660 (2000), G.P.Chrousos, Int. J. Obesity, 24, Suppl. 2, S50-S55 (2000); E.Webster, D.J.Torpy, I.J.Elenkov, G.P.Chousos, Ann. N.Y. Acad. Sci., 840, 21-32 (1998); D.J.Newport and C.B.Nemeroff, Curr. Opin. Neurobiology 10, 211-218 (2000); G.Mastorakos and I.Ilias, Ann. N.Y. Acad. Sci., 900, 95-106 (2000); M.J.Owens and C.B.Nemeroff, Expert Opin. Invest. Drugs, 8, 1849-1858 (1999); G.F.Koob, Ann. N.Y. Acad. Sci., 909, 170-185 (2000)].

In each of the following publications described compounds, CRF antagonists; however, none of them disclosed compounds presented in this description: WO95/10506; WO99/51608; WO97/35539; WO99/01439; WO97/44308; WO97/35846; WO98/03510; WO99/11643; PCT/US99/18707; WO99/01454 and WO00/01675.

The invention

In accordance with one aspect of the present invention relates to a new the th connection, pharmaceutical compositions and methods that can be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, neurotic anorexia or other eating disorders, symptoms of drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorders, disorders of fertility disorders, the treatment of which can be implemented or facilitated by antagonism against CRF, including without limitation disorders, the occurrence of which causes or facilitated by CRF, or disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and various allergies; generalized anxiety disorder; panic associated with phobias, obsessive-compulsive disorder; posttraumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, depression, caused by ill-treatment of children, and postpartum depression; dysthemia; Biol rye disorders; the cyclothymia; fatigue syndrome; stress-induced headache; cancer, infection with human immunodeficiency virus (HIV); neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colitis, diarrhea, and post operative intestinal obstruction and hypersensitivity of the colon associated with psychopathological disturbances or stress; eating disorders such as anorexia and neurotic bulimia nervosa; hemorrhagic stress; psychotic episodes caused by stress; euthyroid syndrome disease; syndrome of inappropriate production of antidiuretic hormone (ADH); obesity; infertility; head traumas; spinal cord injury, ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and related heart disorders, including hypertension, tachycardia and congestive heart failure; stroke, immune dysfunction, including immune dysfunction caused by stress (e.g. caused by stress, fever, stress syndrome swine fever associated with the transportation of cows, equine paroxysmal AF who brilliance and dysfunction, caused by immobilization in a confined space in chickens, the stress in sheep, straying from the flock, or stress in dogs, associated with the interaction between humans and animals); muscular spasms; urinary incontinence; senile dementia of Alzheimer's type; dementia associated with multiple infarctions of the brain; amyotrophic lateral sclerosis; dependence on chemical substances and drug addiction (e.g. alcohol, cocaine, heroin, benzodiazepines, or other drugs); symptoms of drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in a mammal.

The present invention relates to a new compound that binds to receptors releasing factor corticotropin by changing entries the effects of CRF secretion. The compound of the present invention can be used to treat psychiatric disorders and neurological diseases, disorders related to anxiety, posttraumatic stress disorder, supranuclear paralysis and disorders of food intake, as well as treatment of immunological, cardiovascular or heart diseases and hypersensitivity of the colon associated with psychopathological disturbance and stress in a mammal.

In accordance with another aspect of the present the invention relates to a new compound of formula I (described below), which can be used as an antagonist releasing factor corticotropin. The compound of the present invention exhibits activity as an antagonist releasing factor corticotropin and, as it turns out, suppresses hypersecretion of CRF. The present invention also includes pharmaceutical compositions that contain the compound of formula (I), and methods of using the compounds to inhibit hypersecretion of CRF and/or treatment entries disorders.

Using analyses of competitive binding is considered to be particularly valuable for screening candidates for new drugs, for example, to identify new CRF ligands or other compounds with even greater or more selective affinity binding to CRF receptors, and so the candidates could potentially be used as medicines. In the analysis to determine the potential ability of the ligand to displace labeled connection.

So another variant embodiment of the invention includes the use of compounds according to the invention in the analysis of binding in which one or more compounds can be attached to the label, and the label can directly or indirectly provide a detectable signal. Various labels include radioisotopes, fluorescent substances, chemiluminescent ve is esta, the specific binding molecules, particles, e.g. magnetic particles, and the like.

Another variant embodiment of the invention relates to the use of compounds according to the invention (in particular, the labeled compounds of the present invention as probes for the localization of receptors in cells and tissues and as standards and reagents for use in the characterization of binding to receptors of the tested compounds. Labeled compounds according to the invention can be used for in vitro studies, such as autoradiography of tissue sections, or for methods in vivo, for example, positron emission tomography (PET) or single photon emission computed tomography (SPECT) scanning. In particular, preferred compounds according to the invention can be applied as standards and reagents in determining the ability of a potential pharmaceutical agents to contact the receptor CFR1.

Detailed description of the invention

[1] In the first embodiment, the present invention relates to the compound of formula (I):

(I)

and its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or about Carstensen forms.

[2] In another embodiment, the present invention relates to the connection options of implementation [1], its isomers, its stereoisomeric forms, mixtures of its stereoisomeric forms, its pharmaceutically acceptable prodrugs or pharmaceutically acceptable salt forms, with the specified connection is a 4-((R)-2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)[1,5-a]-pyrazolo-1,3,5-triazine and 4-((S)-2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)[1,5-a]-pyrazolo-1,3,5-triazine.

[3] In another embodiment, the present invention relates to a compound of any one of embodiments [1] and [2], its pharmaceutically acceptable prodrugs or pharmaceutically acceptable salt forms, and in the specified connection is essentially missing its (S) stereoisomer.

[4] In another embodiment, the present invention relates to the connection options of implementation [1], with the specified connection is a 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)[1,5-a]pyrazolo-1,3,5-triazine.

[5] In another embodiment, the present invention relates to the connection options of implementation [1], with the specified connection is a 4-((R)-2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)[1,5-a]pyrazolo-1,3,5-triazine.

[6] the Pharmaceutical compositions is Oia, containing a pharmaceutically acceptable carrier and a therapeutically effective amount of any compound of the embodiments[1]-[5].

[7] In another embodiment, the present invention relates to a method antagonistic effects on the CRF receptor in a mammal, comprising the administration to a mammal a therapeutically effective amount of any compound of the embodiments[1]-[5].

[8] In another embodiment, the present invention relates to a method for the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animal, comprising an introduction to the animal a therapeutically effective amount of any compound of the embodiments[1]-[5].

[9] In another embodiment, the present invention relates to a method of treatment of a disorder the treatment of which you can make or facilitate antagonistic effect on CRF, including introduction to the mammal a therapeutically effective amount of any compound of the embodiments[1]- [5].

[10] In another embodiment, the present invention relates to a method antagonistic effects on the CRF receptor in a mammal, comprising the administration to a mammal a therapeutically effective amount of any compound of embodiments [1]-[5].

[11] In another embodiment, the present invention relates to a method of treating anxiety or depression in a mammal, comprising the administration to a mammal a therapeutically effective amount of any compound of the embodiments[1]-[5].

[12] In another embodiment, the present invention relates to a method of screening for identifying ligands of CRF receptors, and the method includes:

a) analysis of competitive binding with the receptor, CRF amounts of any compounds of implementation options [1] to [5], which observed detectable label, and the potential ligand; and

b) determining the ability of the specified potential ligand to replace the specified labeled connection.

[13] In another embodiment, the present invention relates to a method for detection of CRF receptors in the tissue, including:

a) providing contact any of the compounds of embodiments [1]-[5], which observed detectable label, with the tissue under conditions that allow binding of the compound with a cloth; and

b) detecting the labeled compound associated with cloth.

[14] In another embodiment, the present invention relates to a method of inhibiting the binding of CRF to CRF receptor-1, comprising providing contact any connection options for the implementation of the population [1]-[5] with the solution, including cells expressing the CRF1 receptor, and the compound is present in solution at a concentration sufficient to inhibit the binding of CRF to CRF receptor-1.

[15] In another embodiment, the present invention relates to a device, including:

a) packaging material;

b) the compound of any one of embodiments [1]-[5]

C) a label or package insert contained within the specified packaging material indicating that this compound is effective for treatment of anxiety or depression.

[16] the Present invention also includes a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, neurotic anorexia or other eating disorders, drugs, symptoms of drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart disease, fertility problems, infections with human immunodeficiency virus, hemorrhagic stress, obesity, infertility, head and spinal cord, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment to the which can be implemented or facilitated by antagonism against CRF, including, but not limited to, disorders, the occurrence of which causes or facilitated by CRF, in mammals comprising the administration to a mammal a therapeutically effective amount of any compound of the embodiments[1]-[5].

Definition

Used herein, the term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Suitable non-toxic acids include inorganic acids and organic acids of basic residues such as amines, for example acetic, benzosulfimide, benzoic, importantnow, lemon, econsultancy, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, Paveway, Pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluensulfonate and the like; and alkali or organic salts of acidic residues such as carboxylic acids, for example salts of alkali and alkaline earth metals derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, t is iletilammina, triethylamine, Ethylenediamine, n-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenziletilendiaminom, chloroprocaine, diethanolamine, procaine, n-benzylpenicillin, diethylamine, piperazine, Tris(hydroxymethyl)aminomethan, hydroxide of Tetramethylammonium and the like.

Pharmaceutically acceptable salts of the compounds according to the invention can be obtained by reacting the free acid or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or a mixture of both of them; usually the preferred non-aqueous environment, such simple ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Lists of suitable salts can be found in the manual Remington''s Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, PA, 1985, p.1418, the description of which is incorporated herein by reference.

Used herein, the term "pharmaceutically acceptable prodrug" means any covalently associated media, which releases the generic drug of formula (I) in vivo when such prodrug is administered to a mammal subject. Prodrugs of compounds of formula (I), and, if possible, zwitterionic forms of the compounds according to the invention known to specialists in this field of medicine, suitable for use in contact with the tissues of humans and animals and have a level that is lichnosti, irritation, allergic response and the like, commensurate with a reasonable ratio of benefit/risk, and are effective for their intended use. The term "prodrug" means a compound, which rapidly transformed in vivo to obtaining the generic compounds of formula (I), for example, by hydrolysis in blood. Functional groups that can be quickly transformed by metabolic cleavage in vivo, form a class of groups which react with the carboxyl group of the compounds of the present invention. They include such groups as alkanoyl (such as acetyl, propionyl, butyryl and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as etoxycarbonyl), trialkylsilyl (such as trimethyl - and triethylsilyl), complex monetary formed with dicarboxylic acids (such as succinyl) and the like, but are not limited to. Because of the ease with which metabolically degradable group of compounds that can be used in accordance with this invention, broken down in vivo, the compounds bearing such groups, act as prodrugs. Compounds bearing metabolically degradable group, have the advantage that they can exhibit improved bioavailability as a result of intensive dissolve the cost and/or rate of absorption, given a generic connection, thanks to the presence of metabolically degradable group. A detailed discussion of prodrugs is provided in the following publications: Design of Prodrugs, H.Bundgaard, ed., Elsevier, 1985; Methods in Enzymology, K.Widder et al., Ed., Academic Press, 42, p.309-396, 1985; A Texbook of Drug Design and Development, Krogsgaard-Larsen and H.Budgaard, ed. Chapter 5; "Design and Application of Prodrugs" p.113-191, 1991; Advanced Drug Delivery Reviews, H.Bungaard, 8, p.1-38, 1992; Journal of Pharmaceutical Sciences, 77, p.285, 1988; Chem. Pharm. Bull., N.Nakeya et al., 32, p.692, 1984; Pro-drugs as Novel Delivery Systems, and T.Higuchi V.Stella, Vol.14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B.Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated here as reference.

"Prodrugs" is considered to be any covalently associated media, which release the active parent drug of formula (I) in vivo when such prodrug is administered to a mammal. Prodrugs of compounds of formula (I) is obtained by modifying functional groups present in the compounds in such a way that the modifications are split, either during normal manipulation or in vivo, to the generic connection. Prodrugs include compounds in which a hydroxyl, amino or sulfhydryl groups linked to any group which when administered to a mammal subject cleaved with the formation of, respectively, the free hydroxyl, amino or sulfhydryl groups. Examples of prodrugs include acetate, formiate and benzo is atnie alcohol derivatives and amino functional groups in the compounds of formula (I) and the like, but not limited to.

Used here to describe the connection, the term "essentially without its (S) stereoisomer" means that the compound consists of a substantially larger proportion of its (R) stereoisomer than its optical antipode (i.e. its (S) stereoisomer). In a preferred embodiment of the invention, the term "essentially without its (S) stereoisomer" means that the compound is at least about 90 wt.% its (R) stereoisomer and about 10 wt.% or less of its (S) stereoisomer.

In a more preferred embodiment of the invention, the term "essentially without its (S) stereoisomer" means that the compound is at least about 95 wt.% its (R) stereoisomer and about 5 wt.% or less of its (S) stereoisomer. In an even more preferred embodiment of the invention, the term "essentially without its (S) stereoisomer" means that the compound is at least about 99 wt.% its (R) stereoisomer and about 1 wt.% or less of its (S) stereoisomer. In another preferred embodiment of the invention, the term "essentially without its (S) stereoisomer" means that the compound consists of almost 100 wt.% its (R) stereoisomer. The above percentages are based on total number of joint stereozoom the ditch connection.

The term "therapeutically effective amount" of the compounds of this invention means an amount effective to counteract the pathological level of CRF or treatment of symptoms of affective disorder, anxiety or depression from the owner.

Used herein, the term "labeled" means that the connection either directly or indirectly observed label which provides a detectable signal, e.g. radioisotope, fluorescamine substances, enzyme, antibodies, particles such as magnetic particles, chemoluminescence substances, R32I131and At211etc.

The synthesis methods

Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center (centers). The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levogyrate. Connection with the prefix (+) or d is Pervouralsk. For a given chemical structure of these compounds, called stereoisomers that are identical except that they are mirror and the views of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. The mixture of enantiomers of 50:50 is called a racemic mixture.

The present invention includes all stereoisomeric forms of the compounds of formula I. Centers of asymmetry, which are present in the compounds of formula I can independently of each other to have the S configuration or R configuration. The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levogyrate. Connection with the prefix (+) or d is Pervouralsk. The invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios. Thus, the enantiomers are the subject of the invention in enantiomerically pure form and in the form levogyrate, and programada antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of CIS/TRANS isomerism of the invention include CIS-form and TRANS-form, and mixtures of these forms in all ratios. Getting the individual stereoisomers can be carried out if desired, separation of the mixture by conventional means, for example by chromatography or crystallization, COI is whether the stereochemical homogeneous starting materials for the synthesis or stereotypically synthesis. Optional derivatization can be performed before the separation of stereoisomers. Separation of a mixture of stereoisomers can be carried out at the stage of the compounds of the formula I or at the stage of intermediate compounds in the synthesis. The present invention also includes all tautomeric forms of the compounds of formula (I).

The compounds of formula (I) can be obtained using the methods presented in figure 1.

Scheme 1

The compound of formula (II), where X=F, can be treated with a metal alkoxide (e.g. sodium methoxide, potassium methoxide; pre-formed or formed in situ) in an inert solvent to obtain an intermediate compound of formula (III). Inert solvents may include, but are not limited to, alkalemia alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanity (1-6 carbons, preferably acetonitrile), water, simple dialkyl ethers (preferably simple diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylacrylamide (preferably dimethylformamide), N,N-dialkylacrylamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidine-2-one), diallylsulfide (preferably dimethylsulfoxide) or aromatic shall Uglevodorody (preferably benzene or toluene). The preferred reaction temperature is in the range from 0°to 100°C.

The alternate connection of the formula (II), where X=HE, you can handle the alkylating agent in the presence of a base in an inert solvent to form an intermediate product of the formula (III). Alkylating agents include, but are not limited to, halogenoalkane (for example, CH3I), diallylsulfide (for example, Me2SO4or alkylarylsulfonate (for example, CH3O3SCF3).

Reasons may include, but are not limited to, alkali metals, hydrides of alkali metal (preferably sodium hydride), alkoxides of alkali metals (1-6 carbons) (preferably sodium methoxide or ethoxide sodium), alkaline earth metal hydrides, carbonates of alkali metals, carbonates of alkali metals, carbonates of transition metals (for example, silver carbonate), dialkylamide alkali metal (preferably diisopropylamide lithium), bicarbonates of alkali metals, hydroxides of alkaline metals, bis(trialkylsilyl)amides of alkali metals (preferably bis(trialkylsilyl)amide sodium), trialkylamine (preferably N,N-aminobutiramida-N-ethylamine) or aromatic amines (preferably pyridine).

Inert solvents may include, but are not limited to, halogen-substituted hydrocarbons (1-atomov carbon 1 to 8 halogen atoms), lower alkanity (1-6 carbons, preferably acetonitrile), water, simple dialkyl ethers (preferably simple diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylacrylamide (preferably dimethylformamide), N,N-dialkylacrylamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidine-2-one), diallylsulfide (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction temperature is in the range from 50°to 150°C.

The compound of formula (III) can be converted into a compound of formula (IV) interaction with brainwashin agent in an inert solvent in the presence or in the absence of additives. Brainwashee agents include, but are not limited to, N-bromosuccinimide-2,2'-azobisisobutyronitrile (AIBN)), bromine. Additives include, but are not limited to, phosphates of alkali metals (e.g., K3PO4, Na3PO4), hydrogen phosphates of alkali metals (e.g., Na2HPO4, K2HPO4), dihydrophosphate alkali metals (for example, NaH2PO4KH2PO4). Inert solvents include, but are not limited to, halogen-substituted hydrocarbons (1-6 carbon atoms, 1-6 at the MOU halogen, preferably chlorine), water, N,N-dialkylacrylamide (preferably dimethylformamide), N,N-dialkylacrylamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidine-2-one). The reaction temperature is in the range from 0 to 200°With (preferably from 20 to 120°).

The compound of formula (IV) can be converted to the compound of formula (V) sequential response with (1) alkyllithium in an inert solvent at a temperature in the range from -100 to 50°With; (2) the compound of the formula IN(ORa)3(where Rarepresents a branched or remotemachine alkyl of 1-20 carbon atoms) at a temperature in the range from -100 to 50°and (3) acid in the presence or in the absence of water at a temperature in the range from -100 to 100°C. Alkylate can be a branched or remotemachine compound containing 1-20 carbon atoms. Inert solvents include, but are not limited to, simple dialkyl ethers (preferably simple diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene).

Acids may include, but are not confined, alcamovia acid from 2-10 carbon atoms (preferably acetic acid), halogenoalkane acid (2-10 atoms ug is erode, 1-10 halogen atoms, such as triperoxonane acid), arylsulfonic acids (preferably p-toluensulfonate acid or benzolsulfonat acid), alkanesulphonic acid from 1-10 carbon atoms (preferably methanesulfonate acid), hydrochloric acid, sulfuric acid or phosphoric acid.

The compound of formula (VII) can be obtained by the coupling of compounds of formula (V) with the compound of the formula (VI) in the presence of complex salt of palladium or Nickel, base and inert solvent. Complexes of palladium or Nickel include, but are not limited to, phosphine complexes, such as Pd(PPh3)4, PdCl2(PPh3)2, NiCl2(PPh3)2or [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium. Reasons may include, but are not limited to, alkali metals, hydrides of alkali metal (preferably sodium hydride), alkoxides of alkali metals (1-6 carbons) (preferably sodium methoxide or ethoxide sodium), carbonates of alkali metals, carbonates of alkaline earth metals (for example, barium carbonate, carbonates of transition metals (for example, silver carbonate) or trialkylamine (e.g., triethylamine). Inert solvents may include, but are not limited to, simple dialkyl ethers (preferably simple diethyl ether), about the process of cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction temperature is in the range from -100 to 100°C.

The intermediate compound of formula (VII) can react with a base in the presence of an inert solvent to obtain compounds of formula (VIII), where M is a cation of an alkali metal (e.g. sodium or potassium). Reasons may include, but are not limited to, alkali metal hydroxide (e.g. NaOH or KOH), alkoxides of alkali metals (1-6 carbons) (preferably sodium methoxide or ethoxide sodium) or hydroxides of alkaline earth metals. Inert solvents may include, but are not limited to, alkalemia alcohols (1-6 carbon atoms), lower alkanity (1-6 carbons, preferably acetonitrile), water, simple cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylacrylamide (preferably dimethylformamide), N,N-dialkylacrylamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidine-2-one), diallylsulfide (preferably dimethylsulfoxide). The preferred reaction temperature is in the range from 0°to 150°C.

The compounds of formula (VIII) can be treated with hydrazinehydrate in the presence of an acid and an inert solvent at a temperature in the range from 0 to 200°C, preferably from 70 to 150° With obtaining the compounds of formula (IX). Acids may include, but are not confined, alcamovia acid from 2-10 carbon atoms (preferably acetic acid), halogenoalkane acid (2-10 carbon atoms, 1-10 halogen atoms, such as triperoxonane acid), arylsulfonic acids (preferably p-toluensulfonate acid or benzolsulfonat acid), alkanesulphonic acid from 1-10 carbon atoms (preferably methanesulfonate acid), hydrochloric acid, sulfuric acid or phosphoric acid.

Inert solvents may include, but are not limited to, water, alkalemia alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanity (1-6 carbons, preferably acetonitrile), a simple cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylacrylamide (preferably dimethylformamide), N,N-dialkylacrylamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidine-2-one), diallylsulfide (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).

The compound of formula (IX) can react with compounds of the formula H3C(C=NH)ORc(where Rcrepresents alkyl (1-6 carbon atoms) in the presence or in the absence to the slots, in the presence of an inert solvent at a temperature in the range from 0 to 200°obtaining the compounds of formula (X). Acids may include, but are not confined, alcamovia acid from 2-10 carbon atoms (preferably acetic acid), haloalkane acid (2-10 carbon atoms, 1-10 halogen atoms, such as triperoxonane acid), arylsulfonic acids (preferably p-toluensulfonate acid or benzosulfimide acid), alkanesulphonic acid from 1-10 carbon atoms (preferably methanesulfonate acid), hydrochloric acid, sulfuric acid or phosphoric acid. You can use stoichiometric or catalytic amounts of such acids.

Inert solvents may include, but are not limited to, water, alkanity (1-6 carbons, preferably acetonitrile), halogen-substituted hydrocarbons of 1 to 6 carbon atoms and 1 to 6 halogen atoms (preferably dichloroethane or chloroform), alkalemia alcohols of 1 to 10 carbon atoms (preferably ethanol), simple dialkyl ethers (4-12 carbon atoms, preferably a simple diethyl ether or simple diisopropyl ether) or a simple cyclic ethers, such as dioxane or tetrahydrofuran. The preferred reaction temperature is in the range from 0 to 100°C.

The compound of formula (X) can is about to convert to an intermediate compound of formula (XI) by treatment with a connection C=(R d)2(where Rdrepresents a halogen (preferably chlorine), alkoxy (1-4 carbon atoms) or alkylthio (1-4 carbon atoms)in the presence or in the absence of a base in an inert solvent at the reaction temperature from -50 to 200°C. Bases may include, but are not limited to, hydrides of alkali metal (preferably sodium hydride), alkoxides of alkali metals (1-6 carbons) (preferably sodium methoxide or ethoxide sodium), carbonates of alkali metals, hydroxides of alkaline metals, trialkylamine (preferably N,N-aminobutiramida-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine).

Inert solvents may include, but are not limited to, alkalemia alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanity (1-6 carbons, preferably acetonitrile), a simple cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylacrylamide (preferably dimethylformamide), N,N-dialkylacrylamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidine-2-one), diallylsulfide (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).

The compound of formula (XI) can be processed halogenation agent in the Pris is under or in the absence of a base in the presence or absence of an inert solvent at the reaction temperature in the range from -80 to 250° With obtaining halogenated intermediate (XII) (where X is halogen). Halogenation agents include, but are not limited to, SOCl2, POCl3, PCl3, PCl5, POBr3, PBr3or PBr5. Reasons may include, but are not limited to, trialkylamine (preferably N,N-aminobutiramida-N-ethylamine or triethylamine) or aromatic amines (preferably N,N-diethylaniline).

Inert solvents may include, but are not limited to, N,N-dialkylacrylamide (preferably dimethylformamide), N,N-dialkylacrylamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidine-2-one) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction temperature is in the range from 20 to 200°C.

The compound of formula (XII) can react with alkylamines in the presence or in the absence of base at the reaction temperature in the range from -80 to 250°With formation of compounds of formula (I). Reasons may include, but are not limited to, hydrides of alkali metal (preferably sodium hydride), alkoxides of alkali metals (1-6 carbons) (preferably sodium methoxide or ethoxide sodium), alkaline earth metal hydrides, dialkylamide alkali metal (preferably visapro ilamed lithium), carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl)amides of alkali metals (preferably bis(trialkylsilyl)amide sodium, trialkylamine (preferably N,N-aminobutiramida-N-ethylamine) or aromatic amines (preferably pyridine).

Inert solvents may include, but are not limited to, alkalemia alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanity (1-6 carbons, preferably acetonitrile), simple dialkyl ethers (preferably simple diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylacrylamide (preferably dimethylformamide), N,N-dialkylacrylamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidine-2-one), diallylsulfide (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halogenoalkane of 1-10 carbons and 1 to 10 halogen atoms (preferably dichloromethane). The preferred reaction temperature is in the range from 0°to 140°C.

Compounds according to the invention can be obtained in the form of compounds with radioactive label by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. Radio and television the OTOP, preferably selected from at least one of the carbon atoms (preferably14C), hydrogen (preferably3N), sulfur (preferably35S), or iodine (preferably125I). Such radiolabelled probes conveniently synthesized supplier of radioisotopes, specializing in the synthesis on the order of radiolabelled compounds probes. Such providers include firms Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass,; SRI International, Menlo Park, Calif., Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, KS; American Radiolabeled Chemicals, Inc., St.Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.

Tritium-labeled compounds probe can also conveniently obtain a catalytically by platinum catalyzed exchange of tritium-labeled acetic acid, acid catalyzed exchange of tritium-labeled triperoxonane acid, or heterogeneous catalyzed exchange with gaseous tritium. Such methods of obtaining also conveniently carried out in which order a radioactive label any provider listed in the previous paragraphs, using compounds of the invention as a substrate. In addition, some precursors may be subjected to the exchange of tritium-halogen gaseous tritium recovery of gaseous tritium unsaturated bonds or restoring what ispolzovaniem of biotreated sodium, as it is desirable.

The receptor autoradiography (mapping of receptors) can be performed in vitro as described by Kuhar in section 8.1.1 to 8.1.9 publications Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, with the use of the compounds according to the invention is labeled with a radioactive label.

EXAMPLES

Data analyses were recorded for the compounds described below, using the following General methods. Registered proton NMR spectra of the devices Varian VXR or Unity 300 FT-NMR (300 MHz); chemical shifts were measured in ppm (δ) regarding internal tetramethylsilane standard in deuterium chloroform or deuterodiacetylmorphine, as defined below. Mass spectra (MS) or mass high resolution spectra (HRMS) were recorded on a spectrometer Finnegan MAT 8230 or spectrometer model Hewlett Packard 5988A (using chemiionization (CI) with NH3as the carrier gas, electro-spray atomizer (TSI), chemiionization at atmospheric pressure (APCI) or gas chromatography (GC)). Melting points were recorded on a heating block device MelTemp 3.0 and was not resolved. The boiling point was not resolved. All determinations of pH during development conducted test-paper.

Reagents were purchased from commercial sources and, if necessary, were purified before use in accordance with the General methods described DPerrin and W.L.F.Armarego, Purification of Laboratory Chemicals, 3rded., (New York: Pergamon Press, 1988). Chromatography was performed on silica gel using a solvent system, as described below. For the mixed solvent system given volume ratio. Otherwise, parts and percentages are given by weight. Commonly used abbreviations are: DMF for N,N-dimethylformamide) EtOH (ethanol), MeOH (methanol), EtOAc (ethyl acetate), HOAc (acetic acid), DME (1,2-diethoxyethane) and THF (tetrahydrofuran)the Following examples are presented for a more detailed description of the invention. These examples, which represent the best way contemplated at the present time for carrying out the invention are intended to illustrate and not to limit the invention.

Example 1

Obtaining 2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)[1,5-a]pyrazolo-[1,3,5]-triazine-4(3H)-it

A. 2-Methoxy-6-methylpyridin

Sodium (31.0 g, 1.35 mol) was added by portions in methanol (500 ml) for 30 min under stirring in a flask equipped with a reflux condenser. After complete addition, the reaction mixture was allowed to cool to ambient temperature. Portions were added 2-fluoro-6-methylpyridin (50 g, 450 mmol) under stirring. Then the reaction mixture was heated to a temperature of phlegmy and was stirred for 48 hours. The mixture then was cooled to ambient temperature and the solvent UD who ranged in vacuum to obtain a yellow oil. The residue was treated with water (500 ml) and spent three simple extraction with ether (200 ml). The combined organic layers were dried over MgSO4was filtered and the solvent was removed in vacuo from the filtrate to obtain a yellow liquid product:1H-NMR (CDCl3, 300 MHz): δ 7,44 (DD, 1H, J=8, 7), of 6.71 (d, 1H, J=7), 6,53 (d, 1H, J=8), 3,91 (s, 3H), of 2.45 (s, 3H).

Century 2-Methoxy-6-methylpyridin

A mixture of 2-hydroxy-6-methylpyridine (6.85 g, of 62.8 mmol), silver carbonate (22,5 g of 81.6 mmol), iodomethane (39,1 ml, 628 mmol) and chloroform (200 ml) was stirred at room temperature for 40 h in the dark. The reaction mixture was filtered through celite. The collected solid was washed simple ether. The combined filtrates were concentrated in vacuum to form a liquid product (6.25 g), which was identical to the product from step A.

C. 6-Methoxy-3-bromo-2-methylpyridin

A mixture of 2-methoxy-6-methylpyridine (17.0 g, 138 mmol) and a solution of sodium dihydrophosphate (0.15 mol in water, 250 ml) was stirred at room temperature. Bromine (7,1 ml, 139 mmol) was added dropwise over 15 min via addition funnel. The reaction mixture was then stirred at room temperature for 4 hours. Clear colorless solution was diluted with water (500 ml) and was extracted with dichloromethane (200 ml) three times. The combined organic layers were dried over MgSO4was filtered and the solvent in which alali in vacuo from the filtrate to obtain a yellow liquid. Flash chromatography on silica gel (EtOAc:hexane::1:20) and removing the solvent from the desired combined fractions gave a clear, colorless liquid product (15,4 g):1H-NMR (CDCl3, 300 MHz): δ of 7.60 (d, 1H, J=8), 6,46 (d, 1H, J=8), with 3.89 (s, 3H), of 2.54 (s, 3H).

D. 6-Methoxy-2-methylpyridin-3-boric acid

A solution of 6-methoxy-3-bromo-2-methylpyridine (59,8 g, 296 mmol) in dry THF (429 ml) was cooled with stirring to -78°C in nitrogen atmosphere. A solution of n-utility (2.5 mol, 130,4 ml, 326 mmol) in hexane was added dropwise within 30 minutes, the Reaction mixture was stirred for 3 h at ˜-78°C. was Added dropwise over 30 min a solution of triisopropylsilane (102,7 ml, 445 mmol) in dry THF (100 ml). The reaction mixture was heated to room temperature while stirring for 16 hours. In the reaction mixture under stirring was added acetic acid (37,35 g, 622 mmol), then water (110 ml). After 2 h, the layers were separated and the organic layer was concentrated in vacuum. The residue was treated with 2-propanol (750 ml) and the solvent was removed on a rotary evaporator (bath temperature ˜50°). The residue was ground in a simple ether. The product was collected by filtration and dried in vacuum (48,4 g): TPL>200°C;1H-NMR (CDCl3, 300 MHz): δ 7,83 (d, 1H, J=8), 6,56 (d, 1H, J=8), 3,85 (s, 3H), of 2.44 (s, 3H); Gas chromatography-mass spectrometry: 168 (M++H).

That is, 2-Methyl-3-(5-METI is isoxazol-4-yl)-6-methoxypyridine

A mixture of 4-iodine-5-methylisoxazole (18.2 g, 87 mmol), 6-methoxy-2-methylpyridin-3-boric acid (14.6 g, 87 mmol), sodium bicarbonate (22,0 g, 262 mmol), water (150 ml) and DME (150 ml) was degirolami three times by stirring vacuum, and then introducing nitrogen. One portion was added [1,1-bis(Diphenylphosphino)ferrocene]dichloropalladium (II) (2.14 g, 2.6 mmol). The reaction mixture was degirolami, as described above. The reaction mixture was then stirred at 80°C for 4 h, then cooled to room temperature. Three times extraction with EtOAc, drying of the combined organic layers over MgSO4filtering and removal of solvent in vacuo gave an oil. Flash chromatography (EtOAc:hexane::1:9) and removing the solvent in vacuum of the desired fractions gave the product (7,15 g):1H-NMR (CDCl3, 300 MHz): δ is 8.16 (s, 1H), 7,33 (d, 1H, J=8), 6,63 (d, 1H, J=8), of 3.95 (s, 3H), 2,35 (C, 6N); APCI+- mass spectrometry: 205 (M++H).

F. 1-Cyan-1-(2-methyl-6-methoxyphenyl-3-yl)propan-2-he, sodium salt

A mixture of sodium methoxide (25% wt./wt., 13 ml, 70 mmol), 2-methyl-3-(5-methylisoxazol-4-yl)-6-methoxypyridine (7,15 g, 35 mmol) and methanol (50 ml) was stirred at room temperature for 16 hours. The solvent was removed in vacuum to obtain a yellow oil. Rubbing in a simple ether, filtration and drying in vacuo gave the crude product as a white solid (9.3 g).

G. 5-And the Ino-4-(2-methyl-6-methoxyphenyl-3-yl)-3-methylpyrazole

A mixture of 1-cyan-1-(2-methyl-6-methoxyphenyl-3-yl)propan-2-she sodium salt (9.3 g), hydrazine hydrate is added (6 ml, 123,3 mmol) and glacial acetic acid (150 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuum. The residue was dissolved in 1N. HCl and the resulting solution was extracted with EtOAc twice. The water layer was added 1N. the NaOH solution to achieve a pH of 12. The resulting polarstar was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4and filtered. The solvent was removed in vacuum to obtain a viscous oil (5.8 g):1H-NMR (CDCl3, 300 MHz): 7,37 (d, 2H, J=8), 6,62 (d, 2H, J=8), of 3.95 (s, 3H), of 2.36 (s, 3H), of 2.08 (s, 3H); APCI+- mass spectrometry: 219 (M++N); 260 (M++CH3CN).

H. 5-Acetamidino-4-(2-methyl-6-methoxyphenyl-3-yl)-3-methylpyrazole, salt acetic acid

Ethylacetoacetate (6,46 g of 52.2 mmol) was rapidly added to a rapidly stirred mixture of potassium carbonate (6,95 g, 50.0 mol), dichloromethane (60 ml) and water (150 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (CH ml). The combined organic layers were dried over MgSO4and filtered. The solvent was removed by simple distillation and the residue in the tank was used without further purification.

Glacial acetic acid (1.0 ml, of 17.4 mmol) was added to stir the mixture of 5-amino-4-(2-methyl-methoxyphenyl-3-yl)-3-methylpyrazole (3.8 g, to 17.4 mmol), the free base of ethylacetamide and dichloromethane (100 ml). The resulting reaction mixture was stirred at room temperature for 16 hours; at the end of this period was concentrated in vacuum. The residue was ground in a simple ether, the product was filtered and washed with copious quantities of simple ether. White solid was dried in vacuum (5,4 g):1H-NMR (CDCl3, 300 MHz): the 7.43 (d, 2H, J=8), 6,69 (d, 2H, J=8), 4,9 (Sirs, 3H), 3,93 (s, 3H), 2,31 (s, 3H), 2,24 (s, 3H), 2.13 and (s, 3H), of 1.88 (s, 3H); APCI+- mass spectrometry: 260 (M++H).

I. 2,7-Dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)[1,5-a]-pyrazolo-[1,3,5]triazine-4(3H)-he

Granules of sodium (3,9 g, 169 mmol) was added by portions in ethanol (200 ml) with vigorous stirring. After entering into the reaction only sodium was added 5-acetamidino-4-(2-methyl-6-methoxyphenyl-3-yl)-3-methylpyrazole, salt acetic acid, (5,4 g of 16.9 mmol) and diethylmalonate (16.4 ml, 135,3 mmol). The resulting reaction mixture was heated to a temperature of phlegmy and was stirred for 18 hours. The mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was dissolved in water and slowly added 1N. HCl to achieve pH˜6. The aqueous layer was extracted with EtOAc three times, the combined organic layers were dried over MgSO4and filtered. The solvent was removed in vacuum to obtain a solid substance. Rubbing in simple is m the air, filtration and drying in vacuo gave a white solid (3.9 g):1H-NMR (CDCl3, 300 MHz): 7,49 (d, 2H, J=8), 6,69 (d, 2H, J=8), 3,93 (s, 3H), of 2.35 (s, 3H), of 2.28 (s, 3H), 2,24 (s, 3H); APCI+- mass spectrometry: 286 (M++H).

Example 2

Getting 4-((R)-2-butylamino)2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)[1,5-a]pyrazolo-1,3,5-triazine

A. 4-Chloro-2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)[1,5-a]pyrazoloacridine

A mixture of 2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)[1,5-a]-pyrazolo-[1,3,5]triazine-4-it (example 1, 3,9 g, 13.7 mmol), diisopropylethylamine (9,5 ml, 54,7 mmol), phosphorus oxychloride (5,1 ml, 54,7 mmol) and toluene (75 ml) was stirred at a temperature of phlegmy within 4 hours. Volatiles were removed in vacuum. The residue was placed on a pad of silica gel on celite and suirable 1:1 mixture of EtOAc and hexane. The solvent was removed in vacuo from the filtrate to obtain oil.

Century 4-((R)-2-Butylamino)2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)[1,5-a]pyrazolo-1,3,5-triazine

A mixture of 4-chloro-2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)- [1,5-a]pyrazoloacridine, (R)-2-butylamine (2.0 ml, of 20.5 mmol), diisopropylethylamine (9,5 ml, 54,7 mmol) and dry THF (25 ml) was stirred at room temperature for 18 hours. The solvent was removed in vacuum. Chromatography of the residue on a column (first with EtOAc : hexane 1:2, then using EtOAc : hexane 1:4) gave the product. Removal of the solvent in the HAC is mind gave a white solid (2.3 g): TPL 118,3°C;1H-NMR (CDCl3, 300 MHz): δ 7,41 (d, 1H, J=8), 6,63 (d, 1H, J=8), and 6.25 (shirt, 1H, J=9), 4,35-4,30 (m, 1H), 3,95 (s, 3H), 2.49 USD (s, 3H), of 2.35 (s, 3H), of 2.30(s, 3H), 1,76-of 1.66 (m, 2H), of 1.34 (d, 3H, J=7), 1,02 (t, 3H, J=7);13C-NMR (CDCl3, 100,52 MHz): δ 163,8, 163,0, 155,7, 153,7, 147,8, 146,6, 141,6, 118,5, 107,4, 106,6, 53,3, 48,2, 29,7, 26,1, 22,9, 20,4, 13,1, 10,3; IR (without impurities, KBr, cm-1): 3380 (m), 3371 (m), 2968 (m), 2928 (m), 2872 (C), 1621 (s), 1588 (s), 1544 (s), 1489 (s), 1460 (s), 1425 (s), 1413 (s), 1364 (s), 1346 (m), 1304 (s), 1275 (s), 1247 (s), 1198 (m), 1152 (m), 1134 (m), 1112 (m), 1034 (s), 1003 (m); ESI(+)-HRMS: Calculated for C18H24N6O: 341.2089; Found: 341.2093 (M++N). Analytically calculated for C18H24N6O: C, 63,51, N, 7,12, N, 24,69; Found: C, 63,67, N, 7,00, N, 24,49.

Utility

Analysis of binding to CRF receptors in rats to assess biological activity.

The affinity of binding to receptors in relation to cortical receptors of rats were analyzed according to published methods (E.B. De Souza, J. Neuroscience, 7: 88 (1987)Kryvyi inhibition of binding of [125I-Tyr°]-o-CRF with cell membranes at various dilutions of the test drug was analyzed by recurring equalization curve LIGAND [P.J.Munson and D.Rodbard, Anal. Biochem. 107:220 (1980), which provides obtaining values of Ki for inhibition, which is then used to assess biological activity.

Inhibition of adenylate cyclase activity stimulated CRF

Ing the repression activity of adenylate cyclase, stimulated CRF can be performed as described G.Battaglia et al. Synapse 1:572 (1987). Briefly, assays are conducted at 37°C for 10 min in 200 ml of buffer containing 100 mmol Tris-HCl (pH 7.4 at 37° (C), 10 mmol MgCl2, 0.4 mmol of etilenvinilatsetata (EGTA), 0.1% bovine serum albumin (BSA), 1 mmol isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine, 5 mmol of creatine phosphate, 100 mmol of guanosine 5'-triphosphate, 100 nmol oCRF, antagonistic peptides (concentration range from 10-9up to 10-6m) and 0.8 mg original wet weight of tissue (approximately 40-60 mg protein). Reactions are initiated by adding 1 mmol ATP/32P]ATP (approximately 2-4 MCI/tube) and stopped by adding 100 ml of 50 mmol Tris-HCl, 45 mmol ATP and 2% sodium dodecyl sulfate. To control the extraction of camp 1 Ámol of [3H]camp (approximately 40,000 decays in 1 min) is added to each tube before division. The Department of [32P]camp from [32R]AMF perform sequential elution through a column of Dowex and alumina columns.

Biological analysis of in vivo

The activity in vivo of the compounds of the present invention can be evaluated using one of the biological tests available and accepted in this field. Illustrative of these tests include the analysis of the acoustic startle test of stairs and analysis of chronic administration. the data and other models, which can be used to test compounds of the present invention, have been described in the publication C.W.Berridge and A.J.Dunn Brain Research Reviews 15:71 (1990).

The connection can be tested at any kind of rodents or small mammals.

The connection according to this invention can be used in the treatment of imbalances associated with pathological levels releasing factor corticotropin in patients suffering from depression, affective disorders and/or anxiety.

The compound of this invention can be introduced for the treatment of these deviations from the norm means that create the contact of the active agent to the site of action of the agent in the body of a mammal. Connection, you can enter any conventional means available for use in combination with drugs or as individual therapeutic agents or in combination with therapeutic agents. It can be entered separately, but in General it is administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

Entered the dosage will vary depending on use and known factors such as the pharmacodynamic nature of certain tools and the way of its introduction; the age of the recipient, weight and health; the nature and extent of viragen the STI symptoms; view concurrent treatment; frequency of treatment and the desired effect. For use in the treatment of specified diseases or conditions a compound of this invention can be administered orally daily dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. The usual dose of 0.01-10 mg/kg in fractional doses 1-4 times/day or in the composition of extended release is effective in obtaining a desired pharmacological effect.

Dosage forms (compositions)suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will usually be present in an amount of from about 0.5 to 95 wt.% based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms such as capsules, tablets and powders, or in liquid forms, such as elixirs, syrups, and/or suspension. The compounds of this invention can also enter parenterally, in sterile liquid dosage compositions.

Gelatin capsules can be used for content of active ingredient and a suitable carrier, such as lactose, starch, magnesium stearate, stearic acid or derivatives of cellulose, but not limited to them. Similar diluents can be used for producing the surveillance CT. And tablets, and capsules can be manufactured in the form of products extended release for prolonged release of drugs over a period of time. Molded tablets may be coated with sugar or film for masking unpleasant taste or used to protect the active ingredients from the atmosphere or to allow selective disintegration of the tablets in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring or flavoring agents to increase the acceptance by the patient.

Usually water, pharmaceutically acceptable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, semi-solid fatty substance. Protivootecnami agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, or separately, or in combination, are suitable stabilizing agents. Also use citric acid and its salts and EDTA. In addition, parenteral solutions could the t contain preservatives, such as benzylaniline, methyl - or propyl-paraben and chlorbutanol.

Suitable pharmaceutical carriers are described in "Remington''s Pharmaceutical Sciences", A.Osol the standard reference in this field. Pharmaceutical dosage forms that can be used for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of standard dosage forms as capsules obtained by filling each of the standard two-part hard gelatin capsules 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules

The mixture of active ingredient in a digestible oil such as soybean oil, oil of cotton seed or olive oil is prepared and injected by means of a positive displacement injection of gelatin for the formation of soft gelatin capsules containing 100 mg of active ingredient. The capsules are washed and dried.

Tablets

A large number of pills get conventional procedures so that the standard dosage form was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98,8 mg of lactose. Appropriate coatings can be applied to Ulu is deprivation taste or delayed absorption.

The compounds of this invention can also be used as reagents or standards for biochemical analysis of neurological function, dysfunction and pathology. Although the present invention has been described and illustrated from the point of view of certain preferred variants of realization, for specialists in this field will be obvious other options for implementation. Therefore, the invention is not limited to the specific described and illustrated variants of implementation, but can be modified or changed without departing from the essence of the invention, the full range of claims which is defined by the attached claims.

1. 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)pyrazolo[1,5-a]1,3,5-triazine of the formula (I):

its stereoisomeric forms or pharmaceutically acceptable salt form.

2. The compound according to claim 1, its pharmaceutically acceptable salt form, where the specified connection is a 4-(R)-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)pyrazolo-[1,5-a]-1,3,5-triazine.

3. The compound according to claim 1, where the specified connection is a 4-(R)-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxyphenyl-3-yl)pyrazolo-[1,5-a]-1,3,5-triazine.

4. Pharmaceutical composition having anfitrionas activity, including farmacevtichesky acceptable carrier and a therapeutically effective amount of a compound according to claim 1.

5. Pharmaceutical composition having anfitrionas activity, including pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according PZ

6. The use of compounds according to claim 1 to obtain a pharmaceutical composition for the treatment of anxiety in mammals.

7. The use of compounds according to claim 3 to obtain a pharmaceutical composition for the treatment of anxiety in mammals.



 

Same patents:

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

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and its pharmaceutically acceptable salts possessing properties of tumor necrosis factor (TNF-α) and to pharmaceutical composition based on thereof wherein R1 means substituted or unsubstituted phenyl wherein substitutes are chosen from halogen atoms or halide-(C1-C6)-alkyl; R4b is substituted or unsubstituted with 1-3 aryl substituted chosen from phenyl, naphthyl wherein substitutes are chosen from halogen atoms, (C1-C6)-alkyl, halide-(C1-C6)-alkyl, (C1-C6)-alkoxyl, cyano-, amino-, (C1-C6)-acylamino-group, (C1-C6)-alkanesulfonyl, or two adjacent substitutes in benzene ring form dioxol group, or unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with 1-3 nitrogen atoms in ring wherein substitutes are chosen from halogen atoms.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 9 sch, 10 tbl, 15 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel pyrimidotriazines of the general formula (I):

wherein each R1 and R2 is chosen from the group comprising hydrogen atom, or R1 and R2 form in common chemical bond, -CH2-Ar and Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono- or disubstituted with (lower)-alkoxy-group and naphthyl mono- or disubstituted with (lower)-alkyl, or their pharmaceutically acceptable salts. Also, invention relates to a method for synthesis of these compounds, pharmaceutical composition based on thereof and to using novel pyrimidotriazines for prophylaxis and/or treatment of diabetes mellitus as these compounds possess the strong expressed inhibitory effect on activity of protein tyrosine phosphatase PTP1B.

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

15 cl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: chemical industry; method of production of the fluorine-containing compounds.

SUBSTANCE: the invention is pertaining to the chemical industry, in particular, to the improved method of production of fluorine-containing compounds from the halogen-containing, compounds, preferably, from chlorine-containing compounds due to an exchange of halogen for fluorine at presence of the HF-additional compound of the mono- or bicyclic amine with at least two atoms of nitrogen. At that at least one atom of nitrogen is built in the cyclic system as the fluorating agent; or at presence of anhydrous hydrogen fluoride - as the fluorating agent and the indicated HF-additional compound of the mono- or bicyclic amine as the catalyst. At usage of the applicable solvents the reaction mixtures can be divided into two phases and thus to simplify the reprocessing of the products. The invention also is pertaining to the HF-additional compounds of 1.5-diazabicyclo[4.3.0]non-5-en and N,N-dialkylaminopiridin, where alkyl represents C1-C4alkyl and where the molar ratio of HF to amine makes 1:1, and to HF- additional compounds 1.8- diazabicyclo[5.4.0]undecyl-7-ene, where the molar ratio of HF to amine compounds more than 1:1.

EFFECT: the invention ensures at usage of the applicable solvents to divide the reaction mixture into two phases and thus to simplify reprocessing of the products.

17 cl, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel derivative of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole, namely its hydrobromide, eliciting properties of antagonist of serotonin 5-HT3-receptors that can be used in therapy of cytotoxic nausea and vomiting. New salt is low toxic and exceeds bemesetron by anti-serotonin activity that is a selective 5-HT3- antagonist.

EFFECT: improved and valuable medicinal properties of derivative.

2 cl, 2 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

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

15 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to new compounds of the formula (I) wherein R1 and R2 can be similar or different and represent independently (C1-C6)-alkyl that are selective inhibitors of enzyme phosphodiesterase, and to their pharmaceutically acceptable salts or stereoisomers. Also, invention involves a method for preparing the preferable compound, i. e. 5-[[2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulfonyl)phenyl]]-1-methyl-3-n-propyl-7,6-dihydro-1H-pyrazolo[4,3-d]pyrimidine-7-one. Also, invention proposes new intermediate compounds used in method for synthesis of this compound. Compounds of the formula (I) show very high effectiveness in treatment of diseases associated with impotence, such as the male erectile sterility but they exhibit such features as prolonged therapeutic effectiveness and lower toxicity. Also, invention relates to a pharmaceutical composition used in treatment of impotence and using compound of the formula (I) in preparing the medicinal preparation designated for treatment of diseases associated with impotence.

EFFECT: valuable medicinal properties of compound.

8 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: medicine, cardiology, psychiatry.

SUBSTANCE: one should carry out traditional therapy of myocardial infarction and, additionally, prescribe perorally pyrasidol at the dosage of 25 mg twice daily for 21 d in combination with eglonyl at 1 ml (50 mg) once daily intramuscularly for 10 d. The present innovation enables to decrease the tension of regulatory systems due to decreasing sympathetic impacts and activation of parasympathetic department of autonomic nervous system.

EFFECT: higher efficiency of therapy.

1 ex, 3 tbl

FIELD: medicine, in particular clinical pharmacology for treatment of bipolar disorder.

SUBSTANCE: claimed method includes administration of therapeutically effective amount of enantiomere of formula Ib ,namely from 0.01 to 100 mg/kg per day to subject.

EFFECT: agent for effective arresting bipolar disorder of type I and type II, cyclothymic disorder, bipolar depression, acute folie, stroke, associated with bipolar disorder, etc.

5 cl, 2 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutically acceptable 2-ethyl-6-methyl-3-oxypyridine salts with organic carboxylic acids of the general formula: (1-V1): wherein R means -CH2OH (I); R means -CH2-COOH (II); R means -(CH2)3-COOH (III); R means -(CH2)4-COOH (IV); R means -CH(OH)-CH(OH)-COOH (V); R means -CH(NH2)-CH2-COOH (VI) possessing with anxiolytic, antidepressive, antihypoxic, anti-amnestic and anti-oxidative activity and showing decreased toxicity. Also, invention relates to a method for preparing salts and pharmaceutical composition.

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

3 cl, 10 tbl, 10 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new medicinal agents for parenteral using based on an antidepressant agent pirlindole salts. Agent comprises 2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]carbazole (pirlindole) sulfonate salts as an active substance, such as methane sulfonate or benzene sulfonate. The composition for intravenous or intramuscular injection comprises additionally citric acid and water taken in the definite ratios. Invention provides preparing an agent possessing good tolerance, low toxicity and resistance in storage.

EFFECT: improved and valuable medicinal and pharmaceutical properties of agent.

2 cl, 1 tbl, 4 ex

FIELD: pharmacy.

SUBSTANCE: invention proposes pharmaceutical compositions consisting of multiple particles with sustained-release of serotonin reuptake selective inhibitor (SRSI) with membrane cover comprising ammonium-methacrylate copolymer, or compositions comprising SRSI particles mixture, or compositions comprising SRSI particles mixture in form of sustained-release of SRSI, Also, invention relates to method for treatment of depression involving administration of these compositions. In particular, SRSI represents fluoxetine, fluvoxamine, sertraline or their salt. Proposed compositions provide a less index of fluctuations that reflects lower values of maximal concentrations of substance in plasma blood after multiple administrations, safety and good tolerance also.

EFFECT: improved medicinal and pharmaceutical properties of compositions.

11 cl, 5 dwg, 26 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to arylsulfonyl derivatives of the formula (I): , wherein Ar means naphthyl or phenyl substituted optionally with halogen atom or (C1-C6)-alkoxy-group; R1 means (C1-C6)-alkyl; R2 means hydrogen atom or (C1-C6)-alkyl, or their pharmaceutically acceptable salts or solvates. Proposed compounds show affinity to HT6 receptors. Also, the claim describes pharmaceutical compositions comprising indicated compounds, their using as therapeutic agents and a method for their preparing. Compounds can be useful in treatment of some disturbances in the central nervous system (CNS).

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

12 cl, 1 tbl, 12 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a combination comprising mirtazapine or its pharmaceutically acceptable salt or solvate and hepiron, or its pharmaceutically acceptable salt or solvate but optionally in combination with one or some pharmaceutically acceptable carriers. The combination of amounts of hepiron and mirtazapine provide the more favorable effect of this combination as compared with additional effects of each preparation taken separately. Proposed combination can be used in treatment of depression and associated disorders. Also, the invention represents a new method for treatment of depression and associated disorders. The combination of mirtazapine and hepiron shows the better effects in more number of patients as compared with effect of each separate preparation that involve less amounts of adverse effects.

EFFECT: improved and valuable medicinal properties of combination.

5 cl, 5 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to an agent representing 2-allylthiobenzimidazole hydrochloride of the formula:

Proposed agent is used for stimulation of teaching process, recovery of memory and emotional status. Invention can be used in experimental pharmacology and medicine also. Invention provides preparing a new agent based on derivatives of benzimidazole representing the most perspective agent among potential stimulators of mental and physical working ability.

EFFECT: valuable properties of agent.

2 dwg, 16 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine N-oxides of the general formula (I) and their pharmaceutically acceptable acid-additive salts wherein R means hydrogen atom, lower alkyl or halogen atom; R1 means hydrogen atom; R2 and R2' mean independently of one another hydrogen, halogen atom, trifluoromethyl group, (lower)-alkoxy-group; or R2 and R2' can mean in common the group -CH=CH-CH=CH- optionally substituted with one or two substitutes taken among lower alkyl or (lower)-alkoxy-group; R3 and R3' mean independently of one another hydrogen atom, lower alkyl; R4 and R4' mean independently of one another -(CH2)mOR6 or lower alkyl; or R4 and R4' form in common with N-atom to which they are bound substituted R5-cyclic tertiary amine representing pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-dioxomorpholine-4-yl; R5 means hydrogen atom, hydroxyl, -COOR3, -N(R3)CO-lower alkyl or -C(O)R3; R6 means hydrogen atom, lower alkyl; X means -C(O)N(R6)-, -N(R6)C(O)-; n = 0, 1, 2, 3 or 4; m = 1, 2 or 3. Also, invention describes a medicinal agent comprising these compounds. Compounds can be used as drugs in treatment or prophylaxis of diseases associated with antagonists of NK-1 receptor.

EFFECT: valuable medicinal properties of agent.

6 cl, 32 ex

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

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