Phenoxy-substituted pyrimidines for application as opioid receptor modulators

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

 

CROSS-REFERENCES TO RELATED INVENTIONS

The present application claims the priority stated in the provisional application for U.S. patent No. 61/256394, filed October 30, 2009, the contents of which are fully incorporated herein by reference.

The SCOPE of the INVENTION

The present invention relates to new modulators of opioid receptors of formula (I). The present invention also relates to methods for producing such compounds and containing their pharmaceutical compositions and to their use for the treatment of disorders modulated by opioid receptors.

Background of the INVENTION

The term "opiate" is used to refer to a pharmacologically active alkaloids derived from opium, e.g. morphine, codeine, and many semisynthetic analogues of morphine. After isolation of peptide compounds with similar morphine effect was introduced the term "opioid" for the generalized designation of any drugs with a similar morphine action. In the class of opioids can include various peptides with similar morphine effects, such as endorphins, enkephalins and dynorphin. However, in some sources, the term "opiate" is used in a generalized sense, and in such contexts, the terms "opiate" and "opioid" are interchangeable. In addition, the term "opioid" is also being integrated�SJ to denote the morphine antagonists drugs and also for the description of receptors or binding sites that can interact with these substances.

Opioids are widely used as analgesics, but they may also have many other pharmacological actions. Morphine and related opioids have the most pronounced effect on the Central nervous and digestive systems. The action spectrum is quite broad and includes the analgesic effect, causing drowsiness, a change of mood, depression of respiratory functions, dizziness, blurred mind, dysphoria, pruritus, increased pressure in the biliary tract, inhibition of motor function of the gastrointestinal tract, nausea, vomiting, and changes in the endocrine and autonomic nervous systems.

When administered to those suffering from pain patients morphine in therapeutic dosages marked decrease in pain intensity, reduction associated with pain discomfort or complete disappearance of pain. Apart from alleviating a pathological condition of a number of patients also experience a sense of euphoria. However, with the introduction of morphine in the recommended to achieve the anesthetic effect dosages to patients who are not suffering from pain, the effect is not always favorable, often there is nausea, and even vomiting. It is also possible drowsiness, inability to concentration�and, reduced mental alertness, apathy, decreased physical activity, reduced visual acuity, and lethargy.

With opioid receptors can bind two classes of opioid molecules: opioid peptides (e.g. enkephalins, dynorphin, endorphins) and alkaloid opiates (e.g., morphine, Etorphine, diprenorphine and naloxone). After the first demonstration of binding sites for opiates (Pert, C. B. and Snyder, S. H., Science (1973) 179:1011-1014) for the classification of multiple opioid receptors were used differences in pharmacological and physiological actions of peptide analogues of alkaloid opioids and opiates. Respectively, have been described in three different molecular and pharmacological type of opioid receptors: Delta, Kappa and mu. Moreover, in each type, it is common to distinguish subtypes (Wollemann, M., J Neurochem (1990) 54:1095-1101; Lord, J. A., et al., Nature(1977) 267:495-499).

Opioid receptors three of these types have common functional mechanisms at the cellular level. For example, the opioid receptors cause inhibition of adenylate cyclase and secretion of neurotransmitter by activating potassium channels and inhibition of Ca2+channels (Evans, C. J., In: Biological Basis of Substance Abuse, S. G. Korenman &J. D. Barchas, eds., Oxford University Press (in press); North, A. R., et al., Proc Natl Acad Sci USA (1990) 87:7025-29; Gross, R. A., et al., Proc Natl Acad Sci USA (1990) 87:7025-29; Sharma, S. K., et al., Proc Natl Acad Sci USA (1975) 72:3092-96). Despite the fact that specified�s functional mechanisms are the same, behavioral manifestations selective to the type of receptor preparations vary considerably (Gilbert, P. E. & Martin, W. R., J Pharmacol Exp Ther (1976) 198:66-82). Such differences may be partly related to the anatomical localization of receptors of various types.

Receptor type Delta distributed in the CNS of mammals more discretely than receptor type mu and Kappa, their high concentration in the amygdala body, the striatum, the substantia nigra, olfactory bulb, olfactory tubercles, hippocampal and cerebral cortex (Mansour, A., et al., Trends in Neurosci (1988) 11:308-14). Notable is the complete absence of opioid receptors, including the Delta-opioid receptors in the cerebellum of the rat.

There is a need to develop new modulators of Delta-opioid receptors to their use as analgesics. There is also a need to develop selective agonists of the Delta opioid receptors to their use as analgesics with reduced side effects. In addition, there is a need for antagonists of the Delta opioid receptors to their use as immunosuppressants, antiinflammatory agents, agents for the treatment of neurological and psychiatric diseases, remedies for the treatment of urological diseases and diseases of the reproductive system, prep�of ATA for the treatment of alcohol and drug abuse, remedies for treating gastritis and diarrhea, remedies for the treatment of cardiovascular and remedies for the treatment of respiratory diseases with reduced side effects.

There is a need to develop new modulators of opioid receptors for use as analgesics. There is also a need to develop agonists of the Delta - and mu-opioid receptors to their use as analgesics with reduced side effects. There is also a need to develop agonists of mu-opioid receptors to their use as analgesics with reduced side effects in the treatment of pain, modulation of immune function, the treatment of gastro-oesophageal reflux and cough. In addition, there is also a need to develop agonists of the Delta opioid receptor for use as anesthetics, agents for the treatment of respiratory diseases, remedies for the treatment of cardiovascular system, remedies for the treatment of urological disorders and remedies for the treatment of neurological and psychiatric diseases. There is also a need to develop a double-acting agonists for the Delta - and mu-opioid receptors.

BRIEF description of the INVENTION

The present invention relates to compounds of formula (I)

where

R1selected from the group consisting of phenyl, pyridinyl and thiazolyl; and R1optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluorine atom, chlorine atom, bromine atom and cyanide groups; in addition, R1optionally substituted amino group, C1-4alkylaminocarbonyl, di(C1-4alkyl)amino group, aminocarbonyl, C1-4alkylaminocarbonyl or di(C1-4alkyl)aminocarbonyl;

Y represents O, S, NH, vinyl, ethinyl or S(O);

R2represents a Deputy selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy;

Rarepresents hydrogen or methyl;

R3selected from the group consisting of pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidine-2-ylmethyl, piperidine-3-ylmethyl, piperidine-4-ylmethyl, piperidine-2-jatila, piperidine-3-jatila, piperidine-4-jatila, pyridin-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl, morpholine-2-ylmethyl, morpholine-3-ylmethyl, imidazolylidene, triazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane, guanidinylation,4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylamino-2-yl, piperidine-3-yl, piperidine-4-silt and pyrrolidin-3-yl;

and wherein the piperidine-3-yl optionally substituted at a carbon atom with phenyl; and wherein pyrrolidin-2-yl in pyrrolidin-2-yl-bromide, pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-yl optionally substituted on the nitrogen atom bromide, vinylmation, Venetian or methylcarbanilate;

and their enantiomers, diastereomers, solvates and pharmaceutically acceptable salts.

The present invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a compound of formula (I) or its pharmaceutically acceptable salt.

Also in the present invention proposed methods of obtaining pharmaceutical compositions, comprising mixing a compound of formula (I) and a pharmaceutically acceptable carrier.

The present invention additionally relates to methods of treating or alleviating the symptoms of disorders modulated by opioid receptors. In particular, the methods of the present invention directed to the treatment or relief of symptoms of disorders modulated by opioid receptors, including, without limitation, inflammatory pain; pain, mediated by the Central nervous system; pain, mediated peripheral system; visceral pain; pain caused by structure�turno violations; cancer pain; pain associated with soft tissue injury; pain associated with progressive disease; neuropathic pain and acute pain associated with acute lesions; acute pain associated with trauma; acute pain associated with surgery; chronic headache, chronic pain with neuropathic diseases, chronic pain in post-stroke conditions and chronic pain in migraine.

The present invention also proposed methods of obtaining these compounds and pharmaceutical compositions, as well as medicinal preparations made on their basis.

For the purposes of the present document, the following terms have the following definitions:

“Ca-b” (where a and b are integers) refers to a radical containing from a to b carbon atoms inclusive. For example, C1-3denotes a radical containing 1, 2 or 3 carbon atoms.

In relation to substituents, the term "independently" means that when the opportunity to enter more than one of such substituents are introducing substituents may be the same or different. Thus, the specified number of carbon atoms (e.g., C1-8) independently represents the number of carbon atoms in the alkyl or cycloalkyl fragment or the alkyl portion of a larger substituent in the title of Kotor�th root is present "alkyl" as a prefix.

Unless otherwise indicated, the term "alkyl" as used herein by itself or as part of the name of the Deputy, refers to straight and branched carbon chains containing from 1 to 8 carbon atoms or any number of carbon atoms within the indicated range. The term "alkoxy" refers to the Vice-type-O-alkyl, where "alkyl" is used in the sense indicated above. Similarly the terms "alkenyl" and "alkynyl" refers to linear and branched carbon chains containing from 2 to 8 carbon atoms or any number of carbon atoms within the designated range, wherein an alkenyl chain contains at least one double bond in the chain, and Alchemilla chain contains at least one triple bond in the chain. Alkyl and alkoxylic one chain may be substituted on the carbon atom. The substituents containing a variety of alkyl groups, for example, (C1-6alkyl)-2-amino-, C1-6is an alkyl group of dialkylamino may be the same or different.

The term "halogen-substituted alkyl" refers to a saturated alkyl radical branched or linear chain, obtained by separation of one hydrogen atom from the parent molecule alkane. The parent alkyl chain contains from 1 to 8 carbon atoms, wherein 1 or more hydrogen atoms are replaced by atoms g�lagena, until the replacement of all inclusive of the hydrogen atoms by halogen atoms. Preferred halogen-substituted alkyl groups include triftormetilfullerenov alkali, deformalization alkali and perforamance alkali; more preferred fluorinated alkali include trifluoromethyl and deformity.

The term "halogen-substituted alkoxy" refers to a radical derived from halogen-substituted alkyl radical through its accession to the oxygen atom, the oxygen atom has one free valence for attachment to the parent structure.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbons containing from 3 to 20 carbon atoms (preferably 3 to 14 carbon atoms). Examples of such groups include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or adamantyl. The term "cycloalkyl" includes cycloalkyl ring fused with benzene ring (benzoannelirovannykh cycloalkyl) or 5 - or 6-membered heteroaromatic ring (containing one of O, S or N and optionally another nitrogen atom) to form heteroatomcontaining of cycloalkyl.

The term "heterocyclyl" refers to 5-10-membered non-aromatic monocyclic ring, in�the PR from 1 to 4 members are nitrogen atoms, or 5-10-membered non-aromatic monocyclic ring in which none, one or two members are nitrogen atoms and up to two members are oxygen atoms or sulfur; wherein the ring optionally contains from zero to two unsaturated bonds. The term "heterocyclyl" includes a heterocyclic ring condensed with benzene ring (benzoannelirovannykh heterocyclyl), 5 - or 6-membered heteroaromatic ring (containing one of O, S or N and optionally another nitrogen atom), 5-7-membered cycloalkyl or cycloalkenyl ring, a 5-7-membered heterocyclyl ring (in the above sense, with the exception of additional fused rings), or condensed to one atom of carbon cycloalkyl, cycloalkenyl or heterocyclyl ring with the formation of sproramentu. For compounds that are the subject of the present invention, the annular carbon atoms that form geteroseksualnoe ring, are fully saturated. Other compounds forming the subject of the present invention, may be partially saturated heterocyclyl ring. In addition, the term "heterocyclyl" includes bridged heterocyclic ring forming a bicyclic ring. Preferred partially saturated heterocyclyl rings can �have one to two double bonds. Such compounds are not considered to be fully aromatic and are not included in the term heteroaryl compounds. Examples geterotsiklicheskikh groups include without limitation pyrrolyl (including 2H-pyrrole, 2-pyrrolyl or 3-pyrrolyl), pyrrolidinyl, 2-imidazolyl, imidazolidinyl ureido, 2-pyrazoline, pyrazolidine, piperidine, morpholine, thiomorpholine and piperazinyl.

The term "aryl" refers to an unsaturated, aromatic monocyclic ring of 6 carbon atoms or an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon atoms. Examples of such aryl rings include, without limitation, phenyl, naphthalenyl or anthracene. Preferred aryl groups for the practical implementation of the present invention are phenyl and naphthalenyl.

The term "heteroaryl" refers to 5 - or 6-membered aromatic ring, with the specified ring consists of carbon atoms and contains at least one heteroatom. Corresponding heteroatoms include nitrogen, oxygen, or sulfur. In the case of 5-membered rings, the heteroaryl ring contains one nitrogen atom, oxygen or sulfur and can contain up to three additional nitrogen atoms. In the case of 6-membered rings, the heteroaryl ring may contain one to three nitrogen atoms. In the case where the 6-membered ring contains three atoms of nitrogen, not more than �Vuh nitrogen atoms are in adjacent positions.

The term "heteroaryl" includes heteroaryl ring fused with benzene ring (benzoannelirovannykh heteroaryl), 5 - or 6-membered heteroaryl ring (containing one of O, S or N and optionally another nitrogen atom), 5-7-membered cycloalkyl ring or a 5-7-membered heterocyclyl ring (in the above sense, with the exception of additional fused rings).

Examples of heteroaryl groups include, among others, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; condensed heteroaryl groups include indole, isoindole, benzofuran, benzothiazyl, indazoles, benzimidazoles, benzothiazoles, benzoxazoles, benzisoxazoles, benzothiadiazoles, benzotriazolyl, chinoxalin, chinoline, ethenolysis or chinazoline.

The term "arylalkyl" denotes alkyl group, substituted aryl group (e.g., benzyl, phenethyl). Similarly, the term "Allakaket" means alkoxylic one group, substituted aryl group (e.g., benzyloxy).

The term "halogen" refers to fluorine, chlorine, bromine and iodine. The substituents of the substituted Halogens on a few points, is replaced with the ability to obtain sustainable� connections.

The term "vinyl" refers to daugleddau unsaturated bridging group in which the unsaturation is represented by a double bond between two carbon atoms. When vinyl bridging groups appear two deputies, it is understood that the substituents attached to adjacent carbon atoms in such a way that the substituents are in the 1,2-position.

The term "oxo" as used alone or as part of the name of the Deputy, refers to a fragment O= associated with carbon atom, or sulfur. For example, phthalimide and saccharin are examples of compounds with hexosaminidase.

If the term "alkyl" or "aryl" or either of formed from these roots prefixes appears in the name of Deputy (for example, arylalkyl, alkylamino implies that all the limitations mentioned above for the terms "alkyl" and "aryl" refer to derived names. The number of carbon atoms (e.g., C1-C6) applies independently to the number of carbon atoms in the alkyl fragment or to the alkyl portion of a larger substituent in which name the root "alkyl" is used as prefix. For alkyl and alkoxylic one of the substituents specified number of carbon atoms includes all of the independent members of the above range separately, and that�as any combination of ranges within the given limits. For example, C1-6alkyl includes individually methyl, ethyl, propyl, butyl, pentyl and hexyl and their podnominatsii (for example, C1-2, C1-3, C1-4, C1-5, C2-6, C3-6, C4-6, C5-6, C2-5etc).

As used herein, the term "patient" means an animal, preferably a mammal, most preferably human, which is the object of treatment, observation or experiment.

As used herein, the term "therapeutically effective amount" means that amount of active compound or pharmaceutical substance which is expected by the researcher, veterinarian, medical doctor or other Clinician biological or medical response on the part of the tissues of the animal or human body, which includes the relief of symptoms of a disease or condition whose treatment is performed.

As used herein, the term "composition" refers to any product containing these components in the amounts indicated, and any and all products that can be obtained, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

As used herein, the term "acyl" refers to alkylcarboxylic deputies.

In the framework of n�standing document of the first indicate the end portion of the described side chain, and then list the functional groups toward the point of connection of the Deputy. For example, under "phenyl(C1-6)alkylaminocarbonyl(C1-6)alkyl" refers to a group of the formula

Unless otherwise specified, it is assumed that the definition of any Deputy or variable at a particular position in the molecule does not depend on the corresponding definitions in other parts of the molecule. It is assumed that substituents and substitution scheme compounds of formula (I) can be selected by the person skilled in the art to provide a chemically stable compounds, which are easy to synthesize by known in the field methods, and also methods set forth herein.

For the purposes of the present invention, the term "opioid receptor modulated" is used to denote the state-dependent modulation of opioid receptor, including, without limitation, the mediating opioid receptor.

DETAILED description of the INVENTION

Embodiments of the present invention include compounds of formula (I), in which

(a) R1selected from the group consisting of phenyl, pyridinyl and thiazolyl; and R1optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, atom ft�RA, chlorine atom, bromine atom and cyanide groups; in addition, R1optionally substituted by aminocarbonyl, C1-4alkylaminocarbonyl or di(C1-4alkyl)aminocarbonyl;

(b) R1represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, fluorine atom and bromine atom; alternatively, R1optionally substituted di(C1-4alkyl)aminocarbonyl;

c) R1represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy and fluorine atom; in addition, R1optionally substituted di(C1-4alkyl)aminocarbonyl;

(d) R1represents phenyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkoxy and di(C1-4alkyl)aminocarbonyl;

e) Y represents O, NH, vinyl, ethinyl or S(O)

f) Y is O or ethinyl;

g) Y is O;

h) R2represents a Deputy selected from the group consisting of C1-2alkoxy, fluorine atom and bromine atom;

i) R2represents C1-2alkoxy or a fluorine atom;

j) Rarepresents hydrogen;

k) R3selected from the group consisting of pyrrolidin-2-ylmethyl, pyrrolidin-3-ilmet�La, the piperidine-2-ylmethyl, piperidine-3-ylmethyl, piperidine-4-ylmethyl, piperidine-3-jatila, piperidine-4-jatila, azetidin-3-ylmethyl, morpholine-2-ylmethyl, piperidine-3-yl, piperidine-4-silt, pyrrolidin-3-yl, 3-aminocyclohexyl, 4-aminocyclohexyl, 3-hydroxy-2-aminopropyl, 4-diethylamino-2-yl, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octanol and 2-(methylamino)ethyl;

wherein the piperidine-3-yl optionally substituted at a carbon atom with phenyl; and wherein pyrrolidin-2-yl in pyrrolidin-2-yl-bromide, pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-yl optionally substituted on the nitrogen atom bromide, vinylmation, Venetian or methylcarbanilate;

l) R3selected from the group consisting of pyrrolidin-2-yl-methyl, pyrrolidin-3-ylmethyl, piperidine-2-ylmethyl, piperidine-3-ylmethyl, piperidine-4-ylmethyl, azetidin-3-ylmethyl, piperidine-3-yl, piperidine-4-yl, 3-aminocyclohexyl, 4-aminocyclohexyl, 3-hydroxy-2-aminopropyl, 4-diethylamino-2-yl, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octanol and 2-(methylamino)ethyl;

moreover, pyrrolidin-2-yl in pyrrolidin-2-ylmethyl optionally substituted on the nitrogen atom bromide;

m) R3selected from the group consisting of pyrrolidin-2-ylmethyl, piperidine-3-yl and 3-aminocyclohexyl;

moreover, pyrrolidin-2-yl in pyrrolidin-2-ylmethyl optionally substituted on the nitrogen atom bromide;

and any combination� the above-described embodiments (a)-m), if it is assumed that those combinations, in which there are various implementation options for the same Deputy, shall be excluded;

and their enantiomers, diastereomers, solvates and pharmaceutically acceptable salts.

The following variant of implementation of the present invention relates to a compound of formula (I)

where

R1selected from the group consisting of phenyl, pyridinyl and thiazolyl; and R1optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanide groups; in addition, R1optionally substituted by aminocarbonyl, C1-4alkylaminocarbonyl or di(C1-4alkyl)aminocarbonyl;

Y represents O, NH, vinyl, ethinyl or S(O);

R2represents a Deputy selected from the group consisting of C1-2alkoxy, fluorine atom and bromine atom;

Rarepresents hydrogen or methyl;

R3selected from the group consisting of pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidine-2-ylmethyl, piperidine-3-ylmethyl, piperidine-4-ylmethyl, piperidine-3-jatila, piperidine-4-jatila, azetidin-3-ylmethyl, morpholine-2-ylmethyl, piperidine-3-yl, piperidine-4-silt, pyrrolidin-3-yl, 3-aminocyclohexyl, 4-aminotic�of Alexela, 3-hydroxy-2-aminopropyl, 4-diethylamino-2-yl, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane and 2-(methylamino)ethyl;

wherein the piperidine-3-yl optionally substituted at a carbon atom with phenyl; and wherein pyrrolidin-2-yl in pyrrolidin-2-yl-bromide, pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-yl optionally substituted on the nitrogen atom bromide, vinylmation, Venetian or methylcarbanilate;

and its enantiomers, diastereomers, solvates and pharmaceutically acceptable salts.

Another embodiment of the present invention relates to a compound of formula (I)

where

R1represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, fluorine atom and bromine atom; alternatively, R1optionally substituted di(C1-4alkyl)aminocarbonyl;

Y represents O, NH, vinyl, ethinyl or S(O);

R2selected from the group consisting of C1-2alkoxy, fluorine atom and bromine atom;

Rarepresents hydrogen;

R3selected from the group consisting of pyrrolidin-2-yl-methyl, pyrrolidin-3-ylmethyl, piperidine-2-ylmethyl, piperidine-3-ylmethyl, piperidine-4-ylmethyl, azetidin-3-ylmethyl, piperidine-3-yl, piperidine-4-yl, 3-aminocyclohexyl, 4-aminocyclohexyl, 3-hydroxy-2-�of isopropyl, 4-diethylamino-2-yl, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane and 2-(methylamino)ethyl;

moreover, pyrrolidin-2-yl in pyrrolidin-2-yl-bromide optionally substituted on the nitrogen atom bromide;

and its enantiomers, diastereomers, solvates and pharmaceutically acceptable salts.

Another aspect of the present invention relates to a compound of formula (I)

where

R1represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy and fluorine atom; in addition, R1 is optionally substituted di(C1-4alkyl)aminocarbonyl;

Y represents O or ethinyl;

R2represents a Deputy selected from the group consisting of C1-2alkoxy, fluorine atom and bromine atom;

Rarepresents hydrogen;

R3selected from the group consisting of pyrrolidin-2-ylmethyl, piperidine-3-yl and 3-aminocyclohexyl;

moreover, pyrrolidin-2-yl in pyrrolidin-2-ylmethyl optionally substituted on the nitrogen atom bromide;

and its enantiomers, diastereomers, solvates and pharmaceutically acceptable salts.

Another embodiment of the present invention relates to a compound of formula (I)

where

R1represents phenyl, neoba�Acelino substituted by one Deputy, independently selected from the group consisting of C1-4alkoxy and di(C1-4alkyl)aminocarbonyl;

Y represents O;

R2represents C1-2alkoxy or a fluorine atom;

Rarepresents hydrogen;

R3selected from the group consisting of pyrrolidin-2-ylmethyl, piperidine-3-yl and 3-aminocyclohexyl;

moreover, pyrrolidin-2-yl in pyrrolidin-2-ylmethyl optionally substituted on the nitrogen atom bromide;

and its enantiomers, diastereomers, solvates and pharmaceutically acceptable salts.

Compounds of formula (I) include compounds of formula (II)

where R1, R2, Raand R3consistent with the definitions of this document; and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts.

The following variant of implementation of the present invention relates to a compound of formula (I)

selected from the group consisting of:

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Ra represents H and R3is a piperidine-3-yl; (RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 3-aminocyclohexyl; (1RS,3RS)

compounds of formula (I), where R1represents a 2-phenyl, Y is etinil, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1is a 4-diethylpyrocarbonate, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2R)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, R ais methyl and R3is a 1 methylpyrrolidine-2-ylmethyl; (2S)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 1 methylpyrrolidine-2-ylmethyl; (2S)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3represents a 3-hydroxy-2-aminopropyl; (2R)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 8-azabicyclo[3.2.1]Oct-3-yl; (1R, 5S)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a piperidine-4-yl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is azetidin-3-ylmethyl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2is a 4-�ethoxy, Rarepresents H and R3represents 1-azabicyclo[2.2.2]Oct-3-yl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a piperidine-3-ylmethyl; (3RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 4-aminocyclohexyl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a piperidine-4-ylmethyl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 2-methylaminomethyl;

compounds of formula (I), where R1represents a 2-(4-methoxyphenyl), Y is vinyl, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents S(O), R2represents a 4-methoxy, Ra represents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3represents a 3-hydroxy-2-aminopropyl; (2S)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-3-ylmethyl; (3RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents NH, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1represents 4-fluorophenyl, Y is O, R2represents a 4-fluoro, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2*S)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a piperidine-2-ylmethyl; (2RS)

compounds of formula (I), where R1is a 2-bromophenyl, Y represents O, R2is a 2-bromo, Rasubmitted�is H and R 3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 1-femalecelebrity-3-yl; (3RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 1-phenylmaleimide-4-yl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 1-geneticdiversity-4-yl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 1-demerol-4-yl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a morpholine-2-ylmethyl; (2RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H � R 3is a 1-phenylmaleimide-3-yl; (3RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3represents a 2-(piperidine-4-yl)ethyl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3represents a 2-(piperidine-3-yl)ethyl; (3RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 4-phenylpiperidine-3-yl; (3RS, 4RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-3-yl; (3RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3represents a 4-(imidazol-1-yl)phenylmethyl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H � R 3is a 4-diethylamino-2-yl; (2RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3represents pyridin-4-ylmethyl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3represents 1-(pyridin-4-yl)ethyl; (1RS)

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is a 1-methylcarbanilate-4-yl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3represents 1H-imidazol-2-ylmethyl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3represents a thiazol-2-ylmethyl;

compounds of formula (I), where R1is a 4-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3performance�possessing a 2-guanidinate;

compounds of formula (I), where R1represents pyridin-3-yl, Y is O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1represents a 3-fluorophenyl, Y is O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1represents a 3-fluorophenyl, Y is S, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1represents pyridin-3-yl, Y is NH, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1represents a 3-fluorophenyl, Y is NH, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-yl-methyl; (2S)

compounds of formula (I), where R represents a thiazol-2-yl, Y is NH, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1represents 3-chlorophenyl, Y is O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1is a 3-methoxyphenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

compounds of formula (I), where R1is a 3-cyanophenyl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

and

compounds of formula (I), where R1is a 3.5-differenl, Y represents O, R2represents a 4-methoxy, Rarepresents H and R3is pyrrolidin-2-ylmethyl; (2S)

and its pharmaceutically acceptable salts.

For use in medicine the salts of the compounds of formula (I) refer to non-toxic "pharmaceutically acceptable salts". However, to obtain the compounds of formula (I) or their pharmaceutically acceptable salts can be used and other salts. Appropriate pharmaceutically acceptable salts of compounds of formula (I) include salts of joining acids, for example, can be obtained by mixing RA�down connections with a solution of a pharmaceutically acceptable acid, for example, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

In addition, when a compound of formula (I) are acid fragment, their pharmaceutically acceptable acceptable salts may include alkali metal salts, e.g. sodium or potassium salts; salts of alkaline earth metals, e.g. calcium or magnesium salts, and also salts with appropriate organic ligands, e.g. Quaternary ammonium salts. Thus, typical examples of pharmaceutically acceptable salts include the following salts: acetate, benzolsulfonat, benzoates, bicarbonates, bisulfate, bitartrate, borates, bromides, calcium edetate, camsylate, carbonates, chlorides, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glyceryltrinitrate, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodides, isothionate, lactates, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, the muqata, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, Pantothenate, phosphate/diphosphate, polygalacturonate, with�literacy, the stearates, sulfates, subacetate, succinates, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Typical examples of acids and bases that can be used to obtain pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroquinone acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, a mixture of Benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfacid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, Caproic acid, Caprylic acid, cinnamic acid, citric acid, reklamowy acid, dodecylthio acid, ethane-1,2-disulfonate, econsultation, 2-hydroxyethanesulfonic, formic acid, fumaric acid, galactarate acid, entityname acid, glucoheptonate acid, D-gluconic acid, D-glucoronosyl acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, Hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonate, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonate, 1-HYDR�XI-2-natoinal acid, nicotinic acid, nitric acid, oleic acid, Orotava acid, oxalic acid, palmitic acid, pambou acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sabotinova acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, ticinobuy acid, p-toluensulfonate and undecylenic acid;

and bases including ammonia, L-arginine, benethamine, benzatin, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, Ethylenediamine, N-methylglucamine, geranamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)pyrrolidine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

Embodiments of the present invention include prodrugs of compounds of formula (I). In General, such prodrugs are functional derivatives of the compounds which in vivo are easily converted into the required compound. Thus, in embodiments of the present invention relating to methods of treatment, the term "introduction" covers the treatment of various diseases mentioned in the description of the compounds which are the subject of the present invention, or the compounds are not mentioned in the present description, but converted to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and acceptance of appropriate Pro-drug derivatives described, for example, in "Design of Prodrugs", Ed. H. Bundgaard, Elsevier, 1985.

If the connections are in accordance with the variants of implementation of the present invention have at least one chiral center, they may accordingly exist in the form of enantiomers. In those cases where the compounds possess two or more chiral centers, they may additionally exist in the form of diastereoisomers. It should be understood that all such isomers and mixtures thereof fall within the scope of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs and as such they fall under the scope of the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention. Specialists in this field understand that used in the present application the term "compound" shall be considered to include solvated compounds of formula I.

In cases where the methods of obtaining the compounds according to certain embodiments be implemented thr�ment of the present invention lead to the formation of a mixture of stereoisomers, however, these isomers may be isolated by standard techniques such as preparative chromatography. Compounds can be obtained in the form of racemates, or individual enantiomers may be obtained by enantiospecific synthesis or by separation. Compounds can e.g. be separated into their component enantiomers by standard techniques such as the formation of diastereomeric pairs by forming salts with optically active acids, for example, (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and recovery of the free base. The compounds can also be separated by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral partner. In an alternative embodiment, the compounds can be separated using chiral HPLC.

One embodiment of the present invention relates to compositions containing (+)-enantiomer of a compound of formula (I), wherein said composition essentially does not contain (-)-isomer of the compound. In this context, the phrase "essentially does not contain" means the content of (-)-isomer less than 25%, preferably less than 10%, more preferably less than 5%, still bol�e preferably less than 2% and even more preferably less than 1%, calculated as follows:

Another embodiment of the present invention is a composition containing (-)-enantiomer of a compound of formula (I), wherein said composition essentially does not contain (+)-isomer of the compound. In this context, the phrase "essentially does not contain" means the content of (+)-isomer less than 25%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% and even more preferably less than 1%, calculated as follows:

.

During the processes for producing compounds in accordance with the variants of implementation of the present invention, it may be necessary to protect sensitive or reactive groups on any of the considered molecules. For these purposes, can be used with appropriate protective groups, for example, described in the work "Protective Groups in Organic Chemistry", ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene &P. G. M. Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1991. The protective group can subsequently be removed at any convenient stage method known in the art.

Although the compounds in accordance with the options of implementing the present invention (including their pharmaceutically acceptable solii pharmaceutically acceptable solvates) can be administered to the patient separately, as a rule, they will be introduced in the form of a mixture with a pharmaceutically acceptable carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical practice. Thus, specific embodiments of the present invention relate to pharmaceutical compositions containing compounds of formula (I) and one or more pharmaceutically acceptable carriers, excipients or diluents.

As an example, in the pharmaceutical and veterinary compositions in accordance with embodiments of the implementation of the present invention compounds of formula (I) may be present in the form of a mixture with any (s) corresponding (s) of the binder (s) substance (s), lubricant (s) substance (s), suspenders (s) substance (s) that cover (s) substance (s) and/or solubilizers (s) substance (s).

Tablets or capsules of the compounds may be administered on one or two or more at one time, depending on the situation. These compounds can also be used in the form of sustained release compositions.

In an alternative embodiment, the compound of formula (I) can be administered by inhalation (intratracheal or intranasal) or in the form of suppositories or pessaries, or applied topically in the form of a lotion, solution, cream, ointment or price�Ki. For example, the described compounds can be administered in a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. You can also enter them in a concentration of from 1 to 10% by weight. in an ointment, having as the basis of a white wax or white soft paraffin and containing the necessary stabilizers and preservatives. An alternative method of transdermal administration is the use of a patch.

For some applications, preferably the oral administration of the compositions in the form of tablets containing such excipients, such as starch or lactose, or in capsules or dragees, in pure form or in mixture with excipients, either in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.

The compositions (as well as separate connections) can also be administered parenterally by injection, e.g., by vnutrikawernozno, intravenous, intramuscular, subcutaneous, intradermal or spinal injection. In this case, the compositions will contain the corresponding carrier or diluent.

The best form of compositions for parenteral administration is a sterile aqueous solution which may also include other components, for example, enough salts or monosaccharides to obtain isotonic blood solution.

For transbuccal�tion or sublingual method of administration of the composition can be administered to the patient in the form of tablets or lozenges, manufactured by standard methods.

As a further example, pharmaceutical and veterinary compositions containing as an active ingredient one or more compounds of formula (I) can be obtained by mixing the compound or compounds with a pharmaceutical carrier in accordance with standard pharmaceutical techniques. The carrier can have different forms, depending on the intended method of administration (e.g., oral, parenteral, etc.). Thus, for liquid oral dosage forms such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, dyes, etc.; for solid oral dosage forms such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulomatous substances smatiauda substances, binders, additives to improve tablet disintegration, etc. the Solid oral dosage form also can be coated from such substances as sugar, either can be coated with enteric coating to change the principal place of absorption and dissolution of drugs. For parenteral administration the carrier typically consists of sterile �odes, in order to increase solubility or preservation may be added other ingredients. Injection administered suspensions or solutions can also be obtained with the use of water media with appropriate supplements.

A therapeutically effective amount of the compounds of formula (I) or including their pharmaceutical compositions is in the range of dosages from about 0.1 mg to about 3000 mg, more specifically from about 1 mg to about 1000 mg or, more specifically, from about 10 mg to about 500 mg of the active component at the reception frequency from about 1 to 4 times per day for an average (70 kg) person. However, the person skilled in the art will be understood that a therapeutically effective amount for active compounds that are the subject of the present invention will vary, depending on the disease.

For oral administration the pharmaceutical composition is preferably used in the form of tablets containing 0,01, 10,0, 50,0, 100, 150, 200, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage in the patient receiving treatment.

Compounds of formula (I) preferably may be administered in a single daily dose, or the total daily dose can be administered multiple doses DV�GDI, three or four times a day. Moreover, the compounds of formula (I) can be injected intranasally with the help of local intranasal use of appropriate delivery vehicles, or via transdermal skin patches well known to specialists in this field.

The person skilled in the art it is also obvious that a therapeutically effective dose of the active compounds of the formula (I) or containing pharmaceutical compositions will vary depending on the desired effect. Therefore, the optimal assigned dose can be easily determined by experts, and may vary depending on specifically the compounds used, the method of administration, the strength of the drug and the severity of the pathological condition. In addition, factors associated with individual treatment of the patient, such as age, weight, diet, time of administration must also be considered when adjusting the dose to achieve the desired therapeutic level. Therefore, the above dosages are exemplary for some average case. Of course, in some individual cases requires the use of higher or lower range of doses, and such cases are included in the scope of the present invention.

Compounds of formula (I) can be administered to the patient in the form of any of the�'s above compositions and described above in any mode of taking or using any generally accepted in the field of compositions and modes of reception in all cases, when the needy in this patient requires the introduction of the compounds of formula (I).

Examples of pain, falling within the scope of the present invention include, among others, inflammatory pain, pain, mediated by the Central nervous system; pain, mediated peripheral system; visceral pain; pain caused by structural disorders or soft tissue injury; pain associated with progressive disease, neuropathic pain and acute pain such as pain associated with acute lesions, trauma or surgery and chronic pain, such as headache and the pain caused by neuropathic conditions, post-stroke conditions, cancer and migraine.

The compounds forming the subject of the present invention, can also be used as immunosuppressants, antiinflammatory agents, agents for the treatment and prevention of neurological and mental disorders such as depression and Parkinson's disease; agents for the treatment of urological disorders and disorders of the reproductive system, for example, urinary incontinence and premature ejaculation; drugs for the treatment of alcohol and drug addiction, remedies for treating gastritis and diarrhea, remedies for the treatment of cardiovascular, cardiotoxin means and means for l�treatment of respiratory diseases.

The compounds forming the subject of the present invention, applicable in the treatment of pain caused by osteoarthritis, rheumatoid arthritis, fibromyalgia, headache, toothache, burn, sunburn, snake bite (in particular, the snake bite), spider bite, insect bites, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, cellulites, causalgia, neuritis of the sciatic nerve, neuralgia of the temporomandibular joint, peripheral neuritis, polyneuritis, stump pain, phantom pain, post-operative ileus, cholecystitis, pain after mastectomy neuropathic pain in the oral cavity, the syndrome of Charcot, reflex sympathetic dystrophy, Guillain-Barre syndrome, paresthetic meralgia syndrome, burning sensation in the mouth, postherpetic neuralgia, trigeminal neuralgia, cluster headache, migrainea headache, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, optic neuritis, postpuberty neuritis, migrating neuritis, segmental neuritis, neuritis Gombo, the neurons, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia node, n�Brugia glossopharyngeal nerve, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, neuralgia of the mammary glands, Morton's neuralgia, syndrome nourishing nerve, occipital neuralgia, erythromelalgia, neuralgia of Cloudera, sphenopalatine neuralgia node, neuralgia of the supraorbital nerve, neuralgia medieva nerve, inflammatory bowel disease, irritable bowel syndrome, sinus headache, tension headache, contractions, childbirth, menstrual cramps, and cancer.

Regarding the use of these compounds in the treatment of diseases and pathological conditions, similar to the above, a therapeutically effective dosages may be determined by the experts in this field through the application of standard animal models. This dose will most likely be chosen from the range from approximately 0.01 mg to approximately 15,000 mg of the active ingredient, administered 1 to 4 times a day a person of average weight (70 kg).

GENERAL METHODS of SYNTHESIS

Typical examples of the compounds constituting the subject of the present invention, can be synthesized in accordance with the General methods of synthesis described below and shown in the following schemes and examples. Because the schema is given as an illustration, the present invention should not be interpreted as limited by himicheskojproduktsii and conditions described in the schemes. Different educt indicated in the diagrams and used in the examples are commercially available or can be obtained by methods well known to specialists in this field. Variables correspond to the description provided herein.

In the present description, particularly the schemes and examples, the following abbreviations apply:

AcClacetyl chloride
AcOHglacial acetic acid
water.water
Bn or Bzlbenzyl
conc.concentrated
dbadibenzylideneacetone
DBU1,8-diazabicyclo[5.4.0]undec-7-ene
DCEdichloroethane
DCMdichloro methane
DIEAdiisopropylethylamine
DMFN,N-dimethylformamide
DMSOdimethyl sulfoxide
dppf1,1'-bis(diphenylphosphino)ferrocene
ESIelektrorazpredelenie ionization
EtOActhe ethyl acetate
EtOHethanol
p.m.hour(s)
HATUhexaflurophosphate O-(1H-7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium
HOBt1-hydroxy-benzotriazole
HPLChigh performance liquid chromatography
Memethyl
MeOHmethanol
MHzmegahertz
minminutes
GHSDliquid chromatography medium pressure
MSmass spectrometry
NMR nuclear magnetic resonance
Phphenyl
Pd/Cpalladium on activated carbon
Ph3Ptriphenylphosphine
PyBOPhexaflurophosphate (benzotriazole-1-yl-oxy)-triprolidine
rtroom temperature
TEA/ Et3Ntriethylamine
TFAtrifluoroacetic acid
THFtetrahydrofuran
TLCthin-layer chromatography
TMStetramethylsilane

In the diagram A shows the path of synthesis of compounds of formula (I)-A, where R1represents optionally substituted phenyl, Y represents O, S or NH and R3is piperidinyl, amino-C3-6cycloalkyl or pyrrolidinyl.

Scheme A

The compound of the formulaA1can be bought off the shelf or get investigatable, described in the scientific literature. The compound of the formulaA1can be treated with a compound of the formulaA2under basic conditions to form a compound of formulaA3. The nitro group of a compound of formulaA3can be restored to their respective primary amino group of the formulaA4under the influence of a reducing agent, such as zinc, tin or iron in acetic acid or by catalytic hydrogenation. The resulting amino group of a compound of formulaA4can be subjected to reductive alkylation of the ketone of the formulaA5(where the ring R3is piperidinyl, aminosilanes C3-6cycloalkyl or pyrrolidinyl) in the presence of a source of the hydride ion, for example, createtextarea of borhydride, to produce a compound of the formulaA6. The ketones of the formulaA5where the ring R3 represents heterocycle, after stage reductive alkylation may require regular removal of the protective amino group. For example, a protected Boc-protected amines can be removed in acidic conditions using reagents such as HCl, TFA, etc. similarly, you can remove the protection with a Cbz-protected amines in acidic conditions.

The compound of the formulaA6you can handle the R1-substituted nucleophilic reagent of the formulaA7(where YA represents O, S or NH) in the alkaline�'s conditions to produce a compound of formula (I)-A.

In scheme B is the path of synthesis of compounds of formula (I)-B, where R1optionally substituted phenyl, Y represents O, S or NH, and R3selected from the group consisting of pyrrolidinyl, piperidinylmethyl, pyridin-4-yl-C1-2of alkyl, azetidin-3-ylmethyl, morpholinomethyl, imidazolylidene, triazolylmethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl and 2-diethylaminoethyl.

Scheme B

The compound of the formulaA4can be subjected to reductive alkylation using an aldehyde of the formulaB1in the presence of a source of the hydride ion, for example, createtextarea of borhydride, to obtain compounds of the formulaB1that are the subject of the present invention. The ring B of the compounds of the formulaB1selected from the group consisting of pyrrolidinyl, piperidinyl, pyridinyl, azetidine, morpholine, imidazoline, thiazoline and 4-(imidazol-1-yl)phenyl). The aldehydes of the formulaB1where ring B is a nitrogen-containing and rich, after the stage of recovery of alkylation may require regular removal of the protective amino group. The compound of the formulaB1may be treated with R1-substituted nucleophilic reagent of the formulaA7in alkaline conditions to produce a compound of formula (I)-B.

In the diagram C shows the path of synthesis of compounds f�of rmula (I)-C1, of formula (I)-C2, where Rais methyl, and formulas (I)-C3; R3 represents pyrrolidinyl - or piperidinylidene Deputy, and pyrrolidinyl and piperidinyl optionally substituted at the nitrogen atom of bromide, vinylmation or Venetian.

Scheme C

The compound of the formulaC1obtained as described in General form in scheme B, can be subjected to reductive alkylation with formaldehyde in acidic conditions and in the presence of a source of the hydride ion, such as NaBH3CN, to obtain monomethylarsonic compounds of the formula(I)-C1and dimethylarsenic compounds of the formula(I)-C2that are the subject of the present invention. Similarly, the compound of the formulaC1can be subjected to reductive alkylation using the appropriately substituted aldehyde (C2), where Rc represents phenyl or benzyl, in the presence of a source of the hydride ion, with the formation of compounds of formula (I)-C3where Rc represents phenylmethyl or phenethyl, respectively.

In scheme D provides a path of synthesis of compounds of formula (I)-D, where Y represents O, S or NH and R3represents a 3-hydroxy-2-aminopropyl.

Scheme D

The compound of the formulaD1may be subjected�UTO reductive alkylation of the aldehyde of the formula D2(where P represents a suitable protective amino group) in the presence of a source of the hydride ion, for example, createtextarea of borhydride, to produce a compound of the formulaD3. With compounds of the formulaD3you can remove the protection by using a strong acid, e.g. trifluoroacetic acid, to obtain compounds of the formula(I)-D.

In scheme E presents the way of synthesis of compounds of formula (I)-E, where R3 represents guanidinylation.

Scheme E

The compound of the formulaD1can be subjected to reductive alkylation of the aldehyde of the formulaE1(where P represents a suitable protective amino group) in the presence of a source of the hydride ion, for example, createtextarea of borhydride, to produce a compound of the formulaE2. With compounds of the formulaE2you can remove the protection by using a strong acid, e.g. trifluoroacetic acid, to obtain compounds of the formulaE3and the primary amine can be treated with hydrochloride 1H-pyrazol-1-carboxamidine in the presence of a tertiary amine to obtain guanidinylation compounds of the formula(I)-E.

In scheme F presents the way of synthesis of compounds of formula (I) F1 and formula (I)-F2, where Y represents S or S(O), respectively.

Scheme F

The amino group connect�of the formula A4can be subjected to reductive alkylation using appropriately substituted ketone or aldehyde, as defined herein, to obtain R3-substituted compounds of the formulaF1. The compound of the formulaF1may participate in the reaction of aromatic nucleophilic substitution of the compound of the formulaF2to obtain compounds of the formula(I)-F1where Y represents S. In the post-processing air compound of the formula(I)-F1slowly converted into the corresponding compound of the formula(I)-F2where Y represents S(O).

In scheme G presents the way of synthesis of compounds of formula (I)-G, where Y represents the vinyl.

Scheme G

The compound of the formulaG1can be purchased in finished form or to obtain by known methods described in the literature. Chloride formulaA6orF1may be cross-linked bonds with a compound of the formulaG1in the presence of a palladium catalyst, appropriate ligands, and an inorganic base to give compounds of the formula(I)-G.

In scheme H presents the way of synthesis of compounds of formula (I)-H, where Y represents NH.

Scheme H

The compound of the formulaH1you can buy ready made or get the Glo�governmental ways described in the literature. The compound of the formulaF4can be treated with a compound of the formulaH1in the presence of a palladium catalyst, phosphine ligand and an inorganic base to give compounds of the formula(I)-H.

In scheme I provides the path of synthesis of compounds of formula (I)-I, where Y represents etinil.

Scheme I

Compounds of the formulaI1you can buy ready made or obtained by conducting chemical reactions described in the literature. Areshared formulaA6orF1may be cross-linked bonds with a tin reagent of the formulaI1in the presence of a palladium catalyst, e.g., tetrakis(triphenylphosphine)palladium (0), to produce a compound of formula (I)-I.

In scheme J presents the way of synthesis of compounds of formula (I)-J, where R3is pyrrolidinyl - or piperidinylidene Deputy, and pyrrolidinyl and piperidinyl optionally substituted at the nitrogen atom of methylcarbanilate.

Scheme J

The compound of the formulaC1you can allievate using compounds of the formulaJ1where W represents chlorine, acetoxy or activated alkoxide, to produce a compound of formula (I)-J.

In scheme K presents the way of synthesis of compounds of formula (I)-K, where R1 represents optionally substituted phenyl and the substituents, different from R2; and YA represents O, S or NH, and R3is piperidinyl, amino-C3-6cycloalkyl or pyrrolidinyl.

Scheme K

The compound of the formulaA3it is possible to subject the reaction of aromatic nucleophilic substitution with a compound of the formulaK1where YA represents O, S or NH, and R1meets the definitions of this document. The restoration of the nitro group with subsequent reductive alkylation using compounds of the formulaA5allows to obtain the compound of formula (I)-K.

Specific examples

All reagents were purchased from commercially available sources. The spectra of nuclear magnetic resonance (NMR) hydrogen atoms have been removed in the indicated solvent using TMS as internal standard on a Bruker Avance or Varian (300 or 400 MHz). Obtained values are given in ppm to low field from the TMS signal. Mass spectra (MS) were obtained on a spectrometer Micromass Platform LC or Agilent 1100 LCMS in the form (ERIE) m/z (M+H)+when using elektrorazpredelenie ionization. Accelerated microwave heating reaction was carried out using a microwave instrument (CEM Discover or biotage AB, unless otherwise noted, the reaction mixture was placed in a hermetically closed vessel. Stereoisomeric �couplers can be characterized as racemic mixtures or as individual diastereomers and enantiomers using x-ray crystallography and other well-known specialists of ways. Unless otherwise noted, all used in the following examples, materials were obtained from standard commercial suppliers of reagents or synthesized by standard methods known to experts in the field of chemical synthesis. Unless otherwise stated, the varied examples of the group of substituents represent hydrogen.

Example 1

2,4-Bis-(4-methoxyphenoxy)-5-nitropyrimidin (1b).To a solution of 2,4-dichloro-5-nitropyrimidine (compound1a) (0.5 g; 2.6 mmol) in acetone (40 ml) was dropwise added a solution of 4-methoxyphenol (0,71 g; 5.7 mmol) in 1N aqueous NaOH (5.7 ml; 5.7 mmol) and H2O (20 ml). After the addition the reaction mixture was slowly warmed to room temperature, and then stirred at room temperature for 20 hours. After removal of the solvent by evaporation the residue was extracted with EtOAc, sequentially washed 1N NaOH (water.) and brine and dried over MgSO4. The mixture was filtered, concentrated and purified column chromatography (eluent, the ratio of EtOAc/hexane: 1/4 to 1/1), receiving the connection1bin the form of a solid yellow color (1,0; 100%). 1H-NMR (300 MHz, CDCl3): δ 9,16 (c, 1H), 7,03-7,07 (d, 2H), 6,95-6,98 (d, 2H), 6,86-6,89 (d, 2H), about 6,82-of 6.85 (d, 2H), 3,82 (c, 1H), 3,80 (c, 1H); MS: m/z 370,2 (M+H)+.

B.2,4-Bis-(4-methoxyphenoxy)pyrimidine-5-ylamine (1c).To Rast�Ouro connection 1b(1.25 g; 3,38 mmol) in tetrahydrofuran (30 ml) was added 10% Pd-C (0.5 g) and the mixture was shaken in a hydrogen atmosphere 344,7 kPa (50 psi) in hydrogenator Parra for 17 h. After filtration and evaporation to dry condition received connection1cin the form of a solid brown color (1.18 g; 100%). 1H-NMR (300 MHz, CDCl3): δ of 7.82 (c, 1H), 7,09-7,12 (d, 2H), 7,00-7,03 (d, 2H), to 6.88-6,91 (d, 2H), about 6,82-of 6.85 (d, 2H), 3,81 (c, 3H), of 3.78 (3H, s), 3,63 (c, 2H); MS: m/z 340,2 (M+H)+.

C.tert-Butyl ether 4-[2,4-bis(4-methoxyphenoxy)pyrimidine-5-ylamino]piperidine-1-carboxylic acid (1d).To a solution of compound1c(1.12 g; 3.3 mmol) and tert-butyl 4-oxo-1-piperidinecarboxylate (0,67 g; 3.3 mmol) in DCE (17 ml) was added NaBH(OAc)3(1.05 g; 4.95 mmol). The resulting mixture was stirred in a nitrogen atmosphere at room temperature for 22 h. After separation of the product from water and purification column flash chromatography (eluent, the ratio of EtOAc/hexane: 3/7) got connection1d(1,06 g; 61%). 1H-NMR (300 MHz, CDCl3): δ 7,66 (c, 1H), 7,08-7,11 (d, 2H), 7,00-7,03 (d, 2H), 6,89-at 6.92 (d, 2H), 6,83-6,86 (d, 2H), 4,04-4,08 (m, 2H), 3,81 (c, 3H), of 3.78 (c, 3H), 3,36-to 3.38 (m, 1H), 2,90-2,98 (m, 2H), 2,04-of 2.09 (m, 2H), 1,46 (c, 9H), 1,40-of 1.47 (m, 2H); MS: m/z 523,3 (M+H)+.

D.2,4-Bis-(4-methoxyphenoxy)pyrimidine-5-yl]piperidine-4-ylamine (compound 13).To a solution of compound1d(0.08 g; 0.15 mmol) in MeOH (1 ml) was added 4N HCl in dioxane (2 ml). The mixture was stirred at 50°C for 1 h and evaporated to the dry state�of. The precipitate was twice washed with Et2O and dried, obtaining a connection13in the form of HCl salt with a quantitative yield. 1H-NMR (300 MHz, CD3OD): δ 7,94 (c, 1H), 7,01-to 7.04 (d, 2H), of 6.96-of 6.99 (d, 2H), 6,83-6,86 (d, 2H), 6,80-6,83 (d, 2H), of 3.78 (c, 1H), of 3.77 (c, 1H), 3,70-3,73 (m, 1H), 3,48-3,52 (m, 2H), 3,14-3,23 (m, 2H), 2,28-of 2.32 (m, 2H), 1,81-1,85 (m, 2H); MS: m/z 423,3 (M+H)+.

Following the procedure described above for example 1 and substituting the appropriate reagents, starting materials and purification methods known to experts in this field, were obtained the following compounds of the present invention:

ConnectionMS (M+H)+ConnectionMS (M+H)+
2423,23437,2
12449,217437,2
36499,237409,2

Example 2

A.tert-Butyl ether 2-(S)-{[2,4-bis(4-methoxyphenoxy)pyrimidine-5-ylamino]methyl}pyrrolidin-1-carboxylic acid (2a). Crestore connection 1c(0,29 g; 0.85 mmol), N-t-Boc-L-prolinal (0.17 g; 0.85 mmol) in DCE (5 ml) was added acetic acid (0.1 ml) and the reaction mixture was stirred at room temperature in a nitrogen atmosphere for 1 h. Then the reaction mixture was added NaBH(OAc)3(0.27 g; 1,28 mmol). The mixture was continuously stirred for 20 h. the resulting mixture was separated between dichloromethane and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried over Na2SO4and filtered. Then the solvent was evaporated in vacuo to obtain the crude oil. The crude oil was purified column flash chromatography (eluent, a gradient of EtOAc/hexane) and got the connection2ain the form of a colourless gel (0.5 g; yield 100%). 1H-NMR (300 MHz, CDCl3): δ of 7.64 (s, 1H), 7,05-7,13 (m, 2H), 6,98-7,03 (m, 2H), about 6,82-6,90 (m, 4H), of 4.09-to 4.28 (m, 1H), 3,81 (s, 3H), of 3.78 (s, 3H), 3,27-3,68 (m, 4H), 1,74-2,11 (m, 4H), of 1.46 (s, 9H); MS: m/z 523,3 (M+H)+.

B.[2,4-Bis(4-methoxyphenoxy)pyrimidine-5-yl]pyrrolidin-2-(S)-ylmethylamino (compound 1).To a solution of compound2a(0.16 g; 0.3 mmol) in DCM (1 ml) was added TFA (1 ml). The mixture was stirred for 2 hours at room temperature. After concentrating the reaction mixture and purification by HPLC on reversed phase received connection1in the form of the trifluoroacetic salt. MS: m/z 423,3 (M+H)+.

Following the procedure described above for example 2 and substituting the appropriate re�Genty, the starting materials and purification methods known to experts in this field, were obtained the following compounds of the present invention:

ConnectionMS (M+H)+ConnectionMS (M+H)+
6423,18423,1
14409,216437,2
18437,223423,2
26437,232439,2
34451,235451,2

Compound 25:

The inventive compound obtained using the adapted version of the procedure described above in example 2, where instead of compound1cat the stage of A used 2,4-bis-(4-pertenece)pyrimidine-5-ylamine (obtained similarly to the compound1cfrom approx�RA 1 using 4-forfinal instead of 4-methoxyphenol in stage A). 1H NMR (300 MHz, CDCl3): δ 10,02 (ush. S., 1H), 9,27 (ush. S., 1H), 7,74 (s, 1H), 6,89-to 7.04 (m, 8H), 3,90 (ush. S., 1H), 3,41-of 3.60 (m, 2H), 3,12-3,40 (m, 2H), 2,11 and 2.26 (m, 1H), 1,88-2,11 (m, 2H), 1,68-to 1.87 (m, 1H).

Compound 27:

The inventive compound obtained using the adapted version of the procedure described above in example 2, where instead of compound1cat the stage of A used 2,4-bis-(2-bromophenoxy)pyrimidine-5-ylamine (obtained similarly to the compound1cexample 1 using 2-bromophenol instead of 4-methoxyphenol in procedure A). 1H NMR (300 MHz, MeOH-d4): δ 7,95 (s, 1H), 7,45-7,6 (m, 2H), 6,95-7,35 (m, 6H), 3,95 (m, 1H), 3,5 (m, 2H), 3,3 (m, 2H), 2,3 (m, 1H), 2,1 (m, 2H), of 1.85 (m, 1H); MS: m/z 521,1 (M+H)+.

Example 3

A.(1-Benzylpyrrolidine-3-yl)-[2,4-bis(4-methoxyphenoxy)pyrimidine-5-yl]amine (compound 28).The claimed compound 28 was obtained using the adapted version of the procedure described for step A of example 2, replacing N-t-Boc-L-prolinal 1-benzylpyrrolidine-3-one (compound3a). 1H-NMR (300 MHz, CDCl3): δ of 10.05 (ush. S., 2H), 7,76 (s, 1H), 7,41 (s, 5H), 6,98 (d, 2H), 6,91 (d, 2H), 6,76 (d, 4H), 4,00-4,37 (m, 4H), 3,76 (s, 6H), 3,64-3,68 (m, 1H), 3,29-3,35 (m, 1H), 2,99-3,09 (m, 1H), 2,61-2,69 (m, 1H), 2,15-2,25 (m, 1H); MS: m/z 499,2 (M+H)+.

Following the procedure described above for example 3 and substituting the appropriate reagents, starting compounds and purification methods known to experts in this field, we obtained the following connected�I, forming the subject of the present invention:

ConnectionMS (M+H)+ConnectionMS (M+H)+
15449,228499,2
29513,230525,2 (M-1)
31437,233513,2
39RUB 467.241445,2
42465,1

Example 4

A.[2,4-Bis(4-methoxyphenoxy)pyrimidine-5-yl]-(4-imidazol-1-yl-benzyl) - amine (compound 38).The claimed compound 38 was obtained using the adapted version of the procedure described for step A of example 2, replacing N-t-Boc-L-prolinal 4-imidazol-1-yl-benzaldehyde (compound4a). 1H-NMR (300 MHz, CDCl3): δ 12,45 (ush. S., 2H), ,01, 1H), 7,58-to 7.68 (m, 2H), 7,44-EUR 7.57 (m, 5H), of 6.96-to 7.09 (m, 2H), of 6.85-of 6.96 (m, 2H), 6,78-of 6.85 (m, 2H), 6,70-6,78 (m, 2H), 4,51 (s, 2H), of 3.78 (s, 3H), of 3.75 (s, 3H); MS: m/z 496,2 (M+H)+.

Following the procedure described above for example 4 and substituting the appropriate reagents, starting compounds and purification methods known to experts in this field, were obtained the following compounds forming the subject of the present invention:

ConnectionMS (M+H)+
40431,1
44437,1
43420,1

Example 5

A.[2,4-Bis(4-methoxyphenoxy)-pyrimidine-5-yl]-(1-methylpyrrolidine-2-(S)-ylmethyl)amine (compound 10).To a solution of compound2b(0.13 g; 0.3 mmol) in CH3CN (5 ml) and Or (0.08 ml) was added formalin (37%, 0.03 ml) and NaBH3CN (0.08 g; 1,14 mmol). After stirring at room temperature for 30 minutes the mixture was concentrated and the residue was divided between 1N aqueous NaOH and EtOAc. Highlighted the organic phase was concentrated and purified by HPLC to produce a compound10. 1H-NMR (300 MHz, CDCl3): δ of 7.85 (s, 1H), 7,00-7,03 (d, 2H), 6,93-of 6.96 (d, 2H), 6,78-6,80 (d, 4H), 3,80-to 3.96 (m, 2H), 3,9 (s, 3H), of 3.78 (s, 3H), 3,56-3,68 (m, 2H), 2,96 (s, 3H), 2,91-3,05 (m, 1H), 2,29-2,42 (m, 1H), 2,09-of 2.23 (m, 2H), 1.93 and-2,04 (m, 1H); MS: m/z 437,2 (M+H)+.

B.2,4-Bis-(4-methoxyphenoxy)pyrimidine-5-yl]methyl-(1-methylpyrrolidine-2-(S)-ylmethyl)amine (compound 9).To a solution of compound2b(0.16 g; 0.38 mmol) in CH3CN (5 ml) and Or (0.08 ml) was added formalin (37%, 0.15 ml) and NaBH3CN (0.08 g; 1,14 mmol). After stirring at room temperature for 30 minutes the mixture was concentrated and the residue was divided between 1N aqueous NaOH and EtOAc. Highlighted the organic phase was evaporated and purified by HPLC to produce a compound9. 1H-NMR (300 MHz, CDCl3): δ of 7.93 (s, 1H), 7,02-7,05 (d, 2H), at 6.92-6,97 (d, 2H), 6,86-6,89 (d, 2H), 6,80-6,83 (d, 2H), 4,34-of 4.44 (m, 1H), 3,81 (s, 3H), of 3.78 (s, 3H), 3,51-3,93 (m, 4H), 3,41 (s, 3H), 2,95 (s, 3H), 2,56-to 2.65 (m, 1H), 2,36-2,19 (m, 2H), 1,96-of 2.09 (m, 1H); MS: m/z 450,2 (M)+.

Example 6

A.tert-Butyl ether 2-(S)-{[4-(4-methoxyphenoxy)-[2,5']bipyridinyl-5-ylamino]methyl}pyrrolidin-1-carboxylic acid (6b).The claimed connection6bgot using the adapted version of the procedure described for step A of example 2, replacing N-t-Boc-L-prolinal on tert-butyl ether 4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid (compound6a). MS: m/z 553,3 (M+H)+.

B.2-(S)-Amino-3-[2,4-bis(4-methoxyphenoxy)pyrimidine-5-ylamino]propan-1-ol (compound 22).Using an adapted version of the procedures�, described for stage B of example 2 and replacing the connection2aon the connection6breceived the claimed compound22in the form of the trifluoroacetic salt. MS: m/z 413,2 (M+H)+.

Following the procedure described above for example 6, and substituting the appropriate reagents, starting compounds and purification methods known to experts in this field, were obtained the following compounds forming the subject of the present invention:

ConnectionMS (M+H)+
11413,2

Example 7

A.tert-Butyl ether {2-[2,4-bis(4-methoxyphenoxy)pyrimidine-5-ylamino]ethyl}-carbamino acid (7b).The claimed connection7bgot using the adapted version of the procedure described for step A of example 2, replacing N-t-Boc-L-prolinal on tert-butyl ether (2-oxoethyl)-carbamino acid (compound7a). MS: m/z 483,2 (M+H)+.

B.N1-[2,4-Bis(4-methoxyphenoxy)pyrimidine-5-yl]ethane-1,2-diamine (7c).To a solution of compound7b(74 mg; 0.15 mmol) in CH2Cl2(3 ml) was added TFA (0.4 ml) at ambient temperature. The mixture was stirred at room temperature for 20 hours. Obtained�ect concentrated in vacuo. The remainder was divided between CH2Cl2and a saturated aqueous solution of NaHCO3. The aqueous phase was subjected to extraction with CH2Cl2. The combined organic extracts were dried over Na2SO4was filtered and the filtrate was concentrated under reduced pressure to produce a compound7c(42 mg; yield 73%). The crude product was used directly for the next step reaction without further purification. MS: m/z 383,2 (M+H)+.

C.N-{2-[2,4-Bis(4-methoxyphenoxy)pyrimidine-5-ylamino]ethyl}guanidine (compound 45).To a solution of compound7c(42 mg; 0.11 mmol) in acetonitrile (10 ml) was added hydrochloride 1H-pyrazol-1-carboxamidine (compound7d) (16 mg; 0.11 mmol) and N,N-diisopropylethylamine (0,22 mmol). The reaction mixture was stirred at room temperature for 3 days. The resulting mixture was separated between EtOAc and H2O. the Organic phase was washed with H2O and dried over Na2SO4. The mixture was filtered and the solvent was evaporated under reduced pressure to obtain residue, which was purified by HPLC on reversed phase (using as eluent a gradient of CH3CN-H2O, the TFA content of 0.5%), receiving the connection45(11 mg; yield 15%) as a trifluoroacetic salt. MS: m/z 425,2 (M+H)+.

Example 8

A.2-Chloro-4-(4-methoxyphenoxy)-5-nitrophe�imidan (8a). To a solution of compound1a(3 g; 15.5 mmol) in acetone (240 ml) at 0°C dropwise added a solution of 4-methoxyphenol (1,94 g; 15.5 mmol) and 1 N aqueous solution of NaHCO3(15,5 ml; 15.5 mmol) and H2O (60 ml). After the addition the reaction mixture was slowly warmed to room temperature, and then stirred at room temperature for 20 hours. The reaction mixture was concentrated, the residue was extracted in EtOAc, washed successively 1N aqueous NaOH and brine, and dried over MgSO4. The mixture was filtered and concentrated, obtaining a connection8ain the form of a solid brown color. 1H-NMR (300 MHz, CDCl3): δ 9.15, with (s, 1H), 7,10-7,13 (d, 2H), 6,95-of 6.99 (d, 2H), 3,85 (s, 3H); MS: m/z 282,0 (M+H)+.

B.2-Chloro-4-(4-methoxyphenoxy)pyrimidine-5-ylamine (8b).To a solution of compound8a(0.42 g; 1.5 mmol) in Or (5.5 ml) and MeOH (6 ml) was added portionwise iron powder (0.25 g; 4.5 mmol). The mixture was held at 65°C for 2.5 hours. After removal of the solvent by evaporation the residue was divided between 1N aqueous NaOH and DCM, filtered through a pillow with diatomite earth, after which phases were separated. The organic phase was sequentially washed with water and brine, and then dried over Na2SO4. After concentrating the mixture got connection8b(0.49 g; 100%). 1H-NMR (300 MHz, CDCl3): δ 7,92 (s, 1H), 7,0-7,12 (d, 2H), at 6.92-to 6.95 (d, 2H), 3,92 (s, 2H), 3,83 (C, 3H); MS: m/z 252,1 (M+H)+.

Ctert-Butyl ether 2-(S)-{[2-chloro-4-(4-methoxyphenoxy)pyrimidine-5-ylamino]methyl}pyrrolidin-1-carboxylic acid (8c).To a solution of compound8b(1.65 g; 6,6 mmol) and N-tert-Boc-L-prolinal (1.6 g; 7.8 mmol) in DCE (40 ml) was added NaBH(OAc)3(1.12 g; 10 mmol). The resulting mixture was stirred in a nitrogen atmosphere at room temperature for 16 h. After removal of solvents the residue was separated between saturated aqueous solution of NaHCO3and EtOAc, the extract in EtOAc was washed with brine and dried over MgSO4. After evaporation of the solvent and purification using preparative TLC (eluent, EtOAc/hexane: 3/7) got connection8cin the form of a yellow oil (2,51 g; 87%). 1H-NMR (300 MHz, CDCl3): δ of 7.64 (s, 1H), 6,99-7,02 (d, 2H), about 6,82-of 6.85 (d, 2H), of 4.09-4,22 (m, 1H), of 3.78 (s, 3H), 3,27-3,66 (m, 4H), 1,73-of 2.09 (m, 3H), of 1.44 to 1.55 (m, 1H); MS: m/z 523,3 (M+H)+.

D.tert-Butyl ether 2-(S)-{[2-(4-methoxybenzenesulfonyl)-4-(4-methoxyphenoxy)pyrimidine-5-ylamino]methyl}pyrrolidin-1-carboxylic acid (8d).The joint compound8c(0.05 g; 0.11 mmol) and 4-methoxybenzoyl (0,073 ml; 0,57 mmol) in 2-propanol (3.5 ml) was heated to reflux for 20 h. After cooling to room temperature the mixture was passed air bubbles for 20 h. After concentrating the reaction mixture under reduced pressure got connection8dwhich was used for further step without further purification. MS: m/z 555,2 (M+H)+.

E.2-(4-Methoxybenzenesulfonyl)-4-(4-methoxyphenoxy)pyrimidine-5-yl]pyrrolidin-2-(S)-ylmethylamino (compound 21).To a solution of compound8d(0.13 g; 0,24 mmol) in DCM (1 ml) was added TFA (1 ml). The mixture was stirred for 1 h at room temperature. The mixture was concentrated and purified by HPLC on reversed phase to obtain a compound21as trifenatate. 1H-NMR (300 MHz, CDCl3): δ 7,73 (s, 1H), 7,13-made 7.16 interest (d, 2H), 7,06-7,10 (d, 2H), 6,67-6,73 (m, 4H), 4,04-4,18 (m, 1H), 3,84 (s, 3H), 3,82 (s, 3H), 3,53-of 3.75 (m, 2H), 3,27-3,47 (m, 2H), 1,99-of 2.30 (m, 3H), 1,70-to 1.86 (m, 1H); MS: m/z 454,9 (M+H)+.

Example 9

A.4-(4-Methoxyphenoxy)-5-nitropyrimidin-2-yl]-(4-methoxyphenyl)amine (9a).A solution of compound8a(Of 0.14 g; 0.5 mmol) and 4-methoxybenzylamine (0.31 g; 2.5 mmol) in DMF (1 ml) was heated at 60°C for 25 h. the Reaction was quenched by adding saturated aqueous solution of NH4Cl, extracted into EtOAc and the combined extracts were dried over Na2SO4. The mixture was filtered, concentrated and purified flash column-chromatography (eluent, EtOAc/hexane: 1/1) to produce a compound9a. 1H-NMR (300 MHz, CDCl3): ∆ 9,12 (s, 1H), 7,34-7,52 (m, 2H), 6,86-of 6.96 (m, 2H), 6,74-6,83 (m, 4H), of 4.54 (s, 1H), 3,85 (s, 3H), 3,81 (s, 3H); MS: m/z 368,1 ((M)+.

B.4-(4-Methoxyphenoxy)-N2-(4-methoxyphenyl)pyrimidine-2,5-diamine (9b).The claimed connection9bgot using adapted�wow option procedures described for stage B of example 8, replacing the connection8aon the connection9a. MS: m/z 338,1 (M)+.

C.tert-Butyl ether 2-(S)-{[4-(4-methoxyphenoxy)-2-(4-methoxybenzylamine)pyrimidine-5-ylamino]methyl}pyrrolidin-1-carboxylic acid (9c).The claimed connection9cgot using the adapted version of the procedure described in stage C of example 8, replacing the connection8bon the connection9b. MS: m/z 522,0 (M+H)+.

D.4-(4-Methoxyphenoxy)-N2-(4-methoxyphenyl)-N6-pyrrolidin-2-(S)-iletilerimde-2,5-diamine (compound 24).To a solution of compound9c(0.1 g; 0.18 mmol) in DCM (1 ml) was added TFA (1 ml). The mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated, the residue was purified by HPLC on reversed phase to obtain a compound24in the form of TFA salt. 1H-NMR (300 MHz, CDCl3): δ 7,40 (s, 1H), 6,97-7,00 (d, 2H), 6,76-of 6.85 (m, 4H), of 6.49-of 6.52 (d, 2H), 3,86-4,00 (m, 1H), of 3.78 (s, 3H), to 3.67 (s, 3H), of 3.25-to 3.56 (m, 4H), 2,03-2,36 (m, 3H), 1,72-to 1.87 (m, 1H); MS: m/z 422,0 (M+H)+.

Example 10

A.tert-Butyl ether 2-(S)-({4-(4-Methoxyphenoxy)-2-[2-(4-methoxyphenyl)vinyl]pyrimidine-5-ylamino}methyl)pyrrolidin-1-carboxylic acid (10a).A mixture of 1-methoxy-4-vinylbenzene (0.16 ml; 1,17 mmol), compound8c(0.11 g; 0.25 mmol), NaHCO3 (0.15 g; 1.84 mmol), PPh3(0.12 g; 0.46 mmol) and Pd(OAc)2 (0.01 g; 0.046 mmol) in DMF (1 ml) was heated in g�metecno a sealed tube to 130°C for 16 hours The reaction mixture was diluted with water, extracted and purified flash column-chromatography (eluent, EtOAc/hexane: 1/1) to produce a compound10ain the form of a mixture of its TRANS - and CIS-stereoisomers (0.03 g; 23%). MS: m/z 533,5 (M+H)+.

B.{4-(4-Methoxyphenoxy)-2-[2-(4-methoxyphenyl)vinyl]pyrimidine-5-yl}pyrrolidin-2-(S)-ylmethylamino (10b).To a solution of compound10a(0,048 g; 0.09 mmol) in DCM (1 ml) was added TFA (1 ml). The mixture was stirred for 1 h at room temperature. The mixture was concentrated and purified by HPLC on reversed phase with obtaining compounds of10bin the form of a mixture of its TRANS - and CIS-stereoisomers. MS: m/z 432,9 (M+H)+.

Example 11

A.tert-Butyl ether 2-(S)-{[4-(4-methoxyphenoxy)-2-phenylaminopyrimidine-5-ylamino]methyl}pyrrolidin-1-carboxylic acid (11a).In the test tube Slinka, closed septae with Teflon coating, said mixture of compounds of8c(214 mg, 0,49 mmol), tributyltinhydride (289 mg, is 0.739 mmol) and tetrakis-(triphenylphosphine)palladium(0) (57 mg, 0,049 mmol) in dioxane (1.0 ml), then the mixture was irradiated in a microwave reactor at 150°C for 30 minutes. The resulting mixture was diluted with EtOAc and then washed with a saturated aqueous solution of NH4Cl and water. The organic phase was washed with H2O, and then dried over Na2SO4.

The mixture was filtered, the filtrate was evaporated under reduced�th pressure and obtained crude material. The crude material was purified column flash chromatography (SiO2, using as eluent a gradient of heptane-EtOAc) and got the connection11a(120 mg, yield 49%). 1H-NMR (400 MHz, CDCl3): δ 7,84-7,98 (m, 1H), 7,52-to 7.60 (m, 2H), 7,29-7,34 (m, 3H), 7,08-of 7.19 (m, 2H), 6,89-of 6.99 (m, 2H), 5,98 (ush. S., 0,6 H), 4,97 (ush. S., 0,4 H), 4,18-of 4.38 (m, 1H), 3,85 (s, 3H), 3,13-of 3.46 (m, 4H), 2,07-2,17 (m, 1H), 1,90-2,03 (m, 2H), 1,76-of 1.88 (m, 1H), 1,44-of 1.52 (m, 9H); MS: m/z 501,1 (M+H)+.

B.[4-(4-Methoxyphenoxy)-2-phenylaminopyrimidine-5-yl]pyrrolidin-2-(S)-ylmethylamino (11b).

To a solution of compound11a(118 mg; of 0.236 mmol) in CH2Cl2(3 ml) at ambient temperature was added trifluoroacetic acid (0.3 ml). The reaction mixture was stirred 20 hours at room temperature. Then pH of the medium was adjusted to pH 12 using 1N aqueous solution of NaOH. The mixture was divided between CH2Cl2and H2O, the organic phase was washed with H2O and dried over Na2SO4.

Thereafter, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2(3 ml) and treated with 1.0 M HCl solution in Et2O (0,24 ml of 0.24 mmol) at ambient temperature. The reaction mixture was stirred 20 hours at room temperature. The resulting mixture was concentrated under vacuum to give a residue, which was triturated to powder with Et2O. the Solids were collected by the method of filtration and high�stirred to produce a compound 11bas hydrochloride (97 mg; yield 94 %). The HCl salt of 1H-NMR (400 MHz, DMSO-d6): quick 8.94 δ (ush. S., 1H), 8,54 (ush. S., 1H), 8,13 (s, 1H), of 7.48-to 7.55 (m, 2H), value of 7, 37-of 7.46 (m, 2H), 7,14-7,21 (m, 2H), 6,99-7,06 (m, 2H), 6,45 (t, 1H), 3,80-3,88 (m, 1H), 3,79 (s, 3H), 3,49 is 3.57 (m, 2H), 3,16-or 3.28 (m, 2H), 2,07-of 2.21 (m, 1H), 1,84-2,05 (m, 2H), 1,63-1,78 (m, 1H); MS: m/z 401,1 (M+H)+.

Example 12

A.tert-Butyl ether 2-(S)-{[2-(3-pertenece)-4-(4-methoxyphenoxy)pyrimidine-5-ylamino]methyl}pyrrolidin-1-carboxylic acid (12a).In the flask Slanka, closed septae with Teflon coating, was placed a solution of compound8c(150 mg; 0,345 mmol), 3-terfenol (100 mg; 0,89 mmol) and K2CO3(95 mg; 0.69 mmol) in DMSO (1 ml) and put her in a microwave reactor at 180°C for 10 minutes. The obtained diluted mixture was diluted with Et2O and washed with a saturated aqueous solution of NH4Cl and H2O. the Organic phase was separated and successively washed with H2O and saturated brine, and then dried over Na2SO4. The mixture was filtered, the filtrate was evaporated under reduced pressure and obtained crude material. The crude material was purified column flash chromatography (SiO2, using as eluent a gradient of heptane-EtOAc) and got the connection12a(35 mg, yield 20%). 1H-NMR (400 MHz, CDCl3): δ 7.67 per-7,72 (m, 1H), 7,21-of 7.25 (m, 2H), 7,04-7,11 (m, 2H), 6,80-6,93 (m, 4H), 5,71 (ush. S., 0,2 H), to 5.21 (ush. C., 0.5 H), of 4.45 (ush. S., 0,3 H), 4,16-429 (m, 1H), 3,81 (s, 3H), 3,09-3,55 (m, 4H), 1,77-2,11 (m, 4H), 1,45-of 1.48 (m, 9H); MS: m/z 511,2 (M+H)+.

B.[2-(3-Pertenece)-4-(4-methoxyphenoxy)pyrimidine-5-yl]pyrrolidin-2-(S)-ylmethylamino (compound 48).To a solution of compound12a(35 mg, 0,069 mmol) in CH2Cl2(2 ml) was added trifluoroacetic acid (0.25 ml). The reaction mixture was stirred at room temperature for 3 hours, the solvent was evaporated in vacuo to obtain the crude material. The crude material was purified by HPLC on reversed phase (eluent, a gradient of CH3CN-H2O) and got the connection48(23 mg, yield 53%) as a TFA salt. 1H-NMR (400 MHz, CDCl3): δ of 9.56 (ush. S., 1H), 7,66 (s, 1H), 7,20-of 7.24 (m, 2H), 7,00-7,03 (m, 2H), of 6.79-6,86 (m, 4H), 4,87 (ush. S., 1H), 3,80-3,84 (m, 1H), 3,79 (s, 3H), 3.46 in (ush. S., 2H), 3,17-3,26 (m, 2H), 2,10-2,19 (m, 1H), 1,92-of 2.08 (m, 2H), 1,72-to 1.82 (m, 1H); MS: m/z 411,2 (M+H)+.

Following the procedure described above for example 12, and substituting the appropriate reagents, starting compounds and purification methods known to experts in this field, were obtained the following compounds forming the subject of the present invention:

ConnectionMS (M+H)+ConnectionMS (M+H)+
46394,2427,0
52Up 423.053418,0
54429,0

Example 13

A.tert-Butyl ether 2-(S)-{[2-(3-forgenerating)-4-(4-methoxyphenoxy)pyrimidine-5-ylamino]methyl}pyrrolidin-1-carboxylic acid (13a).In the flask Slanka was added a mixture of compound8c(100 mg, 0,23 mmol), 3-ftorhinolona (31 mg; 0.28 mmol), K2CO3(44.5 mg, 0,32 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)Xanten (8 mg; 0,014 mmol) and Tris(dibenzylideneacetone)palladium(0) (4.2 mg; 0,0046 mmol). The flask was closed by septal with Teflon coating, was evacuated and filled with argon. Via a syringe was added toluene (0.8 ml) and few drops of water. The mixture was irradiated in a microwave reactor at 180°C for 30 minutes. The resulting mixture was diluted with EtOAc and sequentially washed with a saturated aqueous solution of NH4Cl and H2O. the Organic phase was washed with H2O, and then dried over Na2SO4.

The mixture was filtered, the filtrate was evaporated under reduced pressure and obtained crude material. The crude material was purified column flash chromatography (SiO2, eluent, g�adient heptane-EtOAc) and got the connection 13a(30 mg, yield 26%). 1H-NMR (400 MHz, CDCl3): δ of 7.77 (s, 1H), 7,34 (dt, 1H), 7,10 (d, 2H), 7,02-was 7.08 (m, 1H), 6,98 (d, 2H), of 6.79 (d, 1H), 6,74 (ush. S., 1H), of 6.52 (dt, 1H), 4,76-4,80 (m, 0,5 H), 4,16-to 4.26 (m, 1.5 H), 3,86 (s, 3H), 3,11-3,52 (m, 4H), 1,87-2,10 (m, 4H), 1,23-of 1.30 (m, 9H); MS: m/z 510,3 (M+H)+.

B.N2-(3-Fluorophenyl)-4-(4-methoxyphenoxy)-N5-pyrrolidin-2-(S)-iletilerimde-2,5-diamine (compound 49).To a solution of compound13a(30 mg, 0,059 mmol) in CH2Cl2(2 ml) was added trifluoroacetic acid (0.3 ml). The reaction mixture was stirred at room temperature for 3 hours, the solvent was evaporated in vacuo to obtain the crude material. The crude material was purified by HPLC on reversed phase (eluent, a gradient of CH3CN-H2O) and got the connection49(25 mg, yield 67%) as a TFA salt. 1H-NMR (400 MHz, DMSO-d6): δ of 9.25 (s, 1H), 8,91 (ush. S., 1H), to 8.41 (ush., 1H), 7,95 (s, 1H), 7,40 (dt, 1H), 7,15-of 7.19 (m, 2H), 7,02-7,13 (m, 4H), a 6.53 (TD, 1H), of 5.34 (ush. S., 1H), 3,81-3,86 (m, 1H), 3,79 (s, 3H), 3,20-3,39 (m, 4H), 2,10-2,17 (m, 1H), 1,87-of 1.99 (m, 2H), 1,66-of 1.73 (m, 1H); MS: m/z 410,3 (M+H)+.

Example 14

A.N,N-Diethyl-4-hydroxybenzamide (14a).A mixture of 4-hydroxybenzoic acid (0.70 g; 5.0 mmol), Et2NH (1 ml; 10.0 mmol), hexaflurophosphate (benzotriazole-1-yl-oxy)triprolidine (5.2 g; 10.0 mmol), N-hydroxybenzotriazole (1.0 g; 7.5 mmol) and N,N-diisopropylethylamine (1,74 ml; 10.0 mmol) in DMF (8 ml) was stirred under nitrogen atmosphere at room�Noah temperature for 20 h. The reaction extinguished with water and then was extracted with EtOAc. The organic phase is successively washed with 1N aqueous HCl solution, a saturated aqueous solution of NaHCO3and brine, then dried over Na2SO4. The mixture was filtered, the filtrate was concentrated and the obtained residue was purified column flash chromatography (eluent, EtOAc/hexane: 1/1) to produce a compound14ain the form of white solids (0.45 g; yield 47%). 1H-NMR (300 MHz, CDCl3): δ 9,22 (s, 1H), 7,17 (d, 2H), 6,72 (d, 2H), 3,33-3,51 (m, 4H), 1,10-of 1.26 (m, 6H); MS: m/z 194,1 (M+H)+.

B.N,N-Diethyl-4-[4-(4-methoxyphenoxy)-5-nitropyrimidin-2-yloxy]benzamide (14b).To a solution of compound8a(Of 0.14 g; 0.5 mmol) in acetone (4 ml) was added dropwise a solution of compound14a(0.11 g; 0.55 mmol) in 1N aqueous NaOH (0.55 ml; 0.55 mmol) and H2O (2 ml). After the addition the reaction mixture was slowly warmed to room temperature, and then stirred at room temperature for 20 hours. After concentrating the reaction mixture, the precipitate was extracted into EtOAc, washed with 1N aqueous NaOH and brine, and dried over MgSO4. After removal of the solvent and subsequent purification column flash chromatography (eluent, EtOAc/hexane: 1/1) got connection14b(0.09 g; 41%). MS: m/z 439,2 (M+H)+.

C.4-[5-Amino-4-(4-methoxyphenoxy)pyrimidine-2-yloxy]-N,N-diethylbenzamide(14c). To a solution of compound14b(0.09 g; 0.2 mmol) in MeOH (10 ml) was added 10% Pd-C (0.1 g) and the reaction mixture was shaken in hydrogenator Parra in the hydrogen atmosphere to 220.6 kPa (32 psi) for 20 h. After filtration and evaporation of received connection14c(0.08 g; 98%). MS: m/z 409,2 ((M+H)+.

D.tert-Butyl ether 2-(S)-{[2-(4-diethylcarbamoyl)-4-(4-methoxyphenoxy)pyrimidine-5-ylamino]methyl}pyrrolidin-1-carboxylic acid (14d).To a solution of compound14c(0.08 g; 0,196 mmol) and N-tert-Boc-L-prolinal (0,043 g; 0,215 mmol) in MeOH (1 ml) and Or (0.1 ml) was added NaBH3CN (0.025 g; 0,392 mmol). After stirring at room temperature for 4 h the reaction was quenched by the addition of salt solution, the volatile components were removed by evaporation and the residue was extracted into EtOAc. The organic phase was sequentially washed with 1N aqueous HCl solution, a saturated aqueous solution of NaHCO3and brine, then dried over Na2SO4. After concentrating the mixture, followed by purification using preparative TLC (eluent, EtOAc/hexane: 1/1) got connection14d. MS: m/z 592,3 (M+H)+.

E.N,N-Diethyl-4-{4-(4-methoxyphenoxy)-5-[(pyrrolidin-2-(S)-ylmethyl)amino]pyrimidine-2-yloxy}benzamide (14e).To a solution of compound14d(0.1 g; 0,19 mmol) in DCM (1 ml) was added TFA (1 ml). The mixture was stirred for 1 h at room temperature. After kontsentrirovannoy mixture and purification by HPLC on reversed phase received connection 5in the form of the trifluoroacetic salt. 1H-NMR (300 MHz, MeOH-d4): δ 7,86 (d, 1H), 7,18-7,41 (m, 3H), 7,00-7,14 (m, 2H), of 6.79-6,97 (m, 3H), 3,93 (ush. S., 1H), of 3.77 (d, 3H), 3.43 points-3,63 (m, 4H), 3,31-of 3.43 (m, 4H), of 2.21-2,39 (m, 1H), 1,98-of 2.21 (m, 2H), 1,76-of 1.93 (m, 1H), 1,25 (ush. S., 3H), 1.14 in (ush. S., 3H); MS: m/z 492,3 (M+H)+.

Using the methods described above, were synthesized are shown in table 1 below, compounds 1-54 of formula (I).

Table 1
The light
kit
R1YR2RaR3Stereo
chem.
14-methoxyphenylO4-methoxyHpyrrolidin-2-ylmethyl(2S)
24-methoxyphenylO4-methoxyHthe piperidine-3-yl(RS)
34-methoxyphenyl O4-methoxyH3-aminocyclohexyl(1RS, 3RS)
4phenylethinyl4-methoxyHpyrrolidin-2-ylmethyl(2S)
54-diethylpyrocarbonateO4-methoxyHpyrrolidin-2-ylmethyl(2S)
64-methoxyphenylO4-methoxyHpyrrolidin-2-ylmethyl(2RS)
74-methoxyphenylO4-methoxyHpyrrolidin-2-ylmethyl(2R)
84-methoxyphenylO4-methoxy methyl1 methylpyrrolidine-2-ylmethyl(2S)
94-methoxyphenylO4-methoxyH1 methylpyrrolidine-2-ylmethyl(2S)
104-methoxyphenylO4-methoxyH3-hydroxy-2-aminopropyl(2R)
114-methoxyphenylO4-methoxyH8-azabicyclo
[3.2.1]
Oct-3-yl
(1RS, 5RS)
124-methoxyphenylO4-methoxyHthe piperidine-4-yl
134-methoxyphenylO4-methoxyHazetidin-
3-and�methyl
144-methoxyphenylO4-methoxyH1-azabicyclo
[2.2.2]
Oct-3-yl
154-methoxyphenylO4-methoxyHthe piperidine-3-ylmethyl(3RS)
164-methoxyphenylO4-methoxyH4-aminocyclohexyl
174-methoxyphenylO4-methoxyHthe piperidine-4-ylmethyl
184-methoxyphenylO4-methoxyH2-methylaminomethyl
19 (4-methoxyphenyl)vinyl4-methoxyHpyrrolidin-2-ylmethyl(2S)
204-methoxyphenylS(O)4-methoxyHpyrrolidin-2-ylmethyl(2S)
214-methoxyphenylO4-methoxyH3-hydroxy-2-aminopropyl(2S)
224-methoxyphenylO4-methoxyHpyrrolidin-3-ylmethyl(3RS)
234-methoxyphenylNH4-methoxyHpyrrolidin-2-ylmethyl(2S)
244-fluorophenylO 4-fluoroHpyrrolidin-2 - ylmethyl(2*S)
254-methoxyphenylO4-methoxyHthe piperidine-2-ylmethyl(2RS)
262-bromophenylO2-bromoHpyrrolidin-2-ylmethyl(2S)
274-methoxyphenylO4-methoxyH1-femalecelebrity-3-yl(3RS)
284-methoxyphenylO4-methoxyH1-phenylmaleimide-4-yl
294-methoxyphenylO4-methoxyH1-f�nativepride-4-yl
304-methoxyphenylO4-methoxyH1-demerol-4-yl
314-methoxyphenylO4-methoxyHthe morpholine-2-ylmethyl(2RS)
324-methoxyphenylO4-methoxyH1-phenylmaleimide-3-yl(3RS)
334-methoxyphenylO4-methoxyH2-(piperidine-4-yl)ethyl
344-methoxyphenylO4-methoxyH2-(piperidine-3-yl)ethyl(3RS)
35 4-methoxyphenylO4-methoxyH4-phenylpiperidine-3-yl(3RS,
4RS)
364-methoxyphenylO4-methoxyHpyrrolidin-3-yl(3RS)
374-methoxyphenylO4-methoxyH4-(imidazol-1-yl)-phenylmethyl
384-methoxyphenylO4-methoxyH4-diethylamino-2-yl(2RS)
394-methoxyphenylO4-methoxyHpyridin-4-ylmethyl
404-methoxyphenylO 4-methoxyH1-(pyridin-4-yl)ethyl(1RS)
414-methoxyphenylO4-methoxyH1-methylcarbanilate-4-yl
424-methoxyphenylO4-methoxyH1H-imidazol-2-ylmethyl
434-methoxyphenylO4-methoxyH- thiazol-2-ylmethyl
444-methoxyphenylO4-methoxyH2-guanidinate
45pyridin-3-ylO4-methoxyHpyrrolidin-2-ILM�Il (2S)
463-fluorophenylO4-methoxyHpyrrolidin-2-ylmethyl(2S)
473-fluorophenylS4-methoxyHpyrrolidin-2-ylmethyl(2S)
48pyridin-3-ylNH4-methoxyHpyrrolidin-2-ylmethyl(2S)
493-fluorophenylNH4-methoxyHpyrrolidin-2-ylmethyl(2S)
50- thiazol-2-ylNH4-methoxyHpyrrolidin-2-ylmethyl(2S)
51 3-chlorophenylO4-methoxyHpyrrolidin-2-ylmethyl(2S)
523-methoxyphenylO4-methoxyHpyrrolidin-2-ylmethyl(2S)
533-cyanophenylO4-methoxyHpyrrolidin-2-ylmethyl(2S)
543.5-differenlO4-methoxyHpyrrolidin-2-ylmethyl(2S)

Biological research

In vitro studies

Example 1

24-Hole analysis of binding to Delta opioid receptors on the cell line NG108-15

Method: the cellular membranes of NG108-15 purchased the company Applied Cell Sciences (Rockville, Maryland). 5 mg/ml of membrane protein suspended in 10 mm TRIS-HCl, pH of 7.2, 2 mm EDTA, 10% sucrose. The contents of each vial of homogenize�up in 5 ml of 50 mm Tris buffer solution at pH of 7.4 using several short pulses on the Polytron homogenizer. The homogenate was diluted in 50 mm Tris-buffer solution containing 5 mm MgCl2to a concentration of 330 μg/ml working solution to obtain final protein concentration of 133 μg/well. The resulting formulation is used to conduct 24-well analysis of binding to the Delta opioid receptor.

After incubation with the Delta selective peptide ligand, ~0.2 nm [3H]naltrindole, at 25°C for 2.5 hours on a 24-well plate with a total volume of 1 ml of the contents of the tablet was filtered through a filter UniFilter24, GF/B. This tablet is pre-soaked in 0.3% PEI and filtered through a 24-well system for collecting cells. Filter UniFilter24 washed three times with 2 ml 10 mm HEPES buffer solution (pH of 7.4) and dried in an oven at 37°C for 1.5 hours. To each well was added 150 μl Scint0 (PerkinElmer, catalog number 6013611). Plates were then analyzed on the scanner TopCount.

Analysis: data from the scintillation counter were used to calculate the percentage degree of inhibition compared to control binding (when determined the effect of only one concentration of the test compound) or a Ki value (when tested concentration range). As a negative control was used for nonspecific binding (researcher - 1 mm naloxone) as a positive control was used a total of CBE�ivanie (S. S. only the membrane and the ligand). When analyzing the same concentration of interest, the degree of inhibition was calculated as (number of counts per min. for total binding minus the number of counts per min for the tested compound) divided by (the number of counts per min. for total binding minus the number of counts per min. for non-specific binding). Each refers to the percentage degree of inhibition was obtained by averaging the results of three measurements. When working with multiple concentrations, the values obtained were analyzed using the nonlinear regression program to link one website from the software package Prism to obtain the value of Ki. The maximum and minimum values was used as globally available. Each shows the Ki value was obtained by averaging the results of three dimensions.

The data obtained are shown in table 2 below.

Example 2

Analysis of binding to Delta opioid receptors in rat brain

Procedure: male Wistar rats (150-250 g, VAF, the company Charles River, Kingston, NY) were killed CO2the brain was removed and immediately placed in ice-cold Tris-HCl buffer solution (50 mm, pH 7,4). Anterior separated from the rest of the brain using coronal sections starting at the top of the hills and spending the incision down through the connection media�his brain with a bridge. After opening the front brain is homogenized in a Tris-buffer solution in a Teflon®-glass homogenizer. The homogenate was diluted to a concentration of 1 g of forebrain tissue with 80 ml of buffer solution and centrifuged at a speed of 39,000×g for 10 minutes. The precipitate was resuspended in the same volume of buffer solution with the addition of 5 mm MgCl2with a few small pulses on the Polytron homogenizer. The resulting preparation was used for analysis of binding to the Delta opioid receptor. After incubation with the Delta selective peptide ligand, ~4 nm [3H]DPDPE, or 0.25 nm [3H]naltrindole, at 25°C for 2.5 hours for 96-well plate with a total volume of 1 ml of the contents of the tablet was filtered through a flat filter Wallac B for 96-well collection system Tomtec cell. The filters are washed three times with 2 ml of 10 mm HEPES solution (pH of 7.4) twice and dried in a microwave oven with power of 650W for 1.75 minutes. For each zone with the sample was placed 2×50 μl of scintillation fluid Betaplate Scint (LKB) and quantitatively determined the radioactivity using a liquid scintillation counter 1205 BetaPlate company LKB (Wallac).

Analysis: data from the scintillation counter were used to calculate the percentage degree of inhibition compared to control binding (when determined eff�CT for only one concentration of the test compound) or a Ki value (when tested concentration range). The percentage degree of inhibition was calculated as [(number of decays per minute for the total binding is the number of disintegrations per minute for the test compound)/(the number of decays per minute for total binding - the number of decays per minute for nonspecific binding)]*100. The values of Kd and Ki was calculated using the data analysis program GraphPad PRISM. The data obtained are shown in table 2 below.

Example 3

Analysis of binding to the mu opioid receptors in the rat brain

Procedure: male Wistar rats (150-250 g, VAF, the company Charles River, Kingston, NY) were killed CO2the brain was removed and immediately placed in ice-cold Tris-HCl buffer solution (50 mm, pH 7,4). Anterior separated from the rest of the brain using coronal sections starting at the top of the hills and spending the incision down through the junction of the midbrain to the bridge. After opening the front brain is homogenized in a Tris-buffer solution in a Teflon®-glass homogenizer. The homogenate was diluted to a concentration of 1 g of forebrain tissue with 80 ml of buffer solution and centrifuged at a speed of 39,000×g for 10 minutes. The precipitate was resuspended in the same volume of buffer solution with the addition of 5 mm MgCl2with a few small pulses on the Polytron homogenizer. Derived drug used� for analysis of binding to the mu opioid receptors. After incubation with the mu-selective peptide ligand, ~0.8 nm [3H]DAMGO, at 25°C for 2.5 hours for 96-well plate with a total volume of 1 ml of the contents of the tablet was filtered through a flat filter Wallac B for 96-well collection system Tomtec cell. The filters are washed three times with 2 ml of 10 mm HEPES solution (pH of 7.4) twice and dried in a microwave oven with power of 650W for 1.75 minutes. For each zone with the sample was placed 2×40 μl of scintillation fluid Betaplate Scint (LKB) and quantitatively determined the radioactivity with a liquid scintillation counter 1205 BetaPlate company LKB (Wallac).

Analysis: data from the scintillation counter were used to calculate the percentage degree of inhibition compared to control binding (when determined the effect of only one concentration of the test compound) or a Ki value (when tested concentration range). The percentage degree of inhibition was calculated as [(number of decays per minute for the total binding is the number of disintegrations per minute for the test compound)/(the number of decays per minute for total binding - the number of decays per minute for nonspecific binding)]*100. The values of Kd and Ki was calculated using the data analysis program GraphPad PRISM. The data obtained are shown in table 2 below.

Table 2
Data for the binding of Delta - and mu-opioid receptors
Compound No.δ-binding on the cell membrane of NG108
Ki(µmol)
δ-binding
(ligand DPDPE)
Ki(µmol)
δ-binding
(the ligand naltrindole)
Ki(µmol)
µ-binding
Ki(µmol)
10,005903,883
20,007612,440
30,01611,667
40,01634,420
50,01830,0182
6 0,04371,836
70,06842,848
80,09257,163
90,1159,289
100,130>10
110,1552,151
120.174 were revealed15,226
130,238>10
140,254>10
15 0,2973,235
160,4553,864
170,47712,316
180,117>10
190,2322,054
200,274>10
210,348>10
220,3579,283
230,363>10
24 0,396>10
250,4892,508
260,8858,782
271,0153,575
281,530>10
291,874162,70
301,956>10
310,723>10
320,876>10
33USD 1,112>10
341,117>10
351,431>10
362,135>10
372,702>10
383,088>10
393,526>10
404,366>10
415,325 >10
423,812>10
434,216>10
450,00145
460,000288
470,000739

Example 4

Analysis of binding of [35S]GTPγS in the cell membranes of NG108-15 (functional test for Delta-opioid receptors) - screening at a concentration of 200 nm

Methods: the cellular membranes of NG108-15 purchased the company Applied Cell Sciences (Rockville, Maryland). 5 mg/ml of membrane protein suspended in 10 mm TRIS-HCl, pH of 7.2, 2 mm EDTA, 10% sucrose. The membrane was kept at a temperature of 4-8°C.

1 ml of the preparation of membranes was added to 10 ml of cold buffer solution to perform the test. Buffer solution for the test contained 50 mm Tris-buffer solution, pH 7,, 5 mm MgCl2, 100 mm NaCl, 1 mm DTT and 1 mm EGTA. The suspension of the membranes twice homogenized in a Polytron homogenizer and centrifuged at the speed of 3000 rpm for 10 minutes. The supernatant is then centrifuged at the speed of 18000 rpm for 20 minutes. In a test tube with debris added to ten ml of buffer solution to the test. Debris and buffer were stirred using a homogenizer Polytron.

The incubation procedure: precipitated membranes (75 μg/ml) were pre-incubated with the particles for scintillation analysis of the approximation (SPA) (10 mg/ml) at 25°C for 45 minutes in a buffer solution for the test. Associated with membranes (37,5 µg/ml) SPA (5 mg/ml) then incubated with 0.1 nm [35S] GTPγS in the same Tris buffer containing 100 μm GDP in total volume of 200 μl.

To stimulate binding of [35S]-GTPγS was added 200 nm of receptor agonists. A basic level of binding was tested in the absence of agonists, and the level of nonspecific binding was tested in the presence of 10 μm unlabeled GTPγS. Data were analyzed on the counter Packard Top Count, the results are shown in table 3 below.

DATA

% of base=(stimulated-non-specific)*100/(baseline-non-specific).

The relative efficacy of compounds at a concentration of 200 nm

= (% of base for the tested compounds at 200 nm)/(calculate how muc�culated the maximum of curve effect of SNC80 dose; the curve in the prism package).

Example 5

Analysis of binding of [35S]GTPγS on cellular membranes of CHO-hMOR (functional test on mu-opioid receptors)

Methods: the cellular membranes of CHO-hMOR can be purchased in the company of Receptor Biology, Inc. (Baltimore, Maryland, USA). Membrane protein can be suspended in a concentration of approximately 10 mg/ml in 10 mm TRIS-HCl buffer solution at a pH of 7.2 with the addition of 2 mm EDTA, 10% sucrose. The suspension was kept on ice. 1 ml of the preparation of the membranes can be added to 15 ml of cold buffer solution to do this test, which contains 50 mm HEPES buffer solution, pH 7.6, 5 mm MgCl2, 100 mm NaCl, 1 mm DTT and 1 mm EDTA. The suspension of the membranes can be homogenized in a Polytron homogenizer and centrifuged at a speed of 3000 rpm for 10 minutes. The supernatant may then be centrifuged at a speed of 18000 rpm for 20 minutes. The resulting precipitate was re-dissolved in 10 ml of buffer solution to the test on the Polytron homogenizer. The membrane can be pre-incubated with covered agglutinin from wheat germ SPA-particles (Amersham) at 25°C for 45 minutes in a buffer solution for the test. Then bound to the membranes (10 μg/ml) SPA-particles (5 mg/ml) can be incubated with 0.5 nm [35S]GTPγS in the buffer solution for the test. Basic binding which �can occur in the absence of added test compounds, was taken as 100%, stimulated by agonist binding may reach levels that significantly exceed this value. To stimulate binding of [35S]GTPγS can be used a range of concentrations of receptor agonists. Both basic and non-specific binding can be tested in the absence of the agonist. To determine the level of nonspecific binding used 10 μm unlabeled GTPγS.

Compounds can be tested for activity as an antagonist by assessing their capacity to inhibit agonist-stimulated GTPγS binding. Radioactivity can be quantified on the counter Packard TopCount. You can calculate the following parameters:

% stimulation = (number of counts per min for the tested compounds, the number of counts per minute for non-specific binding) ×100

(the number of counts per minute for basic binding - the number of counts per minute for non-specific binding).

% inhibition = (% stimulation by 1 μm DAMGO - % stimulation test compound) ×100

(% stimulation by 1 μm DAMGO - 100)

EC50 values can be calculated in the program GraphPad Prism. They are listed in table 3 below.

Table 3
Functional characteristics of Delta - and mu-opioid receptors
Compound No.GTPγS
δ-Rel.
Efficiency at
200 nm
GTPγS
δ-opioid receptor
EC50 (μm)
GTPγS
δ-opioid receptor, % inhib. when 10 µm
GTPγS
δ-opioid receptor, Rel.
efficiency
GTPγS
μ-opioid receptor, EC50 (μm)
GTPγS
μ-opioid receptor
% inhib.
when 10 µm
1Of 0.812
3,653
17,499
16,430
0,66484,33419,461
20,8288,163
30,559, 0,092, 0,20612,801
19,733
1,106
41,0308,9360,923
52,62226,4000,471
612,502
70,22120,645
441,11015,636
450,7341,178
460,7700,0280,983
470,4810,193 1,079
480,267
490,216
500,143
510,8590,0431,040
520,6240,0510,935
530,7050,0531,033
540,066

The in vivo study

Example 6

Model of inflammatory pain on the basis of hypersensitivity to radiated heat in rats caused by the introduction of CFA

The full introduction of adjuvant freind (CFA) in the sole of the foot causes the rodent to strong and long-lasting inflammatory reaction, characterized by chronic pronounced hyperalgesia as to thermal and mechanical stress. These effects reach their maximum expression during the period of 24-72 hours after injection and can last from several days to several weeks. To assess the ability of compounds to conversion of thermal hyperalgesia in the sole of the left hind legs of the male rats line Sprague-Dawley (200-350 g) can be introduced injection of CFA (1:1 CFA:saline, 100 μl). After 24-hour incubation period, you can determine the latency of the response to emitting the heat stimulator pads (RH), which can be compared with background delays before the introduction of the CFA. The stimulator automatically records the raising of the presser foot with the surface of the glass. The analysis was continued only for rats, which occurred at least a 25% reduction in latent period p�shares (that is, there was hyperalgesia). After determining the delay after the administration of CFA rats oral you can enter (2.5 ml/kg) test compound or an inert carrier (hydroxypropyl methylcellulose, HPMC). For each animal, you can calculate the percentage degree of conversion of hyperalgesia as (reaction after administration of the tested compounds, the reaction after the administration of CFA)/(reaction before the introduction of the CFA - reaction after the administration of CFA)×100. Thus, the return to normal thresholds of sensitivity to the introduction of the CFA can be defined as 100% efficiency, whereas no differences from sensitivity thresholds after administration of CFA can be estimated as 0% efficiency. Then for each group it is possible to calculate the average percentage degree of conversion of hyperalgesia (n=6-8 rats/group).

The above technical description contains information about the principles underlying the present invention, and illustrating his examples, however, it should be understood that the practical application of the invention extends to all of the usual variations, adaptations and/or modifications in accordance with the following claims and their equivalents.

1. The compound of formula (I)

where
R1selected from the group consisting of phenyl, pyridinyl and thiazolyl; and R1optionally substituted by one or two substituents, is indep�Simo selected from the group consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanide groups; in addition, R1optionally substituted di(C1-4alkyl)aminocarbonyl;
Υ is O, S, ΝΗ, vinyl, ethinyl or S(O);
R2represents a Deputy selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy;
Rarepresents hydrogen or methyl;
R3selected from the group consisting of pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidine-2-ylmethyl, piperidine-3-ylmethyl, piperidine-4-ylmethyl, piperidine-2-jatila, piperidine-3-jatila, piperidine-4-jatila, pyridin-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl, morpholine-2-ylmethyl, morpholine-3-ylmethyl, imidazolylidene, triazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane, guanidinylation, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylamino-2-yl, piperidine-3-yl, piperidine-4-silt and pyrrolidin-3-yl;
and wherein the piperidine-3-yl optionally substituted at a carbon atom with phenyl; and wherein pyrrolidin-2-yl in pyrrolidin-2-yl-bromide, pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-yl optionally substituted on the nitrogen atom bromide, vinylmation, Venetian or meth�carbonium;
and its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

2. The compound according to claim 1, where R1selected from the group consisting of phenyl, pyridinyl and thiazolyl; and R1optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, fluorine atom, bromine atom and cyanide groups; alternatively, R1optionally substituted di(C1-4alkyl)aminocarbonyl.

3. The compound according to claim 2, where R1represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, fluorine atom and bromine atom; alternatively, R1optionally substituted di(C1-4alkyl)aminocarbonyl.

4. The compound according to claim 3, where R1represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy and fluorine atom; in addition, R1optionally substituted di(C1-4alkyl)aminocarbonyl.

5. The compound according to claim 4, where R1represents phenyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkoxy and di(C1-4alkyl)aminocarbonyl.

6. The compound according to claim 1, where Υ represents OH, ΝΗ, vinyl, ethinyl or S(O).

7. The connection according to claim 6, where Υ is with�fight About or ethinyl.

8. The connection according to claim 7, where Υ represents O.

9. The compound according to claim 1, where R2represents a Deputy selected from the group consisting of C1-2alkoxy, fluorine atom and bromine atom.

10. The connection according to claim 9, where R2represents C1-2alkoxy or a fluorine atom.

11. The compound according to claim 1, where Rarepresents hydrogen.

12. The compound according to claim 1, where R3selected from the group consisting of pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidine-2-ylmethyl, piperidine-3-ylmethyl, piperidine-4-ylmethyl, piperidine-3-jatila, piperidine-4-jatila, azetidin-3-ylmethyl, morpholine-2-ylmethyl, piperidine-3-yl, piperidine-4-silt, pyrrolidin-3-yl, 3-aminocyclohexyl, 4-aminocyclohexyl, 3-hydroxy-2-aminopropyl, 4-diethylamino-2-yl, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane and 2-(methylamino)ethyl;
wherein the piperidine-3-yl optionally substituted at a carbon atom with phenyl; and wherein pyrrolidin-2-yl in pyrrolidin-2-ylmethyl, pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-yl optionally substituted on the nitrogen atom bromide, vinylmation, Venetian or methylcarbanilate.

13. The compound according to claim 12, where R3selected from the group consisting of pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidine-2-ylmethyl, piperidine-3-ylmethyl, piperidine-4-ylmethyl, azetidin-3-ylmethyl, piperidine-3-yl, piperidine-4-and�and, 3-aminocyclohexyl, 4-aminocyclohexyl, 3-hydroxy-2-aminopropyl, 4-diethylamino-2-yl, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane and 2-(methylamino)ethyl;
moreover, pyrrolidin-2-yl in pyrrolidin-2-ylmethyl optionally substituted on the nitrogen atom bromide.

14. The compound according to claim 13, wherein R3selected from the group consisting of pyrrolidin-2-ylmethyl, piperidine-3-yl and 3-aminocyclohexyl;
moreover, pyrrolidin-2-yl in pyrrolidin-2-ylmethyl optionally substituted on the nitrogen atom bromide.

15. The compound of formula (I)

where R1selected from the group consisting of phenyl, pyridinyl and thiazolyl; and R1optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanide groups; in addition, R1optionally substituted di(C1-4alkyl)aminocarbonyl;
Υ represents OH, ΝΗ, vinyl, ethinyl or S(O);
R2represents a Deputy selected from the group consisting of C1-2alkoxy, fluorine atom and bromine atom;
Rarepresents hydrogen or methyl;
R3selected from the group consisting of pyrrolidin-2-yl-methyl, pyrrolidin-3-ylmethyl, piperidine-2-ylmethyl, piperidine-3-ylmethyl, piperidine-4-ylmethyl, piperidine-3-jatila, piperidine-4-jatila, azetidin-3-and�bromide, the morpholine-2-ylmethyl, piperidine-3-yl, piperidine-4-silt, pyrrolidin-3-yl, 3-aminocyclohexyl, 4-aminocyclohexyl, 3-hydroxy-2-aminopropyl, 4-diethylamino-2-yl, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane and 2-(methylamino)ethyl;
wherein the piperidine-3-yl optionally substituted at a carbon atom with phenyl; and wherein pyrrolidin-2-yl in pyrrolidin-2-ylmethyl, pyrrolidin-3-yl, piperidine-3-yl and piperidine-4-yl optionally substituted on the nitrogen atom bromide, vinylmation, Venetian or methylcarbanilate;
and its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

16. The compound of formula (I)

where
R1represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, fluorine atom and bromine atom; alternatively, R1optionally substituted di(C1-4alkyl)aminocarbonyl;
Υ represents OH, ΝΗ, vinyl, ethinyl or S(O);
R2selected from the group consisting of C1-2alkoxy, fluorine atom and bromine atom;
Rarepresents hydrogen;
R3selected from the group consisting of pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidine-2-ylmethyl, piperidine-3-ylmethyl, piperidine-4-ylmethyl, azetidin-3-ylmethyl, piperidine-3-yl, piperidine-4-yl, 3-aminocyclohexyl, 4-aminocyclo�of xela, 3-hydroxy-2-aminopropyl, 4-diethylamino-2-yl, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane and 2-(methylamino)ethyl;
moreover, pyrrolidin-2-yl in pyrrolidin-2-ylmethyl optionally substituted on the nitrogen atom bromide;
and its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

17. The compound of formula (I)

where
R1represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy and fluorine atom; in addition, R1optionally substituted di(C1-4alkyl)aminocarbonyl;
Υ is O or ethinyl;
R2represents a Deputy selected from the group consisting of C1-2alkoxy, fluorine atom and bromine atom;
Rarepresents hydrogen;
R3selected from the group consisting of pyrrolidin-2-ylmethyl, piperidine-3-yl and 3-aminocyclohexyl;
moreover, pyrrolidin-2-yl in pyrrolidin-2-ylmethyl optionally substituted on the nitrogen atom bromide;
and its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

18. The compound of formula (I)

where
R1represents phenyl, optionally substituted by one Deputy, independently selected from the group consisting of C1-4alkoxy and di(C1-4alkyl)amine�carbonyl;
Υ is O;
R2represents C1-4alkoxy or a fluorine atom;
Rarepresents hydrogen;
R3selected from the group consisting of pyrrolidin-2-ylmethyl, piperidine-3-yl and 3-aminocyclohexyl;
moreover, pyrrolidin-2-yl in pyrrolidin-2-ylmethyl optionally substituted on the nitrogen atom bromide;
and its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

19. The compound of formula (I)

selected from the group consisting of:
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-yl-methyl; (2S)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a piperidine-3-yl; (RS)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 3-aminocyclohexyl; (1RS,3RS)
compounds of formula (I), where R1represents a 2-phenyl, Υ represents etinil, R2represents a 4-methoxy, Rarepresents Η and R 3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1is a 4-diethylpyrocarbonate, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2RS)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2R)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rais methyl and R3is a 1 methylpyrrolidine-2-ylmethyl; (2S)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 1 methylpyrrolidine-2-ylmethyl; (2S)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Ra/sub> represents Η and R3represents a 3-hydroxy-2-aminopropyl; (2R)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 8-azabicyclo[3.2.1]Oct-3-yl; (1R,5S)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a piperidine-4-yl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is azetidin-3-ylmethyl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3represents 1-azabicyclo[2.2.2]Oct-3-yl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a piperidine-3-ylmethyl; (3RS)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Raperformance�possessing a Η and R 3is a 4-aminocyclohexyl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a piperidine-4-ylmethyl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 2-methylaminomethyl;
compounds of formula (I), where R1represents a 2-(4-methoxyphenyl),Υ represents vinyl, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents S(O), R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3represents a 3-hydroxy-2-aminopropyl; (2S)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3 is pyrrolidin-3-ylmethyl; (3RS)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents NH, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1represents 4-fluorophenyl, Υ represents Oh, R2represents a 4-fluoro, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2*S)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a piperidine-2-ylmethyl; (2RS)
compounds of formula (I), where R1is a 2-bromophenyl, Υ represents Oh, R2is a 2-bromo, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 1-femalecelebrity-3-yl; (3RS)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 1-phenylmaleimide-4-yl;br/> compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 1-geneticdiversity-4-yl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 1-demerol-4-yl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a morpholine-2-ylmethyl; (2RS)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 1-phenylmaleimide-3-yl; (3RS)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3represents a 2-(piperidine-4-yl)ethyl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3represents a 2-(piperidine-3-yl)ethyl; (3RS)
with�unity of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 4-phenylpiperidine-3-yl; (3RS, 4RS)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-3-yl; (3RS)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3represents a 4-(imidazol-1-yl)phenylmethyl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 4-diethylamino-2-yl; (2RS)
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3represents pyridin-4-ylmethyl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3represents 1-(pyridin-4-yl)ethyl; (1RS)
compounds of formula (I), where R 1
is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 1-methylcarbanilate-4-yl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3represents 1H-imidazol-2-ylmethyl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3represents a thiazol-2-ylmethyl;
compounds of formula (I), where R1is a 4-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is a 2-guanidinate;
compounds of formula (I), where R1represents pyridin-yl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1represents a 3-fluorophenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1is �Wallpaper 3-fluorophenyl, Υ represents S, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1represents pyridin-3-yl, Υ represents NH, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1represents a 3-fluorophenyl, Υ represents NH, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1represents a thiazol-2-yl, Υ represents NH, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1represents 3-chlorophenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1is a 3-methoxyphenyl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
compounds of formula (I), where R1is a 3-cyanophenyl, Υ is with�fight About, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-yl-methyl; (2S) and
compounds of formula (I), where R1is a 3.5-differenl, Υ represents Oh, R2represents a 4-methoxy, Rarepresents Η and R3is pyrrolidin-2-ylmethyl; (2S)
and its pharmaceutically acceptable salts.

20. Pharmaceutical composition having the properties of an inhibitor of the Delta opioid receptor containing a therapeutically effective amount of a compound according to any one of claims. 1-19 and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and a pharmaceutically acceptable diluent.

21. Pharmaceutical composition according to claim 20, wherein the composition is a solid dosage form for oral administration.

22. Pharmaceutical composition according to claim 20, wherein the composition is a syrup, elixir or suspension.

23. A method of treating pain, comprising administering a therapeutically effective amount of a compound of formula (I) according to any one of claims. 1-19, having the ability of binding to Delta opioid receptors.

24. A method according to claim 23 where the pain is selected from inflammatory pain.



 

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FIELD: medicine.

SUBSTANCE: invention relates to a method of treatment or relieving the severity of cystic fibrosis in a patient, where the patient has the cystic fibrosis transmembrane receptor (CFTR) with R117H mutation, including a stage of introduction to the said patient of an effective quantity of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

EFFECT: elaborated is the method of treating cystic fibrosis, based on the application of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

3 cl, 4 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , wherein Y and Z are independently specified in a group of a) or b) so that one of Y or Z is specified in the group a), and another one - in the group b); the group a) represents i) substituted C6-10aryl; ii) C3-8cycloalkyl; iii) trifluoromethyl or iv) heteroaryl specified in a group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furasan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl and [1,2,3]thiadiazolyl; the group b) represents i) C6-10aryl; ii) heteroaryl specified in a group consisting of thiazolyl, pyridinyl, indolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridin-2-yl, furo[2,3-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl, quinolinyl, quinazolinyl, thienyl and benzimidazolyl; iii) benzofused heterocyclyl attached through a carbon atom, and when a heterocyclyl component contains a nitrogen atom, the carbon atom is optionally substituted by one substitute specified in a group consisting of C3-7cycloalkylcarbonyl; C3-7cycloalkylsulphonyl; phenyl; phenylcarbonyl; pyrrolylcarbonyl; phenylsulphonyl; phenyl(C1-4)alkyl; C1-6alkylcarbonyl; C1-6alkylsulphonyl; pyrimidinyl and pyridinyl; C3-7cycloalkylcarbonyl, phenyl, phenylcarbonyl, phenyl(C1-4)alkyl and phenylsulphonyl are optionally substituted by trifluoromethyl, or by one or two fluor-substitutes; iv) phenoxatiynyl; vi) fluoren-9-on-2-yl; vii) 9,9-dimethyl-9H-fluorenyl; viii) 1-chlornaphtho[2,1-b]thiophen-2-yl; ix) xanthen-9-on-3-yl; x) 9-methyl-9H-carbazol-3-yl; xi) 6,7,8,9-tetrahydro-5H-carbazol-3-yl; xiii) 3-methyl-2-phenyl-4-oxochromen-8-yl; or xiv) 1,3-dihydrobenzimidazol-2-on-5-yl optionally substituted by 1-phenyl, 1-(2,2,2-trifluoroethyl), 1-(3,3,3-trifluoropropyl) or 1-(4,4-difluorocyclohexyl); 1-phenyl is optionally substituted by one or more fluor-substitutes or trifluoromethyl; or xv) 4-(3-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl; R1 represents C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo or aryl(C1-3)alkyl; or when s is equal to 2 and R1 represents C1-3alkyl, the substitutes C1-3akyl is taken with a piperazine ring to form 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.2]octanyl ring system, and its pharmaceutical compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of synthesis of compounds with biological activity, namely to method of obtaining compound 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepinane. Essence of method consists in interaction of 3,6-dioxaoctane-1,8-diamine with N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine in medium ethanol-chloroform (1:2 volume) in presence of catalyst SmCl3·6H2O with molar ratio 3,6-dioxaoctane-1,8-diamine:N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine:SmCl3·6H2O=1:2:(0.03-0.07) at temperature (~20°C) and atmospheric pressure for 2.5-3.5 h. Invention also relates to application of 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepinane as agent with fungicidal activity for fighting fungal diseases of agricultural crops.

EFFECT: improved method of obtaining 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepinane, possessing fungicidal activity against Botrytis cinerea.

2 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-hetaryl-substituted 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides of general formula: , where R=5-methyl-1,3-thiazol-2-yl, or 4-ethoxycarbonylmethyl-1,3-thiazol-2-yl, or 6-methylpyridin-2-yl, or 5-chloropyridin-2-yl, or pyrimidin-2-yl. Novel N-hetaryl-substituted 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide derivatives which exhibit analgesic activity are obtained.

EFFECT: high activity of derivatives.

2 tbl, 7 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic compound, representing cyclo-bis[(1Z)-1-imino -2-methyl-1H-inden-3-yl-1,2,4-thiadiazole-3,5-diamine]

EFFECT: compound as acid dye for silk, wool and polyamide 6.

3 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), possessing an activity with respect to cytokines, versions of based on them pharmaceutical compositions and their application. Formula (I) compounds can be applied for treatment or prevention asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gouty arthritis. In general formula (I) L is selected from the group, consisting of -C(O)-, -CH2-, Ar1 represents a mono-, di- or trisubstituted phenyl ring, where substituents are independently selected from the group, consisting of a halogen and -C1-4alkyl; Ar2 represents an optionally substituted thiadiazolyl ring, where the substituent represents -C1-4alkyl, -C3-5cycloalkyl, -methylcyclopropyl, phenyl or a 5- or 6-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring with 9 or 10 atoms, with the said heteroaromatic ring containing 1, 2 or 3 heteroatoms, selected from the group, consisting of S, O and N, where the said phenyl or heteroaromatic ring is optionally mono- or disubstituted with substituents, independently selected from the group, consisting of a halogen, -C1-6alkyl, optionally substituted with 1-4 fluorine atoms, -O-C1-6alkyl, -CF3 and oxo.

EFFECT: increased efficiency of the application of the compounds.

16 cl, 1 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,3,5-dithiazinanes of formula (1): wherein diphenylenediamine (diaminodiphenylmethane, diaminodiphenyl oxide) reacts with N-tert-butyl-1,3,5-dithiazinane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine: N-tert-butyl-1,3,5-dithiazinane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system (1:1, by volume) for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as antimicrobial and antifungual agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-(1,2,5-oxadiazol-3-yl)benzamides of formula , in which R stands for an alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, cyano, nitro, methylsulphenyl, acetylamino, methoxycarbonyl, methylcarbonyl, piperidinylcarbonyl, halogen, amino, or heteroaryl, selected from the group, including 1,2,3-triazolyl, 1,2,4-triazolyl, benzisoxazolyl, thiophenyl, pyridinyl and benzimidazol-2-yl, or heterocyclyl, selected from the group, including piperidinyl, respectively selected with s residues, selected from the group, including methyl, ethyl, methoxy and halogen; X and Z independently on each other respectively stand for nitro, halogen, cyano, alkyl with 1-6 carbon atoms, halogenalkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, OR1, S(O)nR2, alkyl-OR1 with 1-6 carbon atoms in alkyl, or heteroaryl, selected from the group, including 1,2,4-triazolyl; Y stands for nitro, halogen, OR1, S(O)nR2, NR1COR1, O-alkylheterocyclyl with 1-6 carbon atoms in the alkyl, and where heterocyclyl is selected from 1,4-dioxan-2-yl, O-alkyl heteroaryl with 1-6 carbon atoms in the alkyl, and where the heteroaryl is selected from pyrazolyl, alkyl-OR1 with 1-6 carbon atoms in the alkyl, alkyl-NR1SO2R2 with 1-6 carbon atoms in the alkyl, NR1R2, tetrahydrofuranyloxymethyl, tetrahydrofuranylmethoxymethyl, O(CH2)-3,5-dimethyl-1,2-oxazol-4-yl, O(CH2)2-O(3,5-dimethoxypyrimidin-2-yl, O(CH2)-5-pyrrolidin-2-one, O(CH2)-5-2,4-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one, or heteroaryl, selected from the group, including 1,2,3-triazolyl and pyrazolyl, or heterocyclyl, selected from the group, including 4,5-dihydro-1,2-oxazol-3-yl and tetrahydropyrimidi-2(1H)-on-1-yl, respectively substituted with s residues, selected from the group, including methyl, methoxy and cyanomethyl; R1stands for hydrogen, alkyl with 1-6 carbon atoms, alkinyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, cycloalkylalkyl with 2-6 carbon atoms in the cycloalkyl and 1-6 carbon atoms in the alkyl, phenyl or phenylalkyl with 1-6 carbon atoms in the alkyl, with six last residues being substituted with s residues, selected from the group, including a halogen, OR3 and CON(R3)2; R2 stands for alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, phenyl or phenyl with 1-6 carbon atoms alkyl, with the five last residues being substituted with s residues, selected from the group, including a halogen, OR3, OCOR3, CO2R3, COSR3 and CON(R3)2; R3 stands for hydrogen or alkyl with 1-6 carbon atoms; n stands for 0, 1 or 2; s stands for 0, 1, 2 or 3. The invention also relates to the application of N-(1,2,5-oxadiazol-3-yl)benzamides of formula (I), as a herbicidal preparation and for fighting undesirable plants.

EFFECT: N-(1,2,5-oxadiazol-3-yl)benzamides, possessing herbicidal activity.

9 cl, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of treatment or relieving the severity of cystic fibrosis in a patient, where the patient has the cystic fibrosis transmembrane receptor (CFTR) with R117H mutation, including a stage of introduction to the said patient of an effective quantity of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

EFFECT: elaborated is the method of treating cystic fibrosis, based on the application of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

3 cl, 4 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to azetidine-substituted isoxazoline derivatives of formula (1), where A represents phenyl, naphtyl or heteroaryl, where said heteroaryl represents 5-6-membered aromatic monocyclic ring and contains 1 N heteroatom; each of R1a, R1b and R1c independently represents hydrogen, halogen, cyano, nitro or C1-C6halogenalkyl; R2 represents halogen, cyano or nitro; R3 represents hydrogen, halogen, hydroxyl, cyano, N3 or -NHR4; R4 represents hydrogen, -C(O)R5, -C(S)R5, -C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5 or -C(NR7)R5; R5 represents hydrogen, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C6cycloalkyl, C0-C6alkylphenyl, C0-C6alkylheteroaryl, representing 5-6-membered aromatic monocyclic ring, containing from 1 to 3 heteroatoms, each of which is independently selected from N, O and S, or C0-C6alkylheterocycle, where said heterocycle represents 4-membered monocyclic ring, containing 1 heteroatom, selected from N, O and S; R6 represents C1-C6halogenalkyl; R7 represents cyano; Ra represents hydrogen, C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl; Rb represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; Rc represents C1-C6alkyl, C1-C6halogenalkyl, C1-C6halogenalkylC3-C6cycloalkyl, C0-C3alkylC3-C6cycloalkyl or C0-C3alkylphenyl, each of which is possibly substituted with at least one substituent, selected from cyano or halogen, each of groups C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl ad R5 can be possibly and independently substituted with at least one substituent, selected from cyano, halogen, hydroxyl, C1-C6alkoxy, C1-C6halogenalkoxy, C1-C6halogenalkyl, -S(O)pRc, -SH, -S(O)pNRaRb, -NRaC(O)Rb, -SC(O)Rc and -C(O)NRaRb; and where grouping C0-C6alkylheteroaryl or C1-C6alkylheterocycle as R5 can be possibly additionally substituted with at least one substituent, selected from halogen, oxo, hydroxyl, C1-C6alkyl and -SH; n represents integer number 0 or 1, and p represents integer number 0, 1 or 2 and its stereoisomers. Invention also relates to pharmaceutical or veterinary composition, possessing parasiticidal activity, containing therapeutic amount of formula (I) derivative and pharmaceutically or veterinarily acceptable excipient, diluents or carrier.

EFFECT: azetidine-substituted isoxazoline derivatives of formula (1), intended for manufacturing means for treatment or control of parasitic infection or invasion in animal.

20 cl, 5 tbl, 225 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining (S)-2-methoxy-3-{4[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl}propionic acid of formula (I) or its salts, in which formula (II) compound or its salt is hydrated in the presence of an iridium-including catalyst, in which the catalyst includes iridium and formula (III) compound, in which R1 stands for hydrogen, isopropyl, phenyl or benzyl and in which R2 stands for phenyl, 3,5-dimethylphenyl or 3,5-di-tert-butylphenyl. The invention also relates to the application of a complex of the catalyst, containing iridium and the formula (III) compound for obtaining the formula (I) compound.

EFFECT: obtaining the formula (I) compound with a high degree of conversion and enantiomeric purity.

6 cl, 4 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula I, or their racemic mixture, or their individual optic isomers, or pharmaceutically acceptable salts possessing the properties of TGR bile acid receptor agonist. The invention also refers to methods for preparing the compounds. In general formula I , X represents amino group R'R"N, wherein the substitutes R' and R" can be optionally identical, or represents hydrogen, C1-C6alkyl, C3-C6cycloalkyl; substituted C1-C6alkyl, wherein the substitute is specified in phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy, phenyloxy, C3-C6cycloalkyl, 5-6-merous heteroaryl with 1 nitrogen atom; aryl specified in phenyl optionally substituted by fluorine, C1-C3alkyl, C1-C3 alkoxy; 5-6-merous heteroaryl with nitrogen atom as heteroatom; C2-C4alkenyl, acyl specified in C1-C6alkylcarbonyl or C3-C6cycloalkylcarbonyl; or substituted oxygroup, which represents hydroxy group, wherein hydrogen is substituted by C1-C6alkyl optionally substituted by hydroxy, di(C1-C3alkyl)amino, phenyl, which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C2-C4alkenyl; and 5-6-merous heterocyclyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom; R1a and R1b represents hydrogen, C1-C3alkyl, or R1a and R1b together form methylene chain -(CH2)n-, wherein n=2-5; R1c and R1d represents hydrogen, C1-C3alkyl; R2 represents acyl group specified in C1-C6alkylcarbonyl, wherein alkyl can be substituted by phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C3-C6cycloalkylcarbonyl; phenylcarbonyl, which can be substituted by halogen, C1-C3alkyl, C1-C3alkoxygroup, oxygroup, C1-C3alkylene dioxygroup; 5-6-merous heteroarylcarbonyl with nitrogen atom, or oxygen atom, or sulphur atom as heteroatom, optionally substituted by carboxy, halogen or C1-C3alkoxycarbonyl, substituted aminocarbonyl group, wherein the substitute can be specified in C1-C6alkyl optionally substituted by C1-C3alkoxycarbonyl, halogen, 5-6-merous heteroaryl together with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom; C3-C6cycloalkyl; phenyl optionally substituted by halogen, C1-C3alkyl, C1-C3alkoxy, C1-C3alkoxycarbonyl, C1-C3alkylenedioxygroup; 5-6-merous heteroarym with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom optionally substituted by carboxy, C1-C3alkoxycarbonyl; aminocarbonyl group substituted by C1-C3alkyl; sulphonyl group specified in alkylsuphonyl optionally substituted by hydroxyl group, cyano group, phenyl, which is optionally substituted by C1-C3alkyl, halogen, C1-C3alkoxy group; henylsulphonyl oprtionally substituted by C1-C3alkyl, halogen, C1-C3alkoxy group, cyano group, C1-C3alkylene dioxygroup, or 5-6-merous heteroarylsulphonyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom optionally substituted by halogen, C1-C3alkyl, C1-C3alkoxy group; R3 represents hydrogen.

EFFECT: compounds can be used for preparing the pharmaceutical composition applicable in treating or preventing metabolic diseases, such as diabetes, obesity, diabetic obesity, metabolic syndrome, hypercholesterolemia, dislipidemia.

14 cl, 17 dwg, 8 tbl, 16 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining di-{ 4-[(tetrahydro -4H-1,4-oxazin-4-yl)-methylsulphanyl]-phenyl} ether oxalate of formula

as water-soluble substance with fungicidal activity. Essence of method consists in interaction of di-{ 4-[(tetrahydro -4H-1,4-oxazin-4-yl)-methylsulphanyl]-phenyl} ether with equimolar quantity of oxalic acid (COOH)2 at room (~20°C) temperature for 15 min.

EFFECT: output constitutes 99%.

2 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing pyrazoline carboxamidine derivatives of formula . Said compounds are known as powerful 5-HT6 antagonists. The disclosed method comprises reacting a corresponding substituted 4,5-dihydro-(1H)-pyrazole or an isomer thereof with isothiocyanate R6-N=C=S to obtain an amide of substituted 4,5-dihydro-(1H)-pyrazole-1-carbothioic acid or tautomeric substituted 4,5-dihydro-(1H)-pyrazole-1-carboxymidothioic acid . The obtained intermediate compounds are reacted with a corresponding alkylating agent to obtain an intermediate S-alkylated compound . Said intermediate compound is reacted with a sulphonamide derivative R7SO2NH2 and the target compound of formula (I) is separated from the reaction mixture. The invention also relates to novel intermediate products (IIIa), (IIIb) and (IV). Symbols given in the formulae have values given in the description.

EFFECT: providing an alternative method which improves atom efficiency of synthesis of desired compounds with higher output compared to existing methods for synthesis of said compounds.

8 cl, 1 tbl, 3 ex

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