4-substituted-2-phenoxyphenylamine modulators of delta-opioid receptors


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

 

CROSS-REFERENCES TO RELATED INVENTIONS

The present application claims the priority stated in the provisional application for U.S. patent No. 61/256412 on 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 used for about�values antagonists morphine 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 there is a decrease in the intensity of pain 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 concentrate, decrease�their mental activity, 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 these functional tavern�of SMI 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 the compound of the formula I

<>

where

R1selected from the group consisting of

phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, di(C1-4alkyl)aminocarbonyl, chlorine and fluorine; thus, there should be only one di(C1-4alkyl)aminocarbonyl;

naftel;

pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluorine, chlorine or cyano;

(iv) pyrimidine-5-silt;

v) furanyl;

(vi) tanila;

vii) 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; and

(viii) di(C1-2alkyl)aminocarbonyl;

provided that, when R1represents a 5-oxo-4,5-dihydro-[1,2,4]oxidiazol-3-yl, Y is a bond;

Y represents ethyl, vinyl or communication;

or Y is O when R1represents optionally substituted phenyl;

R2represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine, cyano, triptoreline and hydroxy;

or R2represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminomar�by o'neill, C1-4alkoxycarbonyl or carboxylesterases;

R3selected from the group consisting of

3-aminocyclohexyl;

4-aminocyclohexyl;

the piperidine-3-yl;

(iv) piperidine-4-silt;

(v) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted at the 3-th or 4-th position one or two fortuntately;

(vi) azetidin-3-yl-methyl;

vii) 2-(N-methylamino)ethyl;

(viii) 3-hydroxy-2-aminopropyl;

(ix) piperidine-3-yl-methyl;

x) 1-azabicyclo[2.2.2]Octan-3-yl; and

(xi) 8-azabicyclo[3.2.1]Octan-3-yl;

or R3together with Raand the nitrogen atom to which they are both attached to form piperazinyl optionally substituted with 4-C1-4by alkyl;

Rarepresents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted of azetidin-3-yl;

and 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 a method�m cure or alleviate the symptoms of the disorder, modulating 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 structural disorders, cancer pain, pain associated with injury to the soft tissues, 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.

To replaces�NML the term "independently" means, what if it is possible 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 Deputy, whose name has the root of "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-Amin�-, 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 halogen atoms, up to 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 and�amantel. 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 which 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 connections with�component object of the present invention, ring 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 ring may 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-pyrrol, 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 with�faces 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 nitrogen atom, two 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, thinline� 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 possibility of obtaining a stable connection.

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" refers to a derivative called�pits. 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 are given a range of individually, as well 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 alleviation of the symptoms of Zabol�tion or condition, treatment which 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 the present paper is the first to indicate the end portion of the described side chain, and then list the functional groups in the direction 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 modulated Retz�porom" is used to denote the state-dependent modulation of opioid receptor including, without limitation, the mediating opioid receptor.

Embodiments of the present invention include compounds of formula (I)

where

(a) R1selected from the group consisting of

(i) phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, di(C1-4alkyl)aminocarbonyl and fluorine; thus, there should be only one di(C1-4alkyl)aminocarbonyl;

(ii) naftel;

(iii) pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano;

(iv) pyrimidine-5-silt;

v) furanyl;

(vi) tanila; and

(vii) di(C1-2alkyl)aminocarbonyl;

(b) R1selected from the group consisting of

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

(ii) pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano;

pyrimidine-5-silt; and

(iv) di(C1-2alkyl)aminocarbonyl;

c) R1selected from the group consisting of

(i) phenyl, optionally substituted with one methoxypiperidine�;

(ii) pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano;

(iii) pyrimidine-5-silt; and

(iv) di(C1-2alkyl)aminocarbonyl;

d) Y is vinyl or a bond; or Y is O when R1represents optionally substituted phenyl;

e) Y is vinyl or a bond;

f) R2represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine and hydroxy;

or R2represents phenyl, substituted one aminocarbonyl or di(C1-4alkyl)aminocarbonyl Deputy;

(g) R2represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy and hydroxy;

or R2represents phenyl, substituted one aminocarbonyl or di(C1-4alkyl)aminocarbonyl Deputy;

h) R2represents phenyl, optionally substituted by one Deputy, independently selected from the group consisting of methoxy, hydroxy, aminocarbonyl and di(C1-4alkyl)aminocarbonyl;

i) R3selected from the group consisting�from her

i) 3-aminocyclohexyl;

ii) 4-aminocyclohexyl;

(iii) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted at the 3-th or 4-th position one or two fortuntately;

iv) 2-(N-methylamino)ethyl;

the piperidine-3-yl-methyl; and

1-azabicyclo[2.2.2]Octan-3-yl;

or R3together with Raand the nitrogen atom to which they are both attached to form piperazinyl;

j) R3selected from the group consisting of

i) 3-aminocyclohexyl;

ii) 4-aminocyclohexyl; and

(iii) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted at the 3 rd or 4 th position with one fortuntately;

or R3together with Raand the nitrogen atom to which they are both attached to form piperazinyl;

k) Rarepresents hydrogen or C1-2alkyl;

l) Rarepresents hydrogen;

and any combinations of the above-described embodiments (a) to (l), provided that the reader understood that combinations in which there are various options for implementation of one and the same Deputy, shall be excluded; and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts.

Additional variant of implementation of the present invention includes compounds of formula (I)

where

R1selected from the group, comp�of the present

phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, di(C1-4alkyl)aminocarbonyl and fluorine; thus, there should be only one di(C1-4alkyl)aminocarbonyl;

naftel;

pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano;

(iv) pyrimidine-5-silt;

v) furanyl;

(vi) tanila; and

di(C1-2alkyl)aminocarbonyl;

Y is vinyl or a bond; or Y is O when R1represents optionally substituted phenyl;

R2represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine and hydroxy;

or R2represents phenyl, substituted one aminocarbonyl or di(C1-4alkyl)aminocarbonyl Deputy;

R3selected from the group consisting of

3-aminocyclohexyl;

ii) 4-aminocyclohexyl;

(iii) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted at the 3-th or 4-th position one or two fortuntately;

v) 2-(N-methylamino)ethyl;

(vi) piperidine-3-yl-methyl; and

(vii) 1-azabicyclo[2.2.2]Oct�n-3-yl;

or R3together with Raand the nitrogen atom to which they are both attached to form piperazinyl;

Rarepresents hydrogen or C1-2alkyl;

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

Additional variant of implementation of the present invention includes compounds of formula (I)

where

R1selected from the group consisting of

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

pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano;

pyrimidine-5-silt; and

di(C1-2alkyl)aminocarbonyl;

Y is vinyl or a bond;

R2represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy and hydroxy;

or R2represents phenyl, substituted one aminocarbonyl or di(C1-4alkyl)aminocarbonyl Deputy;

R3selected from the group consisting of

3-aminocyclohexyl;

ii) 4-aminocyclohexyl;

(iii) pyrrolidin-2-yl-methyl, in which� pyrrolidin-2-yl optionally substituted on carbon atom by one or two fortuntately;

2-(N-methylamino)ethyl;

the piperidine-3-yl-methyl; and

1-azabicyclo[2.2.2]Octan-3-yl;

or R3together with Raand the nitrogen atom to which they are both attached to form piperazinyl;

Rarepresents hydrogen;

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

Additional variant of implementation of the present invention includes compounds of formula (I)

where

R1selected from the group consisting of

phenyl, optionally substituted with one methoxyaniline;

pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano;

pyrimidine-5-silt; and

di(C1-2alkyl)aminocarbonyl;

Y is vinyl or a bond;

R2represents phenyl, optionally substituted by one Deputy, independently selected from the group consisting of methoxy, hydroxy, aminocarbonyl and di(C1-4alkyl)aminocarbonyl;

R3selected from the group consisting of

3-aminocyclohexyl;

ii) 4-aminocyclohexyl;

(iii) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted on carbon atom by one fortuntately;

or R3together with Raand the nitrogen atom, to Kotor�mu they are both attached, form piperazinyl;

Rarepresents hydrogen;

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

Additional variant of implementation of the present invention includes compounds of formula (I)

selected from the group consisting of:

compounds in which R1represents a 2-(N,N-diethylaminoethyl), Y represents (E)-vinyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents a 2-(N,N-diethylaminoethyl), Y is ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents a 2-(4-methoxyphenyl), Y is ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents a 2-(3-methoxyphenyl), Y is ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents a 2-phenyl, Predstavljaet an ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents a 2-(4-fluorophenyl) -, Y represents ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents a 2-(3-fluorophenyl) -, Y represents ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents a 2-[3-(N,N-diethylaminoethyl]phenyl), Y is ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents N,N-diethylaminoethyl, Y represents a bond, R2represents phenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents N,N-diethylaminoethyl, Y represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1 represents N,N-diethylaminoethyl, Y represents a bond, R2is a 2-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2is a 4-cyanophenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2is a 3-cyanophenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2represents phenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2is a 3-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2represents 4-fluorophenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1submitted�is phenyl, Y represents a bond, R2is a 4-trifloromethyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2represents a 2,6-dichlorophenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2is a 4-methoxyphenyl, R3represents a 2-(N-methylamino)ethyl, and Rarepresents H;

compounds in which R1represents phenyl, Y is a bond, R2is a 4-ethoxycarbonylphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2is a 3-ethoxycarbonylphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2represents 2,4-dichlorophenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1is�Oh phenyl, Y represents a bond, R2is a 4-methoxyphenyl, R3is a piperidine-4-yl, and Rarepresents H;

compounds in which R1is 5-cyanopyridine-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is a 4-ftorpirimidinu-2-yl-methyl, and Rarepresents H; (2S,4R)

compounds in which R1represents a 5-herperidin-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is a 4-ftorpirimidinu-2-yl-methyl, and Rarepresents H; (2S,4R)

compounds in which R1represents a 5-methylthiopyridine-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is a 4-ftorpirimidinu-2-yl-methyl, and Rarepresents H; (2S,4R)

compounds in which R1represents a 5-methoxypyridine-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is a 4-ftorpirimidinu-2-yl-methyl, and Rarepresents H; (2S,4R)

compounds in which R1represents a 5-methylpyridine-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is a 4-ftorpirimidinu-2-yl-methyl, and Rapre�is H; (2S,4R)

compounds in which R1represents phenyl, Y is a bond, R2is a 4-aminocarbonylmethyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2is a 3-aminocarbonylmethyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2is a 4-carboxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2is a 3-carboxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2represents a 4-(N,N-diethylaminomethyl)phenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2represents a 3-(N,N-diethylaminomethyl)phenyl, R3is pyrrolidin-2-�l-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1is a naphthalene-2-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1is a naphthalene-2-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-1-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents pyridin-4-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents pyridin-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents furan-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is a u�Raiden-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1is a thiophene-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents a 5-herperidin-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1is 5-cyanopyridine-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents pyridin-3-yl, Y is a bond, R2is a 4-hydroxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents phenyl, Y is a bond, R2is a 4-methoxyphenyl, R3together � R aand the nitrogen atom to which they are both attached, form a piperazine-1-yl;

compounds in which R1represents phenyl, Y is a bond, R2is a 4-methoxyphenyl, R3together with Raand the nitrogen atom to which they are both attached, form a 4-methylpiperazin-1-yl;

compounds in which R1represents a 5-oxo-4,5-dihydro[1,2,4]oxidiazol-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1represents pyridin-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents ethyl; (2S)

compounds in which R1represents a 5-herperidin-3-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents ethyl; (2S)

compounds in which R1represents pyrimidine-5-yl, Y is a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents ethyl; (2S)

compounds in which R1represents a 5-canopy�idin-3-yl, Y represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents ethyl; (2S)

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3is a piperidine-3-yl, and Rarepresents H; racemic mixture

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3represents a 3-hydroxy-2(R)-aminopropyl, and Rarepresents H;

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3is a piperidine-4-yl, and Rarepresents H;

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3is a 8-azabicyclo[3.2.1]Octan-3-yl, and Rarepresents H; mixture of endo/actisorb

connection, to�Orom R 1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3is azetidin-3-yl-methyl, and Rarepresents H;

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3is azetidin-3-yl-methyl, and Rais azetidin-3-yl-methyl;

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3represents 1-azabicyclo[2.2.2]Octan-3-yl, and Rarepresents H; mixture of endo/actisorb

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3is a piperidine-3-yl-methyl, and Rarepresents H; racemic mixture

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3is a 3-aminocyclohexyl, and Rarepresents H; a mixture of 4 isomers

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3represents a 2-(N-methyl�Ino)ethyl, and Rarepresents H; and

compounds in which R1is a 4-methoxyphenyl, Y represents O, R2is a 4-methoxyphenyl, R3represents a 2-(N-methylamino)ethyl, and Rarepresents a 2-(N-methylamino)ethyl; and

and their 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 the solution of compound with a solution of a pharmaceutically acceptable acid such as 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 the appropriate authority�ical ligands, for example, a Quaternary ammonium salt. 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, salicylates, 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, �unfortulately, (+)-(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-hydroxy-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, DEAT�ol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, Ethylenediamine, N-methyl-glucamine, 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 compounds which are not mentioned in this 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 x�General 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 for obtaining compounds in accordance with certain variants of implementation of the present invention lead to the formation of a mixture of stereoisomers, these isomers may be isolated by standard techniques such as preparative chromatography. Compounds can be obtained in the form of racemic mixtures 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�such 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%, even more 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 p�edocfile - 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 works ofProtective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Presc, 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 salts and 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, auxiliary substance 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 Pharma�efticiency 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 powder. 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./p>

For some applications, preferably the oral administration of the compositions in the form of tablets containing such excipients as starch or lactose, or in capsules or dragees, in pure form or in admixture with excipients, or 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 buccal or sublingual method of administration of the composition can be administered to the patient in the form of tablets or lozenges made 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 compounds or connected�th 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 semisavage 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 comprises sterile water, 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 di�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 twice, thrice 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 pharmacist�tration of the composition 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 compositions described above and in any described above, the receive mode 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�mi disorders or injury of the soft tissues, the 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 the treatment of respiratory diseases.

The compounds forming the subject of the present invention may also find application in the treatment of pain caused by osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite (in particular, the snake bite), spider bite, insect bites, neurogenic bladder �user, 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 in amputated limbs, 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 oral cavity, 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, neuralgia glossopharyngeal neuralgia, 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, vocalite�diesel 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. A therapeutically effective dosage of the compounds of formula (I) when used in such treatment is in the range from about 0.001 to about 300 mg/kg/day. In particular, the specified range is from approximately 0.5 to approximately 5.0 mg/kg of body weight per day, more specifically from about 1.0 to about 3.0 mg/kg of body weight per day. The compounds may be administered with a reception mode from 1 to 4 times daily.

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 chemical reactions and conditions described in the schemes. Various starting substances listed on circuits and ISP�Lithuania 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
CDIN,N'-carbonyldiimidazole
conc.concentrated
DAMGOTyr-D-Ala-Gly-(methyl)Phe-Gly-ol
DBU1,8-diazabicyclo[5.4.0]undec-7-ene
DCE1,2-dichloroethane
DCMdichloro methane
DIEAdiisopropylethylamine
DMFN,N-dimethylformamide
DMSOdimethyl sulfoxide
DPDPE[D-Pen2,D-Pen5]-enkephalin
dppf1,1'-bis(diphenylphosphino)ferrocene
EDC1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
ESIelektrorazpredelenie ionization
EtOActhe ethyl acetate
EtOHethanol
hhour(s)
HATUhexaflurophosphate O-(1H-7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium
HBTUhexaflurophosphate O-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
HEPES2-[4-(2-hydroxyethyl)-1-piperazinyl]econsultancy acid

HOBtN-hydroxy-benzotriazole
HPLChigh performance liquid chromatography
Me methyl
MeOHmethanol
MHzmegahertz
minminutes
GHSDliquid chromatography medium pressure
MSmass spectrometry
NMRnuclear magnetic resonance
n/anot tested
Phphenyl
Pd/Cpalladium on activated carbon
Ph3Ptriphenylphosphine
PPApolyphosphoric acid
PyBOPhexaflurophosphate the benzotriazole-1-yl-oxtriphylline
rtroom temperature
TBDMStert-butyldimethylsilyl
TEA/Et3Ntritium�n
TFAtrifluoroacetic acid
THFtetrahydrofuran
TLCthin-layer chromatography
TMStetramethylsilane or trimethylsilyl

In the diagram A shows the preparation of compounds of formula (I)-A and formula (I) A1 in which Y is vinyl or ethyl, respectively, R1is a di(C1-2alkyl)aminocarbonyl, and R3selected according to the procedure described in this document. R3acompounds A5 represents (N-methylamino)methyl, pyrrolidin-2-yl, azetidin-3-yl or piperidine-3-yl. The ring A of compound A5-1 is a 3 - or 4-aminocyclohexyl, piperidine-3-yl or piperidine-4-yl.

Scheme A

Compound A1 is either commercially available or can be obtained by known methods described in the scientific literature. Reaction with an appropriately substituted alcohol of the formula A2, optionally in the presence of base, allows to obtain a compound of formula A3. The nitro group of a compound of formula A3 may be restored to the corresponding amino group by the action of a reducing agent, such as a metallic Qing�, in the presence of acetic acid in an organic solvent, such as methanol, or by the action of sodium borohydride in the presence of Nickel chloride, or by catalytic hydrogenation. The obtained aniline of the formula A4 may be alkilirovanny R3a-substituted aldehyde (A5) or a ketone of formula A5-1, in the presence of a reducing agent, such as triacetoxyborohydride sodium in acetic acid to produce a compound of formula A6. Catalyzed by palladium reaction combination with a compound of formula A7 in which R represents C1-4alkyl, in the presence or in the absence of ligands for palladium, such as dppf or three-o-tolylphosphino, allows to obtain alkene of formula A8. Alkoxycarbonyl group of a compound of formula A8 may be hydrolysed in the presence of hydroxide ion with formation of the corresponding carboxylic acids, which can then be introduced into the reaction combination with di(C1-4alkyl)amine in the presence of the corresponding binding agent, such as EDCI, and an activating agent such as HOBt, to obtain an amide of formula (I) A. the Restoration of the alkenyl group of the compound of formula (I) A reducing agent, for example, catalytic hydrogenation, allows to obtain the compound of formula (I)-A1. The person skilled in the art will determine that for some compounds of formula A5 and A5-1 can potreboval�Xia introduction of a protective group for amino group (P), which can be brought through the subsequent chemical stage shows synthesis scheme. To remove the protection of the amino group on one of the last stages you can use standard chemical methods. For example, a Boc group can be removed by treatment with mineral acid or organic acid such as trifluoroacetic acid.

In the diagram B shows the preparation of compounds of formula (I)-B in which Y is ethyl, and R1arepresents optionally substituted phenyl, naphthyl, optionally substituted pyridinyl, pyrimidine-5-yl, furanyl or thienyl.

Scheme B

The compound of formula A6 may be introduced into the reaction combination with a compound of formula B1 where R1aselected according to the procedure described in this document the description in the presence of a palladium catalyst and in the presence or in the absence of added ligands for palladium and in the presence of an organic base such as TEA, to obtain alkene of formula B2. The restoration of the alkenyl group may be carried out using a transition metal catalyzed hydrogenation, which, after optional removal of the protective group of amino group, allows to obtain the compound of formula (I)-B.

In the diagram C shows the preparation of compounds of formula (I)-C, where Y represents from�IDE and R 1is a di(C1-2alkyl)aminocarbonyl.

Scheme C

The connection C1 is either commercially available or can be obtained by known methods described in the scientific literature. Connection C1 may be introduced into the reaction combination with an amine of the formula C2 in the presence of an appropriate coupling agent such as EDCI, and an activating agent such as HOBt, to obtain an amide of formula C3. The reaction of aromatic nucleophilic substitution with a compound of formula A2 in the presence of base to obtain compound of formula C4. The nitro group of a compound of formula C4 can be restored to the corresponding amino group by the action of a reducing agent such as zinc metal in the presence of acetic acid in an organic solvent, such as methanol, or by the action of sodium borohydride in the presence of Nickel chloride, or by catalytic hydrogenation. The obtained aniline of formula C5 may be alkilirovanny R3a-substituted aldehyde (A5) or a ketone of formula A5-1, in the presence of a reducing agent, such as triacetoxyborohydride sodium in acetic acid to give, after optional removal of the protective group from the amino group, the compounds of formula (I)-C.

In the diagram D shows the preparation of compounds of formula (I)-D, where Y is a bond and R1 represents optionally substituted phenyl, naphthyl, optionally substituted pyridinyl, pyrimidine-5-yl, furanyl or thienyl (shown as R1a).

Scheme D

The group R1amay be introduced into the compound of formula A6 by palladium catalyzed reaction cross-combination with an appropriately substituted Bronevoy acid or its ester (D1) in the presence of an appropriate base, such as potassium carbonate. The specified reaction can be conducted in the presence or in the absence of added ligands for palladium, which, if used, include one or more of triphenylphosphine, three-on-tolylphosphino, three(tert-butyl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene, bis[2-(diphenylphosphino)phenyl]ether, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, hexaflurophosphate 1-butyl-3-methylimidazole etc solvents include ethanol, THF, DMF, toluene, DME, dioxane and benzene. After an optional stage of removing the protective group from the amino group can be obtained compound of formula (I)-D.

In the diagram E shows the preparation of compounds of formula (I)-E, in which Y represents a bond, R1represents optionally substituted phenyl, naphthyl, optionally substituted pyridinyl, pyrimidine-5-yl, furanyl or thienyl (shown as R1a); and R3 together with the-N-Raform piperazine-1-yl.

Scheme E

The group R1amay be introduced into the compound of formula A1 by palladium catalyzed reaction cross-combination with an appropriately substituted Bronevoy acid or its ester (D1) in the presence of an appropriate base, such as potassium carbonate, as described later in this document. The compound of formula E1 may be introduced into reaction with a compound of formula A2 in the presence of an appropriate base to give the compound of formula E2. The nitro group of a compound of formula E2 can be recovered by obtaining the corresponding aniline as described above herein, to produce a compound of formula E3. The reaction with the protected amine of formula E4 in the presence of an appropriate base, such as potassium carbonate, allows to obtain the compound of formula E5. The removal of the protective group from the amino group (P) allows to obtain the compound of formula (I)-E.

In the diagram F shows the preparation of compounds of formula (I)-F, where Y represents O, R1represents optionally substituted phenyl (shown as R1f) and R3selected according to the present invention to the description.

Scheme F

Diversamente compound of formula F1 or has� on sale, either can be obtained by known methods described in the scientific literature. The reaction of aromatic nucleophilic substitution with a compound of formula A2, optionally in the presence of base, allows to obtain the compound of formula F2. Subsequent reaction with R1f-substituted phenol of the formula F3, optionally in the presence of base, allows to obtain the compound of formula F4. The restoration of the nitro group as described above allows to obtain the compound of formula F5. Treatment of the aldehyde of formula A5 or ketone of formula A5-1 in the presence of a source of the hydride ion, followed by standard operation of removing the protective group from the amino group, if R3contains a protected amino group, allows to obtain a compound of formula (I)-F.

In the diagram G shows the preparation of some useful for the purposes of the present invention, the intermediate R3compounds that can be used for the synthesis of compounds of formula (I) in which R3is pyrrolidin-2-yl-methyl, substituted for the 3rd or 4th position one or two fortuntately.

Scheme G

The compound of the formula G1 either commercially available or can be obtained by known methods described in the scientific literature. The compound of formula G1 (in which G1G1aG2and G2aevery PR�astavliaut a hydrogen or fluorine, so no more than two of the G1G1aG2and G2acan be fluorine atoms) may be treated with the hydrochloride of N,O-dimethylhydroxylamine in the presence of the substance that forms the peptide bond, such as HBTU, and an organic base, such as DIEA, in an organic solvent, such as DMF, to produce a compound of formula G2. The compound of formula G2 can be converted into the corresponding aldehyde of the formula G3 by processing the case of lithium. The compound of formula G3 can be used similarly to the compound of formula A5 to obtain the compounds of formula (I).

In the diagram H shows the preparation of compounds of formula (I)-H, in which R1represents optionally substituted phenyl, naphthyl, optionally substituted pyridinyl, pyrimidine-5-yl, furanyl or thienyl (shown as R1a); Y represents a bond, and R3together with the-N-Raform piperazine-1-yl substituted with 4-C1-4the alkyl.

Scheme H

The compound of formula (I)-E may be introduced into reaction with a compound of the formula H1, where RHrepresents hydrogen or C1-3alkyl, in the presence of a source of the hydride ion, such as cyanoborohydride sodium, obtaining alkilirovanny product of formula (I)-H.

In scheme I shows the preparation of compounds of formula (I)-I in which a represents a bond, R1represents a 5-oxo-4,5-dihydro-[1,2,4]oxidiazol-3-yl and R3selected according to the procedure described in this document.

Scheme I

The compound of formula A6 may be obtained by synthetic methods described in the diagrams in this document. The compound of formula A6 may be treated with zinc cyanide in the presence of a palladium catalyst such as Pd(PPh3)4to obtain the cyanide of the formula I1. The reaction of the cyanide groups with hydroxylamine hydrochloride in the presence of base to obtain compound of formula I3. Condensation of a compound of formula I2 with CDI in the presence of base, such as DBU, allows to obtain the compound of formula (I)-I. For compounds of formula (I)-I, in which R3contains a protected amino group, may require the standard operation of removing the protective group.

In scheme J illustrates the formation of compounds of formulas (I)-J and (I)-J1, in which R3represents a 2-(N-methylamino)ethyl or azetidin-3-yl-methyl, and Rarepresents hydrogen or 2-(N-methylamino)ethyl, respectively. R3Jis a N-protected methylaminomethyl or N-protected azetidin-3-yl.

Scheme J

Compounds of formula C5, E3 F5 or may be introduced into the reaction replacement alkali�hardware using the aldehyde of the formula J1 in the presence of a source of the hydride ion, such as triacetoxyborohydride sodium, followed by standard operation of deprotection of the amino group, to obtain a mixture of compounds of formula (I)-J and formulas (I)-J1. The products of formula (I)-J and formulas (I)-J1 can be separated by standard methods of separation of substances known to specialists in this field.

In scheme K shows the preparation of compounds of formula (I)-K, of the formula (I)-K1 and formulas (I)-K2, where R1, Y, and R3selected according to the information provided in this document is the description and Raoptionally substituted C1-2the alkyl as described herein.

Scheme K

The compound of formula A6 may be introduced into the reaction of reductive alkylation using an aldehyde of the formula K1 in the presence of a source of the hydride ion, such as cyanoborohydride sodium or triacetoxyborohydride sodium, to produce a compound of the formula K2. The compound of the formula K2 may be introduced into the reaction combination with a compound of formula D1, that is, after removing all chemically necessary protective group, and optionally removing protecting the amino group, allows to obtain the compound of formula (I)-K, where Y is a bond. Similarly, the compound of formula K1 may be introduced into the reaction combination with a compound of formula B1 with the formation of a compound of formula (I)-K1, where Y pre�is a vinyl. Standard recovery vinyl group as described in scheme B, allows, after removing the optional protection of the amino group, to obtain the compound of formula (I)-K2, where Y represents ethyl.

In the diagram L shows the preparation of compounds of formula (I)-L in which R1Lis a di(C1-2alkyl)aminocarbonyl or-OR1f, R3selected according to the information provided in this document is the description and Rais an optionally substituted C1-2alkyl, as described herein.

Scheme L

The compound of formula (I) or formula (I)-F may be introduced into the reaction of reductive alkylation using an aldehyde of the formula K1 in the presence of a source of the hydride ion, such as cyanoborohydride sodium or triacetoxyborohydride sodium, to obtain, after optional removal of the protection of the amino group, the compound of formula (I)-L.

In the diagram M shows the preparation of compounds of formula (I)-M in which Y and R1selected according to the information provided in this document is the description and R3together with the-N-Raform piperazine-1-yl.

Scheme M

The compound of formula A4 may be treated with protected amine of formula E4 in the presence of an appropriate base, such as potassium carbonate, to obtain� of a compound of formula M1. Relevant to the purposes of the present invention, the group Y and R1can be entered, for example, in the reaction with compounds of formula A7, B1 or F3, as shown in this document schemas, to produce a compound of formula M2. The release of the amino group standard chemical methods allows to obtain the compound of formula (I)-M.

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 tetramethylsilane (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 compounds may be characterized as racemic mixtures or as individual diastereomers and enantiomers using x-ray crystallography and other well-known specialists of ways. E�if not stated otherwise, everything 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

A. 4-Bromo-2-(4-methoxyphenoxy)nitrobenzene (1c). A mixture of compound 1a (2.20 g, 10.0 mmol), 4-methoxyphenol (compound 1b, 1,32 g, 10.5 mmol), K2CO3(1.52 g, 11.0 mmol) and 6 ml DMF was stirred at a temperature of 75°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue separated between EtOAc and water. The organic layer is successively washed in 2N aqueous NaOH, 2N HCl aqueous solution, a saturated aqueous solution of NaHCO3and brine, dried over Na2SO4and concentrated, obtaining the compound 1c in the form of gel brown (2,95 g, 91%).1H NMR (300 MHz, CDCl3): δ 7,11-7,84 (d, 1H), 7,24-7,27 (m, 1H), 7,01-7,06 (m, 3H), 6,93-6,97 (m, 2H), 3,71 (s, 3H).

B. 4-Bromo-2-(4-methoxyphenoxy)-aniline (1d). A mixture of compound 1c (1.64 g, of 5.06 mmol), zinc (1,98 g, 30.4 mmol), 15 ml Or 50 ml of MeOH was stirred at 20°C for 20 hours. After removal of the solvents the obtained residue was separated between EtOAc and 3N aqueous NaOH. The organic layer was washed with �asystem saline, dried over Na2SO4and concentrated, obtaining the compound 1d in the form of a brown oil (1,54 g, yield 103%). MS: m/z 294,0 (M + H)+.

C. tert-Butyl ether 2-(S)-{[4-bromo-2-(4-methoxyphenoxy)-methyl}-pyrrolidin-1-carboxylic acid (1f). NaBH3CN (0,67 g, 10.1 mmol) was added to a mixture of compound 1d (1.45 g, of 5.06 mmol) and Boc-L-prolinal (compounds 1e, 1.04 g, of 5.06 mmol) in 20 ml of MeOH and 2.5 ml Or. The mixture was stirred at 20°C for 1.5 hours. After evaporation of the solvent, the residue was extracted with EtOAc. The organic layer is successively washed with 1N aqueous NaOH, 1N aqueous HCl solution and saturated brine and dried over Na2SO4. As a result of concentration and purification column flash chromatography (SiO2) using as eluent gradient mixture of hexanol and ether got compound 1f in the form of a yellow oil (2,36 g, yield 98%) MS: m/z 476,9, 478,8 (M + H)+.

D. tert-Butyl ether (E)-2-(S)-{[4-(2-ethoxycarbonylethyl)-2-(4-methoxyphenoxy)-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (1h). A mixture of compound 1f (0.19 g, 0.4 mmol), ethyl acrylate (compound 1g, 0,43 g or 0.045 ml, 0.5 mmol), Pd(OAc)2(0,0009 g, 0,004 mmol), tri-o-tolylphosphino (0,0049 g, 0,016 mmol) and 0.4 ml of DMF was irradiated in a microwave reactor at 160°C for 10 minutes. After purification preparative TLC using as an e�yente mixture of EtOAc and hexanol in the ratio of 3:7 got connection 1h in a solid yellow color (0.15 g, yield 78%). MS: m/z 483,2 (M+H)+.

E. tert-Butyl ether (E)-2-(S)-{[4-(2-carboxyethyl)-2-(4-methoxyphenoxy)-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (1i). A mixture of compound 1h (0.15 g, 0,31 mmol), 1 ml of 3N aqueous solution of NaOH (3 mmol) and 1 ml of MeOH was stirred at 20°C for 20 hours. After evaporation of MeOH, the aqueous phase was acidified with 1N aqueous HCl and was extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4and concentrated, obtaining the compound 1i (0.18 g, exit 124%). MS: m/z 469,3 (M+H)+.

F. tert-Butyl ether 2-(S)-{[4-(2-diethylcarbamoyl)-2-(4-methoxyphenoxy)-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (1k). A mixture of compound 1i (0.18 g, 0.38 mmol), N,N-diethylamine (compound 1j, 0.04 ml, 0.38 mmol), monohydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC-HCl, 0,095 g, 0.49 mmol) and HOBt (0.10 g, 0.76 mmol) was stirred in 3 ml of DMF at 20°C for 20 hours. Added water, after which the mixture was extracted with EtOAc. The organic phase is successively washed with 1N aqueous HCl solution, saturated brine, a saturated aqueous solution of NaHCO3and again with saturated brine, then dried over MgSO4. After evaporation of the solvent and purification preparative TLC using as eluent a mixture of ether and hexanol in the ratio 1:1 sex�or compound 1k (0,100 g, the yield is 50%). MS: m/z 524,2 (M+H)+.

G. Compound 1: (2E)-N,N-diethyl-3-[3-(4-methoxyphenoxy)-4-{[(2S)-pyrrolidin-2-yl-methyl]amino}phenyl]prop-2-UNAMID. A mixture of compound 1k (0,026 g, 0,050 mmol), TFA and CH2Cl2was stirred at 20°C for 4 hours. After concentration the residue was purified by HPLC on reversed phase, receiving the connection 1 in the form of triptoreline (0,0063 g, yield 19%). MS: m/z USD 424.2 (M+H)+.

Example 2

A. tert-Butyl ether 2-(S)-{[4-(2-diethylcarbamoyl)-2-(4-methoxyphenoxy)-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (2a). A mixture of compound 1k (0.050 g, 1.0 mmol) and 10% palladium on carbon in MeOH was shaken in hydrogen atmosphere (234,4 kPa (34 psi) at 20°C for 4 hours. The catalyst was filtered and drove the solvent, obtaining the compound 2a. MS: m/z 526,3 (M + H)+.

B. Compound 2: N,N-diethyl-3-[3-(4-methoxyphenoxy)-4-{[(2S)-pyrrolidin-2-yl-methyl]amino}phenyl]propanamide. A mixture of compound 2a (0.050 g, 0,095 mmol), TFA and CH2Cl2was stirred at 20°C for 4 hours. After concentration the residue was purified by HPLC on reversed phase, receiving compound 2 in the form of triptoreline (0,022 g, yield 36%).1H NMR (300 MHz, CD3OD): δ 6,87-6,91 (m, 5H), 6,78 (d, 1H), 6,60 (d, 1H), 3,90 (m, 1H), 3,79 (s, 3H), 3,42-3,48 (m, 2H) 3,24-to 3.34 (m, 6H), 2,77 (t, 2H), 2,53 (m, 2H), 2,18-of 2.28 (m, 1H), 2.00 in to 2.14 (m, 2H), 1,73-to 1.86 (m, 1H), 1,03-1,08 (m, 6H); MS: m/z 426,3 (M+H)+

Example 3

A. 4-Chloro-2-(4-methoxyphenoxy)nitrobenzene (3b). A mixture of 4-chloro-2-peritrabecular (compound 3a, of 1.76 g, 10 mmol), compound 1b (1,30 g, 10.5 mmol) and K2CO3(1.52 g, 11 mmol) in 6 ml of DMF was maintained at a temperature of 75°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue separated between EtOAc and water. The organic layer is successively washed with 1N aqueous NaOH, 1N aqueous solution of HCl, a saturated aqueous solution of NaHCO3and saturated brine and dried over Na2SO4. After concentration and purification column flash chromatography (SiO2) using as eluent gradient mixture of hexanol EtOAc and received compound 3b in the form of a solid yellow color (2.75 g, yield 98%). MS: m/z 279,9 (M + H)+.

B. 4-Chloro-2-(4-methoxyphenoxy)-aniline (3c). A mixture of compound 3b (2,47 g, 8,83 mmol), zinc (3,46 g, 53 mmol), 60 ml Or, 5 ml THF and 36 ml of MeOH was stirred at 20°C for 20 hours. The solid is filtered and washed with MeOH. The filtrate was separated between EtOAc and 1N aqueous NaOH. The organic layer was washed with saturated brine, dried over Na2SO4and concentrated, obtaining the compound 3c in the form of a gel black, which was used without purification (1.80 g, yield 82%). MS: m/z 249,9 (M+H)+.

C. tert-Butyl ether 2-()-{[4-chloro-2-(4-methoxyphenoxy)-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (3d). NaBH3CN (0.95 g, 14.4 mmol) was added to a mixture of compound 3c (1.80 g, 7.2 mmol) and compound 1e (1,48 g, 7.2 mmol) in 28 ml of MeOH and 3.5 ml Or. The mixture was stirred at 20°C for 1 hour. After evaporation of the solvent, the residue was extracted with EtOAc. The organic layer is successively washed with a saturated aqueous solution of NaHCO3and saturated brine and dried over Na2SO4. After concentration and purification column flash chromatography (SiO2) using as eluent a mixture of EtOAc and hexanol in the ratio of 3:7 got connection 3d in the form of a brown oil (2.84 g, yield 91%). MS: m/z by 433.1 (M+H)+.

D. tert-Butyl ether (E)-2-(S)-({2-(4-methoxyphenoxy)-4-[2-(4-methoxyphenyl)-ethenyl]-phenylamino}-methyl)-pyrrolidin-1-carboxylic acid (3f). A mixture of compound 3d (0.11 g, 0,254 mmol), 4-vigilante (compound 3e, 0,042 g, 0,042 ml, 0,305 mmol), Pd2(dba)3(0.035 g, 0,038 mmol), P(t-Bu)3(0,032 g, 0.04 ml, 0,152 mmol), Cs2CO3(0,091 g, 0,279 mmol) and 0.2 ml of dioxane was irradiated in a microwave reactor at 180°C for 30 minutes. Then added a saturated salt solution and the resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4and concentrated, the residue was purified preparative TLC and received a compound 3f (0.05 g, yield 51%). MS: m/z 531,4 (M+H)+.

E. tert-Butyl e�Il (E)-2-(S)-({2-(4-methoxyphenoxy)-4-[2-(4-methoxyphenyl)-ethyl]-phenylamino}-methyl)-pyrrolidin-1-carboxylic acid (3g). A mixture of compound 3f (0.050 g, 0,094 mmol) and 10% palladium on carbon in MeOH was shaken in hydrogen atmosphere (262,0 kPa (38 psi) at 20°C. the Catalyst was filtered and drove the solvent, having the 3g connection (0.05 g, yield 100%).

F. Compound 3: (S)-{2-(4-methoxyphenoxy)-4-[2-(4-methoxyphenyl)-ethyl]-phenyl}-pyrrolidin-2-yl-methylamine. A mixture of compound 3g (0.050 g, 0,094 mmol), TFA and CH2Cl2was stirred at 20°C for 2 hours. After concentration the residue was dissolved in CH3CN, purified by HPLC on reversed phase and received the compound 3 in the form of triptoreline (0,018 g, yield 29%).1H NMR (300 MHz, CD3OD): δ 6,72-6,94 (m, 10H), 6,38 (m, 1H), 3,81-3,92 (m, 1H), 3,76 (s, 3H), 3,74 (s, 3H), 3,21-3,44 (m, 4H), 2,69-2,71 (m, 4H), 1,98-of 2.28 (m, 3H), 1,71-to 1.82 (m, 1H); MS: m/z 432,9 (M+H)+.

Following the procedure described above for example 3 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:

ConnectionMC
(M+H)+
1H NMR
4433,21H NMR (300 MHz, CD3OD): δ 7,05-7,11 (m, 1H), of 6.49-6,90 (m, 9H), to 6.42 (m, 1H), 3,80-3,92 (m, 1H),3,75 (s, 3H), 3,70 (s, 3H), 3,21-3,52 (m, 4H), 2,73-2,9 (m, 4H), 1,91-of 2.28 (m, 3H), 1,72-of 1.80 (m, 1H)
5402,91H NMR (300 MHz, CD3OD): δ 7,05-to 7.18 (m, 5H), of 6.52-6,86 (m, 6H), 6,44 (m, 1H), 3,80-3,90 (m, 1H), of 3.78 (s, 3H), 3,26 is-3.45 (m, 4H), 2,73-2,77 (m, 4H), 1,92 and 2.26 (m, 3H), 1,72-of 1.80 (m, 1H)

6UAH 421,21H NMR (300 MHz, CD3OD): δ 6,72-was 7.08 (m, 10H), 6,38 (m, 1H), 3,81-of 3.91 (m, 1H), 3,79 (s, 3H), 3,24-of 3.46 (m, 4H), 2,77-2,79 (m, 4H), 1,96-of 2.28 (m, 3H), 1,73-of 1.81 (m, 1H)
7UAH 421,21H NMR (300 MHz, CD3OD): δ 7,14-7,22 (m, 1H), 6,72-6,89 (m, 9H), to 6.42 (m, 1H), 3,80-3,92 (m, 1H), of 3.78 (s, 3H), 3,25-of 3.46 (m, 4H), of 2,75 2,82 (m, 4H), 1,94-of 2.25 (m, 3H), 1,72-to 1.79 (m, 1H)

Example 4

A. tert-Butyl ether 2-(S)-{[4-[2-(3-(carboxyphenyl)-ethyl]-2-(4-methoxyphenoxy)-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (4a). Compound 4a was obtained as described above in example 3, the method of obtaining the compounds 3g, replacing the compound 3e 3-ethenylbenzene acid. MS: m/z 547,2 (M + H)+.

B. tert-Butyl ether 2-(S)-{[4-[2-(3-diethylcarbamoyl)-ethyl]-2-(4-methoxyphenoxy)-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (4b). A mixture of compound 4b (0.016 g, 0,029 mmol), compound 1j (0,0021 g, 0.003 ml, 0,029 mmol), PyBOP (0.030 g, 0,058 mmol), HOBt (0,0059 g, 0,044 mmol), DIEA (0.005 g, 0,010 ml, 0,058 mmol) and 1 ml of DMF was stirred at 20°C for 3 hours. Added water, after which the mixture was extracted with EtOAc. The organic layer is successively washed with 1N aqueous HCl solution, a saturated aqueous solution of NaHCO3and saturated brine and dried over Na2SO4. After evaporation of the solvent and purification preparative TLC using as eluent a mixture of EtOAc and hexanol in the ratio of 3:7 got connection 4b. MS: m/z 602,3 (M+H)+.

C. Compound 8: (S)-N,N-diethyl-3-(2-{3-(4-methoxyphenoxy)-4-[(pyrrolidin-2-yl-methyl)-amino]-phenyl}-ethyl)-benzamide. A mixture of compound 4b, TFA and CH2Cl2was stirred at 20°C for 1.5 hours. After concentration the residue was dissolved in CH3CN, purified by HPLC on reversed phase and got the connection 8 in the form of triptoreline (0.002 g, yield 9%, stage B and C).1H NMR (300 MHz, CD3OD): δ 7,25-to 7.33 (m, 2H), 7,12-7,17 (m, 2H), 7,03 (m, 1H), 6,74-6,86 (m, 5H), gold 6.43 (m, 1H), 3,82-3,90 (m, 1H), of 3.77 (s, 3H), 3,38 is 3.57 (m, 4H), 3,13-of 3.31 (m, 4H), 2,76-2,86 (m, 4H), 2.00 in of 2.28 (m, 3H), 1,75-to 1.82 (m, 1H), 1,21-of 1.26 (m, 3H), 0.98 to 1.04 for (m, 3H); MS: m/z 502,4 (M+H)+.

Example 5

A. N,N-Diethyl-4-nitro-3-perbenzoic (5b). A mixture of compound 5a (0.50 g, 2.7 mmol), compound 1j (0.20 g, 0,28 ml, 2.7 mmol), PyBOP (2,81 g, 5.4 mmol), HOBt (0.55 g, from 4.05 mmol), DIEA (0.70 g, were 0.94 ml, 5.4 mmol) and 8 ml of DMF was stirred at 20°C for 3 hours. Add�and water, then the mixture was extracted with EtOAc. The organic layer is successively washed with 1N aqueous HCl solution, a saturated aqueous solution of NaHCO3and saturated brine and dried over Na2SO4. After evaporation of the solvent and purification preparative TLC using as eluent a mixture of EtOAc and hexanol in the ratio 4:6 got connection 5b (0,67 g, yield 103%). MS: m/z 240,9 (M+H)+.

B. N,N-Diethyl-4-nitro-3-phenoxybenzamide (5d). A mixture of compound 5b (0.22 g, 0,92 mmol), phenol (compound 5c, 0.10 g, 1.1 mmol), Cs2CO3(From 0.90 g, 2.7 mmol) and 4 ml of DMF was stirred at 120°C for 3 hours. Then added water and the mixture extracted with EtOAc. The organic layer is successively washed with 3N aqueous NaOH, 2N aqueous HCl solution and saturated brine, dried over Na2SO4and concentrated. The residue was purified preparative TLC and received a compound 5d in the form of a brown oil. MS: m/z 315,0 (M+H)+.

C. 4-Amino-N,N-diethyl-3-phenoxybenzamide (5e). A mixture of compound 5d, obtained in stage B, and 10% palladium on carbon in MeOH was shaken in hydrogen atmosphere (206,8 kPa (30 psi) at 20°C for 3 hours. The catalyst was collected by filtration and the solvent distilled by evaporation, getting the 5e connection (0,19 g, yield 73%, stage B and C).

D. tert-Butyl ether 2-[(4-dietiker�email-2-phenoxybenzamine)-methyl]-pyrrolidin-1-carboxylic acid (5f). NaBH3CN (0,025 mmol, 0.4 mmol) was added to a mixture of compound 5e (0,063 g, 0.2 mmol) and compound 1e (0.04 g, 0.2 mmol) in 5 ml of MeOH and 0.4 ml Or. The mixture was stirred at 20°C for 1.5 hours. After evaporation of the solvent, the residue was extracted with EtOAc. The organic layer is successively washed with a saturated solution NaHCO3and saturated brine dried over MgSO4. After concentration and purification preparative TLC received compound 5f (0.07 g, 75% yield) MS: m/z 468,3 (M+H)+.

E. the Compound 9: (S)-N,N-diethyl-3-phenoxy-4-[(pyrrolidin-2-yl-methyl)-amino]-benzamide. A mixture of compound 5f (0.07 g, 0.15 mmol), TFA and CH2Cl2was stirred at 20°C for 1.5 hours. After concentration the residue was dissolved in CH3CN, purified by HPLC on reversed phase and got the connection 9 in the form of triptoreline (0,044 g, yield 49%).1H NMR (300 MHz, CD3OD): δ of 7.33-7,39 (m, 2H), 7,10-7,15 (m, 2H), 7,00-7,03 (m, 2H), 6,89-at 6.92 (m, 1H), was 6.77 (m, 1H), 3,88-3,93 (m, 1H), 3,26-3,55 (m, 8H), 1,99-of 2.25 (m, 3H), 1,74-of 1.81 (m, 1H), 1,03-1,17 (m, 6H); MS: m/z 368,0 (M+H)+.

Following the procedure described above for example 5, 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:

Connection1H NMR
10398,01H NMR (300 MHz, CD3OD): δ 6,66-7,05 (m, 6H), 6,66 (m, 1H), 3,89-3,92 (m, 1H), 3,76 (s, 3H), or 3.28-3,56 (m, 8H), of 1.99 and 2.26 (m, 3H), 1,02-1,17 (m, 6H)
11398,01H NMR (300 MHz, CD3OD): δ 7,11-7,21 (m, 2H), 6,97-7,06 (m, 3H), 6,84-6,86 (m, 1H), 6,48 (m, 1H), 3,88-4,00 (m, 1H), of 3.77 (s, 3H), 3,54-3,58 (m, 2H), or 3.28-3,38 (m, 6H), 2.00 in of 2.27 (m, 3H), 1,81-to 1.86 (m, 1H), 0,95-of 1.18 (m, 6H)

Example 6

A. 3-Fluoro-4-nitrobiphenyl (6b). 4-Chloro-2-ftorirovannom (compound 3a, 3.51 g, 20 mmol), phenylboronic acid (compound 6a, 3,77 g, 30 mmol), potassium fluoride (3,49 g, 60 mmol), Pd(OAc)2(0,045 g, 0.2 mmol) and 2-(di-t-butylphosphino)biphenyl (0.12 g, 0.4 mmol) was placed in a dry nitrogen purged flask. The flask was evacuated and purged three times with nitrogen, then added in THF (25 ml). The reaction mixture was stirred at ambient temperature for 20 hours. Then added EtOAc and the organic solution was successively washed with 1N aqueous NaOH and saturated brine, dried over MgSO4and concentrated. The resulting crude substance was purified column flash chromatography (SiO2) using as eluent gradient mixture of hexanol and EtOAc and got pure� compound 6b (1,27 g, yield 30%) and additionally some amount less than the pure compound 6b (3,66 g).1H NMR (300 MHz, CDCl3): δ 8,12-8,18 (m, 1H), 7,47-of 7.62 (m, 7H).

B. 4-(4-Nitrobiphenyl-3-yl-oxy)-benzonitrile (6d). Compound 6b (0.22 g, 1.0 mmol), 4-hydroxybenzonitrile (compound 6c, 0,19 g, 1.5 mmol), Cs2CO3(0,98 g, 3.0 mmol) and 4 ml of DMF was stirred at 120°C for 3.5 hours. The reaction mixture was poured into water and was extracted with EtOAc. The organic layer is successively washed with 3N aqueous NaOH, 2N aqueous HCl solution and saturated brine and dried over Na2SO4. After distilling off the solvent provided crude compound 6d, which was used without purification (to 0.263 g, yield 83%).1H NMR (300 MHz, CDCl3): δ 8,12-8,16 (m, 1H), 7,38-7,66 (m, 9H), 7,06-to 7.09 (m, 2H).

C. 4-(4-Aminobiphenyl-3-yl-oxy)-benzonitrile (6e). A mixture of compound 6d (1.0 mmol) and chloride dihydrate tin (II) (1.13 g, 5 mmol) was heated to reflux in 10 ml of MeOH for 2.5 hours. After cooling to room temperature the solvent is distilled by evaporation and the residue mixed with water. The pH value of the aqueous solution brought to pH 9 using saturated aqueous NaHCO3and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4and evaporated, receiving the connection 6e in the form of a solid brown color, which was used without purification. MS: m/z 287,2 (M+H) +.

D. tert-Butyl ether 2-(S)-{[3-(4-cianfrocca)-biphenyl-4-yl-amino]-methyl}-pyrrolidin-1-carboxylic acid (6f). NaBH3CN (0,066 g, 1.0 mmol) was added to a mixture of compound 6e (0,14 g, 0.50 mmol) and compound 1e (0.10 g, 0.50 mmol) in 4 ml of MeOH and 0.3 ml Or. The mixture was stirred at 20°C for 1.5 hours. After evaporation of the solvent, the residue was extracted with EtOAc. The organic layer is successively washed with a saturated solution NaHCO3and saturated brine dried over MgSO4. After concentration and purification preparative TLC received compound 6f in the form of a brown oil (0,167 g, 71% yield). MS: m/z 470,2 (M+H)+.

E. Connection 12. (S)-4-{4-[(Pyrrolidin-2-yl-methyl)-amino]-biphenyl-3-yl-oxy}-benzonitrile. A mixture of compound 6f (0,167 g, 0.36 mmol), TFA and CH2Cl2was stirred at 20°C for 2 hours. After concentration the residue was dissolved in CH3CN, purified by HPLC on reversed phase and got a connection 12 in the form of triptoreline (0,029 g, yield 13%). MS: m/z 370,2 (M+H)+.

Following the procedure described above for example 6, 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:

Connection MC
(M+H)+
1H NMR
13370,21H NMR (300 MHz, CD3OD): δ 7,18-7,52 (m, 11H), 7,00-7,03 (m, 1H), 3,80-3,90 (m, 1H), 3,48-3,52 (m, 2H), 3,26-of 3.31 (m, 2H), 2,02-of 2.24 (m, 3H), 1,75-to 1.82 (m, 1H)
14345,11H NMR (300 MHz, CD3OD): δ 7,03-of 7.48 (m, 7H), 7,07-7,12 (m, 1H), 6,95-to 7.04 (m, 5H), 3,85-to 3.96 (m, 1H), 3,48-3,54 (m, 2H), 3,26-of 3.31 (m, 2H), 2,03-of 2.30 (m, 3H), 1,70-of 1.84 (m, 1H)
15375,11H NMR (300 MHz, CD3OD): δ 7,44-of 7.46 (m, 2H), 7,32-7,38 (m, 3H), 7,21-of 7.24 (m, 2H), 7,10 (m, 1H), 6,95-6,98 (m, 1H), 6,56 was 6.69 (m, 3H), 3,85-to 3.96 (m, 1H), 3,76 (s, 3H), 3,48-of 3.53 (m, 2H), 3,26-3,30 (m, 2H), 1,97-of 2.30 (m, 3H), 1,73-to 1.86 (m, 1H)
16363,01H NMR (300 MHz, CD3OD): δ of 7.42-7,45 (m, 2H), 7,30-value of 7, 37 (m, 3H), 7,21-of 7.24 (m, 1H), 6,94-7,22 (m, 6H), 3,85-to 3.96 (m, 1H), 3,48-3,54 (m, 2H), 3,27-of 3.33 (m, 2H), 1,99-of 2.32 (m, 3H), 1,74-to 1.87 (m, 1H)

17428,91H NMR (300 MHz, CD3OD): δ 6.97 in-7,50 (m, 12H), 3,83-3,95 (m, 1H), 3,40-of 3.53 (m, 2H), 3,27-of 3.31 (m, 2H), 2,00-of 2.28 (m, 3H), 1,77-to 1.82 (m, 2H)
18412,81H NMR (300 MHz, CD3OD): δ 7,53-7,55 (�, 2H), 7.23 percent-7,32 (m, 7H), 6,93-of 6.96 (m, 1H), of 6.46 (m, 1H), 3,95-4,08 (m, 1H), 3,59-3,63 (m, 2H), 3,31-3,36 (m, 2H), 2,09-of 2.38 (m, 3H), 1,82-of 1.93 (m, 1H)
19348,91H NMR (300 MHz, CD3OD): δ 7,18-7,40 (m, 6H), 6,89-7,02 (m, 6H), 3,79 (s, 3H), 3,56-of 3.60 (m, 2H), 3,26-3,30 (m, 2H), 2,74 (s, 3H)
20402,91H NMR (300 MHz, CD3OD): δ 7,98-8,02 (m, 2H), 7,43-of 7.50 (m, 3H), 7,35-value of 7, 37 (m, 2H), of 7.19-7.23 percent (m, 2H), 6,99-7,06 (m, 3H), 3,82-3,94 (m, 1H), a 3.87 (s, 3H), 3,48-3,52 (m, 2H), 3,25-of 3.31 (m, 2H), 1.93 and-of 2.28 (m, 3H), 1,71-of 1.83 (m, 1H)
21402,91H NMR (300 MHz, CD3OD): δ 7,73-7,76 (m, 1H), 7,60 (m, 1H), 7.23 percent-of 7.50 (m, 8H), 7,13 (m, 1H), 6,99-7,02 (m, 1H), 3,84-3,95 (m, 1H), 3,88 (s, 3H), 3,49-3,54 (m, 2H), 3,26-3,30 (m, 2H), 1,98-to 2.29 (m, 3H), 1,75-of 1.83 (m, 1H)
22412,81H NMR (300 MHz, CD3OD): δ 7,56 (m, 1H), 7,18-7,40 (m, 7H), 6,91-of 6.99 (m, 3H), 3,89-3,95 (m, 1H), 3,53-to 3.56 (m, 2H), or 3.28-3,34 (m, 2H), 2,00-of 2.27 (m, 3H), 1,76-of 1.83 (m, 1H)

23375,01H NMR (300 MHz, CD3OD): δ 7.23 percent-7,44 (m, 6H), 6,93-7,10 (m, 6H), 3,76-3,88 (m, 1H), 3,79 (s, 3H), 3,44-3,48 (m, 2H), 3,14-3,18 (m, 2H), 2,25-of 2.32 (m, 2H), 1,70-of 1.84 (m, 2H)

Example 7

A. tert-Butyl ester (2S,4R)-4-fluoro--(methoxymethylethoxy)-pyrrolidin-1-carboxylic acid (7b). HBTU (12.3 g, of 32.3 mmol) was added to a solution of compound 7a (6,26 g, 26.9 mmol), hydrochloride of N,O-dimethylhydroxylamine (3,15 g of 32.3 mmol) and DIEA (to 5.62 ml of 4.17 g of 32.3 mmol) in 60 ml DMF at 0°C. After 15 minutes the cooling bath was removed and the mixture was stirred for 16 hours at 20°C. Then added EtOAc (200 ml) and a saturated aqueous solution of NH4Cl (100 ml). The organic layer was separated, washed with a saturated aqueous solution of NaHCO3(100 ml) and saturated brine (100 ml) and dried over MgSO4. The solution was concentrated and obtained 7.7 g of grayish-white oil, which was purified column flash chromatography (SiO2) using as eluent a mixture of 10% MeOH/CH2Cl2and received a compound 7b (5,47 g, yield 74%).1H-NMR (DMSO-d6): δ of 5.29 (1H, dt), 4,70 (1H, DD), 3,50 (2H, m), 3,13 (3H, s), 2,69 (3H, s), from 2.00 (2H, m), of 1.34 (9H, s).

B. tert-Butyl ester (2S,4R)-4-fluoro-2-formylpyridine-1-carboxylic acid (7c). 1M solution of LiAlH4 in Et2O (a 19.2 ml, 19.2 mmol) is added dropwise to a solution of compound 7b (3,54 g, 12.8 mmol) in 10 ml of Et2O at 0°C. the Mixture was stirred for 1.5 hours at 20°C. Then successively added 10 ml of a 0.5 N aqueous solution of KHSO4and 25 ml of Et2O. the Organic layer was separated and washed with 1N aqueous NaOH to decompose the aluminum complex. The organic layer was separated, dried over MgSO 4and concentrated, obtaining the compound 7c as an oil (1.33 g, yield 48%).1H NMR (DMSO-d6): δ to 9.45 (1H, C), 5,10 (1H, m), 4,20 (1H, m), 3,50 (2H, m), of 2.20 (2H, m) to 1.48 (9H, s).

Example 8

A. tert-Butyl ester (2S,4R)-2-{[4-bromo-2-(4-methoxyphenoxy)-phenylamino]-methyl}-4-ftorpirimidinu-1-carboxylic acid (8a). A mixture of compound 1d (1.18 g, 4.0 mmol), compound 7c (1.33 g, 6.1 mmol) and 5 drops Or 10 ml of DCE was stirred for 5 minutes at 20°C. Then for 5 minutes parts added NaBH(OAc)3(2,54 g, 12 mmol) and the mixture was stirred at 20°C for 20 hours. Then stir in the mixture was sequentially added saturated aqueous solution of NH4Cl (25 ml), 100 ml of CH2Cl2and 10 ml of water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2(50 ml). The combined organic layers were dried over Na2SO4 and concentrated, obtaining 2 g of crude material. This substance is purified column flash chromatography (SiO2), using as eluent a gradient mixture of hexanol and EtOAc, and received compound 8A (0,496 g; yield 25%). MS: m/z 495,0/497,0 (M+H)+.

B. tert-Butyl ester (2S,4R)-2-{[4-(5-cyanopyridine-3-yl)-2-(4-methoxyphenoxy)-phenylamino]-methyl}-4-ftorpirimidinu-1-carboxylic acid (8c). A mixture of compound 8a (0,124 g, 0.30 mmol), compound 8b (0,096 g, of 0.65 mmol), Pd(dppf)Cl2(0.055 g, 0,075 mmol), Cs2C 3(0,244 g, 0.75 mmol), 0.25 ml of EtOH and 1 ml of dioxane was irradiated in a microwave reactor at 140°C for 15 minutes. The reaction mixture was filtered and the solid residue was washed with 100 ml of EtOAc. The filtrate was washed with a saturated aqueous solution of K2CO3, dried over Na2SO4and activated charcoal and concentrated, obtaining of 0.32 g of crude residue containing compound 8c.

C. Compound 24: (2S,4R)-5-[4-[(4-ftorpirimidinu-2-yl-methyl)-amino]-3-(4-methoxyphenoxy)-phenyl]-nicotinamide. To a solution of the residue obtained in stage B above, in 10 ml of CH2Cl2dropwise added triptorelin (5 ml). The mixture was stirred for 4 h at 20°C and then boiled away. The residue was purified by HPLC on reversed phase and got the connection 24 in the form of triptoreline (0,058 g, yield 36% for 2 stages).1H NMR (300 MHz, CD3OD): 8,76 (1H, d), 8,63 (1H, d), 8,14 (1H, d), 7,31 (1H, dd), 6,98-about 6,82 (6H, m), levels lower than the 5.37 (1H, d), of 4.12 (1H, m), 3,65 is 3.40 (5H, m), 2,50 (1H, m), of 1.95 (1H, m); MS: m/z 419,1 (M+H)+.

Following the procedure described above for example 8, 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:

ConnectionMC
(M+H)+
1H NMR
25412,0
26440,1
27424,31H NMR (400 MHz, CDCl3): δ 8,44 (s, 1H); of 8.33 (s, 1H); 7,86 (s, 1H); to 7.33 (s, 1H); to 6.95 (m, 1H); 4,11 (m, 2H); and 3.8 (s, 6H); 3,4 (m, 1H); 255 (m, 2H); 2,24-2,01 (m, 2H); 1,24 (m, 1H)
28408,31H NMR (400 MHz, CDCl3): δ to 8.7 (s, 1H); 8,5 (m, 2H); of 7.5 (s, 1H); 7,2-6,9 (m, 6H); 4,2 (m, 1H); 3.7 V (s, 3H); 3,7 (m, 3H); 3,5 (m, 1H);to 2.85 (m, 3H); 2,56 (s, 3H)

Example 9

A. tert-Butyl ether 2-(S)-{[3-(4-carbamoylphenoxy)-biphenyl-4-yl-amino]-methyl}-pyrrolidin-1-carboxylic acid (9a).To a solution of compound 6f (0,040 g, 0,085 mmol) in a mixture of 1.5 ml of EtOH and 1.5 ml of dioxane was added 20% aqueous NaOH solution (0.5 ml) and 30% aqueous solution of H2O2(0.4 ml). The resulting mixture was held at 60°C for 2 days. Then the reaction mixture was extracted with EtOAc, dried over MgSO4and concentrated, obtaining the compound 9a. MS: m/z 488,3 (M+H)+.

B. Compound 29: (S)-4-{4-[(pyrrolidin-2-yl-methyl)-amino]-biphenyl-3-yl-oxy}-benzamide. A mixture of compound 9a, TFA and CH2Cl2was stirred at 20°C for 2 hours. Pic�e concentration the residue was dissolved in CH 3CN, purified by HPLC on reversed phase and got the connection 29 in the form of triptoreline (0.015 g, 29% for 2 stages).1H NMR (300 MHz, CD3OD): δ 7.87 ft-to 7.89 (m, 2H), to 7.33-7,49 (m, 5H), 7,18-of 7.19 (m, 2H), 7,00-7,06 (m, 3H), 3,84-3,95 (m, 1H), 3,44 is 3.57 (m, 2H), or 3.28-3,35 (m, 2H), 1,98-of 2.28 (m, 3H), 1,72-to 1.82 (m, 1H); MS: m/z 387,9 (M+H)+.

Following the procedure described above for example 9, 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:

ConnectionMC
(M+H)+
1H NMR
30387,91H NMR (300 MHz, CD3OD): δ 7,55-7,58 (m, 1H), 7,31-7,49 (m, 7H), of 7.14-7.23 percent (m, 3H), 6,98-7,00 (m, 1H), 3,85-to 3.96 (m, 1H), 3,43-3,58 (m, 2H), 3,25-of 3.31 (m, 2H), 1,98-of 2.27 (m, 3H), 1,73-of 1.84 (m, 1H)

Example 10

A. tert-Butyl ether 2-(S)-{[3-(4-ethoxycarbonylmethoxy)-biphenyl-4-yl-amino]-methyl}-pyrrolidin-1-carboxylic acid (10a). Compound 10a was obtained as described above in example 6, the method of obtaining compounds 6f, replacing the compound 6c on methyl-4-hydroxybenzoate. MS: m/z 503,2 (M+H)+.

B. tert-Butyl ether 2-(S)-{[3-(4-carboxyphenoxy)-biphenyl-4-yl-amino]-methyl}-�irreligion-1-carboxylic acid (10b). A mixture of compound 10a (0,034 g, 0,068 mmol), 20% aqueous NaOH and MeOH was stirred at 20°C for 20 hours. After evaporation of MeOH, the aqueous phase was acidified using and was extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4and concentrated, obtaining the compound 10b (0,032 g, yield 95%). MS: m/z 489,2 (M+H)+.

C. Compound 31: (S)-4-{4-[(pyrrolidin-2-yl-methyl)-amino]-biphenyl-3-yl-oxy}-benzoic acid. A mixture of compound 10b (0,032 g, 0,065 mmol), TFA and CH2Cl2was stirred at 20°C for 2 hours. After concentration the residue was dissolved in CH3CN, purified by HPLC on reversed phase and got the connection 31 in the form of triptoreline is 0.019 g, yield 47%).1H NMR (300 MHz, CD3OD): δ 7,98-8,13 (m, 2H), 7,43-of 7.50 (m, 3H), 7,32-value of 7, 37 (m, 2H), 7,20-7,25 (m, 2H), 6,99-7,05 (m, 3H), 3,83-to 3.96 (m, 1H), 3,42-3,58 (m, 2H), 3,25-3,30 (m, 2H), 1,95-of 2.28 (m, 3H), 1,70-1,83 (m, 1H): MS: m/z 389,0 (M+H)+.

Following the procedure described above for example 10, 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:

ConnectionMC
(M+H)+
1H NMR
32389,01H NMR (300 MHz, CD3OD): δ 7,74-7,79 (m, 1H), 7,61-7,62 (m, 1H), 7,14-of 7.48 (m, 9H), 6,97-7,00 (m, 1H), a 3.87-3,90 (m, 1H), 3,49-of 3.53 (m, 2H), 3,25-of 3.32 (m, 2H), 1,99-2,22 (m, 3H), 1,73-of 1.80 (m, 1H)

Example 11

A. tert-Butyl ether 2-(S)-{[3-(4-diethylcarbamoyl)-biphenyl-4-yl-amino]-methyl}-pyrrolidin-1-carboxylic acid (11a). A mixture of compound 10b (0,021 g, 0,043 mmol), compound 1j (0,0094 g, with 0.0013 ml, 0,129 mmol), PyBOP (0.045 g, 0,086 mmol), HOBt (0,0087 g, 0,065 mmol), DIEA (0,011 g, 0,015 ml, 0,086 mmol) and 1 ml of DMF was stirred at 20°C for 3 hours. Added water, after which the mixture was extracted with EtOAc. The organic layer is successively washed with 1N aqueous HCl solution, a saturated aqueous solution of NaHCO3and saturated brine and dried over MgSO4. After evaporation of the solvent and purification by HPLC on reversed phase received connection 11a. MS: m/z to 544.3 (M+H)+.

B. Compound 33: (S)-N,N-diethyl-4-{4-[(pyrrolidin-2-yl-methyl)-amino]-biphenyl-3-yl-oxy}-benzamide. A mixture of compound 11a, TFA and CH2Cl2was stirred at 20°C for 2 hours. After concentration the residue was dissolved in CH3CN, purified by HPLC on reversed phase and got the connection 33 in the form of triptoreline (0.016 g, yield 55% for 2 stages).1H NMR (300 MHz, CD3OD): δ 7,32-7,50 (m, 7H), 7.23 percent-of 7.25 (m, 1H), made 7.16 interest (m, 1H), 7,05-to 7.09 (m, 2H), 6,9-7,01 (m, 1H), a 3.87-of 3.91 (m, 1H), 3,44-to 3.56 (m, 4H), 3,26-3,35 (m, 4H), 2,02-of 2.23 (m, 3H), 1,74-of 1.81 (m, 1H), of 1.09 and 1.28 (m, 6H); MS: m/z 444,0 (M+H)+.

Following the procedure described above for example 11, 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:

ConnectionMC
(M+H)+
1H NMR
34444,01H NMR (300 MHz, CD3OD): δ 7,31-of 7.48 (m, 6H), to 6.88-of 7.24 (m, 6H), 3,87-3,92 (m, 1H), 3,42-3,58 (m, 4H), 3,22-of 3.32 (m, 4H), 2,19-of 2.25 (m, 1H), 2,01-of 2.08 (m, 2H), 1,73-of 1.80 (m, 1H), 1,17-1,22 (m, 3H), 1,00-1,04 (m, 3H)

Example 12

A. tert-Butyl ether 2-(S)-{[3-(4-methoxyphenoxy)-biphenyl-4-yl-amino]-methyl}-pyrrolidin-1-carboxylic acid (12b). Vessel for microwave heating, containing a mixture of compound 3d (0,070 g, 0,16 mmol), compound 6a (0.030 g, 0,24 mmol), Pd(OAc)2(0,0034 g, 0.015 mmol), compound 12a (0.016 g, 0,039 mmol) and K3PO4(0.064 g, 0.30 mmol) was evacuated and purged three times with nitrogen. Then added toluene (0.5 ml) and THF (0.3 ml) and the mixture was irradiated in a microwave reactor at 160°C for 30 minutes. The reaction mixture profilter�Lee and the concentrated filtrate was purified by preparative TLC, after receiving the connection 12b (0.050 g, yield 66%). MS: m/z 475,2 (M+H)+.

B. Compound 35: (S)-[3-(4-methoxyphenoxy)-biphenyl-4-yl]-pyrrolidin-2-yl-methylamine. A mixture of compound 12b (0.050 g, 0.11 mmol), TFA and CH2Cl2was stirred at 20°C for 1 hour. After concentration the residue was dissolved in CH3CN, purified by HPLC on reversed phase and got the connection 35 in the form of triptoreline (0,0063 g, yield 9%).1H NMR (300 MHz, CD3OD): δ 6,68-7,50 (m, 12H), 4,08-to 4.14 (m, 1H), 3,78-3,83 (m, 1H), 3,80 (s, 3H), 3,56-3,61 (m, 1H), 3,32-to 3.41 (m, 2H), 2,00-of 2.27 (m, 3H), 1,77-of 1.88 (m, 1H); MS: m/z 375,1 (M+H)+.

Example 13

A. tert-Butyl ether 2-(S)-{[2-(4-methoxyphenoxy)-4-naphthalene-2-yl-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (13b). A mixture of compound 1f (0,14 g, 0.30 mmol), compound 13a (0,077 g, 0.45 mmol), Pd2(dba)3(0.0011 g, 0,012 mmol), compound 12a (0,010 g, 0,024 mmol), K3PO4(0.13 g, of 0.60 mmol) and 0.6 ml of toluene was irradiated in a microwave reactor at 160°C for 30 minutes. The reaction mixture was filtered and the concentrated filtrate was purified by preparative TLC, receiving the connection 13b. MS: m/z 425,2 (M-Boc)+.

B. Compound 36: (S)-[2-(4-methoxyphenoxy)-4-naphthalen-2-yl-phenyl]-pyrrolidin-2-yl-methylamine. A mixture of compound 13b, TFA and CH2Cl2was stirred at 20°C for 1.5 hours. After concentration the residue was dissolved� in CH 3CN, purified by HPLC on reversed phase and got the connection 36 in the form of triptoreline (proposal is 0.0084 g, yield 3% for 2 stages).1H NMR (300 MHz, CDCl3): δ 7,78-7,81 (m, 4H), 7,32-to 7.55 (m, 4H), 7,11 (m, 1H), 6,83-of 6.99 (m, 5H), 3,84-3,95 (m, 1H), 3.7 V (s, 3H), 3,50-3,70 (m, 2H), 3,26 (m, 2H), 1,98-of 2.23 (m, 3H), 1,73-of 1.83 (m, 1H); MS: m/z 425,0 (M+H)+.

Following the procedure described above for example 13 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:

ConnectionMC
(M+H)+
1H NMR
37424,91H NMR (300 MHz, CDCl3): δ 7,75-a 7.92 (m, 3H), 7,28-7,47 (m, 4H), to 7.09-7,25 (m, 1H), 6,68-6,78 (m, 6H), 3,84-3,95 (m, 1H), 3,73 (s, 3H), 3,53-to 3.67 (m, 2H), 3,18-3,26 (m, 2H), 1,79-of 2.23 (m, 4H).
38To 375.91H NMR (300 MHz, CDCl3): δ 8,44-of 8.47 (m, 2H), 7,45-of 7.48 (m, 2H), 7,25-7,29 (m, 1H), 6.75 in-6,91 (m, 6H), 3,74-4,10 (m, 5H), 3,34-3,61 (m, 3H), 2,13-of 2.30 (m, 3H), 1,84-of 1.93 (m, 1H).
39To 375.91H NMR (300 MHz, CDCl3): δ 8,59-8,69 (m, 2H), 8,14-8,17 (m, 1H), 7,74-7,79 (m, 1H), 7,12-made 7.16 interest (m, 1H), 6,83 (s, 4H), 6,68 to 6.75 (m, 2H), 3,97 of 4.09 (m, 1H), of 3.78 (s, 3H), 3,30-3,70 (m, 4H), 2,07-of 2.28 (m, 3H), 1,841,88 (m, 1H).
40365,01H NMR (300 MHz, CDCl3): δ 6,50-7,54 (m, 10H), 4,02-4,18 (m, 1H), 3,80 (s, 3H), 3,74-with 3.79 (m, 1H), 3,26-3,58 (m, 3H), 2,02 and 2.26 (m, 3H), 1,79-of 1.84 (m, 1H).

41380,91H NMR (300 MHz, CDCl3): δ 7,17-7,30 (m, 4H), was 6.77-of 6.96 (m, 6H), 3,82-3,94 (m, 1H), of 3.77 (s, 3H), 3.43 points-3,63 (m, 2H), 3,14-3,26 (m, 2H), 1,94-of 2.19 (m, 3H), 1,70-to 1.82 (m, 1H).
42377,2
43394,2
44401,1

Example 14

A. tert-Butyl ether 2-{[2-(4-methoxyphenoxy)-4-pyridin-3-yl-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (14a). Compound 14a was obtained as described above in example 13 method, replacing the compound 13a for pyridine-3-Bronevoy acid. MS: m/z 476,3 (M+H)+.

B. Compound 45: (S)-4-{5-pyridin-3-yl-2-[(pyrrolidin-2-yl-methyl)-amino]-phenoxy}-phenol. A mixture of compound 14a (0.18 g, 0.38 mmol), 2 ml of concentrated (12 N) HCl and 2 ml of MeOH was stirred at 20°C for 3 hours. After concentration the residue was purified by preparative TLC, using ka�ETS eluent a mixture of MeOH and CH 2Cl2. The resulting product was dissolved in MeOH, filtered and concentrated, obtaining a solid substance is yellow. The resulting material was neutralized with a saturated aqueous solution of NaHCO3and was extracted with EtOAc. The organic phase is washed with water, concentrated to a small volume, filtered through a filter disc with a cell size of 0.4 μm and using acidified with 2N aqueous HCl. EtOAc was evaporated and the residue dissolved in water, filtered and liofilizirovanny. The resulting material was purified by HPLC on reversed phase. Containing compound 39 fractions were concentrated, neutralized with a saturated aqueous solution of NaHCO3and was extracted with EtOAc. The organic layer was washed with water and concentrated. The residue was dissolved in dilute aqueous HCl solution, filtered and liofilizirovanny, receiving the connection 39 in the form of hydrochloride (0,195 g). Containing compound 45 fractions were concentrated and liofilizirovanny, receiving the connection 45 in the form of triptoreline (0.013 g). MS: m/z 362,2 (M+H)+.

Example 15

A. 3-(4-Methoxyphenoxy)-4-nitrobiphenyl (15a). A mixture of compound 6b (0.22 g, 1.0 mmol), compound 1b (0.19 g, 1.5 mmol), Cs2CO3(0,98 g, 3.0 mmol) and 4 ml of DMF was stirred at 120°C for 3 hours. Then the reaction mixture was poured on ice water and collected fallen hard� the precipitate by filtration. The solid residue was dissolved in EtOAc and dried over Na2SO4. After distilling off the solvent has allocated the connection 15a in the form of a brown oil, which was used without purification (0.45 g, yield ~140%).1H NMR (300 MHz, CDCl3): δ 8,02 (m, 1H), 7,32-7,47 (m, 6H), 7,06-7,10 (m, 3H), 6,91-6,94 (m, 2H), 3,82 (s, 3H).

B. 3-(4-Methoxyphenoxy)-biphenyl-4-yl-amine (15b). A mixture of compound 15a (~1.0 mmol) and 10% palladium on carbon in MeOH was shaken in hydrogen atmosphere (234,4 kPa (34 psi) at 20°C for 3 hours. The catalyst was filtered and drove the solvent, obtaining the compound 15b in the form of a brown oil, which was used without purification (0.33 g, yield 113%). MS: m/z 292,2 (M+H)+.

C. Connection 46: 1-[3-(4-methoxyphenoxy)biphenyl-4-yl]piperazine. A mixture of compound 15b (0.16 g, 0.55 mmol), chloride bis(2-chloroethyl)ammonium (compound 15c, 0.10 g, 0.55 mmol), K2CO3(0,038 g, 0,275 mmol) and 2 ml n-butanol was heated to reflux for 42 hours. After cooling to room temperature, added saturated salt solution and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4and concentrated, obtaining the crude residue, which was purified by HPLC on reversed phase, receiving the connection 46 in the form of triptoreline.1H NMR (300 MHz, CD3OD): δ 7,47-7,50 (m, 2H), value of 7, 37-7,41 (m, 3H), 7,28-7,31 (m, 1H), 7,12-of 7.19 (m, 2H), at 6.92-6,94 (m, 4H), of 3.77 (s, 3H), 3,35-3,39 (m, 4H), 3,18-up 3.22 (m, 4H; MS: m/z 360,9 (M+H)+.

Example 16

Connection 47: 1-[3-(4-methoxyphenoxy)biphenyl-4-yl]-4-methylpiperazine. To a solution of compound 46 (0,090 g, 0.25 mmol) and 37% aqueous formaldehyde solution (0.5 ml) in 0.5 ml of acetonitrile under stirring was added cyanoborohydride sodium (0.06 g, 0.9 mmol) and 0.5 ml of acetic acid. The resulting mixture was stirred at 20°C for 3 hours and then quenched by adding saturated aqueous solution of NaHCO3. The solvent was evaporated and the aqueous residue was extracted with EtOAc. The organic layer is successively washed with 1N aqueous NaOH, 1N aqueous HCl solution and saturated brine, dried over Na2SO4and concentrated. The resulting crude residue was purified by HPLC on reversed phase, receiving the connection 47 in the form of triptoreline.1H NMR (300 MHz, CD3OD): δ made 7.16 interest-of 7.48 (m, 7H), to 7.09 (m, 1H), at 6.92 (m, 4H), of 3.77 (s, 3H), 3,68-and 3.72 (m, 2H), 3,52-3,55 (m, 2H), 3,07-3,13 (m, 4H), 2,90 (s, 3H); MS: m/z 374,9 (M+H)+.

Example 17

A. tert-Butyl ether 2-(S)-{[4-cyano-2-(4-methoxyphenoxy)-methyl}-pyrrolidin-1-carboxylic acid (17a). A mixture of compound 1f (0.13 g, 0.30 mmol), zinc cyanide (II) (0,036 mmol, 0,30 mmol) and Pd(PPh3)4(0,017 g, 0.015 mmol) in 1.2 ml of DMF was irradiated in a microwave reactor at 160°C for 6 minutes. The residue was purified by preparative TLC using C�ve eluent a mixture of EtOAc and hexanol in the ratio 1:1, and got the connection 17a (0,080 g, yield 63%). MS: m/z to 426.2 (M + H)+.

B. tert-Butyl ether 2-(S)-{[4-(N-hydroxycarbonylmethyl)-2-(4-methoxyphenoxy)-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (17b). Of hydroxylamine hydrochloride (0,023 g, 0,32 mmol), NaHCO3(0,040 g, 0.48 mmol) and 0.2 ml of water was stirred until the evolution of CO2. Then added a suspension of compound 17a (0,069 g, 0,16 mmol) in 0.5 ml EtOH. The resulting mixture was irradiated in a microwave reactor at 160°C for 16 minutes. After evaporation of the solvent, the residue was dissolved in EtOAc and purified preparative TLC, using as eluent a mixture of EtOAc and hexanol in the ratio 1:1, receiving the compound 17b (0,038 g, yield 52%). MS: m/z 459,3 (M+H)+.

C. tert-Butyl ether 2-(S)-{[2-(4-methoxyphenoxy)-4-(5-oxo-4,5-dihydro[1,2,4]oxidiazol-3-yl)-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (17c). To a solution of compound 17b (0,053 g, 0,116 mmol) and 1,1'-carbonyldiimidazole (0,021 g of 0.128 mmol) in 1 ml of CH3CN with stirring was added DBU (0,071 g, 0,069 ml, 0,464 mmol). The mixture was stirred in an atmosphere of N2within 2 days, and then purified by solid-phase extraction. After evaporation of the solvent was obtained the compound 17c. MS: m/z 483,2 (M+H)+.

D. Compound 48: (S)-3-{3-(4-methoxyphenoxy)-4-[(pyrrolidin-2-yl-methyl)-amino]-phenyl}-4H-[1,2,4]oxidiazol-5-he. A mixture of compound 17c (0,048 g, 0,099 mmol), TFA and CH2 Cl2was stirred at 20°C for 4 hours. After concentration the residue was purified by HPLC on reversed phase and got the connection 48 in the form of triptoreline (0,018 g, yield 30%).1H NMR (300 MHz, CD3OD): δ 7,39 (d, 1H), at 6.92-7,07 (m, 6H), 3,88-3,98 (m, 1H), 3,80 (s, 3H), 3,53-of 3.60 (m, 2H) 3,30-of 3.33 (m, 2H), 2,23-2,31 (m, 1H), 2,05-to 2.13 (m, 2H), 1,75-of 1.88 (m, 1H); MS: m/z 383,1 (M+H)+.

Example 18

A. tert-Butyl ether 2-(S)-({[4-bromo-2-(4-methoxyphenoxy)-phenyl]-ethylamino}-methyl)-pyrrolidin-1-carboxylic acid (18a). A mixture of compound 1d (11,8 g, 40 mmol) and compound 1e in 5 ml Or 60 ml of 1,2-dichloroethane was stirred for 1 hour at 20°C. and Then for 15 minutes parts added NaBH(OAc)3and the resulting mixture was allowed to stir at 20°C for 2 1/2 days. Then slowly added first a saturated aqueous solution of K2CO3(200 ml) and then CH2Cl2(500 ml). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2(2×200 ml). The combined organic fractions dried over MgSO4, treated with activated charcoal, filtered through celite and evaporated, receiving of 26.9 g of oil is dark brown. The residue was purified column flash chromatography (SiO2), using as eluent a gradient mixture of hexanol and EtOAc, and received compound 1f (6,93 g; yield 36%) and compound 18a (6,63 g; yield 3%). MS: m/z 505,1/507,1 (M+H)+.

B. tert-Butyl ether 2-(S)-({ethyl-[2-(4-methoxyphenoxy)-4-pyridin-3-yl-phenyl]-amino}-methyl)-pyrrolidin-1-carboxylic acid (18c). A mixture of compound 18a (0,51 g, 1 mmol), compound 18b (0,307 g, 2.5 mmol), Pd(dppf)Cl2(0,183 g, 0.25 mmol), Cs2CO3(0,977 g, 3.0 mmol), 0.5 ml of EtOH and 2.5 ml of dioxane was irradiated in a microwave reactor at 140°C for 15 minutes. The reaction mixture was filtered and the solid residue was washed with 100 ml of EtOAc. The filtrate was washed with 30 ml of a saturated aqueous solution of K2CO3, dried over Na2SO4and activated charcoal and concentrated, obtaining 0.36 g of a crude residue containing compound 18c.

C. Compound 49: (S)-ethyl-[2-(4-methoxyphenoxy)-4-pyridin-3-yl-phenyl]-pyrrolidin-2-yl-methylamine. To a solution of the residue obtained in stage B above, in 10 ml of CH2Cl2dropwise added triptorelin (5 ml). The mixture was stirred for 4 h at 20°C and then boiled away. The residue was dissolved in 100 ml of CH2Cl2and was washed with 20 ml of 1N aqueous NaOH solution. The organic layer was dried over Na2SO4and concentrated. The residue was purified by HPLC on reversed phase. Containing the desired product fractions were concentrated, dissolved in 100 ml of CH2Cl2and washed with 10 ml of 1N aqueous NaOH solution. The organic layer was dried over Na2SO4, concentrated, re - �actuarily in CH 2Cl2, treated with 6 ml of 1N HCl solution in Et2O and evaporated, receiving the solid is light yellow in color, the connection 49, as hydrochloride (0,130 g, yield 27% for 2 stages).1H NMR (300 MHz, DMSO-d6): A 9.64 (1H, s, W), 9,20 (1H, d), 8,93, 1H, Shir.), Is 8.84 (1H, d), 8,78 (1H, d), 8,07 (1H, DD), 7, 71 (1H, d), of 7.46 (1H, d), of 7.42 (1H, d), 7,00 (4H, m), with 3.79 (3H, s), 3,7-3,1 (7H, m), 2,0-of 1.75 (3H, m), of 1.55 (1H, m), of 1.02 (3H, t); MS: m/z 404,2 (M+H)+.

Following the procedure described above for example 18 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:

ConnectionMC
(M+H)+
50422,2
51405,1
52429,1

Example 19

A. 2,4-Bis-(4-methoxyphenoxy)-nitrobenzene (19b). A solution of 2,4-deformirovannoe (compound 19a, 0.5 g, 3.1 mmol) in 15 ml of acetone was added to a mixture of compound 1b (0.86 g, 6.9 mmol) and 6.9 ml of 1N aqueous solution of NaOH in 5 ml of acetone. The mixture was held at 55°C for 3 days and then at 80°C for 5 hours. The reaction mixture of concentrated light�whether to remove acetone and the residue placed on a column for solid phase extraction of 10 ml. As a result of concentration of eluent, which used CH2Cl2and received 1.5 g of a mixture of compounds 19c and compound 19b in the ratio 1:4, which was used without purification. MS: m/z 368 (M+H)+.

B. 2,4-Bis-(4-methoxyphenoxy)-aniline (19d). Containing compound 19c and compound 19b mixture obtained in stage A, was mixed with 50 mg of 10% Pd-C in 50 ml EtOH/EtOAc and stirred at 20°C in hydrogen atmosphere (101,4 kPa (14,7 psi) for 17 hours. The mixture was filtered through celite and concentrated. The residue was dissolved in MeOH, filtered through a filter disc with a cell size of 0.4 µm and concentrated, obtaining the compound 19d. MS: m/z 338,1 (M+H)+.

C. tert-Butyl ether (S)-2-{[2,4-bis(4-methoxyphenoxy)-phenylamino]-methyl}-pyrrolidin-1-carboxylic acid (19e). A mixture of compound 19d (0,051 g, 0.15 mmol), compound 1e (0.033 g, 0,31 ml, 0.17 mmol), Or (0,017 ml, 0.3 mmol) and 0.4 ml of DCE was stirred at 20°C for 2.5 hours. Then added NaBH(OAc)3(0,089 g, 0,42 mmol) and the mixture was stirred at 20°C for 20 hours. The reaction mixture was purified on a column for solid phase extraction of 1 ml, using as eluent CH2Cl2and got the connection 19e.

D. Compound 53: (S)-[2,4-bis(4-methoxyphenoxy)-phenyl]-pyrrolidin-2-yl-methylamine. Compound 19e was dissolved in a mixture of 50% TFA/CH2Cl2and shuffle�Wali at 20°C for 45 minutes. After concentration the residue was purified by HPLC on reversed phase and got the connection 53 in the form of triptoreline (0,082 g, yield 84%). MS: m/z UAH 421,2 (M+H)+.

Following the procedure described above for example 19, 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)+
54421,1
55411,1
56421,1
57447,0
60447,2
61435,2
62435,2

Example 20

A. tert-Butyl ether {2-[2,4-bis(4-methoxyphenoxy)-phenylamino]-ethyl}-methylcarbamate acid (20b) and tert-butyl ether (2-{[2,4-bis(4-methoxyphenoxy)-phenyl]-[2-(tert-butoxycarbonylmethylene)-ethyl]-amino}-ethyl)-methylcarbamyl acid (20c). Or (0,034 ml, 0,59 mmol) and NaBH(OAc)3(0.175 g, 0.83 mmol) was added to R�the target compound 19d (is 0.102 g, 0,30 mmol) and compound 20a (0,112 g, 0,32 ml, 0.17 mmol) in DCE and the mixture was stirred at 20°C for 18 hours. Then added water (0.2 ml) and the reaction mixture was purified using a column for solid-phase extraction with 3 ml when using as eluent CH2Cl2receiving a mixture of compounds 20b and the connection 20c.

B. Compound 63: N-[2,4-bis(4-methoxyphenoxy)-phenyl]-N'-mutilate-1,2-diamine; compound 64: N-[2,4-bis(4-methoxyphenoxy)-phenyl]-N'-methyl-N-(2-methylaminomethyl)-ethane-1,2-diamine.

A mixture of compound 20b and the connection 20c, obtained in stage A, was dissolved in a mixture of TFA/CH2Cl2and stirred at 20°C. After concentration the residue was purified by HPLC on reversed phase and received compound 63 (0,139 g, yield 62%) and compound 64 (0.013 g, yield of 5.6%) in the form of triptoreline each. Compound 63: MS: m/z 395,2 (M+H)+. Compound 64: MS: m/z 452,3 (M+H)+.

Following the procedure described above for example 20 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)+
58407,1
59476,3

Using the methods described above, were synthesized in the table below compound 1-64 of formula (I).

4-methoxyphenyltd align="justify"> 2-[3-(N,N-diethyl
aminocarbonyl)
phenyl]
Table 1
Compound No.R1YR2R3RaR3-N-RaR3
stereo chemistry
12-(N,N-diethyl
aminocarbonyl)
(E)-vinyl-4-methoxyphenylpyrrolidin-2-yl-methylH2S
22-(N,N-diethyl
aminocarbonyl)
ethyl4-methoxyphenylpyrrolidin-2-yl-methylH2S
32-(4-methoxyphenyl)ethylpyrrolidin-2-yl-methylH2S
42-(3-methoxyphenyl)ethyl4-methoxyphenylpyrrolidin-2-yl-methylH2S
52-phenylethyl4-methoxyphenylpyrrolidin-2-yl-methylH2S
62-(4-fluorophenyl)ethyl4-methoxyphenylpyrrolidin-2-yl-methylH2S
72-(3-fluorophenyl)ethyl4-methoxyphenylpyrrolidin-2-yl-methylH2S
8ethyl4-methoxyphenylpyrrolidin-2-yl-methylH2S

9N,N-diethyl
aminocarbonyl
connectionphenylpyrrolidin-2-yl-methylH2S
10N,N-diethyl
aminocarbonyl
connection4-methoxyphenylpyrrolidin-2-yl-methylH2S
11N,N-diethyl
aminocarbonyl
connection2-methoxyphenylpyrrolidin-2-yl-methylH2S
12phenylconnection4-�anafanil pyrrolidin-2-yl-methylH2S
13phenylconnection3-cyanophenylpyrrolidin-2-yl-methylH2S
14phenylconnectionphenylpyrrolidin-2-yl-methylH2S
15phenylconnection3-methoxyphenylpyrrolidin-2-yl-methylH2S
16phenylconnection4-fluorophenylpyrrolidin-2-yl-methylH2S
17phenyl connection4 trifter
methoxyphenyl
pyrrolidin-2-yl-methylH2S
18phenylconnection2,6-dichlorophenylpyrrolidin-2-yl-methylH2S
19phenylconnection4-methoxyphenyl2-(N-methylamino)ethylH

20phenylconnection4-methoxy
carbonitril
pyrrolidin-2-yl-methylH2S
21phenylconnection3-methoxy
carbonitril
pyrrolidin-2-yl-methyl2S
22phenylconnection2,4-dichlorophenylpyrrolidin-2-yl-methylH2S
23phenylconnection4-methoxyphenylthe piperidine-4-ylH
245-cyanopyridine-3-ylconnection4-methoxyphenyl4-ftorpirimidinu-2-yl-methylH2S,4R
255-herperidin-3-ylconnection4-methoxyphenyl4-ftorpirimidinu-2-yl-methylH2S,4R
265-methylthiopyridine-3-ylthe connection 4-methoxyphenyl4-ftorpirimidinu-2-yl-methylH2S,4R
275-methoxypyridine-3-ylconnection4-methoxyphenyl4-ftorpirimidinu-2-yl-methylH2S,4R
285-methylpyridine-3-ylconnection4-methoxyphenyl4-ftorpirimidinu-2-yl-methylH2S,4R

29phenylconnection4-amino
carbonitril
pyrrolidin-2-yl-methylH2S
30phenylconnection3-amino
carbonitril
pyrrolidin-2-yl-me�Il H2S
31phenylconnection4-carboxyphenylpyrrolidin-2-yl-methylH2S
32phenylconnection3-carboxyphenylpyrrolidin-2-yl-methylH2S
33phenylconnection4-(N,N-diethylaminoethyl)phenylpyrrolidin-2-yl-methylH2S
34phenylconnection3-(N,N-diethylaminoethyl)phenylpyrrolidin-2-yl-methylH2S
35phenyl connection4-methoxyphenylpyrrolidin-2-yl-methylH2S
36naphthalen-2-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylH2S
37naphthalen-1-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylH2S
38pyridin-4-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylH2S

39pyridin-3-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylH2S
40furan-3-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylH2S
41the thiophene-3-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylH2S
42pyrimidine-5-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylH2S
435-herperidin-3-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylH2S
445-cyanopyridine-3-ylconnection4-meth�xifer pyrrolidin-2-yl-methylH2S
45pyridin-3-ylconnection4-hydroxyphenylpyrrolidin-2-yl-methylH2S
46phenylconnection4-methoxyphenylPiperazine-1-Il
47phenylconnection4-methoxyphenyl4-methyl-piperazine-1-Il

td align="justify"> pyrrolidin-2-yl-methyl
485-oxo-4,5-dihydro-[1,2,4]ox
diazol-3-yl
connection4-methoxyphenylpyrrolidin-2-yl-methylH 2S
49pyridin-3-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylethyl2S
505-herperidin-3-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylethyl2S
51pyrimidine-5-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylethyl2S
525-cyanopyridine-3-ylconnection4-methoxyphenylpyrrolidin-2-yl-methylethyl2S
534-methoxyphenylO4-methoxyphenylH2S
544-methoxyphenylO4-methoxyphenylthe piperidine-3-ylHracemizes-Kai mix
554-methoxyphenylO4-methoxyphenyl3-hydroxy-2(R)-aminopropylH2R
564-methoxyphenylO4-methoxyphenylthe piperidine-4-ylH

574-methoxyphenylO4-methoxyphenyl8-azabicyclo[3.2.1]Octan-3-ylHa mixture of endo/Exo from�'erov
584-methoxyphenylO4-methoxyphenylazetidin-3-yl-methylH
594-methoxyphenylO4-methoxyphenylazetidin-3-yl-methylazetidin-3-yl-methyl
604-methoxyphenylO4-methoxyphenyl1-azabicyclo[2.2.2]Octan-3-ylHa mixture of endo/Exo isomers
614-methoxyphenylO4-methoxyphenylthe piperidine-3-yl
methyl
Hracemic mixture
624-methoxyphenylO 4-methoxyphenyl3-aminocyclohexylHa mixture of 4 isomers
634-methoxyphenylO4-methoxyphenyl2-(N-methylamino)
ethyl
H

644-methoxyphenylO4-methoxyphenyl2-(N-methylamino)ethyl2-(N-methyl-amino)
ethyl

Biological examples

In vitro studies

Example 1

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

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 contents of each vial homogenized 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 cell Harvester. 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 the value of Ki(when tested concentration range). As a negative control was used for nonspecific binding (researcher - 1 mm naloxone) as a positive control was used the total binding (S. S. - only membrane � 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 nonlinear regression 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. Values of Kiwere obtained by averaging the results of three determinations.

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 junction of the midbrain to the bridge. On�Le opening forebrain homogenized in a Tris-buffer solution in Teflon ®-glass homogenizer. The homogenate was diluted to a concentration of 1 g of forebrain tissue in 80 ml of Tris-buffer solution and centrifuged at a speed of 39,000×g for 10 minutes. The pellet was re-dissolved in the same volume of Tris-buffer solution containing 5 mm MgCl2with a few short pulses of a 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 of [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 the effect for only one concentration tested is connected�I) or the value of K i(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 Teflon®-glass homogenizer. The homogenate was diluted to a concentration of 1 g of forebrain tissue in 80 ml of Tris-buffer solution and centrifuged at a speed of 39,000 x g for 10 minutes. The pellet was re-dissolved in the same volume of Tris-buffer solution containing 5 mm MgCl2with a few short�x pulses of a Polytron homogenizer. The resulting preparation was 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 the value of Ki(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 disintegrations per minute for the total binding is the number of disintegrations / minute for nonspecific binding)]*100. The values of Kd and Ki rasschityvala 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
The joint modification No.δ-binding on the cell membrane of NG108 Ki(μm)δ-binding (ligand DPDPE) Ki(μm)δ-binding (ligand naltrindole) Ki(μm)mu-binding (Ki(μm)
10,0060813,3659
20,02641>100
30,1197>10
40,21>10
50,2395>10
6 0,6836>10
70,2288>10
80,12699,00119
91,023>10
100,93560,9356
110,1053>10
120,9959>10
130,4018>10
140,1131150,2886>10
160,4191>10
171,472>10
180,1075>10
190,192>10
200,7789>10
210,8869>10
220,6978>10
23 0,4615>10
271,001>10
280,0068144,673
290,1467>10
300,12655,7956
317,691>10
322,667>10
330,28439,30465

340,3095>10
350,02885>10
360,2905>10
370,3009>10
380,01554,3621
390,0016460,022133,1067
400,2051>10
410,2896>10
420,001388
430,00076
440,000436
450,005424,4555
460,07971>10
472,223>10
480,4929,705
490,02897
500,02303
510,077
520,009328
530,1053>10
540,4929,705
551,367>10
561,729>10
571,43>10
580,7027>10
592,275>10
600,1577>10
61>10
620,040881,6417
630,02374>10
641,536>10

Example 4

Analysis of binding of [35S]GTPγS on 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 7.6, 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 18,000 rpm in the Techa�their 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 of [35S] GTPγS in the same Tris buffer containing 100 μm GDP in total volume of 200 μl. To stimulate the 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)/(maximum 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: to�elochnye membrane CHO-hMOR acquired the company in Receptor Biology, Inc. (Baltimore, Maryland). Membrane protein was 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 membranes was added to 15 ml of cold buffer solution to do this test, which contained 50 mm HEPES, pH 7.6, 5 mm MgCl2, 100 mm NaCl, 1 mm DTT and 1 mm EDTA. A suspension of membranes homogenized in the Polytron homogenizer and centrifuged at the 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 using a Polytron homogenizer. Membranes were 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) particles of the SPA (5 mg/ml) were incubated with 0.5 nm [35S]GTPγS in a buffer solution for the test. Basic binding, which was carried out in the absence of added test compounds was taken as 100%, while agonist-stimulated binding was reached levels significantly higher than this number. To stimulate the binding of [35S]GTPγS used a range of concentrations�tions agonists of the receptor. Both basic and non-specific binding was tested in the absence of agonist, to determine the level of nonspecific binding used 10 μm unlabeled GTPγS.

Compounds were tested for the activity as antagonists by assessing their potential inhibition of agonist-stimulated GTPγS binding. Radioactivity is quantitatively determined on the counter Packard Top Count. Expected the following options:

The values of EC50counted in the program GraphPad Prism and are shown in table 3 below.

Table 3
Functional characteristics of Delta-opioid receptors
The joint modification No.GTPS
δ is the relative efficiency at 200 nm
GTPS
δ-opioid receptor, EC50(μm)
GTPS
δ-opioid receptor, Rel. efficiency
GTPS
δ-opioid receptor, % inhib. when 10 µm
10,10930,83282,2554
2 0,8333Of 22.78
110,3194
181,04280,76323,395
241,010,04611,0158
250,780,09241,0217
260,70,18731,0716
280,16510,8756
301,02450,266836,491
351,46121
380,47820,832316,36
390,11140,924513,425
420,39
430,430,2181,0908
440,450,11761,1554

450,04080,62735,642
530,319428,165
614,072916,134
620,3811 1,733
633,106725,97

The study in vivo

Example 6

Differential test for abdominal irritant in mice (GrAIT)

Test the connection, or a carrier medium injected into mice subcutaneously or orally. After pre-treatment were injected intraperitoneally with 0.5 ml of 0.6% acetic acid. Five minutes after injection of acetic acid, mice were placed in a transparent chamber and continuously watched him for 5 minutes. During the observation period were counted and averaged by group of animals behavioral responses, including the twisting and stretching of the body, passing to the rear legs. The results are shown in table 4 below.

Table 4
The light kitDose (mg/ kg)The carrier mediumMethod of administrationIn the stomach-tionsPreliminary treatment (min)In the abdominal potage current (carrier medium)In the abdominal potage-vany (Conn)
13010% solutolsubcutaneously53014,110,9

103010% solutolsubcutaneously103016,711
103010% solutolpen-Central53019,819
1010010% solutolpen-Central103019,817,9
1030010% solutolpen-Central53019,8 Of 21.2

1. The compound of the formula I

where
R1selected from the group consisting of
(i) phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, di(C1-4alkyl)aminocarbonyl, chlorine and fluorine; thus, there should be only one di(C1-4alkyl)aminocarbonyl;
(ii) naftel;
(iii) pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluorine, chlorine or cyano;
(iv) pyrimidine-5-silt;
v) furanyl;
(vi) tanila;
vii) 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; and
(viii) di(C1-2alkyl)aminocarbonyl;
provided that, when R1represents a 5-oxo-4,5-dihydro-[1,2,4]oxidiazol-3-yl, Υ is a link;
Υ represents ethyl, vinyl or a bond;
or Υ is O when R1represents optionally substituted phenyl, where the Deputy represents C1-4alkoxy;
R2represents phenyl, optionally substituted by one or two substituents, independently selected from the group,
consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine, cyano, triptoreline and hydroxy;
or R2/sub> represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alkoxycarbonyl or carboxylesterases;
R3selected from the group consisting of
i) 3-aminocyclohexyl;
ii) 4-aminocyclohexyl;
(iii) piperidine-3-yl;
(iv) piperidine-4-silt;
(v) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted at the 3-th or 4-th position one or two fortuntately;
(vi) azetidin-3-yl-methyl;
vii) 2-(N-methylamino)ethyl;
(viii) 3-hydroxy-2-aminopropyl;
(ix) piperidine-3-yl-methyl;
x) 1-azabicyclo[2.2.2]Octan-3-yl; and
(xi) 8-azabicyclo[3.2.1]Octan-3-yl;
or R3together with Raand the nitrogen atom to which they are both attached to form piperazinyl optionally substituted with 4-C1-4by alkyl;
Rarepresents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted of azetidin-3-yl;
as well as its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein R1selected from the group consisting of
(i) phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, di(C1-4alkyl)aminocarbonyl and fluorine; thus, there should be only one di(C1-4alkyl)aminocarbonyl;
(ii) naftel;
(iii) pyridinyl needed�optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano;
(iv) pyrimidine-5-silt;
v) furanyl;
(vi) tanila; and
(vii) di(C1-2alkyl)aminocarbonyl.

3. The compound according to claim 2, in which R1selected from the group consisting of
(i) phenyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkoxy, di(C1-4alkyl)aminocarbonyl and fluorine;
(ii) pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano; and
(iii) pyrimidine-5-silt; and
(iv) di(C1-2alkyl)aminocarbonyl.

4. The compound according to claim 3, in which R1selected from the group consisting of
(i) phenyl, optionally substituted with one methoxyaniline;
(ii) pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano; and
(iii) pyrimidine-5-silt; and
(iv) di(C1-2alkyl)aminocarbonyl.

5. The compound according to claim 1, wherein Υ represents vinyl or a bond; or Υ is O when R1represents optionally substituted phenyl.

6. The compound according to claim 5, in which Υ is a vinyl or link.

7. The compound according to claim 1, wherein R2PR�dstanley a phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine and hydroxy;
or R2represents phenyl, substituted one aminocarbonyl or di(C1-4alkyl)aminocarbonyl Deputy.

8. The connection according to claim 7, in which R2represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy and hydroxy;
or R2represents phenyl, substituted one aminocarbonyl or di(C1-4alkyl)aminocarbonyl Deputy.

9. The compound according to claim 8, in which R2represents phenyl, optionally substituted by one Deputy, independently selected from the group consisting of methoxy, hydroxy, aminocarbonyl and di(C1-4alkyl)carbylamine.

10. The compound according to claim 1, wherein R3selected from the group consisting of
i) 3-aminocyclohexyl;
ii) 4-aminocyclohexyl;
(iii) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted at the 3-th or 4-th position one or two fortuntately;
iv) 2-(N-methylamino)ethyl;
v) piperidine-3-yl-methyl; and
vi) 1-azabicyclo[2.2.2]Octan-3-yl;
or R3together with Raand the nitrogen atom to which they are both attached, forms a �piperazinyl.

11. The compound according to claim 10, wherein R3selected from the group consisting of
i) 3-aminocyclohexyl;
ii) 4-aminocyclohexyl; and
(iii) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted at the 3 rd or 4 th position with one fortuntately;
or R3together with Raand the nitrogen atom to which they are both attached, form a piperazinyl.

12. The compound according to claim 1, wherein Rarepresents hydrogen or C1-2alkyl.

13. The compound according to claim 12, in which Rarepresents hydrogen.

14. The compound of formula (I)

where
R1selected from the group consisting of
(i) phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkoxy, di(C1-4alkyl)aminocarbonyl and fluorine; thus, there should be only one di(C1-4alkyl)aminocarbonyl;
(ii) naftel;
(iii) pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano;
(iv) pyrimidine-5-silt;
v) furanyl;
(vi) tanila; and
(vii) di(C1-2alkyl)aminocarbonyl;
Υ represents vinyl or a bond; or Υ is O when R1represents optionally substituted phenyl, where the Deputy Chairman�ulation With a 1-4alkoxy;
R2represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine and hydroxy;
or R2represents phenyl, substituted one aminocarbonyl or di(C1-4alkyl)aminocarbonyl Deputy;
R3selected from the group consisting of
i) 3-aminocyclohexyl;
ii) 4-aminocyclohexyl;
(iii) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted at the 3-th or 4-th position one or two fortuntately; 2-(N-methylamino)ethyl; piperidine-3-yl-methyl; and
iv) 1-azabicyclo[2.2.2]Octan-3-yl;
or R3together with Raand the nitrogen atom to which they are both attached to form piperazinyl;
Rarepresents hydrogen or C1-2alkyl;
as well as its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

15. The compound of formula (I)

where
R1selected from the group consisting of
(i) phenyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkoxy, di(C1-4alkyl)aminocarbonyl and fluorine;
(ii) pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, ft�RA and cyano;
(iii) pyrimidine-5-silt; and
(iv) di(C1-2alkyl)aminocarbonyl;
Υ represents vinyl or a bond;
R2represents phenyl, optionally substituted by one or two substituents, independently selected from the group consisting of C1-4alkyl, C1-4alkoxy and hydroxy;
or R2represents phenyl, substituted one aminocarbonyl or di(C1-4alkyl)aminocarbonyl Deputy;
R3selected from the group consisting of
i) 3-aminocyclohexyl;
ii) 4-aminocyclohexyl;
(iii) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted on carbon atom by one or two fortuntately;
iv) 2-(N-methylamino)ethyl;
v) piperidine-3-yl-methyl; and
vi) 1-azabicyclo[2.2.2]Octan-3-yl;
or R3together with Raand the nitrogen atom to which they are both attached to form piperazinyl;
Rarepresents hydrogen;
as well as its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

16. The compound of formula (I)

where
R1selected from the group consisting of
(i) phenyl, optionally substituted with one methoxyaniline;
(ii) pyridinyl, optionally substituted by one Deputy, selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine and cyano,
(iii) pyrimidine-ILA; and
(iv) di(C1-2alkyl)aminocarbonyl;
Υ represents vinyl or a bond;
R2represents phenyl, optionally substituted by one Deputy, independently selected from the group consisting of methoxy, hydroxy, aminocarbonyl and di(C1-4alkyl)carbylamine;
R3selected from the group consisting of
i) 3-aminocyclohexyl;
ii) 4-aminocyclohexyl;
(iii) pyrrolidin-2-yl-methyl, in which pyrrolidin-2-yl optionally substituted on the 3rd or 4th position one fortuntately; and
or R3together with Raand the nitrogen atom to which they are both attached to form piperazinyl; Rarepresents hydrogen;
as well as its enantiomers, diastereoisomers and pharmaceutically acceptable salts.

17. The compound of formula (I)

selected from the group consisting of:
compounds in which R1represents a 2-(Ν,Ν-diethylaminoethyl), Υ represents (E)-vinyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents a 2-(Ν,Ν-diethylaminoethyl), Υ represents ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
connection, to�Thor R 1represents a 2-(4-methoxyphenyl), Υ represents ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents a 2-(3-methoxyphenyl), Υ represents ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents a 2-phenyl, Υ represents ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents a 2-(4-fluorophenyl), Υ represents ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents a 2-(3-fluorophenyl), Υ represents ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents a 2-[3-(N,N-diethylaminoethyl]phenyl), Υ represents ethyl, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rabefore�provide a N; (2S);
compounds in which R1is a Ν,Ν-diethylaminoethyl, Υ represents a bond, R2represents phenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1is a Ν,Ν-diethylaminoethyl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1is a Ν,Ν-diethylaminoethyl, Υ represents a bond, R2is a 2-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 4-cyanophenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 3-cyanophenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2represents phenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents N; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 3-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2represents 4-fluorophenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 4-trifloromethyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2represents a 2,6-dichlorophenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 4-methoxyphenyl, R3represents a 2-(N-methylamino)ethyl, and Rarepresents N;
compounds in which R1represents phenyl, Υ represents a bond, R2is a 4-ethoxycarbonylphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S)
compounds in which R1represents phenyl, Υ represents a bond, R2is a 3-ethoxycarbonylphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2represents 2,4-dichlorophenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is a piperidine-4-yl, and Rarepresents N;
compounds in which R1is 5-cyanopyridine-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is a 4-ftorpirimidinu-2-yl-methyl, and Rarepresents H; (2S,4R);
compounds in which R1represents a 5-herperidin-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is a 4-ftorpirimidinu-2-yl-methyl, and Rarepresents H; (2S,4R);
compounds in which R2represents a 5-methylthiopyridine-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is a 4-ftorpirimidinu-yl-methyl, and Rarepresents H; (2S,4R);
compounds in which R1represents a 5-methoxypyridine-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is a 4-ftorpirimidinu-2-yl-methyl, and Rarepresents H; (2S,4R);
compounds in which R1represents a 5-methylpyridine-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is a 4-ftorpirimidinu-2-yl-methyl, and Rarepresents H; (2S,4R);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 4-aminocarbonylmethyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 3-aminocarbonylmethyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 4-carboxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 3-carboxyphenyl, R 3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2represents a 4-(N,N-diethylaminomethyl)phenyl,R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2represents a 3-(N,N-diethylaminomethyl)phenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1is naphthalen-2-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1is naphthalen-1-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents pyridin-4-yl, Υ represents a bond, R2 is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents pyridin-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents furan-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1is a thiophene-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents pyrimidine-5-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents a 5-herperidin-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1is 5-cyanopyridine-3-yl Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents pyridin-3-yl, Υ represents a bond, R2is a 4-hydroxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents phenyl, Υ represents a bond, R2is a 4-methoxyphenyl, R3together with Raand the nitrogen atom to which they are both attached, form a piperazine-1-yl;
compounds in which R1represents phenyl, Υ
represents a bond, R2is a 4-methoxyphenyl, R3together with Raand the nitrogen atom to which they are both attached, form a 4-methylpiperazin-1-yl;
compounds in which R1represents a 5-oxo-4,5-dihydro[1,2,4]oxidiazol-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1represents pyridin-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents ethyl; (2S);
connection, to�Thor R 1represents a 5-herperidin-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents ethyl; (2S);
compounds in which R1represents pyrimidine-5-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents ethyl; (2S);
compounds in which R1is 5-cyanopyridine-3-yl, Υ represents a bond, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents ethyl; (2S);
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3is pyrrolidin-2-yl-methyl, and Rarepresents H; (2S);
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3is a piperidine-3-yl, and Rarepresents H; racemic mixture;
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3represents a 3-hydroxy-2(R)-aminopropyl, and Ra represents N;
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3is a piperidine-4-yl, and Rarepresents N;
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3is a 8-azabicyclo[3.2.1]Octan-3-yl, and Rarepresents H; mixture of endo/actisorb;
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3is azetidin-3-yl-methyl, and Rarepresents N;
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3is azetidin-3-yl-methyl, and Rais azetidin-3-yl-methyl;
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3represents 1-azabicyclo[2.2.2]Octan-3-yl, and Rarepresents H; mixture of endo/actisorb;
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, 3is a piperidine-3-yl-methyl, and Rarepresents H; racemic mixture;
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3is a 3-aminocyclohexyl, and Rarepresents H; a mixture of 4 isomers;
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3represents a 2-(N-methylamino)ethyl, and Rarepresents N; and
compounds in which R1is a 4-methoxyphenyl, Υ represents Oh, R2is a 4-methoxyphenyl, R3represents a 2-(N-methylamino)ethyl, and Rarepresents a 2-(N-methylamino)ethyl; and
and its pharmaceutically acceptable salts.

18. 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. 1-17, and at least one substance from a pharmaceutically acceptable carrier, pharmaceutically acceptable excipients and pharmaceutically acceptable diluent.

19. Pharmaceutical composition according to claim 18 in which the composition is a solid dosage form for pearling� introduction.

20. Pharmaceutical composition according to claim 18 in which the composition is a syrup, elixir or suspension.

21. A method of treating pain by introducing a therapeutically effective amount of a compound of formula (I) having the ability of binding to Delta opioid receptors.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 11-(piperazin-1-yl) dibenzo[b,f[1,4]oxazapine compounds of general formula specified below wherein the radicals are presented in the description, to their pharmaceutically acceptable salts and pharmaceutical compositions. There are also described methods for preparing said compounds.

EFFECT: compounds may be used for treating disorders, such as schizophrenia, resistant schizophrenia, bipolar disorder, psychotic depression, resistant depression, depressive conditions related to schizophrenia, treating resistant OCD, autism, senile dementia, psychotic dementia, L-DOPA-induced psychotic disorder, psychogenic polydipsia, psychotic symptoms of neurological disorders, sleeping disorders.

39 cl, 25 ex, 8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) wherein R4 represents a group of formula (II) and R1, R2, R3, R5 and X are those as specified in the patent claim.

EFFECT: preparing the pharmaceutical composition applicable in treating chronic obstructive pulmonary disease and containing the compound of formula (I).

8 cl, 3 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: pharmacology.

SUBSTANCE: invention refers to the compound of formula(I) or to is salt where R1 is -H or C1-6 alkyl; R2 is bridged aza-ring chosen out of group including formula and where ring hydrogen atom in bridged aza-ring may be substituted by one or several groups of R22; m, n and p have respective values 1 or 2; r has the value 0 or 1; R21 is C1-6 alkyl, -C1-6 alkyl-O-phenyl or -C1-6 alkyl-phenyl; R22 is C1-6 alkyl-cycloalkyl or -C1-6 alkyl-phenyl; R2 is thienyl, phenyl, pyridyl, pyranzinyl, thiazolyl or pyrazolyl, each of which can be substituted by one or several R31; R31 is the halogen, -OH, -CN, -CF3, C1-6 alkyl or -O-C1-6 alkyl; ring A is the group consisting of thiophene, thiazole, isothiazole, thidiazole, oxazole, isooxazole, cyclohexan, norboran, benzothiophene and 5,6-dihydro-4H-cyclopentathiophene, each of which can be substituted by the group chosen out of the group consisting out of one or several RA1; where RA1 is a halogen, -CN, -NH2, C1-6 alkyl, -O-C1-6 alkyl, CONH2, - HN-C1-6 alkyl, -HN-C1-6 alkyl-O-C1-6 alkyl-phenyl, -HN-C1-6 alkyl-phenyl or -HN-C1-6 alkyl-OH where C1-6 alkyl can be substituted with one or several halogen atoms; V is -NH- or -O-; W is -(CH2)q-; q has the value 0.1 or 2; X is the counteranion and is an ordinary bond; on condition when in case ring A is cyclohexane, R3 is phenyl which can be replaced with one or several R31. The invention also refers to pharmaceutical composition that has antagonistic effect on muscarine receptor M3, on the basis of said compound.

EFFECT: production of new compound and pharmaceutical composition on its basis, which can be applied in the medicine as an active substance for preventive and/or therapeutic drug for treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like.

14 cl, 60 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 1-azabicyclo[2.2.2]oct-3(R)yl ether of 2-hydroxy-2,2-dithien-2-ylacetic acid and 3-phenoxypropyl bromide, where the reaction takes place in a solvent or mixtures of solvents, having boiling point ranging from 50 to 210°C and selected from a group comprising ketones and cyclic ethers, preferably in acetone, dioxane and tetrahydrofuran.

EFFECT: efficient method of obtaining the compounds.

12 cl, 8 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted quinoxaline-type piperidine compounds of formula or to a pharmaceutically acceptable derivative thereof, wherein: Y1 represents O; Q is specified in condensed benzo or pyridino; each R2 is independently specified in: (a) -halogen or -CN; (b) -(C1-C6)alkyl; a is an integer specified in 0, 1 or 2; a dash line in a 6-member ring containing a nitrogen atom which is condensed with Q group means the presence or absence of a bond, and when the dash line means the absence of the bond, then R3, and one R4 are absent; R3 is specified in: (a) -H; each R4 is independently specified in: (a) -H; or (b) - halogen or CN; or (c) -X, -(C1-C6)alkyl-X, -(5- or 6-member)heterocyclyl-X or -(5- or 6-member)heterocyclyl-(C1-C6)alkyl-X; or (d) -C(=Y)X, -C(=Y)T3, -C(=Y)YX, - C(=Y)YT3, -C(-Y)N(T1)(T2), -C(=Y)N(R9)CN, -C(=Y)N(R9)X, -C(=Y)N(R9)YH, -C(=Y)N(R9)YX, -C(=Y)N(R9)YCH2X, -C(-Y)N(R9)YCH2CH2X or -C(=Y)N(R9)S(K))2T3; or (e) -N(R9)X, -N(R9)-CH2X, -N(R9)-CH2CH2X, -N(R9)CH2N(R9)C(=N(R12))N(R12)2, -N(R9)-CH2CH2N(R9)C(=N(RI2))N(R12)2, -N(T1)(T2), -N(T3)C(=Y)T3, -N(T3)C(=Y)YT3, -N(T3)C(=Y)N(T1)(T2), -N(T3)S(=O)2T3 or -N(T3)S(=O)2N(T1)(T2); X represents: (a) -H, -( C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkoxy, -(C3-C7)cycloalkyl, -(5- or 6-member)heterocycle or -(7-10-member)bicycloheterocycle each of which is unsubstituted or substituted with 1, 2 or 3 of optionally substituted R8 groups; or (b) -phenyl, -naphthalenyl, or -(5- or 6-member)heteroaryl each of which is unsubstituted or substituted with 1 or 2 of independently specified in R7 groups; each Y is independently specified in O; A and B are independently specified in: (a) -H; or (c) A-B together can form a (C2-C6)bridge each can optionally contain -HC=CH- or -O- in a (C2-C6)bridge; wherein the 6-member ring containing a nitrogen atom which is condensed with Q group can be found in the endo- or exo- configuration in relation to the A-B bridge; or (d) A-B together can form the -CH2-N(Ra)-CH2- bridge wherein the 6-member ring containing a nitrogen atom is condensed with Q group, and can be found in the endo- or exo- configuration in relation to the A-B bridge; Ra is specified in -H or -(C1-C6)alkyl; Z represents -[(C1-C10)alkyl optionally substituted with R1]h-, wherein h is equal to 0 or 1; each R1 is independently specified in: (b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl3 -(C3-C7)cycloalkoxy, -(C6-C14)bicycloalkyl, -(C8-C10)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C7-C14)bicycloalkenyl, -(3-7-member)heterocyclyl each of which is unsubtituted or substituted with 1, 2 or 3 of independently specified in R8 groups;

or or (d) -phenyl, -naphthalenyl each of which is unsubstituted or substituted with R7 group; each R6 is optionally specified in -H; each R7 is independently specified in -(C1-C4)alkyl, -OR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, -halogen, -N(R9)2, -C(=O)OR9; each R8 is independently specified in -(C1-C4alkyl, tetrzolyl, imidazolyl, furanyl, -(C1-C6)alkylCOOR9, -OR9, -SR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, =O, -halogen, -N(R9)(C1-C6)alkylCOOR9, -N(R9)2, -N(R9)S(=O)2R12, -N(R9)C(=O)R12, -N(R9)C(=O)OR12, -C(=O)R9, -C(=O)N(T1)(T2), -C(=O)OR9, -OC(=O)R9, or -S(=O)2R9; each R9 is independently specified in -H, -(C1-C6)alkyl, -(C3-C8)cycloalkyl, -phenyl, -benzyl, -(5- to 6-member)heterocycle, -C(halogen)3; -CH(halogen)2 or -CH2(halogen); if h is equal to O, then R11 can be specified in -H, -C(=O)OR9 or -C(=O)N(R6)2 or R11 can be -(C1-C4)alkyl; if h is equal to 1, then R11 can be specified in -H; each R12 is independently specified in -H or -(C1-C4)alkyl; m is equal to an integer specified in 3, 4, 5, 6, 7, 8 or 9; each e and f is equal to an integer independently specified in 0 or 1, provided 2≤(e+f)≤5; each j and k is equal to an integer independently specified in 0 or 1, provided 1≤(j+k)≤4; each p is equal to an integer independently specified in 0 or 1; each T1, T2, and T3 is independently specified in -H or -(C1-C10)alkyl which is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups, or T1 and T2 together can form 5- to 8-member ring wherein the number of ring atoms contains a nitrogen atom wherein T1 and T2 are bound; the above 5- to 8-member ring is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups and optionally any carbon atom in the above 5- to 8-member ring is independently substituted with O or N(R6); each halogen is independently specified in -F, -CI, -Br or -I.

EFFECT: invention refers to the intermediate compounds of formula

, , for preparing the above compounds of formula (II), compositions containing the above compounds and to a method of treating or preventing a diseased state, such as a pain.

36 cl, 58 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel indazole-carboxamide compounds of formula ,

in which radicals and groups are as defined in claim 1 of the formula of invention. Present invention also relates to pharmaceutical compositions containing said compounds, to methods of using such compounds to treat 5-HT4-receptor mediated diseases.

EFFECT: said compounds are 5-HT4-receptor agonists.

16 cl, 10 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) , where Z means where R means hydrogen, C4-C6cycloalkyl group attached either through one of ring carbon atoms, or through a lower alkylene group attached to the ring, or a linearly chained or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or a phenyl(lower alkyl) group optionally substituted with 1-2 substitutes chosen from lower alkyl, lower alkoxy, halogen and hydroxy, or heteroaryl(lower alkyl)group where heteroaryl is chosen from the group consisting from thienyl, substituted with lower alkyl group, imidazolyl, and thiazolyl substituted with the lower alkyl group; n means 0 or 1; or Z means a group where R means the lower alkyl group; X1 means methylene or NH group; and X2 means methylene; or X1 means methylene and X2 means methylene or a bond; or X1 means methylene, and X2 means O, S or a bond; Y1 means methylene, and Y2 means methylene, vinylene, ethylene, or a bond; Ar1 means unsubstituted or substituted phenyl; Ar2 means unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted furyl, unsubstituted or substituted pyridyl; and when Ar1 and Ar2 are substituted, each Ar1 and Ar2 are independently substituted with one or more substituted chosen from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di- and trihaloalkyl, di- and trihaloalkoxy, mono- and dialkylamino, alkilthio, alkyl ester and nitro; provided that Ar1 and Ar2 do not simultaneously mean unsubstituted phenyl; W means oxygen or sulphur; or to their pharmaceutically acceptable salts; provided those specified in cl. 1 of the patent claim. Besides the invention concerns the compounds chosen from the group, to compounds of formula (I), to pharmaceutical compositions, to a method of inhibition of monoamine receptor activity, to a method of inhibition of monoamine receptor activation, to a method of treating a diseased state associated with serotonin receptor, to a method of treating schizophrenia, to a method of treating migraine, and also to a method of treating psychosis.

EFFECT: preparation of the new biologically active compounds capable to inhibit monoamine receptor activity.

65 cl, 140 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: in new compounds of the formula R1 represents hydrogen, halogen; R2 represents C3-4 alkyl, or C3-6 cycloalkyl; R3 represents hydrogen or C1-3 alkyl; R4 represents -S(O)2R6, or -C(O)R7; R5 represents hydrogen, C1-3 alkyl, C2-3 alkyl substituted with -OH or C1-3alkoxy, or -CH2-pyridyl; R6 represents C1-3 alkyl, or R5 and R6 taken together form a C3-4 alkylenyl; and R7 represents hydrogen, C1-3 alkyl or pyridyl; or their pharmaceutically acceptable salts or solvates or stereoisomers. The invention also refers to pharmaceutical composition, to compounds application, to method for treating mammals, to method for treating disorders of reduced motor activity of gastrointestinal tract in a mammal, to method for obtaining compounds according to any of Clauses 1-12, to method for obtaining compounds of formula (I'), as well as to compounds of formula (III).

EFFECT: obtaining new biologically active compounds having activity as 5-NT4 receptors.

24 cl, 29 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula , in which: Ra and Ra' denote hydrogen, R1 denotes cycloalkyl; R2 denotes a group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which x=0, y=1, Y denotes -N-R11R12;- R11 and R12 denote alkyl; R3 denotes a halogen atom; R5 denotes a hydrogen atom; R4 is selected from: (1) a group of formula : in which each of the rings in formulae (a) and (b) can be substituted in any position with 1-4 R7 groups which are identical or different from each other, and in which: a=0; p=0, 1, 2 or 3; m=1; X is an oxygen or sulphur atom or a C(R6)(R7)- or -N(R10)- group; R6 is selected from: a hydrogen atom; a -(CH2)x-NR8R9 group in which x=0, aryl, alkylaryl; R7 is selected from hydrogen atoms; aryl, alkylaryl groups; -OR group; -NRR' groups; R8 and R9 are selected from a hydrogen atom; R10 is selected from: hydrogen atom; aryl, alkylaryl; R and R' denote a hydrogen atom; (2) a group of formula -A-R18, -A-CH=N-R19, in which A denotes a straight or branched alkyl; R18 denotes a halogen atom or a -NH2 group; R19 denotes hydroxyl; (3) a group of formula : in which r equals 1; s equals 1, and one of U, V and W denotes a nitrogen atom while the others denote a methylene group; or (4) -(CH2)r-heteroaryl, where r equals 1; where the heteroaryl denotes a 5-6-member aromatic group containing 1-2 heteroatoms such as nitrogen, oxygen, in form of a base or additive acid salt. The invention also relates to a method for synthesis of formula (I) compounds, to compounds of formulae (IV) and (V), to a medicinal agent, to a pharmaceutical composition, as well as to use of formula (I) compounds.

EFFECT: obtaining new biologically active compounds having melanocortin receptor agonist activity.

11 cl, 28 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds that comply with formula (I) , where: n is equal to 1, Ra, Ra', Rb, Rb', identical or different, mean atom of hydrogen or alkyl or cycloalkyl group, besides, Rb and Rb' may create carbon bridge having 4 links together with hydrogen atoms of cycle, to which they are connected, R1 means cyclohexyl group, R2 means 1,2,4-triazolyl group, R3 means 1-3 groups, selected from atoms of halogen, available in any position of cycle, to which they are connected, R5 means atom of hydrogen, R4 is selected from groups of formulas (a), (b) and (c), given below, mono- or polysubstituted with aryl group: (a), (b), (c), in which: p=0, 1, 2 or 3, m=0, 1 or 2, and either a) X means link -N(R10)-, where R10 is selected from: groups -CO-NR8R9, -COOR8, -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-COR8, in which x=1, 2, 3 or 4, heterocycloalkyl group, condensed with aryl group, cycloalkyl, aryl, heteroaryl, alkylaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-aryl, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarly substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CN, -COOR, COR; or R10 together with atom of nitrogen, to which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not in neighboring position to mentioned atom of nitrogen, creates a bridge that contains 3-5 links, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl or cycloalkyl groups; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, aryl groups; or b) X means link - C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, groups -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0, 1, 2, 3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl group, heterocycloalkyl group, condensed or non-condensed, available in spiro-position to cycle of formula (a), to which it is connected, heterocycloalkyl group, condensed with aryl group, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; and heterocycloalkyl groups are unnecessarily condensed with aryl group; R7 is selected from atoms of hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -OR, -O-aryl, -O-alkylaryl, -O-alkylheteroaryl, groups -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN and -COOR, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -CO-alkyl, -CO-cycloalkyl, -CO-aryl, -(CH2)x-OR, where x=0, 1, 2, 3 or 4, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; or R8 and R9 create together cycloalkyl or heterocycloalkyl; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl, aryl, or may together create cycloalkyl or heterocycloalkyl; besides heteroaryl group represents aromatic group that contains from 5 to 10 atoms and from 1 to 4 heteroatoms, selected from nitrogen, oxygen or sulfur; heterocycloalkyl group represents cycloalkyl group, which contains from 5 to 10 atoms and contains from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (IV) , (V), (VI), (XXVIII), (XXIX), (II).

EFFECT: production of new biologically active compounds, having activity of agonists of melanocortin receptors.

36 cl, 22 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described is a new uniformly tritium-labeled 4,4-fluoro-N-{(1S)-3-[3-(3-isopropyl-5-methyl-4H-1,2,4-trizol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexane carboiimide (maraviroc) of formula I .

EFFECT: said compound can be used in analysis of physiologically active compound-analogue.

1 cl, 1 ex, 2 dwg

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

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