Pyridyl-piperidine antagonists of orexin receptors

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention describes specific compounds, namely pyridyl-piperidine compounds, which represent antagonists of orexin receptors and can be used for treatment or prevention of neurologic and psychiatric disorders and diseases, in development of which orexin receptors participate.

EFFECT: claimed invention relates to pharmaceutical compositions, containing said compounds, as well as to application of said compounds and compositions for prevention or treatment of diseases, in development of which orexin receptors participate.

5 cl, 1 ex, 2 tbl

 

The prior art INVENTIONS

Orexin (hypocretin) include two neuropeptide produced in the hypothalamus: orexin A (OX-A) (peptide that contains 33 amino acids) and orexin B (OX-B) (a peptide containing 28 amino acids) (Sakurai T. et al., Cell, 1998, 92, 573-585). Found that orexin stimulate food intake in rats, this suggests that the physiological role of these peptides is in mediating the Central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). The fact that orexin regulate States of sleep and wakefulness, potentially opens new approaches for the treatment of patients with narcolepsy or insomnia (Chemelli R. et al., Cell, 1999, 98, 437-451). Also it is shown that orexin participate in the revival, reinforcement, learning and memory (Harris, et al., Trends Neurosci., 2006, 29 (10), 571-577). Cloned and characterized two receptor orexin mammals. They belong to the superfamily of receptors associated with G-protein (Sakurai T. et al., Cell, 1998, 92, 573-585): receptor orexin-1 (OX or OX1R) selective with respect to OX-A and the receptor orexin-2 (OX2 or OX2R) able to communicate both with OX-A and OX-b Presumably physiological processes involving orexin carried out through one or both of the two subtypes of receptors orexins, receptor OX1 and OX2 receptor.

Receptors'or is xinou, found in the mammalian brain may be involved in the development of different pathological conditions, such as depression; fear; addictive; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; delimitable disorder; behaviour disorder; mood disorder; sexual dysfunction; envisage psychological sex dysfunction; sexual dysfunction; schizophrenia; manic depression; delirious syndrome; dementia; severe mental retardation and dyskinesias, such as Huntington's disease and Tourette syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; dependency on food intake; feeding behavior, associated with overeating and taking laxatives; cardiovascular disease; diabetes; disorders of appetite/taste; vomiting, nausea; asthma; cancer; Parkinson's disease; syndrome/Cushing disease; basophilic adenoma; prolactinoma; hyperprolactinemia; tumor/adenoma of the pituitary gland; disorders of the hypothalamus; inflammatory bowel disease; dyskinesia stomach; stomach ulcers; syndrome Frehlich; disease adenohypophysis; disease of the pituitary gland; hypothyroidism of adenohypophysis; school of adenohypophysis; hypothalamic hypogonadism; kallmann syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; insufficient the durability pituitary function; hypothalamic hypothyroidism; hypothalamic - adrenal dysfunction; idiopathic hyperprolactinemia; associated with hypothalamic disorders deficiency of growth hormones; idiopathic growth failure; dwarfism; gigantism; acromegaly; violations of biological and circadian rhythms; sleep disturbances associated with such diseases as neurological disorders, neuropathic pain and tired leg syndrome; heart disease and lung, acute and congestive heart failure; hypotension; hypertension; delay urinary tract; osteoporosis; angina pectoris; myocardial infarction; ischemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; disease kidney; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; burning pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; pain sports injuries; pain related to infection e.g. HIV, pain after chemotherapy; pain after stroke, post-operative pain; neuralgia; vomiting, nausea; conditions associated with internal pain such as irritable bowel syndrome and angina; migraines, urinary bladder, for example urgent incontinence; tolerance to narcotics or abstinence from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; syndrome of de-physiological cycles; and neurodegenerative disorders including nosological disorder, such as complex disinhibition-dementia-parkinsonism-disease; paleobotanical degeneration; epilepsy; seizure disorders and other diseases associated with dysfunction of the General system of orexins.

Some receptor antagonists orexin disclosed in patent PCT publications WO 99/09024, WO 99/58533, WO 00/47576, WO 00/47577, WO 00/47580, WO 01/68609, WO 01/85693, WO 01/96302, WO 2002/044172, WO 2002/051232, WO 2002/051838, WO 2002/089800, WO 2002/090355, WO 2003/002559, WO 2003/002561, WO 2003/032991, WO 2003/037847, WO 2003/041711, WO 2003/051368, WO 2003/051872, WO 2003/051873, WO 2004/004733, WO 2004/026866, WO 2004/033418, WO 2004/041807, WO 2004/041816, WO 2004/052876, WO 2004/083218, WO 2004/085403, WO 2004/096780, WO 2005/060959, WO 2005/075458, WO2005/118548, WO 2006/067224, WO 2006/110626, WO 2006/127550, WO 2007/019234, WO 2007/025069, WO 2007/061763, WO 2007/116374, WO 2007/122591, WO 2007/126934, WO 2007/126935, WO 2008/008517, WO 2008/008518, WO 2008/008551, WO 2008/020405, WO 2008//026149, WO 2008/038251.

The INVENTION

The present invention relates to paradiseparadise compounds, which are antagonists of receptors orexin and can be used for treatment or prevention of neurological and psychiatric disorders and ill the deposits, in the development involving receptors orixinal. In addition, the present invention relates to pharmaceutical compositions containing these compounds and to the use of such compounds and compositions for the prevention or treatment of diseases, the development of which involved receptors orexin.

DETAILED description of the INVENTION

The present invention relates to compounds of the formula I:

where

A is selected from the group comprising phenyl, naphthyl and heteroaryl;

R1a, R1band R1cmay be absent if the valency of A1does not permit such substitution and in the presence of they can be independently selected from the group including

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) -(C=O)m-On-C1-6alkyl, where m is 0 or 1, n is 0 or 1 (if m is 0 or n is 0, there is a link) and where the alkyl is not substituted or substituted by one or more substituents selected from R13,

(5) -(C=O)m-On-C3-6cycloalkyl where cycloalkyl not substituted or substituted by one or more substituents selected from R13,

(6) -(C=O)m-C2-4alkenyl, where alkenyl not substituted or substituted by one or more substituents selected from R13,

(7) -(C=O)m-C2-4quinil where quinil not samewe the or substituted by one or more substituents, selected from R13,

(8) -(C=O)m-On-phenyl or -(C=O)m-On-naphthyl, where phenyl or naphthyl are not substituted or substituted by one or more substituents selected from R13,

(9) -(C=O)m-On-heterocycle, where the heterocycle is not substituted or substituted by one or more substituents selected from R13,

(10) -(C=O)m-NR10NR11where R10and R11independently selected from the group including

(a) hydrogen,

(b) C1-6alkyl, unsubstituted or substituted R13,

(c) C3-6alkenyl, unsubstituted or substituted R13,

(d) C3-6quinil, unsubstituted or substituted R13,

(e) C3-6cycloalkyl, unsubstituted or substituted R13,

(f) phenyl, unsubstituted or substituted R13and

(g) heterocycle, unsubstituted or substituted R13,

(11) -S(O)2-NR10R11,

(12) -S(O)q-R12where q is 0, 1 or 2 and where R12selected from the definitions of R10and R11,

(13) -CO2H,

(14) -CN, and

(15) -NO2;

R2a, R2band R2cindependently selected from the group including:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) -(C=O)m-On-C1-6alkyl, where alkyl is not substituted or substituted by one or more substituents selected from R13,

(5) -(C=O)m-On-C3-6cyclol the sludge, where cycloalkyl not substituted or substituted by one or more substituents selected from R13,

(6) -(C=O)m-C2-4alkenyl, where alkenyl not substituted or substituted by one or more substituents selected from R13,

(7) -(C=O)m-C2-4quinil where quinil not substituted or substituted by one or more substituents selected from R13,

(8) -(C=O)m-On-phenyl or -(C=O)m-On-naphthyl, where phenyl or naphthyl are not substituted or substituted by one or more substituents selected from R13,

(9) -(C=O)m-On-heterocycle, where the heterocycle is not substituted or substituted by one or more substituents selected from R13,

(10) -(C=O)m-NR10R11,

(11) -S(Oh)2-NR10R11,

(12) -S(O)q-R12,

(13) -CO2H,

(14) -CN, and

(15) -NO2;

R3denotes hydrogen, C1-6alkyl or C3-6cycloalkyl, which can be unsubstituted or substituted by one or more substituents selected from R13;

R4and R5independently selected from hydrogen and C1-6of alkyl, which may be unsubstituted or substituted by one or more substituents selected from R13or R4and R5together with the carbon atom to which they are attached, may form a C3-6cycloalkyl where cycloalkyl not substituted or substituted by one or more substituents, selected from R13;

R13selected from the group including

(1) halogen,

(2) hydroxyl,

(3) -(C=O)m-On-C1-6alkyl, where alkyl is not substituted or substituted by one or more substituents selected from R14,

(4) -On-(C1-3)perfluoroalkyl,

(5) -(C=O)m-On-C3-6cycloalkyl where cycloalkyl not substituted or substituted by one or more substituents selected from R14,

(6) -(C=O)m-C2-4alkenyl, where alkenyl not substituted or substituted by one or more substituents selected from R14,

(7) -(C=O)m-C2-4quinil where quinil not substituted or substituted by one or more substituents selected from R14,

(8) -(C=O)m-On-phenyl or -(C=O)m-On-naphthyl, where phenyl or naphthyl are not substituted or substituted by one or more substituents selected from R14,

(9) -(C=O)m-On-heterocycle, where the heterocycle is not substituted or substituted by one or more substituents selected from R14,

(10) -(C=O)m-NR10R11,

(11) -S(O)2-NR10R11,

(12) -S(O)q-R12,

(13) -CO2H,

(14) -CN, and

(15) -NO2;

R14selected from the group including

(1) hydroxyl,

(2) halogen,

(3) C1-6alkyl,

(4) -C3-6cycloalkyl,

(5) -O-C1-6alkyl,

(6) -O(C=O)-C 1-6alkyl,

(7) -NH-C1-6alkyl,

(8) phenyl,

(9) heterocycle,

(10) -CO2H and

(11) -CN;

or their pharmaceutically acceptable salts.

The embodiment of the present invention includes compounds of formula Ia:

where A, R1a, R1b, R1c, R2a, R2b, R2C, R3, R4and R5defined in the present description; or their pharmaceutically acceptable salts.

The embodiment of the present invention includes compounds of formula Ia':

Ia'

where A, R1a, R1b, R1c, R2a, R2b, R2c, R3, R4and R5defined in the present description; or their pharmaceutically acceptable salts.

The embodiment of the present invention includes compounds of formula Ia":

where A, R1a, R1b, R1c, R2a, R2b, R2c, R3, R4and R5defined in the present description; or their pharmaceutically acceptable salts.

The embodiment of the present invention includes compounds of formula Ib:

where A, R1a, R1b, R1c, R2a, R2b, R2cand R3defined in the present description; or their pharmaceutically acceptable salts.

The embodiment of the present invention includes compounds of formula Ic:

where R1a, R1b, R1c, R2a, R2b, R2cand R3defined in the present description; or their pharmaceutically acceptable salts.

The embodiment of the present invention includes compounds of formula Id:

where R1a, R1b, R1c, R2aand R3defined in the present description; or their pharmaceutically acceptable salts.

The embodiment of the present invention includes compounds of formula Ie:

where R1a, R1b, R2aand R3defined in the present description; or their pharmaceutically acceptable salts.

The embodiment of the present invention includes compounds of formula If:

where R1a, R1band R2adefined in the present description; or their pharmaceutically acceptable salts.

The embodiment of the present invention includes compounds in which A1denotes phenyl. The embodiment of the present invention includes compounds in which A1denotes heteroaryl. The embodiment of the present invention includes compounds in which A1means pyrazolyl. The embodiment of the present invention includes compounds in which A1means thiazolyl.

The embodiment of the present invention includes compounds in which R1a, R1band R independently selected from the group including

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C1-6alkyl, unsubstituted or substituted with halogen, hydroxyl, phenyl or naphthyl,

(5) -O-C1-6alkyl, unsubstituted or substituted with halogen, hydroxyl or phenyl,

(6) heteroaryl where heteroaryl selected from triazolyl, oxazolyl, pyrrolyl, imidazolyl, indolyl, pyridyl and pyrimidinyl, unsubstituted or substituted with halogen, hydroxyl, C1-6by alkyl, -O-C1-6the alkyl or-NO2,

(7) phenyl, unsubstituted or substituted with halogen, hydroxyl, C1-6by alkyl, -O-C1-6the alkyl or-NO2,

(8) -O-phenyl, unsubstituted or substituted with halogen, hydroxyl, C1-6by alkyl, -O-C1-6the alkyl or-NO2and

(9) -NH-C1-6alkyl or-N(C1-6alkyl)(C1-6alkyl), unsubstituted or substituted with halogen, hydroxyl, C1-6by alkyl, -O-C1-6the alkyl or-NO2.

The embodiment of the present invention includes compounds in which R1a, R1band R1cindependently selected from the group including

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C1-6alkyl, unsubstituted or substituted with halogen, hydroxyl or phenyl or naphthyl,

(5) -O-C1-6alkyl, unsubstituted or substituted with halogen, hydroxyl or phenyl,

(6) heteroaryl, the de heteroaryl selected from triazolyl, oxazolyl and pyrimidinyl, unsubstituted or substituted with halogen, hydroxyl or C1-6the alkyl, and

(7) phenyl, unsubstituted or substituted with halogen, hydroxyl or C1-6the alkyl.

The embodiment of the present invention includes compounds in which R1a, R1band R1cindependently selected from the group including

(1) hydrogen,

(2) halogen,

(3) C1-6alkyl,

(4) triazolyl,

(5) oxazolyl,

(6) pyrimidinyl and

(7) phenyl.

The embodiment of the present invention includes compounds in which R1a, R1band R1cindependently selected from the group including

(1) hydrogen,

(2) chlorine;

(3) fluorine,

(4) methyl,

(5) triazolyl,

(6) oxazolyl,

(7) pyrimidinyl and

(8) phenyl.

The embodiment of the present invention includes compounds in which R2a, R2band R2cindependently selected from the group including

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C1-6alkyl, unsubstituted or substituted with halogen, hydroxyl or phenyl or naphthyl,

(5) -O-C1-6alkyl, unsubstituted or substituted with halogen, hydroxyl or phenyl,

(6) heteroaryl where heteroaryl selected from pyrrolyl, imidazolyl, indolyl, pyridyl and pyrimidinyl, unsubstituted or substituted with halogen, hydroxyl, C1-6by alkyl, -O-C1-6the alkyl or-NO2,

(a) phenyl, unsubstituted or substituted with halogen, hydroxyl, C1-6by alkyl, -O-C1-6the alkyl or-NO2,

(8) -O-phenyl, unsubstituted or substituted with halogen, hydroxyl, C1-6by alkyl, -O-C1-6the alkyl or-NO2and

(9) -NH-C1-6alkyl, or-N(C1-6alkyl)(C1-6alkyl), unsubstituted or substituted with halogen, hydroxyl, C1-6by alkyl, -O-C1-6the alkyl or-NO2.

The embodiment of the present invention includes compounds in which R2a, R2band R2cindependently selected from the group including

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) C1-6alkyl, unsubstituted or substituted with halogen, hydroxyl or phenyl,

(5) -O-C1-6alkyl, unsubstituted or substituted with halogen, hydroxyl or phenyl, and

(6) -NH-C1-6alkyl or-N(C1-6alkyl)(C1-6alkyl), unsubstituted or substituted with halogen.

The embodiment of the present invention includes compounds in which R2a, R2band R2cindependently selected from the group including

(1) hydrogen,

(2) halogen,

(3) C1-6alkyl, unsubstituted or substituted with halogen,

(4) -O-C1-6alkyl, unsubstituted or substituted with halogen, and

(5) -NH-C1-6alkyl or-N(C1-6alkyl)(C1-6alkyl), unsubstituted or substituted with halogen.

The embodiment of the present invention includes the t connection, in which R2a, R2band R2cindependently selected from the group including

(1) hydrogen,

(2) chlorine;

(3) fluorine,

(4) bromo,

(5) methoxy,

(6) tert-butoxy,

(7) deformity and

(8) trifluoromethyl.

The embodiment of the present invention includes compounds in which R2a, R2band R2cindependently selected from the group including

(1) hydrogen,

(2) fluorine and

(3) trifluoromethyl.

The embodiment of the present invention includes compounds in which R3denotes hydrogen, C1-6alkyl or C3-6cycloalkyl. The embodiment of the present invention includes compounds in which R3different from hydrogen. The embodiment of the present invention includes compounds in which R3represents C1-6alkyl. The embodiment of the present invention includes compounds in which R3represents C3-6cycloalkyl. The embodiment of the present invention includes compounds in which R3denotes methyl or ethyl. The embodiment of the present invention includes compounds in which R3denotes methyl. The embodiment of the present invention includes compounds in which R3on piperidinium loop is in the TRANS configuration relative to pyridylacetonitrile Deputy. The embodiment of the present invention includes compounds in which R3the PIP is retinova cycle is in CIS-configuration relative to pyridylacetonitrile Deputy. The embodiment of the present invention includes compounds in which R3on piperidinium cycle is R-configuration. The embodiment of the present invention includes compounds in which the substituent in the 6-position piperidino cycle is R-configuration. The embodiment of the present invention includes compounds in which peridiocally group on piperidinium cycle is R-configuration. The embodiment of the present invention includes compounds in which the substituent in the 3-position piperidino cycle is R-configuration.

The embodiment of the present invention includes compounds in which R4denotes hydrogen or C1-6alkyl. The embodiment of the present invention includes compounds in which R4denotes hydrogen or methyl. The embodiment of the present invention includes compounds in which R4denotes hydrogen. The embodiment of the present invention includes compounds in which R5denotes hydrogen or C1-6alkyl. The embodiment of the present invention includes compounds in which R5denotes hydrogen or methyl. The embodiment of the present invention includes compounds in which R5denotes hydrogen.

A specific embodiment of the present invention relate to a compound selected from the group including joint is shown in the description of the examples and their pharmaceutically acceptable salts.

Compounds of the present invention may contain one or more asymmetric centers and therefore may occur in the form of stereoisomers, including the racemates and racemic mixtures, mixtures of enantiomers, individual enantiomers, mixtures of diastereomers and individual diastereomers. Depending on the nature of the various substituents in the molecule may be present other asymmetric centers. Each such asymmetric center independently gives two optical isomers and it is assumed that the scope of the present invention includes all the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds. It is implied that the present invention covers all such isomeric forms of these compounds. If the formulas of this invention due chiral carbon atoms are depicted as straight lines, it should be understood that the chiral carbon atom may be either (R)-and (S)-configuration, therefore, the formula covers both enantiomers and mixtures thereof. For example, the formula I shows the structure of a class of compounds without regard to the specific stereochemistry. If the compounds of the present invention contain one chiral center, the term "stereoisomer" includes both enantiomers and mixtures of enantiomers, such as, for example, a 50:50 mix, called rat the standard mixture.

Independent synthesis of these diastereomers or their chromatographic separation can be accomplished, as is well known in this field, by suitable modifications disclosed in the description of the methods. The absolute stereochemistry of the diastereomers can be determined by x-ray crystallography of crystalline products or crystalline intermediates, derivatizing, if necessary, a reagent containing an asymmetric center is known absolute configuration. If necessary, racemic mixtures of compounds can be separated and allocate individual enantiomers. The separation can be performed using well-known in the field of methods, such as a mixture of diastereomers by joining a racemic mixture of compounds of enantiomerically pure compounds and subsequent separation of the individual diastereomers using standard techniques such as fractional crystallization or chromatography. The reaction accession is often a education salts using enantiomerically pure acids or bases. Then diastereomeric derivatives can be transformed into pure enantiomers by removal of added chiral residue. In addition, the racemic mixture of compounds can be directly split chromatographic methods the AMI using chiral stationary phases, these methods are well known in this field. Alternative any enantiomer compounds can be obtained by stereoselective synthesis with the help of well-known in the field of methods using optically pure source materials or reagents of known configuration.

In accordance with the adopted in this field terminology, halogen herein includes fluorine, chlorine, bromine and iodine. Similarly, C1-6for example, part of the C1-6of alkyl, defined as a group containing 1, 2, 3, 4, 5 or 6 carbon atoms in linear or branched chain, therefore, C1-8alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl. The group defined as independently substituted by substituents may have a different number of such substituents. The term "heterocycle" in this description includes both unsaturated and saturated heterocyclic fragments, where unsaturated heterocyclic fragments (i.e. "heteroaryl") include benzoimidazolyl, benzimidazolinyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, benzothiophene, benzoxazepin, benzoxazolyl, carbazolyl, carbolines, cinnoline, furanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indazoles, isobenzofuranyl, isoindolyl, ethanolic, isothiazol the sludge, isoxazolyl, naphthyridine, oxadiazole, oxazole, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyrimidines, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, hintline, hinely, honokalani, tetrazolyl, tetrasulphides, thiadiazolyl, thiazolyl, thienyl, triazolyl, and their N-oxides, and saturated heterocyclic fragments include azetidine, 1,4-dioxane, hexahydroazepin, piperazinil, piperidinyl, pyridine-2-IMT, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, thiomorpholine and tetrahydrothieno, and their N-oxides.

The term "pharmaceutically acceptable salt" refers to salts obtained with the use of pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum salts, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, etc. Specific embodiments include salts of ammonium, calcium, magnesium, potassium and sodium. Solid salts can exist in several crystalline structures, as well as in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic base is s, include salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenziletilendiaminom, diethylamin, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polianinova resins, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine and the like

If the connection of the present invention is basic, salts may be obtained by using pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzosulfimide, benzoic, camphorsulfonic, lemon, econsultancy, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate, muzinovy, nitrogen, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate acid, etc. Specific embodiments include citric, Hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acid. It should be understood that h is of this description, reference to compounds of formula I involves the inclusion of their pharmaceutically acceptable salts.

The present invention is illustrated by compounds disclosed in the examples and in this specification. Specific compounds included in the scope of the present invention include compounds selected from the group comprising compounds disclosed in the following examples, their pharmaceutically acceptable salts and individual enantiomers or diastereomers.

Consider connections can be used to regulate the activity of the receptor orexin the patient such as a mammal in need of such regulation, which is achieved by introducing an effective amount of the compounds. The present invention relates to the use of compounds disclosed herein, as antagonists of the activity of the receptor orexin. In addition to primates, especially humans, using the method of the present invention can be treated with a number of other mammals. The present invention relates to the use of compounds of the present invention or its pharmaceutically acceptable salt in medicine. The present invention also relates to the use of compounds of the present invention or its pharmaceutically acceptable salts in the manufacture of drugs to inhibit the activity of the receptor orexin or treatment specified in this description of the disorders and diseases of humans and animals.

The subject to be treated using methods of the present invention, generally, is a mammal such as a human male or a female. The term "therapeutically effective amount" refers to the number of pending connections, which causes the biological or medical response in a tissue, system, animal or person determined by the researcher, veterinarian, medical doctor or other Clinician. Found that specialist in this area can affect neurological and psychiatric disorders by treatment of a patient affected by such violation, or by prophylactic treatment of the patient prone to such abuses an effective amount of the compounds of the present invention. In this description, the terms "treating" and "treatment" refer to all the ways leading to slowing, preventing, blocking, suppressing or stopping the development of neurological and psychiatric disorders described in this document, but they do not necessarily imply complete elimination of all symptoms violation of these terms also apply to preventive therapy of these conditions, especially in patients prone to such disease or disorder. The term "introduction" compound should be understood as granting you connect the Oia of the present invention or proletarienne forms of the compounds of the present invention to a subject, who needs this.

The term "composition" in this description refers to the product containing the specified ingredients in the specified amounts, as well as to the product, which is formed, directly or indirectly, by combining the specified ingredients in the specified amounts. In the case of pharmaceutical compositions such term includes the product containing the active ingredient (the active ingredients) and the inert ingredient (inert ingredients), which is the media, as well as any product which is produced by direct or indirect Association, complexation or aggregation of two or more ingredients, or as a result of dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention include all compositions obtained by mixing the compounds of the present invention and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" means that the carrier, diluent or excipient, which includes this term must be compatible with other ingredients of the composition and must not have a harmful influence on the recipient.

The suitability of the compounds of the present izobreteny is for use as antagonists of receptors orexin OX1R and/or OX2R can be easily identified without undue experimentation using well-known in the field of methods, include "FLIPR Ca2+Flux Assay" (Okumura et al., Biochem. Biophys. Res. Comm. 280:976-981, 2001). Usually antagonistic activity of the compounds of the present invention receptor OX1 and OX2 is determined using the experimental method described below. To measure the level of intracellular calcium, the cells of the Chinese hamster ovary (CHO)expressing the receptor orexin-1 or human receptor orexin-2, grown in DMEM modified by Iscove, which contains 2 mm L-glutamine, 0.5 g/ml G418, 1% gipoksantin-timeinfo Supplement, 100 U/ml penicillin, 100 μg/ml streptomycin and 10% V / V heat inactivated fetal calf serum (FCS). Cells were seeded in the amount of 20,000 cells/well in black 384-well sterile tablet Becton-Dickinson with a transparent bottom, coated with poly-D-lysine. All reagents receive from GIBCO-Invitrogen Corp. After sowing tablets incubated over night at 37°C and 5% CO2. Get the original 1 mm solution of human orexin-A Ala-6,12 used as agonist, in 1% solution of bovine serum albumin (BSA) and then dilute it with buffer for analysis (HBSS containing 20 mm HEPES, 0.1% of BSA and 2.5 mm probenecid, pH of 7.4) to a final concentration of 70 PM. Get the original 10 mm solutions of test compounds in DMSO, then diluted in 384-well tablets initially, DMSO, then buffer the La analysis. On the day of analysis, the cells are washed 3 times with 100 μl of buffer for analysis, and then incubated for 60 min (37°C, 5% CO2in 60 μl of buffer for analysis containing 1 μm, an ester of Fluo-4AM, 0,02% pluranguloj acid and 1% BSA. Then the solution is to download the dye is sucked off and the cells washed 3 times with 100 μl of buffer for analysis. In each well leave 30 μl of this buffer. In the tablet reader with fluorescence visualization (FLIPR, Molecular Devices) in tablet type solutions of the test compounds with a volume of 25 μl, incubated for 5 min and at the end add 25 ál of a solution of the agonist. Fluorescence was measured in each well at intervals of 1 second for 5 minutes, after which the height of each peak fluorescence compared with the height of the peak fluorescence induced under the action of 70 PM solution orexin-A Ala-6,12 using a buffer solution instead of the antagonist. For each antagonist determine the value of the IC50(the concentration of compound required for 50% inhibition of agonist response). Alternative activity of compounds can be determined by analysis of binding radiochango ligand (described in Bergman et al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430), in which the inhibition constant (Kidetermine in membranes derived from CHO cells expressing either receptor OX1 or OX2 receptor. Using these analyses can determine the ü antagonistic activity of the compounds of the present invention in relation to its receptor orexin.

In particular, the results from the above analyses show that the compounds of the following examples have antagonistic activity against rat receptor orexin-1 and/or human receptor orexin-2, as a rule, characterized by the IC50less than about 50 microns. According to the above analysis, many of the compounds of the present invention have an antagonistic activity against rat receptor orexin-1 and/or human receptor orexin-2 with IC50less than about 100 nm. According to the analysis of binding radiochango ligand compounds of the present invention also have activity against receptor orexin-1 and/or orexin-2, as a rule, characterized by the Ki< 100 nm. Additional data are shown in table 2. The results obtained show that the compounds have intrinsic activity when used as antagonists of the receptor orexin-1 and/or receptor orexin-2. In total the present invention also includes compounds with agonistic activity against receptor orexin-1 and/or receptor orexin-2. Compared to other piperidinium connections of the present invention possess unexpected properties, such as increased activity, bidston is here for peroral use, metabolic stability and/or selectivity. For example, compared with compounds that contain unsubstituted piperidinyl cycle, the compounds of the present invention, in which R3substituted, for example, C1-6the alkyl or C3-6cycloalkyl, have unexpectedly high activity against receptor orexin-1 and/or receptor orexin-2.

Receptors orexin participate in the implementation of a wide range of biological functions. This suggests that these receptors may play a role in several pathological processes in humans or other species. Compounds of the present invention can be used to treat, prevent, enhance, suppress or reduce the risk of a number of neurological and psychiatric disorders associated with receptors orexins that include one or more of the following conditions or diseases: insomnia, sleep disturbances, in this case, the connection can be used to improve the quality of sleep, improve sleep quality, improve sleep efficiency, longer sleep; increase value, which is calculated by dividing the time during which the subject is sleeping, the time during which the subject is attempting to sleep; improve the initiation of sleep; reduce waiting time or the occurrence of SN is (time, required to fall asleep); reduce difficulty in falling asleep; improve continuity of sleep; decreasing the number of awakenings during sleep; decreasing periodic awakenings during sleep; decrease nocturnal awakenings; reducing the time that people spent in wakefulness after the initial onset of sleep; increasing the total time of sleep, decrease sleep fragmentation; changes in temporary mode, frequency or duration of periods of REM sleep; change the time mode, frequency or duration of periods of slow wave sleep (i.e. 3 or 4 stage); increasing the number and percentage of stage 2 sleep; stimulation of slow wave sleep; increasing the activity EEG-Delta sleep; decrease nocturnal awakenings, especially revivals in the early morning; increased activity in the daytime; reduce sleepiness in the daytime; treatment or reduce sleepiness in the daytime; the increase of depth of sleep; increasing the duration of sleep; idiopathic insomnia; sleep problems; insomnia, hypersomnia, idiopathic hypersomnia, repetitive hypersomnia, hereditary hypersomnia, narcolepsy, interrupted sleep, sleep apnea, insomnia, night mioclauniei, interrupt REM sleep, disruption of circadian rhythms, sleep disorders removable working, dyssomnia, night is my nightmare insomnia associated with depression, emotional disorders/mood disorders, Alzheimer's disease or cognitive deficits, as well as sleepwalking and enuresis, and age-related sleep disturbances; in the evening the confusion in Alzheimer's disease; conditions associated with circadian rhythms, as well as mental and physical disorders associated with crossing time zones and with alternating schedule of shift work, status, due to drugs, which as a side effect cause a reduction in REM sleep; fibromyalgia; syndromes characterized by non sleep and muscle pain or sleep apnea, is associated with respiratory disorders during sleep; state, due to the low quality of sleep; connections can be used to improve learning ability; improve memory; increase the ability of memorization; eating disorders associated with excessive food intake, and associated complications, disorders associated with an irresistible urge for food, obesity (due to any cause, including genetic factors or environmental factors), disorders associated with obesity, such as overeating and neurogenic bulimia, hypertension, diabetes, elevated concentrations of insulin in plasma and insulin resistance, dyslipidemia, guy who lipidemia, cancer of the endometrium, breast, prostate and rectal cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrhythmias, myocardial infarction, congestive heart failure, ischemic heart disease, sudden death, stroke, polycystic ovary syndrome, craniopharyngioma, Prader-Willi syndrome, syndrome Frohlich, GH deficiency, low growth in the normal version, Turner syndrome, and other pathological conditions characterized by reduced metabolic activity or a decrease in the consumption of residual energy in the form of a percentage of the total do not contain fat mass such as acute lymphoblastic leukemia in children, metabolic syndrome, also known as syndrome X, syndrome of insulin resistance, abnormal sex hormones, sexual dysfunction and reproductive system, such as a violation of fertility, infertility, hypogonadism in males and excessive hair growth in women, the defects of the embryo associated with obesity of the mother, disorders of motility of the gastrointestinal tract, such as the associated with obesity, gastro-esophageal reflux, respiratory disorders such as syndrome obesity-hypoventilation (Pickwickian syndrome), breathlessness, cardiovascular disorders, inflammation, such as systemic inflamed the e vascular network, arteriosclerosis, hypercholesterolemia, hyperuricaemia, pain in lower back, gall bladder disease, gout, kidney cancer, increased anesthetic risk, these compounds reduce the risk of secondary effects of obesity, such as the risk of left ventricular hypertrophy; diseases or disorders characterized by abnormal oscillatory activity of the brain, including depression, migraine, neuropathic pain, Parkinson's disease, psychosis and schizophrenia, as well as diseases or disorders characterized by abnormal transfer activity, in particular, through the thalamus; the compounds of the present invention help to improve cognitive function; improve memory; to increase saving data to memory; to increase immune response; improve immune function; to improve conditions such as hot flashes; night sweats; increased life expectancy; schizophrenia; muscular disorders, which are controlled by the rhythms of the excitation/relaxation, regulated by the nervous system, such as heart rate, as well as other violations of the cardiovascular system; conditions associated with cell proliferation, such as vasodilate or waterstrike and blood pressure; cancer; cardiac arrhythmia; hypertension; congestive heart failure; urinary system; disorders of sexual function and with whom osobnosti to playback; compliance of renal function; sensitivity to anesthetics; mood disorders, such as depression or more particularly depressive disorders, for example, single or repeated bouts of deep depression and estimatesa disorders, or bipolar disorder, for example bipolar I disorder, bipolar II disorder and cyclothymic disorder, mood disorders due to a General medical condition, mood disorders induced by drugs; anxiety disorders including acute stress, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, anxiety disorder, caused separation, social phobia, specific phobia, an anxiety disorder caused by drug abuse, and anxiety disorder due to a General medical condition; acute neurological and psychiatric disorders such as cerebral deficits after grafting and transplantation of the heart, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington's chorea; amyotrophic lateral sclerosis; multiple sclerosis; eye damage; retinopathy is I; cognitive disorders; idiopathic and due to the action of drugs for Parkinson's disease; muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular disorders, or stroke, HIV infection, Parkinson's disease, Huntington's disease, a disease of the Peak, the disease Creutzfeldt-Jacob, perinatal hypoxia, other General medical conditions or drug dependence); delirium, memory impairment or age-related deterioration of cognitive function; schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophrenia-like psychosis disorder, schizoaffective disorder, delusion of rasstroistv, brief mental disorder, a common mental disorder, mental disorder due to a General medical condition, mental disorder, caused by the action of narcotic substances; violation caused by the action of drugs, and drug use (including delirium, caused by the action of narcotic substances, persistent dementia, persistent memory impairment, mental disorder or anxiety disorder; tolerance, you is yuusei dependence of power, dependence or withdrawal of drugs, including alcohol, amphetamines, cannabis, cocaine, hallucinogens, volatile drugs, nicotine, opioids, phenylcyclidine, sedatives, sleep AIDS, or tranquilizers); violations of movements, including akinesia and akineticalkie-rigid syndromes (including Parkinson's disease, caused by drugs parkinsonism postentsefaliticheskom parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, complex parkinsonism-ALS dementia and calcification of the basal nuclei of the brain), syndrome of chronic fatigue, exhaustion, including fatigue in Parkinson's disease, fatigue in multiple sclerosis, fatigue caused by sleep disorders or impaired circadian rhythm, parkinsonism caused by drugs (e.g., parkinsonism induced by neuroleptic means, neuroleptic malignant syndrome, acute dystonia induced neuroleptic means, acute akathisia induced neuroleptic means late dyskinesia caused by neuroleptic agents, and postural tremor caused by drugs), the syndrome of Gilles de La Tourette's, epilepsy, and dyskinesias, including tremor (such as three of the R rest essential tremor, postural tremor and intentsionnogo tremor), chorea (such as chorea of Sydenham, Huntington's disease, benign congenital chorea, neuroacanthocytosis, symptomatic chorea, chorea caused by drugs, and hemiballism), mioclauniei (including generalized mioclauniei and alopecia mioclauniei), tics (including simple tick, integrated tick and symptomatic tick), tired leg syndrome and dystonia (including generalised dystonia such as idiopathic dystonia, dystonia caused by drugs, symptomatic dystonia and proximally dystonia, and focal dystonia, such as blepharospasm, oromandibular dystonia, spastic dystonia, spasmodic torticollis, axial dystonia, dystonic writing spasm and hemiplegic dystonia); attention deficit/hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine like headache), urinary incontinence; tolerance to narcotic substances, withdrawal syndrome narcotic substances (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, sleep AIDS, and others); psychosis; schizophrenia; anxiety disorder (including generalized anxiety disorder, panic disorder and obsessive is-compulsive disorder); mood disorders (including depression, mania, bipolar disorder; trigeminal neuralgia; hearing loss; tinnitus; neural injury, including eye damage; retinopathy; macular degeneration of the eye; vomiting; swelling of brain; pain, including the state of acute and chronic pain, severe pain, fatal pain, pain caused by inflammation, neuropathic pain, post traumatic pain, bone pain and joint pain (osteoarthritis), periodic pain at movement, toothache, cancerous pain, musculo-facial pain (muscular injury, fibromyalgia), perioperative pain (General surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine like headache.

Thus, in specific embodiments the present invention provides methods for improving the quality of sleep; increasing the duration of sleep; increasing the duration of the period of REM sleep; increase stage 2 sleep; reduce fragmentation of the characters sleep; the treatment of insomnia; enhance cognitive abilities; increase store data in memory; the treatment or control of obesity; treatment or regulation of depression; treatment, regulation, improving or reducing the risk of epilepsy, including the elimination of epilepsy; treatment or to regulate the investments of pain, including neuropathic pain; treatment or regulation of Parkinson's disease; treatment or regulation of psychosis; or treatment, control, improve, or reduce the risk of schizophrenia in a patient is a mammal, in need thereof, said methods comprise the administration to a patient a therapeutically effective amount of the compounds of the present invention.

The compounds can also be used in a method of prevention, treatment, control, improve, or reduce the risk mentioned in the description of diseases, disorders and conditions. The dose of the active ingredient in the compositions of this invention can vary, but the amount of active ingredient must comply with the resulting dosage form. The active ingredient can be entered to patients (animals and people)in need of such treatment in dosages that provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, the route of administration and duration of treatment. The dose varies from patient to patient depending on the nature and severity of the disease, weight of patient, individual diet of the patient, concomitant treatment, and other factors known to specialists in this field. In order to achieve effective suppression of the activity of receptors orexins, patients who NTU, such as a person or elderly person, usually daily administered dose in the range from 0.0001 to 10 mg/kg of body weight. The dose is usually approximately from 0.5 mg to 1.0 g per patient per day, you can type in one or several stages. In one embodiment of the dosing interval is from about 0.5 mg to 500 mg per patient per day; in another embodiment from about 0.5 mg to 200 mg per patient per day; and in the following embodiment from about 5 mg to 50 mg per patient per day. The pharmaceutical compositions of the present invention can be obtained in the form of solid dosage forms containing, for example, from about 0.5 mg to 500 mg of active ingredient, or contain from about 1 mg to 250 mg of active ingredient. The pharmaceutical composition can be obtained in the form of a solid dosage form containing about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg of the active ingredient. Compositions for oral administration may be in the form of tablets containing 1.0 to 1000 mg of active ingredient, for example, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 or 1000 mg of the active ingredient, in accordance with symptomatic adjustment of the dosage to the patient to be treated. Connection you can enter from 1 to 4 times a day, for example, once or twice a day.

Compounds of the present invention can be used in combination with the one or more other drugs for treatment prevent, control, improve, or reduce the risk of diseases or conditions that are influenced by compounds of the present invention or other drugs, and the combination of medicines should be safer or more effective than any of the medicines used alone. This(s) other(s) of drug(s) tool(s) can be entered by using the methods and in quantities normally used for such means, simultaneously with the connection of the present invention, or sequentially. If the connection of the present invention is administered concurrently with one or more other drugs, can be used in the pharmaceutical composition in the form of a standard dosage form containing such other drugs and the compound of the present invention. However, combined therapy may also include methods of treatment in which the compound of the present invention and one or more other drugs injected into different overlapping modes. It is also assumed that, in combination with one or more other active ingredients compounds of the present invention and other active ingredients can be used in lower doses than when used separately. According to the respectively, the pharmaceutical compositions of the present invention include compositions which in addition to the compounds of the present invention contain one or more other active ingredients. The above combinations include combinations of compounds of the present invention not only one other active compound, but also with two or more other active compounds.

Similarly, the compounds of the present invention can be used in combination with other drugs used to prevent, treat, control, improve, or reduce the risk of diseases or conditions that can affect the connection of the present invention. These other medicines can be entered by using the methods and in quantities normally used for such means, simultaneously with the connection of the present invention, or sequentially. If the connection of the present invention is administered concurrently with one or more other drugs, you can use a pharmaceutical composition containing such other drugs and the compound of the present invention. Accordingly, the pharmaceutical compositions of the present invention include compositions which in addition to the compounds of the present invention contain one or more others the other active ingredients.

The mass ratio of the compounds of the present invention to the weight of the second active ingredient may be varied and depends on the effective dose of each ingredient. Typically, each ingredient is used as an effective dose. For example, if the connection of the present invention used in combination with another tool, the mass ratio of the compounds of the present invention to the weight of the other tools are typically varies from about 1000:1 to 1:1000, for example from about 200:1 to 1:200. Combinations of compounds of the present invention and other active ingredients typically used in the aforementioned range, but in each case you should use an effective dose of each active ingredient. In these combinations the compound of the present invention and other active funds can be entered separately or together. In addition, the introduction of one tool can be performed before, concurrently or after administration of other funds (other funds).

Compounds of the present invention can be introduced in combination with other compounds, which, in accordance with well-known in this field of practice is used to improve the quality of sleep, as well as for the prevention and treatment of sleep disorders and sleep disorders, such compounds include, for example, sedatives, sleeping pills, anxiolytics medium spans the VA, antipsychotics, sedatives, antigistaminny tools, benzodiazepines, barbiturates, cyclopyrrolone, GABA agonists, antagonists 5HT-2, including antagonists 5HT-2A and 5HT antagonists-2A/2C antagonists of histamine, including antagonists of the histamine H3 inverse agonists of the histamine H3, imidazopyridine, mild tranquilizers, agonists and antagonists of melatonin, melatonergic funds, other antagonists of orexin, agonists orexin, agonists and antagonists prokineticin, pyrazolopyrimidine antagonists calcium channel T-type, triazolopyridine etc. such as: adinazolam, allobarbital, econimic, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capured, carbocloro, coralbean, chloralhydrate, chlordiazepoxide, clomipramine, clonazepam, claparede, clorazepate, clarett, clozapine, clonazepam, kirsebom, desipramine, exclama, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, chlorinol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, postepu, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-10097, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midfloor, midazolam, modafinil, nefazodone, NGD-2-73, Nizamabad, nitrazepam, nortriptyline, oxazepam, paraldehyde is recommended that paroxetine, pentobarbital, perlapi, perphenazine, phenelzine, phenobarbital, diazepam, promethazine, propofol, protriptyline, kwazepam, ramelteon, reclusiam, related, secobarbital, sertraline, supraglan, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromine, trazodone, triazolam, crepidam, triatomid, triclofos, trifluoperazine, trimeton, trimipramine, medazepam, venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and their salts and combinations, and the like, or the compound of the present invention can be introduced in combination with physical methods such as with light therapy or electrical stimulation.

In another embodiment of the inventive compound can be used in combination with other known in this field connections, which can be entered separately or in the same pharmaceutical composition, and which include, without limitation: a means of improving insulin sensitivity, including (i) PPARγ antagonists, such as glitazone (for example, ciglitazone; darglitazone; englitazone; silicate (MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512 and the like); (iii) biguanides, such as m etformin, phenformin; (b) insulin or insulinomimetic, such as biota, LP-100, Novorapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (tapes and ultralente); insulin, Lys-Pro, GLP-1 (73-7) (insulinotropic); and GLP-1 (7-36)-NH2); (c) sulfonylureas such as acetohexamide; hlorpropamid; diabinese; glibenclamide; glipizide; gliburid; glimepiride; gliclazide; ClientID; gliquidone; glysolid; tolazamide; and tolbutamide; (d) inhibitors of α-glucosidase, such as acarbose, adipsin; camiglibose; emiglitate; miglitol; voglibose; progenitin-Q; substation; CKD-711; MDL-25637; MDL-73945; and MOR 14, and the like; (e) means for reducing the level of cholesterol, such as (i) inhibitors of HMG-CoA-reductase inhibitor (atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, mevastatin, rosuvastatin, simvastatin and other statins), (ii) tools that enhance the absorption/excretion of bile acids, such as cholestyramine, colestipol, dialkylaminoalkyl derivatives Poperechnaya dextran; Colestid®; LoCholest®, and the like, (ii) nicotine alcohol, nicotinic acid or a salt thereof, (iii) agonists proliferative-activator receptor α, such as derivatives fenofibrinova acid (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (iv) inhibitors of cholesterol absorption, such as complex esters of stanol, beta-sitosterol, stringlike, such as tiqueside; and azetidinone, such as azeti the IB and the like, and inhibitors (acyl CoA:cholesterol-acyltransferase (ACAT)), such as avasimibe and melinamide, (v) antioxidants, such as probucol, (vi) vitamin E, and (vii) thyromimetics; (f) PPARα agonists such as clofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other derivatives of fibrin acid, such as Atromid®, Lopid® and Tricor®, and the like, and PPARα agonists described in WO 97/36579, Glaxo; (g) PPARδ agonists; (h) agonists, PPARα/δ, such as muraglitazar, and compounds disclosed in US 6414002; (i) anti-obesity, such as (1) a means of improving the secretion of growth hormone agonists/antagonists of receptors means that increase the secretion of growth hormones, such as NN703, hexarelin, MK-0677, SM-130686, CP-424391, L-692429 and L-163255; (2) inhibitors of protein tyrosinosis-1B (PTP-1B); (3) the ligands of receptors cannabinoids, such as antagonists or inverse agonists of the receptor cannabinoid CB1such as rimonabant (Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4) serotonergic anti-obesity, such as fenfluramine, dexfenfluramin, phentermine, and sibutramine; (5) agonists, β3-adrenergic receptors, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, trekkin, Zeneca D7114, SR 59119A; (6) inhibitors of pancreatic lipase, such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, tiapo is in, diethylaminophenyl phosphate; (7) antagonists of the neuropeptide Y1, such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (8) antagonists of neuropeptide Y5, such as GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104; (9) receptor antagonists hormone melaninconcentrating (MCH); (10) receptor antagonists melaninconcentrating hormone 1 (MCH1R), such as T-226296 (Takeda); (11) agonists/antagonists of the receptor melaninconcentrating hormone 2 (MCH2R); (12) receptor antagonists orexin, such as SB-334867-A, and also disclosed in the above description of the patent publications; (13) reuptake inhibitors SSRIs, such as fluoxetine, paroxetine and sertraline; (14) agonists melanocortin, such as Melanotan II; (15) other Mc4r agonists (receptor melanocortin 4), such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melkor), CHIR86036 (Chiron); PT-141, and PT-14 (Palatine); (16) agonists 5HT-2; (17) agonists 5HT2C (serotonin receptor 2C), such as BVT933, DPCA37215, WAY161503, R-1065; (18) antagonists Galanina; (19) CCK agonists; (20) agonists, CCK-A (cholecystokinin-A), such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613; (22) antagonists of corticotropin-releasing hormone; (23) receptor modulators of the histamine-3 (H3); (24) antagonists/inverse agonists of the receptor histamine 3 (H3), such as hyperemia, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, closedprofit, jodieproffit, impressive GT2394 (Gliatech), and O-[3-(1H-imidazol-4-yl)propanol]carbamates; (25) inhibitors of β-hydroxysteroiddehydrogenase-1 (β-HSD-1); (26) inhibitors PDE (phosphodiesterase), such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram and cilomilast; (27) inhibitors of phosphodiesterase-3B (PDE3B); (28) inhibitors of transport NE (norepinephrine), such as GW 320659, despiramine, talsupram and nomifensine; (29) antagonists, ghrelin receptor; (30) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant nationalrevenue human leptin (Amgen); (31) derived leptin; (32) BRS3 agonist (receptor bombezin subtype 3), such as [D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6-13)propylamide, as well as compounds disclosed in Pept. Sci. 2002 Aug; 8(8): 461-75); (33) CNTF (ciliary neurotrophic factors)such as GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo), Buchbinder, PD170292 and PD149164 (Pfizer); (34) CNTF derivatives, such as axokine (Regeneron); (35) inhibitors of reuptake of monoamine, such as sibutramine; (36) activators UCP-1 (uncoupling protein-1), 2, or 3, such as phytanic acid, 4-[((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid; (37) agonists thyroid hormone β, such as KB-2611 (KaroBioBMS); (38) inhibitors of FAS (fatty acid synthase), such as cerulenin and C75; (39) DGAT1 inhibitors (diacylglycerides 1); (40) a DGAT2 inhibitors (diacylglycerides sheraz 2); (41) inhibitors of ACC2 (acetyl-CoA-carboxylase-2); (42) antagonists glucocorticoid; (43) allestree, such as oleoresin, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44) inhibitors dipeptidylpeptidase IV (DP-IV), such as solarindustrie, validperiod, NVP-DPP728, LAF237, MK-431, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, assuming your 274-444; (46) inhibitors of the conveyor in primary forms; (47) inhibitors of glucose Transporter; (48) inhibitor of phosphate Transporter; (49) Metformin (Glucophage®); (50) topiramate (Topimax®); and (50) peptide YY, PYY 3-36, analogs, derivatives and fragments of peptide YY, such as BIM 43073D, BIM-43004C (Olitvak, D.A. et al., Dig. Dis. Sci. 44(3):643-48 (1999)); (51) agonists of the receptor neuropeptide Y2 (NPY2), such as NPY3-36, N-acetyl[Leu(28,31)] NPY 24-36, TASP-V and cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) agonists, neuropeptide Y4 (NPY4), such as the peptide of the pancreas (PP), and other Y4 agonists, such as 1229U91; (54) inhibitors of cyclooxygenase-2 such as etoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070, TIRExB or JTE522, ABT963, CS502 and GW406381, as well as their pharmaceutically acceptable salts; (55) antagonists of neuropeptide Y1 (NPY1), such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56) antagonists of opioids, such as nalmefene (Revex®), 3-methoxyestradiol, naloxone, naltrexone; (57) the inhibitor of 11β HSD-1 (11-beta hydroxysteroiddehydrogenase type 1), such as BVT 3498, BVT 2733; (58) Aminorex; (59) impersonal; (60) amphetamine; (61) benzthe amine; (62) chlorphentermine; (63) clobenzorex; (64) klotrix; (65) glominerals; (66) clortermine; (67) cilexetil; (68) dextroamphetamine; (69) diphemethoxidine, (70) N-ethylamphetamine; (71) fenbutrazate; (72) penetrex; (73) fenproporex; (74) fluorex; (75) glominerals; (76) furfurylmercaptan; (77) levamfetamine; (78) levorotatory; (79) mefenorex; (80) metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83) pentrex; (84) phendimetrazine; (85) phenmetrazine; (86) pillories; (87) Vitapharm 57; and (88) zonisamide.

In another embodiment issleduemoi connection can be used in combination with antidepressant or anxiolytic agent, which include inhibitors of reuptake of norepinephrine (including tricyclic compounds of tertiary amines and tricyclic compounds of secondary amines), selective inhibitors of reuptake of serotonin (SSRI), monoamine oxidase inhibitors (MAOI), reversible inhibitors of monoamine oxidase (RIMA), inhibitors of reuptake of serotonin and norepinephrine (SNRI), antagonists of the corticotropin-releasing factor (CRF)antagonists, α-adrenergic receptors, receptor antagonists neirokinina-1, atypical antidepressants, benzodiazepines, agonists or antagonists of 5-HT1Ain particular, a partial agonist at 5-HT1Aand antagonists of the corticotropin-releasing factor (CRF). Specific tools included the t amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline, protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranilcipromin and selegiline; moclobemide, venlafaxine; either aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and their pharmaceutically acceptable salts.

In another embodiment of the inventive compound can be used in combination with anti-Alzheimer's disease; inhibitors of beta-secretase; inhibitors gamma-secretase; agents that increase the secretion of growth hormones; recombinant growth hormone; inhibitors of HMG-CoA reductase; NSAIDs, including ibuprofen; vitamin E; antibodies against amyloid compounds; antagonists of the receptor CB-1 or inverse agonists of the receptor CB-1; antibiotics, such as doxycycline and rifampin; antagonists of the receptor N-methyl-D-aspartate (NMDA), such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil and taken; agents that increase the secretion of growth hormones, such as ibutamoren, ibutamoren mesilate and capravirine; antagonists of the histamine H3; AMPA agonists; inhibitors of PDE IV; the military agonists GABA A; or agonist at neuronal nicotinic compounds.

In another embodiment of the inventive compound can be used in combination with sedatives, hypnotics means anxiolytic means antipsychotic means, sedatives, cyclopyrrolone, imidazopyridine, pyrazolopyrimidine, mild tranquilizers, agonists and antagonists of melatonin, melatonergic means, benzodiazepines, barbiturates, 5HT antagonists-2, etc. such as: adinazolam, allobarbital, econimic, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capured, carbomoyl, coralbean, chloralhydrate, chlordiazepoxide, clomipramine, clonazepam, claparede, clorazepate, clarett, clozapine, lprazepam, desipramine, exclama, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, postepu, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midfloor, midazolam, nefazodone, Nizamabad, nitrazepam, nortriptyline, oxazepam, paraldehyde is recommended that paroxetine, pentobarbital, perlapi, per anisin, phenelzine, phenobarbital, diazepam, promethazine, propofol, protriptyline, kwazepam, reclusiam, related, secobarbital, sertraline, supraglan, temazepam, thioridazine, tracazolate, tranylcypromine, trazodone, triazolam, crepidam, triatomid, triclofos, trifluoperazine, trimeton, trimipramine, medazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and their salts and combinations, and the like, or the claimed compound can be introduced in combination with physical methods such as with light therapy or electrical stimulation.

In another embodiment of the inventive compound can be used in combination with levodopa (in the presence or in the absence of a selective inhibitor of extracerebral decarboxylase, such as carbidopa or benserazida), anticholinergic means, such as biperiden (optionally as a salt of hydrochloride or lactate) and hydrochloride of trihexyphenidyl (benzhexol), COMT inhibitors such as entacapone, inhibitors MOA-B, antioxidants, antagonists of the adenosine receptor A2a, cholinergic agonists, NMDA receptor antagonists, antagonists of the serotonin receptor and agonists dopamine receptor, such as alenamy, bromkriptin, fenoldopam, lisuride, exagrid, pergolid and pramipexol. It should be understood that the dopamine agonist may be in the form of pharmaceutically acceptable salts, such ka is alentemol hydrobromide, bromocriptine mesilate, fenoldopam mesilate, nakagaito hydrochloride and pergolid mesilate. Lisuride and pramipexol usually used in the form mesolevel form.

In another embodiment of the inventive compound can be used in conjunction with tools such as acetophenazine, alenamy, benzhexol, bromkriptin, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazida, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindone, exagrid, olanzapine, pergolid, perphenazine, pimozide, pramipexol, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene or trifluoperazine.

In another embodiment of the inventive compound can be used in combination with a compound selected from neuroleptic-related funds to classes fenotiazinas, thioxanthene, heterocyclic of dibenzazepines, butyrophenones, diphenylbutylpiperidines and Andronov. Suitable examples fenotiazinas include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. Example dibenzazepine is clozapine. Example butyrophenones is haloperidol. Example difenilbutilpiperidina is pimozide. Example indolene what is malindalo. Other neuroleptic drugs include loxapine, sulpiride and risperidone. It should be understood that the neuroleptic drugs used in combination with the test compound may be in the form of pharmaceutically acceptable salts, such as chlorpromazine hydrochloride, mezoridazina besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine anatot, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are usually used in mesolevel form.

In another embodiment of the inventive compound can be used in combination with analyticheski means, such as Aminorex, impersonal, amphetamine, benzphetamine, chlorphentermine, clobenzorex, klotrix, glominerals, clortermine, cilexetil, dexfenfluramin, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, penetrex, fenproporex, fluorex, luminares, furfurylmercaptan, levamfetamine, levorotatory, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, phenterex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, pillories and sibutramine; selective inhibitor of re is ogloszenia serotonin (SSRI); halogenated derivatives of amphetamine, such as chlorphentermine, klotrix, clortermine, dexfenfluramin, fenfluramin, pillories and sibutramine; and pharmaceutically acceptable salts.

In another embodiment of the inventive compound can be used in combination with an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, an inhibitor of cyclooxygenase, such as an inhibitor of cyclooxygenase-2, an inhibitor of interleukin, such as an inhibitor of interleukin-1, a NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal anti-inflammatory agent, or a cytokine-suppressor anti-inflammatory agent, for example, in combination with such soedinenii as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, Ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic medicine Sufentanil, sulindac, tenidap, etc. in a Similar manner, the inventive compound can be entered with a pain reliever; potentiate means, such as caffeine, an H2 antagonist, simethicone, aluminum hydroxide or magnesium; an antitumor agent such as phenylephrine phenylpropanolamine, pseudoephedrine, Oxymetazoline, epinephrine, nafazolina, Xylometazoline, propylhexedrine or levocetirizine; antitussive agent, so the m as codeine, hydrocodone, caramiphen, cabeamento or dextramethorphan; diuretic; and a sedating or resedation antihistaminic drug.

Compounds of the present invention can be entered via oral, parenteral (e.g., by intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or local routes of administration, these compounds, individually or together, can be included in the compositions are in the form of a suitable standard dosage forms containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and environment suitable for the particular route of administration. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of this invention can be used effectively applied to people.

Pharmaceutical compositions for administration of the compounds of this invention are typically in the form of standard dosage forms and can be obtained using any of the well-known pharmaceutical methods. All methods include the stage of mixing the active ingredient with the carrier which consists of one or not is how many additional ingredients. Typically, the pharmaceutical composition is produced by uniform and homogeneous mixing of the active ingredient with liquid carriers or finely divided solid carrier, or both with another, and then, if necessary, the molded product to produce the desired forms. Active target connection is included in the pharmaceutical composition in a quantity sufficient to achieve the desired effect upon the process or condition of diseases. The term "composition" in this description refers to the product containing the specified ingredients in the specified amounts, as well as to any product, which is formed, directly or indirectly, by combining the specified ingredients in the specified amounts.

Pharmaceutical compositions for oral administration can be obtained using any known in this area of the method for industrial preparation of pharmaceutical compositions and such compositions may contain one or more means selected from the group comprising sweetening means, flavouring tools, painting tools and preservatives that provide pharmaceutically elegant and pleasant drugs. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable fillers, suitably the mi for industrial production of tablets. These fillers may include, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezintegriruetsja tools, such as corn starch or alginic acid; binding agents such as starch, gelatin or gum Arabic, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a continuous action over a long period of time. Compositions for they orally application can also be presented as hard gelatin capsules where the active ingredient is mixed with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active substance in a mixture with fillers, suitable for receiving water suspensions. Oil suspensions can be obtained by suspension of the active ingredient in a suitable oil. You can also use the TB emulsion oil-in-water. Dispersible powders or granules, suitable for obtaining an aqueous suspension by adding water, contain the active ingredient mixed with dispersing or wetting agent, suspendium means and one or more preservatives. The pharmaceutical compositions of the compounds of the present invention can be in the form of a sterile aqueous or oily suspensions for injection. Compounds of the present invention can also be entered in rectal suppository. For local use, you can use creams, ointments, gels, solutions or suspensions, etc. containing compounds of the present invention. Compounds of the present invention can also be included in compositions used for administration by inhalation. In addition, the compounds of the present invention can be introduced through a percutaneous patches using known in the field of methods.

Some methods of making compounds of this invention are illustrated in the following schemes and examples. The initial substance was produced using the known or described herein ways. In this opisanie use the following abbreviations: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl; THF: tetrahydrofuran; DEAD: diethylazodicarboxylate; DIPEA: N,N-diisopropylethylamine; DMSO: dimeji the sulfoxide; EDC: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; HOBT: hydroxybenzotriazole hydrate; Boc: tert-butyloxycarbonyl; Et3N: triethylamine; DCM: dichloromethane; DCE: dichloroethane; BSA: bovine serum albumin; TFA: triperoxonane acid; DMF: N,N-dimethylformamide; MTBE: methyl tert-butyl ether; SOCl2: thionyl chloride; CDI: carbonyldiimidazole; K.T.: room temperature; HPLC: high performance liquid chromatography; T3P: 1-propylphosphonic anhydride. Compounds of the present invention can be obtained in different ways.

In some cases, the final product can be further modified, for example, by the influence of the substituents. Such effects may include, without limitation, reaction, recovery, oxidation, alkylation, acylation and hydrolysis, which are well known to specialists in this field. In some cases, when carrying out the above reaction schemes and examples can be modified to facilitate the flow of the reaction or to avoid unwanted reaction products. The following examples are provided to more fully explain the invention. These examples are only illustrative and should not be construed as limiting in any way the scope of this invention.

An EXAMPLE of A

Methyl ester of 6-methylnicotinate KIS is the notes (A-2)

A solution of 6-methylnicotinic acid (20 g, 146 mmol) in MeOH (300 ml) is treated with gaseous HCl to saturation of the solvent. The reaction mixture was closed and stirred for 1.5 h at K.T. Mixture is treated again with gaseous HCl to saturation of the solvent, cover and stirred overnight at 22°C. the Solution is concentrated and getA-2. Analytical data forA-2: LRMS(mass spectrometry low resolution)m/z (M+H): 152,75.

Methyl ester of 6-methyl-3-piperidinecarboxylic acid (A-3)

SolutionA-2(23 g, 152 mmol) in EtOH (200 ml) is treated with 5 mol.% oxide of platinum (1,728 g, to 7.61 mmol) and acetic acid (8,71 ml, 152 mmol). The flask Steam vacuum, fill the H2(gas) three times and stirred in an atmosphere of H2(gas) (45 psi, reboot 4 times) at 22°C for 3 hours the Mixture is filtered through celite and the filter cake (layer) was washed with MeOH. The filtrate is concentrated and receive a product with a ratio of CIS:TRANS diastereomers approximately 3.5:1. The resulting material is diluted with 300 ml of MeOH, treated with sodium methoxide (from 32.9 g, 183 mmol), heated to 50°C and stirred at the same temperature for 4 days. The mixture is cooled to 22°C, neutralized to pH 7 with concentrated HCl, filtered through celite and concentrated. The residue is suspended in MeOH and again filtered. The obtained filtrate is concentrated and receive A-3 (~3:1 TRANS:the IP). Analytical data for A-3: LRMS m/z (M+H): 158,9.

6-Methyl-3-piperidinemethanol (A-4)

A suspension of amine hydrochloride, ~3:1 TRANS:CIS (500 mg, 2.58 mmol)in THF (15 ml) was slowly treated with aluminum lithium hydride (3,37 ml of 7.75 mmol) at 22°C. the Solution is heated to 0°C, stirred for 20 min and then treated dropwise 0,294 ml of water, 0,294 ml of 15% NaOH and 0,882 ml of water successively. Sodium sulfate is added to the mixture. After stirring for 20 min at 22°C the mixture is filtered, the filtrate concentrated and getA-4in the form of a colorless oil. Analytical data forA-4: LRMS m/z (M+H): 130,2.

Benzyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperidin-1-carboxylate (A-5)

A solution of amineA-4(350 mg, a 2.71 mmol) in DCM (15 ml) is treated with TEA (0,755 ml, 5,42 mmol) and CBZ-Cl (0,387 ml, a 2.71 mmol). The mixture is stirred at 22°C and concentrated. The residue is partitioned between EtOAc and water. The organic phase is dried over Na2SO4filter and concentrate. The crude substance is purified by gradient elution on silica gel (0 to 70% EtOAc in Hex) and receive 377 mg of racemic substances (~3:1 TRANS:CIS). TRANS-diastereomers is separated from the CIS-diastereomers and separated into the enantiomers by chiral column with an external diameter of 5 cm by isocratic elution (93:7 hexane:EtOH; 75 ml/min; 1 respectively) with detection at 215 nm, receiving 120 mgA-5peak 1 (colorless oil, 100% ee) and 14 mg of the fraction of the peak 2 (colorless oil, containing 30% of the CIS isomer, 90% ee). Analytical data forA-5:LRMS m/z (M+H): 264. Similarly CIS-diastereoisomer can be divided into enantiomers, which can then be used to obtain compounds (R,S) and (S,R).

Benzyl (2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-carboxylate (A-6)

A solution of isomerA-5, eluruumideta first (120 mg, 0,456 mmol), 5-fluoro-2-hydroxypyridine (of 56.7 mg, 0,501 mmol) and immobilized on the resin triphenylphosphine (0,254 ml, 0,547 mmol) in DCM (3 ml) is treated with diisopropylcarbodiimide (0,106 ml, 0,547 mmol). The mixture is stirred over night, filtered and concentrated. The crude substance is purified by gradient elution on a reversed phase (from 5 to 95% MeCN in water with 0.1% TFA))to give pure fractions are concentrated, diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic phase is dried over Na2SO4filter, concentrate, and getA-6in the form of a colorless film. Analytical data forA-6: LRMS m/z (M+H): 264.

5-fluoro-2-{[(3R,6R)-6-methylpiperidin-3-yl]methoxy}pyridine (A-7)

A solution of carbamateA-6(107 mg, 0,299 mmol) in EtOH (5 ml) is treated with 10 mol.% of palladium hydroxide-on-coal (20,96 mg 0,030 mmol). The vacuum flask and fill with H2(gas) three times, then stirred in an atmosphere of H2(gas) (1 ATM) at 22°C for 40 minutes the Mixture fil who demonstrate through a syringe filter. The filtrate is concentrated and getA-7in the form of a colorless film. Analytical data forA-7: LRMS m/z (M+H): 225.

2-(2H-1,2,3-triazole-2-yl)-5-methylbenzoic acid (A-8)

A solution of 2-iodine-5-methylbenzoic acid (4.0 g, of 15.3 mmol) in DMF (10 ml) is treated with 1,2,3-triazole (2.1 g, 30,5 mmol), Cs2CO3(9.95 g, 30,5 mmol), CuI (0,145 g, from 0.76 mmol) and TRANS-N,N'-dimethylcyclohexane-1,2-diamine (0,43 g of 3.05 mmol). The mixture is heated at 120°C for 10 min in a microwave reactor. The reaction mixture is cooled to room temperature, diluted with water and washed with EtOAc. The aqueous phase is acidified with 1N HCl and extracted with EtOAc. The organic layer is dried over Na2SO4filter and concentrate. The residue is purified by gradient elution on SiO2(from 0 to 10% MeOH in CH2Cl2in the presence of 0.1% AcOH)to give 2-(2H-1,2,3-triazole-2-yl)-5-methylbenzoic acidA-8that eluted earlier, and thereafter eluted unwanted regioisomer 1-(2H-1,2,3-triazole-2-yl)-5-methylbenzoic acid. Analytical data forA-8:1H NMR (500 MHz, DMSO-d6d 12,98 (users, 1H), 8,04 (s, 2H), 7,72 was 7.45 (m, 3H), 2,41 (s, 3H) ppm

5-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine (A-9)

SolutionA-7(67 mg, 0,299 mmol) in DMF (1 ml) is treated with acidA-8(60,7 mg, 0,299 mmol), EDC (of 68.7 mg, 0,358 mmol), HOBT (54.9 mg, 0,358 mmol) and triethylamine (0.17 ml, 1,195 mmol). After stirring at 22°C overnight the mixture was diluted with EtOAc and washed with water three times. The organic phase is dried over Na2SO4filter and concentrate. The crude substance is purified by gradient elution on silica gel (0 to 75% EtOAc in Hex) and get the crude substance. The resulting material purified by gradient elution on a reversed phase (from 5 to 95% MeCN in water with 0.1% TFA)to give the pure fractions are concentrated, diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic phase is dried over Na2SO4filter, concentrate, and getA-9in the form of a white solid. Analytical data forA-9: HRMS(mass spectrometry high resolution)m/z (M+H): found: 410,1993 calculated: 410,1987.

EXAMPLE B

5-fluoro-2-{[(3R,6R)-1-(2-iodine-5-methylbenzoyl)-6-methylpiperidin-3-yl]methoxy}pyridine (B-2)

To a solution ofA-7(325 mg, 1.5 mmol) in CH2Cl2(50 ml) at 0°C add diisopropylethylamine (506 ml, 2.9 mmol) and thenC-1(447 mg, 1.6 mmol, obtained fromA-8by processing SOCl2and a catalytic amount of DMF in CH2Cl2). After heating to room temperature and stirring for 2 h the reaction mixture was partitioned between CH2Cl2and saturated aqueous NaHCO3. With the ois share, the aqueous layer was again extracted with CH2Cl2combined organic layers washed with water, dried over Na2SO4filter and concentrate. The crude substance is purified by gradient elution on silica gel (0 to 100% EtOAc in Hex) and obtain 530 mgB-2in the form of a white solid. Analytical data forB-2: LRMS m/z (M+H): 469,1.

2-{2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-were}pyrazin (B-3)

To a solution ofB-2(70 mg, 0.15 mmol) in DMF (2 ml) is added 2-tributylstannyl (83 mg, 0.22 mmol), copper iodide(I) (5.7 mg, 0.03 mmol), cesium fluoride (45 mg, 0.3 mmol) and tetranitroaniline(0) (17 mg, 0.015 mmol). After stirring at 80°C overnight, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The layers separated, the organic layer washed with water, saturated salt solution, dried over MgSO4filter and concentrate. The crude substance is purified by gradient elution on silica gel (0 to 100% EtOAc in Hex)followed by a second chromatography on silica gel (0 to 100% of 80:10:10 CHCl3:EtOAc:MeOH in CHCl3and receive 20 mgB-3in the form of a colourless resin. Analytical data forB-3: HRMS m/z (M+H): found: 421,2011 calculated: 421,2034.

EXAMPLE C

[(3R,6R)-6-methylpiperidin-3-yl]methane is (C-1)

To a solution ofA-5(2,75 g, 10.4 mmol) in MeOH (50 ml) is added 20% Pd(OH)2coal (~700 mg), vaccum flask, and the atmosphere replaced with H2. After stirring under pressure H2over night the reaction mixture was filtered through celite and concentrated, obtaining 1.29 g (96%)C-1in the form of a white solid. Analytical data forC-1: LRMS m/z (M+H): 130,2.

{(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methanol (C-3)

To a solution ofC-1(675 mg, with 5.22 mmol) in CH2Cl2(70 ml) at 0°C. add triethylamine (2.9 ml, of 20.9 mmol) and thenC-2(2.17 g, 10.4 mmol, synthesized according to the method of obtainingB-1using as a starting compound 2-identies acid). After heating to room temperature and stirring overnight, the reaction mixture was partitioned between CH2Cl2and water. The layers separated, the organic layer was washed with saturated aqueous NaHCO3, water, dried over Na2SO4filter and concentrate the receiving of 2.46 g of a yellowish brown solid, which is a bis-acetylated compound. To selectively hydrolyze ester, the resulting substance was dissolved in 150 ml of a mixture of 1:1 THF/MeOH and add 50 ml of 1M LiOH. After stirring over night at room temperature the mixture was partitioned between EtOAc and 0.5 M NaOH. Layers is andelat, the organic layer is washed twice with 0.5 M NaOH, saturated salt solution, dried over Na2SO4filter and concentrate. The crude substance is purified by gradient elution on silica gel (0 to 100% EtOAc in Hex) and obtain 890 mgC-3in the form of a white solid. Analytical data forC-3: LRMS m/z (M+H): 301,2.

2-Methyl-6-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine (p-4)

To a solution ofC-3(50 mg, 0.25 mmol) in DMF (2 ml) is added sodium hydride (10 mg, 0.25 mmol, 60% suspension in oil) and then 2-fluoro-6-methylpyridin (21 mg, 0.18 mmol). After stirring at room temperature over night add another portion of NaH and 2-fluoro-6-methylpyridine and stirring is continued for another 8 h, after which the reaction is quenched with saturated aqueous NH4Cl. The mixture is then partitioned between EtOAc and saturated aqueous NaHCO3. The layers separated, the organic layer washed with water, saturated salt solution, dried over MgSO4filter and concentrate. The crude substance is purified by gradient elution on silica gel (0 to 100% EtOAc in Hex) and receive 70 mgC-4in the form of a white solid. Analytical data forC-4: HRMS m/z (M+H): found: 392,2059 calculated: 392,2081.

EXAMPLE D

Dimethyl (3-oxobutyl)malonate (D-1)

In h is out and dry round bottom flask with a volume of 100 l, equipped with an additional funnel, a hole for introducing nitrogen, and a thermocouple, add acetonitrile and potassium carbonate. Add diethylmalonate, after which the resulting mixture was cooled to 17°C (bath containing ice water). Then for 3 h and methyl vinyl ketone are added, keeping the internal temperature did not rise above 26°C. After 18 h according to HPLC is complete metamorphosis. The mixture is transferred to the extractor volume of 100 l containing 60 l of MTBE and 20 l of water. The layers are separated and the aqueous layer was again extracted with 20 l of MTBE. The combined organic layers washed with 20 l of water and leave the emulsion to settle for 5 h Then the organic layer is filtered through solka floc, the party concentrated, washed with 20 l of MTBE and get 15,1 kgD-1(80 wt.% according to the1H NMR, yield 80%). Analytical data forD-1:1H NMR (400 MHz, CDCl3) δ of 3.69 (s, 6H), 3,40 (t, J=7,3 Hz, 1H), 2,50 (t, J=7.2 Hz, 2H), 2,15-to 2.06 (m, 5H).

Methyl (6R)-6-methyl-2-oxopiperidin-3-carboxylate (D-2)

Clean look round bottom flask with a volume of 20 l load 7,15 kg 64 wt.%D-1and evaporated on the rotor to remove the remainder of acetonitrile and MTBE. The concentration of the resulting solution is 83 wt.%. In visually clean reactor Bucha shirt with a volume of 100 l equipped with the upper stirrer, add 45 l of water. Initiate heated to 30°C, then add 852 g of Na2HPO4, 7,2kg D-alanine, 6.48 in kg glucose, 22,5 g NAD and 45 g of PLP. the pH was adjusted to 7.4 using NaOH, then add 450 g transaminase ATA-117, 9 g of lactate dehydrogenase and 45 g of glucosegalactose, after which the vessel rinsed with 2.5 l of water. After all the enzymes go into solution, add one stripped off on the rotor solutionD-1and at the end of 2.5 l of water. Initiate regulation of pH using 5N NaOH. The reaction mixture was left to mix for 42 hours; the reaction is completed after 31 hours. In the reaction vessel add 19,4 kg NaCl and 6.0 l of 5N HCl to bring the pH to 3.5. Add 20 ml of acetonitrile and allowed to mix for 10 minutes the Stirrer is switched off and the reaction mixture is left to settle for 1 h, the acetonitrile Layer produced; the aqueous layer was re-extracted with acetonitrile, and then layers of acetonitrile unite. Received the combined acetonitrile solution is filtered through Solka-floc, combine with the second batch of the same size and concentrated to remove the acetonitrile and water. The resulting oil contains a high concentration of heterogeneous NaCl. The oil is then dissolved in 50 l of EtOAc and transferred to a clean look round bottom flask with a volume of 20 l and evaporated on the rotor, receivingD-2in the form of oil (5.5 kg, 94 wt.%, yield 74%, 99% ee according to HPLC on Chiralpak). Analytical data forD-2: LRMS (M+H) = 172

(6R)-3-(Hydroxymethyl)-6-methylpiperidin-2-he (D-3)

In visually clean the dry extractor 140-litre, equipped with glycol cooling coil inlet for nitrogen, a large outlet for the gas and thermocouple, load of 18.7 wt.% solutionD-2in EtOH [4,6 l/kg] and additionally 71,4 l EtOH [25,4 l/kg]. Calcium chloride add 3 portions over 15 min and then stirred until complete dissolution with decreasing temperature from 26 to 22°C. sodium Borohydride add 3 portions over 20 minutes After the last addition the temperature increased to 25°C. the evolution of gas ceases after 30 minutes the Reaction mixture was allowed to mix for 20 h, installing cooling to maintain the temperature below 22°C. the Mixture is cooled to 5°C, then quenched by careful addition of 11.2 l of 6N HCl for 30 min, keeping the temperature below 9.5°C. the mixture is Then warmed to room temperature and stirred for 2 h Damp indicator paper when immersed in the mixture shows a pH of 2. The mixture is filtered through Solka floc and washed with 2×12 l EtOH. Analysis of all receivers shows the total weight 2.55 kg (108% AY). The filtrate is combined with the second batch of the same size and concentrate. After evaporation of the greater part of ethanol add 8 l of water, to jointly EtOH was evaporated and partially solubilisate sediment. After migration, 23 l water layer in the extractor volume was adjusted with water to 31.6 L. the Mixture is extracted with 53 l, then 2×26,5 l 1-butane is La (HPLC analysis shows 92 g, 1,9% is lost in the aqueous layer). The combined organic layers washed with 10.5 l of saturated brine (HPLC analysis shows 419 g of 8.8% is lost in flushing). The analysis shows in the organic layer is 4.21 kg (yield 92%, 96% AY), after which he concentrated to a minimum volume. Then it is subjected to azeotropic distillation with 12 l of water and then with 120 l of isopropanol. The KF analysis shows a 0.5% water with a total volume of ~40 HP, the Suspension is filtered through Solka floc and washed with 2×10 l of isopropanol. The filtrate is stirred into the extractor to a homogeneous state and analyze the content of the substance, which is 4,13 kg (94% AY, 1,7:1 dr). The solution is divided into two equal portions. Each portion was concentrated to a minimum volume, is subjected to azeotropic distillation with 140 l of THF and getD-3in the form of a beige suspension (yield 94%).1H NMR shows 0.6 EQ. isopropanol. Analytical data forD-3: LRMS (M+H) = 144

[(6R)-6-methylpiperidin-3-yl]methanol (D-4)

In a clean and dry 5-necked round bottom flask with a volume of 100 liters, equipped with a mechanical stirrer, thermocouple, inlet for nitrogen and a cooling bath, loadD-3(2,07 kg, 1.0 EQ.) and THF (20 l, 10 ml/g). The mixture is cooled to -25°C. for 3.5 hours added LiAlH4(2,6M solution of 22.2 l, 4.0 equiv.) maintaining the temperature of the mixture in the range of from -25° to +12°C. When adding the first 6 l of a solution LiAH 4there has been a considerable evolution of gas (H2). After complete addition, the mixture is left to warm to 20°C, then heated with steam to 50°C. the Mixture is kept at this temperature for 12 hours GC-FID and LC-MS show what happened >99% conversion in the target piperidine-alcohol. The mixture is cooled to -25°C and then quenched using the method of Fieser. Within 3 h to the mixture add water (2.2 l), thus there is a considerable evolution of gas and heat (temperature kept in the range from -25°C to +13°C). Then to this mixture 3,75M NaOH (2.2 l) for 1.5 hours And at the end add water (6,6 l) for 1 h the Mixture is cooled to 5°C and hold for 1.5 hours, the Suspension is filtered, the cake washed with THF (20 l). Get 1,54 kg (2,33 wt.%.), therefore, the analytical outputD-4is 82% (dr = 1,7:1, mainly TRANS-isomer). Analytical data forD-4: LRMS (M+H) = 130

[(3R,6R)-6-methylpiperidin-3-yl]methanol CSA salt (D-5)

In a visually clean and dry 5-necked extractor 140-litre, equipped with a mechanical stirrer, thermocouple, inlet for nitrogen and a cooling coil loadD-4(3.04 kg, 1.0 EQ.) and THF (60 l, 20 mg/g). To the mixture add a solution of (D)-(+)-CSA (4,37 kg, 0.8 EQ.) in THF (4 ml/g, 12 l) for 1 h Salt crystallizes without adding salt. After complete addition, the mixture was incubated 45 min at 20°C, then add MTBE (10 ml/g 30 l) in accordance with the s 45 minutes The mixture was incubated for 45 min, then cooled to 2°C within 45 minutes, the Mixture is left to stand at this temperature for 30 min, and then filtered. Salt is washed with 2×6 ml/g (2×18 l) a mixture of THF/MTBE 1/1, then 1×6 ml/g (1×18 l) MTBE and dried on the Frit under nitrogen atmosphere for 16 h, getting to 4.46 kg (52%)D-5in the form of a white solid. The diastereoselectivity of salt (measured on the model of the free base after the destruction of the salt) is 40-50:1.

tert-Butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperidin-1-carboxylate (D-6)

In a visually clean and dry extractor 140-litre, equipped with glycol cooling coil inlet for nitrogen and a thermocouple, load 40 l of dichloromethane and thenD-5(4.2 kg). To the resulting suspension added triethylamine one partiia (4.8 l, the heat is not observed) and then Boc2O (2.66 kg added dropwise within 5 min, observed exothermic effect 4°C). After 30 minutes the reaction mixture becomes homogeneous. Analysis IHMS (after 3 h) shows that the original substance has trashdolls completely. The reaction mixture was diluted with 2M ammonium chloride (40 l) and separate the layers. The organic layer was washed with polysystem salt solution (20 l) and separate the layers. The HPLC analysis of the crude reaction mixture shows 105% AY (2,81 kg). The crude reaction mixture was dried over Na2 SO4(200 wt.%), filtered and transferred into a flask with a volume of 100 l, hosting totalrevenue.

tert-Butyl (2R,5R)-2-methyl-5-({[(4-were)sulfonyl]oxy}methyl)piperidine-1-carboxylate (D-7)

In a visually clean and dry reactor with a volume of 100 liters, equipped with a mechanical stirrer, inlet for nitrogen and a thermocouple, load the crude solutionD-6in dichloromethane (final volume was adjusted to 10 l, about 2.2 ml/g). To the resulting cold solution (0°C) is added pyridine (5.5 litre, heat is not observed) and then TsCl (4 portions over 1 h, the evolution of heat is observed, but is easily adjustable). The reaction mixture is heated to room temperature and stirred for 18 h (HPLC analysis shows that the original substance has trashdolls completely). The reaction mixture is transferred to the extractor 140-litre and diluted with MTBE (7 ml/g), a saturated solution of NH4Cl (20 l) of water (10 l). The layers separated, the organic layer was washed with CuSO4·5H2O (20 l, 10 l), a saturated solution of NaHCO3(10 l) and polysystem salt solution (10 l). The crude organic layer is filtered through a layer of silica gel (1.5 kg), after which the layer is washed with MTBE (10 l). Analytical outputD-7measured on the obtained solution is 93% (4,28 kg). Analytical data forD-7: LRMS (M-Boc) = 284,0.

tert-Butyl (2R,5R)-5-{[(5-forperiod the h-2-yl)oxy]methyl}-2-methylpiperidin-1-carboxylate (D-8)

In a visually clean and dry 5-necked round bottom flask with a volume of 100 liters, equipped with a mechanical stirrer, thermocouple, inlet for nitrogen and a cooling bath, loadD-7(3,23 kg, 1.0 EQ.) and NMP (65 l, 20 ml/g). Add 5-fluoro-2-hydroxypyridine (1.19 kg, 1.25 EQ.) and then Cs2CO3(7,37 kg, 2.7 EQ.). Heat is not observed. The mixture is heated to 60°C and maintained at this temperature for 26 hours HPLC shows >99.9% conversion to the desired product. The mixture is cooled to 15°C, the reaction is quenched by adding water (65 l) for 1 h to control the heat (from 15°C to 28°C). Piperidine-O-pyridine extracted using MTBE (20 ml/g, 65 l). The organic layer was washed with 2×10 ml/g 10% LiCl (2×32 l), then 2×10 ml/g Polynesians NaCl solution (2×32 l). The analysis shows that the content ofD-8measured in the MTBE layer, is 2.16 kg, 79%. Analytical data forD-8: HRMS (M+H) = 325,1922.

5-fluoro-2-{[(3R,6R)-6-methylpiperidin-3-yl]methoxy}pyridin (D-9)

In visually transparent flask with a volume of 50 liters, equipped with a thermocouple and a mechanical stirrer, download solutionD-8(2,15 kg, 6,63 mol) in MTBE, after which the solvent is replaced with dichloromethane (11,40 l). The resulting mixture was cooled to -2°C in a bath containing ice/IPA. Then slowly (over 40 minutes, T°C = -1,9°C to 5.5°C, with a maximum of 5.5°C) is added TFA (5,5 l 71,4 mol). After conclusion of the Oia adding the reaction mixture is removed from the bath with ice and warmed to room temperature with warm water (ranging from 5.7°C, 50 minutes). The reaction is terminated after 3.5 hours. After concentration under reduced pressure, the resulting oil is transferred into a 100 l extractor containing the cooled mixed solution of NaOH (3,0N, 1.1 EQ., 28 l), and add 30 l of MTBE, then the phases are separated. The organic layer was washed with 30 l of 2N HCl and again 10 l of 2N HCl. Then cool water layers (9°C) and add 10N NaOH to achieve pH 13 (T° = 21°C). To the resulting solution add 25 l of MTBE and the layers separated. Finally, the aqueous layer was again extracted with 10 l of MTBE.D-9received, according to quantitative HPLC analysis, with a yield of 98% and a purity of >99.7%of use in the next reaction as is. Analytical data forD-9: LRMS (M+H) = 225,1

EXAMPLE E

Methyl 2-iodine-5-methylbenzoate (E-1)

In visually clean flask with a volume of 100 liters, equipped with a mechanical stirrer, a thermocouple and a water fridge, download MeOH (50 l). Then added with stirring 2-iodine-5-methylbenzoic acid (5,85 kg, 22,32 mol). Portions add concentrated sulfuric acid (0,595 l, 11,16 mol), which causes an increase in temperature from 17°C to 22°C. the Mixture is gradually heated until reaching an internal temperature 64,6°C and incubated overnight (~18 h). The next morning, the transformation according to HPLC exceeds 98%. The flask was cooled to 16°C by placing in a bath of ice and slowly (to use the e 10 minutes) add 850 ml of 10N NaOH (0,98 equiv.) registering pH. By the end of the addition the pH is 5-6 (caution: if the pH exceeds 9, the processing may occur saponification). Then the solution is concentrated to approximately 16 l, and the resulting suspension is transferred to the extractor volume of 100 l Flask was washed with 8 l of IPAc and 4 l of water, after which rinse transferred to the extractor. 32 l IPAc along with 10 l of 5 wt.% NaHCO3and ~10 l 15 wt.% a saline solution. The layers are separated and the aqueous layers again extracted with 20 l of IPAc. Then the organic layers are combined and washed with 10 l 15 wt.% a saline solution. The organic layers are collected, gettingE-1(6,055 kg, 21,93 mol, yield 98%) with a purity of 98.3%.

Methyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (E-2)

SolutionE-1(5,9 kg, 21,37 mol) in iPAc load in visually clean flask with a volume of 100 liters, equipped with a mechanical stirrer and thermocouple. The solvent of the solution changed to 2-MeTHF (~35 l). Add triethylamine (8,94 l, 64.1 mol) and the solution Tegaserod using the N2. To mix the solution, maintaining the blowing, slowly (over 15 minutes) add pinacolborane (4,65 l, 32.1 mol). The solution in addition Tegaserod for 10 minutes, add three-on-tolylphosphino (0,325 kg, 1,069 mol) and then palladium (II) acetate (0.120 kg, 0,534 mol). When this reaction mixture immediately turns black, and the temperature slowly increased from 11.5°C to 30°C. At this point observed the fast delayed the release of heat and the temperature of the reaction mixture increases to 60°C (within 45 minutes). The temperature of the reaction mixture increases to 77°C and the mixture was incubated for another 45 minutes. Then an aliquot of the reaction mixture is subjected to HPLC analysis, which shows that starting material was completely slashdowns. The heat source is removed, under the flask bath with ice and the reaction mixture is cooled for 1.5 hours. Very slowly, in order to control the allocation of gas and heat (within 60 minutes), add 26 wt.% a solution of ammonium chloride, which causes the formation of a black precipitate. The supernatant is transferred into an extractor containing 40 l of water. The remaining black suspension is filtered over Solka Floc and washed with MTBE (~20 l). The filtrate is loaded into the extractor. Layers separated by organic layers according to the results of the analysis containsE-2(4,45 kg, 16,11 mol, 75%yield) with a purity of 81.6%, which is used in the next stage, as is.

Methyl 5-methyl-2-pyrimidine-2-eventout (E-3)

SolutionE-2(of 4.38 kg, 15,84 mol)obtained in the previous phase load in a visually clean reactor with a volume of 100 liters, equipped with a mechanical stirrer and thermocouple. The solvent mixture is replaced with 2-MeTHF (35 l). Then add 2-chloropyrimidine (2,18 kg, 19.01 in mol) (lowering the temperature from 19 to 14°C) and sodium carbonate (5,04 kg and 47.5 mol). To a stirred suspension add water (11,67 l) (lowering the temperature from 15 to 24°C). A dense suspension of Gehazi the coziness of N 2within 40 minutes, then add the adduct PdCl2(dppf)-CH2Cl2(0,518 kg, 0,634 mol), which causes blackening of the reaction mixture. The internal temperature is set at 74°C and the mixture was incubated for 16 hours an Aliquot subjected to HPLC analysis, which shows that happened almost complete consumption of the source boronate (conversion of >97%). The reaction mixture is cooled to room temperature and added to 12 l of water and 24 l of MTBE under stirring for 10 minutes. The resulting solution is filtered over Solka floc and transferred to the extractor volume of 100 l Flask additionally washed with 4 l of MTBE and 4 l of water (×2) and then 4 l of MTBE. The layers are separated, then the aqueous layers again extracted 21,5 l MTBE. Analysis of organic layers indicates the presence of burilovo of ester (2.76 kg, 12,09 mol, yield 76%). The organic layers are again loaded into the extractor, add 1,26 kg Darco KB-G, after which the mixture is stirred for 2 hours and then filtered through Solka floc. The filter cake was washed with 3×10 l of MTBE. Heavy metals analysis shows that there is 427-493 M. D. Pd and 882-934 ppm Fe. According to the results of the analysis, get 2,381 kgE-3(66%, 86% recovered from DARCO). Analytical data forE-3:1H NMR (500 MHz, CDCl3, 293K, TMS): 8,78 (d, J=4,87 Hz, 2H), of 7.97 (d, J=to 7.93 Hz, 1H), 7,51 (s, 1H), 7,39 (d, J=7,99 Hz, 1H), 7,19 (t, J=4,88 Hz, 1H, in), 3.75 (s, 3H), of 2.44 (s, 3H).

5-Methyl-2-feast of midin-2-Albertina acid (E-4)

SolutionE-3obtained in the previous phase load in a visually clean flask with a volume of 100 l via the built-in filter, and concentrate the solvent is replaced with 2-MeTHF (~15 l). To the resulting solution was added water (20 l) and then sodium hydroxide (10N) (2,60 l, 26.0 mol). After the addition, the reaction mixture turns red, the heat source is set at 72°C. the Mixture was kept at this temperature for 1.5 hours, after which, according to HPLC, there is the completion of the reaction. The reaction mixture is cooled and transferred to the extractor volume of 50 l Flask was washed with 4 l of water and 10 l of MTBE, which is added to the mix in the extractor mixture. The layers are separated and the aqueous phase is washed with twice 10 l of MTBE. Then the aqueous layer was again injected into the reactor (100 l) through the built-in filter for acidification. To the cold mixture is added slowly to 2.3 l of 12 N HCl, causing a temperature increase from 7 to 10°C. this is accompanied by the formation of a beige precipitate (pH 1). The precipitate is filtered. Beige filter cake washed twice in 3 ml/g of cold water. Then the cake was washed with 3 ml/g cold mixture of 15% MTBE/heptane and 15% PhMe/heptane. In the end the mixture was washed with 1.5 ml/g MTBE at room temperature and twice in 3 ml/g of heptane at room temperature. Then the solid is dried in a stream of N2within 2 days and getE-4in the form of a light beige powder (2,15 kg, 10,04 mol, o is d 97%). The HPLC analysis shows that the product has a purity of 99.2%. Heavy metals analysis shows that there is 264 ppm Pd and 19.7 ppm Fe. Analytical data forE-4:1H NMR (500 MHz, DMSO-d6) 12,65 (s, 1H), cent to 8.85-8,82 (m, 2H), 7,78 (DD, J=7,89, of 2.34 Hz, 1H), 7,49-7,37 (m, 3H), 2.40 a (s, 3H).

2-{2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-were}pyrimidine (E-5)

SolutionD-9(1 kg of 4.46 mol) is loaded into a visually clean and dry flask with a volume of 50 liters, equipped with a thermocouple and a mechanical stirrer, after which the solvent is replaced with DCM (11,00 l). Add DIPEA (2 l, of 11.45 mol) and then to the resulting solution was added with stirringE-4(1.22 kg, 5,67 mol). The resulting solution was cooled in a bath of ice (12°C). To mix the solution through an additional funnel type T3P (7,87 l, 13,38 mol), maintaining the temperature of the reaction mixture <21°C within 1 h After complete addition, the reaction mixture becomes yellow and homogeneous. To facilitate mixing, add 2 l of DCM. The reaction mixture is heated to 44°C (small heat at 42°C, resulting in a temperature increase to 46.7°C, and maintain the specified temperature for 30 min). The reaction mixture was kept at this temperature during the night. After 17 h the reaction is not completed and to accelerate the transformation, add T3P (1.1 l 1,870 mol). To follow is the third day (42 h) consider, that the reaction was completed, in accordance with the data of HPLC, after which the reaction mixture is cooled in a bath with ice to 4°C. Add 20 l of water (the first 1.5 liters slowly, then quickly), maintaining the temperature of the reaction mixture below 17°C. the resulting mixture was stirred at room temperature for 30 minutes. The mixture is then transferred into the extractor volume of 50 l containing 20 l of MTBE. The flask is washed with another 2 liters of water and 4 l of MTBE. The layers separated, the organic layers washed with 20 l of 1N NaOH and then 10 l of 1N NaOH. Finally, the organic layers washed with twice 10 l 15% salt solution. Then the organic fraction (quantitative HPLC analysis shows 1,65 kg) handle ~50 wt.% Darco KB (750 g) for 1.75 h, filtered over Solka floc and washed with 10 ml/g MTBE (1,559 kg, removing 94,5%). In a visually clean and dry 50 l RBF equipped with a mechanical stirrer, thermocouple, reflux condenser and inlet for nitrogen, download the crude substance obtained in the previous phase (solutionE-5all used solvents are filtered through the built-in filter 1 µm). The solvent of the reaction mixture is replaced by IPAc and the final volume was adjusted to 7.5 liters (about 4 ml/g IPAc). The reaction mixture is heated to 75°C (all substances soluble), slowly cooled to room temperature and bring in as starters at 45°C 18 gE-5(substance, suiryudan front, received the C rex in IPAc/heptane), stirred overnight (16 h) at room temperature, then add heptane (6 ml/g) for 60 minutes the Reaction mixture was incubated for 1 h, then cooled to 5°C and stirred for 30 minutes and Then the suspension is transferred to a filter and washed with a mixture of IPAC/heptane (2×3 ml/g of cold 15% IPAc) and heptane (5 ml/g). The remaining beige solid is dried in a stream of nitrogen for 18 h (detected that the product is dry and contains <0.3 wt.% solvents). 1.2 kgE-5isolated in the form of a light beige solid (99,4 LCAP, >99.5% of ee, >99.5% of the dr, the Pd content is 8 ppm, and KF - 0,1). Analytical data forE-5: HRMS m/z (M+H): found: 421,2067 calculated: 421,2035.

EXAMPLE F

2-({(3R,6R)-1-[5-bromo-2-(2H-1,2,3-triazole-2-yl)benzoyl]-6-methylpiperidin-3-yl}methoxy)-5-herperidin (F-2)

To a solution of 250 mg (1.12 mmol)ofA-7, 299 mg (1.12 mmol)ofF-1(obtained by the method getA-8using as a starting compound 5-bromo-2-identies acid), 182 mg (1,34 mmol) 1-hydroxy-7-isobenzofuranone and 0.47 ml (3,34 mmol) of triethylamine in 3 ml of DMF add 321 mg (1,67 mmol) EDC, after which the reaction mixture is stirred for 4 h at 50°C. the Reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and conc is jut by rotary evaporation, gettingF-2in the form of a resin. Analytical data forF-2: LC/MS: BP. ID = 2,64 min; m/z (M + H): found: 474,1; calculated: 474,1.

Methyl 3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-(2H-1,2,3-triazole-2-yl)benzoate (F-3)

Carbon monoxide is bubbled through a solution of 529 mg (1.12 mmol)ofF-2, 25 mg (0.11 mmol) of palladium(II)acetate, 46 mg (0.11 mmol) of 1,3-bis(diphenylphosphino)propane and 0.62 ml (4.5 mmol) of triethylamine in 15 ml of methanol and 7.5 ml of DMSO at 80°C for 10 minutes. Then the reaction mixture is combined with a balloon of carbon monoxide and stirred at 80°C during the night. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor. The residue is purified column chromatography on silica gel (EtOAc/hexane) and getF-3as not quite white solid. Analytical data forF-3: LC/MS: BP. ID = 2,30; m/z (M + H) = detected 454,1; calculated 454,2.

3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-(2H-1,2,3-triazole-2-yl)benzoic acid (F-4)

To 95 mg (0.21 mmol)ofF-3in 15 ml of a mixture 1:1:1 MeOH/THF/H2O add 0,84 ml (0.84 mmol) of 1M aqueous sodium hydroxide solution, whereupon the mixture is stirred for three hours at 50°C. the Reaction mixture was filtered and conc is tryout, to remove organic solvents, diluted with EtOAc and washed with 1M NaOH three times. The aqueous layers are acidified with 1M HCl, washed three times with DCM and dried over MgSO4. After concentration by evaporation on the rotor, the residue suspended in Et2O/hexano and concentrate, gettingF-4in the form of a white solid. Analytical data forF-4: LC/MS: BP. ID = 2,02 min; m/z (M+H) = detected 440,2; calculated 440,2. HRMS (ESI) m/z (M+H): found 440,1744; calculated 440,1729.

EXAMPLE G

[3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-(2H-1,2,3-triazole-2-yl)phenyl]methanol (G-1)

To 175 mg (0,39 mmol)F-3in 20 ml of THF at 0°C add 1.89 ml (of 3.78 mmol) of a 2M solution of aluminum lithium hydride in THF, after which the mixture under stirring, allowed to warm to room temperature for 3.5 hours. The reaction is quenched with 0.15 ml of water, 0.15 ml of 15% aqueous NaOH solution and 0.45 ml of water, after which the mixture is filtered through a layer of celite. After concentration by evaporation on the rotor, the residue is purified column flash chromatography (hexane/EtOAc), concentrated, suspended in a mixture of Et2O/hexane and again concentrate, gettingG-1in the form of a white solid. Analytical data forG-1: LC/MS: BP. ID = 2,00 min; m/z (M+H): found to 426.2; designed to 426.2. HRMS (ESI) m/z (M+H) found 426,1943; calculated 426,1936.

EXAMPLE H

2-{[(3R,6R)-1-(5-bromo-2-Ioganson)-6-methylpiperidin-3-yl]methoxy}-5-herperidin (H-1)

To a solution of 350 mg (1.56 mmol)ofA-7, 510 mg (1.56 mmol) of 5-bromo-2-identies acid, 255 mg (1,87 mmol) 1-hydroxy-7-isobenzofuranone and 0.65 ml (4,68 mmol) of triethylamine in 5 ml of DMF add 449 mg (2.34 mmol) of EDC, after which the reaction mixture is stirred for chevreh hours at 50°C. the Reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor, receivingH-1in the form of a resin. Analytical data forH-1.: LC/MS: BP. ID = 2,81 min; m/z (M+H): found 533,0; calculated 533,0.

2-{4-Bromo-2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine (H-2)

To a suspension of 230 mg (0.43 mmol)ofH-1, 207 mg (0,56 mmol) of 2-tributylstannyl, 131 mg (0.86 mmol) of CsF and 8 mg (0.04 mmol) of CuI in 3 ml of DMF are added 50 mg (0.04 mmol) tetranitroaniline(0), after which the reaction mixture is heated in a microwave reactor for 10 minutes at 130°C. the Reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor. The residue is purified column chromatography on silica gel (EtOAc/hexane), gettingH-2 in the form of a yellow resin. Analytical data forH-2: LC/MS: BP. ID = 2,61 min; m/z (M + H): found 485,1; calculated 485,1.

Methyl 3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-pyrimidine-2-eventout (H-3)

Carbon monoxide is bubbled through a solution of 500 mg (1,03 mmol)H-2, 23.1 mg (0.10 mmol) of palladium(II)acetate, 43 mg (0.10 mmol) of 1,3-bis(diphenylphosphino)propane and 0.57 ml (4.1 mmol) of triethylamine in 15 ml of methanol and 7.5 ml of DMSO at 80°C for 10 minutes. Then the reaction mixture is combined with a balloon of carbon monoxide and stirred at 80°C for 2.5 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor. The residue is purified column chromatography on silica gel (EtOAc/hexane), gettingH-3as not quite white solid. Analytical data forH-3: LC/MS: BP. ID = 2,30; m/z (M+H): found 465,2; calculated 465,2. HRMS (ESI) m/z (M+H) found 465,1944; calculated 465,1933.

3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-pyrimidine-2-Albertina acid (H-4)

To 150 mg (0.32 mmol)H-35 ml each of MeOH/THF/H2O add to 0.97 ml (0.97 mmol) of 1M aqueous sodium hydroxide solution, whereupon the mixture is stirred for 30 min at 50°C. Reactio the ing the mixture is neutralized to pH 7 using 1M HCl and washed with EtOAc three times. The organic layers washed with saturated saline solution, dried over MgSO4and concentrated by evaporation on the rotor, receivingH-4as not quite white solid. Analytical data forH-4: LC/MS: BP. ID = 1,91 min; m/z (M+H): found 451,2; calculated 451,2. HRMS (ESI) m/z (M+H) found 451,1761; calculated 451,1776.

EXAMPLE I

2-{[(3R,6R)-1-(2-bromo-5-Ioganson)-6-methylpiperidin-3-yl]methoxy}-5-herperidin (I-1)

To a solution of 3 g (a 13.4 mmol)A-7, 4.59 g (14.1 mmol) of 2-bromo-5-identies acid, 2,46 g (16,1 mmol) of the monohydrate of 1-hydroxybenzotriazole and 5.6 ml (40,1 mmol) of triethylamine in 60 ml of DMF type of 3.85 g (20,1 mmol) EDC, after which the reaction mixture is stirred for eighteen hours at room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor. The residue is purified column chromatography on silica gel (EtOAc/hexane), gettingI-1in the form of a resin. Analytical data forI-1: LC/MS: BP. ID = 2,75 min; m/z (M + H): found 532,9; calculated 533,0.

2-{[(3R,6R)-1-(2-bromo-5-vinylbenzyl)-6-methylpiperidin-3-yl]methoxy}-5-herperidin (I-2)

To a suspension of 6.85 g (12.9 mmol)ofI-1, 2.24 g (of 16.7 mmol) of potassium vinyltrifluoroborate and 5,33 g (a 38.5 mmol) K2CO3 in 35 ml of DMF add 940 mg (1.3 mmol) PdCl2(dppf), after which the reaction mixture is blown with argon for 5 minutes and then heated at 85°C for four hours. The reaction mixture was stirred at room temperature for 3 days and then partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor. The residue is purified column chromatography on silica gel (EtOAc/hexane), gettingI-2in the form of a resin. Analytical data forI-2: LC/MS: BP. ID = 2,80 min; m/z (M + H): found 433,0; calculated 433,1.

4-Bromo-3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]benzaldehyde (I-3)

To a solution of 4.2 g (9.7 mmol)ofI-2and 5.7 g (to 26.6 mmol) periodate sodium in 50 ml of THF and 20 ml of water is added to 1.42 ml (0.11 mmol) of 2.5 wt.% a solution of osmium tetroxide in tert-butanol, after which the reaction mixture is stirred at room temperature for four hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor, receivingI-3in the form of a resin. Analytical data forI-3: LC/MS: BP. ID = 2,38 min; m/z (M + H): found 435,0; calculated 435,1.

{4-Bromo-3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]IU the Il}-2-methylpiperidin-1-yl)carbonyl]phenyl}methanol (I-4)

To a solution of 3.94 g (9.1 mmol)ofI-3in 50 ml of THF added to 5.4 ml (10.9 mmol) of a 2M solution of lithium borohydride in THF, after which the reaction mixture is stirred at room temperature for thirty minutes. The reaction is quenched with saturated aqueous NH4Cl and partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor, receivingI-4in the form of a resin. Analytical data forI-4: LC/MS: BP. ID = 2,16 min; m/z (M + H): found 437,0; calculated 437,1.

4-Bromo-3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]benzoylacetate (I-5)

To a solution of a 3.87 g (8.9 mmol)I-4, 22 mg (0.18 mmol) of DMAP in 50 ml of pyridine added to 1.67 ml (about 17.7 mmol) of acetic anhydride and the reaction mixture was stirred at room temperature for thirty minutes. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor. The residue is purified column chromatography on silica gel (EtOAc/hexane), gettingI-5in the form of a resin. Analytical data forI-5: LC/MS: BP. ID = 2,55 min; m/z (M + H): found 479,0; calculated 479,1.

3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-pyrimid is n-2-eventrated (I-6)

To a suspension of 134 mg (0.28 mmol)ofI-5, 310 mg (0.84 mmol) of 2-tributylstannyl, 170 mg (1.12 mmol) of CsF and 16 mg (0.08 mmol) of CuI in 3 ml of DMF added 32 mg (0.03 mmol) tetranitrophenylnitramine(0), after which the reaction mixture is heated in a microwave reactor at 150°C for 25 minutes. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor. The residue is purified column chromatography on silica gel (EtOAc/hexane), gettingI-6in the form of a resin. Analytical data forI-6: LC/MS: BP. ID = 2.26 and min; m/z (M + H): found 479,1; calculated 479,2.

{3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-pyrimidine-2-ylphenyl}methanol (I-7)

To 830 mg (1,74 mmol)I-65 ml each of MeOH/THF/H2O add to 5.2 ml (5.2 mmol) of 1M aqueous sodium hydroxide solution, whereupon the mixture is stirred for three hours at room temperature. The reaction mixture was concentrated to remove organic solvents, and then partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, saturated salt solution, dried over MgSO4and concentrated by evaporation on the rotor. The residue is purified column chromatography on silica gel (CHCl3:EtOAc:MeOH/CHCl3 with the subsequent concentration by evaporation on the rotor, the residue suspended in a mixture of Et2O/hexane and concentrate, gettingI-7in the form of a white solid. Analytical data forI-7: LC/MS: BP. ID = 1,97 min; m/z (M + H): found 437,1; calculated 437,2. HRMS (ESI) m/z (M+H): found 437,1966; calculated 437,1983.

The following compounds are obtained by methods described above, using the appropriately substituted reagent, as described in the above schemes reactions and examples. Need the original substances are commercially available, are described in the literature or can be synthesized by a specialist in the field of organic synthesis without undue experimentation. Some final products purified flash chromatography (SiO2; using a mixture of EtOAc/hexane or other suitable solvent system) and emit in the form of a free base; alternatively, some products purified by HPLC on reversed phase (using a mixture of CH3CN/H2O containing 0.1% TFA as a modifier additives) and was isolated as TFA salt, in this case, the calculated and detected masses are given for the free base. Alternate fractions containing the product, alkalinized NaHCO3, extracted with EtOAc, dried over Na2SO4and concentrate, receiving freedoms of the first base.

Connection.StructureNameHRMS m/z (M+H)
1-15-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(1,3-thiazol-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine426,166 detected, 426,1646 calculated.

1-22-({(3R,6R)-6-methyl-1-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)-5-(trifluoromethyl)pyridine460,1955 detected, 460,1955 calculated.
1-32-({(3R,6R)-6-methyl-1-[5-methyl-2-(2N1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine392,2095 detected, 392,2081 calculated.
1-45-fluoro-2-({(3R,6R)-6-methyl-1-[2-(2N-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine396,1831 detected, 396,1831 calculated.
1-55-fluoro-2-({(3R,6R)-6-methyl-1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]piperidine-3-yl}methoxy)pyridine426,164 detected, 426,1646 calculated.
1-65-fluoro-2-({(3R,6R)-6-methyl-1-[(1-methyl-4-phenyl-1N-pyrazole-3-yl)carbonyl]piperidine-3-yl}methoxy)pyridine409,2051 detected, 409,2035 calculated.
1-75-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(1,3-oxazol-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine410,1875 detected, 410,1875 calculated.
1-85-fluoro-2-({(3R,6R)-1-[5-fluoro-2-(2N-1,2,3-triazole-2-yl)benzoyl]-6-methylpiperidin-3-yl}methoxy)pyridine414,1747 detected, 414,1736 calculated.
1-92-({(3R,6R)-1-[5-chloro-2-(2N-1,2,3-triazole-2-yl)benzoyl]-6-methylpiperidin-3-yl}methoxy)-5-herperidin 430,1442 detected, 430,1441 calculated.

1-105-fluoro-2-({(3R,6R)-6-methyl-1-[(4-methylbiphenyl)2-yl)carbonyl]piperidine-3-yl}methoxy)pyridine419,2127 detected, 419,2129 calculated.
1-115-chloro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine426,1702 detected, 426,1691 calculated.
1-125-fluoro-4-methyl-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine424,2145 detected, 424,2143 calculated.
1-132-methyl-6-({(3R,6R)-6-methyl-1-[5-methyl-2-(2N-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine406,2241 detected, 406,2238 calculated.
1-145-methyl-2-({(3R,6R)-6-IU the Il-1-[5-methyl-2-(2 N-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine406,2241 detected, 406,2238 calculated.
1-155-fluoro-2-{[(3R,6R)-6-methyl-1-(5-methyl-2-pyridine-2-aventyl)piperidine-3-yl]methoxy}pyridin420,2082 detected, 420,2082 calculated.
1-165-fluoro-2-{[(3R,6R)-6-methyl-1-(5-methyl-2-pyridin-3-aventyl)piperidine-3-yl]methoxy}pyridin442,1875 detected, 442,1901 calculated. (M+Na)

1-175-fluoro-2-({(3R,6R)-1-[2-(5-herperidin-2-yl)-5-methylbenzoyl]-6-methylpiperidin-3-yl}methoxy)pyridine438,1966 detected, 438,1988 calculated.
1-182-{4-chloro-2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine441,1496 detected, 441,1488 calculated.
1-19 2-{4-fluoro-2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine425,1786 detected, 425,1784 calculated.
1-205-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(1,3-thiazol-4-yl)benzoyl]piperidine-3-yl}methoxy)pyridine426,1623 detected, 426,1646 calculated.
1-215-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(1N-pyrazole-4-yl)benzoyl]piperidine-3-yl}methoxy)pyridine409,2013 detected, 409,2034 calculated.
1-225-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2N-tetrazol-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine411,1917 detected, 411,1939 calculated.
1-235-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(1N-pyrazole-1-yl)benzoyl]piperidine-3-yl}methoxy)pyridine409,2020 detected, 409,2034 calculated.

1-242-{[(3R,6R)-1-(2-ethoxybenzoyl)-6-methylpiperidin-3-yl]methoxy}-5-herperidin373,1924 detected, 373,1922 calculated.
1-252-{[(3R,6R)-1-(biphenyl-2-ylcarbonyl)-6-methylpiperidin-3-yl]methoxy}-5-herperidin405,1975 detected, 405,1973 calculated.
1-265-fluoro-2-({(3R,6R)-6-methyl-1-[2-(2-phenylethyl)benzoyl]piperidine-3-yl}methoxy)pyridine433,2287 detected, 433,2286 calculated.
1-277-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-1H-indole368,1780 detected, 368,1769 calculated.
1-282-{2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine407,1879 detected, 407,1878 calculated.
1-29 3-methyl-2-({(3R,6R)-6-methyl-1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoyl]piperidine-3-yl}methoxy)pyridine407,2068 detected, 407,2078 calculated.
1-302-{2-[((2R,5R)-2-methyl-5-({[6-(1,3-oxazol-2-yl)pyridine-2-yl]oxy}methyl)piperidine-1-yl]carbonyl}phenyl)pyrimidine456,2026 detected, 456,2030 calculated.
1-312-{2-[((2R,5R)-5-{[(6-isopropylpyridine-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine431,2435 detected, 431,2442 calculated.

1-324-{2-[((2R,5R)-2-methyl-5-{[(3-methylpyridin-2-yl)oxy]methyl}piperidine-1-yl)carbonyl]phenyl}-1,3-thiazol-2-amine423,1842 detected, 423,1849 calculated.
1-335-fluoro-2-({(3R,6R)-1-[2-fluoro-6-(2H-1,2,3-triazole-2-yl)benzoyl]-6-methylpiperidin-3-yl}methoxy)pyridine414,1738 detected, 414,1736 calculated.
1-342-{3-fluoro-2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine425,1786 detected, 425,1784 calculated.
1-355-fluoro-2-({(3R,6R)-6-methyl-1-[2-(1H-1,2,4-triazole-5-yl)benzoyl]piperidine-3-yl}methoxy)pyridine396,1833 detected, 396,1830 calculated.
1-363-chloro-2-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine412,1516 detected, 412,1535 calculated.
1-375-fluoro-2-({(3R,6R)-6-methyl-1-[2-(1H-pyrazole-1-yl)benzoyl]piperidine-3-yl}methoxy)pyridine395,1881 detected, 395,1878 calculated.
1-382-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-3-vinylpyridin406,1924 detecting the woman, 406,1925 calculated.
1-395-fluoro-2-({(3R,6R)-6-methyl-1-[(4-vinylpyridin-3-yl)carbonyl]piperidine-3-yl}methoxy)pyridine406,1931 detected, 406,1925 calculated.

1-403-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-2-phenylpyridine406,1936 detected, 406,1925 calculated.
1-412-chloro-3-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine412,1552 detected, 412,1535 calculated.
1-422-bromo-5-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine456,1039 detected, 456,1030 calculated.
1-432-chloro-4-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)the feast of the Dean 412,1553 detected, 412,1535 calculated.

Table 2 presents data characterizing described in the examples of compounds as antagonists of receptors orexin OX1R and/or OX2R, as defined in the above-described assays.

Table 2
Connection.StructureOX1R Ki(nm)OX2R Ki(nm)
2-19629
A-91,00,24
B-33,30,54

C-4220,67
E-52,90,31
F-4260410
G-1141,7
H-48437
I-7302,0
1-11,80,24
1-4120,37

1-86,80,50
1-100,710,08
1-15 3,20,35
1-19100,53
1-217,10,48
1-24361,7
1-277510
1-28170,67
1-348,20,68

1-37551,5
1-38 861,9
1-4264the 3.8
1-4314022

Although the present invention is described and illustrated with reference to some specific embodiments, the specialists in this area should be clear that various adaptations, changes, modifications, replacement, removal or additions of procedures and methods can be made without departing from the essence and scope of this invention.

1. Paradiseparadise a compound selected from the group including
5-fluoro-2-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-{2-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-were}pyrazin;
2-{2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-were}pyrazin;
2-methyl-6-({6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-methyl-6-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-{2-[(5-{[(5-herperidin-2-yl)oxy]methyl}2-methylpiperidin-1-yl)carbonyl]-4-were}pyrimidine;
2-{2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-were}pyrimidine;
3-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-(2H-1,2,3-triazole-2-yl)benzoic acid;
3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-(2H-1,2,3-triazole-2-yl)benzoic acid;
[3-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-(2H-1,2,3-triazole-2-yl)phenyl]methanol;
[3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-(2H-1,2,3-triazole-2-yl)phenyl]methanol;
3-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-pyrimidine-2-Albertina acid;
3-[((2R,5R)-5-([(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-pyrimidine-2-Albertina acid;
{3-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-pyrimidine-2-ylphenyl}methanol;
{3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-pyrimidine-2-ylphenyl}methanol;
5-fluoro-2-({6-methyl-1-[5-methyl-2-(1,3-thiazol-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(1,3-thiazol-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)-5-(trifluoromethyl)pyridine;
2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)-5-(trifluoromethyl)pyridine;
2-({6-methyl-1-[5-methyl-2-(2H-1,2,3-t is eazol-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({6-methyl-1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({6-methyl-1-[(1-methyl-4-phenyl-1H-pyrazole-3-yl)carbonyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[(1-methyl-4-phenyl-1H-pyrazole-3-yl)carbonyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({6-methyl-1-[5-methyl-2-(1,3-oxazol-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(1,3-oxazol-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({1-[5-fluoro-2-(2H-1,2,3-triazole-2-yl)benzoyl]-6-methylpiperidin-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-1-[5-fluoro-2-(2H-1,2,3-triazole-2-yl)benzoyl]-6-methylpiperidin-3-yl}methoxy)pyridine;
2-({1-[5-chloro-2-(2H-1,2,3-triazole-2-yl)benzoyl]-6-methylpiperidin-3-yl}methoxy)-5-herperidin;
2-({(3R,6R)-1-[5-chloro-2-(2H-1,2,3-triazole-2-yl)benzoyl]-6-methylpiperidin-3-yl}methoxy)-5-herperidin;
5-fluoro-2-({6-methyl-1-[(4-methylbiphenyl-2-yl)carbonyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[(4-methylbiphenyl-2-yl)carbonyl]piperidine-3-yl}methoxy)pyridine;
5-chloro-2-({(6-methyl-1-[5-methyl-2-(2H-1,23-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-chloro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-4-methyl-2-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-4-methyl-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-methyl-6-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-methyl-6-({(3R,6R)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-methyl-2-({6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-methyl-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-{[6-methyl-1-(5-methyl-2-pyridine-2-aventyl)piperidine-3-yl]methoxy}pyridine;
5-fluoro-2-{[(3R,6R)-6-methyl-1-(5-methyl-2-pyridine-2-aventyl)piperidine-3-yl]methoxy}pyridine;
5-fluoro-2-{[6-methyl-1-(5-methyl-2-pyridin-3-aventyl)piperidine-3-yl]methoxy}pyridine;
5-fluoro-2-{[(3R,6R)-6-methyl-1-(5-methyl-2-pyridin-3-aventyl)piperidine-3-yl]methoxy}pyridine;
5-fluoro-2-({1-[2-(5-herperidin-2-yl)-5-methylbenzoyl]-6-methylpiperidin-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-1-[2-(5-herperidin-2-yl)-5-methylbenzoyl]-6-methylpiperidin-3-yl}methoxy)pyridine;
2-{4-chloro-2-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine;
2-{4-chloro-2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimid is n;
2-{4-fluoro-2-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine;
2-{4-fluoro-2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine;
5-fluoro-2-({6-methyl-1-[5-methyl-2-(1,3-thiazol-4-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(1,3-thiazol-4-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({6-methyl-1-[5-methyl-2-(1H-pyrazole-4-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(1H-pyrazole-4-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(6-methyl-1-[5-methyl-2-(2H-tetrazol-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(2H-tetrazol-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({6-methyl-1-[5-methyl-2-(1H-pyrazole-1-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[5-methyl-2-(1H-pyrazole-1-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-{[1-(2-ethoxybenzoyl)-6-methylpiperidin-3-yl]methoxy}-5-herperidin;
2-{[(3R,6R)-1-(2-ethoxybenzoyl)-6-methylpiperidin-3-yl]methoxy}-5-herperidin;
2-{[1-(biphenyl-2-ylcarbonyl)-6-methylpiperidin-3-yl]methoxy}-5-herperidin;
2-{[(3R,6R)-1-(biphenyl-2-ylcarbonyl)-6-methylpiperidin-3-yl]methoxy}-5-herperidin;
5-fluoro-2-({6-methyl-1-[2-(2-phenylethyl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[2-(2-phenylethyl)benzoyl]piperidine-3-yl}methoxy)pyridine;
7-[(5-{[(5-perperidis the-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-1H-indole;
7-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-1H-indole;
2-{2-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine;
2-{2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine;
3-methyl-2-({6-methyl-1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
3-methyl-2-({(3R,6R)-6-methyl-1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-(2-{[2-methyl-5-({[6-(1,3-oxazol-2-yl)pyridine-2-yl]oxy}methyl)piperidine-1-yl]carbonyl}phenyl)pyrimidine;
2-(2-{[(2R,5R)-2-methyl-5-({[6-(1,3-oxazol-2-yl)pyridine-2-yl]oxy}methyl)piperidine-1-yl]carbonyl}phenyl)pyrimidine;
2-{2-[(5-{[(6-isopropylpyridine-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine;
2-{2-[((2R,5R)-5-{[(6-isopropylpyridine-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine;
4-{2-[(2-methyl-5-{[(3-methylpyridin-2-yl)oxy]methyl}piperidine-1-yl)carbonyl]phenyl}-1,3-thiazol-2-amine;
4-{2-[((2R,5R)-2-methyl-5-{[(3-methylpyridin-2-yl)oxy]methyl}piperidine-1-yl)carbonyl]phenyl}-1,3-thiazol-2-amine;
5-fluoro-2-({1-[2-fluoro-6-(2H-1,2,3-triazole-2-yl)benzoyl]-6-methylpiperidin-3-yl)methoxy)pyridine;
5-fluoro-2-({(3R,6R)-1-[2-fluoro-6-(2H-1,2,3-triazole-2-yl)benzoyl]-6-methylpiperidin-3-yl}methoxy)pyridine;
2-{3-fluoro-2-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine;
2-{3-fluoro-2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]IU the Il}-2-methylpiperidin-1-yl)carbonyl]phenyl}pyrimidine;
5-fluoro-2-({6-methyl-1-[2-(1H-1,2,4-triazole-5-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[2-(1H-1,2,4-triazole-5-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
3-chloro-2-({6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
3-chloro-2-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({6-methyl-1-[2-(1H-pyrazole-1-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[2-(1H-pyrazole-1-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-3-vinylpyridine;
2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-3-vinylpyridine;
5-fluoro-2-({6-methyl-1-[(4-vinylpyridin-3-yl)carbonyl]piperidine-3-yl}methoxy)pyridine;
5-fluoro-2-({(3R,6R)-6-methyl-1-[(4-vinylpyridin-3-yl)carbonyl]piperidine-3-yl}methoxy)pyridine;
3-[(5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-2-phenylpyridine;
3-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-2-phenylpyridine;
2-chloro-3-({6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-chloro-3-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-bromo-5-({6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-bromo-5-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl 1 piperidine-3-yl}methoxy)pyridine;
2-chloro-4-({6-METI the-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine;
2-chloro-4-({(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazole-2-yl)benzoyl]piperidine-3-yl}methoxy)pyridine,
or stereoisomers or pharmaceutically acceptable salts, or pharmaceutically acceptable salts, their stereoisomers.

2. The compound according to claim 1, which represents 2-{2-[((2R,5R)-5-{[(5-herperidin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl)carbonyl]-4-were}pyrimidine or its pharmaceutically acceptable salt.

3. Pharmaceutical composition having antagonistic activity against receptor orexin, which contains an inert carrier and a compound according to claim 1 or its pharmaceutically acceptable salt.

4. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment or prevention of diseases involving receptors orexin.

5. The use of compounds according to claim 1 or its pharmaceutically acceptable salts in the manufacture of a medicinal product for the treatment or prevention of sleep disorders.



 

Same patents:

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: improved method.

15 cl, 227 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 denotes an ethoxy group; R2 denotes hydrogen; R3 denotes a cyano group; R4 denotes hydrogen; R5 denotes hydrogen, a methoxy group or an ethoxy group; R6 denotes hydrogen or a methoxy group; R7 denotes hydrogen, methyl, ethyl, n-propyl or isopropyl; X1 denotes -NH-; X2 denotes N or CH; X3 denotes N or CH; where X2 and X3 do not denote N at the same time; and pharmaceutically acceptable salts and tautomeric forms thereof. The invention also relates to a medicinal agent for treating and/or preventing a vasopressin-dependent disease, which contains the compound given in claim 1, use of the compound of formula I to prevent and/or treat vasopressin-dependent diseases, as well as a method of treating and/or preventing said diseases.

EFFECT: novel compounds which can be useful in treating vasopressing-dependent diseases are described.

22 cl, 90 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: it has been confirmed that the new azolcarboxamide compound or its pharmaceutically acceptable salt wherein a thiazole ring or an oxazole ring is bound to a benzene ring, a pyridine ring, a pyridazine ring, a thiophen ring, a pyrazole ring or a pyrrol ring through carboxamide or its ring possess high activity of receptor trkA inhibition; it has been found that they may be used as a therapeutic and/or preventive agent which is different in the fact concerning the effectiveness and safety for repeated urination, frequent micturate urge and urine incontinence associated with various urogenital diseases, including higher bladder activity, various lower bladder diseases accompanied with urogenital pain, such as interstitial cystitis, chronic prostatitis and others, and various diseases accompanied by pain; thereby the present invention has been created.

EFFECT: provided therapeutic and/or preventive agent for repeated urination, frequent micturate urge and urine incontinence associated with various urogenital diseases, including higher bladder activity, various lower bladder diseases accompanied with urogenital pain, such as interstitial cystitis, chronic prostatitis and others, and various diseases accompanied by pain on the basis of excellent inhibitory action on the receptor trkA.

24 cl, 1195 ex, 215 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-aza-bicyclo[3,1,0]hexane derivatives of formula (I), where A, B, n and R1 are defined in the description, and to use of such compounds or pharmaceutically acceptable salts of such compounds as medicinal agents, particularly as orexin receptor antagonists. The present invention also describes use of compounds of general formula (I) to produce a medicinal agent for preventing or treating insomnia.

EFFECT: improved method.

11 cl, 279 ex, 1 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing compounds of formula I The method is realised via cyclisation of a compound of formula (IV) with an intermediate compound Int4 at room temperature to obtain a compound of formula (III), reducing the nitro group in the compound of formula (III) to obtain a compound of formula (II). Further, by bonding the compound of formula (II) to a compound of formula Int5 in an aprotic solvent, a compound of formula (I) is obtained (structural formulae of compounds (II), (III), (IV), Int4, Int5 are given in the claim).

EFFECT: improved method of producing compounds of formula (I).

25 cl, 3 dwg, 4 ex

Indole derivative // 2454415

FIELD: medicine, pharmaceutics.

SUBSTANCE: object of the present invention is preparing a glucokinase activator effective as a pharmaceutical agent, such as an agent for preventing or treating diabetes, obesity and similar. The present invention presents the glucokinase activator containing a compound presented by formula :

wherein R1 represents hydrogen atom or halogen atom; R2 represents a group presented by formula or wherein each symbol is such as specified in the description, or its pharmaceutically acceptable salt.

EFFECT: developing the agent for preventing or treating diabetes, obesity.

16 cl, 536 ex, 1 tbl, 9 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide, and/or their mixture, as well as to applying it in a pharmaceutical composition, a method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease. Also, the invention refers to methods for preparing N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide and its intermediate compounds. .

EFFECT: developing the method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease.

12 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is oxazolidinone of general formula , where values of radicals are given in invention formula, and pharmaceutical antibiotic composition, which includes as active ingredient novel oxazolidinone derivative, its hydrate, solvate, isomer or pharmaceutically acceptable salt.

EFFECT: compounds are characterised by wide antibacterial spectrum and high antibacterial activity against gram-positive and gram-negative resistant bacteria, low toxicity and can be applied as antibiotic.

7 cl, 3 tbl, 106 ex

FIELD: medicine.

SUBSTANCE: described are novel heterocyclic compounds of general formulae and (values of radicals are given in invention formula), pharmaceutical compositions containing them and application of said heterocyclic compounds for treatment disorders mediated with MAP kinase cascade.

EFFECT: increase of compound efficiency.

67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula , where A, Q, R1, R2, R3, R4, R5' are represented in i.1 of the formula, as well as to its hydrates, solvates and pharmaceutically acceptable salts, Also described are application of said compound and pharmaceutical composition, including such compound, for treatment of disease condition in mammals, which is sensitive to action of antagonists of vasopressin V1a, V1b or V2 receptors.

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention is a 6-10-member aryl selected from phenyl, naphthyl, tetrahydronaphthalenyl, indanyl or a 6-member heteroaryl containing 1-2 N atoms, selected from pyridyl or pyrimidinyl, where the aryl and heteroaryl groups can be unsubstituted or substituted with 1-3 substitutes selected from a group consisting of C3-6-cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, halogen atom, C1-7-alkyl, C1-7-alkoxy, oxazolyl, piperidin-1-yl, or C1-7-alkyl, substituted with a halogen atom, or represents phenyl, where at least one hydrogen atom is substituted with deuterium or tritium; R2 is a hydrogen atom, C1-7-alkyl or is benzyl, unsubstituted or substituted C1-7-alkoxy or halogen atom; or R1 and R2 together with a N atom with which they are bonded form 2,3-dihydroindol-1-yl or 3,4-dihydro-1quinolin-1-yl. The invention also relates to a method of producing compounds of formula and to a pharmaceutical composition having high affinity for the TAAR1 receptor.

EFFECT: compounds of formula (I), having high affinity for the TAAR1 receptor.

29 cl, 4 dwg, 1 tbl, 183 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are produced new diazepane substituted compounds representing various heterocyclic systems, including condensed, pharmaceutical compositions containing said compounds.

EFFECT: producing the compounds and compositions for preventing and treating neurological and mental disorders and diseases with involved orexin receptors.

13 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel cyanoisoquinoline derivatives of formula I , where R is selected from a group comprising hydrogen and C1-C10 alkyl, R1, R2, R3 and R4 are independently selected from a group comprising hydrogen, halogen, hydroxy, C1-C10 alkyl, substituted with 1-3 halogen atoms or C6-C14 acryl, C6-C14 aryl, -OR7, -SR7 and -SO2R7, where R7 is selected from a group comprising C1-C10 alkyl, C1-C10 alkyl substituted with C6-C14 aryl, C3-C10 cycloalkyl, C6-C14 aryl and C7-C8 heteroaryl containing 1-2 heteroatoms selected from a group comprising N, O and S, where C6-C14 aryl and C7-C8 heteroaryl are optionally substituted with 1-3 substitutes selected from a group comprising halogen, C1-C6 alkoxy, C1-C10 alkyl, C1-C6 dialkylamino and C4 heterocyclyl containing 2 heteroatoms selected from a group comprising nitrogen and oxygen, and R5 and R6 are independently selected from a group comprising hydrogen and C1-C3 alkyl, or pharmaceutically acceptable salts thereof. The invention also relates to novel cyanoquinoline derivatives of formula II , where R31, R32, R33 and R34 are independently selected from a group comprising hydrogen, hydroxy, halogen, C1-C10 alkyl substituted with 1-3 halogen atoms or with C6-C14 aryl, C6-C14 aryl, -OR37, -SR37 and -SO2R37, where R37 is selected from a group comprising C1-C10 alkyl, C1-C10 alkyl substituted with C6-C14aryl, C3-C10 aryl, C7-C8 heteroaryl containing 1-2 heteroatoms selected from a group comprising N, O and S, where C6-C14 aryl and C7-C8 heteroaryl are substituted with 1-3 substitutes selected from a group comprising halogen, C1-C6 alkoxy, C1-C10 alkyl, C1-C6 dialkylamino C4 heterocyclyl containing 2 heteroatoms selected from a group comprising nitrogen and oxygen, R35 denotes hydrogen or methyl, or pharmaceutically acceptable salts thereof. The invention also relates to specific cyanoisoquinoline compounds, a pharmaceutical composition based on the compound of formula I, a hypoxia-inducible factor (HIF) hydroxylase inhibiting method, a method of treating, preventing or slowing down development of a condition associated with hypoxia-inducible factor (HIF), a condition associated with erythropoietin (EPO), anaemia, based on use of the compound of formula I.

EFFECT: obtaining novel cyanoisoquinoline compounds having useful biological properties.

42 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof: (I) where R1, R2 and R3, which are identical or different, denote H, lower alkyl; R4, R5, R6, R7 and R8, which are identical or different, denote H, lower alkyl, halogen, nitro, -X-OR0, -X-NR10R11, -X-NR0C(O)R10, -X-O-halogen lower alkyl, -X-O-X-phenyl; or R6 and R7 are combined to form -O-lower alkylene-O-; R, which is identical or different, denotes H, lower alkyl; R10, R11, which are identical or different, denote H, lower alkyl; X, which is identical or different, denotes a bond, lower alkylene.

EFFECT: compounds exhibit type 5 17βHSD inhibiting activity, which enables their use in producing a pharmaceutical composition and in a method of inhibiting type 5 17βHSD.

15 cl, 11 tbl, 13 ex

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