Derivatives of piperidine, pharmaceutical composition on their basis and their application

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

 

Description

The present invention relates to novel antagonists neurokinin receptor 1 (NK1or NK-1), more specifically, to the derivatives of piperidine, pharmaceutical compositions on their basis and their application.

Neurokinin receptors, such as NK1NK2and NK3participate in various biological processes. They can be found in the nervous system and the circulatory system of mammals, as well as in peripheral tissues. For this reason, the modulation of these types of receptors is investigated from the point of view of treatment or prevention of various pathological States in mammals. In particular, reported that receptors NK1participate in capillary bleeding and mucus production. Typical types of antagonists neurokinin receptors and disorders that can cure with their help, include, for example, drowsiness, pain, migraine, vomiting, nociception and inflammation; see, for example, US 6329401, US 5760018, US 5620989, WO 95/19344, WO 94/13639, WO 94/10165, Wu et al, Tetrahedron, 56, 6279-6290 (2000), Rombouts et al., Tetrahedron, 59, 4721-4731 (2003) and Rogiers et al., Tetrahedron, 57, 8971-8981 (2001).

The closest to the invention to the technical essence and the achieved effect of solution are described in the application WO 03/051840 derivatives of piperidine are antagonists neurokinin receptor NK1.

Object of the invention is the extension of the ar is anal derivatives of piperidine, which is highly active antagonists neurokinin receptor NK1.

The problem is solved proposed derivatives piperidine formula

in which:

R1and R2selected from the group comprising alkyl, halogenated, alkyl, substituted by one or more hydroxy groups, -CN, quinil, -N(R6)2, -N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2-alkylen-CN, -cycloalkyl-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2and groups

,,,,

provided that at least one of R1and R2means-CN or a group

,,,,

W means =C(R8)- or =N-;

X is-C(O)- or-S(O2)-;

Y is selected from the group comprising-CH2-, -O -, and-N(R6)-C(O)-, provided that:

(a) the nitrogen atom of the group-N(R6)-C(O)- associated with X, and

(b) if R1and/or R2meansand Y represents-O-, then X does not means-S(O2)-;

Z denotes-C(R7)2-, -N(R6)-, or-O-;

R 3selected from the group comprising H and unsubstituted alkyl;

R4means N;

R5means H or alkyl;

R6selected from the group comprising H, alkyl, cycloalkyl and aryl;

each R7independently denotes H or alkyl; or

each R7together with the ring carbon atom to which, as shown, they are attached, forms cycloalkene ring;

R8selected from the group comprising H, alkyl, alkyl substituted with one or more hydroxy groups, -N(R6)2, -N(R6)-S(O2)-alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -- CN;

R9selected from the group comprising H, alkyl and aryl, or each R9together with the nitrogen atom to which, as shown, they are attached, forms geteroseksualnoe ring;

AG1means phenyl;

AG2means phenyl, substituted by 0-3 substituents selected from the group comprising halogenated;

n is 0, 1 or 2; and

m is 1, 2 or 3,

and their pharmaceutically acceptable salts and hydrates.

A preferred form of execution are derivatives of piperidine having the structure IA:

,

in which R1, R2, R3, R4, AG1, AG2and n have the above meanings, and their pharmaceutically acceptable the e salts and hydrates.

Preferred meanings of the radicals R1-R3, R8, AG2X, Y, Z, m and n shown in formula (I) and formula (IA), are summarized in dependent clauses 2-23 claims.

Other preferred derivatives of piperidine are the compounds of formula (IB)

in which R1and R2selected from the group consisting of:

ConnectionR1R2
1-CN
2-CN
3-CH2CN
4-CH3
5-CN
6-C(O)-O-CH3
7 -CN
8-C(O)-NH2
9-CH2OH
10-CH2Och3

ConnectionR1R2
11-CH2Och3
12-CN
13-CN
14-CN
15-CN
16-NH-S(O2 )-CH3-CN
17-CN-NH-S(O2)-CH3
18-CH2CN
19-CN-NH2
20-NH2-CN
21-NH-C(O)-NH2-CN
22-CN

and their pharmaceutically acceptable salts and hydrates.

Particularly preferred derivatives of piperidine of the formula:

,,

,,

and their pharmaceutically acceptable salts and hydrates.

Fragments of chemical formulas enclosed in round brackets represent the side groups, for example, -C(O)- means a carbonyl group (i.e.), -N(alkyl)- means a divalent amino group with the alkyl side group (i.e.and-C(=[DOWN )-CH3means.

"Alkyl" means an aliphatic hydrocarbon group which may be linear or branched and contain from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain from about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain from about 1 to about 6 carbon atoms in the chain. "Branched" means that linear alkyl chain attached one or more alkyl groups such as methyl, ethyl or propyl. "Lower alkyl" means a group containing from about 1 to about 6 carbon atoms in the chain, which may be linear or branched.

"Alkylene" means a divalent aliphatic hydrocarbon group which may be linear or branched and contains from about 1 to about 20 carbon atoms in the chain. Preferred alkylene groups contain from about 1 to about 12 carbon atoms in the chain. More preferred alkylene groups contain from about 1 to about 6 carbon atoms in the chain. Non-limiting examples of suitable alkilinity groups include methylene (i.e.- CH2- ), ethylidene (-CH2CH2- or-CH(CH3)-).

"Quinil" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, and which mo is et to be linear or branched and contain from about 2 to about 15 carbon atoms in the chain. Preferred alkyline groups contain from about 2 to about 12 carbon atoms in the chain; and more preferably from about 2 to about 4 carbon atoms in the chain. "Branched" means that linear alkenylphenol chain attached one or more alkyl groups such as methyl, ethyl or propyl. "Lower quinil" means a group containing from 2 to about 6 carbon atoms in the chain, which may be linear or branched. Non-limiting examples alkenyl groups include: etinilnoy, propenyloxy, 2-butenyloxy and 3-methylbutylamine.

"Aryl" means an aromatic monocyclic or polycyclic ring system containing from about 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms.

"Cycloalkyl" means a non-aromatic mono - or polycyclic ring system containing from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain from about 5 to about 7 ring atoms. Non-limiting examples of suitable monocyclic cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl etc. non-limiting examples of suitable polycyclic cycloalkyl include 1-decaline, norbornyl, substituted and the like, and partially nassen the e system, such as, for example, indanyl, tetrahydronaphtyl etc.

"Cycloalkyl" means a divalent cycloalkyl ring system containing from about 3 to about 10 carbon atoms, preferably from about to about 10 carbon atoms. Preferred cycloalkene rings contain from about 5 to about 7 ring atoms. Non-limiting examples of suitable monocyclic alkylenes include cyclopropyl (i.e.or).

"Halogen" means fluorine, chlorine, bromine or iodine. The preferred Halogens are fluorine, chlorine and bromine. "Halogen-substituted" group (for example, halogenoalkane group) mean group substituted by one or more fluorine atoms, chlorine, bromine and/or iodine.

"Heteroseksualci" means a non-aromatic saturated monocyclic or polycyclic ring system containing from about 3 to about 10 cyclic atoms, preferably from about 5 to about 10 cyclic atoms in which one or more atoms of the ring system is an element that is not carbon, for example nitrogen, oxygen or sulfur, alone or in combination. In the ring system does not include adjacent oxygen atoms and/or sulfur. Preferred heterocicluri contain from about 5 to about 6 cyclic atom of the century The prefix Aza-, oxa - or thia - before the name geteroseksualnoe system means that as the ring atom contains at least one nitrogen atom, oxygen or sulfur, respectively. Any group-NH in heterocyclicamines ring may be in protected form, such as, for example, in the form of a group-N(Boc), -N(CBz), -N(Tos) and the like; such protected functional groups are also considered part of the present invention. The nitrogen atom or sulfur of geterotsiklicheskie optional can be oxidized with the formation of the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclic geterotsiklicheskikh rings include piperidyl, pyrrolidinyl, piperazinil, morpholinyl, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrofuranyl, tetrahydrothiophene, lactam, lactone, etc.

The term "purified form" in relation to the connection according to the invention refers to the physical condition of the specified connection after receiving using the method or methods of purification described in this invention are well known to the person skilled in the art with sufficient purity, characterized by standard methods of analysis described in this invention are well known to the person skilled in the technical field.

It should also be noted that in the text, schemes, etc the measures and tables, in the present invention, it is understood that any heteroatom with unsaturated valences has the atom (atoms) of hydrogen, sufficient to saturate the valences.

The wavy linelink usually points to the mixture or any possible isomer, for example, containing (R)- and (S)- stereoisomer. For example,

If the stereochemical configuration of the structure is not specifically indicated, the structure may correspond to mixtures of the stereoisomers or any possible individual stereoisomer. Thus, if the stereochemical configuration of the structure is not specifically shown, the structure includes all stereochemical configuration having a specified system of relations (e.g., all possible enantiomers or diastereoisomers), as well as mixtures of such stereoisomers (e.g., racemic mixtures), for example,

The compounds of formula I form salts, which are also included in the scope of the present invention. If not stated otherwise, it should be understood that reference to a compound of formula I refers to the inclusion of a link on its salts. When used in the present invention, the term "salt (salt)" means salts with acids, formed with inorganic and/or organic acids, and that the same salt with a base formed with inorganic and/or organic bases. In addition, if the compound of formula I contains both a fragment of a base, such as (without restrictions) pyridine or imidazole, and a portion of the acid, such as (without restrictions) carboxylic acid, can be formed zwitterions ("inner salts") and when used in the present invention are included in the term "salt (salt)". Preferred pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts, although applicable, and other salts. Salts of compounds of formula I can be formed, for example, through reaction of compounds of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as the medium in which the salt precipitates or in an aqueous medium followed by lyophilization.

Examples of salts with acids include acetates, adipate, alginates, ascorbates, aspartate, benzoate, bansilalpet, bisulfate, borates, butyrate, citrates, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecenal-veils, econsultancy, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-econsultancy, lactates, maleate, methanesulfonate, methylsulfate, 2-naphthalene-sulfonates, nicotinate, nitrate is, oxalates, pamoate, pectinate, persulfates, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylates, succinate, sulfates, sulfonates (such as those described in the present invention), tartratami, thiocyanates, toluensulfonate (also known under the name of tozilaty), undecanoate etc.

Examples of salts with bases include ammonium salts, alkali metal salts, such as salts of sodium, lithium and potassium, salts of alkaline earth metals such as calcium salts and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines)such as benzathine, diethylamin, dicyclo-hexylamine, geranamine (formed with N,N-bis(dehydroabietyl)Ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamine, tert-butylamine, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and other Basic nitrogen-containing groups can be converted into a Quaternary group with the help of compounds such as the halides of lower Akilov (for example, methyl-, ethyl - and butylchloride, -bromides and iodides), diallylsulfide (for example, dimethyl-, diethyl-, dibutil and dimycolate), halides with long chains (e.g., decyl-, lauryl-, myristyl and sterilgarda, -bromides and iodides), arylalkylamine (for example, benzyl and peptibody) and other Acids (and bases), which is generally considered suitable for the formation of pharmaceutically applicable salts of the basic (acidic) pharmaceutical compounds, discussed, for example, in the publications by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P.Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, p.330-331, and all of them are included in the present invention by reference.

In the scope of the present invention assumes that all such salts of acids and bases are pharmaceutically acceptable salts and for the purposes of the present invention, all salts of acids and bases are considered equivalent to the free forms of the corresponding compounds.

The compounds of formula I and their salts and hydrates may exist in their tautomeric form (for example, in the form of simple amido - or aminoether). It is implied that all such tautomeric forms are part of the present invention.

Polymorphic forms of the compounds of formula I and salts and hydrates of the compounds of formula I are included in the present invention.

In the scope of the present invention includes all stereoisomers (for example, geometric isomers, optical isomers and the like) compounds of the present invention (including isomers salts, solvate, and prodrugs of these compounds, and salts and solvate of the prodrugs), such as those that may exist is a consequence of the presence of asymmetric carbon atoms in different substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotamania isomeric forms, atropisomers and diastereoisomeric form. Individual stereoisomers of compounds of the present invention, may, for example, generally do not contain other isomers, or may be mixed, for example, as racemates or with all other, or other selected stereoisomers. Chiral centers corresponding to the present invention can have the S - or R-configuration in accordance with the definition given in the IUPAC 1974 Recommendations. It is implied that the use of the terms "salt", "hydrate", etc. are equally applicable to salt and hydrate enantiomers, stereoisomers, rotamers, tautomers, positional isomers and racemates of the compounds of the present invention. "At least one" means, for example, 1-3, 1-2 or 1.

The compounds of formula I are effective antagonists of the receptor NK1and affect its endogenous agonist, substance P, in the area of receptor NK1and therefore can be used in the treatment of diseases, disorders or pathological conditions caused by the bacterium or growing due to the activity of the receptor.

Therefore, another object of the invention is a pharmaceutical composition, irradiation of the surrounding properties antagonist neurokinin receptor NK 1comprising at least one compound of the above formula I or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable carrier.

A further object of the invention is the use of at least one compound of the above formula I or its pharmaceutically acceptable salt or hydrate to obtain drugs for the treatment of physiological disorders, elimination of a symptom or treatment of diseases and physiological disorder, symptom or disease is selected from the group including respiratory diseases, inflammatory diseases, skin disorders, ophthalmologic disorders, pathological conditions of the Central nervous system, depression, anxiety, phobia, bipolar disorder, addiction, alcohol addiction, substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, dementia in AIDS, the disease of the Town, stress-related disorders, obsessive-compulsive disorders, eating disorders, bulimia, nervous anorexia, overeating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, atherosclerosis, fibrotic disorders, obesity, diabetes type II, associated with pain disorders, headache, neuropathic pain, postoperative pain is, chronic pain syndrome, disorders of the bladder, urinary disorders, cough, vomiting and nausea.

In the below examples used the following abbreviations.

AC means acetyl.

Asón (or SPLA) means of acetic acid.

Boc means tert-butoxycarbonyl.

Bu means butyl.

t-Bu or Butmeans tertiary butyl.

Bn means benzyl.

Cbz means carbobenzoxy (i.e. Ph-CH2-O-C(O)-).

DHM means dichloromethane.

DIEA means diisopropylethylamine.

DMF means dimethylformamide.

DMAP means dimethylaminopyridine.

DMPM means N,N - dimethylpropyleneurea.

DMSO means dimethylsulfoxide.

DFFA means diphenylphosphonate.

Et means ethyl.

Ejh means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

The Belarusian library Association means fast atom bombardment.

HOTs means p-toluensulfonate acid.

HATU means O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine.

HPLC means high performance liquid chromatography.

Msvr means of mass spectroscopy high resolution.

IHMS means liquid chromatography/mass spectroscopy.

Li means hexamethyldisilazide lithium.

Me means methyl.

Meon means methanol.

MS means mass spectroscopy.

High "mesyl" means methanesulfonyl.

Ni (Ra) means Raney Ni.

OP means the optical density.

Ph means phenyl.

i-RA (or IPA or iPA) means isopropyl.

Ppts means pyridine-p-toluensulfonate.

PTSC means p-toluensulfonate acid.

PYBOP means (benzotriazol-1 yloxy)tripyridyltriazine.

KG means room temperature.

TBAF means tetrabutylammonium.

TBI means tetrabutylammonium.

TPA means triperoxonane acid.

THF means tetrahydrofuran.

TLC means thin layer chromatography.

TMS means trimethylsilyl.

TMCCI means trimethylsilane.

"Toil" means toluensulfonyl.

The activity of the compounds of formula I against NK1NK2and PC3in vitro and in vivo can be identified by various methods known in the art, such as the study of their ability to inhibit the activity of the agonist NK1substances R. (in percent) activity inhibition of agonist neirokinina is the difference expressed in percent of the maximum specific binding ("MCC") and 100%. Expressed as the percentage of MSS is determined by the following equation, where "LOC" means the number of disintegrations per minute":

The concentration at which the compound actuator is t to inhibition, equal to 50%, then used to determine the inhibition constants (Ki") by the equation Chang-Prusova.

Activity in vivo can be identified by suppression caused by agonist twitching feet from pygmy gerbil, as described in the publication Science, 281. 1640-1695 (1998), which in its entirety is included in the present invention by reference. It should be understood that the compounds of formula I may have a different degree of antagonistic activity against NK1. For example, some compounds can have more antagonistic activity against NK1than others.

Compounds corresponding to the present invention, have a high tool relative to the receptor NK1that is expressed by the values of Ki(in nm). The activity of the compounds of the present invention is determined by measuring their values of Ki. The smaller the value of Kithe more active antagonistic effect connection has on the receptor NK1. Compounds corresponding to the present invention have a wide range of activities. The average values of Kifor compounds of formula I relative to the receptor NK1are usually in the range from 0.01 to about 1000 nm, preferably from about 0.1 nm to about 100 nm, and more predpochtitelnye values, equal to from about 0.1 nm to about 10 nm. Even more preferred are compounds with the average values of Kiin relation to the receptor NK1equal to from 0.1 to about 5 nm. Especially preferred compounds have average values of Kiin relation to the receptor MCC equal to from 0.1 to about 1 nm. Even more preferred compounds have average values of Kiin relation to the receptor NK1equal to from 0.1 to about 0.3 nm. Connection 2, 9, 10, 12, 14, 16, 19, 20, 23, 29, 30, 42 and 54 (see above table I) have values of Kiequal respectively 0,12, 0,18, 0,1, 0,05, 0,1, 0,13, 0,1, 0,11, 0,12, 0,11, 0,54, 0,28 and 0.12 nm.

The compounds of formula I are used in a number of cases. For example, compounds corresponding to the present invention, can be used as antagonists neurokinin receptors, preferably NKi receptors in a mammal, such as man. As such, they can be used in the treatment and prevention of one or more of a variety of pathological conditions (physiological disorders, symptoms and diseases) of a mammal (human and animal) in a patient in need of such treatment, wherein the pathological condition is selected from the group including: (1) respiratory diseases (e.g. chronic lung disease, bronchitis, pneumonia, asthma, who large, cough and bronchospasm), (2) inflammatory diseases (such as arthritis and psoriasis), (3) skin disorders (for example, atopic dermatitis and contact dermatitis), (4) eye disorders (eg, retinitis, hypertension eye and cataract), (5) pathological conditions of the Central nervous system such as depression (e.g., neurotic depression), anxiety (e.g., generalized anxiety, social anxiety and panic anxiety disorder), phobias (e.g., social phobia) and bipolar disorder (6) addiction (for example, alcohol dependence and substance abuse), (7) epilepsy, (8) nociception, (9) psychosis, (10) schizophrenia, (11) Alzheimer's disease, (12) dementia in AIDS, (13) disease of Town, (14) stress-related disorders (eg, post-traumatic stress disorder), (15) obsessive/compulsive disorders, (16) eating disorders (e.g. bulimia, anorexia nervosa and binge eating), (17) sleep disturbance, (18) mania, (19) premenstrual syndrome, (20) gastrointestinal disorders (e.g. irritable bowel syndrome, Crohn's disease, colitis and vomiting), (21) atherosclerosis, (22) fibrotic disorders (eg, pulmonary fibrosis), (23) obesity, (24) diabetes type II (25) associated with pain disorders (eg, headache, such as migraine, neuropathic pain, postoperative pain, and XP is clinical pain syndromes), (26) violation of the bladder and urinary disorders (eg, interstitial cystitis and urinary incontinence), (27) vomiting (e.g. caused by chemotherapy (for example, caused by cisplatin, doxorubicin and taxonom)caused by radiation, sickness, caused by ethanol and post-operative nausea and vomiting) and (28) vomiting. Compounds corresponding to the present invention, can preferably be used in the treatment and prevention of one of the following pathological conditions of a mammal (e.g. human) in a patient in need of such treatment: respiratory diseases (for example, cough), depression, anxiety, phobia, and bipolar disorder, alcohol dependence, substance abuse, nociception, psychosis, schizophrenia, stress-related disorders, obsessive/compulsive violation, bulimia, anorexia nervosa and binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, obesity-related pain disorders, disorders of the bladder, urinary disorders, vomiting and nausea. In particular, the compounds of formula 1 are applicable for the treatment of pathological conditions associated with capillary bleeding and mucus discharge. Therefore, compounds corresponding to the present invention is particularly useful in the treatment and limits the capacity of asthma, vomiting, nausea, depression, anxiety, cough and related pain disorders, more preferably vomiting, depression, anxiety and cough.

In another embodiment, the present invention relates to pharmaceutical compositions comprising at least one connection (e.g., one to three compounds, preferably one connection)described by formula I, and at least one pharmaceutically acceptable excipient or carrier. The present invention also relates to the use of such pharmaceutical compositions in the treatment of pathological conditions of a mammal (e.g. human), such as those listed above.

In yet another embodiment, the present invention relates to a method antagonistic influence on the effects of substance P on the plot neurokinin receptor 1 or blocking of one or more neurokinin of 1 receptors in a mammal (i.e. patient, e.g., human)in need of such treatment, comprising administration to the mammal of an effective amount of at least one (e.g. one) compounds of formula I.

In another embodiment of the present invention an effective amount of one or more antagonists of the receptor NK1of the present invention, the mod is but to combine with an effective amount of one or more anti-depressive drugs and/or one or more sedatives (for example, of gepirone, Geirangerfjord, nefazodone or nefazodonetreated (for example, serzone®)for the treatment of depression and/or anxiety. In U.S. patent US 6117855 (2000), the disclosure of which is included in the present invention by reference, disclosed a method for the treatment or prevention of depression or anxiety using the combined tools, including specific receptor antagonist NK1together with antidepressant agent and/or sedative. Thus, antidepressant and/or sedatives such as disclosed in U.S. patent US 6117855 (2000), can be combined with one or more (e.g. one) compounds of formula I for the treatment of depressive and/or anxiety pathological conditions in a mammal, preferably human.

In yet another embodiment of the present invention an effective amount of one or more (e.g. one) antagonists of the receptor NK1of the present invention, can be combined with an effective amount of one or more (e.g. one) of selective inhibitors of reuptake of serotonin ("SEPS") for the treatment of mammalian pathological conditions, such as described above. SEPS alters presynaptic availability of serotonin by suppressing presi opticheskogo re-accumulation secreted by neurons to serotonin. In U.S. patent US 6162805 (2000), the disclosure of which is included in the present invention by reference, disclosed a method of treating obesity using the combined tools, including receptor antagonist NK1and SEPS. One or more compounds of formula I of the present invention, can be combined with one or more SEPS in the same pharmaceutical composition or can be administered simultaneously, separately or sequentially with SEPS. This combination can be applied in the treatment and prevention of obesity or other of the above pathological conditions of human and mammal. In particular, an effective amount of at least one (e.g. one) compounds of formula I, alone or together with an effective amount of at least one (e.g. one), a selective inhibitor of reuptake of serotonin may be applicable in the treatment and prevention of depression and/or anxiety.

It is known that many chemical substances that modify the synaptic availability of serotonin by the presynaptic suppression of re-accumulation of secreted serotonin neurons. Typical SEPS include, without limit, the following: fluoxetine, fluoxetinetramaro (e.g., prozac®), fluvoxamine, fluvoxamine (e.g. the measures luvox®), paroxetine, paroxetinetreated (such as paxil®), sertraline, sertralinetreated (e.g., zoloft®), citalopram, cyclopropylboronic (for example, celexa®), DULOXETINE, duloxetinezapomnit, venlafaxine and venlafaxinetreated (for example, effexor®). Other SEPS are disclosed in U.S. patent US 6162805 (2000). Other compounds can be easily assess and determine their ability to selectively inhibit the re-uptake of serotonin. Thus, in one embodiment, the present invention relates to pharmaceutical compositions comprising at least one (e.g. one) receptor antagonist NK1described by formula I, at least one (e.g. one) of SEPS and at least one pharmaceutically acceptable excipient or carrier. In another embodiment, the present invention relates to a method of treatment of the above pathological conditions of a mammal (e.g. human), the method comprises administration to a patient in need of such treatment, an effective amount of a pharmaceutical composition comprising at least one (e.g. one) receptor antagonist NK1described by formula I, in combination with at least one (e.g. one) of SEPS, such as the one above, and at least one of pharmace is almost acceptable inert excipient or carrier.

In a preferred embodiment, the present invention relates to a method for the treatment of depression and anxiety, the method comprises administration to a patient in need of such treatment, an effective amount of at least one (e.g. one) receptor antagonist NK1described by formula I, in combination with at least one (e.g. one) of SEPS, such as the one described above. If receptor antagonist NK1corresponding to the present invention, combined with SEPS for administration to a patient in need of such treatment, the two active ingredients can be administered simultaneously, separately (one after another in a relatively short period of time) or sequentially (first one and then the other for some period of time). Usually, if these two active ingredient is administered separately or sequentially, the antagonist of the receptor NK1corresponding to the present invention, preferably prior to the introduction of SEPS.

Another variant of implementation of the present invention relates to the treatment of a patient suffering from multiple diseases with combination therapy, therapy comprises administration to the patient (e.g., mammal, preferably human)in need of such treatment at least one compound of formulas which I and at least one other active ingredient (i.e. drug)used to treat one or more diseases afflicting the patient. The compounds of formula I and other active ingredients can be administered simultaneously, separately and/or sequentially. The compounds of formula I and other active ingredients can be entered separately in the form of any dosage form. The introduction is preferably carried out with the use of oral dosage forms or using percutaneous patches. The compounds of formula I and other active ingredients can be combined with each other and be entered in a combined dosage forms.

Thus, the compounds corresponding to the present invention can be used alone or in combination with other active agents. Combination therapy includes the introduction of two or more active ingredients to a patient in need of such treatment. In addition to the above-described combination therapy type receptor antagonist NK1/SEPS compounds described by formula I, can be combined with one or more other active agents, such as the following: other types of receptor antagonists NK1(for example, disclosed in the above patents related to antagonists neurokinin receptor), prostanoids,antagonists of receptor H 1, agonists, α-adrenergic receptor agonists dopamine receptor agonists melanocortin receptor antagonists endothelioma receptor inhibitors endotheliumderived enzyme antagonists angiotensin II receptor inhibitors angiotenzinkonvertiruyuschego enzyme, inhibitors of neutral metalloendopeptidases antagonists EMA, renin inhibitors, antagonists of the serotonin receptor 5-HT3(for example, ondansetron, ondansetroncheapest (for example, SAFRAN®), palonosetron, granisetron and granisetron.html (for example, kytril®), agonists of serotonin receptor 5-HT2C, agonists nociceptive receptor, glucocorti-coida (e.g., dexamethasone), inhibitors urokinase, calcium channel modulators and/or inhibitors of protein 5 multidrug resistance.

Therapeutic agents, particularly suitable for combination therapy with the compounds disclosed in this invention are the following: prostanoids, such as prostaglandin E1; α-adrenergic agonists, such as phentolamine; agonists dopamine receptor, such as apomorphine; antagonists of angiotensin II, such as losartan, irbesartan, valsartan and candesartan; antagonists of ETAsuch as bosentan and ABT-627; antagonists of serotonin what about the receptor 5-HT 3such as ondansetron; and glucocorticoids, such as dexamethasone. In preferred embodiments of implementing the present invention is compounds corresponding to the present invention, can be combined with other types of receptor antagonists NK1, SEPS, agonists dopamine receptor antagonists, serotonin receptor 5-HT3, agonists of the serotonin receptor 5-HT2C, agonists nociceptive receptor, glucocorticoids and/or inhibitors of protein 5 multidrug resistance.

Another variant of implementation of the present invention relates to a method for treating physiological disorders, elimination of a symptom or treatment of a disease in a patient in need of such treatment, comprising administration to the patient an effective amount of at least one of the compounds of formula I and an effective amount of at least one active ingredient selected from the group including: other antagonists of the receptor NK1selective inhibitors of reuptake of serotonin, dopamine agonists receptor antagonists, serotonin receptor 5-HT3the agonists of the serotonin receptor 5-HT2C, agonists nociceptive receptor, glucocorticoids and inhibitors of protein 5 multidrug resistance, in which f is Biologicheskie violation, the symptom or the disease is selected from the group including: respiratory disease, depression, anxiety, phobia, bipolar disorder, alcohol dependence, substance abuse, nociception, psychosis, schizophrenia, associated with stress disturbance, obsessive/compulsive violation, bulimia, anorexia nervosa, overeating, insomnia, mania, premenstrual syndrome, gastrointestinal disturbance, obesity, headache, neuropathic pain, postoperative pain, chronic pain syndrome, impaired bladder, urinary disturbance, cough, vomiting and nausea.

The pharmaceutical compositions can contain from about 0.1 to about 99.9 wt.%, or from about 5 to about 95 wt.%, or from about 20 to about 80 wt.% active ingredient (compound of formula (I). In the manufacture of pharmaceutical compositions from the compounds described in this invention, inert, pharmaceutically acceptable carriers can be solid or liquid. The solid form preparations include powders, tablets, dispergirujutsja granules, capsules, pills and suppositories. The powders and tablets may contain from about 5 to about 95% active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar and lactose. Tablets, powders, Burgas region, the TCA and the capsules can be used as solid dosage forms, suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions are given in the publication A.Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20thEdition, (2000), Lippincott Williams &Wilkins, Baltimore, MD, which is incorporated into this invention by reference.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and cloud emulsions in solutions, suspensions and emulsions for oral administration. To liquid form compositions can also include solutions for vnutripuzarnogo introduction.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which can be combined with a pharmaceutically acceptable carrier, such as a compressed inert gas, such as nitrogen.

In the scope of the present invention also includes a solid form preparations which are intended for conversion into liquid form preparations intended for oral or parenteral administration, which is shortly before use. Such liquid forms include solutions, suspensions and emulsions.

Compounds corresponding to the present invention, it is also possible to enter percutaneous. Percutaneous compositions which may be a cream, lotions, aerosols and/or emulsions and can be included in the matrix patch percutaneous exposure or patch reservoir of the type that is commonly used in the art for such purpose.

Preferably the oral connection.

Preferably, the pharmaceutical preparation was in the form of a single dosage form. In this form, the drugs are divided into single doses of appropriate size containing appropriate quantities of the active component, for example, a quantity sufficient to achieve the necessary goals.

The term "pharmaceutical composition" also includes bulk composition and individual dosage forms in the form of any of the forms described in the present invention, containing more than one (e.g., two) pharmaceutically active means, such as, for example, the connection corresponding to the present invention, and additional means selected from the list of active agents described in this invention, together with any pharmaceutically inactive inert fillers. Bulk composition and each individual dosage form may contain a constant number of said "more than one pharmaceutically active agents". The term "bulk composition" means a material that is not yet processed the separate dosage forms. An example of a dosage form is an oral dosage form such as tablets, pills, etc. in a Similar manner described in this invention is a method of treatment of a patient by injecting the pharmaceutical composition corresponding to the present invention, also includes the introduction of specified bulk composition and individual dosage forms.

The number of active compounds contained in one dose of the drug, in accordance with the specific case of application is usually can be changed or adjusted from about 0.01 to about 4000 mg, preferably from about 0.02 to about 1000 mg, more preferably from about 0.3 to about 500 mg, and most preferably from about 0.04 to about 250 mg in accordance with the specific application.

Real used the dose may vary depending on the needs of the patient and severity at treatment of a pathological condition. Determination of appropriate dosing regime for a specific case by the person skilled in the art. For convenience, the total daily dose can be divided and enter portions throughout the day in accordance with the necessity.

The amount and frequency of administration of compounds of the present invention, and/or their pharmaceutically acceptable salts will be regulated according to the accordance with the decision of the attending physician, taking into account such factors as age, condition and weight of the patient, and the severity of symptoms during treatment. A typical recommended daily dosage regime for oral administration can be an introduction from about 0.02 to about 2000 mg/day, administered in two to four divided doses.

Pharmaceutical compositions corresponding to the present invention, it is possible to introduce from about 1 to about 5 times per day or alternatively, by continuous infusion. This introduction can be used as a long-term or emergency treatment.

The number of receptor antagonist NK1in combination with a selective inhibitor of reuptake of serotonin ("SEPS") in a single dose can be from about 10 to about 300 mg receptor antagonist NK1in combination with components from about 10 to about 100 mg number of SEPS. In another combination, the number of receptor antagonist NK1in combination with SEPS in a single dose can be from about 50 to about 300 mg receptor antagonist NK1in combination with components from about 10 to about 100 mg number of SEPS. In another combination, the number of receptor antagonist NK1in combination with SEPS in a single dose can be from about 50 to about 300 mg receptor antagonist NK1in combination comprising from about 20 to about 50 mg number of SEPS.

Real used the dose may vary depending on the needs of the patient and severity at treatment of a pathological condition. Determination of appropriate dosing regime for a specific case by the person skilled in the art. For convenience, the total daily dose can be divided and enter portions throughout the day in accordance with the necessity. After improvement of the patient if necessary, you can enter a maintenance dose of a compound, composition or combination corresponding to the present invention. Then the dose or frequency of administration, or both can be reduced depending on the symptoms and the extent to which remains superior condition. If the symptoms of weakened to the extent necessary, the treatment should be discontinued. However, any recurrence of symptoms may require periodic treatment of patients on long-term basis.

Specific dosage and treatment regimens for each patient may vary and will depend on various factors including the activity of the specific compound, the age, body weight, General health, sex and diet of the patient, time of administration, rate of excretion, the particular combination of drugs, the severity and onset of symptoms, elimination of which e.g. is established with representation from the treatment, predisposition of the patient to the manifestation of undergoing the treatment of pathological conditions and the decision of the attending physician. Determination of appropriate dosing regime for a particular case is within the competence of a person skilled in the technical field.

Examples

The described invention as examples includes the following examples of the preparation and examples, which should not be construed, as limiting the scope of the present description. For specialists in this field of technology can be obvious alternative mechanisms of synthesis and similar structures.

Example obtain 1

Stage 1:

In a round bottom flask with a volume of 25 ml of compound 42b (0,253 g, 0.42 mmol, 1.0 EQ.) dissolve in 5 ml of CH2Cl2and the resulting reaction mixture is cooled to 0°C in the bath with ice. Then to the reaction mixture was added Et3N (0,088 ml, was 0.63 mmol, 1.5 equiv.) then 4-chlorobutyrate (0,065 ml, 0.5 mmol, 1.2 EQ.) and then slowly warmed to room temperature and stirred for 14 hours Over the course of the reaction is monitored by TLC (60:40 tO/hexane) and MC. After completion of the reaction, the reaction mixture was diluted with CH2Cl2the reaction is stopped saturated aqueous Panso3and then brine. The organic layer su is at over Na 2SO4and concentrate and get the crude compound 1A (0.3 g), which is used in the next stage without additional purification.

MS elektrorazpredelenie [M+1] 724,4.

Stage 2:

In dried by the fire round bottom flask with a volume of 25 ml of compound 1A (0.3 g, 0.4 mmol, 1.0 EQ.) dissolved in dry THF. To this reaction mixture was added 60% NaH (0.025 g, of 0.62 mmol, 1.5 EQ.) and the reaction mixture was stirred at room temperature for 2 hours Over the course of the reaction is monitored by TLC (60:40 tO/hexane) and MC. After completion of the reaction, the reaction mixture was diluted with tO and the reaction stopped by saturated aqueous Panso3. The organic layer is dried over Na2SO4and concentrate and get the connection 1b (0.25 g), which is used in the next stage without additional purification.

Stage 3:

Compound 1b (0.25 g, and 0.37 mmol, 1.0 EQ.) dissolved in dry Meon (2.0 ml) and treated with 20% Pd(OH)2(60 wt.%) in an inert atmosphere. The reaction mixture hydronaut at atmospheric pressure and the reaction monitored by TLC (60:40 tO/hexane). The reaction is finished after 45 min and then the reaction mixture was filtered through celite (diatomaceous earth), washed with tO, concentrate, and get the crude product. the cleaning is carried out using preparative thin-layer chromatography (60/40 tO/hexane) and get a connection 1 (0.10 g, 49%).

MS elektrorazpredelenie [M+1] 554,3.

Msvr (the Belarusian library Association) calculated for C28H29F6N3O2(M+1) 554,2242 found 554,2249.

Example of getting 2

Stage 1:

In a round bottom flask with a volume of 25 ml of compound 42b (0,3264 g, 0.44 mmol, 1.0 EQ.) dissolved in 5 ml THF and the reaction mixture is cooled to 0°C in the bath with ice. Then to the reaction mixture was added Et3N (0,073 ml, 0.44 mmol, 1.2 equiv.) then 2-chloroethylphosphonic (0,054 ml, 0.44 mmol, 1.2 EQ.) and it is slowly warmed to room temperature and stirred for 14 hours Over the course of the reaction is monitored by TLC (40:60 tO/hexane) and MC. The reaction does not reach the end and therefore the reaction mixture was diluted with tO and the reaction stopped with saturated solution of NaHCO3and then brine. The organic layer is dried over Na2SO4and concentrate and get (0.3 g) of the crude product, which is treated using chromatography on a BIOTAGE column (40:60 tO/hexane) and get a connection 2A (0.125 g).

MS elektrorazpredelenie [M+1] 712,4.

Stage 2:

In dried by the fire round bottom flask with a volume of 25 ml of compound 2A (0.125 g, 0,175 mmol, 1.0 EQ.) dissolved in dry THF. To this reaction mixture was added 60% NaH (0.10 g, 0.26 mmol, 1.5 EQ.) and the reaction mixture is peremeshivayte at room temperature over night. Over the course of the reaction is monitored by TLC (40:60 tO/hexane) and MC. After completion of the reaction, the reaction mixture was diluted with tO and the reaction stopped by saturated aqueous Panso3. The organic layer is dried over Na2SO4and concentrate and get the connection 2b (0.11 g), which is used in the next stage without additional purification. MS elektrorazpredelenie [M+1] 676,2.

Stage 3:

Compound 2b (0.11 g, 0.16 mmol, 1.0 EQ.) dissolved in dry Meon (2.0 ml) and treated with 20% Pd(OH)2(60 wt.%) in an inert atmosphere. The reaction mixture hydronaut at atmospheric pressure and the reaction monitored by TLC (40:60 tO/hexane). The reaction is finished after 45 min, the reaction mixture was filtered through celite, washed with tO and concentrate and get the crude product. The crude product was then purified using preparative thin-layer chromatography (45/55 tO/hexane) and get a connection 2 (0.04 g, 45%). MS elektrorazpredelenie [M+1] USD 542.3.

Msvr (the Belarusian library Association) calculated for C26H26FN3About3(M+1) 542,1897 found 542,1878.

Examples for the preparation of 3 and 4

NaBH4(60 mg, 1.53 mmol, 8 EQ.) at 0°With portions added to a solution of compound 30 (109 mg, ~0,19 is mol, 1 EQ.) in absolute ethanol (2 ml). After stirring at 0°C for 30 min analysis of the reaction mixture by TLC (MeOH/CH2Cl2=10%) only detects the product. The product was then purified using chromatography on a BIOTAGE column (2-10% Meon in CH2CL2and get a clean mixture of two diastereoisomers. These two diastereoisomers separated using chiral HPLC (ChialCel OD, IPA/hexane=10%) and get a connection example 3, MS [M+1]+573,1; and the compound of example 4 MS [M+1]+573,1.

Example of getting 5

Stage A:

MsCl (is 0.102 ml, of 1.32 mmol) was added to a solution of compound 26a (0.375 g, 0,528 mmol) and Et3N (0,368 ml of 2.64 mmol) in CH2Cl2(5.0 ml) at 0°C. the Reaction is stopped by the water (15.0 ml) over 30 min and then diluted with CH2Cl2(50 ml). The resulting aqueous phase extracted with CH2CL2(3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude mesilate dissolved in DMF (3.0 ml) and treated with KCN (0,344 g, 5,28 mmol). The resulting mixture is heated at 100°C for 12 h and then cooled to room temperature. The reaction mixture was diluted with tO (100 ml) and washed with water (3×15 ml). Then the organic layer washed the Ute brine (25 ml) and dried over MgSO 4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=7/1) and get a connection 5b (0.14 g, 37% over 2 stages).

Stage:

A solution of compound 5b (0.14 g, of € 0.195 mmol) in TFA (2.5 ml) was stirred at room temperature for 20 min, and then the solvent is removed under reduced pressure. The residue is dissolved in tO (50 ml) and washed with NaOH solution (4,0 N., 15 ml). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (15 ml), brine (15 ml) and then dried over MgSO4. After filtration and concentration the crude product is passed through a thin layer of silica gel using tO/Meon (about./about.=10/1) as eluent and after removal of the solvent receive amine (90 mg). The amine is dissolved in pyridine (1.0 ml) and at room temperature in an airtight vessel is treated with HC(O)NHNHC(O)H (to 38.3 mg, 0,435 mmol), TMCCl (0,276 ml, 2,175 mmol) and Et3N (0,152 ml, 1,088 mmol). Then the reaction mixture is heated at 100°C for 2.5 h and then cooled to room temperature. The mixture is then diluted with tO (40 ml) and washed with HCl (10 ml, 2,0 BC). The resulting aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with water (15 ml), brine (25 ml) and the shat over gS 4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (tO/Meon, vol./about.=10/1) and get a connection 5C (40 mg, 31% over 2 stages).

Stage With:

Compound 5C (40 mg, 0,0595 mmol) in tO (2.0 ml) at room temperature is treated with Pd(OH)2/C (8 mg, 10 wt.%) and hydronaut for 30 min using a cylinder with H2. The reaction mixture was filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified using preparative TLC (tO/Meon, vol./about.=40/1) and get a connection 5 (18 mg, 56%, MS elektrorazpredelenie [M+1]+538,1) and compound 5d (6 mg, 19%, MS elektrorazpredelenie [M+1]+538,1).

An example of obtaining 6

Stage A:

MsCl (75 ml, 0,969 mmol) was added to a solution of compound 23d (0,248 g, 0,388 mmol) and Et3N (of 0.27 ml, 1.94 mmol) in CH2Cl2(3.0 ml) at room temperature. The reaction is stopped by the water (10.0 ml) over 30 min and diluted with CH2Cl2(30 ml). The aqueous phase is extracted with CH2Cl2(3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over gS4. After filtration and concentration neo is ewenny mesilate dissolved in anhydrous DMSO (3.0 ml) and treated with NaBH 4(59,0 mg, 1,552 mmol). The reaction mixture is heated at 85°C for 48 h, and then cooled to room temperature. The mixture is then diluted with tO (50 ml) and washed with aqueous HCl solution (10 ml, 1.0 M). The resulting aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with water (3×15 ml), brine (15 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=5/1) and get a connection 6A (0.11 g, 45% over 2 stages).

Stage:

A mixture of compound 6A (0.11 g, 0,176 mmol) and zinc dust (0,114 g of 1.76 mmol) in SPLA (1.5 ml) is heated at 60°C for 2 h, the Reaction mixture was cooled and filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the residue is dissolved in tO (25 ml) and washed with NaOH solution (4,0 N., 10 ml). The resulting aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (15 ml), brine (15 ml) and dried over MgSO4. After filtration and concentration the crude amine (67,1 mg, 0,113 mmol) dissolved in pyridine (1.0 ml) and at room temperature in an airtight vessel is treated with HC(O)NHNHC(O)H (29,8 mg, 0,339 mmol), TMCCl (0,214 ml, was 1.69 mmol) and Et3N (amount of 0.118 ml, 0,847 mmol) Then the mixture is heated at 100°C for 2.5 h, and then cooled to room temperature. The mixture is then diluted with tO (40 ml) and washed with HCl (10 ml, 2,0 BC). The resulting aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with water (15 ml), brine (15 ml) and dried over gS4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (tO/Meon, vol./about.=20/1) and get a connection 6b (37 mg, 33% over 2 stages).

Stage With:

Compound 6b (to 36.5 mg, 0,0565 mmol) in tO (2.0 ml) is treated at room temperature by means of Pd(OH)2/C (7,3 mg, 10 wt.%) and hydronaut for 30 min using a cylinder with H2. The reaction mixture was filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified using preparative TLC (EtOAc/MeOH/Et3N,./about./about.=40/1/0,1) and get a connection 6 (20 mg, 69%). MS elektrorazpredelenie [M+1]+513,1.

Example of getting 7

Stage A:

Periodinane dessa-Martin (0,114 g, 0,268 mmol) was added to a mixture of compound 12A (and 70.5 mg, 0,107 mmol) and NaHCO3(0,112 g of 1.34 mmol) in CH2CL2(3.0 ml) at room temperature. The reaction mixture is stirred during the s 1 h and then diluted, adding tO (30 ml) and water (10 ml). The organic phase is washed with a saturated solution PA2S2O3(3×10 ml). The combined aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with NaOH solution (10 ml, 1.0 N.), water (10 ml), brine (15 ml) and dried over MgSO4. After filtration and concentration the crude aldehyde (70,5 mg, 0,107 mmol) dissolved in tO (3.0 ml) and treated with HONH2·HCl (74,4 mg, 1.07 mmol) and NaOAc (43,9 mg, 0,535 mmol) at room temperature. The reaction mixture was stirred for 12 h and then diluted with tO (20 ml) and washed with aqueous solution of NaHCO3(10 ml). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration get the crude oxime (63 mg, 0,093 mmol)which is dissolved in benzene (2.0 ml) and treated with 1,1'-oxalylamino (35.4 mg, 0,186 mmol). The reaction mixture is heated at 80°C for 3 h, and then cooled to room temperature and diluted with tO (20 ml) and washed with aqueous solution of Hcl (0,5 N., 5 ml). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude etc the product is purified using chromatography on a BIOTAGE column (tO) and get a connection 7a (39 mg, 55% for stage 3).

Stage:

Compound 7a (39 mg, 0,059 mmol) in tO (2.5 ml) is treated at room temperature with Pd(OH)2/C (7.8 mg, 10 wt.%) and hydronaut for 30 min using a cylinder with H2. Solution the reaction mixture is filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified using preparative TLC (tO/Et3M,./about.=100/0,1) and get a connection 7 (12,2 mg, 40%). MS elektrorazpredelenie [M+]+524,3.

Example obtain 8

Stage A:

Periodinane dessa-Martin (0,325 g, 0,767 mmol) was added to a mixture of compound 12A (0,202 g, 0,306 mmol) and NaHCO3(0,322 g, a 3.83 mmol) in CH2Cl2(5.0 ml) at room temperature. The reaction mixture was stirred for 1 h and then diluted with tO (50 ml) and water (10 ml). The organic phase is washed with a saturated solution PA2S2O3(3×15 ml). The combined aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with NaOH solution (15 ml, 1.0 N.), water (10 ml), brine (15 ml) and dried over gSO4. After filtration and concentration the crude aldehyde (0,202 g) dissolved in tert-butanol (4.0 ml) and water (1.0 ml) and the settlement of adavale treated with NaH 2PO4·H2O (84,4 mg, 0,612 mmol), NaClO2(96.8 mg, 1.07 mmol) and 2-methyl-2-butene (0,227 ml, 2.14 mmol). The reaction mixture was stirred for 2 h and then diluted with tO (30 ml) and washed with aqueous solution of NH4Cl. The resulting aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude acid was dissolved in benzene (4.0 ml) and Meon (1.0 ml). The resulting solution is treated with TMCCHN2(0,306 ml, 0,612 mmol) at room temperature and stirred for 20 minutes the Solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (hexane/tO, vol./about.=from 5/1 to 1/3) and get a connection 8A (62 mg, 29% for 3 stages).

Stage:

Compound 8A (62 mg, 0,090 mmol) in tO (3.0 ml) is treated at room temperature with Pd(OH)2/C (12,4 mg, 10 wt.%) and for 30 min hydronaut using a cylinder with H2. The reaction mixture was filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (tO/Meon, vol./about.=6/1) and get a connection 8 (42 mg, 84%). MS from electrorash what Elenium [M+] +557,3.

Example of getting 9

Stage 1:

In a round bottom flask with a volume of 25 ml of compound 42b (0.21 g, 0.35 mmol, 1.0 EQ.) dissolved in 2 ml of toluene. Then to the reaction mixture was added 3-chloropropionitrile (0.037 ml, 0.38 mmol, 1.1 EQ.) and it was stirred at room temperature for 5 hours Over the course of the reaction is monitored by TLC (60:40 tO/hexane) and MS, which show that still contains some amount of the original substance. Then the reaction mixture is heated at 80°C. After completion of the reaction by heating for several hours the mixture is concentrated and get the crude compound 9a (0.2 g), which is used in the next stage without additional purification.

Stage 2:

In dried by the fire round bottom flask with a volume of 25 ml of compound 9a (0.2 g, 0,287 mmol, 1.0 EQ.) dissolved in a 0.5 solution of the dry mixture of CH2CL2/DMF ratio (4/1) (4.59 ml/1,15 ml). To this mixture using a syringe pump for 3.5 hours very slowly added 0.5 M solution of 60% NaH (0,012 g, 0,316 mmol, 1.1 EQ.) in dry mixture of CH2CL2/DMF (ratio of 4/1; 5,06 ml/1,26 ml) and the reaction mixture was stirred at room temperature overnight. Over the course of the reaction is monitored by TLC (40:60 tO/hexa is) and MC. The reaction proceeds at 60% and then the reaction mixture was diluted with CH2CL2and the reaction stopped by saturated aqueous NH4Cl. The organic layer is dried over Na2SO4and concentrate and get the crude product (0.18 g)which is purified by chromatography on BIOTAGE column (30/70 tO/hexane) and get a connection 9b (0.125 g).

MS elektrorazpredelenie [M+1] 660,2.

Stage 3:

Compound 9b (0.125 g, 0,189 mmol, 1.0 EQ.) dissolved in dry Meon (1.0 ml) and treated with 20% Pd(OH)2(60 wt.%) in an inert atmosphere. The reaction mixture hydronaut at atmospheric pressure and the reaction monitored by TLC (60:40 EtOAc/hexane). The reaction is completed within 20 min and the reaction mixture was filtered through celite, washed with tO and concentrate and get the crude product. The cleaning is performed using preparative thin-layer chromatography (45/55 tO/hexane) and get a connection 9 (0,071 g, 71%).

MS elektrorazpredelenie [M+1] 526,3.

Msvr (the Belarusian library Association) calculated for C26H26F6N3O2(M+1) 526,1932 found 526,1929.

Example 10

Stage A:

A solution of compound 8 (35 mg, 0,063 mmol) in methanolic ammonia solution (3.0 ml, 7.0 M) in the pressure vessel Parra n is grebaut at 80°C for 5 days. The system is cooled to room temperature and the solvent is removed under reduced pressure. The crude product is purified by chromatography on BIOTAGE column (tO/Meon, vol./about.=10/1) and get a connection 10 (to 26.8 mg, 79%).

MS elektrorazpredelenie [M+1]+542,1.

Example of getting 11

Stage 1:

The solution methylacrylamide in tert-butyl methyl ether (0,42 ml, 1.0 M, 0.42 mmol, 6.2 equiv.) the syringe was added to a solution of compound 30b (48 mg, 0,068 mmol, 1.0 EQ.) in anhydrous THF (1 ml) at 0°C. Then the reaction mixture is heated to room temperature. After TLC (eluent-tO) shows that the reaction was completed, the reaction mixture is diluted with ether and washed with saturated aqueous NH4Cl. The combined organic layers dried over gS4filter and concentrate and get the crude product, compound 11a, which is used in the next stage without purification.

Stage 2:

By the same procedure as described in example 31, step 6, the crude compound 11a hydronaut and get a pure compound of example 30b (output 52,6% of the compound (11). MS [M+]+587,1.

Example 12

Stage A:

HC(O)NHNHC(O)H (0.28 g, 3,18 mmol), TMCCl (2.0 ml, 15,mmol) and Et 3N (1.1 ml, of 7.95 mmol) at room temperature in a sealed vessel successively added to a solution of compound 23d (0,647 g, 1.06 mmol) in pyridine (5.0 ml). Then the mixture is heated at 100°C for 2.5 h and then cooled to room temperature. The mixture is then diluted with tO (100 ml) and washed with HCl (35 ml, 2,0 BC). The aqueous phase is extracted with tO (3×25 ml) and the combined organic layers washed with water (15 ml), brine (25 ml) and dried over gS4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (tO/Meon, vol./about.=5/1) and get a connection 12A (0,48 g, 68%).

Stage b:

Compound 12A (a 32.6 mg, 0,049 mmol) in tO (2.0 ml) is treated at room temperature with Pd(OH)2/C (6,5 mg, 10 wt.%) and for 30 min hydronaut using a cylinder with H2. Then the reaction mixture was filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (eluent-tO/Meon, vol./about.=6/1) and get a connection 12 (17,2 mg, 66%).

MS elektrorazpredelenie [M+1]+529,1.

Examples get 13 and 14

Stage A:

HC(O)NHNHC(O)H (67,1 the g 0,762 mmol), TMCCl (0,484 ml, 3,81 mmol) and Et3N (0,266 ml, 1,905 mmol) at room temperature in a sealed vessel successively added to a solution of compound 26a (0,155 g, 0,254 mmol) in pyridine (2.0 ml). Then the mixture is heated at 100°C for 2.5 h and then cooled to room temperature. The mixture is diluted with tO (40 ml) and washed with HCl (15 ml, 2,0 BC). The aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with water (15 ml), brine (25 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (eluent - tO/Meon, vol./about.=10/1) and get a connection 14a (0,129 g, 75%).

Stage:

Compound 14a (129 mg, 0,19 mmol) in tO (4,0 ml) is treated at room temperature with Pd(OH)2/C (from 25.8 mg, 10 wt.%) and for 30 min hydronaut using a cylinder with H2. The reaction mixture was filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified using preparative TLC (EtOAc/Et3N,./about.=100/0,1) and get a connection 13 (36 mg, 35%, MS elektrorazpredelenie [M+1]+543,1) and compound 14 (30 mg, 29%, MS elektrorazpredelenie [M+1]+543,1).

Example get 15

Stage A:

Periodinane dessa-Martin (57,7 mg, 0,136 mmol) at room temperature was added to a mixture of compound 23g (46 mg, 0,0678 mmol) and NaHCO3(57 mg, 0,678 mmol) in CH2Cl2(2.5 ml). The reaction mixture was stirred for 1 h and then diluted with tO (20 ml) and water (10 ml). The organic phase is washed with a saturated solution of Na2S2C3(3×10 ml). The combined aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with NaOH solution (10 ml, 1.0 N.), water (10 ml), brine (15 ml) and dried over gSO4. After filtration and concentration the crude aldehyde (46 mg, 0,0679 mmol) dissolved in ClCH2CH2Cl (1.0 ml) and treated with molecular sieves 4Å (15 mg) and para-methoxybenzylamine (26,7 μl, 0,204 mmol), and then add the N(SLA)3(to 86.4 mg, 0,408 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours Then the system is diluted with tO (20 ml) and washed with aqueous solution of NaHCO3(10 ml). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=2/3) and get connected to the e 15A (38 mg, 70% over 2 stages).

Stage:

A mixture of compound 15A (46.6 mg, 0,0584 mmol), Pd/C (46.6 mg, 10 wt.%) and NH4CO2H cases (36.8 mg, 0,584 mmol) in Meon (2.0 ml) is heated under reflux for 5 hours the Mixture is cooled to room temperature and filtered through a thin layer of celite, and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and get the crude product which is dissolved in tO (20 ml) and washed with an aqueous solution Panso3(10 ml). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using preparative TLC (Meon/tO, vol./about.=1/10) and get a connection 15b (18 mg, 57%).

Stage With:

MsCl (2,5 μl, 0,0324 mmol) at 0°C was added to a solution of compound 15b (8,8 mg, 0,0162 mmol) and Et3N (5,4 μl, 0,0388 mmol) in CH2CL2(1.0 ml). The reaction is stopped by the water (5.0 ml) over 30 min and diluted with tO (15 ml). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using preparative TLC (hexane/tO, vol./about.=15) and get a connection 15 (7.2 mg, 72%).

MS elektrorazpredelenie [M+1]+622,3.

Example 16

Stage 1:

By the same procedure as described in example 30, step 1, compound 16A is obtained using ethylamine instead of N,N-dimethylammoniumchloride and without the use of diisopropylethylamine. The crude product used in the next stage without purification.

Stage 2:

By the same procedure as described in example 31, step 6, the crude compound 16A hydronaut and get a pure compound of example 16 (yield of 70.5% from compound 16). MS [M+1]+600,1.

Example of getting 17

Stage 1:

A solution of compound 31h (46,3 mg, of 0.066 mmol, 1.0 EQ.) in anhydrous dichloromethane (1 ml) cooled to 0°C. To this solution are successively added, DMAP (8 mg, of 0.066 mmol, 1.0 EQ.) and ethanol (36 ml). The reaction mixture is allowed to warm to room temperature and then concentrated to dryness. The residue is dissolved in tO and washed with saturated aqueous NaHCO3. The organic layer is dried over Na2SO4filter and concentrate and get the crude product, compound 17A, which is used in the next stage without purification.

Stage 2:

/p>

By the same procedure as described in example 31, step 6, the crude compound 17A hydronaut and get a pure compound 17 (exit 46% from compound 31h). MC [M+1]+601,1.

Example of getting 18

Stage A:

Compound 19 (10 mg, 0,0175 mmol) in tO (1.5 ml) at room temperature is treated with HONH2·HCl (12,2 mg, 0,175 mmol) and NaOAc (7.2 mg, 0,0876 mmol). Then the reaction mixture was stirred at 60°C for 12 hours the Mixture is diluted with tO (20 ml) and washed with an aqueous solution Panso3. The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using preparative TLC (hexane/tO, vol./about.=2/3) and get a connection 18 (10 mg, 98%). MS elektrorazpredelenie [M+1]+586,1.

Example of getting 19

Stage A:

Periodinane dessa-Martin (0,252 g, 0,595 mmol) at room temperature was added to a mixture of compound 23h (0,202 g, 0,297 mmol) and Panso3(0.25 g, of 2.97 mmol) in CH2Cl2(4,0 ml). The reaction mixture was stirred for 1 h and then diluted with tO (50 ml) and water (10 ml). The organic phase is washed with saturated R is the target Na 2S2O3(3×15 ml). The combined aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with NaOH solution (15 ml, 1.0 N.), water (10 ml), brine (15 ml) and dried over gS4. After filtration and concentration the crude aldehyde (0,202 g) dissolved in anhydrous THF (4.0 ml) and treated with CH3MDG (1,19 ml, 1,19 mmol, 1.0 M in THF) at -78°C. the reaction Temperature is slowly increased to room temperature and the reaction stopped after 2 h by slow addition of a saturated aqueous solution of NH4Cl (10 ml). Then the reaction mixture was diluted with tO (50 ml) and neutralized with a 0.5 N. HCl until the aqueous phase becomes slightly acidic. The aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude secondary alcohol (0.21 g) was dissolved in CH2Cl2(5.0 ml) and treated with periodinane dessa-Martin (0,379 g, 0,894 mmol) and Panso3(0.375 g, 4,47 mmol) at room temperature. The reaction mixture was stirred for 1 h and then diluted with tO (50 ml) and water (10 ml). The organic phase is washed with a saturated solution of Na2S2O3(3×15 ml). The combined aqueous phase is extracted with tO (3×15 ml). The combined organic is Lois washed with aqueous NaOH solution (15 ml, 1,0 N.), water (10 ml), brine (15 ml) and dried over gS4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/1) and get a connection 19a (90 mg, 43% for stage 3).

Stage:

Compound 19a (57.4 mg, 0,0816 mmol) in tO (3.0 ml) is treated at room temperature with Pd(OH)2/C (11,5 mg, 10 wt.%) and for 30 min hydronaut using a cylinder with H2. The reaction mixture was filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (hexane/tO, vol./about.=2/3) and get a connection 19 (41 mg, 88%).

MS elektrorazpredelenie [M+1]+571,1.

Example of getting 20

Stage A:

The N(SLA)3(81,4 mg, 0.384 mmol) was added at room temperature to a solution of compound 26b (79,9 mg, 0,128 mmol), CHOCO2Et (37,8 μl, 0,192 mmol, 45% and 50% in toluene) and 4 Å molecular sieves (30 mg) in ClCH2CH2Cl (1.0 ml). The reaction mixture was stirred for 12 h and then diluted with tO (20 ml) and washed with aqueous solution of NaHCO3(10 ml). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers is raybaut water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude product (91 mg, 0,128 mmol) dissolved in ClCH2CH2Cl (0.5 ml) and treated with TMCN=C=O (2.5 ml). The reaction mixture is heated at 70°C for 72 h and then the solvent is removed under reduced pressure. The crude product is purified by chromatography on BIOTAGE column (hexane/tO, vol./about.=1/1) and get a mixture of compounds 20A and 20b, which is optionally purified using chiral HPLC on a column of OD and get a pure compound 20A (30 mg, 33%) and compound 20b (25 mg, 28%).

Stage:

Compound 20A (23 mg, 0,0325 mmol) in tO (2.0 ml) is treated at room temperature with Pd(OH)2/C (4.6 mg, 10 wt.%) and for 30 min hydronaut using a cylinder with H2. Solution the reaction mixture is filtered through a thin layer of celite and the residue is washed with tOH/H (15 ml). The solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/3 to 1/9) and get a connection 20 (14.3 mg, 77%).

MS elektrorazpredelenie [M+1]+574,3.

Examples get 21 and 22

Compound 21A (1.0 g, 1.4 mmol, 1.0 EQ.) dissolved in CH2Cl2(16 ml) and the solution cooled to 0°C. To the reaction mixture add Diisopropylamine (0.54 g, 4.2 mmol, 3.0 equiv.) then PYBOP (0.88 g, 1.7 mmol, 1.2 EQ.) and the reaction mixture was stirred at 0°C for 5 min, then warmed to room temperature. After 20 min the excess of methylamine (7.0 ml, 14 mmol, 10.0 EQ.) add in the form of a 2.0 M solution in THF. The little flask is heated and the contents stirred at room temperature overnight. Over the course of the reaction is monitored by TLC (eluent - 95/5 tO/Meon). After completion of the reaction, the reaction mixture was diluted with H2O and tO, organic and aqueous layers are separated and the organic layer washed with brine, dried over Na2SO4and concentrate and get the crude product (1.9 g) as a white solid. The cleaning is performed using chromatography on a BIOTAGE column (from 1:1 to 2:1 tO/hexane) and get a connection 21b in the form of a white solid (0,72 g, 72%).

MS elektrorazpredelenie [M+1]+738,2.

Compound 21 (0.7 g, 0.95 mmol, 1.0 EQ.) dissolved in CH2CL2(10 ml) in an atmosphere of N2. To the reaction mixture was added excess TFA (2.0 g, with 19.4 mmol, 20.0 EQ.) and the reaction mixture was stirred at room temperature overnight. Over the course of the reaction is monitored by TLC (eluent-1/1 tO/Meon), which shows that it still contains some to the number of original substance. Therefore, add 10.0 EQ. TFA and the reaction mixture is stirred for 3 hours After completion of the reaction, the reaction mixture was cooled to 0°C, the reaction is stopped with saturated solution of Panso3and diluted with tO. Organic and aqueous layers are separated and the organic layer washed with brine, dried over Na2SO4and concentrate and get the connection 21d (0.6 g, 99%) as a white foam substance.

Connection s (0.24 g, 0.38 mmol, 1.0 EQ.) dissolve in 5 ml of anhydrous THF under nitrogen atmosphere. The solution is cooled to 0°C. In a separate round bottom flask unite carbonyldiimidazole (CBI) (0.15 g, 0.90 mmol, 2.4 EQ.) and tert-BUTYLCARBAMATE (0.1 g, from 0.76 mmol, 2.0 EQ.) in anhydrous THF (2 ml). The solution is stirred for 30 min and for 1 min was added via cannula to a solution of compound 21 C. the Cannula was washed with anhydrous THF (1×0.8 ml). The reaction mixture is heated under reflux until no educt. Then the reaction mixture is cooled to room temperature and concentrated in vacuo and receive a colorless foam substance. The crude mixture was purified using chromatography on a BIOTAGE column (2%-5% MeOH/CH2Cl2and get the connection 21d (0,22 g, 74%) as a white solid.

Compound 21d (0,22 g, 0.28 mmol, 1 the square) is dissolved in 15 ml of anhydrous CH 2Cl2in nitrogen atmosphere. The solution is cooled to 0°C. was Added HCl (1.4 ml, 5.6 mmol, 20 EQ., 4 M solution in dioxane) and the solution is allowed to warm to room temperature and stirred over night. The solution is cooled to 0°C and the reaction stopped with a saturated solution Panso3(5 ml) and diluted with tO. Organic and aqueous layers are separated and the organic layer washed with brine (10 ml) and dried over Na2SO4. The organic layer was filtered and concentrated in vacuo and receive a white solid. The crude mixture was purified using chromatography on a BIOTAGE column (5%-8% Meon/CH3CL2and get the connection a (0.15 g, 79%) as a white solid.

Compound 21e (0.15 g, 0.22 mmol, 1.0 EQ.) dissolved in anhydrous DMF (1 ml). Add formamidine (0.126 g, 1.2 mmol, 5.5 equiv.) then acetic acid (0,69 ml, 1.2 mmol, 5.5 EQ.) and the reaction mixture is heated at 80°C for 30 minutes Analysis by TLC shows the presence of a residue of the original substance and the reaction mixture heated under reflux for a further 6 hours Over the course of the reaction is monitored by TLC (eluent - 9/1 CH3CL2/Meon). After completion of the reaction, the reaction mixture was cooled to room temperature, the reaction is stopped using H2O and diluted with t. Organic and aqueous layers are separated and the organic layer washed with brine, dried over Na2SO4 and concentrate and get the crude product (0,131 g) as a white foam substance. The cleaning is performed using chromatography on a BIOTAGE column (gradient mode from 100% CH2Cl2to (95:5) Meon) and get a connection 21f in the form of a white solid (0.11 g, 72%).

MS elektrorazpredelenie [M+1] 706,4.

Connection 21f (0.02 g, 0,028 mmol, 1.0 EQ.) dissolved in dry Meon (1.0 ml) and treated with 10% Pd/C (40 wt%), then by ammonium formate (0.09 g, 0.14 mmol, 5.0 equiv.) in an inert atmosphere. The reaction mixture is heated under reflux and the reaction monitored by TLC (eluent - 9/1 CH2Cl2/MeOH). The reaction is finished after 1 h the Reaction mixture was filtered through celite, washed with tO and concentrated in vacuo. The resulting residue is dissolved in tO and washed with saturated solution of NaHCO3and then brine and H2O and get the crude product is 0.019 g) in the form of a solid film. The cleaning is performed using chromatography on a BIOTAGE column (gradient mode from 2% to 6% Meon/CH3CL2. Deaerated product is converted into the salt with HCl and receive a mixture of compounds 21 and 22 (0,014 g) as a white solid. Msvr (the Belarusian library Association) calculated for C26H28F 6N3O2(M+1) 572,2096 found 572,2103.

An example of retrieving 23

Stage A:

NaBH4(2,42 g, 64.1 mmol) in 4 portions added to a solution of compound 23a in the Meon (160 ml) at 0°C. the Reaction mixture was stirred for 4 h and the reaction temperature slowly increased to KG. The reaction is stopped by the slow addition of a saturated aqueous solution of NH4Cl (50 ml). Then the reaction mixture was diluted with tO (400 ml) and neutralized with a 0.5 N. HCl until the aqueous phase becomes slightly acidic. The aqueous phase is extracted with tO (3×100 ml). The combined organic layers washed with water (100 ml), brine (100 ml) and dried over MgSO4. After filtration and concentration the crude product is passed through a thin layer of silica gel (hexane/tO, vol./about.=7/1). The solvent is removed under reduced pressure and get a connection 23b, 17,4 g (89%) as a pale yellow syrup.

Stage:

TBAF (2,23 ml of 2.23 mmol, 1.0 M in THF) are added dropwise to a mixture of compound 23b (9,1 g, 14,89 mmol) with the paraformaldehyde (of 3.85 g) in THF (100 ml) at 0°C. the Reaction mixture was stirred at 0°C for 8 h and then the reaction is stopped by adding a saturated aqueous solution of NH4Cl (50 ml). Then the reaction mixture was diluted with p the power tO (250 ml) and the aqueous phase extracted with tO (3×50 ml). The combined organic layers washed with water (50 ml), brine (100 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified on a BIOTAGE column (CH2Cl2/EtOAc, vol./about.=100/0,5) and get a connection 23C (6.0 g, 63%) and 23d (2,34 g, 24%).

Stage With:

A mixture of compound 23 (rate of 7.54 g, 11,76 mmol) and zinc dust (of 7.68 g of 117.6 mmol) in SPLA (120 ml) is heated at 60°C for 2 h, the Reaction mixture was cooled and filtered through a thin layer of celite and the residue is washed with tO (50 ml). The solvent is removed under reduced pressure and the residue is dissolved in tO (250 ml) and washed with NaOH solution (50 ml, 4,0 BC). The aqueous phase is extracted with tO (3×50 ml). The combined organic layers washed with water (50 ml), brine (100 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/3 and tO/Meon, vol./about.=10/1) and get a connection 23rd (6.4 g, 89%).

Stage D:

BnBr (0,668 ml, to 5.58 mmol) in kg, with vigorous stirring, added to a mixture of compound 23rd (3.1 g, 5,07 mmol) and BU4NHSO4(0,334 g 1,014 registered mmol) in THF (20 ml) and aqueous NaOH (20 ml, 50 wt.%). The reaction mixture was stirred at room temperature for 12 h and then diluted with tO (25 ml) and washed with water (100 ml). The aqueous phase is extracted with tO (3×50 ml). The combined organic layers washed with water (50 ml), brine (100 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/3 to 1/7) and get a connection 23f (2.8 g, 79%).

Stage E:

A solution of compound 23f (2,72 g, 3.88 mmol) and reagent s (i.e. methyl ester N-ethoxymethyleneamino acid) (2.83 g, and 19.4 mmol) in tO (15 ml) is heated at 60°C for 18 hours, the Reaction mixture was diluted with Meon (15 ml) and then treated with the help of N3(7,0 ml, to 38.8 mmol, 30% in the Meon). The resulting reaction mixture is heated at 80°C for 4 h and then cooled to room temperature. The reaction mixture was diluted with tO (200 ml) and aqueous solution of NH4Cl (75 ml). The aqueous phase is extracted with tO (3×50 ml). The combined organic layers washed with water (50 ml), brine (100 ml) and dried over gSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=from 2.5/1 to 1/1) and get a connection 23g (2,54 g, 85%).

Stage F:

l3(3,26 ml, 3,26 mmol, 1.0 M in hexane) with stirring, added dropwise to a solution of the is placed 23g (0,502 g, 0,653 mmol) in CH3CL2(45 ml) at

-78°C. the Reaction is stopped after 1 h by adding an aqueous solution Panso3(50 ml) at -78°C. the Mixture is diluted with tO (100 ml) and vigorously stirred at room temperature for 2 hours the Aqueous phase is extracted with tO (3×30 ml). The combined organic layers washed with water (50 ml), brine (50 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/3 to 1/9) and get a connection 23h (0.39 g, 91%).

Stage G:

Connection 23h (100 mg, 0,152 mmol) in tO (5.0 ml) is treated at room temperature with Pd(OH)2/C (20 mg, 10 wt.%) and for 30 min hydronaut using a cylinder with H2. The reaction mixture was filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/7) and get a connection 23 (68 mg, 82%).

MS elektrorazpredelenie [M+1]+545,1.

Example of getting 24

A solution of compound 31g (83,3 mg, 0.12 mmol, 1.0 EQ.) in anhydrous dichloromethane (4 ml) cooled to -78°C. Then O3pass the Ute through the solution, until it becomes blue. Then the solution is rinsed with N2to remove excess O3and the reaction mixture is concentrated to dryness. Then the obtained residue is dissolved in ethanol (2 ml) and treated with sodium borohydride (46 mg, 1.2 mmol, 10 EQ.). The reaction mixture was stirred at room temperature until TLC (50% tO/hexane) shows that the starting material is completely consumed. Then the reaction mixture is concentrated to dryness. The residue is dissolved in absolute ethanol (4 ml) and treated with Pd(OH)2/C (80 mg, 20 wt.%, 0.11 mmol, 0,88 equiv.) and then hydronaut hydrogen from a cylinder. The reaction mixture was stirred at room temperature until TLC (5% MeOH/CH2Cl2do not indicate that the starting material is completely consumed. The reaction mixture is again concentrated to dryness. The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and the aqueous and organic layers separated. The aqueous layer was additionally extracted with ethyl acetate. The combined organic layers dried over anhydrous Na2SO4filter, concentrate, and get the crude product, which was purified using preparative TLC (MeOH/CH2Cl2=5%) and get a pure compound 24 (42 mg, yield 63%). MS [M+1]+559,1.

Example get 25

To a solution of compound 31g (83,3 mg, 0.12 mmol, 1.0 EQ.) in absolute ethanol (3 ml) was added Pd(OH)2/C (20 mg, 20 wt.%, 0,028 mmol, 0,88 equiv.) and then hydronaut hydrogen from a cylinder. The reaction mixture was stirred at room temperature until TLC (50% tO/hexane) shows that the starting material is completely consumed. Then the reaction mixture is concentrated to dryness. The resulting residue is dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and the aqueous and organic layers separated. The aqueous layer was additionally extracted with ethyl acetate. The combined organic layers dried over anhydrous Na2SO4filter and concentrate and get the crude product, which was purified using preparative TLC (50% tO/hexane) and get a pure compound 25 (15 mg, yield 84%). MS [M+1]+557,1.

Example of getting 26

Stage A:

Et3N (0,129 ml of 0.93 mmol) was added to a solution of compound 26a (0,472 g, 0.77 mmol) and Vos2O (has 0.168 g, 0.77 mmol) in dioxane (3.0 ml) at room temperature. The resulting solution was stirred for 8 h and then diluted with tO (50 ml). The organic phase is washed with a 0.5 N. HCl (10 ml). The aqueous phase is extracted with tO (3×15 ml). The combined organic layers are washed in the Oh (15 ml), brine (15 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/1) and get a connection 26b (0,465 g, 85%).

Stage:

CH3I (0,372 ml, 5,98 mmol) at RT with vigorous stirring, added to a mixture of compound 26b (0,425 g, 0,598 mmol) and BU4NHSO4(40,6 mg, 0.12 mmol) in THF (5.0 ml) and aqueous NaOH (5.0 ml, 50 wt.%). The reaction mixture was stirred at room temperature for 12 h and then diluted with tO (50 ml) and washed with water (15 ml). The aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with water (15 ml), brine (15 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=5/1) and get a connection 26C (0,345 g, 80%).

Stage With:

A solution of compound 26C (0,345 g, 0,476 mmol) in TFA (3.0 ml) was stirred at room temperature for 20 min, and then the solvent is removed under reduced pressure. The residue is dissolved in tO (50 ml) and washed with NaOH solution (4,0 N., 15 ml). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (15 ml), brine (15 ml) and dried over MgSO4. the donkey filtration and concentration the crude amine (0.29 grams, 0,464 mmol) dissolved in tO (3.0 ml) and treated with reagent C (0,4,6 g, 2,78 mmol). The resulting solution was heated at 60°C for 18 hours, the Reaction mixture was diluted with Meon (3.0 ml) and then treated with NaOCH3(0,672 ml, 3,712 mmol, 30% in the Meon). The resulting reaction mixture is heated at 80°C for 4 h and then cooled to room temperature. The system is diluted by adding tO (50 ml) and aqueous solution of NH4CL (15 ml). The aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with water (15 ml), brine (15 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/3) and get a mixture of compounds 26d and 26th (0,275 g, 83% for stage 3), which is shared with the help of HPLC on a chiral OD column (hexane/isopropanol.about.=95/5) and get a clean connection 26d and 26th.

Stage D:

Connection 26d (38 mg, 0,0548 mmol) in tO (3.0 ml) at room temperature is treated with Pd(OH)2/C (7,6 mg, 10 wt.%) and for 30 min hydronaut using a cylinder with H2. Solution the reaction mixture is filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified by x is omatography on BIOTAGE column (hexane/tO, about./about.=1/4) and get a connection 26 (25 mg, 82%).

MS elektrorazpredelenie [M+1]+559,1.

Example of getting 27

Stage A:

Connection 26th (41 mg, 0,0592 mmol) in tO (3.0 ml) at room temperature is treated with Pd(OH)2/C (8.2 mg, 10 wt.%) and for 30 min hydronaut using a cylinder with H2. Solution the reaction mixture is filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/4) and get a connection 27 (26 mg, 79%).

MS elektrorazpredelenie [M+1]+559,1.

Example of getting 28

Stage A:

In a round bottom flask with a volume of 25 ml of compound 44b (0.2 g, 0.45 mmol, 1.0 EQ.) dissolved in DMF (5.0 ml). Added HATU (0,342 g, 0.90 mmol, 2.0 equiv.) Ejh (0.172 g, 0.90 mmol, 2.0 EQ.) and DIEA (amount of 0.118 ml of 0.68 mmol, 1.5 EQ.). The reaction mixture was cooled to 0°C and added to the BOC-α-methylalanine (0,109 g, 0.54 mmol, 1.2 EQ.). The reaction mixture was stirred over night. Then the reaction is stopped with saturated solution of NaHC3(5 ml), the reaction mixture is diluted with tO (10 ml) and extracted with tO (2×5 ml). The organic layer was washed with Russ the scrap (10 ml), dried over MgSO4and concentrate. The resulting residue is purified using preparative TLC (9/1 hexane/tO) and obtain 0.12 g (43%) of compound 28a.

Stage:

Compound 28b according to the method similar to the method for obtaining compounds of 45C, described below, in which removal of the protective group BOC solution of compound 28a in DHM enter into reaction with TFA.

Stage With:

In a round bottom flask with a volume of 10 ml compound 28b (0,050 g, 0,094 mmol, 1.0 EQ.) dissolved in toluene (1 ml) and then added triethylorthoformate (0,012 ml, 0,113 mmol, 1.2 EQ.) and 1 drop of acetic acid. The solution is heated at 60°C. the Reaction mixture is stirred for 48 hours Then the reaction mixture is dissolved in tO (5 ml) and washed with a saturated solution Panso3(5 ml). The organic layer was washed with brine (5 ml), dried over MgSO4and concentrate. The crude product was then purified using preparative TLC (tO) and get 0,010 g of compound 28. Msvr calculated for C27H29F6N3O2(M+N) 542,2242 found 542,2222.

An example of obtaining 29

A solution of compound 31h (39 mg, by 0.055 mmol, 1.0 EQ.) in anhydrous dichloromethane (1 ml) cooled to -20°C. Then added triethylamine (10 ml, 0,069 mmol, 1.25 EQ.) and etelcharge is at (6,5 ml, of 0.066 mmol, 1.2 EQ.). The obtained pale-green solution was stirred at -15°C for 30 minutes Through the solution for 20 min miss gaseous ammonia. TLC (tO) shows that the reaction was completed. The reaction mixture was diluted with ethyl acetate, sequentially washed with 1 N. HCl (1 ml), saturated aqueous sodium carbonate and brine. The organic layer is dried over Na2SO4filter and concentrate. The resulting residue is dissolved in absolute ethanol (6 ml) and to it was added Pd(OH)2/C (17 mg, 20 wt.%, 0,024 mmol, 0.43 equiv.) and then to the reaction flask attach the balloon with hydrogen. The reaction mixture was stirred at room temperature until TLC (5% Meon/tO) shows that the starting material is completely consumed. The reaction mixture is concentrated to dryness and the residue is dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and the organic and aqueous layers separated. The aqueous layer was additionally extracted with ethyl acetate. The combined organic layers dried over anhydrous Na2SO4filter and concentrate and get the crude product, which was purified using preparative TLC (5% Meon/tO), and get a pure compound of example 29 (18 mg, yield 57%). MS [M+1]+572,1.

Example 30

Stage 1:

To a solution of compound 31h (450 mg, 0.64 mmol, 1.0 EQ.) in anhydrous DMF (3.5 ml), was added HATU (290,5 mg, 0,764 mmol, 1.2 equiv.) N,N-dimethylaminopropane (99 mg, 1.01 mmol, 1.6 EQ.) and diisopropylethylamine (0,50 μl, 2,87 mmol, 4.5 EQ.). Received the orange solution was stirred at room temperature until TLC (5% Meon/tO) shows that the starting material is completely consumed. The reaction mixture was poured into dichloromethane (200 ml), successively washed with diluted twice with saturated aqueous citric acid solution, saturated solution Panso3and brine. The organic layer is dried over anhydrous Na2SO4filter and concentrate and get the crude product, which was purified using chromatography on a BIOTAGE column (tO/hexane=3:1), and receive connection 30a in the form of a brown solid (208 mg, yield 43,6%).

Stage 2:

Methylanisole (1.65 ml, 1.0 M in tert-butyl methyl ether, of 1.65 mmol, 6.0 EQ.) added dropwise to a solution of compound 30A (206 mg, 0,275 mmol, 1.0 EQ.) in anhydrous THF (3 ml). TLC (tO) shows that the starting material is completely consumed, and then the reaction mixture was stirred at room temperature for 30 minutes and Then the reaction mixture was diluted with ethyl acetate, the reaction is stopped saturated aqueous NH4Cl and xtraceroute using tO. The combined organic layers dried over Na2SO4filter and concentrate and get the crude product, compound 30b. Compound 30b used in the next stage without purification.

Stage 3:

By the same procedure as described in example 31, step 6, the crude compound 30b hydronaut and get a pure compound of example 30 (150 mg, yield 95.6% of the of the connection 30a). MS [M+1]+571,1.

An example of retrieving 31

Stage 1:

Compound 31b (32 ml) was added to a solution of compound 31A (1.0 g, 11.1 mmol, 1.0 EQ.) in triethylorthoformate. The solution is heated at 88°C for 36 h and then concentrated to dryness in vacuo. The obtained residue is recrystallized from tO and get a connection s (0,94 g, yield 58%).

Stage 2:

To a solution of compound 23b (2.5 g, 4.1 mmol) in THF (20 ml) was added allylmethylamine (0,465 ml, 8.2 mmol) and PD(h3)4(236 mg, 0,205 mmol). The reaction vessel is rinsed three times with nitrogen and then a solution is stirred for 16 h Then the solvent is removed and the residue filtered through a short column with silica using a mixture of 20% tO/hexane as eluent. The filtrate is concentrated and compound 31d and 31E separated using preparative HPLC. M is [M+1] +651,1 for both connections.

Stage 3:

In a round bottom flask was placed compound 31d (3,84 g 5,90 mmol, 1.0 EQ.) and glacial acetic acid (20 ml). To the resulting yellow solution at 0°With several small portions was added zinc dust (3,86 g, or 59.0 mmol, 10 EQ.). The reaction mixture was stirred at room temperature for 6 h, until TLC (30% tO/hexane) shows that the starting material, the compound 31d, completely spent. Then the reaction mixture was diluted with ethyl acetate and passed through a layer of celite in the funnel. Layer Celica thoroughly washed with ethyl acetate and wash solution combined with the filtrate. The filtrate is concentrated and get the crude product, which was purified using chromatography on a BIOTAGE column (30% tO/hexane) and in the form of a colourless oil are pure product, compound 31f (3 g, yield 81.9 percent).

A solution of compound 31f (of 33.4 mg, 0,054 mmol, 1.0 EQ.) in ethanol (0.4 ml) is treated with a reagent s (67.5 mg, 0.46 mmol, 5 EQ.) and stirred at room temperature overnight. Then it is diluted with anhydrous methanol (1 ml) and treated with sodium methoxide, and then heated at 88°C until TLC (tO) shows that only contains the product. Its concentrated to dryness and then dissolved in ethyl acetate, washed on Ishenim solution of sodium bicarbonate and the layers separated. The aqueous layer was additionally extracted with ethyl acetate. The combined organic layers dried over anhydrous Na2SO4filter and concentrate and get the crude product, which was purified using chromatography on a BIOTAGE column (25-40% tO/hexane) and get a pure compound 31g (of 22.4 mg, yield >60%).

Stage 4:

Connection 31g (306 mg, 0.44 mmol, 1.0 EQ.) dissolved in anhydrous dichloromethane (5 ml). The obtained colorless solution is cooled to -78°C, then rinsed with About3until the solution becomes purple. Then the solution is rinsed with N2to remove excess O3. After this, the solution concentrated to dryness. The obtained white foamed substance is dissolved in formic acid (1.5 ml) and treated with hydrogen peroxide (1.5 ml, 30% aqueous solution) and get a white slurry, which is heated at 80°C during the night. Analysis using IHMS detects peak only product. The solvent is removed in vacuum and the residue is dissolved in ethyl acetate and washed with diluted twice with a saturated aqueous solution of Na2S2O3. Resulting two layers are separated and the aqueous layer was additionally extracted with ethyl acetate. The combined organic layers dried over anhydrous Na2SO4filter and concentrate and get the connection 31h (284,2 mg, output is 90,6%). Connection 31h use in the next stage without purification.

Stage 5:

To a solution of compound 31h (104 mg, 0.147 mmol, 1.0 EQ.) in benzene (4 ml) and methanol (1 ml) added dropwise 2.0 solution trimethylsilyldiazomethane in hexano (88 μl, 0,177 mmol, 1.2 EQ.). After stirring the reaction mixture at room temperature for 30 min TLC (10% MeOH/CH2Cl2) shows that the starting material is completely consumed. The solvent is removed and get the crude product, which is used in the next stage without purification.

Step 6:

The crude product obtained in stage 5, the connection 31i, dissolved in absolute ethanol (4.5 ml). To this solution was added Pd(OH)2/C (to 46.7 mg, 20 wt.%, 0,067 mmol, of 0.45 EQ.) and then the reaction mixture hydronaut hydrogen from a cylinder. The hydrogenation reaction is stopped when TLC (10% Meon/CH2CL2) shows that the starting material had been consumed. Diluted the reaction mixture is gently passed through a funnel filled with telicom, and a layer of celite thoroughly washed with methanol. The filtrate is concentrated to dryness. The resulting residue is purified using preparative TLC (10% MeOH/CH2Cl2and get a pure compound 31 (56,2 mg, yield 65% from compound 31g), MS [M+1]+587,1.

Example of getting 32

Stage 1:

In a round bottom flask with a volume of 25 ml of compound 42b (0,142 g, 0.23 mmol, 1.0 EQ.) dissolved in 3 ml of dichloroethane in an atmosphere of N2and the reaction mixture is treated with Et3N (0,0,48 ml, 0.34 mmol, 1.5 equiv.) then 3-chlorosulfonylphenyl (0.037 ml, 0.3 mmol, 1.2 EQ.). The reaction mixture was stirred at room temperature overnight. Over the course of the reaction is monitored by TLC (60:40 tO/hexane) and MS, which show that a waste product is not formed. Then the reaction mixture is heated under reflux. After 1 h of heating, the reaction is finished. Then the reaction mixture is cooled and diluted with CH2Cl2and the reaction stopped with 1 N. HCl. The organic layer is dried over PA2SO4and concentrate and get the crude compound 32A (0.11 g), which is used in the next stage without additional purification.

Stage 2:

In dried by the fire round bottom flask with a volume of 15 ml of compound 32A (0.11 g, 0.23 mmol, 1.0 EQ.) dissolved in dry DMF. To this reaction mixture was added 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (0,044 g, 0.29 mmol, 1.2 EQ.) and the reaction mixture was stirred at room temperature overnight. Over the course of the reaction is monitored by TLC (30:70 is tO/hexane) and MC. After completion of the reaction, the reaction mixture was diluted with tO and the reaction stopped using H2O. the Organic layer is dried over Na2SO4and concentrate and get the crude compound 32b (0.1 g). The cleaning is performed using chromatography on a BIOTAGE column (30/70 tO/hexane) and obtain the purified compound 32b (0,072 g). MS elektrorazpredelenie [M+1] 710,2.

Stage 3:

Compound 32b (0,072 g, 0.1 mmol, 1.0 EQ.) dissolved in dry Meon (1.5 ml) and treated with 20% PD(OH)3(60 wt.%) in an inert atmosphere. The reaction mixture hydronaut at atmospheric pressure and the reaction monitored by TLC (40:60 tO/hexane). The reaction is finished after 45 min and the reaction mixture was filtered through celite, washed with tO and concentrate and get the crude product. The crude product was then purified using preparative chromatography (60/40 tO/hexane) and get a connection 32 (0.04 g, 70%). MS elektrorazpredelenie [M+1]576,2. Msvr (the Belarusian library Association) calculated for C26H28F6N3O2(M+1) 576,1756 found 576,1764.

An example of obtaining 33

Stage 1:

In a round bottom flask with a volume of 25 ml of compound 42b (0,322 g of 0.53 mmol, 1.0 EQ.) dissolve in 5 ml of CH2Cl2and the reaction mixture is cooled to 0°C in banesa ice. Then to the reaction mixture was added Et3N (0,111 ml of 0.79 mmol, 1.5 equiv.) then 4-chlorobutyrate (0,072 ml, 0.64 mmol, 1.2 EQ.) and it is slowly warmed to room temperature and stirred for 14 hours Over the course of the reaction is monitored by TLC (60:40 tO/hexane eluent) and MC. After completion of the reaction, the reaction mixture was diluted with CH2Cl2and the reaction stopped with a saturated solution Panso3and then brine. The organic layer is dried over Na2SO4and concentrate and get the crude compound 33a (0.32 g), which is used in the next stage without additional purification.

Stage 2:

In dried by the fire round bottom flask with a volume of 25 ml of compound 33a (0.32 g, 0.45 mmol, 1.0 EQ.) dissolved in dry THF. To this solution was added 60% NaH (0.025 g, of 0.68 mmol, 1.5 EQ.) and the reaction mixture was stirred at room temperature for 2 hours Over the course of the reaction is monitored by TLC (60:40 tO/hexane) and MC. After completion of the reaction, the reaction mixture was diluted with tO and the reaction stopped with saturated solution of NaHCO3. The organic layer is dried over Na2SO4and concentrate and get the connection 33b (0.4 g) as a yellow oil, which was used in the next stage without additional purification.

Stage 3:

Compound 33b (0.4 g, 0.59 mmol, 1.0 EQ.) dissolved in dry Meon (4,0 ml) and treated with 20% Pd(OH)2(60 wt.%) in an inert atmosphere. The reaction mixture hydronaut at atmospheric pressure and the reaction monitored by TLC (eluent to 40:60 tO/hexane). The reaction is finished after 45 min, the reaction mixture was filtered through celite and washed with tO and concentrate and get the crude product. Purification of the crude product is carried out using chromatography on a BIOTAGE column (60/40 EtOAc/hexane) and get a connection 33 (0.18 g, 59%).

Msvr (the Belarusian library Association) calculated for C26H28F8N3O2(M+1) 540,2086 found 540,2078.

An example of retrieving 34

Stage 1:

In a round bottom flask with a volume of 25 ml of compound 42 (0,23 g, 0.38 mmol, 1.0 EQ.) dissolved in 3 ml of CH2Cl2and the reaction mixture is cooled to 0°C in the bath with ice. Then to the reaction mixture was added Et3N (0.079 in ml, of 0.57 mmol, 1.5 equiv.) then 4-chlorobutyrate (0,051 ml, 0.45 mmol, 1.2 EQ.) and it is slowly warmed to room temperature and stirred for 14 hours Over the course of the reaction is monitored by TLC (eluent - 60:40 tO/hexane) and MC. After completion of the reaction, the reaction mixture was diluted with CH2Cl2and the reaction stopped with a saturated solution of N the 3and then brine. The organic layer is dried over Na2SO4and concentrate and get the crude compound 34a (0,23 g), which is used in the next stage without additional purification.

Stage 2:

In dried by the fire round bottom flask with a volume of 25 ml of compound 34a (0,23 g, 0.38 mmol, 1.0 EQ.) dissolved in dry THF (1 ml). To this reaction mixture was added 60% NaH (0,022 g, or 0.57 mmol, 1.5 EQ.) and the reaction mixture was stirred at room temperature for 2 hours Over the course of the reaction is monitored by TLC (60:40 tO/hexane eluent) and MC. After completion of the reaction, the reaction mixture was diluted with tO and the reaction stopped with a saturated solution Panso3. The organic layer is dried over Na2SO4and concentrate and get the connection 34b (0.21 g) as a yellow oil, which was used in the next stage without additional purification.

MS elektrorazpredelenie [M+1] 674,2.

Stage 3:

Compound 34b (0.21 g, 0.31 mmol, 1.0 EQ.) dissolved in dry Meon (2.0 ml) and treated with 20% Pd(OH)2(40 wt.%) in an inert atmosphere. The reaction mixture hydronaut at atmospheric pressure and at a flow hydrogenation monitored by TLC (eluent to 40:60 tO/hexane). After 45 min the reaction mixture was filtered through celite, washed through the Yu tO and concentrate and get the crude product. The crude product is purified by chromatography on BIOTAGE column (60/40 tO/hexane) and get a connection 34 (0.10 g, 59%).

Msvr (the Belarusian library Association) calculated for C26H28F6N3O2(M+1)540,2086 found 540,2078.

Example of getting 35

The connection 35 receive according to the method similar to the method for obtaining compounds 23rd in example 23.

Similarly, the connection 35b receive according to the method similar to the method used to produce compound 23f in example 23.

Connection 35C get by the method similar to the method used to produce compound 23g in example 23.

Connection 35d get by the method similar to the method for obtaining compounds of 23 in example 23.

Connection I get by the method similar to the method for obtaining compounds 23h in example 23.

Connection 35f get by the method similar to the method for obtaining compounds of e in example 42.

Connection 35g get by the method similar to the method for obtaining compounds 42g in example 42.

The connection 35 get method, analogichnoi method for obtaining compounds of 42 in example 42. Msvr calculated for C25H23F6N5O2(M+N) 540,1834 found 540,1822.

Example 36

Stage A:

The tea - triethanolamine

Connection 36A receive according to the method similar to the method of obtaining compound 47 in example 47.

Stage:

The connection 36 receive according to the method similar to the method for obtaining compounds of 23 in example 23. Msvr calculated for C24H25F6N3About3S (M+N) 550, 1599, found 550,1603.

An example of retrieving 37

Stage A:

Compound 37A receive according to the method similar to the method of obtaining compound 47 in example 47.

Stage:

The connection 37 get by the method similar to the method for obtaining compounds of 23 in example 23. Msvr calculated for C24H25F6N3About3S (M+N) 550, 1599, found 550,1603.

An example of retrieving 38

Stage 1:

Through a solution of compound 31g (640 mg, of 0.93 mmol) in 10 ml of CH2Cl2, the temperature of which is supported by equal -78°C, pass gas About3until the reaction mixture turns blue. Then the reaction mixture is blown with nitrogen, until it becomes colorless. Then PR is billaut TBI (412 mg, 1.11 mmol) and the reaction mixture is stirred at 20°C for 2 h, the Reaction mixture was diluted with diethyl ether, washed with saturated aqueous PA2S2O3, water and brine and dried and concentrated. The resulting residue is dissolved in tO (22 ml) and NaOAc (262,7 mg, 3.2 mmol) and added gidroxinimesoulid (222 mg, 3.2 mmol), and the mixture is stirred over night. Then the reaction mixture was concentrated and the residue is subjected to distribution between 20 ml tO and water. The organic layer is dried and concentrated. The crude intermediate product is dissolved in toluene (6.8 ml) and then added 1,1'-oxalylamino (165 mg, 1.8 mmol) and the mixture is heated at 80°C for 2 hours, After cooling the reaction mixture to 23°C in toluene solution is injected into a column with silica gel and elute with a mixture of 20-100% tO/hexane and get a connection 33a. [MS]+688,1.

By the method similar to the method of example 31, step 6, compound 38A hydronaut and get a connection 38. MS [M+1]+554,1.

Examples of making 39 and 40

Stage A:

Compounds 39 and 40 receive according to the method similar to the method for obtaining compounds of 38. Msvr calculated for C23H23F6N3O (M+N) 472,1824 found 472,1820.

The application is receiving 41

Stage A:

In a round bottom flask with a volume of 25 ml of compound 42b (0.15 g, 0,248 mmol, 1.0 EQ.) dissolved in 6 ml of EDC (ethylene dichloride). Add trimethylsilyltriflate (0.51 ml, 3.72 mmol, 15.0 EQ.) and the reaction mixture is heated under reflux at 80°C during the night. The reaction mixture is cooled and the reaction stopped with a saturated solution Panso3(10 ml). The aqueous phase is extracted with tO (2×10 ml). The organic layers washed with brine (5 ml), dried over gSO4and concentrate. The crude product was then purified using preparative TLC (1:1 tO:hexane) and get to 0.060 g (37%) of compound 41A.

Stage:

The connection 41 get by the method similar to the method for obtaining compounds of 23 in example 23. Msvr calculated for C24H24F6N4O2(M+N) 515,1882 found 515,1874.

An example of retrieving 42

Stage A:

Compound 41A (6,87 g, up 11,86 mmol) in tO (7 ml) at room temperature in an airtight vessel is added to a solution of NaCN (0,767 g), NH4Cl (0.889 g) and NH3·H2On (3,84 ml) in tO (7.0 ml) and water (7.0 ml). Then the sealed vessel is heated at 60°C for 12 h, and then cooled to room temperature. The reaction mixture once ablaut using tO (200 ml) and washed with water (50 ml). The aqueous phase is extracted with tO (3×30 ml). The combined organic layers washed with brine (30 ml) and dried over gS4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=from 7/2 to 5/2) and get a connection 42b (2.6 g, 36%) and the connection 42s (1.8 g, 25%).

Stage:

The phosgene in (6.67 ml, 12.4 mmol, 20% in toluene) at 0°C With vigorous stirring, added dropwise to a mixture of compound 42b (1.5 g, 2.48 mmol) in CH2Cl2(30 ml) and a saturated solution of Panso3(30 ml). The mixture is stirred at 0°C for 3 h and then diluted with CH2Cl2(50 ml) and the aqueous phase is separated from the organic phase. The organic phase is washed with a cold aqueous solution of NH4Cl, brine and dried over gS4. To remove excess phosgene, the volume of solvent is reduced to about 5 ml under reduced pressure at room temperature. The residue is dissolved in CH2Cl2(15 ml) and treated with NH2NHC(O)H (0,446 g, 7,44 mmol) and pyridine (1.2 ml, 14,88 mmol) at room temperature. The resulting solution was stirred at room temperature for 12 hours Then the reaction mixture was diluted with tO (200 ml) and washed with HCl (50 ml, of 0.5 N.). The aqueous phase is extracted with tO (3×30 ml). Unite the military organic layers washed with brine (30 ml) and dried over MgSO 4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column, elwira a mixture of hexane/tO (about./about.=from 1/2 to 1/7), and get a connection 42d (1.1 g, 64%).

Stage With:

TMCCl (50 μl) with stirring was added to the mixture of compound 42d (15 mg, 0,0217 mmol) and LiI (2,9 mg, 0,0217 mmol) in HMDS (hexamethyldisilazane) (0.5 ml) at room temperature. The resulting reaction mixture is heated at 140°C (bath temperature) for 30 h, and then cooled to room temperature. The reaction mixture was diluted with tO (25 ml) and washed with HCl (5 ml, 1.0 BC). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with brine (10 ml) and dried over gS4. After filtration and concentration the crude product was then purified using preparative TLC (hexane/tO, vol./about.=6/4) and get a connection 42 (4 mg, 34%).

An alternative method to example 42

Alternatively, the connection 42 can also be obtained from compound 23g as follows

Stage A:

In a round bottom flask with a volume of 10 ml compound 23g (0.02 g, 0,037 mmol, 1.0 EQ.) dissolve in DHM (3 ml) and the reaction mixture is cooled to 0°C. Add periodinane dessa-Martin (0.02 g, 0,048 mmol, 1.3 EQ.) and the reaction mixture was stirred in the atmosphere and the PTA at room temperature for 45 minutes Over the course of the reaction is monitored by TLC (eluent - 9/1 tO/Meon) and the reaction stopped after 1.5 hours, pouring the reaction mixture into a separating funnel containing a saturated solution of PA2S2About3/Panso3(1:1) (5 ml). The mixture into a separating funnel vigorously shaken and the aqueous layer was extracted with Et2O (2×5), dried over MgSO4and concentrate and get the crude compound e (0.02 g), which is used in the next stage without additional purification.

Stage:

In a round bottom flask with a volume of 25 ml connection 42f (0.09 g, 0.13 mmol, 1.0 EQ.) and sodium acetate (0,032 g 0,39 mmol, 3.0 EQ.) dissolve in tO (6 ml) and added gidroxinimesoulid (0,056 g 0,080 mmol, 6.0 EQ.). The reaction mixture was stirred in nitrogen atmosphere at room temperature overnight. Then the reaction mixture was diluted with tO (15 ml), the reaction is stopped with saturated solution of Panso3(5 ml) and the organic layer washed with brine (5 ml) and dried over MgSO4and get the crude compound 42D (0.95 g), which is used in the next stage without additional purification.

Stage

In a round bottom flask of 50 ml volume connection 42g (1.1 g, 0.59 mmol, 1.0 EQ.) dissolved in benzene (25 ml). To the solution was added 1,1'-oxalylamino (0,g, 1,89 mmol, 1.5 EQ.) and the reaction mixture is heated at 75°C. in a nitrogen atmosphere for 4 hours and Then the reaction is stopped with water (20 ml), diluted with tO (30 ml), dried over MgSO4and concentrate and get the crude product. The crude product is purified by chromatography on BIOTAGE column (1/1 tO/hexane) and get a connection 42h (0.7 g, 66% for stage 3).

Stage D:

In a round bottom flask of 50 ml volume connection 42i (0.5 g, 0,742 mmol, 1.0 EQ.) dissolved in acetonitrile (9 ml). The reaction mixture was cooled to 0°C and with a syringe added dropwise TMCl (0,742 ml, 5,19 mmol, 7.0 EQ.). The reaction mixture was stirred over night at room temperature. Over the course of the reaction is monitored with the help of MS, which shows that it still contains a number of original substance. The reaction is stopped with saturated solution of PA2S2O3/Panso3(1:1) (10 ml) and diluted with tO (20 ml). The organic layer was washed with brine (10 ml), dried over gSO4and concentrate and get the crude product. The crude product is purified by chromatography on BIOTAGE column (60/40 tO/hexane) and get a connection 42 (0.4 g). Msvr calculated for C25H23F6N5O2(M+H) 540,1834 found 540,1813.

An example of retrieving 43

Stage And

Compound 43A receive according to the method similar to the method for obtaining compounds 28a.

Stage:

Connection 43b get by the method similar to the method for obtaining compounds of 45C.

Stage With:

The connection 43 receive according to the method similar to the method for obtaining compounds 28 (stage C).

An example of retrieving 44

Stage A:

In a round bottom flask with a volume of 50 ml of compound 44a (1.1 g, 2,31 mmol, 1.0 EQ.) dissolved in acetic acid (20 ml) and the resulting reaction mixture is cooled to 0°C. was Added Zn powder (1.51 g, 23,1 mmol, 10.0 EQ.) and the mixture is heated under reflux for 2.5 hours and Then the reaction mixture was filtered through celite, concentrated, diluted with tO (30 ml) and neutralized with saturated solution of Panso3(30 ml). The aqueous phase is extracted with tO (2×10 ml), washed with brine (20 ml), dried over MgSO4and concentrate. The crude product was then purified using a filter column and obtain 1.0 g (99%) of compound 44b.

Stage:

Connection s get by the method similar to the method for obtaining compounds 45b.

Stage With:

Connection 44d get by the method similar to the method for obtaining compounds of 45C.

Stage D:

Connection 44th get by the method similar to the method for obtaining compounds of 45d.

Stage E:

In a round bottom flask with a volume of 10 ml connection 44th (0.34 g, 0.54 mmol, 1.0 EQ.) dissolved in 5.5 ml Meon/N2O (10:1). A round bottom flask Tegaserod and added Pd/C (10 wt.%, 0.18 g), then the HCO2NH4(0,174 g, 2.68 mmol, 5.0 EQ.). The obtained heterogeneous mixture is heated under reflux overnight, cooled, filtered through celite, concentrated, diluted with tO (10 ml), washed with saturated solution of NaHCO3(10 ml) and dried over Na2SO4. The crude product is purified by chromatography on BIOTAGE column (9:1 tO:Meon) and obtain 0.11 g (38%) of compound 44. Msvr calculated for C25H26F6N4O3(M+N) 545,1987 found 545,1988.

Examples of receiving 45 and 46

Stage A:

Compound 41A (2.8 g, 4,59 mmol, 1.0 EQ.) dissolved in ethanol (15 ml), to the solution was added Raney Nickel and the reaction mixture hydronaut in shaking the device Parra at a pressure of 60 pounds-force/inch2. Over the course of hydrogenation after the Yat using TLC (4/1 tO/hexane). After 3 h the reaction mixture was filtered through celite, washed with ethanol (30 ml) and concentrated. The crude product is purified by chromatography on BIOTAGE column (4/1 tO/hexane) and get a connection 45A (1.75 g, 65%).

Stage:

In a round bottom flask with a volume of 50 ml of compound 45A (1.0 g, 1,72 mmol, 1.0 EQ.) dissolved in dry THF (20 ml) and cooled to 0°C. To this cooled solution via cannula was added a solution of tert-BUTYLCARBAMATE (0,228 g, 1,72 mmol, 1.0 EQ.) and carbonyldiimidazole (0,335 g of 2.06 mmol, 1.2 equiv.) which previously was stirred in dry THF (10 ml). The reaction mixture is allowed to warm to room temperature and stirred over night. Then the reaction mixture was concentrated and purified by chromatography on BIOTAGE column (1/1 tO/hexane) and get a connection 45b of 0.85 g, 67%).

Stage With:

In a round bottom flask of 50 ml volume connection 45b (0.39 g, of 0.53 mmol, 1.0 EQ.) dissolved in CH2CL2(10.0 ml) and cooled to 0°C. To the solution was added triperoxonane acid (1,02 ml, 13,2 mmol, 25,0 EQ.) and the reaction mixture was stirred at room temperature. Over the course of the reaction is monitored with the help of MS (i.e., before the disappearance of the original substance). The reaction mixture is concentrated in 7 hours and use in the next stage without any additional the additional purification. The crude intermediate product is dissolved in THF (5 ml) and cooled to 0°C. was Added 20% aqueous NaOH solution (5.0 ml), then methoxyacetanilide (0,096 ml, 1.06 mmol, 2.0 EQ.). The reaction mixture was stirred at room temperature overnight and then diluted with N2O (10 ml), extracted with Et2O (2×10 ml), washed with brine (10 ml), dried over MgSO4and concentrate and get the crude compound 45C (0.35 g, 95%), which is used in the next stage without any further purification.

Stage D:

In a round bottom flask with a volume of 25 ml compound 45C (0.35 g, 0.49 mmol, 1.0 EQ.) dissolve in tO (3.0 ml). Add 3.0 ml of 6 M NaOH solution and the reaction mixture is heated under reflux during the night. Then the reaction mixture was concentrated and purified using preparative TLC (tO) and get 0,145 g (42%) of compound 45d.

Stage E:

In a round bottom flask with a volume of 10 ml compound 45d (0.125 g, 0.18 mmol, 1.0 EQ.) dissolved in 3 ml of Meon. Added Pd(OH)2(0,010 g, 0,072 mmol, 40 wt.%) and heterogeneous mixture hydronaut at room temperature. Over the course of hydrogenation've been using MC. The reaction mixture was filtered through celite, concentrated and purified using preparative TLC (tO) and get a mixture of compounds 45 and 46 (0,008 is, 8%). Msvr calculated for C26H28F6N4O3(M+H) 559,2144 found 559,2146.

Examples of making 47 and 48

Stage A:

In a round bottom flask with a volume of 10 ml of a mixture of compounds 49 and 50 (0.025 g, 0,047 mmol, 1.0 EQ.) dissolved in 2 ml DHM and cooled to 0°C. Added triethylamine (0,0073 ml, 0,052 mmol, 1.1 equiv.) then MeSO2Cl (0,004 ml, 0,052 mmol, 1.1 EQ.). The reaction mixture was stirred over night. Then the reaction mixture was diluted with tO (10 ml) and the reaction stopped with a saturated solution Panso3(5 ml). The aqueous phase is extracted with tO (2×5 ml), dried over Na2SO4and concentrate. The crude product was then purified using preparative TLC (4:1 tO/hexane) and get 0,028 g (100%) of a mixture of compounds 47 and 48. Msvr calculated for C25H27F6N5O4S (M+H) 608,1766 found 608,1785.

Examples get 49 and 50

Stage A:

Compound 49A (0.50 g, 0.77 mmol, 1.0 EQ.) placed in a round bottom flask. Then the flask was added fuming NGO3(3 ml) and the resulting reaction mixture was incubated for 1 h After completion of the reaction was added ice (10 g). The reaction mixture was diluted with tO (25 ml) and eutrality a saturated solution of NaOH (3 ml). The aqueous phase is extracted with tO (2×10 ml). The organic layers washed with brine (10 ml), dried over gS4and concentrate. The crude product is purified by chromatography on BIOTAGE column (7:3 tO:hexane) and obtain 0.45 g (79%) of compound 49b.

Stage:

Compounds 49 and 50 receive according to the method similar to the method for obtaining compounds 44b. Msvr calculated for C24H25F6N5O2(M+N) 530,1991 found 530,1977.

An example of retrieving 51

Compound 55 (0,078 g, 0.11 mmol, 1.0 EQ.) dissolved in 7 M ammonia solution in the Meon (3.0 ml) and placed in a small pressure vessel Parra, which is heated at 80°C for 2 days. Over the course of the reaction is monitored by TLC (9/1 CH2CL2/Meon). After completion of the reaction, the reaction mixture was concentrated and get the crude product as a white solid. The crude product is purified by chromatography on BIOTAGE column (from 2:1 to 4:1 tO/hexane) and get a connection 51A in the form of a white solid (0,48 g). MS elektrorazpredelenie [M+1] 692,2.

Compound 51A (0,045 g, 0,065 mmol, 1.0 EQ.) dissolved in dry Meon (2.0 ml) and treated with 10% Pd/C (40 wt%), then by ammonium formate (0.02 g, 0.03 mmol, 5.0 equiv.) in an inert atmosphere. The reactions is nnow the mixture is heated under reflux and the reaction monitored by TLC (100% tO). The reaction is finished after 1 h the Reaction mixture was filtered through celite, washed with tO and concentrated in vacuo. The resulting residue is dissolved in tO, washed with a saturated solution Panso3and then brine and H2O and get your desired product, compound 51, in the form of a white solid, which is transformed into its salt with HCl (0,034 g, 94%).

Msvr (the Belarusian library Association) calculated for C26H28F6N3O2(M+1)558,19242 found 558,19398.

Method of obtaining 52

Stage A:

Compound 53 (18,1 mg, 0,0325 mmol) in tO (2.5 ml) is treated with MeONH2·HCl (24,4 mg, 0,292 mmol) and NaOAc (12.0 mg, 0,146 mmol) at room temperature. The reaction mixture was stirred at 60°C for 12 h, then diluted with tO (20 ml) and washed with an aqueous solution Panso3. The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over gS4. After filtration and concentration the crude product was then purified using preparative TLC (hexane/tO, vol./about.=from 1/1 to 1/9) and get a connection 52 (16 mg, 84%). MS elektrorazpredelenie [M+1]+586,1.

Example of getting 53

Stage A:

Periodinane dessa-Martin (0,234 g, 0.55 mmol) at room temperature was added to a mixture of compound 23h (0.25 g, 0,369 mmol) and NaHCO3(0,232 g, was 2.76 mmol) in CH2CL2(5.0 ml). The reaction mixture was stirred for 1 h and then diluted with tO (50 ml) and water (10 ml). The organic phase is washed with a saturated solution PA2S2O3solution (3×15 ml). The combined aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with NaOH solution (15 ml, 1.0 N.), water (10 ml), brine (15 ml) and dried over MgSO4. After filtration and concentration the crude aldehyde (0.25 g) dissolved in anhydrous THF (4.0 ml) and treated with MeMgBr (0,49 ml, 1.48 mmol, 3.0 M in Et2O) at -78°C. the reaction Temperature slowly increased to room temperature and the reaction stopped after 2 h by slow addition of a saturated aqueous solution of NH4Cl (10 ml). Then the reaction mixture was diluted with tO (50 ml) and neutralized with a 0.5 N. HCl until the aqueous phase becomes slightly acidic. The aqueous phase is extracted with tO (g ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude secondary alcohol (0.26 g) was dissolved in CH2Cl2(5.0 ml) and treated with periodinane dessa-Martin (0,468 g, 1.11 mmol) and using Panso3(0,466 g, 5,55 mmol) at room temperature. The reaction mixture is stirred for which the 1 h and then diluted with tO (50 ml) and water (10 ml). The organic phase is washed with a saturated solution of Na2S2O3(3×15 ml). The combined aqueous phase is extracted with tO (3×15 ml). The combined organic layers washed with NaOH solution (15 ml, 1.0 N.), water (10 ml), brine (15 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/1) and get a connection 53A (0.11 g, 43% for stage 3).

Stage:

Compound 53A (107 mg, 0,155 mmol) in tO (5.0 ml) is treated at room temperature with Pd(OH)2/C (21,5 mg, 10 wt.%) and for 30 min hydronaut using H2from the container. Solution the reaction mixture is filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (hexane/tO, vol./about.=1/3 to 1/9) and get a connection 53 (66 mg, 76%). MS elektrorazpredelenie [M+1]+557,3.

An example of retrieving 54

Compound 53 (14.3 mg, 0,0257 mmol) in tO (2.5 ml) is treated with N2·HCl (10,7 mg, 0,154 mmol) and NaOAc (6.3 mg, 0,077 mmol) at room temperature. The reaction mixture was stirred at 60°C for 12 h, then diluted with tO (20 is l) and washed with an aqueous solution Panso 3. The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over gS4. After filtration and concentration the crude product was then purified using preparative TLC (hexane/tO, vol./about.=1/2) and get a connection 54 (11 mg, 75%). MS elektrorazpredelenie [M+1]+572,1.

Example of getting 55

Stage A:

Periodinane dessa-Martin (0.12 g, 0,284 mmol) at room temperature was added to a mixture of compound 23h (96,3 mg, 0,142 mmol) and NaHCO3(0.12 g, of 1.42 mmol) in CH2Cl2(3.0 ml). The reaction mixture was stirred for 1 h and then diluted by adding tO (50 ml) and water (10 ml). The organic phase is washed with a saturated solution PA2S2O3(3×15 ml). The combined aqueous phase is extracted with tO (g ml). The combined organic layers washed with NaOH solution (15 ml, 1.0 N.), water (10 ml), brine (15 ml) and dried over MgSO4. After filtration and concentration the crude aldehyde (96,3 mg) is dissolved in tert-butanol (2.0 ml) and water (0.5 ml) and successively treated with NaH2PO4·H2O (39,2 mg, 0,284 mmol), NaClO2(of 44.9 mg, 0,497 mmol) and 2-methyl-2-butene (0,105 ml, 0,994 mmol). The reaction mixture was stirred for 2 h and then resbala the t using tO (20 ml) and washed with aqueous solution of NH 4Cl. The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over gS4. After filtration and concentration the crude acid (95 mg) dissolved in benzene (2.8 ml) and Meon (0.7 ml). The resulting solution is treated with TMCCHN2(82,2 μl, 0,164 mmol) at room temperature and stirred for 20 minutes the Solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (hexane/tO, vol./about.=2/3) and get a connection 55A (70 mg, 35% over 3 stages).

Stage:

Compound 55A (38 mg, 0,0537 mmol) in tO (3.0 ml) is treated at room temperature with Pd(OH)2/C (7,6 mg, 10 wt.%) and for 30 min hydronaut using H2from the container. Solution the reaction mixture is filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified using preparative TLC (hexane/tO, vol./about.=2/3) and get a connection 55 (24 mg, 78%). MS elektrorazpredelenie [M+1]+573,1.

An example of receiving 56

Stage A:

Compound 56a (15 mg, 0,0227 mmol) in tO (2.0 ml) is treated at room temperature with Pd(OH)2/C (3.6 m is, 10 wt.%) and for 30 min hydronaut using H2from the container. Solution the reaction mixture is filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product is dissolved in Et2O (0.5 ml) and treated with HCl in ether (to 0.23 ml, 0.23 mmol, 1.0 M in ether). The mixture is stirred at room temperature for 12 hours the mixture is Then diluted with tO (20 ml) and washed with aqueous NaOH solution (5 ml of 0.5 N.). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over gSO4. After filtration and concentration the crude product was then purified using preparative TLC (hexane/tO, vol./about.=1/1) and get a connection 56 (8.5 mg, 67%). MS elektrorazpredelenie [M+1]+563,1.

An example of retrieving 57

Stage A:

MsCl (11,7 μl, 0,151 mmol) at room temperature was added to a solution of compound 23h (42,8 mg, 0,063 mmol) and Et3N (26,4 μl, 0,189 mmol) in CH2Cl2(1.0 ml). The reaction is stopped by the water (5.0 ml) over 30 min and diluted with CH2Cl2(15 ml). The aqueous phase is extracted with CH2Cl2(3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over gS4 . After filtration and concentration the crude mesilate (44 mg, 0,0582 mmol) dissolved in anhydrous DMF (2.0 ml) and treated with NaBH4(11.0 mg, 0,291 mmol). The reaction mixture is heated at 90°C for 1 h, and then cooled to room temperature. After that the reaction mixture is diluted with tO (20 ml) and washed with aqueous HCl solution (5 ml, 1.0 M). The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (3×10 ml), brine (10 ml) and dried over MgSO4. After filtration and concentration the crude product was then purified using preparative TLC (hexane/tO, vol./about.=3/2) and get a connection 57a (18 mg, 43%) and compound 56a (15 mg, 36%).

Stage B:

Compound 57a (18 mg, or 0.027 mmol) in tO (3.0 ml) at room temperature is treated with Pd(OH)2/C (3.6 mg, 10 wt.%) and for 30 min hydronaut using H2from the container. Solution the reaction mixture is filtered through a thin layer of celite and the residue is washed with tO (15 ml). The solvent is removed under reduced pressure and the crude product purified using preparative TLC (hexane/tO, vol./about.=1/1) and get a connection 57 (10 mg, 70%). MS elektrorazpredelenie [M+1]+529,1.

An example of retrieving 58

Compound 9 (10.0 mg, 0,0175 mmol) in tO (1.5 ml) at room temperature is treated with N2·HCl (14.6 mg, 0,175 mmol) and NaOAc (7.2 mg, 0,0876 mmol). The reaction mixture was stirred at 60°C for 12 h and then diluted with tO (20 ml) and washed with aqueous solution of NaHCO3. The aqueous phase is extracted with tO (3×10 ml). The combined organic layers washed with water (10 ml), brine (10 ml) and dried over gSO4. After filtration and concentration the crude product was then purified using preparative TLC (hexane/tO, vol./about.=2/3) and get a connection 58 (10.5 mg, 100%). MS elektrorazpredelenie [M+1]+600,1.

Example retrieve 59

Stage A:

To a solution of compound 59A (0,53 g, from 0.76 mmol) in CH2CL2(4 ml) was added Et3N (of 0.14 ml, 0.98 mmol). The reaction mixture was cooled to -78°C and added acetylchloride (0,065 ml of 0.91 mmol). The reaction mixture is slowly warmed to room temperature and stirred for 72 h To the reaction mixture was added an additional amount of Et3N (0,068 ml) and acetylchloride (0,033 ml) and then stirred at room temperature for 4 h, the Reaction mixture was concentrated and purified by chromatography on BIOTAGE column (hexane/tO, vol./about.=3/2) and get a connection 59b (0.5 g).

Stage:

l3(to 3.7 ml, 3.7 mmol, 1.0 M in hexane) with stirring, added dropwise to a solution of compound 59b (0.55 g, of 0.74 mmol) in CH2Cl2(9 ml) at -78°C. the Reaction is stopped after 1 h by adding an aqueous solution Panso3(50 ml) at

-78°C. the Reaction mixture was diluted with tO (200 ml) and washed with saturated aqueous Panso3(100 ml) and dried over Na2SO4. The mixture is filtered and concentrated and get the crude compound 59S (0.4 g), which is used in the next reaction without further purification.

Stage With:

Periodinane dessa-Martin (0.12 g, 0.28 mmol) at room temperature was added to a mixture of compound 59S (0.12 g, 0.18 mmol) and Panso3(0.17 g, 2.0 mmol) in CH2Cl2(5.0 ml) and stirred for 45 minutes To the reaction mixture was added an additional amount periodinane dessa-Martin (50 mg) and stirred at room temperature for 2 h Then the reaction mixture was concentrated and purified by chromatography on BIOTAGE column (hexane/tO, vol./about.=1/1) and get a connection 59d (0.1 g).

Stage D:

A mixture of compound 59d (0.11 g, 0,17 mmol), potassium bicarbonate (26 mg, 0,19 mmol), toiletrieschoice (36 mg, 0,19 mmol) and methanol (3 ml) is heated at 80°C for 48 hours Then the reaction mixture to the will centerour and diluted with tO (200 ml) and washed with saturated aqueous Panso 3(2×100 ml). The organic layer is dried over Na2SO4filter and concentrate. The crude product is purified by chromatography on BIOTAGE column (hexane/tO, vol./about.=from 2/3 to 0/100) and get a connection a (50 mg).

Stage E:

Compound 59d (0,31 mg, 0.45 mmol) in Meon (10.0 ml) is treated at room temperature with Pd(OH)2/C (0.2 g, 20 wt.%) and for 2 h hydronaut using H2from the container. Solution the reaction mixture is filtered through a thin layer of celite and the residue is washed with Meon (30 ml). The solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (EtOAc/MeOH, vol./about.=9/1) and receive a mixture of two isomers (190 mg), additionally purified by HPLC (chiral OD column) using a mixture of hexane/IPA (about./about.=9/1) and get a connection 59 (90 mg).

Example of getting 60

Stage A:

To a solution of compound 60A (0.26 g, 0.43 mmol) in CH2Cl2(4 ml) at 0°C was added Et3N (0,071 ml, 0.51 mmol), then ethylchloride (0,052 ml of 0.56 mmol) and the reaction mixture stirred for 1 h Then the reaction mixture was added sodium azide (64 mg, 0.98 mmol) and tetramethyleneglutaric (43 mg, 0.13 mmol) and stirring is continued for 1 h Then the reaction mixture was diluted with CH 2Cl2(100 ml) and washed with water (1×100 ml) and brine (1×100 ml). The organic layer is dried over Na2SO4filter and concentrate. The residue is dissolved in dry toluene (4 ml) and heated at 80°C for 2 h, and then cooled to room temperature. Add N3(0,13 ml of 0.94 mmol) and the reaction mixture is heated at -110°C for 18 h Then the reaction mixture is cooled to room temperature, concentrated and purified by chromatography on BIOTAGE column (hexane/tO, vol./about.=2/1, then the Meon/tO, vol./about.=1/99) and get a connection 60b (0.17 g).

Stage:

Compound 60b (0.17 mg, 0.26 mmol) in Meon (10.0 ml) is treated at room temperature with Pd(OH)2/C (15 mg, 20 wt.%) and for 2 h hydronaut using H2from the container. Solution the reaction mixture is filtered through a thin layer of celite and the residue is washed with Meon (30 ml). The solvent is removed under reduced pressure and the crude product purified via chromatography on a BIOTAGE column (tO/Meon, vol./about.=98/2) and get a connection 60 (20 mg).

Although the present invention is described using the above specific embodiments, for professionals with a common training in the art should be evident from their numerous alternatives, modifications, and changes. It assumes that all such alternatives, modifications and changes are included in the nature and scope of the present invention.

1. Derivatives of piperidine of formula I:

in which R1and R2selected from the group comprising alkyl, halogenated, alkyl, substituted by one or more hydroxy groups, -CN, quinil, -N(R6)2, -N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2-alkylen-CN, -cycloalkyl-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2and groups
,,,,
provided that at least one of R1and R2means-CN or a group
,,,,
W means =C(R8)- or =N-;
X is-C(O)- or-S(O2)-;
Y is selected from the group comprising-CH2-, -O -, and-N(R6)-C(O)-, provided that:
(a) the nitrogen atom of the group-N(R6)-C(O)- associated with X, and
(b) if R1and/or R2meansand Y represents-O-, then X does not means-S(O2)-;
Z denotes-C(R7)2-, -N(R6)-, or-O-;
R3selected from the group comprising H and unsubstituted alkyl;
R4means N;
R5 means H or alkyl;
R6selected from the group comprising H, alkyl, cycloalkyl and aryl;
each R7independently denotes H or alkyl; or
each R7together with the ring carbon atom to which, as shown, they are attached, forms cycloalkene ring;
R8selected from the group comprising H, alkyl, alkyl substituted with one or more hydroxy groups, -N(R6)2, -N(R6)-S(O2)-alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -- CN;
R9selected from the group comprising H, alkyl and aryl, or each R9together with the nitrogen atom to which, as shown, they are attached, forms geteroseksualnoe ring;
AG1means unsubstituted phenyl;
AG2means phenyl, substituted by 0-3 substituents selected from the group comprising halogenated;
n is 0, 1 or 2; and
m is 1, 2 or 3,
and their pharmaceutically acceptable salts and hydrates.

2. Derivatives of piperidine according to claim 1 having the formula IA:

in which R1, R2, R3, R4, Ar1, Ar2and n are specified in claim 1 values, and their pharmaceutically acceptable salts and hydrates.

3. Derivatives of piperidine according to claim 1, in which:
R3means unsubstituted alkyl;
Ar2means substituted phenyl;
legal 1;
and their pharmaceutically acceptable salts and hydrates.

4. Derivatives of piperidine according to claim 2, in which:
R3means unsubstituted alkyl;
Ar2means substituted phenyl;
n = 1;
and their pharmaceutically acceptable salts and hydrates.

5. Derivatives of piperidine according to claim 4, in which:
Ar2means 3,5-bis(trifluoromethyl)phenyl, and pharmaceutically acceptable salts and hydrates.

6. Derivatives of piperidine according to claim 5, in which:
R3means-CH3;
and its pharmaceutically acceptable salts and hydrates.

7. Derivatives of piperidine according to claim 6, in which:
one of the radicals R1or R2meansand their pharmaceutically acceptable salts and hydrates.

8. Derivatives of piperidine according to claim 6, in which:
one of the radicals R1or R2means;
where W means =C(R8)-;
and their pharmaceutically acceptable salts and hydrates.

9. Derivatives of piperidine according to claim 6, in which:
one of the radicals R1or R2means,
and their pharmaceutically acceptable salts and hydrates.

10. Derivatives of piperidine according to claim 6, in which:
one of the radicals R1or R2means-CN,
and their pharmaceutically acceptable salts and hydrates.

11. Derivatives of piperidine according to claim 7, in which:
X is-S(O2)-;
Y represents-CH2 -; and
m is 2,
and their pharmaceutically acceptable salts and hydrates.

12. Derivatives of piperidine according to claim 7, in which:
X is-C(O)-;
Y represents-CH2-; and
m is 2,
and their pharmaceutically acceptable salts and hydrates.

13. Derivatives of piperidine according to claim 7, in which:
X is-C(O)-;
Y represents-CH2-; and
m is 3,
and their pharmaceutically acceptable salts and hydrates.

14. Derivatives of piperidine according to claim 7, in which:
X is-C(O)-;
Y represents-O-; and
m is 2,
and their pharmaceutically acceptable salts and hydrates.

15. Derivatives of piperidine according to claim 7, in which:
X is-C(O)-;
Y represents-CH2-; and
m is 1,
and their pharmaceutically acceptable salts and hydrates.

16. Derivatives of piperidine according to claim 7, in which:
X is-C(O)-;
Y represents-NH-C(O)-; and
m is 1,
and their pharmaceutically acceptable salts and hydrates.

17. Derivatives of piperidine of claim 8, in which:
Z denotes-NH-; and
R8means N
and their pharmaceutically acceptable salts and hydrates.

18. Derivatives of piperidine of claim 8, in which
Z denotes-NH-; and
R8means-NH-S(O2)-CH3,
and their pharmaceutically acceptable salts and hydrates.

19. Derivatives of piperidine of claim 8, in which:
Z denotes-NH-; and
R8means-CH2HE,
and their pharmaceutically acceptable salts and hydrates.

20. Derivatives of piperidine of claim 8, in which the s:
Z denotes-NH-; and
R8means-CH2-O-CH3,
and their pharmaceutically acceptable salts and hydrates.

21. Derivatives of piperidine of claim 8, in which:
Z denotes-NH-; and
R8means-NH2,
and their pharmaceutically acceptable salts and hydrates.

22. Derivatives of piperidine of claim 8, in which:
Z means;
R8means N;
and their pharmaceutically acceptable salts and hydrates.

23. Derivatives of piperidine of claim 8, in which:
Z means- (CH3)2-; and
R8means N;
and their pharmaceutically acceptable salts and hydrates.

24. Derivatives of piperidine according to claim 1, having formula IB

in which R1and R2selected from the group consisting of:

ConnectionR1R2
1-CN
2-CN
3-CH2CN
4CH3
5-CN
6-C(O)-O-CH3
7-CN
8-C(O)-NH2
9-CH2OH
10-CH2OCH3
11-CH2OCH3
12-CN
13-CN
14-CN
15-CN
16-NH-S(O2)-CH3-CN
17-CN-NH-S(O2)-CH3
18-CH2CN
19-CN-NH2
20-NH2-CN
21-NH-C(O)-NH2-CN
22-CN

and their pharmaceutically acceptable salts and hydrates.

25. A derivative of piperidine according to claim 1, described by the following formula:
,
and its pharmaceutically acceptable salts and hydrates.

26. A derivative of piperidine according to claim 1, described by the following formula:

and its pharmaceutically acceptable salts and hydrates.

27. A derivative of piperidine according to claim 1, described by the following formula:

and its pharmaceutically acceptable salts and hydrates.

28. Derivatives of piperidine according to claim 1 or their pharmaceutically acceptable salts or hydrates, available in purified form.

29. Pharmaceutical composition having the antagonist properties neurokinin receptor NK1comprising at least one compound according to claim 1 or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable carrier.

30. The use of at least one compound according to claim 1 or its pharmaceutically acceptable salt or hydrate to obtain drugs for the treatment of physiological disorders, elimination of a symptom or treatment of diseases and physiological disorder, symptom or disease is selected from the group including respiratory diseases, inflammatory diseases, skin disorders, ophthalmologic disorders, pathological conditions of the Central nervous system, depression, anxiety, phobia, bipolar disorder, addiction, alcohol addiction, substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, dementia in AIDS, the disease of the Town, a stress-related disorders, obsessive-compulsive disorders, eating disorders, bulimia, nervous anorexia, overeating, sleep disorders, mania, premenstrual the initial syndrome, gastrointestinal disturbances, atherosclerosis, fibrotic disorders, obesity, diabetes type II, associated with pain disorders, headache, neuropathic pain, postoperative pain, chronic pain syndrome, disorders of the bladder, urinary disorders, cough, vomiting and nausea.

31. The application of article 30, in which the physiological disorder, symptom or disease is vomiting, depression, anxiety or cough.

32. The application of article 30, in which the physiological disorder, symptom or disease is depression or anxiety.

33. The application of article 30, in which the physiological disorder, symptom or disease is vomiting and/or nausea.

34. The application of article 30, in which the physiological disorder, symptom or disease is coughing.

35. The use of at least one compound according to claim 1 or its pharmaceutically acceptable salt or hydrate to obtain drugs for antagonistic influence on the effects of substance P on the plot neurokinin receptor 1 or block at least one neurokinin receptor 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I and to its pharmaceutically acceptable salts. In formula I R1 is selected from C1-6alkyl, C3-12cycloalkyl, phenyl, furanyl, thienyl, pyridyl, where phenyl of radical R1, is optionally substituted with radical, which is selected from halogen, nitro, C1-6alkyl, C1-6alkoxy, substituted with halogen of C1-6alkyl and -XC(O)YR5; where X represents C1-4alkylene, Y represents O, and R5 represents hydrogen; R2 represents -C(O)NR4XOR5, where X represents C1-4alkylene; R4 is selected from hydrogen and C1-6alkyl; R5 represents phenyl; where any phenyl of radical R2, is optionally substituted with two radicals, which are independently selected from halogen, nitro and halogen-substituted C1-6alkyl; R3 represents phenyl, which is optionally substituted with radicals in number from 1 to 2, which are independently selected from halogen, C1-6alkyl, C1-6alkoxy, -XOXC(O)OR5, -XC(O)OR5, where X is independently selected from simple link and C1-4alkylene; and R5 is selected from hydrogen and C1-6alkyl. Invention also relates to compounds selected from 2-(2-nitro-4-trifluoromethylphenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 2-(2,4-dichlorophenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 3-(2,6-dichlorophenyl)-5-methyl-4-[2-(2-nitro-4-trifluoromethylphenoxy)ethoxymethyl]isoxazole, other compounds are specified in invention formula.

EFFECT: compounds of present invention may find application as medicinal agent that modulates activity of receptors activated by PPARδ.

7 cl, 2 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula [I]: where A cycle represents a benzene cycle optionally having substitute(s) different from R1, R1 represents a group of formula RaSO2NH-, RaSO2NH-CH2- or (Rb)(Rc)NSO2-, Ra represents C1-C6 alkyl group, C3-C10cycloalkyl group, an amino group, 6-10-member monocyclic or bicyclic aryl group or 5-10-member monocyclic or bicyclic heteroaryl group containing 1-2 heteroatoms, chosen from oxygen, sulphur and nitrogen atoms, Rb and Rc are identical or different, and each represents hydrogen atom, C1-C6alkyl group or C3-C10cycloalkyl group, one of R2 and R3 represents hydrogen atom, halogen atom or C1-C6alkyl group, and the other represents hydrogen atom, C1-C6alkyl group, C1-C6alkoxycarbonyl group or phenyl group, or both are combined with each other together with the neighbouring carbon atom to form C3-C10cycloalkyl group, X represents oxygen atom, sulphur atom, or formula group of -NR4-; Y represents a group of formula -C(=O)-, -C(=S)- or CH(R5)-; Ar represents optionally substituted 6-10-member monocyclic or bicyclic aryl group or 5-10-member monocyclic or bicyclic group; Q represents a simple bond, C1-C6alkylene group or C2-C6alkenylene group, or its pharmaceutically acceptable salts There are described specific compounds of formula [I], and also intermediate compounds.

EFFECT: presented compounds exhibit affinity to mineralocorticoid receptor (MR) and are applicable for prevention or treatment of various diseases or diseased states associated with such receptor.

11 cl, 54 tbl, 410 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where X is C(R8R9), NR10, O, S; R1 is phenyl which is substituted with 1-3 substitutes selected from a group which includes halogen, hydroxy group, lower alkyl, hydroxy-lower alkyl and CN; R2 is hydrogenor lower alkyl; R3 and R4 are hydrogen; R5 and R6 are hydrogen; R7 is oxadiazolyl or triazolyl, where oxadiazolyl or triazolyl is substituted with R11; R8 and R9 denote hydrogen; R10 denotes hydrogen, lower alkyl, lower alkyl-carbonyl or lower alkyl-sulfonyl, R11 denotes aryl or hetearyl, selected from a group comprising pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl-2-one, oxadiazolyl, indazolyl, 1,3-dihydrobenzimidazol-2-one, 1,3-dihydroindol-2-one, benzotriazolyl, imidazopyridinyl, triazolepyridinyl, tetrazolepyridinyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-indol-5-yl, pyrimidin-4-one, furanyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyrimidin-2,4-one, benzoxazin-3-one, 1,4-dihydrobenzoxazin-2-one, indolyl, thiophenyl, oxazolyl, benzooxazin-2-one; 3,4-dihydroquinazolin-2-one, pyridazinyl, quinoxalinyl, benzothiazolyl, benzothiadiazolyl, naphthyridinyl, cinnolinyl, 1,4-dihydroquinoxalin-2,3-dione and 1,2-dihydroindazol-3-one, where the aryl or heteroaryl is optionally substituted with 1-3 substitutes selected from a group which includes lower alkyl, hydroxy group, B(OH)2, carboxy-lower alkoxy group, carbamoyl-lower alkoxy group, cyano group, hydroxy-lower alkyl, fluoro-lower alkyl, lower alkoxy group, halogen, S(O2)R13, C(O)R14, NO2, NR15R16, phenyl-lower alkoxy group, [1,3,4]oxadiazol-2-one, oxadiazolyl, triazolyl and isoxazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, where imidazolyl is optionally substituted with lower alkyl, and where isoxazolyl is substituted with lower alkyl; R12 denotes hydrogen or lower alkyl; R13 denotes lower alkyl, NR17R18 or fluoro-lower alkyl; R14 denotes NR19 R20, lower alkoxy group, lower alkenyl-oxy group or lower alkyl; R15 and R16 independently denote hydrogen, lower alkyl, lower alkyl-carbonyl, lower alkyl-SO2, lower alkenyl-oxycarbonyl and lower alkyl-NH-carbonyl; or NR15R16 denotes heterocyclyl selected from a group which includes morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, pyrrolidinyl, 1,1-dioxoisothiazolidinyl, pyrrolidin-2-one, imidazolidine-1,4-dione, 2,4-dihydro[1.2.4]triazol-3-one, pyrrolidine-2,5-dione, azetidin-2-one and 1,3-dihydroimidazol-2-one, where the heterocycle is optionally substituted with hydroxy-lower alkyl or lower alkyl-carbonyl; R17 and R18 independently denote hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl; or NR17 R18 denotes morpholinyl; R19 and R20 independently denote hydrogen, lower alkyl, cycloalkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl or cyano-lower alkyl; or NR19 R20 denotes heterocyclyl selected from a group which includes morpholinyl, pyrrolidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, piperazin-2-one, thiazolidinyl, thiomorpholinyl, 1,3,8-triaza-spiro[4.5]decane-2,4-dione and spiro(1- phthalan)piperidin-4-yl, where the heterocyclyl is optionally substituted with a hydroxy group, lower alkyl-(SO2), lower alkyl, lower alkyl-carbonyl or lower alkoxy group, carboxyl group, carbamoyl, cyano group and phenyl; and to their pharmaceutically acceptable salts. Invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which inhibit hepatic carnitine palmitoyltransferase 1 (L-CPT1).

35 cl, 565 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel salt form of 5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]piridine-2-amine (I): , and specifically to 5-[2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridine-2-amine di-(1S)-camphorsulphonate (di-S-camsylate), to a pharmaceutical composition having effect on dopamine D3 receptor, as well use of the given compound in preparing a medicinal agent for treating sexual dysfunction and neuropsychiatric disorders and a method of obtaining the said compound and an intermediate compound.

EFFECT: novel salt form of a dopamine agonist which has advantages, specifically is not hygroscopic, has a crystalline form and has high melting point is obtained and described.

11 cl, 9 ex, 2 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compound of general formula (I): , where Ar1 is a phenyl group substituted with 1-3 halogen atoms; Ar2 is a phenyl group which can be substituted with a halogen, alkoxyalkyl, alkoxyhalogenalkyl, or pyridyl group which can be substituted with halogenalkyl; X is -S-, -SO- or -SO2-; Y is a hydrogen atom, -NR1R2 (where R1 is a hydrogen atom, lower alkyl group or hydroxy group; and R2 is a hydrogen atom, lower alkyl group which can be substituted, lower alkanoyl group, alkoxycarbonyl group which can be substituted, lower alkoxy group which can be substituted, amino group which can be substituted; or R1 and R2 together with a nitrogen atom with which they are bonded form a piperidine, morpholine, azetidine or piperazine ring, which can be substituted wiht a hydroxy group) or -OR1', where R1 is a hydrogen atom); Z is an oxygen atom or sulphur atom; and R is a hydrogen atom or a lower alkyl group; or to salts thereof. The invention also relates to a medicinal agent and a pharmaceutical composition which inhibit production/secretion of β- amyloid protein, to use of said compounds to prepare a medicinal agent and to a method of treating diseases caused by abnormal production or secretion of β- amyloid protein.

EFFECT: novel compounds which can inhibit production/secretion of β- amyloid protein and which can be used in treating Alzheimer disease or Down syndrome are obtained and described.

30 cl, 136 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

EFFECT: novel compounds which can be useful in treating and preventing diabetes and obesity are obtained and described.

29 cl, 227 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of synthesising compounds of formula (I), which involves reacting compounds of formulae (II) and (III) and sulfonyl chloride in a suitable organic solvent in the presence of a base to form a formula (I) compound, where the solvent and/or base is combined with compounds of formulae (II) and (III). Described also are compounds of formula (III), which are used as initial compounds for this method. Radicals R1-R6 are as described in the formula of invention.

EFFECT: design of a cheap, more efficient, flexible and easy to implement method for synthesis of formula (I) compounds.

13 cl, 2 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (1) , where substitutes are as defined in paragraph 1 of the invention. The compounds have fungicide properties. The method of obtaining formula (1) compounds is described, in which n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining novel compounds which can be used as fungicides.

24 cl, 312 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to dosage forms containing an active amount of pharmacologically acceptable Buproprion salt - Bupropion Hydrobromide, as well as to the administration of such dosage forms in treating one or more conditions of patients wherein the administration of Bupropion or its pharmacologically acceptable salt is allowed.

EFFECT: Bupropion Hydrobromide dosage forms exhibit with higher stability in comparison with the dosage forms containing Bupropion Hydrochloride that is proven by smaller reduction of activity of the compositions when stored for 3 or 6 months minimum under the forced conditions at 40°C and relative humidity 75%.

81 cl, 69 dwg, 73 tbl, 17 ex

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